Pharmaceutical Process Scale-Up edited by Michael Levin

DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William
S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa
and Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems, edited by
Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher
T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A.
Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David O.
Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner
and Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by
James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo
Gibaldi and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Second Edition, Revised and Expanded, Sidney H.
Willig, Murray M. Tuckerman, and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W.
Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited
by Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A.
Roe and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and
Robert A. Nash
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by
Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford
Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists,
Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J.
Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second
Edition, Revised and Expanded, edited by Joseph R. Robinson and
Vincent H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management,
edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W.
Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by
Praveen Tyle
33. Pharmacokinetics: Regulatory · Industrial · Academic Perspectives,
edited by Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives,
edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,
edited by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-
Sellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and
Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded,
edited by Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production
Technology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne and
Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications, Second
Edition, Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark
Chasin and Robert Langer
46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S.
Tse and James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and
Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L.
S. Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and
Expanded, Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto
and Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Third Edition, edited by Sidney H. Willig and James
R. Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B.
Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J.
Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by
Adrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded,
edited by Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded,
edited by Ira R. Berry and Robert A. Nash
58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A.
Walters and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited
by Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications, edited by
Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A.
Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jorg Kreuter
67. Pharmacokinetics: Regulatory · Industrial · Academic Perspectives,
Second Edition, edited by Peter G. Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revised and
Expanded, Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revised and
Expanded, edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited by Harry
G. Brittain
71. Pharmaceutical Powder Compaction Technology, edited by Goran Alderborn
and Christer Nystrom
72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited
by Gilbert S. Banker and Christopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications, edited by
Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone
75. Clinical Research in Pharmaceutical Development, edited by Barry
Bleidt and Michael Montagne
76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness,
edited by Peter G. Welling, Louis Lasagna, and Umesh
V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines,
edited by Smadar Cohen and Howard Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Fourth Edition, Revised and Expanded, Sidney H.
Willig and James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:
Second Edition, Revised and Expanded, edited by James W.
McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications, Third
Edition, Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip
M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,
edited by William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts
and Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon
Scharpe
85. Development of Biopharmaceutical Parenteral Dosage Forms, edited
by John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation
· Production · Quality Control, edited by Donald C. Monkhouse
and Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms: Second
Edition, Revised and Expanded, edited by Gregory E. Hardee and J.
Desmond Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing,
edited by Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S.
Roberts and Kenneth A. Walters
92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier
Mathieu, and Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D.
Hynes III
94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR
Spectroscopy, David E. Bugay and W. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,
edited by Louis Rey and Joan C. May
97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Third Edition, Revised and Expanded, edited by Robert L.
Bronaugh and Howard I. Maibach
98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches,
and Development, edited by Edith Mathiowitz, Donald E.
Chickering III, and Claus-Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge,
edited by Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited by Gordon L.
Amidon, Ping I. Lee, and Elizabeth M. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A.
Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited by Michael
R. Hamrell
105. Pharmaceutical Emulsions and Suspensions, edited by Francoise
Nielloud and Gilberte Marti-Mestres
106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer
B. Dressman and Hans Lennernas
107. Drug Stability: Principles and Practices, Third Edition, Revised and
Expanded, edited by Jens T. Carstensen and C. T. Rhodes
108. Containment in the Pharmaceutical Industry, edited by James P.
Wood
109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control from Manufacturer to Consumer, Fifth Edition, Revised
and Expanded, Sidney H. Willig
110. Advanced Pharmaceutical Solids, Jens T. Carstensen
111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second
Edition, Revised and Expanded, Kevin L. Williams
112. Pharmaceutical Process Engineering, Anthony J. Hickey and David
Ganderton
113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and Rachel
F. Tyndale
114. Handbook of Drug Screening, edited by Ramakrishna Seethala and
Prabhavathi B. Fernandes
115. Drug Targeting Technology: Physical • Chemical • Biological Methods,
edited by Hans Schreier
116. Drug–Drug Interactions, edited by A. David Rodrigues
117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian
and Anthony J. Streeter
118. Pharmaceutical Process Scale-Up, edited by Michael Levin
119. Dermatological and Transdermal Formulations, edited by Kenneth A.
Walters
120. Clinical Drug Trials and Tribulations: Second Edition, Revised and
Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III
121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited
by Gilbert S. Banker and Christopher T. Rhodes
122. Surfactants and Polymers in Drug Delivery, Martin Malmsten
123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,
edited by Richard H. Guy and Jonathan Hadgraft
124. Good Laboratory Practice Regulations: Second Edition, Revised and
Expanded, edited by Sandy Weinberg
125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package
Integrity Testing: Third Edition, Revised and Expanded, Michael
J. Akers, Daniel S. Larrimore, and Dana Morton Guazzo
126. Modified-Release Drug Delivery Technology, edited by Michael J.
Rathbone, Jonathan Hadgraft, and Michael S. Roberts
127. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharmacodynamic
Modeling Perspective, edited by Hui C. Kimko and Stephen
B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,
edited by Reinhard H. H. Neubert and Hans-Hermann Ruttinger
129. Pharmaceutical Process Validation: An International Third Edition,
Revised and Expanded, edited by Robert A. Nash and Alfred H.
Wachter
130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and
Expanded, edited by Ashim K. Mitra
131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and
Sean M. Sullivan
ADDITIONAL VOLUMES IN PREPARATION
Biomarkers in Clinical Drug Development, edited by John Bloom
Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revised
and Expanded, edited by Anthony J. Hickey
Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie
and Charles Martin
Pharmaceutical Compliance, edited by Carmen Medina
To my wife Sonia,
my children Hanna, Daniela, Ilan, and Emanuel,
and to the memory of my parents.

Preface
Pharmaceutical Process Scale-Up deals with a subject both fascinating and vitally
important for the pharmaceutical industry—the procedures of transferring
the results of R&D obtained on laboratory scale to the pilot plant and finally to
production scale. The primary objective of the text is to provide insight into the
practical aspects of process scale-up. As a source of information on batch enlargement
techniques, it will be of practical interest to formulators, process engineers,
validation specialists and quality assurance personnel, as well as production
managers. The book also provides interesting reading for those involved in technology
transfer and product globalization.
Since engineering support and maintenance are crucial for proper scale-up
of any process, Chapter 10 discusses plant design and machinery maintenance issues.
Regulatory aspects of scale-up and postapproval changes are addressed
throughout the book but more specifically in Chapter 11. A diligent attempt was
made to keep all references to FDA regulations as complete and current as possible.
Although some theory and history of process scale-up are discussed, knowledge
of physics or engineering is not required of the reader since all theoretical
considerations are fully explained.
Michael Levin

Introduction
Scale-up is generally defined as the process of increasing the batch size. Scale-up
of a process can also be viewed as a procedure for applying the same process to
different output volumes. There is a subtle difference between these two definitions:
batch size enlargement does not always translate into a size increase of the
processing volume.
In mixing applications, scale-up is indeed concerned with increasing the
linear dimensions from the laboratory to the plant size. On the other hand, processes
exist (e.g., tableting) for which “scale-up” simply means enlarging the
output by increasing the speed. To complete the picture, one should point out
special procedures (especially in biotechnology) in which an increase of the
scale is counterproductive and “scale-down” is required to improve the quality
of the product.
In moving from R&D to production scale, it is sometimes essential to have
an intermediate batch scale. This is achieved at the so-called pilot scale, which is
defined as the manufacturing of drug product by a procedure fully representative
of and simulating that used for full manufacturing scale. This scale also makes
possible the production of enough product for clinical testing and samples for
marketing. However, inserting an intermediate step between R&D and production
scales does not in itself guarantee a smooth transition. A well-defined process may
generate a perfect product in both the laboratory and the pilot plant and then fail
quality assurance tests in production.
Imagine that you have successfully scaled up a mixing or a granulating process
from a 10-liter batch to a 75-liter and then to a 300-liter batch. What exactly
happened? You may say, “I got lucky.” Apart from luck, there had to be some
physical similarity in the processing of the batches. Once you understand what
makes these processes similar, you can eliminate many scale-up problems.
A rational approach to scale-up has been used in physical sciences, viz. fluid
dynamics and chemical engineering, for quite some time. This approach is based
on process similarities between different scales and employs dimensional analysis
that was developed a century ago and has since gained wide recognition in
many industries, especially in chemical engineering [1].
Dimensional analysis is a method for producing dimensionless numbers that
completely characterize the process. The analysis can be applied even when the
equations governing the process are not known. According to the theory of models,
two processes may be considered completely similar if they take place in similar
geometrical space and if all the dimensionless numbers necessary to describe
the process have the same numerical value [2]. The scale-up procedure, then, is
simple: express the process using a complete set of dimensionless numbers, and
try to match them at different scales. This dimensionless space in which the measurements
are presented or measured will make the process scale invariant.
Dimensionless numbers, such as Reynolds and Froude numbers, are frequently
used to describe mixing processes. Chemical engineers are routinely concerned with
problems of water-air or fluid mixing in vessels equipped with turbine stirrers in
which scale-up factors can be up to 1:70 [3]. This approach has been applied to pharmaceutical
granulation since the early work of Hans Leuenberger in 1982 [4].
One way to eliminate potential scale-up problems is to develop formulations
that are very robust with respect to processing conditions. A comprehensive
database of excipients detailing their material properties may be indispensable for
this purpose. However, in practical terms, this cannot be achieved without some
means of testing in a production environment, and, since the initial drug substance
is usually available only in small quantities, some form of simulation is required
on a small scale.
In tableting applications, the process scale-up involves different speeds of
production in what is essentially the same unit volume (die cavity in which the
compaction takes place). Thus, one of the conditions of the theory of models (similar
geometric space) is met. However, there are still kinematic and dynamic parameters
that need to be investigated and matched for any process transfer. One of
the main practical questions facing tablet formulators during development and
scale-up is whether a particular formulation will sustain the required high rate of
compression force application in a production press without lamination or capping.
Usually, such questions are never answered with sufficient credibility, especially
when only a small amount of material is available and any trial-and-error
approach may result in costly mistakes along the scale-up path.
As tablet formulations are moved from small-scale research presses to highspeed
machines, potential scale-up problems can be eliminated by simulation of
production conditions in the formulation development lab. In any process transfer

Introduction
from one tablet press to another, one may aim to preserve mechanical properties
of a tablet (density and, by extension, energy used to obtain it) as well as its
bioavailability (e.g., dissolution that may be affected by porosity). A scientifically
sound approach would be to use the results of the dimensional analysis to model
a particular production environment. Studies done on a class of equipment generally
known as compaction simulators or tablet press replicators can be designed to
facilitate the scale-up of tableting process by matching several major factors, such
as compression force and rate of its application (punch velocity and displacement),
in their dimensionless equivalent form.
Any significant change in a process of making a pharmaceutical dosage form
is a regulatory concern. Scale-Up and Postapproval Changes (SUPAC) are of special
interest to the FDA, as is evidenced by a growing number of regulatory documents
released in the past several years by the Center for Drug Evaluation and Research
(CDER), including Immediate Release Solid Oral Dosage Forms (SUPAC-IR),
Modified Release Solid Oral Dosage Forms (SUPAC-MR), and Semisolid Dosage
Forms (SUPAC-SS). Additional SUPAC guidance documents being developed include:
Transdermal Delivery Systems (SUPAC-TDS), Bulk Actives (BACPAC),
and Sterile Aqueous Solutions (PAC-SAS). Collaboration between the FDA, the
pharmaceutical industry, and academia in this and other areas has recently been
launched under the framework of the Product Quality Research Institute (PQRI).
Scale-up problems may require postapproval changes that affect formulation
composition, site, and manufacturing process or equipment (from the regulatory
standpoint, scale-up and scale-down are treated with the same degree of scrutiny).
In a typical drug development cycle, once a set of clinical studies has been completed
or an NDA/ANDA has been approved, it becomes very difficult to change
the product or the process to accommodate specific production needs. Such needs
may include changes in batch size and manufacturing equipment or process.
Postapproval changes in the size of a batch from the pilot scale to larger or
smaller production scales call for submission of additional information in the application,
with a specific requirement that the new batches are to be produced using
similar test equipment and in full compliance with CGMPs and the existing
SOPs. Manufacturing changes may require new stability, dissolution, and in vivo
bioequivalence testing. This is especially true for Level 2 equipment changes
(change in equipment to a different design and different operating principles) and
the process changes of Level 2 (process changes, e.g., in mixing times and operating
speeds within application/validation ranges) and Level 3 (change in the type
of process used in the manufacture of the product, such as from wet granulation to
direct compression of dry powder).
Any such testing and accompanying documentation are subject to FDA approval
and can be very costly. In 1977, the FDA’s Office of Planning and Evaluation
(OPE) studied the impact on industry of the SUPAC guidance, including its
effects on cost. The findings indicated that the guidance resulted in substantial
Introduction ix
savings because it permitted, among other things, shorter waiting times for site
transfers and more rapid implementation of process and equipment changes, as
well as increases in batch size and reduction of quality control costs.
In early development stages of a new drug substance, relatively little information
is available regarding its polymorphic forms, solubility, and other aspects.
As the final formulation is developed, changes to the manufacturing process may
change the purity profile or physical characteristics of the drug substance and thus
cause batch failures and other problems with the finished dosage form.
FDA inspectors are instructed to look for any differences between the process
filed in the application and the process used to manufacture the bio/clinical
batch. Furthermore, one of the main requirements of a manufacturing process is
that it will yield a product that is equivalent to the substance on which the biostudy
or pivotal clinical study was conducted. Validation of the process development
and scale-up should include sufficient documentation so that a link between
the bio/clinical batches and the commercial process can be established. If the process
is different after scale-up, the company has to demonstrate that the product
produced by a modified process will be equivalent, using data such as granulation
studies, finished product test results, and dissolution profiles.
Many of the FDA’s postapproval, premarketing inspections result in citations
because validation (and consistency) of the full-scale batches could not be established
owing to problems with product dissolution, content uniformity, and potency.
Validation reports on batch scale-ups may also reflect selective reporting of
data. Of practical importance are the issues associated with a technology transfer
in a global market. Equipment standardization inevitably will cause a variety of engineering
and process optimization concerns that can be classified as SUPAC.
This book presents the significant aspects of pharmaceutical scale-up to illustrate
potential concerns, theoretical considerations, and practical solutions based
on the experience of the contributing authors. A prudent reader may use this handbook
as a reference and an initial resource for further study of the scale-up issues.


Contents
Preface v
Introduction vii
Contributors xv
1. Dimensional Analysis and Scale-Up in Theory and Industrial
Application . . . . . . . 1
Marko Zlokarnik
2. Parenteral Drug Scale-Up . . . . . . . . . . . . . 43
Igor Gorsky
3. Nonparenteral Liquids and Semisolids . . . 57
Lawrence H. Block
4. Scale-Up Considerations for Biotechnology-Derived
Products . . . . . . . . . 95
Marco A. Cacciuttolo, Erica Shane, Roy Kimura, Cynthia Oliver,
and Eric Tsao
5 (1). Batch Size Increase in Dry Blending and Mixing . . . . . . . . . . . 115
Albert W. Alexander and Fernando J. Muzzio
5 (2). Powder Handling . . 133
James K. Prescott
xi
6. Scale-Up in the Field of Granulation and Drying . . . . . . . . . . . . 151
Hans Leuenberger
7. Batch Size Increase in Fluid Bed Granulation . . . . . . . . . . . . . . 171
Dilip M. Parikh
8 (1). Scale-Up of the Compaction and Tableting Process . . . . . . . . . 221
Joseph B. Schwartz
8 (2). Practical Aspects of Tableting Scale-Up . 239
Walter A. Strathy and Adolfo L. Gomez
8 (3). Dimensional Analysis of the Tableting Process . . . . . . . . . . . . . 253
Michael Levin and Marko Zlokarnik
9. Scale-Up of Film Coating . . . . . . . . . . . . . 259
Stuart C. Porter
10. Engineering Aspects of Process Scale-Up and Pilot Plant
Design . . . . . . . . . . . 311
Adolfo L. Gomez and Walter A. Strathy
11. A Collaborative Search for Efficient Methods of Ensuring
Unchanged Product Quality and Performance During Scale-Up
of Immediate-Release Solid Oral Dosage Forms . . . . . . . . . . . . 325
Ajaz S. Hussain
APPENDIXES: GUIDANCE FOR INDUSTRY
A. Immediate Release Solid Oral Dosage Forms—Scale-Up and
Postapproval Changes: Chemistry, Manufacturing, and
Controls, In Vitro Dissolution Testing, and In Vivo
Bioequivalence Documentation . . . . . . . . 353
B. SUPAC-MR: Modified Release Solid Oral Dosage
Forms—Scale-Up and Postapproval Changes: Chemistry,
Manufacturing, and Controls; In Vitro Dissolution Testing and
In Vivo Bioequivalence Documentation . . 373
C. SUPAC-IR/MR: Immediate Release and Modified Release
Solid Oral Dosage Forms—Manufacturing Equipment
Addendum . . . . . . . . 415
xii Contents
D. Extended Release Oral Dosage Forms—Development,
Evaluation, and Application of In Vitro/In Vivo Correlations . . 447
E. Nonsterile Semisolid Dosage Forms—Scale-Up and
Postapproval Changes: Chemistry, Manufacturing, and
Controls; In Vitro Release Testing and In Vivo Bioequivalence
Documentation SUPAC-SS . . . . . . . . . . . . 469
F. SUPAC-SS: Nonsterile Semisolid Dosage
Forms—Manufacturing Equipment Addendum . . . . . . . . . . . . . 499
G. Changes to an Approved NDA or ANDA . 517
H. Waiver of In Vivo Bioavailability and Bioequivalence Studies
for Immediate-Release Solid Oral Dosage Forms Based on a
Biopharmaceutics Classification System . 551
Index 565
Contents xiii

Contributors
Albert W. Alexander Department of Chemical and Biochemical Engineering,
Rutgers University, Piscataway, New Jersey
Lawrence H. Block Division of Pharmaceutical Sciences, Duquesne University,
Pittsburgh, Pennsylvania
Marco A. Cacciuttolo Cell Culture Development, Biopharmaceutical Production,
Medarex, Inc., Bloomsbury, New Jersey
Adolfo L. Gomez I.D.E.A.S., Inc., Wilson, North Carolina
Igor Gorsky Department of Technical Services, Alpharma, Baltimore, Maryland
Ajaz S. Hussain Center for Drug Evaluation and Research, U.S. Food and Drug
Administration, Rockville, Maryland
Roy Kimura Onyx Pharmaceuticals, Inc., Richmond, California
Hans Leuenberger Institute of Pharmaceutical Technology, University of
Basel, Basel, Switzerland
Michael Levin Metropolitan Computing Corporation, East Hanover, New
Jersey
Fernando J. Muzzio Department of Chemical and Biochemical Engineering,
Rutgers University, Piscataway, New Jersey
Cynthia Oliver Process Biochemistry, MedImmune, Inc., Gaithersburg, Maryland
Dilip M. Parikh APACE Pharma Inc., Westminster, Maryland
Stuart C. Porter Pharmaceutical Technologies International, Inc., Belle Mead,
New Jersey
James K. Prescott Jenike & Johanson, Inc., Westford, Massachusetts
Joseph B. Schwartz Philadelphia College of Pharmacy, Philadelphia, Pennsylvania
Erica Shane Process Biochemistry, MedImmune, Inc., Gaithersburg, Maryland
Walter A. Strathy I.D.E.A.S., Inc., Wilson, North Carolina
Eric Tsao Process Cell Culture, MedImmune, Inc., Gaithersburg, Maryland
Marko Zlokarnik Graz, Austria

Contributors
1
Dimensional Analysis and Scale-Up
in Theory and Industrial Application
Marko Zlokarnik
Graz, Austria
I. INTRODUCTION
A chemical engineer is generally concerned with the industrial implementation of
processes in which chemical or microbiological conversion of material takes place
in conjunction with the transfer of mass, heat, and momentum. These processes are
scale dependent; that is, they behave differently on a small scale (in laboratories or
pilot plants) and on a large scale (in production). They include heterogeneous
chemical reactions and most unit operations. Understandably, chemical engineers
have always wanted to find ways of simulating these processes in models to gain
insights that will assist them in designing new industrial plants. Occasionally, they
are faced with the same problem for another reason: An industrial facility already
exists but will not function properly, if at all, and suitable measurements have to be
carried out to discover the cause of the difficulties and provide a solution.
Irrespective of whether the model involved represents a “scale-up” or a
“scale-down,” certain important questions always apply:
1. How small can the model be? Is one model sufficient, or should tests be
carried out in models of different sizes?
2. When must or when can physical properties differ? When must the
measurements be carried out on the model with the original system of
materials?
3. Which rules govern the adaptation of the process parameters in the
model measurements to those of the full-scale plant?
4. Is it possible to achieve complete similarity between the processes in
the model and those in its full-scale counterpart? If not, how should one
proceed?

These questions touch on the fundamentals of the theory of models, which
are based on dimensional analysis. Although they have been used in the field of
fluid dynamics and heat transfer for more than a century—cars, aircraft, vessels,
and heat exchangers were scaled up according to these principles—these methods
have gained only a modest acceptance in chemical engineering. University graduates
are usually not skilled enough to deal with such problems at all. On the other
hand, there is no motivation for this type of research at universities, since, as a rule,
they are not confronted with scale-up tasks and are not equipped with the necessary
apparatus on the bench scale. All this gives a totally wrong impression that these
methods are, at most, of marginal importance in practical chemical engineering, for
otherwise would they have been taught and dealt with in greater depth.
II. DIMENSIONAL ANALYSIS
A. The Fundamental Principle
Dimensional analysis is based upon the recognition that a mathematical formulation
of a physicotechnological problem can be of general validity only when the
process equation is dimensionally homogenous, which means that it must be valid
in any system of dimensions.
B. What Is a Dimension?
A dimension is a purely qualitative description of a perception of a physical entity
or a natural appearance. A length can be experienced as a height, a depth, a
breadth. A mass presents itself as a light or heavy body, time as a short moment
or a long period. The dimension of a length is length (L), the dimension of a mass
is mass (M), etc.
C. What Is a Physical Quantity?
Unlike a dimension, a physical quantity represents a quantitative description of a
physical quality (e.g., a mass of 5 kg). It consists of a measuring unit and a numerical
value. The measuring unit of length can be a meter, a foot, a cubit, a yardstick,
a nautical mile, a light year, etc. The measuring units of energy are, e.g.,
joules, cal, eV. (It is therefore necessary to establish the measuring units in an appropriate
measuring system.)
D. Basic and Derived Quantities, Dimensional Constants
A distinction is being made between basic and secondary quantities, the latter often
being referred to as derived quantities. Basic quantities are based on standards
and are quantified by comparison with them. Secondary units are derived from the
2 Zlokarnik
primary ones according to physical laws, e.g., velocity 
 length/time. (The borderline
separating both types of quantities is largely arbitrary: 50 years ago a measuring
system was used in which force was a primary dimension instead of mass!)
All secondary units must be coherent with the basic units (Table 1); e.g., the
measuring unit of velocity must not be miles/hr or km/hr but meters/sec!
If a secondary unit has been established by a physical law, it can happen that
it contradicts another one. Example: According to the Newton’s second law of
motion, the force F is expressed as a product of mass m and acceleration a:
F 
 ma, having the measuring unit of [kgm/sec2 
 N]. According to the Newton’s
law of gravitation, force is defined by F  m1m2 /r2, thus leading to a completely
different measuring unit [kg2/m2 ]. To remedy this, the gravitational constant
G—a dimensional constant—had to be introduced to ensure the dimensional
homogeneity of the latter equation: F 
 Gm1m2 /r2. Another example affects the
universal gas constant R, the introduction of which ensures that in the perfect gas
equation of state pV 
 nRT, the secondary unit for work W 
 pV [ML2T2] is not
offended.
Another class of derived quantities is represented by the coefficients in diverse
physical equations, e.g., transfer equations. They are established by the respective
equations and determined via measurement of their constituents, e.g.,
heat and mass transfer coefficients.
E. Dimensional Systems
A dimensional system consists of all the primary and secondary dimensions and
corresponding measuring units. The currently used International System of Dimensions
(Systeme International d’unites, SI) is based on seven basic dimensions.
They are presented in Table 1 together with their corresponding basic units. For
some of them a few explanatory remarks may be necessary.
Temperature expresses the thermal level of a system and not its energetic
contents. (A fivefold mass of a matter has the fivefold thermal energy at the same
temperature!) The thermal energy of a system can indeed be converted into me-
Dimensional Analysis 3
Table 1 Base Quantities, Their Dimensions, and Their Units According to SI
Base quantity Base dimension Base unit
Length L m (meter)
Mass M kg (kilogram)
Time T sec (second)
Thermodynamic temperature  K (Kelvin)
Amount of substance N mol (mole)
Electric current I A (ampere)
Luminous intensity Iv cd (candela)
chanical energy (base unit, joule). Moles are the amount of matter and must not be
confused with the quantity of mass. The molecules react as individual entities regardless
of their mass: One mole of hydrogen (2 g/mol) reacts with one mole of
chlorine (71 g/mol) to produce two moles of hydrochloric acid, HCl. Table 2
shows the most important secondary dimensions. Table 3 refers to some very frequently
used secondary units that have been named after famous researchers.
4 Zlokarnik
Table 2 Often-Used Physical Quantities and Their
Dimensions According to the Currently Used SI in
Mechanical and Thermal Problems
Physical quantity Dimension
Angular velocity T1
Shear rate, frequency
Mass transfer coefficient kLa
Velocity L T1
Acceleration L T2
Kinematic viscosity L2 T1
Diffusion coefficient
Thermal diffusivity
Density M L3
Surface tension M T2
Dynamic viscosity M L1 T1
Momentum M L T1
Force M L T2
Pressure, stress M L1 T2
Angular momentum M L2 T1
Energy, work, torque M L2 T2
Power M L2 T3
Heat capacity L2 T2 1
Thermal conductivity M L T3 1
Heat transfer coefficient M T3 1
Table 3 Important Secondary Measuring Units in Mechanics, Named After Famous
Researchers
Secondary Abbreviation
quantity Dimension Measuring unit for:
Force M L T2 kg m sec2 (N) Newton
Pressure M L1 T2 kg m1 sec2 (Pa) Pascal
Energy M L2 T2 kg m2 sec2 (J) Joule
Power M L2 T3 kg m2 sec3 (W) Watt
F. Dimensional Homogeneity of a Physical Content
The aim of dimensional analysis is to check whether or not the physical content
under examination can be formulated in a dimensionally homogeneous manner.
The procedure necessary to accomplish this consists of two parts:
1. First, all physical parameters necessary to describe the problem are
listed. This so-called “relevance list” of the problem consists of the
quantity in question and of all the parameters that influence it. In each
case only one target quantity must be considered; it is the only dependent
variable. On the other hand, all the influencing parameters must be
primarily independent of each other.
2. In the second step the dimensional homogeneity of the physical content
is checked by transferring it into a dimensionless form. Note: A physical
content that can be transformed into dimensionless expressions is
dimensionally homogeneous!
The information given to this point will be made clear by the following
amusing but instructive example.
Example 1: What Is the Correlation Between the Baking Time and the Weight of
a Christmas Turkey? We first recall the physical situation. To facilitate this we
draw a sketch (Sketch 1). At high oven temperatures the heat is transferred from
the heating elements to the meat surface by both radiation and heat convection.
From there it is transferred solely by the unsteady-state heat conduction that surely
represents the rate-limiting step of the whole heating process.
Physical quantity Symbol Dimension
Baking time  T
Surface of meat A L2
Thermal diffusivity a L2 T1
Temperature on the surface T0 
Temperature distribution T 
The higher the thermal conductivity  of the body, the faster the heat
spreads out. The higher its volume-related heat capacity Cp, the slower the heat
transfer. Therefore, the unsteady-state heat conduction is characterized by only
one material property, the thermal diffusivity a 
 /Cp of the body.
Baking is an endothermal process. The meat is cooked when a certain temperature
distribution (T) is reached. It’s about the time  necessary to achieve this
temperature range.


G. B. West [1] refers to (inferior) cookbooks that simply say something like
“20 minutes per pound,” implying a linear relationship with weight. However, superior
cookbooks exist such as the Better Homes and Gardens Cookbook (Des
Moines Meredith Corp., 1962), that recognize the nonlinear nature of this relationship.
The graphical representation of measurements in this book confirms the
relationship
  m0.6 (8)
which is very close to the theoretical evaluation giving   m2–3 
 m0.67.
The elegant solution of this first example should not tempt the reader to
believe that dimensional analysis can be used to solve every problem. To treat
this example by dimensional analysis, the physics of unsteady-state heat conduction
had to be understood. Bridgman’s [2] comment on this situation is particularly
appropriate: “The problem cannot be solved by the philosopher in his
armchair, but the knowledge involved was gathered only by someone at some
time soiling his hands with direct contact.” This transparent and easy example
clearly shows how dimensional analysis deals with specific problems and what
conclusions it allows. It should now be easier to understand Lord Rayleigh’s sarcastic
comment with which he began his short essay on “The Principle of Similitude”
[3]: “I have often been impressed by the scanty attention paid even by
original workers in physics to the great principle of similitude. It happens not infrequently
that results in the form of ‘laws’ are put forward as novelties on the
basis of elaborate experiments, which might have been predicted a priori after a
few minutes’ consideration.”
From the foregoing example we also learn that a transformation of a physical
dependency from a dimensional into a dimensionless form is automatically accompanied
by an essential compression of the statement: The set of the dimensionless
numbers is smaller than the set of the quantities contained in them, but it
describes the problem equally comprehensively. In our example the dependency
between five dimensional parameters is reduced to a dependency between only
two dimensionless numbers! This is the proof of the so-called pi theorem (pi after
	, the sign used for products).
8 Zlokarnik
G. The Pi Theorem
Every physical relationship between n physical quantities can be reduced to a
relationship between m 
 n  r mutually independent dimensionless groups,
whereby r stands for the rank of the dimensional matrix, made up of the physical
quantities in question and generally equal to the number of the basic
quantities contained in them.
(The pi theorem is often associated with the name of E. Buckingham [4], because
he introduced this term in 1914. But the proof of it had already been accomplished
in the course of a mathematical analysis of partial differential equations by A. Federmann
in 1911; see Ref. 5.)
III. THE DETERMINATION OF A PI SET BY MATRIX
CALCULATION
A. The Establishment of a Relevance List of a Problem
As a rule, more than two dimensionless numbers will be necessary to describe a
physicotechnological problem, and therefore they cannot be derived by the
method just described. In this case the easy and transparent matrix calculation introduced
by J. Pawlowski [6] is increasingly used. It will be demonstrated by the
following example. It treats an important problem in industrial chemistry and
biotechnology, because the contact between gas and liquid in mixing vessels occurs
very frequently in mixing operations.
Example 2: The Determination of the Pi Set for the Stirrer Power in the Contact
Between Gas and Liquid. We examine the power consumption of a turbine stirrer
(so-called Rushton turbine; see inset in Fig. 1) installed in a baffled vessel and
supplied by gas from below (see Sketch 2). We facilitate the procedure by systematically
listing the target quantity and all the parameters influencing it:
1. Target quantity: mixing power P
2. Influencing parameters
a. Geometrical: stirrer diameter d
b. Physical properties:
Fluid density 
Kinematic viscosity 

c. Process related:
Stirrer speed n
Gas throughput q
Gravitational acceleration g
The relevance list is:
{P; d; , 
; n, q, g} (9)
Dimensional Analysis 9
We interrupt the procedure to ask some important questions concerning: (1)
the determination of the characteristic geometric parameter, (2) the setting of all
relevant material properties, and (3) the taking into account the gravitational
acceleration.
1. Determination of the characteristic geometric parameter: It is obvious
that we could name all the geometric parameters indicated in Sketch 2. They were
all the geometric parameters of the stirrer and of the vessel, especially its diameter
D and the liquid height H. In case of complex geometry such a procedure
would necessarily deflect us from the problem. It is therefore advisable to introduce
only one characteristic geometric parameter, knowing that all the others can
be transformed into dimensionless geometric numbers by division with this one.
As the characteristic geometric parameter in the Example 2, the stirrer diameter
was introduced. This is reasonable. One can imagine how the mixing power would
react to an increase in the vessel diameter D: It is obvious that from a certain D
on, it would have no influence, but a small change of the stirrer diameter d would
always have an impact!
2. Setting of all relevant material properties: In the preceding relevance
list, only the density and the viscosity of the liquid were introduced. The material
properties of the gas are of no importance as compared with the physical properties
of the liquid. It was also ascertained by measurements that the interfacial tension 

does not effect the stirrer power. Furthermore, measurements [7] revealed that the
coalescence behavior of the material system is not affected if aqueous glycerol or
cane syrup mixtures are used to increase viscosity in model experiments.
10 Zlokarnik
Sketch 2
3. The importance of the gravitational constant: Due to the extreme density
difference between gas and liquid (ca. 1:1.000), it must be expected that the
gravitational acceleration g will exert a big influence. One should actually write
g, but—since  
 L  G  L—the dimensionless number would contain
g/L  gL/L 
 g.
We now proceed to solve Example 2.
B. Constructing and Solving the Dimensional Matrix
In transforming the relevance list—Eq. (9)—of the preceding seven physical
quantities into a dimensional matrix, the following should be kept in mind in order
to minimize the calculations required.
1. The dimensional matrix consists of a square core matrix and a residual
matrix.
2. The rows of the matrix are formed of base dimensions, contained in the
dimensions of the quantities, and they will determine the rank r of the
matrix. The columns of the matrix represent the physical quantities or
parameters.
3. Quantities of the square core matrix may eventually appear in all of the
dimensionless numbers as “fillers,” whereas each element of the residual
matrix will appear in only one dimensionless number. For this reason
the residual matrix should be loaded with essential variables like
the target quantity and the most important physical properties and process-
related parameters.
4. By the—extremely easy!—matrix rearrangement (linear transformations),
the core matrix is transformed into a matrix of unity. The main
diagonal consists only of ones and the remaining elements are all zero.
One should therefore arrange the quantities in the core matrix in a way
to facilitate this procedure.
5. After the generation of the matrix of unity, the dimensionless numbers
are created as follows: Each element of the residual matrix forms the
numerator of a fraction, while its denominator consists of the fillers
from the matrix of unity with the exponents indicated in the residual
matrix.

The interdependence of seven dimensional quantities of the relevance list, Eq. (9),
reduces to a set of only 7  3 
 4 dimensionless numbers:
{Ne, Re, Q, Fr} or ?(Ne, Re, Q, Fr) 
 0 (10)
thus again confirming the pi theorem.
C. Determination of the Process Characteristics
The functional dependency, Eq. (10), is the maximum that dimensional analysis
can offer here. It cannot provide any information about the form of the function ?.
This can be accomplished solely by experiments.
The first question we must ask is: Are laboratory tests, performed in one
single piece of laboratory apparatus—i.e., on one single scale—capable of providing
binding information on the decisive process number? The answer here is
affirmative. We can change Fr by means of the rotational speed of the stirrer, Q
by means of the gas throughput, and Re by means of the liquid viscosity independent
of each other.
The results of these model experiments are described in detail in Ref. 7. For
our consideration, it is sufficient to present only the main result here. This states
that, in the industrially interesting range (Re  104 and Fr  0.65), the power
12 Zlokarnik
number Ne is dependent only on the gas throughput number Q; see Figure 1. By
raising the gas throughput number Q and thus enhancing gas hold-up in the liquid,
liquid density diminishes and the Newton number Ne decreases to only one-third
of its value in a nongassed liquid.
Knowledge of this power characteristic, the analytical expression for
which is
Ne 
 1.5  (0.5Q0.075  1600Q2.6)1 (Q  0.15) (11)
can be used to reliably design a stirrer drive for the performance of material conversions
in the gas/liquid system (e.g., oxidations with O2 or air, fermentations)
as long as the physical, geometric, and process-related boundary conditions (Re,
Fr, and Q) comply with those of the model measurement.
IV. FUNDAMENTALS OF THE THEORY OF MODELS AND
OF SCALE-UP
A. Theory of Models
The results in Figure 1 have been obtained by changing the rotational speed of
the stirrer and the gas throughput, whereas the liquid properties and the characteristic
length (stirrer diameter d ) remained constant. But these results could
have also been obtained by changing the stirrer diameter. It does not matter by
which means a relevant number (here Q) is changed because it is dimensionless
and therefore independent of scale (“scale-invariant”). This fact presents the ba-
Dimensional Analysis 13
Figure 1 Power characteristics of a turbine stirrer (Rushton turbine) in the range Re 
104 and Fr  0.65 for two D/d values. Material system: water/air. (From Ref. 7.)
sis for a reliable scale-up:
Two processes may be considered completely similar if they take place in
similar geometrical space and if all the dimensionless numbers necessary to
describe them have the same numerical value (	i 
 identical or idem).
Clearly, the scale-up of a desired process condition from a model to industrial
scale can be accomplished reliably only if the problem was formulated and dealt
with according to dimensional analysis!
B. Model Experiments and Scale-Up
In the foregoing example the process characteristics (here power characteristics)
presenting a comprehensive description of the process were evaluated. This often
expensive and time-consuming method is certainly not necessary if one only has
to scale-up a given process condition from the model to the industrial plant (or
vice versa). With the last example, and assuming that the Ne(Q) characteristic like
that in Figure 1 is not explicitly known, the task is to predict the power consumption
of a Rushton turbine of d 
 0.8 m, installed in a baffled vessel of D 
 4 m
(D/d 
 5) and rotating with n 
 200 min1. The air throughput is q 
 500 m3/hr
and the material system is water/air.
One only needs to know—and this is essential—that the hydrodynamics in
this case are governed solely by the gas throughput number and that the process is
described by an unknown dependency Ne(Q). Then one can calculate the Q number
of the industrial plant:
Q 
 q/nd3 
 8.14  102

From Ne 
 1.75 found in laboratory measurement, the power P of the industrial
turbine stirrer of d 
 0.8 m and a rotational speed of n 
 200 min1 is calculated
14 Zlokarnik
as follows:
P 
 Nen3d5 
 1.75  1  103  (200/60)3  0.85 
 21,200 W  21 kW
This results in 21/50 kW/m3 
 0.42 kW/m3, which is a fair volume-related power
input for many conversions in the gas/liquid system.
We realize that in scale-up, comprehensive knowledge of the functional dependency
?(	i) 
 0—like that in Figure 1—is not necessary. All we need is to
know which pi space describes the process.
V. FURTHER PROCEDURES TO ESTABLISH A
RELEVANCE LIST
A. Consideration of the Acceleration Due to Gravity g
If a natural or universal physical constant has an impact on the process, it has to
be incorporated into the relevance list, whether it will be altered or not. In this context
the greatest mistakes are made with regard to the gravitational constant g.
Lord Rayleigh [3] complained bitterly, saying: “I refer to the manner in which
gravity is treated. When the question under consideration depends essentially
upon gravity, the symbol of gravity (g) makes no appearance, but when gravity
does not enter the question at all, g obtrudes itself conspicuously.” This is all the
more surprising in view of the fact that the relevance of this quantity is easy
enough to recognize if one asks the following question: Would the process function
differently if it took place on the moon instead of on Earth? If the answer to
this question is affirmative, g is a relevant variable.
The gravitational acceleration g can be effective solely in connection with
density as gravity g. When inertial forces play a role, the density  has to be listed
additionally. Thus it follows that:
1. In cases involving the ballistic movement of bodies, the formation of
vortices in stirring, the bow wave of a ship, the movement of a pendulum,
and oher processes affected by the Earth’s gravity, the relevance
list comprises g and .
2. Creeping flow in a gravitational field is governed by the gravity g
alone.
3. In heterogeneous physical systems with density differences (sedimentation
or buoyancy), the gravity difference g and  play a decisive
role.
In the second example we already treated a problem where the gravitational
constant is of prime importance, due to extreme difference in densities in the
gas/liquid system, provided that the Froude number is low: Fr  0.65.
Dimensional Analysis 15
B. Introduction of Intermediate Quantities
Many engineering problems involve several parameters that impede the
elaboration of the pi space. Fortunately, in some cases a closer look at a problem
(or previous experience) facilitates reduction of the number of physical quantities
in the relevance list. This is the case when some relevant variables affect the process
by way of a so-called “intermediate” quantity. Assuming that this intermediate
variable can be measured experimentally, it should be included in the problem
relevance list if this facilitates the removal of more than one variable from the list.
The fluid velocity v in pipes—or the superficial gas velocity vG in mixing
vessels or in bubble columns—presents a well-known intermediate quantity. Its
introduction into the relevance list removes two others (throughput q and diameter
D), because v  q/D2 and vG  qG/D2, respectively.
The impact, which the introduction of intermediate quantities can have on
the relevance list, will be demonstrated in the following by one elegant example.
Example 3: Mixing-Time Characteristics for Liquid Mixtures with Differences in
Density and Viscosity. The mixing time  necessary to achieve a molecular homogeneity
of a liquid mixture—normally measured by decolorization methods—depends,
in material systems without differences in density and viscosity, on only four
parameters: stirrer diameter d, density , kinematic viscosity 
, rotational speed n:
{; d; , 
; n} (13)
From this, the mixing-time characteristics are
n 
 ?(Re) Re 
 nd2/
 (14)
See Example 5.2 later and Figure 10.
In material systems with differences in density and viscosity, the relevance
list, Eq. (13), enlarges by the physical properties of the second mixing component,
by the volume ratio of both phases 
V2 /V1, and, due to the density differences,
inevitably by the gravity difference g to nine parameters:
{; d; 1, 
1, 2, 
2, ; g, n} (15)
This results in a mixing-time characteristics incorporating six numbers:
n 
 ?(Re, Ar, 2/1, 
2/
1, ) (16)
Re 
 nd2/
1  Reynolds number,
Ar 
 g d3/(1
2
1)  Archimedes number
Meticulous observation of this mixing process (the slow disappearance of
the Schlieren patterns as result of the disappearance of density differences) reveals
that macromixing is quickly accomplished compared to the micromixing. This
time-consuming process already takes place in a material system that can be fully
16 Zlokarnik
described by the physical properties of the mixture:

* 
 ?(
1, 
2, ) and * 
 ?(1, 2, ) (17)
By introducing these intermediate quantities 
* and *, the nine-parameter relevance
list, Eq. (15), reduces by three parameters to a six-parametric one:
{; d; *, 
*; g, n} (18)
and gives a mixing characteristics of only three numbers:
n 
 ?(Re, Ar) (19)
(In this case, Re and Ar have to be formed by * and 
*!)
The process characteristics of a cross-beam stirrer was established in this pi
space by evaluation of corresponding measurements in two different-size mixing
vessels (D 
 0.3 and 0.6 m) using different liquid mixtures (/* 
 0.01  0.29
and 
2/
1 
 1  5300). It reads [8]:
n 
 51.6 Re1(Ar1/3  3) Re 
 101  105; Ar 
 102  1011 (20)
This example clearly shows the big advantages achieved by the introduction
of intermediate quantities. This will also be made clear by upcoming Example 4.
C. Material Systems of Unknown Physical Properties
With the foams, sludges, and slimes often encountered in biotechnology, we are
confronted with the problem of not being able to list the physical properties because
they are still unknown and therefore cannot be quantified. This situation often
leads to the opinion that dimensional analysis would fail in such cases.
It is obvious that this conclusion is wrong: Dimensional analysis is a method
based on logical and mathematical fundamentals [2,6]. If relevant parameters cannot
be listed because they are unknown, one cannot blame the method! The only
solution is to perform the model measurements with the same material system and
to change the model scales.
Example 4: Scale-Up of a Mechanical Foam Breaker. The question is posed
about the mode of performing and evaluating model measurements with a given
type of mechanical foam breaker (foam centrifuge; see sketch in Fig. 2) to obtain
reliable information on dimensioning and scale-up of these devices. Preliminary
experiments have shown that for each foam emergence—proportional to the gas
throughput qG—for each foam breaker of diameter d, a minimum rotational speed
nmin exists that is necessary to control it. The dynamic properties of the foam (e.g.,
density and viscosity, elasticity of the foam lamella) cannot be fully named or
measured. We will have to content ourselves with listing them wholesale as material
properties Si. In our model experiments we will of course be able to replace
Si by the known type of surfactant (foamer) and its concentration c? [ppm].
Dimensional Analysis 17
In discerning the process parameters we realize that the gravitational acceleration
g has no impact on the foam breaking within the foam centrifuge: The centrifugal
acceleration n2d exceeds the gravitational one (g) by far! However, we
have to recognize that the water content of the foam entering the centrifuge depends
very much on the gravitational acceleration: On the moon the water
drainage would be by far less effective! In contrast to the dimensional analysis
presented in Ref. 9, we are well advised to add g to the relevance list:
{nmin; d; type of foamer, c?; qG, g} (21)
For the sake of simplicity, in the following nmin will be replaced by n and qG
by q. 
To prove this pi space, measurements in different-size model equipment are necessary
to produce reliable process characteristics. For a particular foamer (Mersolat
H of Bayer AG, Germany) the results are given in Figure 2. They fully confirm
the pi space [Eq. (22)].
The straight line in Figure 2 corresponds to the analytic expression
Q1 
 Fr0.4c?
0.32 (23)
18 Zlokarnik
Figure 2 Process characteristics of the foam centrifuge (sketch) for a particular foamer
(Mersolat H of Bayer AG, Germany). (From Ref. 9.)
which reduces to
nd 
 const q0.2?(c?) (24)
Here, the foam breaker will be scaled up according to its tip speed u 
 nd in
model experiments, which will also depend moderately on the foam yield (q).
In all other foamers examined [9], the correspondence Q1  Fr0.45 was
found. If the correlation
Q1  Fr0.5?(c?) (25)
proves to be true, then it can be reduced to
n2d/g 
 const(c?) (26)
In this case the centrifugal acceleration (n2d) would present the scale-up criterion
and would depend only on the foamer concentration and not on foam yield (q).
D. Short Summary of the Essentials of Dimensional
Analysis and Scale-Up
The advantages made possible by correct and timely use of dimensional analysis
are as follows.
1. Reduction of the number of parameters required to define the problem.
The pi theorem states that a physical problem can always be described
in dimensionless terms. This has the advantage that the number of dimensionless
groups that fully describe it is much smaller than the number
of dimensional physical quantities. It is generally equal to the number
of physical quantities minus the number of base units contained in
them.
2. Reliable scale-up of the desired operating conditions from the model to
the full-scale plant. According to the theory of models, two processes
may be considered similar to one another if they take place under geometrically
similar conditions and all dimensionless numbers which describe
the process have the same numerical value.
3. A deeper insight into the physical nature of the process. By presenting
experimental data in a dimensionless form, one distinct physical state
can be isolated from another (e.g., turbulent or laminar flow region) and
the effect of individual physical variables can be identified.
4. Flexibility in the choice of parameters and their reliable extrapolation
within the range covered by the dimensionless numbers. These advantages
become clear if one considers the well-known Reynolds number,
Re 
 vL/
, which can be varied by altering the characteristic velocity
v or a characteristic length L or the kinematic viscosity 
. By choosing
Dimensional Analysis 19
appropriate model fluids, the viscosity can very easily be altered by several
orders of magnitude. Once the effect of the Reynolds number is
known, extrapolation of both v and L is allowed within the examined
range of Re.
E. Area of Applicability of the Dimensional Analysis
The application of dimensional analysis is indeed heavily dependent on the available
knowledge. The following five steps (see Fig. 3) can be outlined as:
1. The physics of the basic phenomenon is unknown—Dimensional analysis
cannot be applied.
2. Enough is known about the physics of the basic phenomenon to compile
a first, tentative relevance list—The resultant pi set is unreliable.
3. All the relevant physical variables describing the problem are known—
The application of dimensional analysis is unproblematic.
4. The problem can be expressed in terms of a mathematical equation—A
20 Zlokarnik
Figure 3 Graphical representation of the four levels of knowledge and their impact on
the treatment of the problem by dimensional analysis. (From J. Pawlowski, personal communication,
1984.)
closer insight into the pi relationship is feasible and may facilitate a reduction
of the set of dimensionless numbers.
5. A mathematical solution of the problem exists—The application of dimensional
analysis is superfluous.
It must, of course, be said that approaching a problem from the point of view
of dimensional analysis also remains useful even if all the variables relevant to the
problem are not yet known: The timely application of dimensional analysis may
often lead to the discovery of forgotten variables or the exclusion of artifacts.
F. Experimental Methods for Scale-Up
In Section I, a number of questions were posed that are often asked in connection
with model experiments.
How small can a model be? The size of a model depends on the scale factor
LT /LM and on the experimental precision of measurement. Where LT /LM 
 10, a
10% margin of error may already be excessive. A larger scale for the model will
therefore have to be chosen to reduce the error.
Is one model scale sufficient, or should tests be carried out in models of different
sizes? One model scale is sufficient if the relevant numerical values of the
dimensionless numbers necessary to describe the problem (the so-called “process
point” in the pi space describing the operational condition of the technical plant)
can be adjusted by choosing the appropriate process parameters or physical properties
of the model material system. If this is not possible, the process characteristics
must be determined in models of different sizes, or the process point must
be extrapolated from experiments in technical plants of different sizes.
When must model experiments be carried out exclusively with the original
material system? Where the material model system is unavailable (e.g., in the case
of non-Newtonian fluids) or where the relevant physical properties are unknown
(e.g., foams, sludges, slimes), the model experiments must be carried out with the
original material system. In this case measurements must be performed in models
of various sizes (cf. Example 4).
G. Partial Similarity
The theory of models requires that in the scale-up from a model (index M) to the
industrial scale (index T) not only the geometric similarity be ensured but also all
dimensionless numbers describing the problem retain the same numerical values
(	i 
 idem). This means, e.g., that in scale-up of boats or ships the dimensionless
numbers governing the hydrodynamics here

must retain their numerical values: FrT 
 FrM and ReT 
 ReM. It can easily be
shown that this requirement cannot be fulfilled here!
Due to the fact that the gravitational acceleration g cannot be varied on
Earth, the Froude number Fr of the model can be adjusted to that of the full-scale
vessel only by its velocity vM. Subsequently, Re 
 idem can be achieved only by
adjusting the viscosity of the model fluid. In the case where the model size is only
10% of the full size (scale factor LT /LM
10), Fr 
idem is achieved in the model
at vM 
 0.32vT. 
No liquid exists whose viscosity would be only 3% of that of water!
We have to realize that sometimes requirements concerning physical properties
of model materials exist that cannot be implemented. In such cases only a
partial similarity can be realized. For this, essentially only two procedures are
available (for details see Refs. 5 and 10). One consists of a well-planned experimental
strategy, in which the process is divided into parts that are then investigated
separately under conditions of complete similarity. This approach was first
applied by William Froude (1810–1879) in his efforts to scale up the drag resistance
of the ship’s hull.
The second approach consists in deliberately abandoning certain similarity
criteria and checking the effect on the entire process. This technique was used by
Gerhard Damkohler (1908–1944) in his trials to treat a chemical reaction in a catalytic
fixed-bed reactor by means of dimensional analysis. Here the problem of a
simultaneous mass and heat transfer arises—they are two processes that obey
completely different fundamental principles!
It is seldom realized that many “rules of thumb” utilized for scale-up of different
types of equipment are represented by quantities that fulfill only a partial
similarity. As examples, only the volume-related mixing power P/V—widely used
for scaling-up mixing vessels—and the superficial velocity v, which is normally
used for scale-up of bubble columns, should be mentioned here.
The volume-related mixing power P/V presents an adequate scale-up criterion
only in liquid/liquid dispersion processes and can be deduced from the pertinent
process characteristics dp/d  We0.6 (dp is the particle or droplet diameter;
We is the Weber number). In the most common mixing operation, the homogenization
of miscible liquids, where a macro- and back-mixing is required, this criterion
fails completely [10]!
Similarly, the superficial velocity v or vG of the gas throughput as an intensity
quantity is a reliable scale-up criterion only in mass transfer in gas /liquid systems
in bubble columns. In mixing operations in bubble columns, requiring that
22 Zlokarnik
the whole liquid content be back-mixed (e.g., in homogenization), this criterion
completely loses its validity [10].
We have to draw the following conclusion: A particular scale-up criterion
that is valid in a given type of apparatus for a particular process is not necessarily
applicable to other processes occurring in the same device.
VI. TREATMENT OF VARIABLE PHYSICAL PROPERTIES
BY DIMENSIONAL ANALYSIS
It is generally assumed that the physical properties of the material system remain
unaltered in the course of the process. Process equations, e.g., the heat characteristics
of a mixing vessel or a smooth straight pipe
Nu 
 ?(Re, Pr) (27)
are valid for any material system with Newtonian viscosity and for any constant
process temperature, i.e., for any constant physical property.
However, constancy of physical properties cannot be assumed in every
physical process. A temperature field may well generate a viscosity field or even
a density field in the material system treated. In non-Newtonian (pseudoplastic or
viscoelastic) liquids, a shear rate can also produce a viscosity field.
In carrying out a scale-up, the industrial process has to be similar to the laboratory
process in every relation. Besides the geometric and process-related similarity,
it is self-evident that the fluid dynamics of the material system also has to
behave similarly. This requirement normally represents no problems when Newtonian
fluid are treated. But it can cause problems, when—e.g., in some biotechnological
processes—material systems are involved that exhibit non-Newtonian
viscosity behavior. Then the shear stress exerted by the stirrer causes a viscosity
field.
Although most physical properties (e.g., viscosity, density, heat conductivity
and capacity, surface tension) must be regarded as variable, it is particularly
the value of viscosity that can be varied by many orders of magnitude under certain
process conditions [5,11]. In the following, dimensional analysis will be applied,
via examples, to describe the temperature dependency of the density und
viscosity of non-Newtonian fluids as influenced by the shear stress.
A. Dimensionless Representation of the Material Function
Similar behavior of a certain physical property common to different material systems
can only be visualized by dimensionless representation of the material function
of that property (here the density ). It is furthermore desirable to formulate
Dimensional Analysis 23
this function as uniformly as possible. This can be achieved by the “standard representation”
[6] of the material function in which a standardized transformation of
the material function (T ) is defined in such a way that the expression produced,
/0 
 {0(T  T0)} (28)
meets the requirement
(0) 
(0) 
 1
where 0 
 
1
0 


T

0
 temperature coefficient of the density and 0 
 (T0).
T0 is any reference temperature.
Figure 4A shows the dependency (T) for four different liquids, and Figure
4B depicts the standard representation of this behavior. This confirms that
propene, toluene, and CCl4 behave similarly with regard to (T), whereas water
behaves differently. This implies that water cannot be used in model experiments
if one of the other three liquids will be employed in the industrial plant.
B. Pi Set for Temperature-Dependent Physical Properties
The type of dimensionless representation of the material function affects the (extended)
pi set within which the process relationship is formulated (for more information
see Ref. 5). When the standard representation is used, the relevance list
must include the reference density 0 instead of  and incorporate two additional
parameters 0, T0. This leads to two additional dimensionless numbers in the process
characteristics. With regard to the heat transfer characteristics of a mixing
vessel or a smooth straight pipe, Eq. (27), it now follows that
Nu 
 ?(Re0, Pr0, 0T, T/T0) (29)
where the subscript zero in Re and Pr denotes that these two dimensionless numbers
are to be formed with 0 (which is the numerical value of  at T0).
If we consider that the standard transformation of the material function can
be expressed invariantly with regard to the reference temperature T0 (Fig. 4b),
then the relevance list is extended by only one additional parameter, 0. This, in
turn, leads to only one additional dimensionless number. For the foregoing problem
it now follows that
Nu 
 ?(Re0, Pr0, 0T ) (30)
C. Non-Newtonian Liquids
The main characteristics of Newtonian liquids is that simple shear flow (e.g., Couette
flow) generates shear stress  that is proportional to the shear rate ? 
 dv/dy
24 Zlokarnik
Dimensional Analysis 25
Figure 4 (A) Temperature dependency of the density, (T), for four different liquids. (B)
The standard representation of the behavior (T) for the same liquids.
[sec1]. The proportionality constant, the dynamic viscosity , is the only material
constant in Newton’s law of motion:
 
 ? (31)
 depends only on temperature.
In the case of non-Newtonian liquids,  depends on ? as well. These liquids
can be classified into various categories of materials depending on their flow behavior:
(?) 
 flow curve and () 
 viscosity curve.
D. Pseudoplastic Fluids
An extensive class of non-Newtonian fluids is formed by pseudoplastic fluids
whose flow curves obey the so-called “power law”:
 
 K? m > eff 
 K? (m1) (32)
These liquids are known as Ostwald–de Waele fluids. Figure 5 depicts a typical
course of such a flow curve. Figure 6 shows a dimensionless standardized material
function of two pseudoplastic fluids often used in biotechnology. It proves that
they behave similarly with respect to viscosity behavior under shear stress.
E. Viscoelastic Liquids
Almost every biological solution of low viscosity [but also viscous biopolymers
like xanthane and dilute solutions of long-chain polymers, e.g., carboxymethylcellulose
(CMC), polyacrylamide (PAA), and polyacrylnitrile (PAN)] displays
26 Zlokarnik
Figure 5 Typical flow behavior of pseudoplastic fluids.
not only viscous but also viscoelastic flow behavior. These liquids are capable of
storing a part of the deformation energy elastically and reversibly. They evade mechanical
stress by contracting like rubber bands. This behavior causes a secondary
flow that often runs contrary to the flow produced by mass forces (e.g., the liquid
“climbs” the shaft of a stirrer, the so-called “Weissenberg effect”).
Elastic behavior of liquids is characterized mainly by the ratio of first differences
in normal stress, N1, to the shear stress, . This ratio, the Weissenberg
number Wi 
 N1/, is usually represented as a function of the rate of shear ?. Figure
7 depicts flow curves of some viscoelastic fluids, and Figure 8 presents a dimensionless
standardized material function of these fluids. It again verifies that
they behave similarly with respect to viscoelastic behavior under shear stress.
F. Pi Set for Non-Newtonian Fluids
The transition from a Newtonian to a non-Newtonian fluid results in the following
consequences regarding the extension of the pi set.
1. All pi numbers of the Newtonian case also appear in the non-Newtonian
case, whereby  is exchanged by a quantity H with the dimension of
viscosity (mostly 0).
Dimensional Analysis 27
Figure 6 Dimensionless standardized material function of some pseudoplastic fluids
used as model substances in biotechnological research. (From Ref. 2.)
28 Zlokarnik
Figure 7 Flow curves of viscoelastic fluids often used in the biotechnological research
(PAA, CMC). (From Ref. 12.)
Figure 8 Dimensionless standardized material function of the fluids in Figure 7, verifying
the similar viscoelastic behavior under shear stress. (From Ref. 12.)
2. An additional pi number appears that contains a quantity  with the dimension
of time (mostly 1/0).
3. The pure material numbers are extended by 	rheol.
The table below illustrates this using the example chosen at the beginning
of this chapter, namely the heat transfer characteristics of a mixing vessel or a
smooth straight pipe, Eq. (27). It shows the complete set of pi numbers for a temperature
independent (a) and temperature dependent (b) viscosity of a Newtonian
and a non-Newtonian fluid.
(33)
Newtonian fluid non-Newtonian fluid
a Nu, Re, Pr Nu, ReH, PrH, v/L, 	rheol
b Nu, Re0, Pr0, 0 T Nu, ReHo, PrHo, v0 /L, HoT, /H, 	rheol
In (b), the pi numbers w/ and HoT as well as  /H, have to be added ( 

ln/T). Besides this, completely other phenomena can occur (e.g., creeping of
a viscoelastic liquid on a rotating stirrer shaft opposite to gravity—the so-called
Weissenberg effect) that require additional parameters (in this case g) to be incorporated
into the relevance list.
VII. DETERMINATION OF OPTIMUM PROCESS
CONDITIONS BY COMBINING PROCESS
CHARACTERISTICS
The next example shows how a meaningful combination of appropriate process
characteristics makes it possible to gain the information necessary for the optimization
of the process in question.
Example 5: Optimum Conditions for the Homogenization of Liquid Mixtures.
The homogenization of miscible liquids is one of most frequent mixing operations.
It can be executed properly if the power characteristics and the mixing-time
characteristics of the stirrer in question are known. If these characteristics are
known for a series of common stirrer types under favorable installation conditions,
one can go on to consider optimum operating conditions by asking the following
question: Which type of stirrer operates within the requested mixing time
 with the lowest power consumption P and hence the minimum mixing work (P

 min) in a given material system and a given vessel (vessel diameter D)?
Example 5.1: Power Characteristics of a Stirrer. The relevance list for this task
consists of the target quantity (mixing power P) and the following parameters:
stirrer diameter d, density  and kinematic viscosity 
 of the liquid, and stirrer
Dimensional Analysis 29
speed n:
{P; d; , 
; n} (34)
By choosing the dimensional matrix
 d n P 

Mass M 1 0 0 1 0
Length L 3 1 0 2 2
Time T 0 0 1 3 1
core matrix residual matrix
only one linear transformation is necessary to obtain the unity matrix:
 d n P 

M 1 0 0 1 0
3M L 0 1 0 5 2
T 0 0 1 3 1
unity matrix residual matrix
The residual matrix consists of only two parameters, so only two pi numbers
result:
	1 

1n
P
3d5  

n
P
3d5  
 Ne (Newton number)
	2 

0n


1d2  
 
n


d2  
 Re1 (Reynolds number)
The process characteristics
Ne 
 ?(Re) (35)
for three well-known, slowly rotating stirrers (leaf, frame, and cross-beam stirrers)
is presented in Fig. 9.
1. In the range Re  20, the proportionality Ne  Re1 is found, thus resulting
in the expression NeRe 
 P/(n2d3) 
 const. Density is irrelevant
here—we are dealing with the laminar flow region.
2. In the range Re  50 (vessel with baffles) or Re  5  104 (unbaffled
vessel), the Newton number Ne 
 P/(n3d5) remains constant. In
this case, viscosity is irrelevant—we are dealing with a turbulent flow
region.
30 Zlokarnik
3. Understandably, the baffles do not influence the power characteristics
within the laminar flow region, where viscosity forces prevent rotation
of the liquid. However, their influence is extremely strong at Re  5 
104. Here, the installation of baffles under otherwise unchanged operating
conditions increases the power consumption of the stirrer by a factor
of 20!
4. The power characteristics of these three stirrers do not differ much from
each other. This is understandable because their mixing patterns are
very similar.
Example 5.2: Mixing-Time Characteristics of a Stirrer. Mixing time  is the
time necessary to completely homogenize an admixture with the liquid contents
of the vessel. It can easily be determined visually by a decolorization reaction
(neutralization, redox reaction in the presence of a color indicator). The relevance
list of this task consists of the target quantity (mixing time ) and of the same parameters
as in the case of mixing power—on condition that (contrary to Example
3) both liquids have similar physical properties):
{; d; , 
; n} (36)
This relevance list yields the two parametric mixing-time characteristics
n 
 ?(Re) (37)
Dimensional Analysis 31
Figure 9 Power characteristics for three slowly rotating stirrers (leaf, frame, cross-beam
stirrers) installed in a vessel with and without baffles. Stirrer geometry and the installation
conditions are given in Figure 10. (From Ref. 13.)
For the three stirrer types treated in this example, the mixing-time characteristics
are presented in Fig. 10.
One should not be mistaken by the course of the n(Re) curves: The mixing
time does not increase with higher Re numbers, it simply diminishes more slowly
until at Re  106 the minimum achievable mixing time is reached:
n  Re >   d2/
 (Re  106) (38)
From Eq. (38) we learn that the minimum achievable mixing time corresponds
to the square of the stirrer diameter: Bigger volumes require longer mixing
times.
A. Minimum Mixing Work (P
  min) for Homogenization
To gain the information on minimum mixing work (P
min) necessary for a homogenization,
the mixing-time characteristics as well as the power characteristics
have to be combined in a suitable manner. Both of them contain the rotational
speed n and the stirrer diameter d, knowledge of which would unnecessarily con-
32 Zlokarnik
Figure 10 Mixing-time characteristics for three slowly rotating stirrers (leaf, frame,
cross-beam stirrers) in a vessel with and without baffles. To correlate the data in order to
emphasize the similarity, n values of the cross-beam stirrer were multiplied by 0.7 and of
the leaf stirrer by 1.25. Full signs: unbaffled vessel. (From Ref. 13.)
strict the statement. Therefore the ratio D/d, tank diameter/stirrer diameter, which
is known for frequently used stirrer types, also has to be incorporated.
From the pi frame
{Ne, n, Re, D/d} (39)
the following two dimensionless numbers can now be formed:
	1 
 Ne Re D/d 
 

P


D
3 


PD
3
2
 (40)
	2 
 n Re1 (D/d)2 
 
D


2 

 
D

2
 (41)
These numbers could have been extracted in advance from the following relevance
list:
{P, ; D; 
, } (42)
which results in the following dimensional matrix:
 d n P 

M 1 0 0 1 0
L 3 1 0 2 2
T 0 0 1 3 1
M 1 0 0 1 0
L  3M 0 1 0 5 2
T 0 0 1 3 1
Figure 11 shows this relationship 	1 
 ?(	2) for those stirrer types that exhibit the
lowest 	1 values within a specific range of 	2, i.e., the stirrers requiring the least
power in this range. It represents the working sheet for the determination of optimum
working conditions on the homogenization of liquid mixtures in mixing vessels.
This graph is extremely easy to use. The physical properties of the material
system, the diameter of the vessel (D), and the desired mixing time () are all
known, and this is enough to generate the dimensionless number 	2.
1. From the numerical value of 	2 the stirrer type and baffling conditions
can be read off the abscissa. The diameter of the stirrer and the installation
conditions can be determined from data on stirrer geometry in the
sketch.
The curve 	1 
 ?(	2) in Figure 11 then provides the following information.
2. The numerical value of 	1 can be read off at the intersection of the
	2 value with the curve. The power consumption P can then be calculated
from this.
Dimensional Analysis 33
3. The numerical value of Re can be read off the Re scale at the same intersection.
This, in turn, makes it possible to determine the rotational
speed of the stirrer.
For further examples of this optimization technique see Refs. 5 and 11.
VIII. DIMENSIONAL ANALYSIS AND SCALE-UP OF MILLS
FOR EMULSIFICATION AND FOR GRINDING
In this section, two unit operations will be discussed that are often encountered in
the pharmaceutical industry.
Example 6: Emulsification of Nonmiscible Liquids. Liquid/liquid emulsions
consist of two (or more) nonmiscible liquids. Classic examples of oil in water
(O/W) emulsions are milk, mayonnaise, lotions, creams, water-soluble paints,
and photo emulsions. As appliances serve dispersion and colloid mills, as well
as high-pressure homogenizers. All of them utilize a high-energy input to produce
the finest droplets of the disperse (mostly oil) phase. The aim of this oper-
34 Zlokarnik
Figure 11 Working sheet for the determination of optimum working conditions in the
homogenization of liquid mixtures in mixing vessels. (From Ref. 13.)
ation is the narrowest possible droplet size distribution. It is normally characterized
by the “Sauter mean diameter” d32 [14] or by the median d50 of the size distribution.
d32 or d50, respectively, therefore has to be regarded as the target quantity
of this operation.
The characteristic length of the dispersion chamber, e.g., the slot width between
rotor and stator in dispersion mills or the nozzle diameter in high-pressure
homogenizers (utilizing high-speed fluid shear), will be denoted as d.
As material parameters, the densities and the viscosities of both phases as
well as the interfacial tension 
 must be listed. We incorporate the material parameters
of the disperse phase d and d in the relevance list and note separately
the material numbers /d and /d. Additional material parameters are the (dimensionless)
volume ratio of both phases  and the mass portion ci of the emulsifier
(surfactant) (e.g., given in ppm).
The process parameters have to be formulated as intensive quantities. In appliances
where liquid throughput q and power input P are separated from each
other as two freely adjustable process parameters, the volume-related power input
P/V and the period of its duration ( 
 V/q) must be considered:
(P/V)  
 E/V [M L1 T2] (43)
In appliances with only one degree of freedom (e.g., high-pressure homogenizers),
the power is being introduced by the liquid throughput. Here, the relevant intensively
formulated power P is therefore power per liquid throughput, P/q. In
nozzles, P  p q, which results in
P/q 
 (p q)/q 
 p[M L1 T2] (44)
Therefore, the volume-related energy input E/V and the throughput-related power
input P/q (
 p) represent homologous quantities of the same dimension. For the
sake of simplicity p will be introduced in the relevance list.
Now, this six-parameter relevance list of the dimensional parameters (the
dimensionless parameters /d, /d, , ci are excluded) reads
{d32; d; d, d, 
; p} (45)
The corresponding dimensional matrix
d d 
 p d d32
M 1 0 1 1 1 0
L 3 1 0 1 1 0
T 0 0 2 2 1 0
M  T/2 1 0 0 0 1 0
3M  L  3T/2 0 1 0 3 2 1
T/2 0 0 1 1 1 2
Dimensional Analysis 35
delivers the remaining three dimensionless numbers:
	1 




p d
 
 Eu We 
 La (Laplace number)
	2 

(d

d
d

)1–2
 
 
Oh (Ohnesorge number)
	3 
 d32 /d
The complete pi set is given as
{d32 /d, La, Oh, /d, /d, , ci} (46)
Assuming a quasi-uniform power distribution in the throughput or in the volume,
a characteristic length of the dispersion space becomes irrelevant. In the relevance
list, Eq. (45), the parameter d must be cancelled. The target number 	3 

d32/d has to be dropped and the dimensionless numbers La* and Oh* have to be
built by d32 instead of d. At given and constant material conditions (/d, /d, ,
ci
const) the process characteristics will be represented in the following pi space:
Oh*2 
 ?(La*Oh*2) > d32 


d
d


2 
 
 f {p 


d
d


2
2 

}
(47)
This dependency has been confirmed on two colloid mills in the scale 1:2.2
[15]; see Fig. 12. For a material system of vegetable oil /water and  
 0.5, the
following correlation is found:
d32 
 4.64  105p2–3 d32[m]; p[M/(L T2)] (48)
Similar results have been presented for other two-parameter appliances [16].
We1–2
Re
36 Zlokarnik
Figure 12 The relationship d32 
 ?(p) for two colloid mills of different size. Material
system: vegetable oil/water and  
 0.5. (From Ref. 15.)
It should be pointed out that the dimensional representations in the form of
Eq. (48) as d32 
 ?(p) present a serious disadvantage as compared to the dimensionless
one: Eq. (48) is valid only for the investigated material system and
tells nothing about the influence of the physical parameters!
Example 7: Fine Grinding of Solids in Stirred-Ball Mills. The fine grinding of
solids in mills of different shape and mode of operation is used to produce finest
particles with a narrow particle size distribution. Therefore—as in the previous
example—the target quantity is the median value d50 of the particle size distribution.
The characteristic length of a given mill type is d. The physical properties
are given by the particle density p, the specific energy of the fissure area , and
the tensile strength 
Z of the material. Should there be additional material parameters
of relevance, they can easily be converted to material numbers by the aforementioned
ones.
As process parameter, the mass-related energy input E/V must be taken
into account. The relevance list reads
{d50; d; p, , 
Z; E/V} (49)
p d  E/V 
Z d50
M 1 0 1 0 1 0
L 3 1 0 2 1 1
T 0 0 2 2 2 0
M  T/2 1 0 0 1 0 0
3M  L  3T/2 0 1 0 1 1 1
T/2 0 0 1 1 1 0
From this dimensional matrix the following pi set arises:
{d50 /d, (E/V)d/, 
Zd/} (50)
Assuming a quasi-uniform energy input in the mill chamber, its characteristic diameter
d will be irrelevant. Then the pi set is reduced to
{(E/V)d50 /, 
Zd50 /} > d50(
Z/) 
 ?{(E/V)(/
Z)} (51)
In the case of unknown physical properties, 
Z and , Eq. (51) is reduced to d50

 ?(E/V), which is then used for the scale-up of a given type of mill and a given
grinding material.
For fine-grinding of, e.g., limestone for paper and pottery manufacturing,
bead mills are widely used. The beads of steel, glass, or ceramic have a diameter
of 0.2–0.3 mm and occupy up to 90% of the total mill volume ( 0.9). They are
Dimensional Analysis 37
kept in motion by perforated stirrer discs while the liquid/solid suspension is
pumped through the mill chamber. Mill types frequently in use are stirred disc
mill, centrifugal fluidized-bed mill, ring gap mill.
H. Karbstein et al. [17] pursued the question of the smallest size of the laboratory
bead mill that would still deliver reliable data for scale-up. In different-size
rigs (V 
 0.25–25 liters) a sludge consisting of limestone (d50 
 16 m) and 10%
aqueous Luviscol solution (mass portion of solids  
 0.2) was treated. It was
found that the minimum size of the mill chamber should be V 
 1 liter. A further,
unexpected but dramatic result was that the validity of the process characteristics
d50  (E/V)0.43 E/V 104 (52)
expires at E/V  104 and the finest particle diameter cannot fall below d50  1
m.
These facts and the scattering of the results made a systematic investigation
of the grinding process necessary [18]. The grinding process in bead mills is determined
by the frequency and the intensity of the collision between beads and
grinding medium. According to this assumption, the grinding result will remain
constant if both these quantities are kept constant. The intensity of the collision is
essentially given by the kinetic energy of the beads:
Ekin  mMu2  VM M u2  d3
M M u2 (53)
(dM, M 
 diameter and density of the mill beads, u 
 tip velocity of the stirrer).
On the other hand, the frequency depends on the size of the mill chamber and
therefore on the overall mass-related energy input. To achieve the same grinding
result in different-size bead mills, Ekin as well as E/V have to be kept idem. The
input of the mechanical energy can be measured from the torque and the rotational
speed of the perforated discs, and the kinetic energy can be calculated from
Eq. (53).
The preceding assumption was examined with the same material system
and the same grinding media (beads). Three different-size bead mills were used
(V [liters] 
 0.73; 5.54; 12.9). Figure 13 shows the results. To achieve a satisfactory
correlation, the size of the mill chamber d will have to be introduced in
the relevance list. A further finding is that under the same conditions a smaller
mill delivers a coarser product. This had already been found in the previously
cited paper [17].
As to the course of the function d50 
 ?(Ekin) at E/V 
 103 kJ/kg 
 const,
the following explanation is given in Ref. 18. With Ekin increasing, the particle
size first diminishes but later increases. This is plausible if the introduced specific
energy is viewed as a product of the frequency and the intensity of the collision.
At E/V 
 const and increasing the intensity of the collision, the frequency has to
diminish, resulting in a coarser product.
38 Zlokarnik
IX. NOMENCLATURE
a thermal diffusivity (
/Cp)
A surface
c? concentration of foamer and flocculant, resp.
Cp heat capacity at constant pressure
d stirrer diameter
dp particle or droplet diameter
D vessel diameter
D diffusivity
F force
g gravitational accleration
G gravitational constant
l, L characteristic length
m mass
M dimension of mass
n rotational speed
p, p pressure, pressure difference
P power
q volumetric throughput
Dimensional Analysis 39
Figure 13 The relationship d50 
 ?(Ekin) for three colloid mills of the same type but different
size. Identical material system and constant E/V 
 103 kJ/kg. (From Ref. 18.)
R universal gas constant
t (running) time
T dimension of time
v velocity
vs velocity of sound
V liquid volume
A. Greek Characters
 temperature coefficient of density; specific energy of the fissure area in
grinding
 degree of filling
 temperature coefficient of dynamic viscosity
? shear rate

 kinematic viscosity
 dynamic viscosity; scale-up factor ( 
 lT /lM)
 volume or mass portion
 termal conductivity
	 dimensionless product
,  density, density difference

 (interfacial) surface tension

Z tensile strength
 period of time
T, T temperature, temperature difference
 dimension of temperature
 residence time; shear stress
B. Subscripts
G gas
L liquid
S solid
M model, laboratory scale
T technological, industrial scale
REFERENCES
1. G. B. West. Scale and dimensions—from animals to quarks. Los Alamos Science
11:2–20, 1984.
2. P. W. Bridgman. Dimensional Analysis. Yale University Press, New Haven, 1922,
1931, 1951; Reprint by AMS Press, New York, 1978, p. 12.
40 Zlokarnik
3. Lord Rayleigh. The principle of similitude. Nature 95, No 2368 (March 18), 1915, pp.
66–68.
4. E. Buckingham. On physically similar systems: illustrations of the use of dimensional
equations. Physical Review (New York) 2nd Series 4:345–376, 1914.
5. M. Zlokarnik. Dimensional Analysis and Scale-up in Chemical Engineering.
Springer Berlin, New York, 1991.
6. J. Pawlowski. Die Ahnlichkeitstheorie in der physikalisch-technischen Forschung
(Theory of Similarity in Physico-Technological Research; in German). Springer
Berlin, New York, 1971.
7. M. Zlokarnik. Ruhrleistung in begasten Flussigkeiten (Mixing power in gassed liquids).
Chem.-Ing.-Tech. 45:689–692, 1973.
8. M. Zlokarnik. Einfluss der Dichte- und Zahigkeitsunterschiede auf die Mischzeit
beim Homogenisieren von Flussigkeitsgemischen, Chem.-Ing.-Tech. 42:1009–1011,
1970.
9. M. Zlokarnik. Design and scale-up of mechanical foam breakers. Ger. Chem. Eng.
9:314–320, 1986.
10. M. Zlokarnik. Scale-up under conditions of partial similarity. Int. Chem. Eng. 27:1–9,
1987.
11. M. Zlokarnik. Dimensional Analysis, Scale-Up. In: Encyclopedia of Bio process
Technology: Fermentation, Biocatalysis, Bioseparation. Vol. 2, 840–861. (M.C.
Flickinger and S. W. Drew, eds.) Wiley, 1999.
12. H.-J. Henzler. Rheologische Stoffeigenschaften—Erklarung, Messung, Erfassung
und Bedeutung. Chem.-Ing.-Tech. 60:1–8, 1988.
13. M. Zlokarnik. Eignung von Ruhrern zum Homogenisieren von Flussigkeitsgemischen.
Chem.-Ing.-Tech. 39:539–548, 1967.
14. J. Sauter. Die Grossenbestimmung von Brennstoffeilchen. Forschungsarbeiten, vol.
279, 1926.
15. H. Schneider, T. Roth. Emulgierverfahren in der Lebensmittelindustrie.
Hochschulkurs Emulgiertechnik, Universitat Karlsruhe, 1996, XIII-1/18.
16. H. Karbstein, H. Schubert. Einflussparameter auf die Auswahl einer Maschine zum
Erzeugen feindisperser O/W-Emulsionen. Chem.-Ing.-Tech. 67:616–619, 1995.
17. H. Karbstein, F. Muller, R. Polke. Scale up bei der Echtzerkleinerung in Ruhrwerkskegelmuhlen.
Aufbereitungstechnik 37:469–479, 1996.
18. A. Kwade, H.-H. Stender. Konstantes Zerkleinerungsergebnis beim Scale-up von
Ruhrwerkskugelmuhlen. Aufbereitungstechnik 39:373–382, 1998.
Dimensional Analysis 41

2
Parenteral Drug Scale-Up
Igor Gorsky
Alpharma, Baltimore, Maryland
I. INTRODUCTION
The term parenteral is applied to preparations administered by injection through
one or more layers of skin tissue. The word, derived from the Greek words para
and etheron, meaning “outside of the intestine,” is used for those dosage forms administered
by routes other than the oral route. Because the administration of injectables,
by definition, requires circumventing the highly protective barriers of
the human body, the skin, and the mucous membranes, the dosage form must
achieve an exceptional purity. This is generally accomplished by strict adherence
to good manufacturing practices.
The basic principles employed in the preparation of parenteral products do
not vary from those widely used in other sterile and nonsterile liquid preparations.
However, it is imperative that all calculations be accurate and precise. Therefore,
the issue of parenteral solution scale-up essentially becomes a liquid scale-up task,
which requires a high degree of accuracy. A practical yet scientifically sound
means of performing this scale-up analysis of liquid parenteral systems is presented
in this chapter. The approach is based on the scale-of-agitation method. For
single-phase liquid systems, the primary scale-up criterion is equal liquid motion
when comparing pilot-size batches to a larger, production-size batches.
One of the most important processes involved in the scale-up of liquid parenteral
preparations is mixing [1]. For liquids, mixing can be defined as a transport
process that occurs simultaneously in three different scales, during which one
substance (solute) achieves a uniform concentration in another substance (solvent).
On a large, visible scale, mixing occurs by bulk diffusion, in which the elements
are blended by the pumping action of the mixer’s impeller. On the microscopic
scale, elements that are in proximity are blended by eddy currents, and they
43
create drag, where local velocity and shear-stress differences act on the fluid. On
the smallest scale, final blending occurs via molecular diffusion, whose rate is unaffected
by the mechanical mixing action. Therefore, large-scale mixing depends
primarily on flow within the vessel, whereas small-scale mixing is dependent
mostly on shear. This approach focuses on large-scale mixing using three viable
approaches, specifically concentrating on the scale-of-agitation method.
II. GEOMETRIC SIMILARITY
There are several methods to achieve appropriate scale-up of mixing. The first involves
geometric similarity. This technique employs proportional scale-up of geometric
parameters of the vessel. The scaled-up parameters may include such geometric
ratios as D/T, where D is the diameter of the impeller and T is the
diameter of the tank, and Z/T, where Z is the height of the liquid in the vessel. Similar
ratios are compared for both small-scale equipment (D1T1) and the largerscale
equipment (D2T2). For example,
R 
 D1T1 
 D2T2 (1)
where R is the geometric scaling factor.
After R has been determined, other required parameters, such as the rotational
speed of the larger equipment, can then be calculated by power law relationships.
In the preceding example, the required rotational speed, N, can be calculated
as
N2 
 N1
R
1
n
(2)
Rotational speeds may be expressed either in terms of rpm or in terms of
sec1. The power law exponent, n, has a definite physical significance. The value
of n and its corresponding significance are determined either empirically or
through theoretical means. Table 1 lists the most common values assigned to n.
The scale-up can be completed by using predicted values of N2 to determine
the horsepower requirements of the large-scale system. In most designs, D/T will
be in the following range:
0.15 ! 
D
T
 ! 0.6 (3)
and Z/T will be in the range
0.3 ! 
Z
T
 ! 1.5 (4)
These values, in conjunction with N and the horsepower requirements, completely
define the major parameters of the systems.
44 Gorsky
III. DIMENSIONLESS NUMBERS METHOD
The second method for achieving appropriate scale-up of mixing uses dimensionless
numbers to predict scale-up parameters. The use of dimensionless numbers
simplifies design calculations by reducing the number of variables to consider.
The dimensionless-number approach has been used with good success in heat
transfer calculations and to some extent in gas dispersion (mass transfer) for mixer
scale-up. Usually, the primary independent variable in a dimensionless-number
correlation is the Reynolds number:
NRe 

D2

N
 (5)
where
N 
 shaft speed (sec1)
D 
 propeller blade diameter (cm)
 
density of solution dispersion (g/cm3)
 
viscosity of solution dispersion (g/[cm /sec]).
Other dimensionless numbers are used widely for various scale-up applications.
One example is the Froude number:
NFr 

D
g
N2
 (6)
where g is acceleration due to gravity in cm/sec1. The Froude number compares
inertial forces to gravitational forces inside the system.
Another example is the power number, which is a function of the Reynolds
number and the Froude number:
NP 

N
P
3
g
D
c
5 
(7)
Parenteral Drug Scale-Up 45
Table 1 Common Values Assigned to the Power Law
Exponent, n, When Comparing Large- to Small-Scale
Equipment
n Physical interpretation
0 Equal blend time
1–2
Equal surface motion
2–3
Equal mass transfer rates
3–4
Equal solids supension
1 Equal liquid motion (equal average fluid velocity)
where P is power and gc is a gravitational conversion factor. This number relates
density, viscosity, rotational speed, and the diameter of the impeller. The power
number correlation has been used successfully for impeller geometric scale-up.
Approximately half a dozen other dimensionless numbers are involved in the various
aspects of mixing, heat and mass transfer, etc.
Both of the preceding methods belong to a traditional fluid mechanical approach
known as dimensional analysis [2]. Unfortunately, these methods cannot
always achieve results in certain manufacturing environments. Therefore, a third
method is introduced, which can be applied easily to the various research and production
situations. This method actually is a combination of the first two methods.
IV. SCALE-OF-AGITATION APPROACH
The basis of the scale-of-agitation approach is a geometric scale-up with the
power law exponent, n 
 1 (see Table 1). This provides for equal fluid velocities
in both large- and small-scale equipment. Furthermore, several dimensionless
groups are used to relate the fluid properties to the physical properties of the
equipment being considered. In particular, bulk-fluid velocity comparisons are
made around the largest blade in the system. This method is best suited to turbulent
flow agitation in which tanks are assumed to be vertical cylinders.
Although good success may be achieved in applying this technique to marine-
type propeller systems, the original development was based on low-rpm, axial,
or radial impeller arrangements. Because the most intensive mixing occurs in
the volume immediately around the impeller, this discussion focuses on this particular
region of mixing. Table 2 describes the nomenclature used to develop the
theory behind the approach.
The analysis proceeds as follows. First, determine the D/T ratio of the tank,
based on the largest impeller, in which the original (usually R&D) batches had
46 Gorsky
Table 2 Nomenclature
Q Effective pumping capacity or volumetric pumping flow, in cm3/sec
N Shaft speed, in sec1
NRe Impeller Reynolds number, dimensionless
NQ Pumping number, dimensionless
D Diameter of the largest mixer blade, in cm
 Density of the fluid, in g/cm3
 Viscosity of the fluid, in g/[cm/sec]
vb Bulk fluid velocity, in cm
T Diameter of the tank, in cm
A Cross-sectional area of the tank, in cm2
been compounded. It is also necessary to know the rotational speed and the horsepower
of the mixer used.
The only two product physical properties needed are density and viscosity.
Generally, parenterals, like most solution-type products, will follow Newtonian
fluid behavior and may also be considered incompressible. Therefore, point densities
and viscosities can be used satisfactorily.
The next step in the analysis is to calculate the impeller Reynolds number
achieved during this original compounding using Eq. (5). The impeller Reynolds
number must be greater than 2000 to proceed with the analysis [3]. Mixing
achieved in the initial R&D processing must be in the turbulent range. If the impeller
Reynolds number is less than 2000, then mixing in the pilot tank was either
inadequate or represented some other special case, such as moderately viscous fluids.
In these situations, another D/T ratio curve must be used.
Proceeding further, obtain the value of the terminal pumping number in the
R&D pilot process by using the following formula:
NQ 
 1.1283  1.07118
D
T (8)
Equation (8) is an empirical relationship obtained by the linear regression between
D/T and the terminal pumping numbers [4]. It is important to note that a family
of curves exists for each D/T ratio when NQ (pumping number) is plotted against
the impeller Reynolds number [5]. In the turbulent range (NRe  2000), the NQ
curves flatten out and thus are independent of the Reynolds number. The terminal
pumping number, NQ/Re2000, plotted against the D/T ratio results in Eq. (8). The
cross-sectional area of the pilot-size tank is determined by using Eq. (9):
A 
 

4
T2
 cm2 (9)
Then the value of the effective pumping capacity for the pilot-size mixer is calculated
using Eq. (10):
Q 
 NQND3 cm3/sec (10)
Finally, by inserting the values derived in Eqs. (9) and (10) into Eq. (11), the value
for bulk-fluid velocity around the largest impeller of the system is obtained:

b 
 
Q
A cm/sec (11)
The bulk-fluid velocity can be inserted into Table 3 to determine the level
of agitation achieved in the original R&D pilot batch. The larger-size production
tank and mixer are then designed so that the scale of agitation produced in the
larger vessel matches that required for the pilot-size batches. The scale-of-agitation
approach was first developed in the mid-1970s by engineers at Chemineer,
Parenteral Drug Scale-Up 47
Inc. [6]. Table 3 summarizes the scale-of-agitation parameters and gives a qualitative
description of the type of mixing associated with the various levels. According
to this approach, mixing is a similar process if the calculated bulk-fluid
velocities for the production-size vessels lie within 1 unit level of the scale of
agitation required from an analysis of the R&D pilot batches. It is quite easy to
match the required scale of agitation by simply adjusting the rpm when working
48 Gorsky
Table 3 Process Requirements: The Set Degree of Agitation for Blending and Motion
Scale Bulk-fluid
of velocity
agitation (cm/sec) Description of mixing
1
2
3
4
5
6
7
8
9
10
3
6
9
12
15
18
21
24
27
30
Agitation levels 1 and 2 are characteristic of applications requiring
minimum fluid velocities to achieve the product result
Agitators capable of level 2 will:
a. Blend miscible fluids to uniformity if specific gravity differences
are less than 0.1 and if the viscosity of the most viscous
is less than 100 times that of the other
b. Establish complete fluid-batch control
c. Produce a flat but moving fluid-batch surface
Agitation levels 3–6 are characteristic of fluid velocities in most
chemical (including pharmaceutical) industries agitated
batches
Same as 3
Same as 3 and 4
Agitators capable of level 6 will:
a. Blend miscible fluids to uniformity if specific gravity differences
are less than 0.6 and if the viscosity of the most viscous
is less than 10,000 times that of the other
b. Suspend trace solids (2%) with settling rates of 2–4 ft/min
c. Produce surface rippling at lower viscosities
Agitation levels 7–10 are characteristic of applications requiring
high fluid velocities for process result, such as mixing of the
high-viscosity suspension preparations
Same as 7
Same as 7 and 8
Agitators capable of level 10 will:
a. Blend miscible fluids to uniformity if specific gravity differences
are less than 1.0 and if the viscosity of the most viscous
is less than 100,000 times that of the other
b. Suspend trace solids (2%) with settling rates of 4–6 ft/min
c. Provide surging surface at low viscosities
with variable-speed equipment. Thus, a given tank equipped with a variable-speed
mixer will generally be capable of several agitation levels.
V. SCALE-OF-AGITATION APPROACH EXAMPLE
To illustrate the actual application of the scale-of-agitation approach to scale-up,
the method was applied to the scale-up of typical injectables solution from a 378
liter pilot batch to a 3780 liter production-size batch. The example product is a
Newtonian fluid with density of 1.018 g / cm3 and a viscosity of 0.0588
g/(cm/sec)(5.88 cps). The tank used in the manufacturing of the pilot batch had the
following parameters:
T 
 diameter of the tank 
 74.6 cm
A 
 cross-sectional area 
 4371 cm2
The agitation was accomplished with a turbine-type mixer, and the largest
axial impeller was 40.64 cm. The pilot batch was mixed at 90 rpm (1.5 sec1).
From the initial known data the D/T ratio was determined:
 D
T3
3
7
7
8
8
L
L


4
7
0
4
.
.
6
6
4
0
c
c
m
m 

 0.54 (12)
Then the value of the impeller Reynolds number was obtained by plugging known
values into Eq. (5):
NRe(3785L) 

D2
378L

N378L 

 
44449
(13)
Because the value of the Reynolds number is greater than 2000, Eq. (8) is used to
obtain the pumping number. The pumping number is inserted into Eq. (10) to obtain
the effective pumping capacity:
Q378L 
 (NQ(378L))(N378L)(D3
378L) 
 (0.55)(1.5 sec1)(40.64 cm)3

 55375 cm3/sec
(14)
Knowing the effective pumping capacity of agitation and the cross-sectional
area of the pilot-batch tank, bulk-fluid velocity is obtained by using Eq. (11):

b(378L) 

Q
A3
3
7
7
8
8
L
L


55,
4
3
3
7
7
5
1
c
c
m
m
3/
2
sec

 12.6 cm/sec (15)
Inserting this bulk-fluid velocity into Table 3, one can calculate the level of
agitation used in the pilot batch of indictable solution as 4, which is described as
(40.64 cm)2 (1.018 g/cm3)(1.5 sec1)

0.0588 g/(cm/sec)
Parenteral Drug Scale-Up 49
characteristic of fluid velocities in most chemical process industries’ agitated
batches.
Now the appropriate shaft speed for scaled-up production equipment can be
calculated. The tank used for production batches has a capacity of 3780 L. It is
equipped with a turbine-type agitator, which has a shaft speed range of 20–58 rpm.
The diameter of this tank is 167 cm. The diameter of the largest axial impeller is
87 cm. Given the diameter of the production tank, the cross-sectional area can be
determined as
A3780L
 

(167
4
cm)2

 21,904 cm2 (16)
The next step is solving Eq. (10) for effective pumping capacity in the larger
vessel:
Q3780L 
 (
b(378L))(A3780L) 
 (12.6 cm/sec)(21,904 cm2) 
 275,990 cm3/sec
(17)
Earlier, the analysis established that the mixing of this product occurs in the turbulent
flow regime because the Reynolds number obtained far exceeds the minimally
required 2000. Therefore, the pumping number can be calculated for the
3780-L tank by using Eq. (8) to obtain
NQ(3780L) 
 1.1283 
(1.07118)1
8
6
7
7
c
c
m
m 
 
 0.57 (18)
Finally, Eq. (10) is rearranged to solve for the appropriate shaft speed to be
used in a 3780-L batch:
N3780L
 
 
 0.73 sec1 
 44 rpm
(19)
The shaft speed value obtained is well within the rpm range of the 3780-L tank agitator.
To determine the rpm range for production batches, start with level-3 agitation
at the low rpm end and level-5 agitation at the high rpm end. Table 3 provides
bulk velocities for levels 3 and 5. In turn, these are used to calculate the
respective pumping capacities, defined via Eq. (11). The low and high speeds are
then calculated, as described earlier, by rearranging Eq. (10).
This method can easily be used to show the logic behind the scale-up from
original R&D batches to production-scale batches. Although scale-of agitation
analysis has its limitations, especially in the mixing of suspension, non-Newtonian
fluids and gas dispersions, similar analysis could be applied to these systems,
provided that pertinent system variables were used. These variables may include
superficial gas velocity, dimensionless aeration numbers for gas systems, and terminal
settling velocity for suspensions.
275,990 cm3/sec

(0.57)(87 cm)3
Q3780L 
NQ(3780L)D3
3780L
T2
3780L 
4
50 Gorsky
VI. LATEST REVISIONS OF THE APPROACH
As was discussed earlier, the scale-of-agitation approach has been successfully
used in the scale-up of various liquid systems, including parenteral drugs. However,
in the late 1990s, it was revised slightly to ensure even more accurate results
[7]. We have already determined that the mixing in the agitated tank must be in
the turbulent state in order for Eq. (8) to work properly. Therefore, an assumption
is made that the full turbulence is achieved at NRe above 2000. However, one
should be aware that this assumption may result in an error of 12% in the NQ calculation.
One may come to the conclusion that some inadequacies may be encountered
in the areas of mixing close to NRe
2000. This later revision of the approach
thrived on the fact that because this scale-up process was based on the use
of existing equipment, it may not be possible to build in as much of a safety factor
as possible when engineering a new facility. Therefore, it would be important
to determine NQ very accurately. Trying to achieve an even more accurate NQ determination,
the relationship between the D/T ratio on the NRe vs. NQ grid was reexamined.
Upon replotting Figure 1 using linear coordinates, the following trend
was observed (see Fig. 2). The curves rise sharply at first, which somewhat resembles
the dissolution profile for a solid dosage form. Lagenbucher’s equation
for dissolution profile curves is:
Y 
 1  exp

(
b
X)a
 (20)
Similarly, an equation for curves in Figure 2 may be expressed as follows:
NQ 
 1  exp

(N
b
Re)a
 (21)
Parenteral Drug Scale-Up 51
Figure 1 Pumping number versus impeller Reynolds number for turbine- and marinetype
propeller agitators.
where a and b are constants. Further, the equation for constant a was determined
by
a
0.272
D
T  0.39 (22)
The constant b was found to be independent of the D/T ratio and had a value of
7.7.
However, Eq. (21) covered applications only where NRe were below 1000.
Another equation [8] to determine NQ in the systems where NRe is higher than
1000 is
NQ 

N
A
Re
N

Re
B 
(23)
where both A and B are functions of the D/T ratio and were determined to be
A
1.08
D
T  1.12 (24)
B 
 578  1912
D
T  1980
D
T2
(25)
These equations yield an approximate 5% maximum error, as compared to an approximate
10% error in Eq. (8).
However, it is also necessary to mention that the strength of the analysis is
in its ability to mathematically transfer the mixing environment from the bench
scale to the maximum compounding vessel, as close to the original pilot batch as
possible. In our experience, the maximum rpm ranges empirically achieved dur-
52 Gorsky
Figure 2 Pumping number versus impeller Reynolds number for turbine- and marinetype
propeller agitators on linear coordinates.
ing compounding equal 6–20 rpm, which are well within the maximum 10% error
that one may encounter via Eq. 8 in the marginal cases, where NRe is close to 2000.
Therefore, it is safe to conclude that the method outlined in Eq. (8) through (11)
is the most efficient for finding mixing parameters of the scaled-up system. Yet
Eq. (25) and (23) show the way for a closer NQ determination, which may be more
useful for the systems with higher viscosities and thus with lower NRe.
VII. SCALE-OF-AGITATION APPROACH FOR
SUSPENSIONS
In order to reduce the problem of adequately dispersing the insoluble drug during
the formulation of sterile aqueous suspensions, the micronized material, i.e., material
with a particle size of 10–30 m, is used. Uniform distribution of the drug
is required to ensure an adequate dose at the concentration per unit volume indicated
on the label. Improper formulation or scale-up can result in caking of the insoluble
material at the bottom of the container, making it difficult to disperse, to
take up in a syringe, and thus to administer. To avoid caking, various flocculating
agents are added to the product. Proper scale-up, however, is essential for adequate
mixing conditions, which affect the caking process. During scale-up of a
suspension product, along with the parameters, already discussed, the settling rate
should be considered. The presence of a two-phase, solid–liquid system classifies
an agitation problem as a solid–suspension one. In such problems, the suspension
of solid particles having a settling velocity greater than 0.5 ft/min (0.25 cm/sec)
within a continuous liquid phase is the purpose of the proper agitation and scaleup.
The estimated terminal settling velocity, ut, of spherical particles of a 10- to
30 size in low-viscosity 1- to 300-cps suspensions is empirically determined as
1. For ease of analysis, the particle shape is assumed to be a sphere, since most of
the studies for settling velocities are conducted on spherical beads. A different
particle geometry (cylinders, disks, crushed solids, many crystalline forms) would
not compromise the integrity of the analysis, due to the usage of micronized materials.
First, one must determine the design settling velocity ud, which is a product
of the terminal settling velocity ut and a correction factor ?w, from Table 4.
ud 
 ut ?w (26)
Upon determination of the design settling velocity, one must choose the
scale of agitation required, using Table 5 [9], which serves as a suspension products
equivalent of Table 3. The chosen scale of agitation is than plugged into the
chart of Figure 3 to find the value of constant . Rearranging Eq. (27) for constant
, we get
 

N 3.75
ud
D2.81
 (27)
Parenteral Drug Scale-Up 53
54 Gorsky
Table 4 % Solids vs. Correct
Factor fw in Suspensions
Solids, % Factor, ?w
2 0.8
5 0.84
10 0.91
15 1.0
20 1.10
25 1.20
30 1.30
35 1.42
40 1.55
Table 5 Process Requirements Set the Degree of Agitation for Solids Suspension
Scale of agitation Description of mixing
1–2
3–5
6–8
9–10
Agitation levels 1 and 2 are characteristic of applications requiring
minimal solids-suspension levels to achieve the process result. Agitators
capable of scale levels of 1 and 2 will:
a. Produce motion of all of the solids of the design settling velocity
in the vessel
b. Permit moving fillets of solids on the tank bottom, which are periodically
suspended.
Agitation levels 3–5 are characteristic of most chemical process industry
solids-suspension applications and are typically used for dissolving
solids. Agitators capable of scale levels of 3–5 will:
a. Suspend all the solids of design settling velocity completely off the
vessel bottom
b. Provide slurry uniformity to at least 1/3 of fluid-batch height
c. Be suitable for slurry drawoff at low exit-nozzle elevations
Agitation levels 6–8 characterize applications where the solids-suspension
levels approach uniformity. Agitators capable of scale levels
of 6–8 will:
a. Provide concentration uniformity of solids to 95% of the fluidbatch
height.
b. Be suitable for slurry drawoff up to 80% of fluid-batch height
Agitation levels 9 and 10 characterize applications where the
solid–suspension uniformity is the maximum practical. Agitators
capable of scale levels of 9 and 10 will:
a. Provide slurry uniformity of solids to 98% of the fluid-batch height
b. Be suitable for slurry drawoff by means of overflow
Plugging this into Eq. (28) for mixer speed we easily find the agitation rpm:
N 

1 –––
3.75 
D
 
2
u
. 
8
d
1 

(
28)
VIII. CONCLUSIONS
The foregoing scale-up approach for liquid parenteral solutions provides a precise
transfer of the compounding mixing equipment environment to the production
scale. Due to the unsurpassed importance of proper agitation during the preparation
of injectables, the lion’s share of this chapter was devoted to the scale-up of
agitating equipment. Other pieces of equipment used during the manufacture of
parenteral drugs, such as sterilization equipment, filtration systems, various
pumps, and packaging equipment, are geometrically scalable and are easily selected
from the wide variety available.
One must also stress the importance of quality considerations during compounding
and full adherence to current Good Manufacturing Practices while producing
parenteral products. Personnel responsible for the process design and
scale-up of the equipment must ensure proper documentation of the scale-up with
tractability of all the preparatory work from the pilot batch(es) to the manufacture
of the marketed products. Spreadsheet programs are useful for documenting
equipment parameters and for the subsequent calculations required for proper
scale-up.
REFERENCES
1. J. T. Cartensen, M. Ashol. Scale-up factors in the manufacturing of solution dosage
forms. Pharm. Technol. 6:64–77, 1982.
Parenteral Drug Scale-Up 55
Figure 3 Solid-suspension scale value vs. 
2. J. A. Von Essen. Liquid Mixing: Scale-Up Procedures. Presented at Inter-American
Congress and VII Chilean Congress of Chemical Engineering, Santiago, Chile,
November 6–11, 1983.
3. P. R. Hollman. Consistent Mixing: The Key to Uniform Quality. Conference, College
of Engineering, Department of Engineering Professional Development, University of
Wisconsin–Madison, May 1991.
4. I. Gorsky, R. K. Nielsen. Scale-up methods used in liquid pharmaceutical manufacturing.
Pharm. Technol. 16:112–120, 1992.
5. J. Y. Oldshue. Fluid Mixing Technology. New York: McGraw-Hill, 1983.
6. J. R. Morton, R. W. Hicks, J. G. Fenic. How to design agitatiors for desired process response.
Chem. Engineering 26:102–110, 1976.
7. G. F. Klein. A new approach to the scale-up of liquid pharmaceuticals. Pharm. Technol.
23:136–144, 1999.
8. B. Y. Tao. Optimization via the simplex method. Chemical Engineering 95:85, 1988.
9. L. E. Gates, J. R. Morton, P. L. Fondy. Selecting agitator system to suspend solids in
liquid. Chem. Engineering 24:144–150, 1976.
56 Gorsky
3
Nonparenteral Liquids and
Semisolids
Lawrence H. Block
Duquesne University, Pittsburgh, Pennsylvania
I. INTRODUCTION
A manufacturer’s decision to scale up (or scale down) a process is ultimately
rooted in the economics of the production process, i.e., in the cost of materiel, personnel,
and equipment associated with the process and its control. While process
scale-up often reduces the unit cost of production and is therefore economically
advantageous per se, there are additional economic advantages conferred on the
manufacturer by scaling up a process. Thus, process scale-up may allow for faster
entry of a manufacturer into the marketplace or improved product distribution or
response to market demands and correspondingly greater market-share retention.1
Given the potential advantages of process scale-up in the pharmaceutical industry,
one would expect the scale-up task to be the focus of major efforts on the part of
pharmaceutical manufacturers. However, the paucity of published studies or data
on scale-up—particularly for nonparenteral liquids and semisolids—suggests otherwise.
On the other hand, one could argue that the paucity of published studies or
data is nothing more than a reflection of the need to maintain a competitive advantage
through secrecy.
One could also argue that this deficiency in the literature attests to the complexity
of the unit operations involved in pharmaceutical processing. If pharma-
57
1 On the other hand, the manufacturer may determine that the advantages of process scale-up are compromised
by the increased cost of production on a larger scale and/or the potential loss of interest or
investment income. R. G. Griskey [1] addresses the economics of scale-up in some detail in his chapter
on engineering economics and process design, but his examples are taken from the chemical industry.
For a more extensive discussion of process economics, see Holland and Wilkinson [2].
ceutical technologists view scale-up as little more than a ratio problem, whereby
scale-up ratio 
 (1)
then the successful resolution of a scale-up problem will remain an empirical,
trial-and-error task, rather than a scientific one. In 1998, in a monograph on the
scale-up of disperse systems, Block [3] noted that due to the complexity of the
manufacturing process that involves more than one type of unit operation2 (e.g.,
mixing, transferring), process scale-up from the bench or pilot plant level to commercial
production is not a simple extrapolation:
The successful linkage of one unit operation to another defines the functionality
of the overall manufacturing process. Each unit operation per se may be
scalable, in accordance with a specific ratio, but the composite manufacturing
process may not be, as the effective scale-up ratios may be different from one
unit operation to another. Unexpected problems in scale-up are often a reflection
of the dichotomy between unit operation scale-up and process scaleup.
Furthermore, commercial production introduces problems that are not a
major issue on a small scale: e.g., storage and materials handling may become
problematic only when large quantities are involved; heat generated in the
course of pilot plant or production scale processing may overwhelm the system’s
capacity for dissipation to an extent not anticipated based on prior laboratory-
scale experience [3].
Furthermore, unit operations may function in a rate-limiting manner as the scale
of operation increases. When Astarita [4] decried the fact, in the mid-1980s, that
“there is no scale-up algorithm which permits us to rigorously predict the behavior
of a large-scale process based upon the behavior of a small-scale process,” it
was presumably as a consequence of all of these problematic aspects of scale-up.
A clue to the resolution of the scale-up problem for liquids and semisolids
resides in the recognition that their processing invariably involves the unit operation
of mixing. Closer examination of this core unit operation reveals that flow
conditions and viscosities during processing can vary by several orders of magnitude,
depending upon the scale of scrutiny employed, i.e., whether on a microscopic
(e.g., molecular) or a macroscopic (e.g., bulk) scale. Therefore, the key to
effective processing scale-up is the appreciation and understanding of microscale
and macroscale transport phenomena, i.e., diffusion and bulk flow, respectively.
Transport by diffusion involves the flow of a property (e.g., mass, heat, momentum,
electromagnetic energy) from a region of high concentration to a region of
large-scale production rate
 small-scale production rate
58 Block
2 The term unit operations, coined by Arthur D. Little in 1915, is generally used to refer to distinct
physical changes or unit actions (e.g., pulverizing, mixing, drying), while unit operations involving
chemical changes are sometimes referred to as unit processes. The physical changes comprising unit
operations involve primarily contact, transfer of a physical property, and separation between phases
or streams.
low concentration as a result of the microscopic motion of electrons, atoms,
molecules, etc. Bulk flow, whether convection or advection, however, involves
the flow of a property as a result of macroscopic or bulk motion induced artificially
(e.g., by mechanical agitation) or naturally (e.g., by density variations) [5].
II. TRANSPORT PHENOMENA IN LIQUIDS AND
SEMISOLIDS AND THEIR RELATIONSHIP TO UNIT
OPERATIONS AND SCALE-UP
Over the last four decades or so, transport phenomena research has benefitted
from the substantial efforts made to replace empiricism by fundamental knowledge
based on computer simulations and theoretical modeling of transport phenomena.
These efforts were spurred on by the publication in 1960 by Bird, Stewart,
and Lightfoot [6] of their quintessential monograph on the interrelationships
among three fundamental types of transport phenomena: mass transport, energy
transport, and momentum transport. All transport phenomena follow the same pattern
in accordance with the generalized diffusion equation, or GDE. The unidimensional
flux, or overall transport rate per unit area in one direction, is expressed
as a system property multiplied by a gradient [5]:
 

"
t 
x

  


2
x
"
2 
 
   
  


E
x (2)
The letter " represents the concentration of a property Q (e.g., mass, heat, electrical
energy) per unit volume, i.e., " 
 Q/V, t is time, x is the distance measured in
the direction of transport,  is the generalized diffusion coefficient, and E is the
gradient or driving force for transport.
Mass and heat transfer can be described in terms of their respective concentrations
Q/V. While the concentration of mass, m, can be specified directly, the
concentration of heat is given by

mC
V
pT 
 CpT (3)
where Cp is the specific heat capacity and T is temperature. Thus, the specification
of CpT in any form of the generalized diffusion equation will result in the elimination
of Cp, assuming it to be a constant, thereby allowing the use of temperature
as a measure of heat concentration [5]. In an analogous manner, momentum
transfer can be specified in terms of the concentration of momentum u when its
substantial derivative is used instead of its partial derivative with respect to time:

D
D
u
t 

 
2u (4)



"
x
Nonparenteral Liquids and Semisolids 59
where 
 is the kinematic viscosity. If pressure and gravitational effects are introduced,
one arrives at the Navier–Stokes relationships that govern Newtonian fluid dynamics.
When the flux of " is evaluated three-dimensionally, it can be represented
by [5]:
 d
d
"
t 

 


"
t 
 


"
x 

d

x
t 
 


"
y 

d

y
t 
 


"
z 

d

z
t 
(5)
At the simplest level, as Griskey [1] notes, Fick’s law of diffusion for mass transfer
and Fourier’s law of heat conduction characterize mass and heat transfer, respectively,
as vectors; i.e., they have magnitude and direction in the three coordinates
x, y, and z. Momentum or flow, however, is a tensor, which is defined by
nine components rather than three. Hence, its more complex characterization at
the simplest level, in accordance with Newton’s law,
yx 
 $ 
d
d


y
x
 (6)
where yx is the shear stress in the x-direction, d
x /dy is the rate of shear, and $ is
the coefficient of Newtonian viscosity. The solution of Eq. (2), the generalized
diffusion equation,
" 
 ?(t,x,y,z) (7)
will take the form of a parabolic partial differential equation [5]. However, the
more complex the phenomenon—e.g., with convective transport a part of the
model—the more difficult it is to achieve an analytic solution to the GDE. Numerical
solutions, however, where the differential equation is transformed to an
algebraic one, may be somewhat more readily achieved.
A. Transport Phenomena and Their Relationship to Mixing
as a Unit Operation3
As noted earlier, virtually all liquid and semisolid products involve the unit of operation
of mixing.4 In fact, in many instances, it is the primary unit operation.
60 Block
3 Reprinted in part, with revisions and updates, by courtesy of Marcel Dekker, Inc., from L. H. Block,
“Scale-up of disperse systems: theoretical and practical aspects,” in Pharmaceutical Dosage Forms:
Disperse Systems (H. A. Lieberman, M. M. Rieger, and G. S. Banker, eds.), 2nd ed., vol. 3, Marcel
Dekker, New York, 1998, pp. 366–378.
4 Mixing, or blending, refers to the random distribution of two or more initially separate phases into
and through one another, while agitation refers only to the induced motion of a material in some sort
of container. Agitation does not necessarily result in an intermingling of two or more separate components
of a system to form a more or less uniform product. Some authors reserve the term blending
for the intermingling of miscible phases, while mixing is employed for materials that may or may not
be miscible.
Even its indirect effects, e.g., on heat transfer, may be the basis for its inclusion in
a process. Yet mechanistic and quantitative descriptions of the mixing process remain
incomplete [7–9]. Nonetheless, enough fundamental and empirical data are
available to allow some reasonable predictions to be made.
The diversity of dynamic mixing devices is unsettling: Their dynamic, or
moving, component’s blades may be impellers in the form of propellers, turbines,
paddles, helical ribbons, Z-blades, or screws. In addition, one can vary the number
of impellers, the number of blades per impeller, the pitch of the impeller
blades, and the location of the impeller and thereby affect mixer performance to
an appreciable extent. Furthermore, while dispersators or rotor/stator configurations
may be used rather than impellers to effect mixing, mixing may also be accomplished
by jet mixing or static mixing devices. The bewildering array of mixing
equipment choices alone would appear to make the likelihood of effective
scale-up an impossibility. However, as diverse as mixing equipment may be, evaluations
of the rate and extent of mixing and of flow regimes5 make it possible to
find a common basis for comparison.
In low-viscosity systems, miscible liquid blending is achieved through the
transport of unmixed material, via flow currents (i.e., bulk or convective flow), to
a mixing zone (i.e., a region of high shear or intensive mixing). In other words,
mass transport during mixing depends on streamline or laminar flow, involving
well-defined paths, and turbulent flow, involving innumerable, variously sized,
eddies or swirling motions. Most of the highly turbulent mixing takes place in the
region of the impeller, fluid motion elsewhere serving primarily to bring fresh
fluid into this region. Thus, the characterization of mixing processes is often based
on the flow regimes encountered in mixing equipment. Reynolds’ classic research
on flow in pipes demonstrated that flow changes from laminar to irregular, or turbulent,
once a critical value of a dimensionless ratio of variables has been exceeded
[10,11]. This ratio, universally referred to as the Reynolds number, NRe, is
defined by Eqs. (8a) and (8b),
NRe 
 
L
$


 (8a)
NRe 

D2
$
N
 (8b)
where  is density, 
 is velocity, L is a characteristic length, and $ is the Newtonian
viscosity; Eq. (8b) is referred to as the impeller Reynolds number, since D is
the impeller diameter and N is the rotational speed of the impeller. NRe represents
the ratio of the inertia forces to the viscous forces in a flow. High values of NRe
Nonparenteral Liquids and Semisolids 61
5 The term flow regime is used to characterize the hydraulic conditions (i.e., volume, velocity, and direction
of flow) within a vessel.
correspond to flow dominated by motion, while low values of NRe correspond to
flow dominated by viscosity. Thus, the transition from laminar to turbulent flow
is governed by the density and viscosity of the fluid, its average velocity, and the
dimensions of the region in which flow occurs (e.g., the diameter of the pipe or
conduit, the diameter of a settling particle). For a straight circular pipe, laminar
flow occurs when NRe  2,100; turbulent flow is evident when NRe  4,000. For
2,100  NRe %4,000, flow is in transition from a laminar to a turbulent regime.
Other factors, such as surface roughness, shape, and cross-sectional area of the affected
region, have a substantial effect on the critical value of NRe. Thus, for particle
sedimentation, the critical value of NRe is 1; for some mechanical mixing processes,
NRe is 10–20 [12]. The erratic, relatively unpredictable nature of turbulent
eddy flow is further influenced, in part, by the size distribution of the eddies,
which are dependent on the size of the apparatus and the amount of energy introduced
into the system [10]. These factors are indirectly addressed by NRe. Further
insight into the nature of NRe can be gained by viewing it as inversely proportional
to eddy advection time, i.e., the time required for eddies or vortices to form.
In turbulent flow, eddies move rapidly, with an appreciable component of
their velocity in the direction perpendicular to a reference point, e.g., a surface
past which the fluid is flowing [13]. Because of the rapid eddy motion, mass transfer
in the turbulent region is much more rapid than that resulting from molecular
diffusion in the laminar region, with the result that the concentration gradients existing
in the turbulent region will be smaller than those in the laminar region [13].
Thus mixing is much more efficient under turbulent flow conditions. Nonetheless,
the technologist should bear in mind potentially compromising aspects of turbulent
flow, e.g., increased vortex formation [14] and a concomitant incorporation
of air, increased shear and a corresponding shift in the particle size distribution of
the disperse phase.
Although continuous-flow mixing operations are employed to a limited extent
in the pharmaceutical industry, the processing of liquids and semisolids most
often involves batch processing in some kind of tank or vessel. Thus, in the general
treatment of mixing that follows, the focus will be on batch operations6 in
which mixing is accomplished primarily by the use of dynamic mechanical mixers
with impellers, although jet mixing [17,18] and static mixing devices [19]—
long used in the chemical process industries—are gaining advocates in the pharmaceutical
and cosmetic industries.
Mixers share a common functionality with pumps. The power imparted by
the mixer, via the impeller, to the system is akin to a pumping effect and is characterized
in terms of the shear and flow produced:
62 Block
6 The reader interested in continuous-flow mixing operations is directed to references that deal specifically
with that aspect of mixing, such as the monographs by Oldshue [15] and Tatterson [16].
P %QH ?
or ?
H %
Q
P
 
? (9)
where P is the power imparted by the impeller, Q is the flow rate (or pumping capacity)
of material through the mixing device,  is the density of the material, and
H is the velocity head, or shear. Thus, for a given P, there is an inverse relationship
between shear and volume throughput.
The power input in mechanical agitation is calculated using the power number,
NP,
NP 

N
P
3
g
D
c
5 
(10)
where gc is the force conversion factor
gc
 

N is the impeller rotational speed (sec1), and D is the diameter of the impeller.
For a given impeller/mixing tank configuration, one can define a specific relationship
between the Reynolds number [Eq. (8)]7 and the power number [Eq. (10)]
in which three zones (corresponding to the laminar, transitional, and turbulent
regimes) are generally discernible. Tatterson [20] notes that for mechanical agitation
in laminar flow, most laminar power correlations reduce to NPNRe 
 B,
where B is a complex function of the geometry of the system,8 and that this is
equivalent to P %$  N2D3; “if power correlations do not reduce to this form for
laminar mixing, then they are wrong and should not be used.” Turbulent correlations
are much simpler: for systems employing baffles,9 NP 
 B; this is equivalent
to P %  N3D5. Based on this function, slight changes in D can result in substantial
changes in power.
Valuable insights into the mixing operation can be gained from a consideration
of system behavior as a function of the Reynolds number, NRe [21]. This is
shown schematically in Figure 1 in which various dimensionless parameters (dimensionless
velocity, 
/ND; pumping number, Q/ND3; power number, NP 

Pgc/N3D5; and dimensionless mixing time, tmN) are represented as a log-log
function of NRe. Although density, viscosity, mixing vessel diameter, and impeller
rotational speed are often viewed by formulators as independent variables, their
gcmsec2

dyne
kgmsec2

newton
Nonparenteral Liquids and Semisolids 63
7 Here, the Reynolds number for mixing is defined in SI-derived units as NRe 
 (1.667  105
ND2)/$, where D, impeller diameter, is in millimeters, $ is in Pasec, N is impeller speed, in r.p.m.,
and  is density.
8 An average value of B is 300, but B can vary between 20 and 4000 [20].
9 Baffles are obstructions placed in mixing tanks to redirect flow and minimize vortex formation.
interdependency, when incorporated in the dimensionless Reynolds number, is
quite evident. Thus, the schematic relationships embodied in Figure 1 are not
surprising.10
Mixing time is the time required to produce a mixture of predetermined
quality; the rate of mixing is the rate at which mixing proceeds toward the final
state. For a given formulation and equipment configuration, mixing time, tm, will
depend upon material properties and operation variables. For geometrically similar
systems, if the geometrical dimensions of the system are transformed to ratios,
mixing time can be expressed in terms of a dimensionless number, i.e., the dimensionless
mixing time, m or tmN:
tmN 
 m 
 ?(NRe,NFr) ? ?(NRe) (11)
The Froude number, NFr 
 
/Lg, is similar to NRe; it is a measure of the inertial
stress to the gravitational force per unit area acting on a fluid. Its inclusion in
Eq. (11) is justified when density differences are encountered; in the absence of
substantive differences in density, e.g., for emulsions more so than for suspensions,
the Froude term can be neglected. Dimensionless mixing time is independent
of the Reynolds number for both laminar and turbulent flow regimes, as in-
64 Block
10 The interrelationships are embodied in variations of the Navier–Stokes equations, which describe
mass and momentum balances in fluid systems [22].
Figure 1 Various dimensionless parameters (dimensionless velocity, 
*

/ND; pumping
number, NQ 
 Q/ND3; power number, NP 
 Pgc\N3D5; and dimensionless mixing
time, t* 
 tmN) as a function of the Reynolds number for the analysis of turbine-agitator
systems. (Adapted from Ref. 21.)
dicated by the plateaus in Figure 1. Nonetheless, because there are conflicting data
in the literature regarding the sensitivity of m to the rheological properties of the
formulation and to equipment geometry, Eq. (11) must be regarded as an oversimplification
of the mixing operation. Considerable care must be exercised in applying
the general relationship to specific situations.
Empirical correlations for turbulent mechanical mixing have been reported
in terms of the following dimensionless mixing time relationship [23]:
m 
 tmN 
 K D
T
a
(12)
where K and a are constants, T is tank diameter, N is impeller rotational speed, and
D is impeller diameter. Under laminar flow conditions, Eq. (12) reduces to
m 
 H0 (13)
where H0 is referred to as the mixing number or homogenization number. In the
transitional flow regime,
H0 
 C(NRe)a (14)
where C and a are constants, with a varying between 0 and 1.
Flow patterns in agitated vessels may be characterized as radial, axial, or
tangential relative to the impeller but are more correctly defined by the direction
and magnitude of the velocity vectors throughout the system, particularly in a
transitional flow regime: While the dimensionless velocity, 
*, or 
/ND, is essentially
constant in the laminar and turbulent flow zones, it is highly dependent on
NRe in the transitional flow zone (Fig. 1). Initiation of tangential or circular flow
patterns, with minimal radial or axial movement, is associated with vortex formation,
minimal mixing, and, in some multiphase systems, particulate separation and
classification. Vortices can be minimized or eliminated altogether by redirecting
flow in the system through the use of baffles11 or by positioning the impeller so
that its entry into the mixing tank is off-center. For a given formulation, large
tanks are more apt to exhibit vortex formation than small tanks. Thus, full-scale
production tanks are more likely to require baffles, even when smaller (laboratory-
or pilot-plant scale) tanks are unbaffled.
Mixing processes involved in the manufacture of disperse systems, whether
suspensions or emulsions, are far more problematic than those employed in the
blending of low-viscosity miscible liquids, due to the multiphasic character of the
Nonparenteral Liquids and Semisolids 65
11 The usefulness of baffles in mixing operations is offset by increased cleanup problems (due to particulate
entrapment by the baffles or congealing of product adjacent to the baffles). Furthermore,
“overbaffling”—excessive use of baffles—reduces mass flow and localizes mixing, which may be
counterproductive.
systems and deviations from Newtonian flow behavior. It is not uncommon for
both laminar and turbulent flow to occur simultaneously in different regions of the
system. In some regions, the flow regime may be in transition, i.e., neither laminar
nor turbulent but somewhere in between. The implications of these flow
regime variations for scale-up are considerable. Nonetheless, it should be noted
that the mixing process is only completed when Brownian motion occurs to a sufficient
extent that uniformity is achieved on a molecular scale.
B. Viscous and Non-Newtonian Materials
Mixing in high-viscosity materials ($  ~104 cPs) is relatively slow and inefficient.
Conventional mixing tanks and conventional impellers (e.g., turbine or propellor
impellers) are generally inadequate. In general, due to the high viscosity, NRe
may well be below 100. Thus, laminar flow is apt to occur rather than turbulent
flow. As a result, the inertial forces imparted to a system during the mixing process
tend to dissipate quickly. Eddy formation and diffusion are virtually absent. Thus,
efficient mixing necessitates substantial convective flow, which is usually achieved
by high velocity gradients in the mixing zone. Fluid elements in the mixing zone,
subjected to both shear and elongation, undergo deformation and stretching, ultimately
resulting in the size reduction of the fluid elements and an increase in their
overall interfacial area. The repetitive cutting and folding of fluid elements also result
in decreasing inhomogeneity and increased mixing. The role of molecular diffusion
in reducing inhomogeneities in high-viscosity systems is relatively unimportant
until these fluid elements have become small and their interfacial areas
have become relatively large [24]. In highly viscous systems, rotary motion is more
than compensated for by viscous shear, so baffles are generally less necessary [25].
Mixing equipment for highly viscous materials often involves specialized
impellers and configurations that minimize high shear zones and heat dissipation.
Accordingly, propeller-type impellers are not generally effective in viscous systems.
Instead, turbines, paddles, anchors, helical ribbons, screws, and kneading
mixers are resorted to, successively, as system viscosity increases. Multiple impellers
or specialized impellers (e.g., sigma-blades, Z-blades) are often necessary,
along with the maintenance of narrow clearances, or gaps, between impeller
blades and between impeller blades and tank (mixing chamber) walls in order to
attain optimal mixing efficiency [24,25]. However, narrow clearances pose their
own problems. Studies of the power input to anchor impellers used to agitate Newtonian
and shear-thinning fluids showed that the clearance between the impeller
blades and the vessel wall was the most important geometrical factor: NP at constant
NRe was proportional to the fourth power of the clearance divided by tank diameter
[26]. Furthermore, although mixing is promoted by these specialized impellers
in the vicinity of the walls of the mixing vessel, stagnation is often
encountered in regions adjacent to the impeller shaft. Finally, complications (wall
effects) may arise from the formation of a thin, particulate-free, fluid layer adja-
66 Block
cent to the wall of the tank or vessel that has a lower viscosity than the bulk material
and allows slippage (i.e., nonzero velocity) to occur, unless the mixing tank
is further modified to provide for wall-scraping.
Rheologically, the flow of many non-Newtonian materials can be characterized
by a time-independent power law function (sometimes referred to as the
Ostwald–deWaele equation):
 
 K . a or log  
 K  a(log Y? ) (15)
where  is the shear stress, log  
 K  a(log  .) is the rate of shear, K is the logarithmically
transformed proportionality constant K with dimensions dependent
upon a, the so-called flow behavior index. For pseudoplastic or shear-thinning
materials, a  1; for dilatant or shear-thickening materials, a  1; for Newtonian
fluids, a 
 1. For a power law fluid, the average apparent viscosity, $avg, can be
related to the average shear rate by the following equation:
$avg 
 K 
d
d


y 
n1
avg
(16)
Based on this relationship, a Reynolds number can be derived and estimated for
non-Newtonian fluids from

NRe 
 
L
$


 ? 
NRe,nonN 
  (17)
Dispersions that behave, rheologically, as Bingham plastics require a minimum
shear stress (the yield value) in order for flow to occur. Shear stress variations
in a system can result in local differences wherein the yield stress point is not
exceeded. As a result, flow may be impeded or absent in some regions compared
to others, resulting in channeling or cavity formation and a loss of mixing efficiency.
Only if the yield value is exceeded throughout the system will flow and
mixing be relatively unimpeded. Helical ribbon and screw impellers would be
preferable for the mixing of Bingham fluids, in contrast to conventional propeller
or turbine impellers, given their more even distribution of power input [27]. From
a practical vantage point, monitoring power input to mixing units could facilitate
process control and help to identify problematic behavior. Etchells et al. [28] analyzed
the performance of industrial mixer configurations for Bingham plastics.
Their studies indicate that the logical scale-up path from laboratory to pilot plant
to production, for geometrically similar equipment, involves the maintenance of
constant impeller tip speed, which is proportional to N  D, the product of rotational
speed of the impeller (N) and the diameter of the impeller (D).
Oldshue [25] provides a detailed procedure for selecting mixing times and
optimizing mixer and impeller configurations for viscous and shear-thinning materials
that can be adapted for other rheologically challenging systems.
Gate and anchor impellers, long used advantageously for the mixing of viscous
and non-Newtonian fluids, induce complex flow patterns in mixing tanks: both
NDi
2 

K(d 
/dy)avg
n1
Nonparenteral Liquids and Semisolids 67
primary and secondary flows may be evident. Primary flow or circulation results
from the direct rotational movement of the impeller blade in the fluid; secondary
flow is normal to the horizontal planes about the impeller axis (i.e., parallel to the
impeller axis) and is responsible for the interchange of material between different
levels of the tank [29]. In this context, rotating viscoelastic systems, with their normal
forces, establish stable secondary flow patterns more readily than Newtonian
systems. In fact, the presence of normal stresses in viscoelastic fluids subjected to
high rates of shear (~104 sec1) may be substantially greater than shearing stresses,
as demonstrated by Metzner et al. [30]. These observations, among others, moved
Fredrickson [31] to note that “neglect of normal stress effects is likely to lead to large
errors in theoretical calculations for flow in complex geometries.” However, the effect
of these secondary flows on the efficiency of mixing, particularly in viscoelastic
systems, is equivocal. On the one hand, vertical velocity near the impeller blade
in a Newtonian system might be 2–5% of the horizontal velocity, whereas in a non-
Newtonian system, vertical velocity can be 20–40% of the horizontal. Thus, the
overall circulation can improve considerably. On the other hand, the relatively
small, stable toroidal vortices that tend to form in viscoelastic systems may result in
substantially incomplete mixing. Smith [29] advocates the asymmetric placement
of small deflector blades on a standard anchor arm as a means of achieving a dramatic
improvement in mixing efficiency of viscoelastic fluids without resorting to
expensive alternatives, such as pitched blade anchors or helical ribbons.
Side-wall clearance, i.e., the gap between the vessel wall and the rotating
impeller, was shown by Cheng et al. [32] to be a significant factor in the mixing
performance of helical ribbon mixers not only for viscous and viscoelastic
fluids but also for Newtonian systems. Bottom clearance, i.e., the space between
the base of the impeller and the bottom of the tank, however, had a negligible,
relatively insignificant effect on power consumption and on the effective shear
rate in inelastic fluids. Thus, mixing efficiency in nonviscoelastic fluids would
not be affected by variations in bottom clearance. For viscoelastic fluids, on the
other hand, bottom clearance effects were negligible only at lower rotational
speeds (!60 rpm); substantial power consumption increases were evident at
higher rotational speeds.
The scale-up implications of mixing-related issues, such as impeller design
and placement, mixing tank characteristics, new equipment design, and the mixing
of particulate solids, are beyond the scope of this chapter. However, extensive
monographs are available in the chemical engineering literature (many of which
have been cited herein12) and will prove to be invaluable to the formulator and
technologist.
68 Block
12 The reader is directed to previously referenced monographs by Oldshue and by Tatterson as well as
to standard textbooks in chemical engineering, including the multivolume series authored by Mc-
Cabe et al., and the encyclopedic Perry’s Chemical Engineers’ Handbook.
C. Particle Size Reduction
Disperse systems often necessitate particle size reduction, whether it is an integral
part of product processing, as in the process of liquid–liquid emulsification, or an
additional requirement insofar as solid particle suspensions are concerned. (It
should be noted that solid particles suspended in liquids often tend to agglomerate.
Although milling of such suspensions tends to disrupt such agglomerates and
produce a more homogeneous suspension, it generally does not affect the size of
the unit particles comprising the agglomerates.) For emulsions, the dispersion of
one liquid as droplets in another can be expressed in terms of the dimensionless
Weber number, NWe:
NWe 





2d0 (18)
where  is the density of a droplet, 
 is the relative velocity of the moving droplet,
d0 is the diameter of the droplet, and 
 is the interfacial tension. The Weber number
represents the ratio of the driving force causing partial disruption to the resistance
due to interfacial tension [33]. Increased Weber numbers are associated with
a greater tendency for droplet deformation (and consequent splitting into still
smaller droplets) to occur at higher shear, i.e., with more intense mixing. This can
be represented by
NWe 

Di
3N


2cont.  (19)
where Di is the diameter of the impeller, N is the rotational speed of the impeller,
and cont. is the density of the continuous phase. For a given system, droplet size
reduction begins above a specific critical Weber number [34]; above the critical
NWe, average droplet size varies with N1.2Di
0.8, or, as an approximation, with
the reciprocal of the impeller tip speed. In addition, a better dispersion is achieved,
for the same power input, with a smaller impeller rotating at high speed [35].
As the particle size of the disperse phase decreases, there is a corresponding
increase in the number of particles and a concomitant increase in interparticulate
and interfacial interactions. Thus, in general, the viscosity of a dispersion is
greater than that of the dispersion medium. This is often characterized in accordance
with the classical Einstein equation for the viscosity of a dispersion,
$ 
 $o(1  2.5) (20)
where $ is the viscosity of the dispersion, $o is the viscosity of the continuous
phase, and  is the volume fraction of the particulate phase. The rheological behavior
of concentrated dispersions may be demonstrably non-Newtonian (pseudoplastic,
plastic, or viscoelastic) and its dependence on  more marked due to
disperse phase deformation and/or interparticulate interaction.
Nonparenteral Liquids and Semisolids 69
Maa and Hsu [36] investigated the influence of operation parameters for rotor/
stator homogenization on emulsion droplet size and temporal stability in order
to optimize operating conditions for small- and large-scale rotor/stator homogenization.
Rotor/stator homogenization effects emulsion formation under much
more intense turbulence and shear than that encountered in an agitated vessel or a
static mixer. Rapid circulation, high shear forces, and a narrow rotor/stator gap
(0.5 mm) contribute to the intensity of dispersal and commingling of the immiscible
phases, since turbulent eddies are essential for the breakup of the dispersed
phase into droplets. Maa and Hsu’s estimates of the circulation rates in
small- and large-scale rotor/stator systems—based on the total area of the
rotor/stator openings, the radial velocity at the openings (resulting from the pressure
difference within the vortex that forms in the rotor/stator unit), and the centrifugal
force caused by the radial deflection of fluid by the rotor—appear to be
predictive for the scale-up of rotor/stator homogenization [36].
Dobetti and Pantaleo [37] investigated the influence of hydrodynamic parameters
per se on the efficiency of a coacervation process for microcapsule formation.
They based their work on that of Armenante and Kirwan [38], who described
the size of the smallest eddies or vortices generated in a turbulent regime
on a microscopic scale in the vicinity of the agitation source, i.e., microeddies,13
as
de 
 
P

3
s
1–4 (21)
where de is the diameter of the smallest microeddy, 
 is the kinematic viscosity of
the fluid (i.e., $/, or viscosity/density), and Ps is the specific power, i.e., power
input per unit mass. Hypothetically, if mass transfer of the coacervate and particle
encapsulation occurred only within the microeddies, then the diameter of the hardened
microcapsules would depend on the size of the microeddies produced by the
agitation in the system. They dispersed a water-insoluble drug in a cellulose acetate
phthalate (CAP) solution to which a coacervation-inducing agent was gradually
added to facilitate microencapsulation by the CAP coacervate phase. The
stirring rate and the tank and impeller configuration were varied to produce an array
of microeddy sizes. However, the actual size of the hardened microcapsules
was less than that calculated for the corresponding microeddies (Fig. 2). The authors
attributed the inequality in sizes, in part, to relatively low agitation energies.
Their conclusion is supported by their calculated NRe values, ranging from 1184
to 2883, which are indicative of a flow regime ranging from laminar to transitional,
rather than turbulent.
70 Block
13 Deduced in 1941 by A. N. Kolmogorov, it is generally referred to as the Kolmogorov length or dissipation
scale [9].
Comminution, or particle size reduction of solids, is considerably different
from that of the breakup of one liquid by dispersal as small droplets in another.
Particle size reduction is generally achieved by one of four mechanisms: (1) compression,
(2) impact, (3) attrition, or (4) cutting or shear. Equipment for particle
size reduction or milling includes crushers (which operate by compression, e.g.,
crushing rolls), grinders (which operate principally by impact and attrition, although
some compression may be involved, e.g., hammer mills, ball mills), ultrafine
grinders (which operate principally by attrition, e.g., fluid-energy mills), and
knife cutters. Accordingly, a thorough understanding of milling operations requires
an understanding of fracture mechanics, agglomerative forces (dry and wet)
involved in the adhesion and cohesion of particulates, and flow of particles and
bulk powders. These topics are dealt with at length in the monographs by Fayed
and Otten [39] and Carstensen [40,41].
As Austin [42] notes, the formulation of a general theory of the unit operation
of size reduction is virtually impossible given the multiplicity of mill types
and mechanisms for particulate reduction. The predictability of any comminution
process is further impaired given the variations among solids in surface characteristics
and reactivity, molecular interactions, crystallinity, etc. Nonetheless,
some commonalities can be discerned. First, the particle size reduction rate is dependent
upon particle strength and particle size. Second, the residence time of particles
in the mill is a critical determinant of mill efficiency. Thus, whether a given
mill operates in a single-pass or a multiple-pass (retention) mode can be a limiting
factor insofar as characterization of the efficacy of comminution is concerned.
Third, the energy required to achieve a given degree of comminution is an inverse
Nonparenteral Liquids and Semisolids 71
Figure 2 Microcapsule size as a function of calculated microeddy size. (Adapted from
Ref. 37.)
function of initial particle size. This is due to (1) the increasing inefficiency of
stress or shear application to each particle of an array of particles as particle size
decreases, and (2) the decreasing incidence of particle flaws that permit fracture
at low stress [42].
If monosized particles are subjected to one pass through a milling device,
the particle size distribution of the resultant fragments can be represented in a cumulative
form. Subsequent passes of the comminuted material through the milling
device often result in a superimposable frequency distribution when the particle
sizes are normalized, e.g., in terms of the weight fraction less than size y resulting
from the milling of particles of larger size x. The mean residence time, , of material
processed by a mill is given by
 
 
M
F
 (22)
where M is the mass of powder in the mill and F is the mass flow rate through the
mill. Process outcomes for retention mills can be described in terms of residence
time distributions, defined by the weight fraction of the initial charge at time t 

0 that leaves between (t  dt). If the milling operation is scalable, the particle size
distributions produced by a large and a small mill of the same type would be comparable
and would differ only in the time scale of operation, i.e., the operation can
be characterized as a ?(t/). The prospect for scalability may be further enhanced
when the weight fraction remaining in an upper range is a log-linear (first order)
function of total elapsed milling time14 [42]. Corroboration of the likelihood of
scalability of milling operations is Mori’s finding that most residence time distributions
for milling conform to a log-normal model [43].
One estimate of the efficacy of a crushing or grinding operation is the crushing
efficiency, Ec, described as the ratio of the surface energy created by crushing
or grinding to the energy absorbed by the solid [44]:
Ec 


s(Aw
W
p 
n
Awf) (23)
where 
s is the specific surface or surface per unit area, Awp and Awf are the areas
per unit mass of product particulates and feed particulates, i.e., after and before
milling, respectively, and Wn is the energy absorbed by the solid per unit mass.
The energy absorbed by the solid per unit mass is less than the energy W supplied
to the mill per unit mass i.e., Wn  W. While a substantial part of the total energy
input W is needed to overcome friction in the machine, the rest is available for
crushing or grinding. However, of the total energy stored within a solid, only a
small fraction is converted into surface energy at the time of fracture. Because
72 Block
14 Total elapsed milling time encompasses the time during which solids are subjected to a milling operation,
whether the particulates undergo single or multiple passes through the mill.
most of the energy is converted into heat, crushing efficiency values tend to be
low, i.e., 0.0006  Ec  0.01, principally due to the inexactness of estimates of 
s
[44].
A number of quasi-theoretical relationships have been proposed to characterize
the grinding process: Rittinger’s “law” (1867),

m
P
. 
 KR
D
1
p
  
D
1
?
 (24)
which states that the work required in crushing a solid is proportional to the new
surface created, and Kick’s “law” (1885),

m
P
. 
 Kk ln 
D
D


?
p
 (25)
which states that the work required to crush or grind a given mass of material is
constant for the same particle size reduction ratio. In Eqs. (24) and (25), Dp and
D? represent the final and initial average particle sizes,15 P is the power (in kilowatts),
and m
.
is the rate at which solids are fed to the mill (in tons/hr). KR and KK
are constants for the Rittinger equation and the Kick equation, respectively.
Bond’s “law” of particle size reduction provides an ostensibly more reasonable
estimate of the power required for crushing or grinding of a solid [45]:

m
P
. 
 (26)
where KB is a constant that is mill dependent and solids dependent and Dp is the
particle size (in mm) produced by the mill. This empirical equation is based on
Bond’s hypothesis that the work required to reduce very large particulate solids to
a smaller size is proportional to the square root of the surface-to-volume ratio of
the resultant particulate product. Bond’s work index, Wi, is an estimate of the
gross energy required, in kilowatt hours per ton of feed, to reduce very large particles
(80% of which pass a mesh size of D? mm) to such a size that 80% pass
through a mesh of size Dp mm:
Wi 
 (27)
Combining Bond’s work index [Eq. (27)] with Bond’s law [Eq. (26)] yields

m
P
. 
 WiDp    (28)
1
D?
1
Dp
KB
Dp
KB
Dp
Nonparenteral Liquids and Semisolids 73
15 In this section, particle size refers to the nominal particle size, i.e., the particle size based on sieving
studies or on the diameter of a sphere of equivalent volume.
which allows one to estimate energy requirements for a milling operation in which
solids are reduced from size D? to Dp (Wi for wet grinding is generally smaller than
that for dry grinding: Wi,wet is equivalent to (Wi,dry)3/4 [44].)
These relationships are embodied in the general differential equation
dE
CdX/Xn (29)
where E is the work done and C and n are constants. When n 
 1, the solution of
the equation is Kick’s law; when n 
 2, the solution is Rittinger’s law; and when
n 
 1.5, the solution is Bond’s law [46].
Although these relationships [Eqs. (24)–(29)] are of some limited use in
scaling up milling operations, their predictiveness is limited by the inherent complexity
of particle size reduction operations. Virtually all retentive or multiplepass
milling operations become increasing less efficient as milling proceeds, since
the specific comminution rate is smaller for small particles than for large particles.
Computer simulations of milling for batch, multiple-pass, and continuous modes
have been outlined by Snow et al. [47]. They describe a differential equation for
batch grinding for which analytical and matrix solutions have been available for
some time:
 d
d
w
t
k

?
k
u
1
[wuSu(t) Bk,u]  Sk (t)wk (30)
Equation (30) includes a term Su, a grinding-rate function that corresponds to
Su

dw
w
u
u
/dt
 (31)
i.e., the rate at which particles of upper size u are selected for breakage per unit
time relative to the amount, wu, of size u present, and a term Bk,u, a breakage
function that characterizes the size distribution of particle breakdown from size u
into all smaller sizes k. Equation (30) thus defines the rate of accumulation of particles
of size k as the difference between the rate of production of particles of size
k from all larger particles and the rate of breakage of particles of size k into smaller
particles. Adaptation of Eq. (30) to continuous milling operations necessitates the
inclusion of the distribution of residence time,  
 M/F, as discussed earlier.
Additional complications in milling arise as fines build up in the powder bed
[42]: (a) the fracture rate of all particle sizes decreases, the result, apparently, of a
cushioning effect by the fines that minimizes stress and fracture; (b) fracture kinetics
become nonlinear. Other factors, such as coating of equipment surfaces by
fines, also affect the efficiency of the milling operation.
Nonetheless, mathematical analyses of milling operations, particularly for
ball mills, roller mills, and fluid energy mills, have been moderately successful.
There continues to be a pronounced need for a more complete understanding of
74 Block
micromeritic characteristics, the intrinsic nature of the milling operation itself, the
influence of fines on the milling operation, and phenomena such as flaw structure
of solids, particle fracture, particulate flow, and interactions at both macroscopic
and microscopic scales.
D. Material Transfer
Movement of liquids and semisolids through conduits or pipes from one location
to another is accomplished by inducing flow with the aid of pumps. The induction
of flow usually occurs as a result of one or more of the following energy transfer
mechanisms: gravity, centrifugal force, displacement, electromagnetic force, mechanical
impulse, or momentum transfer. The work expended in pumping is the
product of pump capacity, Q, i.e., the rate of fluid flow through the pump (in
m3/hr), and the dynamic head, H:
P 

3.67
H
0
Q


105  (32)
where P is the pump’s power output, expressed in kW, H is the total dynamic
head, in Nmkg1, and  is the fluid density, in kgm3. Due to frictional heating
losses, power input for a pump is greater than its power output. As pump efficiency
is characterized by the ratio of power output to power input, the pumping
of viscous fluids would tend to result in decreased pump efficiency due to the increase
in power required to achieve a specific output. Another variable, &, the surface
roughness of the pipe, has an effect on pump efficiency as well and must also
be considered. The Fanning friction factor ? is a dimensionless factor that is used
in conjunction with the Reynolds number to estimate the pressure drop in a fluid
flowing in a pipe or conduit. The relative roughness, &/D, of a pipe—where D is
the pipe diameter—has an effect on the friction factor ?. When laminar flow conditions
prevail, ? may be estimated by
? 
 
N
1
R
6
e
 (33)
When turbulent flow in smooth pipes is involved,
? 

0
N
.0
R
7
e
0.2
9
5 
(34)
A useful discussion of incompressible fluid flow in pipes and the influence of surface
roughness and friction factors on pumping is found in Perry’s Chemical Engineer’s
Handbook [48].
The transfer of material from mixing tanks or holding tanks to processing
equipment or to a filling line, whether by pumping or by gravity feed, is potentially
problematic. Instability (chemical or physical) or further processing, (e.g.,
Nonparenteral Liquids and Semisolids 75
mixing, changes in the particle size distribution) may occur during the transfer of
material (by pouring or pumping) from one container or vessel to another due to
changes in the rate of transfer or in shear rate or shear stress. While scale-up-related
changes in the velocity profiles of time-independent Newtonian and non-
Newtonian fluids due to changes in flow rate or in equipment dimensions or geometry
can be accounted for, time dependence must first be recognized in order to
be accommodated.
Changes in mass transfer time as a consequence of scale-up are often overlooked.
As Carstensen and Mehta [49] note, mixing of formulation components in
the laboratory may be achieved almost instantaneously with rapid pouring and
stirring. They cite the example of pouring 20 mL of liquid A, while stirring, into
80 mL of liquid B. On a production scale, however, mixing is unlikely to be as
rapid. A scaled-up batch of 2000 L would require the admixture of 400 L of A and
1600 L of B. If A were pumped into B at the rate of 40 L min1, then the transfer
process would take at least 10 min while additional time would also be required
for the blending of the two liquids. If, for example, liquids A and B were of different
pH (or ionic strength or polarity etc.), the time required to transfer all of A
into B and to mix A and B intimately would allow some intermediate pH (or ionic
strength or polarity etc.) to develop and to persist long enough for some adverse
effect to occur, such as precipitation, adsorption, or change in viscosity. Thus,
transfer times on a production scale need to be determined so that the temporal impact
of scale-up can be accounted for in laboratory or pilot-plant studies.
E. Heat Transfer
On a laboratory scale, heat transfer occurs relatively rapidly, for the volume-to-surface-
area ratio is relatively small; cooling or heating may or may not involve jacketed
vessels. However, on a pilot-plant or production scale, the volume-to-surfacearea
ratio is relatively large. Consequently, heating or cooling of formulation
components or product takes a finite time, during which system temperature, T°C,
may vary considerably. Temperature-induced instability may be a substantial problem
if a formulation is maintained at suboptimal temperatures for a prolonged period
of time. Thus, jacketed vessels or immersion heaters or cooling units with rapid
circulation times are an absolute necessity. Carstensen and Mehta [49] give an example
of a jacketed kettle with a heated surface of A cm2, with inlet steam or hot
water in the jacket maintained at a temperature T0°C. The heat transfer rate (dQ/dt)
in this system is proportional to the heated surface area of the kettle and the temperature
gradient, T0T (i.e., the difference between the temperature of the kettle
contents, T, and the temperature of the jacket, T0) at time t:
 d
d
Q
t 

 Cp
d
d
T
t 
 
 kA(T0  T ) (35)
76 Block
where Cp is the heat capacity of the jacketed vessel and its contents and k is the
heat transfer coefficient. If the initial temperature of the vessel is T1°C, Eq. (35)
becomes
T0  T 
 (T0  T1)eat (36)
where a 
 kA/Cp. The time t required to reach a specific temperature T2 can be
calculated from Eq. (36), if a is known, or estimated from time–temperature
curves for similar products processed under the same conditions. Scale-up studies
should consider the effect of longer processing times at suboptimal temperatures
on the physicochemical or chemical stability of the formulation components and
the product. A further concern for disperse system scale-up is the increased opportunity
in a multiphase system for nonuniformity in material transport (e.g.,
flow rates and velocity profiles) stemming from nonuniform temperatures within
processing equipment.
III. HOW TO ACHIEVE SCALE-UP16
Full-scale tests using production equipment and involving no scale-up studies whatsoever
are sometimes resorted to when single-phase low-viscosity systems are involved
and processing is considered to be predictable and directly scalable. By and
large, these are unrealistic assumptions when viscous liquids, dispersions, or
semisolids are involved. Furthermore, the expense associated with full-scale testing
is substantial: Commercial-scale equipment is relatively inflexible and costly to
operate. Errors in full-scale processing involve large amounts of material. Insofar
as most liquids or semisolids are concerned then, full-scale tests are not an option.
On the other hand, scale-up studies involving relatively low scale-up ratios
and few changes in process variables are not necessarily a reasonable alternative
to full-scale testing. For that matter, experimental designs employing minor, incremental,
changes in processing equipment and conditions are unacceptable as
well. These alternative test modes are inherently unacceptable because they consume
time, an irreplaceable resource [50] that must be utilized to its maximum advantage.
Appropriate process development, by reducing costs and accelerating
lead times, plays an important role in product development performance. In The
Development Factory: Unlocking the Potential of Process Innovation, author
Gary Pisano [51] argues that while pharmaceuticals compete largely on the basis
of product innovation, there is a hidden leverage in process development and man-
Nonparenteral Liquids and Semisolids 77
16 Reprinted in part, with revisions and updates, by courtesy of Marcel Dekker, Inc., from L. H. Block,
“Scale-up of disperse systems: theoretical and practical aspects,” in Pharmaceutical Dosage Forms:
Disperse Systems (H. A. Lieberman, M. M. Rieger, and G. S. Banker, eds.), 2nd ed., Vol. 3, Marcel
Dekker, New York, 1998, pp. 378–388.
ufacturing competence that provides more degrees of freedom, in developing
products, to more adroit organizations than to their less adept competitors. Although
Pisano focuses on drug synthesis and biotechnology process scale-up, his
conclusions translate effectively to the manufacturing processes for drug dosage
forms and delivery systems. In effect, scale-up issues need to be addressed jointly
by pharmaceutical engineers and formulators as soon as a dosage form or delivery
system appears to be commercially viable. Scale-up studies should not be relegated
to the final stages of product development, whether initiated at the behest
of the FDA (to meet regulatory requirements) or marketing and sales divisions (to
meet marketing directives or sales quotas). The worst scenario would entail the
delay of scale-up studies until after commercial distribution (to accommodate unexpected
market demands).
Modular scale-up involves the scale-up of individual components or unit
operations of a manufacturing process. The interactions among these individual
operations comprise the potential scale-up problem, i.e., the inability to achieve
sameness when the process is conducted on a different scale. When the physical
or physicochemical properties of system components are known, the scalability of
some unit operations may be predictable.
Known scale-up correlations thus may allow scale-up when laboratory or
pilot plant experience is minimal. The fundamental approach to process scaling
involves mathematical modeling of the manufacturing process and experimental
validation of the model at different scale-up ratios. In a paper on fluid dynamics
in bubble column reactors, Lubbert and coworkers [52] noted: “Until very recently
fluid dynamical models of multiphase reactors were considered intractable.
This situation is rapidly changing with the development of high-performance
computers. Today’s workstations allow new approaches to . . . modeling.”
Insofar as the scale-up of pharmaceutical liquids (especially disperse systems)
and semisolids is concerned, virtually no guidelines or models for scale-up
have generally been available that have stood the test of time. Uhl and Von Essen
[54], referring to the variety of rules of thumb, calculation methods, and extrapolation
procedures in the literature, state, “Unfortunately, the prodigious literature
and attributions to the subject [of scale-up] seemed to have served more to confound.
Some allusions are specious, most rules are extremely limited in application,
examples give too little data and limited analysis.” Not surprisingly, then, the
trial-and-error method is the one most often employed by formulators. As a result,
serendipity and practical experience continue to play large roles in the successful
pursuit of the scalable process.
A. Principles of Similarity
Irrespective of the approach taken to scale-up, the scaling of unit operations and
manufacturing processes requires a thorough appreciation of the principles of sim-
78 Block
ilarity. “Process similarity is achieved between two processes when they accomplish
the same process objectives by the same mechanisms and produce the same
product to the required specifications.” Johnstone and Thring [53] stress the importance
of four types of similarity in effective process translation: (a) geometric
similarity, (b) mechanical (static, kinematic, and dynamic) similarity, (c) thermal
similarity, and (d) chemical similarity. Each of these similarities presupposes the
attainment of the other similarities. In actuality, approximations of similarity are
often necessary due to departures from ideality (e.g., differences in surface roughness,
variations in temperature gradients, changes in mechanism). When such departures
from ideality are not negligible, a correction of some kind has to be applied
when scaling up or down: These scale effects must be determined before
scaling of a unit operation or a manufacturing process can be pursued. It should be
recognized that scale-up of multiphase systems, based on similarity, is often unsuccessful,
since only one variable can be controlled at a time, i.e., at each scaleup
level. Nonetheless, valuable mechanistic insights into unit operations can be
achieved through similarity analyses.
1. Geometric Similarity
Point-to-point geometric similarity of two bodies (e.g., two mixing tanks) requires
three-dimensional correspondence. Every point in the first body is defined by specific
x-, y-, and z-coordinate values. The corresponding point in the second body
is defined by specific x-, y-, and z-coordinate values. The correspondence is defined
by the following equation

x
x


 
y
y


 
z
z


 L (37)
where the linear scale ratio L is constant. In contrasting the volume of a laboratory-
scale mixing tank (V1) with that of a geometrically similar production scale
unit (V2), the ratio of volumes (V1/V2) is dimensionless. However, the contrast between
the two mixing tanks needs to be considered on a linear scale; e.g., a 1000-
fold difference in volume corresponds to a 10-fold difference, on a linear scale, in
mixing tank diameter, impeller diameter, etc.
If the scale ratio is not the same along each axis, the relationship between
the two bodies is of a distorted geometric similarity, and the axial relationships are
given by

x
x


 X, 
y
y


Y, 
z
z


 Z (38)
Thus, equipment specifications can be described in terms of the scale ratio L or, in
the case of a distorted body, two or more scale ratios (X, Y, Z ). Scale ratios facilitate
the comparison and evaluation of different sizes of functionally comparable
equipment in process scale-up.
Nonparenteral Liquids and Semisolids 79
2. Mechanical Similarity
The application of force to a stationary or moving system can be described in
static, kinematic, or dynamic terms that define the mechanical similarity of processing
equipment and the solids or liquids within their confines. Static similarity
relates the deformation under constant stress of one body or structure to that of another;
it exists when geometric similarity is maintained even as elastic or plastic
deformation of stressed structural components occurs [53]. In contrast, kinematic
similarity encompasses the additional dimension of time, while dynamic similarity
involves the forces (e.g., pressure, gravitational, centrifugal) that accelerate or
retard moving masses in dynamic systems. The inclusion of time as another dimension
necessitates the consideration of corresponding times, t and t, for which
the time scale ratio t, defined as t 
 t/t, is a constant.
Corresponding particles in disperse systems are geometrically similar particles
that are centered on corresponding points at corresponding times. If two geometrically
similar fluid systems are kinematically similar, their corresponding
particles will trace out geometrically similar paths in corresponding intervals of
time. Thus, their flow patterns will be geometrically similar and heat- or masstransfer
rates in the two systems will be related to one another [53]. Pharmaceutical
engineers may prefer to characterize disperse systems’ corresponding velocities,
which are the velocities of corresponding particles at corresponding times:







 v 
 
L
t (39)
Kinematic and geometric similarity in fluids ensures geometrically similar
streamline boundary films and eddy systems. If forces of the same kind act upon
corresponding particles at corresponding times, they are termed corresponding
forces, and conditions for dynamic similarity are met. While the scale-up of power
consumption by a unit operation or manufacturing process is a direct consequence
of dynamic similarity, mass and heat transfer—direct functions of kinematic similarity—
are only indirect functions of dynamic similarity.
3. Thermal Similarity
Heat flow, whether by radiation, conduction, convection, or the bulk transfer of
matter, introduces temperature as another variable. Thus, for systems in motion,
thermal similarity requires kinematic similarity. Thermal similarity is described by

H
H

r
r

 
H
H

c
c

 
H
H






 
H
H
?
? 
 H (40)
where Hr, Hc, H
, and H?, are the heat fluxes or quantities of heat transferred per
second by radiation, convection, conduction, and bulk transport, respectively, and
H, the thermal ratio, is a constant.
80 Block
4. Chemical Similarity
This similarity state is concerned with the variation in chemical composition from
point to point as a function of time. Chemical similarity, i.e., the existence of comparable
concentration gradients, is dependent upon both thermal and kinematic
similarity.
5. Interrelationships Among Surface Area and Volume Upon
Scale-Up
Similarity states aside, the dispersion technologist must be aware of whether a
given process is volume dependent or area dependent. As the scale of processing
increases, volume effects become increasingly more important while area effects
become increasingly less important. This is exemplified by the dependence of
mixing tank volumes and surface areas on scale-up ratios (based on mixing tank
diameters) in Table 1. The surface-area-to-volume ratio is much greater on the
small scale than on the large scale; surface area effects are thus much more important
on a small scale than on a large one. Conversely, the volume-to-surfacearea
ratio is much greater on the large scale than on the small scale; volumetric effects
are thus much more important on a large scale than on a small scale. Thus,
volume-dependent processes are more difficult to scale-up than surface-area-dependent
processes. For example, exothermic processes may generate more heat
than can be tolerated by a formulation, leading to undesirable phase changes or
product degradation unless cooling coils, or other means of intensifying heat
transfer, are added. A further example is provided by a scale-up problem involving
a tenfold increase in tank volume, from 400 L to 4000 L, and an increase in
surface area from 2 m2 to 10 m2. The surface-area-to-volume ratio is 1/200 and
1/400, respectively. In spite of the tenfold increase in tank volume, the increase in
surface area is only fivefold, necessitating the provision of additional heating or
cooling capacity to allow for an additional 10 m2 of surface for heat exchange.
Nonparenteral Liquids and Semisolids 81
Table 1 Dependence of Area and Volume on Scale-Up Ratios
Tank diameter, Area, Volume,
Scale m m2 m3 Area/volume Volume/area
1 0.1 0.0393 0.000785 50 0.02
10 1 3.93 0.785 5 0.2
20 2 15.7 6.28 2.5 0.4
50 5 98.2 98.2 1 1
Assumptions: Tank is a right circular cylinder; batch height 
 tank diameter; area calculations are
the sum of the area of the convex surface and the area of the bottom of the cylinder.
Source: Ref. 55.
As Tatterson [55] notes, “There is much more volume on scale-up than is typically
recognized. This is one feature of scale-up that causes more difficulty than
anything else.” For disperse systems, a further mechanistic implication of the
changing volume and surface-area ratios is that particle size reduction (or droplet
breakup) is more likely to be the dominant process on a small scale while aggregation
(or coalescence) is more likely to be the dominant process on a large scale [55].
6. Interrelationships Among System Properties Upon Scale-Up
When a process is dominated by a mixing operation, another gambit for the effective
scale-up of geometrically similar systems involves the interrelationships
that have been established for impeller-based systems. Tatterson [56] describes a
number of elementary scale-up procedures for agitated tank systems that depend
upon operational similarity. Thus, when scaling up from level 1 to level 2,
 (
(
P
P
/
/
V
V
)
)
1
2


?
N
N
1
2
3
D
D
1
2
2
for turbulent flow
??


N
N
1
2
2
for laminar flow
(41)
power per unit volume is dependent principally on the ratio N1/N2 since impeller
diameters are constrained by geometric similarity.
A change in size on scale-up is not the sole determinant of the scalability of
a unit operation or process. Scalability depends on the unit operation mechanism(
s) or system properties involved. Some mechanisms or system properties
relevant to dispersions are listed in Table 2 [57]. In a number of instances, size has
82 Block
Table 2 Influence of Size on System Behavior or Important Unit Operation
Mechanisms
System behavior or unit
operation mechanisms Important variablesa Influence of size
Chemical kinetics C, P, T None
Thermodynamic properties C, P, T None
Heat transfer Local velocities, C, P, T Important
Mass transfer within a phase NRe, C, T Important
Mass transfer between phases Relative phase velocities, Important
C, P, T
Forced convection Flow rates, geometry Important
Free convection Geometry, C, P, T Crucial
a C, P, and T are concentration, pressure, and temperature, respectively.
Source: Adapted from Ref. 57.
little or no influence on processing or on system behavior. Thus, scale-up will not
affect chemical kinetics or thermodynamics, although the thermal effects of a reaction
could perturb a system, e.g., by affecting convection [57]. Heat or mass
transfer within or between phases is indirectly affected by changes in size, while
convection is directly affected. Thus, since transport of energy, mass, and momentum
are often crucial to the manufacture of disperse systems, scale-up can
have a substantial effect on the resultant product.
B. Dimensions, Dimensional Analysis, and the Principles
of Similarity
Just as process translation or scaling up is facilitated by defining similarity in
terms of dimensionless ratios of measurements, forces, or velocities, the technique
of dimensional analysis per se permits the definition of appropriate composite dimensionless
numbers whose numeric values are process specific. Dimensionless
quantities can be pure numbers, ratios, or multiplicative combinations of variables
with no net units.
Dimensional analysis is concerned with the nature of the relationship
among the various quantities involved in a physical problem. An approach intermediate
between formal mathematics and empiricism, it offers the pharmaceutical
engineer an opportunity to generalize from experience and apply knowledge
to a new situation [58,59]. This is a particularly important avenue, for many engineering
problems—scale-up among them—cannot be solved completely by theoretical
or mathematical means. Dimensional analysis is based on the fact that if a
theoretical equation exists among the variables affecting a physical process, that
equation must be dimensionally homogeneous. Thus, many factors can be
grouped, in an equation, into a smaller number of dimensionless groups of
variables [59].
Dimensional analysis is an algebraic treatment of the variables affecting a
process; it does not result in a numerical equation. Rather, it allows experimental
data to be fitted to an empirical process equation that results in scale-up being
achieved more readily. The experimental data determine the exponents and coefficients
of the empirical equation. The requirements of dimensional analysis are
that (1) only one relationship exists among a certain number of physical quantities,
and (2) no pertinent quantities have been excluded or extraneous quantities
included.
Fundamental (primary) quantities, which cannot be expressed in simpler
terms, include mass (M), length (L), and time (T). Physical quantities may be expressed
in terms of the fundamental quantities: e.g., density is ML3, velocity is
LT1. In some instances, mass units are covertly expressed in terms of force (F)
in order to simplify dimensional expressions or render them more identifiable.
Nonparenteral Liquids and Semisolids 83
The MLT and FLT systems of dimensions are related by the equations
F 
 Ma 
 
M
T
L
2 
??
M 
 
F
L
T2
 ?
According to Bisio [60], scale-up can be achieved by maintaining the dimensionless
groups characterizing the phenomena of interest constant from small
scale to large scale. However, for complex phenomena this may not be possible.
Alternatively, dimensionless numbers can be weighted so that the untoward influence
of unwieldy variables can be minimized. On the other hand, this camouflaging
of variables could lead to an inadequate characterization of a process and
a false interpretation of laboratory or pilot plant data.
Pertinent examples of the value of dimensional analysis have been reported
recently in a series of papers by Maa and Hsu [19,36,61]. In their first report, they
successfully established the scale-up requirements for microspheres produced by
an emulsification process in continuously stirred tank reactors (CSTRs) [61].
Their initial assumption was that the diameter of the microspheres, dms, is a function
of phase quantities, physical properties of the dispersion and dispersed
phases, and processing equipment parameters:
dms 
 ?(D', D/T, H, B, nimp, gc, g, c, $o, $a, o, a, 
o, 
a, 
) (42)
Gravitational acceleration, g, is included to relate mass to inertial force. The conversion
factor, gc, was included to convert one unit system to another. The subscripts
o and a refer to the organic and aqueous phases, respectively. The remaining
notation is as follows:
D impeller diameter (cm)
' rotational speed (angular velocity) of the impeller(s) (sec1)
T tank diameter (cm)
H height of filled volume in the tank (cm)
B total baffle area (cm2)
n number of baffles
nimp number of impellers

o, 
a phase volumes (mL)
c polymer concentration (g/mL)
$o, $a phase viscosities (g-cm1-sec1)
o, a phase densities (g-mL1)

 interfacial tension between organic and aqueous phases (dyne-cm1)
The initial emulsification studies employed a 1-L “reactor” vessel with baffles
originally designed for fermentation processes. Subsequent studies were suc-
84 Block
cessively scaled-up from 1 L to 3, 10, and 100 L. Variations due to differences in
reactor configuration were minimized by utilizing geometrically similar reactors
with approximately the same D/T ratio (i.e., 0.36–0.40). Maa and Hsu contended
that separate experiments on the effect of the baffle area (B) on the resultant microsphere
diameter did not significantly affect dms. However, the number and location
of the impellers had a significant impact on dms. As a result, to simplify the
system, Maa and Hsu always used double impellers (nimp 
2), with the lower one
placed close to the bottom of the tank and the other located in the center of the total
emulsion volume. Finally, Maa and Hsu determined that the volumes of the organic
and aqueous phases, in the range they were concerned with, played only a
minor role in affecting dms. Thus, by the omission of D/T, B, and 
o, and 
a, Eq.
42 was simplified considerably to yield
dms 
 ?(D', gc, g, c, $o, $a, o, a, 
) (43)
Equation (43) contains ten variables and four fundamental dimensions (L, M, T,
and F). Maa and Hsu were able subsequently to define microsphere size, dms, in
terms of the processing parameters and physical properties of the phases:

 (44)
where ?i
are dimensionless multiplicative groups of variables. [The transformation
of Eq. (43) into Eq. (44) is described by Maa and Hsu [61] in an appendix to
their paper.] Subsequently, linear regression analysis of the microsphere size parameter,
g(o  a)d2
ms/
, as a function of the right-hand side of Eq. (43); i.e.,
( resulted in r0.973 for 1-L, 3-L, 10-L,
and 100-L reactors, at two different polymer concentrations. These composite
data are depicted graphically in Figure 3.
Subsequently, Maa and Hsu [19] applied dimensional analysis to the scaleup
of a liquid–liquid emulsification process for microsphere production utilizing
one or another of three different static mixers, which varied in diameter, number
of mixing elements, and mixing element length. Mixing element design differences
among the static mixers were accomodated by the following equation:
dms 
 0.483d1.202V0.556
0.556$a
0.560 $o
0.004nhc0.663 (45)
where dms is the diameter of the microspheres (m) produced by the emulsification
process, d is the diameter of the static mixer (cm), V is the flow rate of the
continuous phase (mL-sec1), 
 is the interfacial tension between the organic and
aqueous phases (dyne/cm), $a and $o are the viscosities (g-cm1-sec1) of the
aqueous and organic phases, respectively, n is the number of mixing elements, h
is an exponent the magnitude of which is a function of static mixer design, and c
g(o  a)d2
ms 


Nonparenteral Liquids and Semisolids 85
??0.280??0.108 ??0.056 (0.255?e
 0.0071) 2 3 4 5
??0.280??0.108??0.056 (0.255?e
 0.0071)), 2 3 4 5
is the polymer concentration (g-mL1) in the organic phase. The relative efficiency
of the three static mixers was readily determined in terms of emulsification
efficiency, &, defined as equivalent to 1/dms: better mixing results in smaller microspheres.
In this way, Maa and Hsu were able to compare and contrast continuously
stirred tank reactors (CSTRs) with static mixers.
Houcine et al. [62] used a nonintrusive laser-induced fluorescence method
to study the mechanisms of mixing in a 20 dm3 CSTR with removable baffles, a
conical bottom, a mechanical stirrer, and two incoming liquid jet streams. Under
certain conditions, they observed an interaction between the flow induced by the
stirrer and the incoming jets that led to oscillations of the jet stream with a period
of several seconds and corresponding switching of the recirculation flow between
several metastable macroscopic patterns. These jet feedstream oscillations or intermittencies
could strongly influence the kinetics of fast reactions such as precipitation.
The authors used dimensional analysis to demonstrate that the intermittence
phenomenon would be less problematic in larger CSTRs.
86 Block
Figure 3 Microsphere diameter parameter, dms, as a function of processing parameters
and physical properties of the phases (	 functions of the right-hand side of Eq. 31). (From
Ref. 61.)
Additional insights into the application of dimensional analysis to scale-up
can be found in Chapter 1 of this volume, by Zlokarnik [63], and in his earlier
monograph on scale-up in chemical engineering [64].
C. Mathematical Modeling and Computer Simulation
Basic and applied research methodologies in science and engineering are undergoing
major transformations. Mathematical models of “real-world” phenomena
are more elaborate than in the past, with forms governed by sets of partial differential
equations that represent continuum approximations to microscopic
models [65]. Appropriate mathematical relationships would reflect the fundamental
laws of physics regarding the conservation of mass, momentum, and energy.
Euzen et al. [66] list such balance equations for mass, momentum, and energy
(e.g., heat), for a single-phase Newtonian system (with constant density, ,
viscosity, $, and molar heat capacity at constant pressure, Cp) in which a process
takes place in an element of volume, V (defined as the product of dx, dy,
and dz):
 

C
t
i


x


C
x
i
 
y


C
y
i
 
z


C
z
i
	
 Dix


2
x
C
2
i
 Diy


2
y
C
2
i
 Diz


2
z
C
2
i 	

Ri
Mass balance





t
x
 
x




x
x
 
y




y
x
 
z




z
x
	
(
46)

 


P
x 
 $


2
x


2
x
 

2
y


2
x
 


2
z


2
x
	


gx
Momentum balance (e.g., in x-direction)}
Cp


T
t 
 
x


T
x 
 
y


T
y 


z
 

T
z 
	

 kx


2
x
T
2 
 ky


2
y
T
2 
 kz


2
z
T
2 
	  SR
Energy balance
where P is pressure, T is temperature, t is time, 
 is fluid flow velocity, k is thermal
conductivity, and Ri, gx, and SR are kinetic, gravitational, and energetic parameters,
respectively. Equation (46) is presented as an example of the complex
Nonparenteral Liquids and Semisolids 87
??
?
?
?
???
?
relationships that are becoming increasingly more amenable to resolution by computers,
rather than for its express utilization in a scale-up problem.
However, most computational fluid dynamics (CFD) software programs
available to date for simulation of transport phenomena require the user to define
the model equations and parameters and specify the initial and boundary conditions
in accordance with the program’s language and code, often highly specialized.
A practical interim solution to the computational problem presented by Eq.
(46) and its non-Newtonian counterparts is at hand now in the form of software
developed by Visimix Ltd. [67]—VisiMix 2000 Laminar and VisiMix 2000 Turbulent—
for personal computers! These interactive programs utilize a combination
of classical transport equations in conjunction with algorithms for computation of
mixing processes and actual laboratory, pilot plant, and production data to simulate
macro- and microscale transport phenomena. VisiMix’s user friendly, menudriven
software uses physical and mathematical models of mixing phenomena
based on fundamental transport equations and on extensive theoretical and experimental
research [68–70]. Graphical menus allow the user to select and define process
equipment from a wide range of options, including vessel shape, agitator
type, jacketing, and baffle type. VisiMix not only addresses most unit operations
with a mixing component (e.g., blending, suspension of solids, emulsification,
dissolution, gas dispersion) but also evaluates heat transfer/exchange (e.g., for
jacketed tanks). Tangential velocity distributions, axial circulation, macro- and
microscale turbulence, mixing time, equilibrium droplet size distribution, and
droplet breakup and coalescence are just some of the calculations or simulations
that VisiMix can provide.
Liu and Neeld [71] used VisiMix software to calculate shear rates in laboratory-,
pilot-plant-, and production-scale vessels. Their results (Table 3)
showed marked differences, by as much as two orders of magnitude, in the shear
rates calculated in the conventional manner (from tip speed and the distance
from impeller tip to baffle, i.e.,  . 
 ND/(T  D), and the shear rates computed
by VisiMix. The latter’s markedly higher shear rates resulted from VisiMix’s
definition of the shear rate in terms of Kolmogorov’s model of turbulence and
the distribution of flow velocities. Note that VisiMix’s estimates of the respective
shear rates in the vicinity of the impeller blade are comparable at all scales,
while the shear rates in the bulk volume or near the baffle are not, except on the
laboratory scale. If the efficacy of the mixing process were dependent upon the
shear achieved adjacent to the impeller, the VisiMix scaling simulations would
predict comparable outcomes for the equipment parameters employed. However,
if the shear rate in the vicinity of the impeller were not the controlling factor in
achieving similitude, then scale-up relying on adjustments in agitator speed or
tip velocity would be unsuccessful.
88 Block
IV. SCALE-UP PROBLEMS
As Baekland [72] said, “Commit your blunders on a small scale and make your
profits on a large scale.” Effective scale-up mandates an awareness of the relative
importance of various process parameters at different scales of scrutiny. Heat
transfer, molecular diffusion, and microscopic viscosity operate on a so-called microscopic
or molecular scale. On a macroscopic scale, these parameters may not
appear to have a noticeable effect, yet they cannot be ignored: Were there no energy,
mass, or momentum transport at the microscopic scale, larger-scale processes
would not function properly [55]. On the other hand, a system’s flow
regimes operate at both the microscopic and macroscopic levels. Turbulent flow,
characterized by random swirling motions superimposed on simpler flow patterns,
involves the rapid tumbling and retumbling of relatively large portions of fluid, or
eddies. While turbulence, encountered to some degree in virtually all fluid systems,
tends to be isotropic on a small scale, it is anisotropic on a large scale.
Among some of the more common scale-up errors are:
• Scaling based on wrong unit operation mechanism(s)
• Incompletely characterized equipment, e.g., multishaft mixers/homogenizers
• Insufficient knowledge of process; lack of important process information
• Utilization of different types of equipment at different levels of scale-up
Nonparenteral Liquids and Semisolids 89
Table 3 Shear Rates at Different Processing Scales
Average
shear
rate 
 (tip VisiMix VisiMix
speed/ simulation: simulation: VisiMix
distance shear rate shear rate simulation:
Agitator Tip from tip in bulk near the shear rate
speed, velocity, to baffle), volume, impeller blade, near baffle,
Scale rpm m/s 1/sec 1/sec 1/sec 1/sec
Laboratory 700 3.11 37 902 12,941 902
reactor
Pilot plant 250 5.98 118 2,470 12,883 4,146
reactor
Production 77 8.60 15 1,517 11,116 1,678
plant
reactor
Source: Adapted from Ref. 71.
• Unrealistic expectations (e.g., heat dissipation)
• Changes in product or process (e.g., altered formulation, phase changes,
changes in order of addition) during scale-up
These last issues, in particular, are exemplified by the recent report of
Williams et al. [73] on problems associated with the scale-up of an o/w cream containing
40% diethylene glycol monoethyl ether and various solid, waxy excipients
(e.g., cetyl alcohol; polyoxyethylene-2-stearyl ether). Preparation of 300-g batches
in the laboratory in small stainless steel beakers proceeded without incident while
7-kg batches made with a Brogli-10 homogenizer were subject to precipitation in
or congealing of the external phase in the region between the sweep agitation blade
and the discharge port. Low levels of congealed or precipitated excipient that went
undetected on the laboratory scale, marked differences in the rate and extent of heat
exchange at the two levels of manufacturing, and the presence of cold spots or nonjacketed
areas in the Brogli-10 homogenizer contributed to the problem.
Unfortunately, the publication by Williams and coworkers is one of the only
reports of a scale-up problem involving liquids or semisolids in the pharmaceutical
literature. A number of papers that purport to deal with scale-up issues and
even go so far as to compare the properties of small versus large batches fail to apply
techniques such as dimensional analysis that could have provided the basis for
a far more substantial assessment or analysis of the scale-up problem for their system.
Worse yet, there is no indication of how scale-up was achieved or what scaleup
algorithm(s), if any, were used. Consequently, their usefulness, from a pedagogical
point of view, is minimal.
V. CONCLUSIONS
Process scale-up of liquids and semisolids not only is an absolutely essential part
of pharmaceutical manufacturing but also is a crucial part of the regulatory process.
The dearth of research publications to date must reflect either the avoidance
of scale-up issues by pharmaceutical formulators and technologists due to their inherent
complexity or a concern that scale-up experimentation and data constitute
trade secrets that must not be disclosed lest competitive advantages be lost. The
emergence of pharmaceutical engineering as an area of specialization and the advent
of specialized software capable of facilitating scale-up warrant a change in
these attitudes.
REFERENCES
1. R. G. Griskey. Chemical Engineering for Chemists. Washington, DC: American
Chemical Society, 1997, pp. 283–303.
90 Block
2. E. A. Holland and J. K. Wilkinson. Process economics. In: R. H. Perry, D. W. Green,
and J. O. Maloney, eds. Perry’s Chemical Engineers’ Handbook. 7th ed. New York:
McGraw-Hill, 1997, pp 9-1–9-79.
3. L. H. Block. Scale-up of disperse systems: Theoretical and practical aspects. In: H.
A. Lieberman, M. M. Rieger, and G. S. Banker, eds. Pharmaceutical Dosage Forms:
Disperse Systems. 2nd ed. Vol. 3. New York: Marcel Dekker, 1998, p 363.
4. G. Astarita. Scaleup: overview, closing remarks, and cautions. In: A. Bisio and R. L.
Kabel, eds. Scaleup of Chemical Processes: Conversion from Laboratory Scale Tests
to Successful Commercial Size Design. New York: Wiley, 1985, p 678.
5. V. Gekas. Transport Phenomena of Foods and Biological Materials. Boca Raton, FL:
CRC Press, 1992, pp 5–62.
6. R. B. Bird, W. E. Stewart, and E. N. Lightfoot. Transport Phenomena. New York: Wiley,
1960.
7. D. S. Dickey and R. R. Hemrajani. Recipes for fluid mixing. Chem. Eng.
99(3):82–89, 1992.
8. J. M. Ottino. The mixing of fluids. Sci. Am. 260(1):56–57, 60–67, 1989.
9. U. Frisch. Turbulence: The Legacy of A. N. Kolmogorov, Cambridge: Cambridge
University Press, 1995.
10. D. Bershader. Fluid physics. In: R. G. Lerner and G. L. Trigg, eds. Encyclopedia of
Physics. 2nd ed. New York: VCH, 1991, pp 402–410.
11. R. J. Stokes and D. F. Evans. Fundamentals of Interfacial Engineering. New York:
Wiley-VCH, 1997, pp 88–89.
12. Z. Sterbacek and P. Tausk. Mixing in the Chemical Industry. Oxford: Pergamon
Press, 1965, p 8.
13. R. E. Treybal. Mass-Transfer Operations. 3rd ed. New York: McGraw-Hill, 1980, p
45.
14. H. J. Lugt. Vortices and vorticity in fluid dynamics. Amer. Sci. 73:162–167, 1985.
15. J. Y. Oldshue. Fluid Mixing Technology. New York: McGraw-Hill, 1983, pp
338–358.
16. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 125–131.
17. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 15–18.
18. H. Gladki. Power dissipation, thrust force and average shear stress in the mixing tank
with a free jet agitator. In: G. B. Tatterson, R. V. Calabrese, and W. R. Penny, eds.
Industrial Mixing Fundamentals with Applications. New York: American Institute of
Chemical Engineering 1995, pp 146–149.
19. Y. F. Maa and C. Hsu. Liquid-liquid emulsification by static mixers for use in microencapsulation.
J. Microencaps. 13:419–433, 1996.
20. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 67–74.
21. D. S. Dickey and J. G. Fenic. Dimensional analysis for fluid agitation systems. Chem.
Eng. 83(1):139–145, 1976.
22. R. B. Bird, W. E. Stewart, and E. N. Lightfoot. Transport Phenomena. New York: Wiley,
1960, pp 71–122.
Nonparenteral Liquids and Semisolids 91
23. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 117–125.
24. J. M. Coulson, J. F. Richardson, J. R. Backhurst, and J. H. Harker. Chemical Engineering:
Fluid Flow, Heat Transfer and Mass Transfer. 4th ed. Vol. 1. Oxford: Pergamon
Press, 1990, pp 227–230.
25. J. Y. Oldshue. Fluid Mixing Technology. New York: McGraw-Hill, 1983, pp 72–93,
295–337.
26. J. L. Beckner and J. M. Smith. Trans. Instn. Chem. Engrs. 44:T224, 1966; through H.
W. Fowler. Progress report in pharmaceutical engineering. Mfg. Chemist Aerosol
News 37(11):60, 1966.
27. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 97–101.
28. A. W. Etchells, W. N. Ford, and D. G. R. Short. Mixing of Bingham plastics on an industrial
scale. In: Fluid Mixing III, Symposium Series 108, Institution of Chemical
Engineers. Rugby, UK: Hemisphere, 1985, pp 271–285.
29. J. M. Smith. The mixing of Newtonian and non-Newtonian fluids. J. Soc. Cosmet.
Chem. 21:541–552, 1970.
30. A. B. Metzner, W. T. Houghton, R. A. Sailor, and J. L. White. A method for measurement
of normal stresses in simple shearing flow. Trans. Soc. Rheol. 5: 133–147,
1961.
31. A. G. Fredrickson. Viscoelastic phenomena in thick liquids: phenomenological analysis.
In: A. Acrivos, ed. Modern Chemical Engineering. Vol. I: Physical Operations.
New York: Reinhold, 1963, pp 197–265.
32. J. Cheng, P. J. Carreau, and R. P. Chhabra. On the effect of wall and bottom clearance
on mixing of viscoelastic fluids. In: G. B. Tatterson, R. V. Calabrese, W. R. Penny,
eds. Industrial Mixing Fundamentals with Applications. New York: American Institute
of Chemical Engineers, 1995, pp 115–122.
33. J. A. Skidmore. Some aspects of the mixing of liquids. Am. Perf. Cosmetics
84(1):31–35, 1969.
34. J. Hinze. Amer. Inst. Chem. Engg. J. 1:289–295 (1955); through Z. Sterbacek and P.
Tausk. Mixing in the Chemical Industry. Oxford: Pergamon Press, 1965, pp 47–
48.
35. W. L. McCabe, J. C. Smith, and P. Harriott. Unit Operations of Chemical Engineering.
5th ed. New York: Mc-Graw Hill, 1993, p 276.
36. Y.-F. Maa and C. Hsu, Liquid–liquid emulsification by rotor/stator homogenization.
J. Contr. Rel. 38:219–228, 1996.
37. L. Dobetti and V. Pantaleo. Hydrodynamics in microencapsulation by coacervation.
American Association of Pharmaceutical Scientists, Annual Meeting and Exposition,
Indianapolis, IN, October 29–November 2, 2000.
38. P. M. Armenante and D. J. Kirwan. Mass transfer to microparticles in agitated systems.
Chem. Eng. Sci. 44(12):2781–2796, 1989.
39. M. E. Fayed and L. Otten, eds. Handbook of Powder Science and Technology. New
York: Van Nostrand Reinhold, 1984.
40. J. Carstensen. Solid Pharmaceutics: Mechanical Properties and Rate Phenomena.
New York: Academic Press, 1980.
41. J. Carstensen. Advanced Pharmaceutical Solids. New York: Marcel Dekker, 2000.
92 Block
42. L. G. Austin. Size reduction of solids: crushing and grinding equipment. In: M. E.
Fayed and L. Otten, eds. Handbook of Powder Science and Technology. New York:
Van Nostrand Reinhold, 1984, pp 562–606.
43. S. Mori. Chem. Eng. (Japan) 2(2):173 (1964); through R. H. Perry, D. W. Green, and
J. O. Maloney, eds. Perry’s Chemical Engineers’ Handbook. 7th ed. New York: Mc-
Graw-Hill, 1997, pp 20–19.
44. W. L. McCabe, J. C. Smith, and P. Harriott. Unit Operations of Chemical Engineering.
5th ed. New York: Mc-Graw Hill, 1993, pp 960–993.
45. F. C. Bond. Crushing and grinding calculations. Brit. Chem. Eng. 6:378, 1965.
46. W. H. Walker, W. K. Lewis, W. H. McAdams, and E. R. Gilliland. Principles of
Chemical Engineering. 3rd ed. New York: McGraw-Hill, 1937.
47. R. H. Snow, T. Allen, B. J. Ennis, and J. D. Lister. Size reduction and size enlargement.
In: R. H. Perry, D. W. Green, and J. O. Maloney, eds. Perry’s Chemical Engineers’
Handbook. 7th ed. New York: McGraw-Hill, 1997, pp 20-13–20-22.
48. M. P. Boyce. Transport and storage of fluids. In: R. H. Perry, D. W. Green, and J. O.
Maloney, eds. Perry’s Chemical Engineers’ Handbook. 7th ed. New York: McGraw-
Hill, 1997, pp 10-20–10-23.
49. J. T. Carstensen and A. Mehta. Scale-up factors in the manufacture of solution dosage
forms. Pharm. Technol. 6(11):64, 66, 68, 71, 72, 77, 1982.
50. W. J. Dale. The scale-up process: optimize the use of your pilot plant. Abstract 108c,
Session 108 on Experimental Strategies for Pilot Plants, 1996 Spring Meeting, American
Institute of Chemical Engineers, New York.
51. G. P. Pisano. The Development Factory: Unlocking the Potential of Process Innovation.
Boston: Harvard Business School Press, 1997.
52. A. Lubbert, T. Paaschen, and A. Lapin. Fluid dynamics in bubble column bioreactors:
experiments and numerical simulations. Biotechnol. Bioeng. 52:248–258, 1996.
53. R. E. Johnstone and M. W. Thring. Pilot Plants, Models, and Scale-up Methods in
Chemical Engineering. New York: McGraw-Hill, 1957, pp 12–26.
54. V. W. Uhl and J. A. Von Essen. Scale-up of equipment for agitating liquids. In: V. W.
Uhl and J. B. Gray, eds. Mixing Theory and Practice. Vol. III. New York: Academic
Press, 1986, p 200.
55. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 112–113.
56. G. B. Tatterson. Scaleup and Design of Industrial Mixing Processes. New York: Mc-
Graw-Hill, 1994, pp 243–262.
57. J. P. Euzen, P. Trambouze, and J. P. Wauquier. Scale-Up Methodology for Chemical
Processes. Paris: Editions Technip, 1993, p 15.
58. E. S. Taylor. Dimensional Analysis for Engineers. Oxford: Clarendon Press, 1974,
p. 1.
59. W. L. McCabe, J. C. Smith, and P. Harriott. Unit Operations of Chemical Engineering.
5th ed. New York: Mc-Graw Hill, 1993, pp 16–18.
60. A. Bisio. Introduction to scaleup. In: A. Bisio and R. L. Kabel, eds. Scaleup of Chemical
Processes: Laboratory Scale Tests to Successful Commercial Size Design. New
York: Wiley, 1985, pp. 15–16.
61. Y.-F. Maa and C. Hsu. Microencapsulation reactor scale-up by dimensional analysis.
J. Microencaps. 13(1):53–66, 1996.
Nonparenteral Liquids and Semisolids 93
62. I. Houcine, E. Plasari, R. David, and J. Villermaux. Feedstream jet intermittency phenomenon
in a continuous stirred tank reactor. Chem. Eng. J. 72:19–29, 1999.
63. M. Zlokarnik. Dimensional analysis and scale-up in theory and industrial application.
In: M. Levin, ed. Pharmaceutical Process Scale-Up. New York: Marcel Dekker,
2001.
64. M. Zlokarnik. Dimensional Analysis and Scale-Up in Chemical Engineering. Berlin:
Springer Verlag, 1991.
65. G. E. Karniadakis. Simulation science? Brown Faculty Bull. 8(3):1996; through
www.cfm.brown.edu/crunch/article.html.
66. J. P. Euzen, P. Trambouze, and J. P. Wauquier. Scale-Up Methodology for Chemical
Processes. Paris: Editions Technip, 1993, pp. 13–15.
67. VisiMix Ltd., P.O. Box 45170, Jerusalem, Israel; (http://www.visimix.com).
68. L. N. Braginsky, V. I. Begachev, and V. M. Barabash. Mixing in Liquid Media: Physical
Foundations and Methods of Technical Calculations. Jerusalem: VisiMix, 1996;
excerpts from the Russian edition published by Khimya, Leningrad, 1984.
69. A Review of Main Mathematical Models Used in the VisiMix Software. Jerusalem:
VisiMix, 1998.
70. Selected Verification & Validation Examples: The Comparison between Published
Experimental Data and VisiMix Calculations. Jerusalem: VisiMix, 1999.
71. K. Liu and K. Neeld. Simulation of mixing and heat transfer in stirred tanks with
VisiMix®. Conference on Process Development from Research to Manufacturing: Industrial
Mixing and Scale-Up, Annual Meeting, American Institute of Chemical Engineers,
1999.
72. L. H. Baekeland. Practical life as a complement to university education—medal address.
J. Ind. Eng. Chem. 8:184–190, 1916.
73. S. O. Williams, S. Long, J. Allen, and M. L. Wells. Scale-up of an oil/water cream
containing 40% diethylene glycol monoethyl ether. Drug Dev. Ind. Pharm. 26:71–77,
2000.
94 Block
4
Scale-Up Considerations for
Biotechnology-Derived Products
Marco A. Cacciuttolo
Medarex, Inc., Bloomsbury, New Jersey
Erica Shane, Cynthia Oliver, and Eric Tsao
MedImmune, Inc.,Gaithersburg, Maryland
Roy Kimura
Onyx Pharmaceuticals, Inc., Richmond, California
I. INTRODUCTION
This chapter covers the general principles involved in the scale-up of biotechnology-
derived products. Sections I and II focus on technologies currently used in the
manufacture of commercial products. Sections III and IV include a practical approach
to process design and scale-up strategies used to translate process development
to large-scale production.
In addition to basic engineering design principles, the scale-up of biotechnology
products requires an understanding of the cellular and regulatory mechanisms
that govern cell physiology and the biophysical and biochemical characteristics of
products. A thorough understanding of process operations and process limitations is
essential for successful technology transfer from development to manufacturing. The
design and operation of the facility, including appropriate segregation of products,
personnel and equipment at each stage of manufacturing, must comply with current
regulatory guidelines. The true measure of successful scale-up is validation of the process
at manufacturing scale and ultimate approval of the biopharmaceutical product.
Due to the complexity of biological systems and the physical and biochemical
characteristics of the protein products, the design and scale-up of biological
processes can be challenging. Batch sizes for the production of biotechnology-derived
products can reach 10,000 L [1] to 12,500 L [2,3] and above. Although these
95
scales of operation are often smaller than conventional fermentation, the high
value of individual production lots requires careful planning and process control.
For this reason, laboratory- and pilot-scale data together with actual experience
are essential for the effective selection of scale-up strategies, equipment, and process
parameters [4].
The efficient and timely completion of scale-up to commercial manufacture
is critical to biotechnology companies. In some cases, novel unit operations or techniques
are required to achieve adequate expression, recovery, quality, or integrity
of the product, which may not be feasible with more conventional techniques.
However, this may cause costly delays in product approval because the use of new
technologies may be associated with a greater uncertainty as the scale of the operation
increases. In addition, the ease of process validation may be an important factor
influencing the selection of novel versus conventional process techniques [2,5].
For example, cell culture processes can be conducted either as a batch process or
as a continuous process. However, the time required to validate a continuous process
may be longer than that for a batch process. As a consequence, this may impact
the time required for preparation and submission of documents to regulatory
agencies as well as the time needed for review and approval. For many companies,
the duration of clinical development and the strategy for efficacy studies may determine
the difference between success in the marketplace and total failure.
The time lines needed to complete technology transfer may vary with the
complexity of the process. A team composed of manufacturing and development
personnel is responsible for facility design or integration of a process into an existing
facility. The team is also responsible for equipment specifications and
defining the physical relationship of process operations in order to comply with
regulatory standards. The team must be aware of the relevant scale-up criteria to
be used because their misapplication can lead to significant performance differences
between benchtop and manufacturing-plant scales [6]. For this reason, stepwise
scale-up is recommended. In addition, successful scale-up requires that manufacturing
personnel be properly trained on process requirements and Good
Manufacturing Practices to provide an efficient and seamless transition into commercial
production within the shortest time possible.
Recent advances in safety, selectivity, quality, and integrity of molecules obtained
from recombinant microorganisms and immortalized cell lines have provided
a wide range of products used as therapeutic agents. Marketed biotechnology
products can be classified into five categories [1]: coagulation factors, enzymes,
hormones and growth factors, molecular inhibitors/antagonists, and vaccines. Examples
of marketed biotechnology products are presented in Table 1. This table illustrates
the diversity of cell lines (bacteria, yeast, and mammalian cells) used to
produce licensed products. In addition to the expression systems listed later, other
expression systems, such as insect cells, plant cells, and transgenic animals and
plants, are currently being evaluated at preclinical and clinical stages.
96 Cacciuttolo et al.
Scale-Up of Biotechnology-Derived Products 97
Table 1 Examples of Biotechnology-Derived Products
Protein Clinical application Production process
Coagulation factors
Recombinate (F VIII)a Hemophilia rCHO, bleed-feed
Kogenate (F VIII)a Hemophilia rBHK-21, bleed-feed
Novo Seven (F VIIa)a Hemophilia A rBHK
Bene Fix (FIX)a Hemophilia B rCHO
Enzymes
Pulmozyme (Dnase1)a Cystic fibrosis rCHO, suspension
Cerezymea Gaucher’s disease rCHO, microcarriers
Activase (tPA)a Thrombolytic agent rCHO, suspension
Abbokinase (Urokinase) Pulmonary embolism Human kidney cells
Growth factors and hormones
Welferon (IFN alfa)a Hep C treatment Namalva
Roferon (IFN alfa-b) Hep C treatment rE. coli
Infergen (IFN alfa) Hep C treatment rE. coli
Intron A (IFN alfa) Hairy cell lymphoma rE. coli
Epogen (Epo)a Stimulation of erithropoiesis rCHO, Roller bottles
Avonex (IFN beta)a Multiple sclerosis rCHO
Betaseron (IFN beta) Multiple sclerosis rE. coli
Proleukin (IL) Metastatic renal carcinoma rE. coli
Gonal F (FSH)a Induction of ovulation rCHO
Saizen (hGH)a Growth hormone deficiency rC127, Roller bottles
Molecular inhibitors/antagonists
Rituxan (Mab) B-cell non-Hodgkin’s lymphoma rCHO
Synagis (Mab) Prevention of RSV disease rNS/0, suspension
Herceptin (Mab) Breast cancer rCHO, supension
OKT3 (Mab)a Rescue of acute renal Mouse ascites
rejection/GVHD
Zenapax (Mab) Prevention of acute rNS/0, suspension
renal rejection
Reopro (Mab) Prevention of cardiac ischemic rSP2/0
complications
Leukine (GMCSF) Induction chemotherapy for rYeast
acute leukemia
Neupogen (GCSF) Treatment of neutropenia rE. coli
Remicade (Mab) Reumathoid arthritis rSP2/0
Embrel Rheumatoid arthritis rCHO
Simulect (Mab) Acute rejection kidney transplants Recombinant myeloma
Mylotarg (Mab) Relapsed acute myeloid leukemia rNS/0, suspension
Campath (Mab) B cell chronic lymphocytic leukemia rCHO, suspension
continues
II. FUNDAMENTALS: TYPICAL UNIT OPERATIONS
Comprehensive descriptions of the basic unit operations commonly used in the
production of biotechnology products are available in the literature [8]. This section
focuses on the typical unit operations currently used for production of biological
molecules in cell culture and the technologies used for the purification of
pharmaceutical proteins. For each of these operations, laboratory- and pilot-scale
experiments provide the basis for scale-up, especially to define the expected range
of process operating parameters.
A. Bioreactor Operation
Commercial manufacturing operations in biotechnology usually employ mechanical
bioreactors or fermentors for product expression. In this discussion the term
fermentor will refer to bacterial or fungal processes and the term bioreactor to animal
cell cultures. While extensive description of the operation of fermentors is
available elsewhere [6,8], this chapter will focus on bioreactors used in the manufacture
of complex proteins.
There are a variety of types of bioreactors described in the literature. Among
them, the stirred tank bioreactor is the most commonly employed due to its record
of performance and ease of operation. Cells growing in bioreactors take up nutrients
from the culture medium and release products, byproducts, and waste
98 Cacciuttolo et al.
Table 1 Continued
Protein Clinical application Production process
Vaccines
Vaqta Hep A Vaccine MRC5 cells
Recombivax (HbsAg) Hep B Vaccine rYeast
Engerix-B (HbsAg) Hep B vaccine rYeast
GenHevac B (HbsAg)a Hep B vaccine rCHO, microcarriers
HB Gamma (HbsAg)a Hep B vaccine rCHO
Comvax (HbsAg) Combination of PedvaxHIB Microbial fermentation
and recombivax HB
Infanrix Tetanus toxoids, diphtheria, Bacterial fermentation
acellular pertussis vaccine
Certiva Tetanus toxoids, diphtheria, Bacterial fermentation
acellular pertusis vaccine
LYMErix (OspA) Lyme disease vaccine rE. coli
RotaShield Rotavirus vaccine FRhk2
Varivax Varicella vaccine MRC5 cells
a Ref. 7.
metabolites. Mass transport phenomena required for adequate supply of nutrients
and removal of waste metabolites are greatly influenced by mixing and aeration
rates. Agitation is used to maintain cells in suspension, to provide a homogeneous
mix of nutrients, and to prevent the accumulation of toxic gases [9].
Aeration is also an essential requirement for aerobic cell lines. The design of
aeration devices includes single-orifice tubes, sparger rings, and diffuser membranes.
Bubble sizes may vary with each device, and optimization is required to
achieve the maximum ratio of surface area to gas volume transfer rate that generates
a minimal of foaming to prevent damaging effects on cell viability [10,11]. The
effect of aeration on cell productivity is complex and depends on cell line, medium
components (including cell proteins), and characteristics of foam formation and
collapse. The optimal aeration rate then is determined empirically at each scale.
B. Filtration Operations
Filtration technologies are used extensively throughout the biotechnology industry
[12,13]. Membranes and filters can be used for medium exchange during cell
growth, cell harvest, product concentration, diafiltration, and formulation or for
removal of viruses and control of bioburden. For example, microfiltration is used
to replace spent medium with fresh medium [14] or to recover secreted proteins
[3,14]. Ultrafiltration membranes with submicron pore sizes are used for product
concentration and buffer exchange by diafiltration. Nanometer ultrafiltration using
filters with tightly controlled pore sizes can be used for virus removal [15]. Filtration
with 0.2-micron dead-end filters is used for removal of microorganisms
[16]. Sterilizing filters are validated for product-specific bubble point, product
compatibility, and microbial retention. The key process parameters for filtration
scale-up are pressure, volume, operating time, temperature, flux rate, protein concentration,
and solution viscosity.
C. Centrifugation
Centrifugation is used in fermentation processes as well as in blood serum fractionation.
Scale-up of operations for separation of product-containing cells from
supernatant fluid or secreted products from host cells is well established [17]. Although,
batch centrifugation is often used at the laboratory scale, continuous centrifugation
is preferred at production scale. When centrifugation is used for
biotechnology applications, it is preferable to use high-throughput low-shear centrifuges
to minimize the shear sensitivity of animal cells. For this reason, filtration
may be the preferable unit operation for separating excreted products from host
cells because of the relatively mild operating conditions. A second advantage of
filtration is that the cleaning validation is relatively simple compared to the elaborated
cleaning validation required for continuous centrifuges.
Scale-Up of Biotechnology-Derived Products 99
D. Chromatography
Chromatography is a commonly used unit operation for the purification of proteins
in biotechnology applications. It is capable of combining relatively high
throughputs with high selectivity. A major advantage of this technique is that it
can be optimized to achieve high resolution of the desired product from its contaminants.
The selection of the appropriate gel is very much dependent on an understanding
of the physical and chemical characteristics of the target protein product.
Chromatography steps can be designated selectively to either capture the
product or remove contaminants. For ion exchange gels, contaminant removal is
achieved by optimizing the pH and conductivity of the equilibration, wash, and
elution buffers. Affinity chromatography is often used as an initial capture step to
provide high specificity, high selectivity, and volume reduction. However, affinity
chromatography gels such as Protein A and Protein G are costly, especially in
early process steps with crude product streams. The use of crude material on affinity
matrices may require extensive cleaning, which contributes to the cost and can
reduce the effective lifetime of the gel. Hydrophobic interaction chromatography
(HIC), which takes advantage of the different hydrophobicity of proteins and contaminants,
also exhibits selectivity and specificity. Because proteins bind effectively
to HIC gels at high conductivity, HIC can be integrated effectively with
both ion exchange and affinity chromatography. Key parameters for chromatography
scale-up are gel capacity, linear velocity, buffer volume, bed height, temperature,
cleanability, and gel lifetime.
E. Dimensional Analysis
Dimensional analysis is a useful tool for examining complex engineering problems
by grouping process variables into sets that can be analyzed separately. If appropriate
parameters are identified, the number of experiments needed for process
design can be reduced, and the results can be described in simple mathematical expressions.
In addition, the application of dimensional analysis may facilitate the
scale-up for selected biotechnology unit operations. A detailed description of dimensional
analysis is reviewed by Zlokarnik [18].
These analysis techniques provide a macroscopic description of the process
and offer the possibility of qualitative assessment, although detailed mechanistic
information is not captured. Due to the complexity of living systems, it may be impractical
to provide a detailed description of the reaction parameters or to determine
the specific dimensionless parameters for modeling cell growth and product
production. However, models for mixing and aeration are well described in the literature.
Similarly, for chromatography steps, it is often difficult to describe the purification
of a single protein from a complex mixture of contaminants that range in
concentration. However, parameters such as column volumes of solution (liters solution
per liter of gel volume) may be used to maintain similarity between scales.
100 Cacciuttolo et al.
The scale-up of fermenters and bioreactors has been based on chemical industry
methods for design and operation of chemical reactors. Most of the correlations
used in the scale-up of fermentors and bioreactors pertain to mixing and
aeration. Because agitation rates have a strong effect on cell culture performance,
these rates must be optimized at each production scale. Although the effect of mechanical
agitation on cell culture has been examined extensively [19,20], it should
be noted that models describing mass transfer in agitated vessels are of limited
value when scaling up biological processes [6]. While the experience available
from fermentation technology has been adapted for scale-up of suspension cultures
of animal cells, the scale-up of anchorage-dependent cell lines is more complicated
[21] and will not be addressed here.
In a 1991 study by Van Reis et al. [3], a filtration operation as applied to harvest
of animal cells was optimized by the use of dimensional analysis. The fluid
dynamic variables used in the scale-up work were the length of the fibers (L, per
stage), the fiber diameter (D), the number of fibers per cartridge (n), the density of
the culture (), and the viscosity of the culture (). From these variables, scale-up
parameters such as wall shear rate (w) and its effect on flux (L-m2-hr1) were
derived. Based on these calculations, an optimum wall shear rate for membrane
utilization, operating time, and flux was found. However, because there is no single
mathematical expression relating all of these parameters simultaneously, the
optimal solution required additional experimental research.
III. SCALE-UP OF UPSTREAM OPERATIONS
Unit operations for biological products obtained from fermentation or cell culture
can largely be subdivided into four parts: medium preparation, inoculum expansion,
bioreactor, and harvest operations.
A. Medium Preparation
In development or small clinical production runs, complete liquid medium may be
most convenient. Economic issues may dictate that at large scale, powdered or liquid
concentrate medium be used. Shipment and storage of large volumes of complete
liquid medium is less practical at scales greater than 1,000 L.
Culture medium is typically prepared by addition of the base powder or liquid
concentrate mixtures to appropriate grade water. These base media mixtures
usually contain aminoacids, vitamins, cell membrane precursors, antioxidants,
and growth factors to mention some major categories of nutrients. Additional
components such as proteins or lipids may need to be added separately, since they
are usually not compatible in powder blends.
Scale-Up of Biotechnology-Derived Products 101
At present, powdered medium is the formulation of choice for large-scale
operations. Powdered medium is easy to ship and store and has a longer shelf life
compared to liquid formulations. Medium components are reduced in particle size
by ball milling or micronization, mixed, and charged into appropriate-sized containers.
Regardless of which process is used to prepare the powder, homogeneity
of the powder blend has always been a concern. Because each component will
have a different particle size distribution, it may be difficult to be certain that each
container of powder will have the exact same composition. Ray [22] reported on
a study examining blend uniformity in powder-medium production. A model
powder was used to demonstrate homogeneity of medium components that are
present at high (glucose) and low (phenol red) concentrations. Large drums of
powdered medium were sampled from several locations within the drum to
demonstrate homogeneity of amino acids. One issue that has not been adequately
addressed yet is whether powder-medium components settle and segregate during
the course of shipping and storage.
Liquid-concentrate medium has emerged recently as an alternative to powdered
medium [23,24]. For liquid-concentrate preparation, medium components
are grouped according to solubility criteria. Liquid-medium concentrates allow
for the preparation of medium in-line, by automated dilution of the concentrates
with water of the appropriate quality [25]. This would be particularly useful in
continuous or perfused processes that require constant preparation of medium.
Medium cost and component stability make it a secondary option for batch or fedbatch
processes.
B. Cell Culture Inoculum Expansion
The objective of inoculum expansion is to increase the number of cells to an appropriate
amount for inoculation of the production bioreactor. Cells are cultured
in successively larger flasks by adding fresh medium during exponential growth
phase. Cells should be maintained in a rapidly growing state to ensure a vigorous
culture for the production stage. If cells are allowed to reach the plateau phase,
growth of the culture may lag or cease, depending on the cell line and growth
medium used. Each step of expansion is determined in laboratory experiments
where culture growth curves are measured. There is a minimum seed cell density
necessary to minimize the lag phase, as well a maximum cell density to avoid losing
the culture due to starvation or accumulation of toxic metabolites. In the case
of fermentation, the usual culture expansion ratio is 1 volume of inoculum to 10
volumes of fresh medium. In the case of animal cells, this ratio may be as high as
1 volume of inoculum to 1 volume of fresh medium.
For the cultivation of animal cells, inoculum expansions have traditionally
been conducted in T-flasks, shake flasks, spinner flasks, or roller bottles. Typi-
102 Cacciuttolo et al.
cally, T-flasks and shake flasks are used for smaller volumes at the beginning of
inoculum expansion, roller bottles or spinner flasks for the larger volumes. However,
one drawback of roller bottle inoculum expansion is that an increase in process
scale requires an increase in the number of bottles, rather than an increase in
the volume of the roller bottles, in order to keep the optimum surface-to-volume
ratio. This approach, however, can quickly become cumbersome and labor intensive.
Unlike roller bottles, spinner flasks offer the convenience of using-larger
sizes of flasks as the amount of inoculum increases. Thus, the number of inoculum
vessels can be kept to a minimum, reducing the number of manipulations conducted
under sterile conditions. However, it should be noted that in many cases
the expansion of inoculum in these types of vessels may have significant oxygen
transfer limitations. If larger flasks are to be used in the preparation of an inoculum
train, an aeration strategy should be considered. Spinner flasks can be aerated
either through the headspace or by sparging through a diptube. The inoculum can
be expanded to 10–20 L using these types of flask systems. Beyond that volume,
bioreactors of successively larger volume will be used for expansion of the cells
until the working volume of the production bioreactor is reached. An alternative
method for inoculum expansion is to grow cells in a disposable plastic bag on a
rocking platform [26]. The bag can be configured with sterile hydrophobic filters
to allow for aeration of the culture. Systems are currently available for culture volumes
up to 100 L. Ultimately, the decision about choosing among the alternative
methods will depend on cost, reliability, and confidence in the technique used to
expand the inoculum.
One consideration to bear in mind during the design of inoculum expansion
is to demonstrate the genetic stability of the cell line beyond the expected number
of generations required to operate at large scale. This is usually accomplished by
conducting measurements of product expression and genetic markers in cells from
an extended cell bank (ECB).
C. Bioreactor Operation
Several different bioreactor configurations have been described for use in cell culture
and fermentation applications. These include stirred tanks, airlift, and hollowfiber
systems. The majority of bioreactor systems in use for cell culture applications
are still of the stirred-tank type. These systems have been used for batch,
fed-batch, and perfusion operations. It would not be possible to adequately cover
the field of stirred-tank scale-up in the space available here. Instead, this section
will touch briefly on the important issues in bioreactor scale-up. For detailed
methodologies on stirred-tank bioreactor scale-up, the reader is referred to several
review papers on the topic [20,27,28].
Scale-Up of Biotechnology-Derived Products 103
1. Stirred-Tank Bioreactor
As a stirred-tank bioreactor is scaled up, the majority of operating parameters
would stay the same as found at bench scale. The optimal range for parameters
such as temperature, dissolved oxygen, and pH are scale independent. Among
the scale-dependent parameters are the mixing efficiency given by the impeller
rate and aeration rate, and hydrostatic pressure. Agitation and aeration rates determine
the quality of mixing, the gas–liquid mass transfer rates, and the hydrodynamic
stress that the cells experience. Poor mixing can result in inhomogeneities
in pH, nutrient concentration, and metabolic byproduct concentrations.
In addition to the oxygen gas–liquid transfer rate, the carbon dioxide gas–liquid
transfer rate should be taken into account. In the case of animal cells, carbon
dioxide is a metabolic byproduct that can accumulate to inhibitory levels unless
adequate ventilation is provided [9,29]. Strategies to minimize gas sparging (to
reduce sparging-induced cell damage) can inadvertently result in accumulation
of carbon dioxide [30,31].
The basic problem in scaling up a stirred tank bioreactor used in animal
cell cultivation is that at larger scales, quality of mixing, gas–liquid mass transfer
rates, and hydrodynamic stress to the cells cannot all be kept identical to conditions
at bench scale. An impeller rate and sparge rate must be chosen that provide
adequate mixing and gas–liquid mass transfer rates but minimize cell
damage due to shear stress. Animal cells are especially sensitive to mechanical
stress, because they lack the protective cell wall of bacteria and fungi. Although
many correlations have been described for quality of mixing, gas–liquid mass
transfer rates, and hydrodynamic stress, they should be used as guidelines rather
than as a predictor of bioreactor performance at large scale. They will rarely predict
accurately the properties of a bioreactor system under real operating conditions.
For example, measurements of glucose and lactate in a murine hybridoma
culture showed a shift toward anabolic metabolism at the 200-L scale that was
not observed at the 3-L scale. This observation indicated that oxygen limitation
was present at the larger scale, even by using constant impeller tip speed as a
scale-up criterion. This problem could be obviated by, for instance, increasing
the agitation rate at production scale or the set point for dissolved oxygen tension
[14].
Quality of mixing is usually described in terms of a mixing (or circulation)
time. Mixing times are generally determined by injecting a tracer into a bioreactor
and monitoring the signal until it decays to a predetermined level (for example,
99% of the final value). The simplest tracer is either acid or base, with pH
probes to monitor pH fluctuations. As bioreactor volumes increase, mixing times
for equivalent impeller tip speeds inevitably increase. For instance, calculations of
the theoretical mixing time in a 10-L bioreactor and a 10,000-L bioreactor, under
104 Cacciuttolo et al.
typical operating conditions, show that this parameter can increase by an order of
magnitude [32].
Aeration of stirred-tank bioreactors can be accomplished by several methods,
including direct sparging of gas through the culture, surface aeration, and silicon-
tubing aeration. Of these possibilities, direct sparging is the simplest method
for supplying a production bioreactor with oxygen. The most commonly used parameter
to quantify the gas transfer efficiency is the mass transfer coefficient expressed
in terms of the total transfer area, or kLa. Correlations for oxygen mass
transfer rates based upon tank and impeller geometry can be found in many
sources [6,29]. However, it may not always be possible to find a correlation for a
specific reactor configuration, i.e., geometry, impeller types, number of impellers,
etc. Therefore, these correlations should be used as a rough estimation of the
power input required to reach a certain gas transfer efficiency. Gas sparging has
also been implicated in damaging animal cells [11]. The high velocity gradients
that develop around bursting bubbles can generate enough mechanical stress to
damage animal cells. Addition of surfactants to the culture medium, such as
Pluronic F68™, may prevent the attachment of cell to rising bubbles, reducing
their exposure to shear stress [10].
The impact of hydrodynamic stress on animals cells has been reviewed extensively
[19,33]. Most of the work reported in the literature on cell damage in agitated
bioreactors has been done at bench scale. Kunas and Papoutsakis [34] reported
that in 1- to 2-L bioreactors equipped with a 7-cm-diameter pitched-blade
impeller, cell damage was not observed until the impeller rate was raised to above
700 rpm (tip speed: 513 cm/sec) as long as air entrapment did not occur. However,
it is not clear how these bench-scale observations translate into damaging impeller
rates at manufacturing scale.
2. Mode of Operation of Bioreactors
The mode of operation of bioreactors can largely be classified as batch or continuous.
The advantages or disadvantages of using either method are still the subject
of controversy, for proponents and detractors for each method are always well
prepared to defend their positions.
Batch cultivation is perhaps the simplest way to operate a fermentor or
bioreactor. It is easy to scale up, easy to operate, quick to turn around, and reliable
for scale-up. Batch sizes of 15,000 L have been reported for animal cell cultivation
[2], and vessels of over 100,000 L for fermentation are also available. Continuous
processes can be classified into cell retention and non-cell retention. The
devices typically used for cell retention are spin filters, hollow fibers, and decanters.
Large-scale operation of continuous processes can reach up to 2,000 L of
bioreactor volume. Typically, the process is operated at 1–2 bioreactor volumes
Scale-Up of Biotechnology-Derived Products 105
per day. Perfusion is one variation of a continuous process, in which cells are retained
to achieve the highest level of product expression possible [35]. Usually,
high productivity in cell culture is achieved by a high specific productivity and/or
high cell density. The major limitation of a batch is the accumulation of toxic
metabolites and the depletion of nutrients. This is resolved in continuous systems,
such as perfusion, where spent medium is continuously removed from the culture
vessel and replaced by fresh medium. It is claimed to sustain high productivity for
months of continuous operation [35].
The main disadvantage of a continuous system is the long time required for
validation and timely submission of product application to the appropriate regulatory
agency. This time line is drastically reduced with the use of a batch system of
equivalent volumetric productivity.
D. Harvest Operation
Biotechnology products synthesized by living cells either are contained within the
cells (intracellular) or are secreted by the cells into the liquid broth (extracellular).
A clarification step is employed to remove the cells and debris before the purification
process is initiated. Typical unit operations available for performing the
clarification step include tangential-flow filtration [3,14,36], dead-end filtration
[37], and centrifugation [38]. Tangential-flow filtration is the most extensively
used method because it minimizes cell damage and maximizes effective membrane
surface use, flux, and membrane lifetime. It is readily scalable and can provide
high processing rates with good efficiency without adversely affecting the
cell viability. Critical operating parameters for optimizing the filtration condition
are transmembrane pressure, retentate flow rate, and permeate flux. High-shear
conditions should be avoided to minimize cell rupture that leads to increased levels
of contaminating cellular proteins and nucleic acids. The resulting increase in
cell debris under such conditions also reduces the capacity of downstream sterile
filters. Conventional dead-end filters are designed for sterile filtration of relatively
clean fluids. The high amount of cells and debris in a typical cell culture broth
makes the dead-end filtration approach impractical in terms of equipment size and
filtration cost. A viable alternative is the use of depth filters that typically have
graded porosity, allowing substantially higher processing capacities. An in-line
sterile filtration step is then used to eliminate the debris. Continuous centrifugation
offers scalable high processing rates. Its disadvantages include higher equipment
and maintenance costs. Typically, the clarification efficiency of centrifugation
is lower than that of the filtration operations because of the lower resolution
of particle densities compared to size differences. This leads to an increased burden
for downstream sterile filtration and additional efforts to remove process contaminants
such as DNA.
106 Cacciuttolo et al.
IV. DOWNSTREAM OPERATIONS
A. Design of Purification Processes
From the many options available for purification, process design should be based
on selecting among the multiple unit operations that maximize ease of purification,
product purity, and overall yield. In general, a simple stepwise purification
design utilizing orthogonal methods of purification with maximum compatibility
between steps is preferred. The use of orthogonal purification techniques is important
for the removal of process contaminants to trace levels and for robust viral
clearance. The number of product manipulations as well as the quantities and
number of buffers can be minimized by maximizing the compatibility of process
steps. This consideration should be exercised early in the development of the process,
for it may have a huge impact later on buffer-handling operations at large
scale. Initial steps using highly selective capture chromatography facilitate volume
reduction and effective removal of the most problematic process contaminants.
Effective intermediate and final polishing steps are necessary for the removal
of process contaminants to trace levels and virus inactivation and/or
removal. The formulation step is designed to produce the final bulk dosage form
of the product with appropriate concentration and long-term product stability.
Careful and effective optimization for all process steps is essential for successful
scale-up to manufacturing.
For purification, scale-up considerations are important even in the earliest
phases of development. It is important to avoid the use of purification techniques
of limited scale-up potential even for early clinical production, because thorough
justification of process changes and demonstration of biochemical comparability
are necessary prior to product licensure. For successful scale-up, it is important to
understand the critical parameters affecting the performance of each purification
step at each scale. Conversely, it is important to verify that the scaled-down process
is an accurate representation of the scaled-up process so that process validation
studies such as viral clearance and column lifetime studies can be performed
at the laboratory scale.
B. Chromatography
The majority of the processes currently used to manufacture biotechnology products
employ chromatography columns as the main tool for effective product recovery
and purification. The scale-up [39] and validation [40] of this vastly popular
unit operation is key for successful implementation of the overall production
strategy at large scale and eventual product approval for commercialization.
If an ion exchange step will be used as an initial capture chromatography
step, pH or conductivity adjustment of the conditioned medium might be necesary.
At large scale, conductivity adjustment can be accomplished by in-line dilu-
Scale-Up of Biotechnology-Derived Products 107
tion without increasing the number or volume of the vessels required. Some manufacturers
carry out a concentration and/or diafiltration for buffer exchange and
volume reduction prior to the capture chromatography step. In this case, whatever
time and effort saved in loading the initial capture chromatography must be
weighed against the time for the concentration/diafiltration, the time for cleaning
and preparation of ultrafiltration cartridges, as well as additional buffer preparation
time.
Many manufacturers prefer to use an initial capture affinity chromatography
step. The affinity gels are highly selective and generally require little or no manipulation
of a feedstream. Some possible disadvantages of using an initial affinity
column step are the expense of the affinity matrix and the fact that repetitive
exposure of the matrix to conditioned medium may require stringent cleaning procedures,
which may reduce the effective lifetime of the gel. The cost issue can be
obviated somewhat by using smaller columns and multiple cycles. However, this
will extend processing time and increase labor costs. For subsequent chromatography
steps, ion exchange frequently may follow or precede hydrophobic interaction
chromatography (HIC). The HIC product is often eluted at low salt concentrations,
which is compatible with the low conductivity necessary for binding to
ion exchange gels. Conversely, an ion exchange product is often eluted at high salt
conditions, which may provide conditions compatible with HIC chromatography.
C. Viral Clearance
Viral inactivation and/or removal steps are a critical part of the process design for
biotechnology products derived from mammalian cell culture systems. Regulatory
agencies are concerned with the presence of endogenous and/or adventitious
agents in the cell lines an/or raw materials employed to manufacture pharmaceutical
proteins from cell culture [41]. The best approach to ensure adequate viral
clearance is to have multiple orthogonal virus-removal steps and at least one
virus-inactivation step. Virus removal, demonstrated with spiking studies using
model viruses, should be carried out with a scaled-down version of the purification
process that accurately represents the process used at manufacturing scale. In
addition, it is recommended that studies include the use of typical critical operating
parameters for each step as well as conditions that represent a worst case for
virus removal. For instance, for process validation of chromatography steps extremes
of linear velocity, protein concentration, reduced bed height or contact
time, and total protein capacity should be tested. Although it is often difficult to
adequately quantitate viruses in various column fractions, it is important whenever
possible to characterize viral removal in the product fraction as well as in the
nonbound flowthrough, wash, and strip fractions. Viral-inactivation steps using
chemical or physical conditions such as low pH, heat, irradiation, and chemical
agents should be characterized by performing kinetic inactivation studies. For
108 Cacciuttolo et al.
these studies, typical and worst-case conditions should be evaluated. For example,
if a product is eluted with a low pH buffer, a manufacturer might consider holding
the product at the same low pH as the viral-inactivation step. However, because
the product has some inherent buffering capacity, the final pH value of the
eluted product may change based on the protein concentration or, as the process is
scaled up, the eluted product pH may shift slightly due to subtle modifications in
the collected-product peak. The low pH tested in viral-inactivation studies must
be based on the maximum-eluted-product pH, which may not be known prior to
scale-up. For these reasons, it may be preferable to define a separate inactivation
step in a single vessel with subsurface addition and mixing of the inactivating
agent to provide precise control of the hold time, temperature, and pH.
V. FACILITY DESIGN
Facility design is also an important consideration in process design and scale-up.
Although it is easy to design a process to fit into a new facility, retrofitting an existing
facility for commercial manufacture can be costly. Sometimes the design of
a process has to consider the constraints imposed by an existing plant. In this case,
it is helpful to create a spreadsheet template for scale-up calculations to test and
evaluate the operation of the process in an existing environment with minimal
changes in existing equipment. Examples of such calculations are found for buffer
preparation, bioreactor and harvest operations, filtration operations, product and
buffer tanks, chromatography controllers, hard piping, and flow patterns. For example,
if existing product tanks are too small, chromatography column sizes can
be reduced and multiple cycles need to be performed. However, the long-term
costs associated with smaller chromatography columns and extended processing
times must be weighed against the initial costs of purchasing and installing larger
vessels or columns. The operational segregation of pre- and postviral clearance
steps may also require redesign of a facility and should be considered in the early
stages of process development.
A. Examples of Process Scale-Up
Once process design is complete and each of the process steps characterized, the
process is ready for scale-up to pilot or manufacturing scale. A spreadsheet template
for scale-up calculations is important and provides a mass balance of buffer
volumes, column volumes, priming volumes, product volumes, and waste volumes
as well as the tank size and column size. Product volumes can be expressed
relative to column volume or can be calculated from a constant concentration, depending
on the process step. In addition, starting volumes and titers of conditioned
medium as well as step yields and gel or membrane capacity are necessary to cal-
Scale-Up of Biotechnology-Derived Products 109
culate bed volumes and membrane surface area for the purification steps. A worstcase
approach assuming maximum step yields, product volume, and starting titer
is recommended, except for cases where underloading a column or a membrane
step is problematic.
Some general observations were made during the scale-up of a process using
microfiltration operations at the bioreactor stage [14]. One was that when using
tangential flow filtration, the ratio between retentate flow and permeate flow
has to be at least 5 to 1 in order to avoid the effect know as “dead-end filtration.”
This finding clearly indicated the need for an additional control on the permeate
flow that was not necessary in the small-scale experiments. Another observation
was that the ratio of filtration area (FA) to process volume (PV) usually employed
as a rule for scale-up may actually decrease as the scale of operation increases.
This is due to a more efficient utilization of the membrane surface, with the consequent
savings in filtration equipment.
It is also important to recognize the interaction between the scaling parameters.
Simply multiplying an existing process by the next scale-up factor
may lead to errors. For example, if a single 10-inch filter is used at 66% capacity
in the pilot scale, a fourfold increase in scale does not require four 10-inch
filters. Rather, three 10-inch filters or a single 30-inch filter can be used at 88%
capacity.
Another example demonstrating the interaction between scaling factors
comes from chromatography operation. As the process scale increases, the available
column volume must increase, either by packing larger columns or by running
multiple cycles. Columns are generally available with 30-, 45-, 60-, and 100-
cm diameters. It is necessary to select a column diameter when doing calculations
and then determine the resulting bed height based on the required volume. Using
a narrower-diameter column will result in increased processing time because generally
the linear velocity is held constant during scale-up. The alternative is to use
a shorter, wider column, but there is a minimum bed height that can be used at
large scales, generally 10 cm or larger. The use of a larger-diameter column will
increase flow rate and decrease operating time. However, the use of a wider column
may necessitate packing a column of larger volume than necessary from the
given gel capacity. The larger-volume column means that greater volumes of
buffer are needed and that product volumes will likely increase. It is important to
determine if tanks are available for the additional volumes of product and buffers.
In this example (Table 2), as the effective gel capacity decreases, the processing
time decreases and the buffer volumes increase.
For buffer exchange or formulation steps using ultrafiltration, membrane
capacity and processing time are closely linked. In contrast with the previous example,
focusing on chromatography capacity, as membrane capacity decreases
there is no dramatic increase in buffer usage. In general, decreasing the mem-
110 Cacciuttolo et al.
brane capacity reduces processing time, because the gel layer is thinner and has
less impact on permeate flux. However, as the membrane surface area increases,
a larger size ultrafiltration system is required and larger pumps are required to
maintain the recirculation flux. For a highly concentrated product, a large system
hold-up volume increases the potential for product loss. For concentration/
diafiltration operations, scale-up may require reoptimization of process parameters,
especially if membrane capacities are changed. However, every effort
should be made to keep recirculation flux constant with similar inlet and outlet
pressures.
Scale-Up of Biotechnology-Derived Products 111
Table 2 Sample Scale-Up Calculation for a Chromatography Step
Units
Assumptions:
Titer 0.5 g/L
Harvest volume 2000 L
Total product 1000 g
Maximum gel capacity 20.0 g/L gel
Minimum gel volume 50 L
Minimum bed height 10.0 cm
Linear velocity 300 cm/hr
Case 1 Case 2
Column diameter (cm) 60 100
Calculated bed height (cm) 17.7 6.4
Actual bed height (cm) 17.7 10.0
Actual column volume (L) 50 79
Actual capacity used (g/L gel) 20.0 12.7
Flow rate (L/min) 14.1 39.3
Solution Solution Solution Solution
usage volume Duration usage volume Duration
Operation (L/L) (L) (min) (L/L) (L) (min)
Equilibration 5 250 17.7 5 393 10.0
Load 2000 141.5 2000 50.9
Post-load equilibration 3 150 10.6 3 236 6.0
Wash 5 250 17.7 5 393 10.0
Elution 6 300 21.2 6 471 12.0
Sanitization 3 150 10.6 3 236 6.0
Storage 3 3
Grand totals 3250 229.9 3964 100.9
6.0 236 10.6 150
VI. SUMMARY
Once the scale-up factors have been established, the scale-up of the process from
pilot to manufacturing scale should be relatively straightforward. There are, of
course, important considerations for working in a commercial manufacturing environment
that have not been addressed in this chapter. These include, but are
not limited to, cGMP and regulatory issues, segregation of pre- and postviral
clearance steps, flow of material and personnel, waste handling, and environmental
monitoring [27,42]. In order to scale up and transfer a process successfully
from laboratory scale to pilot scale and multiple commercial manufacturing
scales, a thorough understanding of the integration of scale factors, facility
design, equipment design, and process performance is necessary. A scale-up
template spreadsheet can be a useful tool to provide the critical integration of
multiple factors.
REFERENCES
1. A. S. Lubiniecki, J. H. Lupker. Purified protein products of rDNA technology expressed
in animal cell culture. Biologicals 22:161–169, 1994.
2. R. Werner, F. Walz, W. Noe, A. Konrad. Safety and economic aspects of continuous
mammalian cell culture. J Biotechnol 22:51, 1992.
3. R. Van Reis, L. C. Leonard, C. C. Hsu, S. E. Builder. Industrial-scale harvest of proteins
from mammalian cell culture by tangential flow filtration. Biotechnol Bioeng
38:413–422, 1991.
4. M. S. Peters, K. D. Timmerhaus. Plant design and economics for chemical engineers.
4th ed. New York: McGraw-Hill, 1991.
5. J. B. Griffiths. Animal cell culture processes—batch or continuous? J Biotechnol
22:21–30, 1992.
6. J. E. Bailey, D. F. Ollis. Biochemical Engineering Fundamentals. 2nd ed. New York:
McGraw-Hill, 1986.
7. A. S. Lubiniecki. Historial reflections on cell culture engineering. Cytotechnology
28:139–145, 1998.
8. M. Moo-Young. Comprehensive Biotechnology: The Principles, Applications and
Regulations of Biotechnology in Industry, Agriculture, and Medicine. 1st ed. Vols.
1– 4. New York: Pergamon Press, 1985.
9. R. Kimura, W. M. Miller. Effects of elevated pCO2 and/or osmolality on the growth
and recombinant tPA production of CHO cells. Biotechnol Bioeng 52:152–160,
1996.
10. F. Bavarian, L. S. Fan, J. J. Chalmers. Microscopic visualization of insect cell-bubble
interactions. I: Rising bubbles, air–medium interface, and the foam layer.
Biotechnol Bioeng 7:140 –150, 1991.
11. E. T. Papoutsakis. Fluid-mechanical damage of animal cells in bioreactors. Trends
Biotechnol 9:427–437, 1991.
112 Cacciuttolo et al.
12. A. Michaels, S. Matson. Membranes in biotechnology: state of the art. Desalination
53:231–258, 1985.
13. C. L. Cooney. Upstream and downstream processing. In: M Moo-Young, ed. Comprehensive
Biotechnology: The Principles, Applications and Regulations of Biotechnology
in Industry, Agriculture, and Medicine. Sec. 2. New York: Pergamon Press,
1985, pp 347–438.
14. M. A. Cacciuttolo, M. Patchan, K. Harrig, E. Allikmets, E. I. Tsao. Development of
a high-yield process for the production of an IgM by a murine hybridoma. Biopharmaceuticals
(April 1998), p. 49.
15. J. O’Grady, A. Losikoff, J. Poiley, D. Fickett, C. Oliver. Virus removal studies using
nanofiltration membranes. Dev Biol Stand 88:319–326, 1996.
16. F. D. A. Guidelines on Sterile Drug Products Produced by Aseptic Processing. June
1987.
17. H. A. C. Axelsson. Centrifugation. In: M Moo-Young, ed. Comprehensive Biotechnology:
The Principles, Applications and Regulations of Biotechnology in Industry,
Agriculture, and Medicine. Vol. 2. New York: Pergamon Press, 1985, Chap. 21.
18. M. Zlokarnik. Dimensional analysis, scale-up. In: MC Flickinger SW Drew, eds. Encyclopedia
of Bioprocess Technology: Fermentation, BioCatalysis, and Bioseparation.
New York: Wiley, 1999, pp 840–861.
19. J. Hua, L. E. Erickson, T.-Y. Yiin, L. A. Glasgow. A review of the effects of shear and
interfacial phenomena on cell viability. Crit Rev Biotechnol 13(4):305–328, 1993.
20. J. Tramper, K. D. de Gooijer, J. M. Vlak. Scale-up considerations and bioreactor development
for animal cell cultivation. Bioprocess Technol 17:139–177, 1993.
21. B. Griffiths, D. Looby. Scale-up of suspension and anchorage-dependent animal
cells. Methods Mol Biol 75:59–75, 1997.
22. K. Ray. Validation of a novel process for large-scale production of powdered media:
evaluation of blend uniformity. Presented at the Raw Materials and Contract Services
Conference (Williamsburg Bioprocessing Foundation), St. Louis, MO, May 19–21,
1999.
23. D. W. Jayme, D. M. Disorbo, J. M. Kubiak, R. M. Fike. In: H Murakami, ed. Animal
Cell Technology: Basic and Applied Aspects. Vol. 4. New York: Kluwer 1992, pp
143–148.
24. D. W. Jayme, R. M. Fike, J. M. Kubiak, C. R. Nash, P. J. Price. In: S Kaminogawa,
ed. Animal Cell Technology: Basic and Applied Aspects. Vol. 5. New York: Kluwer,
1993. pp 215–222.
25. D. W. Jayme, J. M. Kubiak, P. J. Price. In: T. Kobayashi., Y. Kitagawa., K. Okumura.,
ed. Animal Cell Technology: Basic and Applied Aspects. Vol. 6. New York:
Kluwer, 1994, pp 383–388.
26. V. Singh. Wave Bioreactor™—scalable cell culture for 100 ml to 500 liters. Genetic
Engineering News, April 1999.
27. H. B. Reisman. Problems in scale-up of biotechnology production processes. Crit Rev
Biotechnol 13(3):195–253, 1993.
28. D. E. Leng. Succeed at scale-up. Chem Eng Prog (June 1991), pp. 23–31.
29. J. G. Aunins, H. J. Henzler. Aeration in cell culture bioreactors. In: GN
Stephanopolous, HJ Rehm, G Reed, eds. Biotechnology Vol. 3, Bioprocessing. 2nd
ed. Weinheim, Germany: VCH, 1993.
Scale-Up of Biotechnology-Derived Products 113
30. J. G. Aunins, K. Glazomitsky, B. C. Buckland. Aeration in pilot-scale vessels for animal
cell culture. Presented at the AIChE Annual Meeting, Los Angeles, CA, Nov.
17–21, 1991.
31. R. Taticek, S. Peterson, K. Konstantinov, D. Naveh. Effect of dissolved carbon dioxide
and bicarbonate on mammalian cell metabolism and recombinant protein productivity
in high-density perfusion culture. Presented at Cell Culture Engineering VI
Conference, San Diego, CA, Feb. 7–12, 1998.
32. J. Tramper. Oxygen gradients in animal-cell bioreactors. Animal Cell Technol
883–891, 1995.
33. Fluid-mechanical damage of animal cells in bioreactors. Trends Biotechnol
9:427–437, 1990.
34. K. Kunas, E. T. Papoutsakis. Damage mechanisms of suspended animal cells in agitated
bioreactors with and without bubble entrainment. Biotechnol Bioeng
36:476–483, 1990.
35. Y. M. Deo, M. D. Mahadevan, R. Fuchs. Practical considerations in operation and
scale-up of spin-filter-based bioreactors for monoclonal antibody production.
Biotechnol Prog 12:57–64, 1996.
36. B. Maiorella, G. Dorin, A. Carion, D. Harano D. Crossflow microfiltration of animal
cells. Biotechnol Bioeng 37:121–126, 1990.
37. D. Brose, S. Cates, A. Hutchinson. Studies on the scale-up of microfiltration membrane
devices. PDA J Pharmac Sci Technol 48(4):184–188, 1994.
38. R. Dream. Centrifugation and its application in the biotechnology industry. Pharmaceut
Eng (Nov./Dec., 1992), pp 44–52.
39. F. G. Lode, A. Rosenfeld, Q. S. Yuan, T. W. Root, EN Lightfoot. Refining the scaleup
of chromatographic separations. J Chromatography 796:3–14, 1998.
40. H. L. Levine, S. J. Tarnoski. Industry perspective on the validation of column-based
separation processes for the purification of proteins. PDA J Pharmac Sci Technol
46(3):87–97, 1992.
41. J. K. Walter, W. Werz, W. Berthold. Process-scale considerations in evaluation studies
and scale-up. Dev Biol Stand 88:99–108, 1996.
42. C. Pepper, M. Patel, H. Hartounian. CGMP pharmaceutical scale-up. Part 4: installation,
commissioning, development. BioPharm (Feb. 2000), pp. 28–34.
114 Cacciuttolo et al.
5 (1)
Batch Size Increase in Dry Blending
and Mixing
Albert W. Alexander and Fernando J. Muzzio
Rutgers University, Piscataway, New Jersey
I. BACKGROUND
In the manufacture of many pharmaceutical products (especially tablets and capsules),
dry particle blending is often a critical step that has a direct impact on content
uniformity. Tumbling blenders remain the most common means for mixing
granular constituents in the pharmaceutical industry. Tumbling blenders are hollow
containers attached to a rotating shaft; the vessel is partially loaded with the
materials to be mixed and rotated for some number of revolutions. The major advantages
of tumbling blenders are large capacities, low shear stresses, and ease of
cleaning. These blenders come in a wide variety of geometries and sizes, from laboratory
scale (16 qt) to full-size production models (500 ft3). A sampling of
common tumbling blender geometries include the V-blender (also called the twinshell
blender), the double cone, the in-bin blender, and the rotating cylinder.
There are currently no mathematical techniques to predict blending behavior
of granular components without prior experimental work. Therefore, blending
studies start with a small-scale, try-it-and-see approach. The first portion of this
chapter is concerned with the following typical problem: a 5-ft3-capacity tumble
blender filled to 50% of capacity and run at 15 rpm for 15 minutes produces the
desired mixture homogeneity. What conditions should be used to duplicate these
results in a 25-ft3 blender? The following questions might arise.
1. What rotation rate should be used?
2. Should filling level be the same?
3. How long should the blender be operated?
4. Are variations to the blender geometry between scales acceptable?
115
Unfortunately, there is no generally accepted method for approaching this problem;
therefore, ad hoc approaches tend to be the rule rather than the exception.
Further complicating the issue is that rotation rates for typical commercially available
equipment are often fixed, obviating question 1 and suggesting that, under
such conditions, true dynamic or kinematic scale-up may not be possible.
II. GENERAL MIXING GUIDELINES
A. Defining Mixedness
Before specifically addressing scale-up of tumbling blenders, this section discusses
some general guidelines that cover the current understanding of the important
issues in granular blending. The final objective of any granular mixing process
is to produce a homogeneous blend. But even determining mixture
composition throughout the blend is a difficulty for granular systems. As yet, no
reliable techniques for on-line measuring of composition have been developed;
hence, granular mixtures are usually quantified by removing samples from the
mixture. To determine blending behavior over time, the blender is stopped at fixed
intervals for sampling; the process of interrupting the blend cycle and repeated
sampling may change the state of the blend. Once samples have been collected,
the mean value and sample variance are determined and then often used in a mixing
index. Many mixing indices are available; however, there is no “general mixing
index,” so the choice of index is left to the individual investigator [1]. Once a
measure of mixedness has been defined, it is then tracked over time until suitable
homogeneity is achieved. Ideally, this minimum level of variance would stay relatively
constant over a sufficiently long time. This procedure is simple in concept,
but many problems have been associated with characterization of granular mixtures
[2].
One dangerous assumption is that a small number of samples can sufficiently
characterize variability throughout the blend. Furthermore, sample size
can have a large impact on apparent variability. Samples that are too small can
show exaggerated variation, while too large a sample can blur concentration gradients.
Unlike miscible fluids, which, through the action of diffusion are continually
mixing on a microscale, granular blends mix only when energy is input to the
system. Hence, it is important that a sufficient number of samples be taken representing
a large cross section of the blender volume.
Another concern is assuming that standard sampling techniques retrieve
samples that are truly representative of local concentration at a given location.
Thief probes remain the most commonly employed instrument for data gathering.
These instruments have been demonstrated to sometimes induce large sampling
errors coming from poor flow into the thief cavity or sample contamination (carryover
from other zones of the blender) during thief insertion [2]. Care and skep-
116 Alexander and Muzzio
ticism have to be employed whenever relying on thief probe data. One method to
assess blend uniformity and blend sampling error is given in PDA Technical Report
No. 25 [3].
Finally, the degree of mixedness at the end of a blending step is not always
a good indicator of the homogeneity to be expected in the final product. Many
granular mixtures can spontaneously segregate into regions of unlike composition
when perturbed by flow, vibration, shear, etc. Once a good blend is achieved, the
mixture still must be handled carefully to avoid any “de-mixing” that might occur.
Chapter 5(2) deals with the scaling of flow from blenders, bins, and hoppers and
the effect of segregation during handling.
B. Mixing Issues in Tumbling Blenders
Mixing in tumbling blenders takes place as the result of particle motions in a thin,
cascading layer at the surface of the material, while the remainder of the material
below rotates with the vessel as a rigid body. Current thinking describes the blending
process as taking place by three essentially independent mechanisms: convection,
dispersion, and shear. Convection causes large groups of particles to move in
the direction of flow (orthogonal to the axis of rotation), the result of vessel rotation.
Dispersion is the random motion of particles as a result of collisions or interparticle
motion, usually orthogonal to the direction of flow (parallel to the axis
of rotation). Shear separates particles that have joined due to agglomeration or cohesion
and requires high forces. While all mechanisms are active to some extent
in any blender, tumbling blenders impart very little shear, unless an intensifier bar
(I-bar) or chopper blade is used (in some cases, high shear is detrimental to the active
ingredient and so is avoided). While these definitions are helpful from a conceptual
standpoint, blending does not take place as merely three independent, scalable
mechanisms. However, attentive planning of the blending operation can
emphasize or de-emphasize specific mechanisms and have significant impact on
mixing rate.
Most tumbling blenders are symmetrical in design; this symmetry can be the
greatest impediment to achieving a homogeneous mixture. The mixing rate often
becomes limited by the amount of material that can cross from one side of the
symmetry plane to the other [4–8]. Some blender types have been built asymmetrically
(e.g., the slant cone, the offset V-blender), and show greater mixing proficiency.
Furthermore, by rocking the vessel as it rotates, mixing rate can also be
dramatically increased [9]. Asymmetry can be “induced” through intelligent
placement of baffles, and this approach has been successfully tested on smallscale
equipment [7,10–12] and used in the design of some commercial equipment.
But when equipment is symmetrical and baffles unavailable, careful attention
should be paid to the loading procedure, for this can have an enormous impact on
mixing rate.
Batch Size Increase in Dry Blending and Mixing 117
Nonsystematic loading of multiple ingredients will have a dramatic effect on
mixing rate if dispersion is the critical blending mechanism. For instance, in a Vblender,
it is preferable to load the vessel either through the exit valve or equally
into each shell. This ensures that there are near-equal amounts of all constituents in
each shell of the blender. Care must be taken when loading a minor (~1%) component
into the blender—adding a small amount early in the loading process could accidentally
send most of the material into one shell of the blender and substantially
slow the mixing process. Smaller blenders entail shorter dispersal distances necessary
for complete homogeneity and thus may not be as affected by highly asymmetrical
loading. As a final caution, the order of constituent addition can also have
significant effects on the degree of final homogeneity, especially if ordered mixing
(bonding of one component to another) can occur within the blend [13].
Intershell flow is the slowest step in a V-blender, because it is dispersive in
nature, while intrashell flow is convective. Both processes can be described by
similar mathematics, typically using an equation such as

2 
 AekN (1)
where 
2 is mixture variance, N is the number of revolutions, A is an unspecified
constant, and k is the rate constant [6,14]. The rate constants for convective mixing,
however, are orders of magnitude greater than for dispersive mixing. Thus,
unequal loading across the symmetry plane places emphasis on dispersive mixing
and is comparatively slow compared to top-to-bottom loading, which favors convective
mixing.
C. Process Parameters
When discussing tumbling blender scale-up, one parameter consideration that
arises is whether rotation rate should change with variations in size. Previous studies
on laboratory-scale V-blenders and double cones have shown that, when far
from the critical speed of the blender, the rotation rate does not have strong effects
on the mixing rate [6,7] (the critical speed is the speed at which tangential acceleration
due to rotation matches the acceleration due to gravity). These same studies
showed that the number of revolutions was the most important parameter governing
the mixing rate. Equation (1) was derived by assuming that the mixture
went through a specific incremental increase in mixedness with each revolution
(either by dispersion or by convection). While this approach has been shown to be
successful at modeling increases in mixture homogeneity, no scaling rules have
been determined for the rate constants that govern this equation, and this remains
an open question for further inquiry.
Given a geometrically similar blender and the same mixture composition, it
would seem obvious that the fill level should also be kept constant with changes
in scale. However, an increase in vessel size at the same fill level may correspond
118 Alexander and Muzzio
to a significant decrease in the relative volume of particles in the cascading layer
compared to the bulk—this could accompany a large decrease in mixing rate. It
has been shown in 1-pint V-blenders that running at 40% fill brings about a mixing
rate that is nearly three times faster than at 60% fill [6]. Thus, although fill
level should be kept constant for geometric similarity, it may be impossible to
match mixing rate per revolution across changes in scale if the depth of the flowing
layer is a critical parameter.
III. SCALE-UP APPROACHES
In the literature, the Froude number (Fr 
 (2R/g, where ( is the rotation rate, R
is the vessel radius, and g is the acceleration from gravity) is often suggested for
tumbling blender scale-up [15–18]. This relationship balances gravitational and
inertial forces and can be derived from the general equations of motion for a general
fluid. Unfortunately, no experimental data have been offered to support the
validity of this approach. Continuum mechanics may offer other dimensionless
groups, if a relationship between powder flow and powder stress can be determined.
However, Fr is derived from equations based on continuum mechanics,
whereas the scale of the physical system for blending of granular materials is on
the order of the mean free path of individual particles, which may invalidate the
continuum hypothesis. A less commonly recommended scaling strategy is to
match the tangential speed (wall speed) of the blender; however, this hypothesis
also remains untested (Patterson-Kelly, personal communication, 2000).
We now look at our general problem of scaling the 5-ft3 blender using Fr as
the scaling parameter: The requisites are to ensure geometric similarity (i.e., all
angles and ratios of lengths are kept constant) and to keep the total number of revolutions
constant. With geometric similarity, the 25-ft3 blender must look like a
photocopy enlargement of the 5-ft3 blender. In this case, the linear increase is 51/3,
or 71%. Also for geometric similarity, the fill level must remain the same. To
maintain the same Froude number, since R has increased by 71%, the rpm (()
must be reduced by a factor of (1.71)1/2 
 0.76, corresponding to 11.5 rpm. In
practice, since most blends are not particularly sensitive to blend speed and available
blenders are often of fixed speed, the speed closest to 11.5 rpm would be selected.
If the initial blend time were 15 minutes at 15 rpm, the total revolutions of
225 must be maintained with the 25-ft3 scale. Assuming 11.5 rpm were selected,
this would amount to a 19.5-minute blend time. Though this approach is convenient
and used often, it remains empirical.
Common violations of this approach that can immediately cause problems
include the attempt to scale from one geometry to another (e.g., V-blender to inbin
blender), changing fill level without concern to its effect, and keeping blending
time constant while changing blender speed.
Batch Size Increase in Dry Blending and Mixing 119
The lack of first-principle, reliable scale-up criteria can have major impacts
on development time and costs. Nonsystematic means of scale-up can often lead
to excessively long processing times and inefficient use of existing capacity. Long
processing times can lead to unwanted side effects, such as particle sintering, heat
buildup, attrition, and excessive agglomeration. The advantages to rigorous scaleup
include decreased process uncertainty, for we “know” what is going on. It also
cuts down on development time and on experimental failures because experiments
are done in a systemic manner based on science (not art).
IV. NEW APPROACH TO THE SCALE-UP PROBLEM IN
TUMBLING BLENDERS
Herein, we offer a first step toward the definition of rigorous scale-up rules for
tumbling blenders. We begin by proposing a set of variables that may control the
process. The driving force for flow in tumbling blenders is the acceleration from
gravity, which must be included in our analysis. Vessel size is obviously a critical
parameter, as is the rotation rate, which defines the energy input to the system.
These variables define the system parameters (i.e., the driving forces) but do not
cover the mixture response. In the case of Newtonian fluids, fluid viscosity connects
the driving force (pressure gradients, gravity, shear) to the fluid response
(velocity gradients). For granular mixtures, no similar parameter has been derived;
hence, we will define particle size and particle velocity as our “performance
variables.” Particle size plays a large role in determining mixing (or segregation)
rates because dispersion distance is expected to vary inversely with particle size.
For granular processes, individual particles drive bulk mixture behavior and we
have assumed particle velocity to be an important variable. Because all transport
and mixing phenomena are driven by the motions of individual particles, it is a priori
impossible to scale transport phenomena without first scaling the velocities of
individual particles. Although previous studies have indicated that rotation rate
(and, hence, probably particle velocities) does not affect mixing rate, these experiments
were done in very small blenders. It is conceivable that at larger scales,
these variables could become important. Given these assumptions, we can now
address the development of nondimensional scaling criteria.
A. Applying Rayleigh’s Method
Our hypothesized set of variables that is believed to govern particle dynamics in
tumbling blenders is shown in Table 1. Using these variables and the Rayleigh
method, we derive the following equation:
V 
 k(aRbdcge (2)
120 Alexander and Muzzio
Applying the rule of dimensional homogeneity and making c and e the unrestricted
constants leads to
V 
 k(12eR1cedcge (3)
To solve Eq. (3), a correlation relating particle velocities to vessel radius and rotation
rate is discussed in the forthcoming sections.
B. Correlating Particle Velocities to Vessel Rotation Rate
and Radius
In order to determine particle velocities, an empirical approach is taken. A digital
video camera was used to record the positions of individual particles on the flowing
surface in clear acrylic, rotating cylinders of 6.3-, 9.5-, 14.5-, and 24.8-cm diameter
filled to 50% of capacity. Experiments were performed using nearly
monodisperse 1.6-mm glass beads (Jaygo, Inc.) dyed for visualization. The displacement
of particles from one frame to the next was converted into velocities.
To calculate velocity, only the motion down the flowing layer was used, and all
cross-stream (i.e., dispersive) motion was ignored. Figure 1 shows an example of
the data obtained from a typical experiment. Moving top to bottom in the rotating
cylinder is equivalent to moving left to right on this graph (see Ref. 19 for details).
Figure 2 shows the mean cascading velocity versus distance down the granular
cascade for experiments run at the same tangential velocity. Despite a nearly
fourfold difference in diameter, the velocity data all fall on nearly the same curve
over the first 3 cm down the flowing layer. This agreement indicates that initial
particle accelerations may be nearly equivalent, regardless of vessel size. Scatter
in the experimental data shown in Figure 2 precludes direct calculation of accelerations,
so least-square polynomials were fit to the experimental data. By differentiating
the polynomial fit, we obtain an estimate of the downstream acceleration,
shown in Figure 3. Over the initial upper third [0 to (
1
3
)L] of the flowing
layer, the acceleration profiles for all cylinders are nearly identical, with only mi-
Batch Size Increase in Dry Blending and Mixing 121
Table 1 Variables Important to Scaling Particle Velocities in
Cylinders
Variable Symbol Dimensions
Particle velocity V L/T
Vessel rotation rate ( 1/T
Vessel radius R L
Acceleration from gravity g L/T2
Particle diameter d L
L 
 length; T 
 time.
122 Alexander and Muzzio
Figure 1 Typical velocity profile. Moving from top to bottom (O–L) in the rotating
cylinder (inset) is equivalent to moving left to right in the graph.
Figure 2 Velocity profiles for a series of experiments run at the same tangential velocity
(26.4 cm/sec) in cylinders with inner diameters of 6.3 cm (), 9.5 cm (), 14.4 cm (),
and 24.8 cm (), which correspond to rotation rates of 40 rpm, 26.5 rpm, 17.4 rpm, and
10.2 rpm, respectively.
nor variations in magnitude. Although the qualitative trend is the same for all
curves, the distance taken to reach zero acceleration is very different, nearly twothirds
of the vessel diameter in the 6.3-cm cylinder as opposed to only half the diameter
in the 24.8-cm cylinder.
In Figure 3, maximum accelerations are nearly equal, implying that tangential
velocity may be proportional to maximum acceleration. Maximum accelerations
were determined for all experiments; the results are plotted against the tangential
velocity in Figure 4. An approximate linear fit
amax 
 %  TV (4)
where TV is the tangential velocity (
 2R() and % 
 17 sec1, is seen relating
acceleration and tangential velocity for all cylinders and rotation rates. While the
data clearly display curvature, this linear fit is used as a first-order approximation
for scaling purposes.
In Figure 3, the distance to reach zero acceleration varies greatly among the
four different velocity profiles. This parameter, denoted 
, is quantitatively measured
as the distance at which the relative change in velocity drops below a preset
limit. However, by itself, the value of 
 has little meaning; it is the parameter 
/,
where  is the cylinder radius, that has a quantitative effect on the velocity profile
Batch Size Increase in Dry Blending and Mixing 123
Figure 3 Acceleration profiles for experiments run at the same tangential velocity (13.2
cm/sec); 
 marks the distance to reach 0 acceleration. The velocity profiles are shown in
Figure 2.
and maximum velocities. When all values of 
/ were compiled, a strong correlation
to rotation rate was noted. Because most pharmaceutical blenders are run at
low rotation rates, we restrict the remaining discussion to vessel rotation rates below
30 rpm. Figure 5 plots 
/ against3
(, showing a nearly linear relationship
below ~30 rpm. An equation for 
/ becomes

/ 
 3
(, (!30 (5)
where  
 0.37 sec1/3. Because 
/ determines the shape of the velocity profile,
experiments run at the same rotation rate should show qualitatively similar velocity
profiles, regardless of cylinder size.
C. Developing a Model
The simplest possible model for particle velocity relates velocity and distance
when acceleration is constant,
V2 
 V20
 2ax (6)
where V0 is the initial downstream velocity and x is the downstream coordinate.
Acceleration has been shown, though, to vary along the length of the flowing re-
124 Alexander and Muzzio
Figure 4 Plot of the maximum acceleration against the tangential velocity for all experiments;
a near-linear relationship is noted. Data are calculated from experiments in 6.3-cm-
(), 9.5-cm-(), 14.5-cm-(), and 24.8-cm-() diameter cylinders.
gion. Also, the distance to reach zero acceleration depends on the rotation rate. It
may be possible, however, to scale peak velocities using Eq. (6) subject to some
simplifying assumptions:
1. Particles emerge into the flowing layer with zero initial downstream velocity
(V0 
 0).
2. Peak acceleration is proportional to the tangential velocity (TV), Eq.
(4).
3. Particles accelerate over the distance 
.
4. Acceleration (a) is not constant over the distance 
, but the rate
of change in acceleration scales appropriately with the value of 

(i.e., a 
 amax?(x/
), where x is the distance down the cascade).
Using these assumptions and Eqs. (4), (5), and (6), a new relation for particle velocity
would be
V  R(2/32% (7)
Equation (7), which relates particle velocities to the rotation rate and the radius,
can be used as the basis for scaling particle velocities with changes in cylinder diameter
and rotation rate.
Batch Size Increase in Dry Blending and Mixing 125
Figure 5 The value of 
/ is plotted against the cube root of rotation rate, showing a linear
relationship.
126 Alexander and Muzzio
(a)
Figure 6 (a) Scaled velocity profiles for all experiments run between 10 and 30 rpm; (b)
unscaled profiles.
(b)
D. Returning to Dimensional Analysis
Equation (7) gives a relationship between velocity, rotation rate, and cylinder radius
that can be used to complete the dimensional analysis discussed earlier. Applying
dimensional homogeneity and solving leads to
V 
 kR(2/3 
g
d1/6
(8)
To test the scaling criteria suggested by Eq. (8), we will look at velocity profiles
between 10 and 30 rpm. Figure 6(a) shows the scaled velocity profiles (i.e., all
data are divided by using R(2/3 (g/d)1/6, and the distance down the cascade is divided
by the cylinder diameter) for experiments run between 10 and 30 rpm [the
unscaled data are shown in Figure 6(b)]. We see very good agreement in velocity
magnitudes across all rotation rates and cylinder sizes (which incorporate a 4
range in vessel radii and a 3 range in rotation rates). Equation (8) indicates that
particle size has an independent and measurable, though small, effect on particle
velocities, which is further discussed elsewhere [19].
Returning to our example of scaling from a 5-ft3 blender to a 25-ft3 blender,
again the relative change in length is 71%. This time, to scale surface velocities
using this approach, the blending speed (() must be reduced by a factor of
(1.71)3/2
0.45, corresponding to 6.7 rpm (assuming the particle diameter, d, remains
constant). Again, the total number of revolutions would remain constant at
225, for a blend time of 33.6 min.
V. TESTING VELOCITY SCALING CRITERIA
Experimental work has not validated the preceding scaling procedure with respect
to scale-up of blending processes. Since this approach also relies on empirical
work, this model should not be favored over other approaches currently in use,
though it may provide additional insight.
However, recent work has indicated that particle velocities may be critical
for determining segregation dynamics in double-cone blenders and V-blenders
[20,21]. Segregation occurs within the blender as particles begin to flow in regular,
defined patterns that differ according to their particle size. Experimental work
demonstrates how this occurs. In a 1.9-quart-capacity V-blender at fixed filling
(50%), incrementally changing rotation rate induced a transition between two segregation
patterns, as seen in Figure 7(a). At the lower rotation rate, the “small-out”
pattern forms; the essential feature of the “small-out” pattern is that the smaller red
particles dominate the outer regions of the blender while the larger yellow particles
are concentrated near the center. At a slightly higher rotation rate, the
“stripes” pattern forms; in this case, the small particles form a stripe near the mid-
Batch Size Increase in Dry Blending and Mixing 127
dle of each shell in the blender. Both patterns are symmetrical with respect to the
central vertical symmetry plane orthogonal to the axis of rotation.
To validate both the particle velocity hypothesis and our scaling criteria,
similar experiments were run in a number of different-capacity V-blenders. Vessel
dimensions are shown in Table 2, along with a schematic, shown in Figure 8.
128 Alexander and Muzzio
Figure 7 Changes in segregation pattern formation in the (a) 1.9-quart and (b) 12.9-quart
V-blenders.
Table 2 Vessel Dimensions
Nominal Vessel volume L R D
capacity (quarts) (cm) (cm) (cm) 
1 P 0.8 10.5 7.9 6.7 80)
1 Q 1.9 13.9 10.6 9.2 80)
4 Q 6.5 21.2 14.6 13.8 75)
8 Q 12.9 24.7 18.8 17.6 75)
16 Q 26.5 33 24.2 21.6 75)
(a)
(b)
All the vessels are constructed from clear plexiglass, enabling visual identification
of segregation patterns.
For these experiments, a binary mixture of sieved fractions of 150- to 250-
 (nominally 200-) and 710- to 840- (nominally 775-) glass beads was
used. A symmetrical initial condition (top-to-bottom loading) is implemented.
The blender is run at constant rotation rate; a segregation pattern was assumed to
be stable when it did not discernibly change for 100 revolutions. In many pharmaceutical
operations, the mixing time is on the order of 100–500 revolutions, and
experiments are run with regard to this timeframe.
The transition speeds (rotation rates) were determined for the change from
the “small-out” pattern to “stripes” at 50% filling for all the blenders listed in
Table 2 (Figure 7 shows results from the 1.9- and 12.9-quart blenders). As discussed
earlier, the most commonly accepted methods for scaling tumbling
blenders have used one of two parameters, either the Froude number (Fr) or the
tangential speed of the blender. Earlier, we derived R(2/3 (g/d)1/6 and showed that
it effectively scales particle velocities when the rotation rate is below 30 rpm. We
note that all three of these criteria indicate an inverse relationship between rotation
rate and blender size. Table 3 shows the parameter values at the transition ro-
Batch Size Increase in Dry Blending and Mixing 129
Figure 8 A sketch of the relevant dimensions for a V-blender; the actual values for the
five blenders used are shown in Table 2.
Table 3 Parameter Values at Transition rpm
Blender Transition Fr, (2R/g Tangential velocity
R(2/3 
g
d
1/6
size rotation rate ( 105) (R (cm/sec) (cm/sec)
1 P 9.5 20 7.9 9.9
1 Q 7.7 18 8.5 11.5
4 Q 3.5 5 5.4 9.4
8 Q 2.5 3 4.9 9.6
16 Q 1.7 2 4.3 9.6
tation rate for R(2/3 (g/d)1/6, Fr, and the tangential velocity. The R(2/3 (g/d)1/6 parameter
gives much better agreement than either Fr or tangential velocity; the relative
standard deviation for R(2/3 (g/d)1/6 is 8.5%, compared to 89% for Fr and
30% for tangential velocity.
VI. RECOMMENDATIONS AND CONCLUSIONS
The analysis of particle velocities provides a good first step toward the rigorous
development of scaling criteria for granular flow, but it is far from conclusive.
While particle velocities may control the development of segregation patterns in
small-capacity V-blenders, velocity may not be the most important dynamic variable
affecting the mixing rate. If we regard mixing and segregation as competing
processes, however, then knowing that one is velocity dependent and the other is
not could be significant. Earlier, we discussed that mixing rate shows little change
with rotation rate but large variation with changes in fill level. These results may
indicate that a proportionality factor such as (mass of contents in motion)/(total
mass) may be important for scaling the mixing process. It is important in granular
systems to first determine the dynamic variable that governs the process at hand
before determining scaling rules—the basic caveats that particle size, particle velocities,
flowing layer depth, and the relative amount of particles in motion may
all play a role in a given process, making it important to identify the crucial variables
before attempting scale-up.
A systematic, generalized approach for the scale-up of granular mixing devices
is still far from attainable. Clearly, more research is required both to test current
hypotheses and to generate new approaches to the problem. Still, we can offer
some simple guidelines that can help the practitioner wade through the
scale-up process.
1. Make sure that changes in scale have not changed the dominant mixing
mechanism in the blender (i.e., convective to dispersive). This can often
happen by introducing asymmetry in the loading conditions.
2. Number of revolutions is a key parameter, but rotation rates are largely
unimportant.
3. When performing scale-up tests, be sure to take enough samples to give
an “accurate” description of the mixture state in the vessel. Furthermore,
be wary of how you interpret your samples; know what the mixing
index means and what your confidence levels are.
4. One simple way to increase mixing rate is to decrease the fill level—
while this may be undesirable from a throughput point of view, decreased
fill level also reduces that probability that dead zones will form.
5. Addition of asymmetry into the vessel, either by design or the addition
of baffles, can have a tremendous impact on mixing rate.
130 Alexander and Muzzio
Until rigorous scale-up rules are determined, these cautionary rules are the
state of the art for now. We offer a first step toward rigorous scaling rules by scaling
particle surface velocities but caution that this work is only preliminary in nature.
The best advice is to be cautious—understand the physics behind the problem
and the statistics of the data collected. Remember that a fundamental
understanding of the issues is still limited and luck is unlikely to be on your side;
hence, frustrating trial and error is still likely (unfortunately) to be employed.
REFERENCES
1. Poux, M., et al. Powder mixing: Some practical rules applied to agitated systems.
Powder Technol. 68:213–234, 1991.
2. Muzzio, F. J., et al. Sampling practices in powder blending. Int. J. Pharm.
155:153–178, 1997.
3. Blend uniformity analysis: validation and in-process testing. Technical Report No.
25. J. Pharmaceu. Sci. Technol. 51(suppl):53, 1997.
4. Carstensen, J. T., and M. R. Patel. Blending of irregularly shaped particles. Powder
Technol. 17:273–282, 1977.
5. Adams, J., and A. Baker. An assessment of dry blending equipment. Trans. Institution
Chem. Engineers 34:91–107, 1956.
6. Brone, D., A. Alexander, and F. J. Muzzio. Quantitative characterization of mixing
of dry powders in V-blenders. AlChE J. 44(2):271–278, 1998.
7. Brone, D., and F. Muzzio. Enhanced mixing in double-cone blenders. Powder Technol.
110(3):179–189, 2000.
8. Wiedenbaum, S. S. Mixing of solids in a twin shell blender. Ceramic Age, pp. 39–43,
August 1963.
9. Wightman, C., and F. J. Muzzio. Mixing of granular material in a drum mixer undergoing
rotational and rocking mogions. I. Uniform particles. Powder Technol.
98:113–124, 1998.
10. Carley-Macauly, K. W., and M. B. Donald. The mixing of solids in tumbling mixers—
I. Chem. Eng. Sci. 17:493–506, 1962.
11. Carley-Macauly, K. W., and M. B. Donald. The mixing of solids in tumbling mixers—
II. Chem. Eng. Sci. 19:191–199, 1964.
12. Sethuraman, K. J., and G. S. Davies, Studies on solids mixing in a double-cone
blender. Powder Technol. 5:115–118, 1971.
13. Lacey, P. M. C. Developments in the theory of particulate mixing. J. Appl. Chem.,
pp. 257–268, May 4, 1954.
14. Sudah, O., D, Coffin-Beach, and F. J. Muzzio. Quantitative characterization of mixing
of free-flowing granular materials in tote(bin)-blenders. Powder Technol. (in
press), 2001.
15. Wang, R. H., and L. T. Fan. Methods for scaling-up tumbling mixers. Chem. Engineering
81(11):88–94, 1974.
16. Lloyd, P. J., P. C. M. Yeung, and D. C. Freshwater. The mixing and blending of powders.
J. Soc. Cosmetic Chemists 21:205–220, 1970.
Batch Size Increase in Dry Blending and Mixing 131
17. Roseman, B., and M. B. Donald. Mixing and de-mixing of solid particles: part 2: effect
of varying the operating conditions of a horizontal drum mixer. Brit. Chem. Engineering
7(1):823, 1962.
18. Wiedenbaum, S. S. Mixing of solids. In: T. B. Drew and J. W. Hoopes, eds. Advances
in Chemical Engineering. Academic Press: New York, 1958, p. 209–324.
19. Alexander, A. W., T. Shinbrot, and F. J. Muzzio. Scaling surface velocities in rotating
cylinders. (in press) 2001.
20. Alexander, A. W., T. Shinbrot, and F. J. Muzzio. Segregation patterns in V-blenders.
(in press) 2001.
21. Alexander, A. W., T. Shinbrot, and F. J. Muzzio. Granular segregation in the doublecone
blender: transitions and mechanisms. Phys. Fluids 13(3):2001.
132 Alexander and Muzzio
5 (2)
Powder Handling
James K. Prescott
Jenike & Johanson, Inc., Westford, Massachusetts
I. INTRODUCTION
The goal in any blending operation is to have a properly blended powder mixture
at the point in the process where it is needed, for example, during filling of the
tablet die. This is not at all the same as requiring that all constituent powders in a
blender be properly blended, since subsequent handling of a well-blended powder
can result in significant deblending due to segregation. Segregation is as much a
threat to product uniformity as poor or incomplete blending. An ability to control
particle segregation during powder handling and transfer is critical to producing a
uniform product. Understanding the flow behavior in bins and hoppers is a vital
necessity for understanding segregation tendencies. Further consideration must be
given to maintaining reliable flow of powder, since no flow or erratic flow can
slow production or stop a process altogether.
The balance of this chapter will focus on achieving the uniformity requirements
for the product, given a well-mixed blend has been achieved in the blender.
Typical processing steps will be reviewed. The major concerns with powder flow
through these steps will be illustrated, along with methods to determine the flow
behavior in these processes. The mechanisms of segregation and methods to identify
problems will be presented. Finally, with an understanding of these processes,
scaling issues will be discussed.
Upon first reading the balance of this chapter, the reader will undoubtedly
call into question why, for a chapter on blending, there is heavy emphasis on flow
behavior in bins or a discussion of flow properties. The author’s experience is that
many pharmaceutical companies are equally likely to have problems with both
producing a well-mixed blend and having an otherwise acceptable blend segregate
upon further handling. Further, many firms have sufficient knowledge to diagnose
133
and solve blending problems but lack understanding of powder flow behavior that
results in the content uniformity problem that they may be facing. Lastly, these
problems of no flow and segregation are less likely to occur at smaller scales and
often appear for the first time at the full-scale batch, long after clinical trials are
complete and the formulation and processing equipment are cast in stone.
II. REVIEW OF TYPICAL POWDER TRANSFER
PROCESSES
Powder that has been blended in a blender must be discharged for further processing.
Often, discharge is driven by gravity alone (such as out of a V-blender),
though powder may also be forced out of the blender by way of mechanical agitation
(e.g., a ribbon blender). The powder is often discharged into one or more
portable containers, such as bins or drums, though some form of conveying system,
such as vacuum transfer, may also be used. If drums are used, powder may
be hand-scooped from the drums into downstream equipment, or a hopper may be
placed on the drum, followed by inversion of the drum for gravity discharge. Powder
in bins is usually discharged by gravity alone. Powder then feeds into one or
more press hoppers, either directly or through a single or bifurcated chute, depending
on the press configuration. With many modern presses, powder is fed by
way of a feed frame or powder feeder from the press hopper into the die cavities.
Each of these transfer and handling steps is deceptively simple. Each of
these steps can have a dramatic effect on the product quality, even if no effect is
desired. Powder transfer should not be taken for granted and instead should be
considered a critical unit operation for which bins, chutes, and press hoppers are
major, design-critical pieces of equipment.
III. CONCERNS WITH POWDER-BLEND HANDLING
PROCESSES
There are two primary concerns with powder handling that cannot be overlooked
when scaling processes: achieving reliable flow and maintaining blend uniformity.
To address these issues when scaling processes, knowledge of how powders
flow and segregate is required.
A. How Powders Flow
A number of problems can develop as powder flows through equipment such as
bins, chutes, and press hoppers. If the powder has cohesive strength, an arch or
rathole may form. An arch is a stable obstruction that usually forms within the
134 Prescott
hopper section (i.e., converging portion of the bin) near the bin outlet. Such an
arch supports the rest of the bin’s contents, preventing discharge of the remaining
powder. A rathole is a stable pipe or vertical cavity that empties out above the bin
outlet. Powder remains in stagnant zones until an external force is applied to dislodge
it. Erratic flow is the result of the blend’s alternating between arching and
ratholing, while flooding or uncontrolled flow may occur if a rathole spontaneously
collapses. On the other hand, a deaerated bed of fine powder may experience
flow rate limitations or no-flow conditions.
One of the most important factors in determining whether powder will discharge
reliably from bins or hoppers is establishing the flow pattern that will develop
as powder is discharged. The flow pattern is also critical in understanding
segregation behavior.
1. Flow Patterns
Two flow patterns can develop in a bin or hopper: funnel flow and mass flow. In
funnel flow (Fig. 1), an active flow channel forms above the outlet, which is surrounded
by stagnant material. This is a first-in, last-out flow sequence. As the
level of powder decreases, stagnant powder may slough into the flow channel if
the material is sufficiently free flowing. If the powder is cohesive, a stable rathole
may remain.
In mass flow (Fig. 2), all of the powder is in motion whenever any is withdrawn.
Powder flow occurs throughout the bin, including at the walls. Mass flow
provides a first-in, first-out flow sequence, eliminates stagnant powder, provides
Powder Handling 135
Figure 1 Funnel flow behavior in a bin.
a steady discharge with a consistent bulk density, and provides a flow that is uniform
and well controlled.
Requirements for achieving mass flow include sizing the outlet large enough
to prevent arch formation and ensuring the hopper walls are steep and smooth
enough to allow flow along them. Several flow properties are relevant to making
such predictions. These properties are based on a continuum theory of powder behavior—
namely, that powder behavior can be described as a gross phenomenon
without describing the interaction of individual particles. The application of this
theory using these properties has been proven over the last 40 years in thousands
of installations handling the full spectrum of powders used in industry [1].
2. Flow Properties
In order to select, design, retrofit, or scale-up powder handling equipment, knowledge
of the range of flow properties for all of the powders to be handled is critical.
Formulators can also use these properties during product development to predict
flow behavior in existing equipment. Though there are many tests that
measure “flowability,” it is important to measure flow properties relevant to the
flow of equipment in the actual process [2]. The flow properties of interest to those
involved with scale-up of processes include cohesive strength, wall friction, and
compressibility.
136 Prescott
Figure 2 Mass flow behavior in a bin; all material is moving during discharge.
a. Cohesive Strength. The consolidation of powder may result in arching
and ratholing within transfer equipment. These behaviors are related to the cohesive
strength of the powder, which is a function of the applied consolidation
pressure. Cohesive strength of a powder can be measured accurately by a direct
shear method. The most universally accepted method is described in ASTM standard
D 6128-97 [3].
By measuring the force required to shear a bed of powder that is under various
vertical loads, a relationship describing the cohesive strength of the powder
as a function of the consolidating pressure can be developed [4]. This relationship,
known as a flow function, FF, can be analyzed to determine the minimum outlet
diameters for bins to prevent arching and ratholing.
b. Wall Friction. Used in a continuum model, wall friction (friction of
powder sliding along a surface) is expressed as the wall friction angle , or coefficient
of sliding friction  [where  
 tangent ()]. This flow property is a
function of the powder handled and the wall surface in contact with it. The wall
friction angle can be measured by sliding a sample of powder in a test cell across
a stationary wall surface using a shear tester (Fig. 3) [4]. Wall friction can be used
to determine the hopper angles required to achieve mass flow. As the wall friction
angle increases, steeper hopper walls are needed for powder to flow along them.
c. Bulk Density. The bulk density of a given powder is not a single or
even a dual value, but varies as a function of the consolidating pressure applied to
it. The degree to which a powder compacts can be measured as a function of the
applied pressure [4]. For many materials, in a plot of the log of the bulk density,
, vs. log of the consolidating pressure, 
, a straight-line curve fit is obtained. The
resulting data can be used to accurately determine capacities for storage and transfer
equipment of any scale, as well as to provide information to evaluate wall friction
and feeder operation requirements.
If a flow problem is encountered in solids-handling equipment, at any scale,
the most likely reason is that equipment was not based on the flow properties of
the material handled. Often, when flow problems are encountered, the group re-
Powder Handling 137
Figure 3 Setup of test apparatus for a wall friction test.
sponsible for selecting handling equipment had little or no knowledge of flow patterns
or flow properties.
With an understanding of powder flow behavior and flow properties, segregation
can be considered. Ultimately, as material is handled, stored, and transferred,
the flow pattern that occurs will dictate how segregated the material will
be when fed to downstream equipment.
B. How Powders Segregate
Segregation is the unwanted separation of differing components of the blend . This
separation action is often referred to as a segregation mechanism. A second action
is required for segregation to manifest itself, specifically, the flow from the
blender to the creation of the dose. As material flows, the segregated zones may
be reclaimed in such a way as to be effectively reblended; or these zones may be
reclaimed one at a time, exacerbating segregation.
1. Segregation Mechanisms
Segregation can take place whenever forces are applied to the powder, for example,
by way of gravity, vibration, or air flow. These forces act differently on particles
with different physical characteristics, such as particle size, shape, and density.
Most commonly, particles separate as a result of particle size differences. The
result of segregation is that particles with different characteristics end up in different
zones within the processing equipment (e.g., bin).
Typical pharmaceutical blends separate from each other by three common
mechanisms: sifting/percolation, air entrapment (fluidization), and particle entrapment
(dusting).
a. Sifting/Percolation. Under appropriate conditions, fine particles tend
to sift or percolate through coarse particles. For segregation to occur by this mechanism
there must be a range of particle sizes (a ratio of 2:1 is often more than sufficient).
In addition, the mean particle size of the mixture must be sufficiently
large (greater than about 100 microns), the mixture must be relatively free flowing,
and there must be relative motion between particles. This last requirement is
very important, since without it even blends of ingredients that meet the first three
criteria will not segregate.
Relative motion can be induced, for example, as a pile is being formed, as
particles tumble and slide down a chute. The result of sifting/percolation segregation
is usually a side-to-side variation of particles. In the case of a bin, the smaller
particles will generally be concentrated under the fill point, with the coarse particles
concentrated at the outside of the pile (Fig. 4).
b. Air Entrainment (Fluidization). Handling of fine, aerated powders with
variations in particle size or particle density often results in a vertical striation pattern,
with the finer /lighter particles concentrated above larger/denser ones. This can
138 Prescott
occur, for example, during the filling of a bin. Whether or not the powder is pneumatically
conveyed into the container or simply free-falls through an air stream, it
may remain fluidized for an extended period after filling. In this fluidized state,
larger and/or denser particles tend to settle to the bottom (Fig. 5). Air counterflow
that occurs while filling an enclosed container can also cause these problems.
Powder Handling 139
Figure 4 Photo of sifting segregation after pile formation; light-colored fines remain in
the center, while darker, coarse particles concentrate at the perimeter.
Figure 5 Fluidization segregation can take place when a bed of aerated material settles,
driving fines to the top of the bin.
c. Particle Entrainment (Dusting). Similar to the air entrainment mechanism,
particle entrainment, or dusting segregation, occurs primarily with fine
powders that vary in particle size or density. Because of these variations, the
finer / lighter particles remain suspended in air longer than larger/denser ones. For
example, when powder drops into a container, the larger/denser particles will tend
to remain concentrated in an area near the incoming stream, whereas
smaller/ lighter particles will be transported into slower-moving or even stagnant
air (Fig. 6). This problem is particularly acute with pyramidal bins, as airborne
fines that settle toward the walls eventually slide to the valleys (corners) of the
bins. The powder in the corners of the bin discharges last, because of the funnel
flow pattern that usually develops. The resulting trend across one bin usually involves
a steady climb in the concentration of the finer components toward the end
of the run.
2. Identifying Segregation Problems
a. At the Bench Scale. Two basic bench-scale evaluations serve as relative
indicators of potential segregation problems. Neither approach provides a
quantitative result that correlates to what could be expected at a pilot or production
scale; however, they can be used as an indicator of the potential problems that
may lie ahead. One approach is to sieve the blend and then assay individual screen
cuts. If there is a wide variation of the assay across particle sizes, this serves as a
warning that content uniformity problems may occur. The concern with this ap-
140 Prescott
Figure 6 Dusting segregation can take place when airborne dust settles along the walls
of a bin.
proach is that the sieving process may separate particles in a more vigorous manner
than would be experienced in the actual process.
A second type of bench-scale evaluation is generically called a segregation
test. In this type of test, the blend is subjected to forces expected to be induced in
a “real” application. If the material is prone to segregation, these forces would segregate
the material into different zones of the test apparatus. Samples are then collected
and analyzed. Assay or particle size differences across different zones of
the tester serve as a warning that segregation problems may occur. The quality of
the information gleaned from these segregation tests is highly dependent upon the
test method (how well the tester reproduces the forces induced in the process) as
well as on avoiding sampling error (how samples from the segregation tester are
collected, handled, and analyzed).
b. At a Pilot or Production Scale. The effects of segregation are usually
recognized by comparing the standard deviation of samples of the final product
(dosage form) to those collected either within a blender or upon blender discharge.
The best way to diagnose problems is to take stratified, nested samples of powder
from within the blender of dosage forms through the production run [5]. Segregation
usually results in distinct trends across the run. To diagnose the problem,
these trends must be correlated with the flow sequence (from the blender to the
dosage formation) and the likely segregation mechanisms.
IV. SCALE EFFECTS
At the smaller scale, powder may be discharged from the blender into one or more
containers and then hand-scooped from these containers into a small press hopper.
Seldom is a batch left in storage for significant time after blending prior to compression.
At this scale, the forces induced on the particles during bulk transport
and handling are lower than full scale; further, distances across which the particles
can separate are smaller, thereby reducing the tendency for segregation to occur.
Hand-scooping obviates concerns about reliable discharge of powder from a
bin. So if this process at the small scale works well, what must be considered when
larger batch sizes are needed?
A. Analysis of Flow
In situations where a complete description of the physical behavior of a system is
unknown, scale-up approaches often involve the use of dimensionless groups, as
described in Chapter 1. Unlike flow behavior in a blender, the flow behavior of
powder through bins and hoppers can be predicted by a complete mathematical relationship.
In light of this, analysis of powder flow in a bin or hopper by dimen-
Powder Handling 141
sional relationships would be superfluous and, as will be illustrated, irrelevant,
since nondimensional groups cannot be derived.
1. Bin or Hopper Outlet Size
If gravity discharge is used, the minimum outlet size required to prevent arching
is dependent upon the flow pattern that occurs. Regardless of the flow pattern,
though, the outlet size is determined with the powder’s flow function, which is
measured by way of cohesive strength tests described earlier.
The outlet size required to overcome no-flow conditions depends highly on
the flow pattern that develops. If mass flow develops, the minimum outlet diameter,
Bc to overcome arching is [4]:
Bc 
 H()?crit / (1)
H() is a dimensionless function derived from first principles and is given by Figure
7 [for the complete derivation of H(), which is beyond the scope of this chapter,
see Ref. 4]. ?crit, with units of force/area, is the unconfined yield strength at the
intersection of the hopper flow factor (ff, a derived function based on powder flow
properties and the hopper angle) and the powder flow function (FF) (see Fig. 8).
Bulk density , with units of weight /volume, is the bulk density determined by
compressibility tests described earlier. This calculation yields a dimensional value
of Bc in units of length, which is scale independent. The opening size required is
142 Prescott
Figure 7 Plot showing derived function H() used in calculating arching potential in
mass flow bins.
not a function of the diameter or the height of the bin or the height-to-diameter ratio.
In other words, as a formulation is developed, one can run the shear tests described
earlier to determine the cohesive strength (flow function). This materialdependent
flow function, in conjunction with Eq. (1), will yield a minimum opening
(outlet) size in order to avoid arching in a mass flow bin. For example, this
opening size may be calculated to be 8 inches. This 8-inch diameter will be needed
whether the bin holds 10 kilos or 1000 kilos, regardless of the hopper or cylinder
height or diameter, and is scale independent. In this example, since an 8-inch-diameter
opening is required, feeding this material through a press hopper or similarly
small openings would pose real problems; it would be advisable to consider
reformulating the product to improve flowability.
If funnel flow develops instead of mass flow, the minimum outlet diameter
is given by the tendency for a stable rathole to occur, because this diameter is usually
larger than that required to overcome arching. In this case, the minimum outlet
diameter is:
Df 
 G(t)?c(
1)/ (2)
G(t) is also a derived function and is given by Figure 9. ?c(
1), the unconfined
yield strength of the material, is determined by the flow function (FF) at the actual
consolidating pressure 
1. The consolidation pressure 
1 is a function of the head
or height of powder above the outlet of the bin, as given by Janssen’s equation:

1 
 (R/k)(1  ekh/R) (3)
where R is the hydraulic radius (area /perimeter),  is the coefficient of friction
(tangent ), k is the ratio of horizontal to vertical pressures (often, 0.4 is used),
and h is the depth of the bed of powder within the bin.
Powder Handling 143
Figure 8 Sample flow function (FF) and flow factor (ff), showing Fcrit at their intersection.
This relationship in Eq. (2) cannot be reduced further, for the function
?c(
1) is highly material dependent.
2. Hopper Angle
Design charts describe which flow pattern would be expected to occur, dependent
on the hopper angle (c, as measured from vertical), wall friction angle
(), and internal friction () of the material being handled. An example of such
a design chart for a conical hopper is shown in Figure 10. For any combination
of  and c that lies in the mass flow region, mass flow is expected to occur;
if the combination lies in the funnel flow region, funnel flow is expected. The
uncertain region is an area where mass flow is expected to occur but represents
a 4° margin of safety on the design, to account for inevitable variations in test
results and surface finish.
The wall friction angle  is determined by wall friction tests, as described
earlier. The resulting wall yield locus (Fig. 11) is a function of the normal pressure
against the surface. For many combinations of wall surfaces and powders, the
wall friction angle changes depending on the normal pressure. When mass flow
develops, the solids pressure normal to the wall surface is given by the following
relationship:

n 
 (
/b)  B. (4)
Reference 4 provides charts giving (
/b). Assuming (
/b) and the bulk density
 are constant for a given powder and hopper (a reasonable assumption for a
144 Prescott
Figure 9 Plot showing derived function G(t) used in calculating ratholing potential in
funnel flow bins.
first approximation), the pressure normal to the wall is simply a linear function of
the span of the hopper, B, at any given point. Generally,  increases with decreasing
normal pressure, 
n. Therefore, the critical point is at the outlet of the
hopper; this is the smallest span B, with the correspondingly lowest normal pressure
to the wall, 
n. Hence, this point usually has the highest value of wall friction
for a given design, so long as the hopper interior surface finish and angle remain
constant above the outlet.
When considering scale effects, the implication of the foregoing analysis is
that the hopper angle required for mass flow is principally dependent on the out-
Powder Handling 145
Figure 11 Sample wall yield locus generated from wall friction test data.
Figure 10 Mass flow/funnel flow design chart for a conical hopper handling a bulk material
with a 40° effective angle of internal friction.
let size selected for the hopper under consideration. Note that the hopper angle required
for mass flow is not a function of the flow rate, the level of powder within
the hopper, or the diameter or height of the bin (as was also the case for minimum
outlet size).
Since the wall friction angle generally increases with lower normal pressures,
a steeper hopper is often required to achieve mass flow at smaller scales
(smaller outlets). For example, assume that a specific powder discharges in mass
flow from a bin with a certain outlet size. A second bin with an equal or larger outlet
size will also discharge in a mass flow pattern for this powder, provided that
the second bin has an identical hopper angle and surface finish. This is true regardless
of the actual size of either bin; only the outlet size needs to be considered.
The reverse, of using the same hopper angle with a bin with a smaller outlet, will
not always provide mass flow.
Of course, mass flow is highly dependent upon conditions below the hopper;
a throttled valve, a lip or other protrusion, or anything that can initiate a zone
of stagnant powder can convert any hopper into funnel flow, regardless of the hopper
angle or surface finish.
In scaling the flow behavior of powders, it is better to rely on first principles
and material flow properties, as opposed to reliance on observations or data
gleaned from the initial scale.
B. Scaling Segregation
Although basic concepts are understood, equations based on the physics of segregation
within bins are not well described. At best, a list of relevant variables can
be described, but such a list would likely be incomplete. Even the process of mathematically
describing a segregated powder bed beyond a “mixing index” is not
well defined. After all, in addition to quantifying the variability, the spatial arrangement
of the different zones is also significant. These limitations make even
simple dimensional analyses of segregation within bins impossible at this time. Instead,
for the pharmaceutical scientist seeking guidance during scaling, there is
heavy reliance on empirical considerations, experience, and judgment and on conservative
design approaches. This may also put the scientist into a “hope-and-see”
or reactionary position, an uncomfortable position given the repercussions of
product uniformity failure.
C. Avoiding Segregation
There are three basic approaches to defeat segregation [6]:
1. Modify the powder in a way to reduce its inherent tendency to segregate.
2. Modify the equipment to reduce forces that act to segregate the powder.
146 Prescott
3. Remedy segregation that takes place by reblending the powder during
subsequent transfer.
1. Modify the Powder to Reduce its Tendency to Segregate
There are several ways to change the powder to reduce its tendency to segregate.
One way is to change the particle size distribution of one or more of the components.
If the components have a similar particle size distribution, they will generally
have a lesser tendency to segregate. Another option is to change the particle
size such that the active segregation mechanism(s) become less dominant. For instance,
one way to reduce fluidization segregation is to make the particles sufficiently
large that the powder cannot fluidize. However, one must be careful in this
approach not to activate a new segregation mechanism.
Another option is to change the cohesiveness of the powder, such that the
particles in a bed of powder are less likely to move independent of each other. Increasing
the tendency of one component to adhere to another will also reduce segregation.
This is referred to as an ordered, adhesive, or structured blend. Granulation,
whether wet or dry, is also implemented to, among other reasons, reduce
segregation tendencies and improve powder flow. Bear in mind that, even if each
particle is chemically homogeneous (which is never absolutely the case, even with
granulations), segregation by particle size can result in variations that effect the
end product, such as tablet weight or hardness.
2. Change the Equipment to Reduce the Chance of
Segregation
Forces exerted on particles can induce segregation by many mechanisms. When
handling a material where segregation is a concern, the designer must minimize
these forces. Unfortunately, there are no scaling criteria available for guidance.
Worse yet, when scaling up, forces acting on the particles increase significantly,
as well as distances across which the particles can separate.
Here are some general guidelines:
Minimize transfer steps. With each transfer step and movement of the bin or
drum, the tendency for segregation increases. Ideally, the material would
discharge directly from the blender into the tablet press feed frame with
no additional handling. In-bin blending is as close to this as most firms
can practically obtain and is the best one can ask for—so long as a wellmixed
blend can be obtained within the bin in the first place.
Minimize drop height. Drop height serves to aerate the material, induce dust,
and increase momentum of the material as it hits the pile, increasing the
tendency for each of the three segregation mechanisms described earlier.
Control dust generation. Dust can be controlled by way of socks or sleeves,
to contain the material as it drops from the blender to the bin, for exam-
Powder Handling 147
ple. Some devices are commercially available specifically for this purpose.
Control fluidization of powder. Beware of processes, such as pneumatic
conveying, that increase the potential for the material to become aerated.
Restriction. Slowing the fill rate can reduce fluidization and dusting segregation
tendencies.
Venting. Air that is in an otherwise “empty” bin, for example, must be displaced
from the bin as powder fills it. If this air is forced through material
in the V-blender, perhaps sealed tight in the interest of containment,
this can induce fluidization segregation within the blender. To avoid this,
a separate pathway or vent line to allow the air to escape without moving
through the bed of material can reduce segregation.
Distributor. A deflector or distributor can spread the material stream as it
enters the bin. Instead of forming a single pile, the material is spread
evenly across the bin. This reduces sifting segregation but may cause additional
dust generation, making dusting segregation worse.
Proper hopper, Y-branch design. Press hoppers, transfer chutes, and Ybranches
must be designed correctly, to avoid stagnant material and to
minimize air counterflow.
Operate the valve correctly. Butterfly valves should be operated in full open
position, not throttled to restrict flow. Restricting flow will virtually ensure
a funnel flow pattern, which is usually detrimental to uniformity.
3. Change the Equipment to Provide Remixing
The concept of knowingly letting materials segregate and then counting on material
transfer to provide reblending is frankly quite scary to both pharmaceutical
scientists as well as regulatory personnel. Make no mistake, however, that this is
a better approach than letting materials segregate and doing nothing about it. Ignorance
is not bliss. The following concepts are not radical and, in fact, have been
used for many decades in the pharmaceutical and other industries.
Use mass flow. In a mass flow pattern, material that has segregated in a sideto-
side segregation pattern because of sifting or air entrainment will be reblended
during discharge. In most applications, this reblending is sufficient
to return the blend to its initial state of uniformity. However, a mass
flow pattern will not remedy a top-to-bottom segregation pattern, such as
caused by fluidization segregation; the top layer will discharge last. Note
that if top-to-bottom segregation occurs, funnel flow will simply result in
the top layer’s discharging at some point in the middle of the run, also not
providing any reblending.
Beware of velocity gradients. With mass flow, all the material is in motion
during discharge, but the velocity will vary. The material will always be
148 Prescott
somewhat slower at the walls than at the center of the bin (assuming a
symmetrical bin with a single outlet in the center). In critical applications,
the velocity profile could effect uniformity, with the material at the walls
discharging at a slightly slower rate than that from the center. While far
superior to a funnel flow pattern, a mass flow pattern with high velocity
gradients may not be desired. To remedy this, either a hopper that is designed
well into the mass flow regime is needed, or a flow-controlling insert,
such as a Binsert®, must be used. Velocity profiles, and their effect
on blending material, can be calculated a priori given the geometry of the
bin and measured flow properties. As a point of interest, velocity profiles
can be carefully controlled to force a bin to behave as a static blender,
used in other industrial applications.
The scientist seeking to scale blending processes must be well aware of the
limitations of the state of science in this area. Equal consideration must be given to
the state of the blend in the blender as well as the effects of subsequent handling.
REFERENCES
1. J. W. Carson and J. Marinelli. Characterize bulk solids to ensure smooth flow. Chem.
Eng. 101(4):78–90, 1994.
2. J. K. Prescott and R. A. Barnum. On powder flowability. Pharm. Technol.
24(10):60–236, 2000.
3. Standard Shear Testing Method for Bulk Solids Using the Jenike Shear Cell. ASTM
Standard D6128-97. American Society for Testing and Materials, 1998.
4. A. W. Jenike. Storage and flow of solids. Bulletin 123 of the Utah Engineering Experimental
Station 53(26), 1964, revised 1980.
5. J. K. Prescott and T. P. Garcia. A solid dosage and blend uniformity troubleshooting
diagram. Pharm. Technol. 25(3):68–88, 2001.
6. J. K. Prescott and R. J. Hossfeld. Maintaining product uniformity and uninterrupted
flow to direct-compression tableting presses. Pharm. Technol., 18(6):98–114, 1994.
Powder Handling 149

6
Scale-Up in the Field of Granulation
and Drying
Hans Leuenberger
University of Basel, Basel, Switzerland
I. INTRODUCTION
Today the production of pharmaceutical granules is still based on the batch concept.
In the early stage of the development of a solid dosage form the batch size
is small, e.g., for first clinical trials. In a later stage the size of the batch produced
in the pharmaceutical production department may be up to a 100 times
larger. Thus the scale-up process is an extremely important one. Unfortunately,
in many cases the variety of the equipment involved does not facilitate the task
of scale-up. During the scale-up process the quality of the granules may change.
A change in granule size distribution, final moisture content, friability, compressibility,
and compactibility of the granules may strongly influence the properties
of the final tablet, such as tablet hardness, tablet friability, disintegration
time, dissolution rate of the active substance, and aging of the tablet. In the following
sections, the scale-up process is analyzed, taking into account mathematical
considerations of scale-up theory [1], the search for scale-up invariants
[2–5], the establishment of in-process control methods [6–9], as well as the design
of a robust dosage form [10–13]. In this respect new concepts such as percolation
theory [13] play an important role. Finally, a new concept concerning a
quasi-continuous production line of granules is presented [14–20]. This concept
permits the production of small-scale batches for clinical trials and of production
batches using the same equipment. Thus scale-up problems can be avoided
in an elegant and cost-efficient way.
151
II. THEORETICAL CONSIDERATIONS
A. Principle of Similarity
1. Definition of Similarity and Dimensionless Groups
The important concept for scale-up is the principle of similarity [1–6]. When scaling
up any mixer/granulator (e.g., planetary mixer, high-speed mixer, pelletizing
dish) the following three types of similarity need to be considered: geometric,
kinematic, and dynamic. Two systems are geometrically similar when the ratio of
the linear dimensions of the small-scale and scaled-up system are constant. Two
systems of different size are kinematically similar when, in addition to the systems’
being geometrically similar, the ratio of velocities between corresponding
points in the two systems are equal. Two systems of different size are dynamically
similar when in addition to their being geometrically and kinematically similar,
the ratio of forces between corresponding points in the two systems are equal.
a. Similarity Criteria. There are two general methods of arriving at similarity
criteria:
1. When the differential equations, or in general the equations, that govern
the behavior of the system are known, they can be transformed into
dimensionless forms.
2. When the differential equations, or in general the equations, that govern
the behavior of a system are not known, such similarity criteria can
be derived by means of dimensional analysis.
Both methods yield dimensionless groups, which correspond to dimensionless
numbers [1], e.g.:
Reynolds number Re
Froude number Fr
Nusselt number Nu
Sherwood number Sh
Schmidt number Sc etc. [2]
The classical principle of similarity can then be expressed by an equation of the form
1 
 F(2, 3, . . .) (1)
This equation may be a mechanistic one (case A) or an empirical one (case B).
Case A: 1 
 e2, with the dimensionless groups:
1 

P
P
(
(
0
x)
) 
where
P(x) 
 pressure at level x
P(0) 
 pressure above sea level (x 
 0)
152 Leuenberger
2 
 
E
R
(
T
x) (2)
with
E(x) 
 Mgx
where
E(x) 
 molar potential energy
M 
 molecular weight
g 
 gravitational accelaration
x 
 height above sea level
RT 
 molar kinetic energy
Case B:
1 
 a(2)b  (3)c (3)
The unknown parameters a, b, c are usually determined by nonlinear regression
calculus.
2. Buckingham’s Theorem
For a correct dimensional analysis it is necessary to consider Buckingham’s theorem,
which may be stated as follows [3,4]:
1. The solution to every dimensionally homogeneous physical equation
has the form
F(1, 2, 3 . . .) 
 0
in which 1, 2, 3 . . . represent a complete set of dimensionless groups of the
variables and the dimensional constants of the equation.
2. If an equation contains n separate variables and dimensional constants
and these are given dimensional formulas in terms of m primary quantities
(dimensions), the number of dimensionless groups in a complete
set is (n  m).
III. SCALE-UP AND MONITORING OF THE WET
GRANULATION PROCESS
A. Dimensionless Groups
Because the behavior of the wet granulation process cannot yet be described adequately
by mathematical equations, the dimensionless groups have to be deter-
Scale-Up in Granulation and Drying 153
mined by a dimensional analysis. For this reason the following idealized behavior
of the granulation process in the high-speed mixer is assumed:
The particles are fluidized.
The interacting particles have similar physical properties.
There is only a short-range particle–particle interaction.
There is no system property equivalent to viscosity, i.e., (1) there are no
long-range particle–particle interactions and (2) the viscosity of the dispersion
medium air is negligible.
According to Buckingham’s theorem, the following dimensionless groups
can be identified:
1 

r5'
P
3
 Power number
2 
 V
q

t
Specific amount of granulation liquid
3 
 V
V
* 
Fraction of volume loaded with particles
4 
 
r'
g
2
 Froude number (centrifugal/gravitational energy)
5 
 d
r
 Geometric number (ratio of characteristic lengths)
where
P 
 Power consumption
r 
 Radius of the rotating blade (first characteristic length of the mixer)
' 
 Angular velocity
 
 Specific density of the particles
q 
 Mass (kg) of granulating liquid added per unit time
t 
 Process time
V 
 Volume loaded with particles
V* 
 Total volume of the vessel (mixer unit)
g 
 Gravitational acceleration
d 
 Diameter of the vessel (second characteristic length of the mixer)
In principle the following scale-up equation can be established:
1 
 a(2)b  (3)c  (4)d  (5)e (4)
154 Leuenberger
In general, however, it may not be the primary goal to know exactly the empirical
parameters a, b, c, d, e of the process under investigation, but to check or monitor
pragmatically the behavior of the dimensionless groups (process variables, dimensionless
constant) in the small- and large-scale equipment. The ultimate goal
would be to identify scale-up invariants.
B. Experimental Evidence for Scale-Up Invariables
In the case of the wet granulation process in a mixer /kneader, the granulation process
can easily be monitored by the determination of the power consumption [6–9]
(Fig. 1).
Scale-Up in Granulation and Drying 155
Figure 1 Block diagram of measuring equipment.
The typical power profile consists of five different phases (Fig. 2). Usable
granulates can be produced in a conventional way only within the plateau region
S3–S4 according to the nomenclature in Figure 2. As Figure 3 indicates, changing
the type of mixer has only a slight effect on the phases of the kneading process.
However, the actual power consumption of mixers of different type differs greatly
for a given granulate composition.
The important point now is that the power consumption profile as defined
by the parameters S3, S4, S5 is independent of the batch size. For this investigation,
mixers of the planetary type (Dominici, Glen, Molteni) were used. The batch size
ranged from 3.75 kg up to 60 kg. To obtain precise scale-up measurements, the excipients
used belonged to identical lots of primary material (10% (W/W) corn
starch, 4% (W/W) polyvinylpyrrolidone as binder, and 86% (W/W) lactose). As
can be seen from Figure 4, the amount of granulating liquid is linearly dependent
on the batch size. During the scale-up exercise the rate of addition of the granulation
liquid was enhanced in proportion to the larger batch size. Thus the power
profile, which was plotted on the chart recorder, showed the characteristic S3, S4,
S5—values independent of batch size within the same amount of time since the
start of the addition of granulation liquid. This fact is not surprising because in
terms of scale-up theory, the functional dependencies of the dimensionless group
numbers 1 and 2 were measured:
1 
 F(2) (5)
156 Leuenberger
Figure 2 Division of a power consumption curve. (From Ref. 8.)
Scale-Up in Granulation and Drying 157
Figure 3 Power consumption profiles of two types of a mixer/kneader.
Figure 4 Scale-up precision measurements with identical charges. (From Ref. 6.)
The other numbers 3, 4, 5, were kept essentially constant. From these findings
one can conclude that the correct amount of granulating liquid per amount of
particles to be granulated is a scale-up invariable [6–9]. It is necessary, however, to
mention that during this scale-up exercise only a low-viscous granulating liquid was
used. The exact behavior of a granulation process using high-viscous binders and
different batch sizes is unknown. It is evident that the first derivative of the power
consumption curve is a scale-up invariant and can be used as an in-process control
and for a fine-tuning of the correct amount of granulating liquid (see Fig. 5).
C. Use of the Power Consumption Method in Dosage Form
Design
Robust formulations are today an absolute prerequisite. Concerning the production
of granules, the granule size distribution should not vary from batch to batch.
The key factors are the correct amount and the type of granulating liquid. The interpretation
of the power consumption method can be very important for an optimal
selection of the type of granulating liquid. The possible variation of the initial
particle size distribution of the active substance and/or excipients can be compen-
158 Leuenberger
Figure 5 Power consumption profile of a high-speed-mixer (Collette–Gral 75 l) with
peak and level detection. (From Ref. 8.)
sated in case of an intelligent in-process control method, e.g., based on the power
consumption profile (see Table 1). However, the formulation may not be very robust
if the volume-to-volume ratio of certain excipients, such as maize starch and
lactose, correspond to a critical ratio or percolation threshold.
With dosage form design it is often necessary to compare the performance
of two different granule formulations. These two formulations differ in composition
and as a consequence vary also in the amount of granulating liquid required.
Thus the following question arises: How can the quantity of granulating liquid be
adjusted to achieve a correct comparison? The answer is not too difficult, because
it is based on identified physical principles. A correct comparison between two
formulations is often a prerequisite because the dissolution process of the active
substance in the final granulate or tablet can be affected by both the amount of
granulating liquid and the qualitative change (excipients) in the formulation. In order
to calculate corresponding, i.e., similar amounts of, granulating liquid in different
compositions, it is necessary to introduce a dimensionless amount of granulating
liquid . This amount  can be defined as degree of saturation of the
interparticulate void space between the solid material:
 
S
S
5


S
S
2
2 
where
S 
 Amount of granulating liquid (in liters)
S2 
 Amount of granulating liquid (in liters) necessary, which
corresponds to a moisture equilibrium at approx. 100% relative
humidity
S5 
 Complete saturation of interparticulate void space before a slurry is
formed (amount in liters)
Power consumption is used as an analytical tool to define S values for different
compositions. Thus the granule formation and granule size distribution of a
Scale-Up in Granulation and Drying 159
Table 1 Comparison Between the Manual and the Automatic Mode of Controlling the
Moist Agglomeration Process
Yield (% w/w) % Undersize % Undersize
Type of mode 90–710 m 710 m 90 m
Manual mode, 82.03  2.42 88.30  2.05 6.80  0.51
n 
 20 batches
Automatic mode, 91.45  0.36 96.80  0.31 5.40  0.35
n 
 18 batches
Source: Ref. 9.
binary mixture of excipients are analyzed as a function of the dimensionless
amount of granulating liquid . This strategy allows an unbiased study of the
growth kinetics of granules consisting of a single substance or of a binary mixture
of excipients. Thus it is important to realize that the properties of the granule
batches are analyzed as a function of the dimensionless amount of granulating liquid
[6–9].
1. Materials
The physical characteristics of the starting materials are compiled in Table 2.
Polyvinylpyrrolidone was added in a dry state to the powder mix of lactose and
corn starch at a level of 3% (w/w). As a granulating liquid, demineralized water
was used and pumped to the powder mix at constant rate of 15 g min1kg1.
2. Methods
The principle of power consumption method was described in detail in Refs. 6–9
and 14. As a high-shear mixer, a Diosna V 10 was used, keeping constant impeller
speed (270 rpm) and chopper speed (3000 rpm) during the experiments.
In order to reduce the possible effects of friability or second agglomeration
during a drying process in dish dryers on the granule size distribution as a function
of the amount  of granulating liquid added, the granules are dried for 3–5
min in a fluidized bed (Glatt Uniglatt) and subsequently for 15–25 min in a dish
dryer to obtain moisture equilibrium corresponding to 50% relative humidity of
the air at ambient temperature (20°C). The particle size distributions were determined
according to DIN 4188 using ISO-norm sieve sizes [9].
IV. ROBUST FORMULATIONS AND DOSAGE FORM
DESIGN
In the case of binary mixtures consisting of different substances, which, individually,
may have a considerable effect on the physical properties (e.g., electrical con-
160 Leuenberger
Table 2 Physical Properties of Lactose and Corn Starch
Property Lactose Corn starch
Bulk density (g/cm3) 0.58 0.49
Tapped density (g/cm3) 0.84 0.65
True density (g/cm3) 1.54 1.50
Sm (mass specific surface) (cm2/g) 3055
Mean diameter (m) 40 25
ductivity) of the final product (granules, tablets, etc.), the ratio of components is
essential. Thus with a mixture between Al2O3 (an electrically insulating material)
and copper powder, electrical conductivity of the Al2O3/copper tablet is observed
only if the copper powder forms an electrical pathway between the electrodes attached
to the surface of the tablet produced. The critical ratio where conductivity
is measured corresponds to the so-called percolation threshold pc [10]. In the case
of a fixed normalized amount  of granulating liquid, it is interesting to note that
the granules obtained from a lactose/corn starch powder mixture lead to granule
size distributions equivalent to the granule size distribution of either lactose or
corn starch. This result can be interpreted on the basis of percolation theory (Fig.
6), i.e., that the properties differ for compositions below or above a critical ratio
pc of components between lactose and corn starch (Table 2).
Scale-Up in Granulation and Drying 161
Figure 6 Cumulative particle size distribution of the agglomerates at a fixed normalized
amount  (
 0.62) of granulating liquid for different ratios of the binary powder mixture
lactose/corn starch.
V. A QUASI-CONTINUOUS GRANULATION AND DRYING
PROCESS (QCGDP) TO AVOID SCALE-UP PROBLEMS
A. Continuous Processes and the Batch Concept
In the food and chemical industries, continuous production lines play an important
role, whereas pharmaceutical industry production is based mainly on a batch-type
procedure. Concerning the safety of a dosage form and quality assurance, the batch
concept is very convenient. Thus a well-defined batch can be accepted or rejected.
In the case of a continuous process, a batch has to be defined somehow artificially,
i.e., the amount of product, e.g., amount of granules produced within
6–8 hours. On the other hand, continuous processes offer two important advantages:
(1) there is no difficult scale-up exercise necessary for larger “batches”; (2)
a 24-hour automatic production line should be possible.
B. Development of the Quasi-Continuous Production Line
for Granules
In order to combine the advantages of batch-type and continuous production, a prototype
for a quasi-continuous production line was developed [15–18]. The principle
of this quasi-continuous production line is based on a semicontinuous production
of minibatches in a specially designed high-shear mixer/granulator connected
to a continuous multicell-fluidized-(Glatt Multicell®) bed dryer (see Fig. 7).
162 Leuenberger
Figure 7 A quasi-continuous production line for granules with three drying cells (Glatt
AG, CH-4133 Pratteln).
In order to study the feasibility of such a quasi-continuous production line,
different formulations were tested and compared with a conventional batch process.
The weighing system available on the market was not involved in the first
experiments. Thus a prefixed amount of powder of the placebo formulation was
added to the specially designed high-shear mixer and thoroughly mixed. Subsequently
this amount of powder is granulated by continuously adding granulating
liquid up to a fixed amount. The ideal amount of granulating can be defined according
to the results of a power consumption measurement [6–9]. Afterwards the
moist granules are discharged through a screen into the first cell of the multicellfluidized-
bed dryer unit to avoid any formation of lumps. Thus the quasi-continuous
production of granules can be described as a train of minibatches passing like
parcels through the compartments of dry mixing, granulation, and drying. The
multicell dryer consists in general of three cells designed for different air temperatures;
i.e., in the first cell the granules are dried at a high temperature, e.g., 60°C,
and in the last cell ambient air temperature and humidity can be used to achieve
equilibrium conditions. If appropriate, more cells can be added.
Due to this principle, a batch defined for quality control purposes consists
of a fixed number of n minibatches. Thus a tight in-process control of the mixing/
granulation [6–9] and drying step [14] provides an excellent “batch record” of
the quasi-continuous production of granules and an excellent opportunity for a
continuous validation of the process and the equipment [14–20].
Thus, based on the positive results obtained with the thesis work of Schade
and Leuen berger [15] and B. Dorr [17] a new plant for quasi-continuous wet granulation
and multiple-chambered fluid-bed drying was developed by Glatt AG CHPratteln
in cooperation with F. Hoffmann-La Roche Ltd. Basel and the Institute of
Pharmaceutical Technology of the University of Basel. For this achievement the
Institute of Pharmaceutical Technology received the Innovation Award of the
Cantons Basel–City and Basel–Country in 1994.
The system provides a new possibility for industrial manufacturing and
galenical development of pharmaceutical solids specialties and has following purposes:
to make possible automated, unattended production, withdrawing from
scale-up experiments, and thus a shorter development time for new specialties,
with the aim of a shorter time to market. Manufacturing procedures can be simplified
and validated faster, and the quality of granules, tablets, and kernels compared
to common production is equal or better. Different solids specialties have
been tested and validated.
1. Goals of the Quasi-Continuous Granulation and Drying Line
a. Unattended Production. One of the general aims of quasi-continuous
granulation and fluid-bed drying is unattended production. The production of
Scale-Up in Granulation and Drying 163
small subunits of 7–9 kg instead of a whole batch allows an automated, iterative
granulation and drying procedure. The division of the process into different compartments
(mixing, sieving, and drying compartments) guarantees the reproducibility
of the galenical properties of each subunit.
b. No Necessity for Scale-Up Experiments. The granulation and drying
of subunits of 7–9 kg instead of a whole batch leads to the possibility of using the
plant for laboratory and production scale, because the batch size is no longer characterized
by machine size but by the number of produced subunits. Using the same
plant in galenical research, development and production may shorten the time to
market for new solids specialties.
c. Simplification of Manufacturing Procedures. Existing manufacturing
procedures can be taken over from common equipment without changing components.
In certain cases it’s possible to simplify the procedures. The small mixer
size and the geometry of the mixing elements allow the binders to be added to the
premixture and granulation just with water.
d. Identical or Better Quality of Granules and Tablets. The quality of
the produced granules and tablets has to be equal or better and fulfill product specifications.
2. Results
Constant values and the reproducibility of the process are important benefits of
quasi-continuous granulation. The tests could also show equal or better quality of
granules and tablets compared to common granulation equipment (Diosna P-600
high-speed granulator). Figures 8–13 show the results obtained during the devel-
164 Leuenberger
Figure 8 Yield (Formulation 1).
Scale-Up in Granulation and Drying 165
Figure 9 Yield (Formulation 2).
Figure 10 Bulk volume/tapped volume (Formulation 1).
Figure 11 Bulk volume/tapped volume (Formulation 2).
opment of the equipment, where the high-shear mixer/granulator was operated
separately from the subsequent drying system. The tests show the performance of
the individual minibatches as a function of the subunit number. Because the subunits
are collected in the container (see Layout 1) for the preparation of the final
tablet blend, these tests are not necessary with the fully equipped quasi-continuous
system.
In case of the yield (e.g., mass) per subunit, a negative deviation from
the mean was followed by a positive deviation, showing the “self-cleaning”
property of the mixer (Figs. 8–9). This test is not needed if the system is
166 Leuenberger
Figure 12 Compression force/hardness profile (Formulation 1).
Figure 13 Compression force/hardness profile (Formulation 2).
equipped with an in-process control based on power consumption measurement
[6–9].
3. Materials and Methods
a. Materials.
Formulation 1 Formulation 2
Lactose 350 M 65.5% Lactose 350 M 68.7% (W/W)
Maize starch 25.5% Maize starch 27.0% (W/W)
Povidone K-30 6.5% HPMC 2910/3 cP 4.3% (W/W)
Primojel 2.5% Granulation liquid: Aqua purificata Ph. Eur. II
Granulation liquid: Aqua purificata Ph. Eur. II
b. Production Parameters.
Subunit size: 7.0 kg
Rotational speed of mixer: 206 rpm
Granulation liquid per subunit: 1.0 kg (Formulation 1); 1.3 kg (Formulation
2)
Spray rate: 800 g/min (Formulation 1); 900 g/min (Formulation 2)
Mixing time: 85 sec (Formulation 1); 90 sec (Formulation 2)
Sieve diameter: 5 mm wet sieving, 1.5/1.0 mm dry sieving
Drying temperature: 60°C
Inlet air quantity: 600 m3/hr
c. Test Methods.
Relative humidity (Rotronic® hygroscope)
Loss on drying (Mettler® LP 16/PM 480 Deltarange infrared balance)
Sieve analysis (Fritsch® Analysette laboratory sieving machine)
Bulk volume/tapped volume (Jel STAV® 2003 volumeter)
Compression force/hardness profile (Manesty® Deltapress tableting machine
with Tegimenta® Pharmatest PTB 301 hardness tester)
Hardness (Tegimenta® Pharmatest PTB 301 and Kramer® Computest
hardness tester)
Disintegration time (Tegimenta® Pharmatest PT 21 and Kramer® DES-2A
disintegration tester)
Friability/abrasion (Roche® friabilator)
Scale-Up in Granulation and Drying 167
VI. DESCRIPTION OF THE PRODUCTION PLANT
The Glatt Multicell® unit for quasi-continuous granulation and fluid-bed drying
(see Layouts 1 and 2) consists of the following elements: a transport and dosage
system for mixer filling (1), a horizontal high-speed plough-share mixer (subunits
of 4–9 kg of premixture can be granulated) with an airless spray pump for the granulation
liquid (2), rotary sieving machines for wet and final sieving (3), a threechambered
fluid-bed dryer for predrying, final drying, and cooling down to room
temperature (4), a transport system to collect the granulated subunits in a container
(5), and an integrated washing-in-place or cleaning-in-place (CIP) system.
A. Layout
168 Leuenberger
Layout 1 Top view of the Glatt Multicell®.
Scale-Up in Granulation and Drying 169
Layout 2 Front view of the Glatt Multicell®.
1. Transport and dosage system for mixer filling
2. Horizontal high-speed plough-share mixer
3. Rotary sieving machines for wet and final sieving
4. Three-chambered fluid-bed dryer
5. Transport system
B. Advantages of the Quasi-Continuous Granulation and
Drying Line (Glatt Multicell®)
Such a production line is now successfully in operation at the Roche pharma production
plant in Basel. A further-developed version has been installed at the technology
center at Goedecke (Pfizer Group) in Freiburg, Germany. From the experience
obtained so far the following conclusions can be drawn: The production line can be
fully automated and equipped with a a CIP (cleaning-in-place) system. The moist agglomeration
process can be monitored for each subunit by a power consumption inprocess
control device. Due to the three different cells of the Glatt Multicell® drying
equipment, a gentle drying of temperature-sensitive drug substances is possible. According
to need, a “just-in-time” production of the desired batch size B can be implemented.
Early, small-sized batches can be already considered as production
batches of identical quality. Thus these early batches can be put on a long-term stability
test even at the beginning of the development of the dosage form. Because the
early clinical batches are produced on exactly the same equipment as the large production
batches, no bioequivalence test between early clinical batches and later production
batches is needed. Due to these facts, no scale-up development is necessary.
Thus the development time and the time needed to get to market can be reduced.
REFERENCES
1. Zlokarnik, M. Dimensional analysis, scale-up. In: Encyclopedia of Bioprocess Technology:
Fermentation, Biocatalysis and Bioseparation. Flickinger, M.C., Drew, St.
W., eds. Wiley, New York, 1999, pp 840–861.
2. Dimensionless Groups. See Handbook of Chemistry and Physics, e.g., 67th ed.
(1986–1987) pp F307–324.
3. Pharmaceutical Manufacturers’ Association. Remington’s Pharmaceutical Sciences.
15th ed. Mack, Easton PA, 1975, p 1429.
4. Johnstone, R. W., Thring, M. W. Pilot Plants, Models and Scale-up Methods in
Chemical Engineering. McGraw-Hill, New York 1957, p 12.
5. Leuenberger, H. In: Pharm. Technologie. Sucker, H., Fuchs P., Speiser P. eds. G.
Tieme Verlag, Stuttgart, Germany, 1978, pp 80–92.
6. Leuenberger, H. Scale-up of granulation processes with reference to process monitoring.
Acta Pharm. Technol. 29(4):274–280, 1983.
7. Leuenberger, H. Moist agglomeration of pharmaceutical powders. In: Powder Technology
and Pharmaceutical Processes. Handbook of Powder Technology. Vol. D.
Chulia, M. Deleuil, Y. Pourcelot, eds. Elsevier, 1994, pp 377–389.
8. Leuenberger, H. Granulation, New Techniques, Pharm. Acta Helv. 57(3):72–82,
1982.
9. Durrenberger, M., Werani, J. Proceedings of the 4th Int. Symposium on Agglomeration.
Toronto, June 2–5, 1985, p. 489.
10. Stauffer, H. Introduction to Percolation Theory. Taylor and Francis, London, 1985.
11. Leuenberger, H., Holman, L., Usteri, M., Winzap, S. Percolation theory, fractal geometry
and dosage form design. Pharm. Acta Helv. 64(2):34–39, 1989.
12. Bonny, J. D., Leuenberger. H. Matrix type controlled release systems: II percolation
effects in non-swellable matrices. Pharm. Acta Helv. 68:25–33, 1993.
13. Leuenberger, H. The application of percolation theory in powder technology. (Invited
review) Advanced Powder Technology 10:323–352, 1999.
14. Leuenberger, H. From a pharmaceutical powder to a tablet—novel concepts in the
field of granulation and tableting. Proceed. 6th Int. Symposium on Agglomeration,
Nov. 15–17, 1993, Nagoya, Japan, pp. 665–673.
15. Schade, A. Herstellung von pharmazeutischen Granulaten in einem kombinierten
Feuchtgranulations- und Mehrkammer-Wirbelschichttrocknungsverfahren. Ph.D.
dissertation, University of Basel, 1992.
16. Schade, A., Leuenberger, H. Herstellung pharmazeutischer Granulate in einem kombinierten
Feuchtgranulations- und Mehrkammer-Wirbelschichttrockungsverfahren.
Chem. Ing. Tech. 64(II):1016–1018, 1992.
17. Dorr, B. Entwicklung einer Anlage zur quasikontinuierlichen Feuchtgranulierung
und Mehrkammer-Wirbelschichttrocknung von pharmazeutischen Granulaten. Ph.D.
dissertation, University of Basel, 1996.
18. Dorr, B., Leuenberger, H. Development of a quasi-continuous production line—a
concept to avoid scale-up problems. Preprints First European Symposium on Process
Technologies in Pharmaceutical and Nutritional Sciences, PARTEC 98 Nurnberg (H.
Leuenberger, ed.), 1998, pp. 247–256.
19. Leuenberger H., New Trends in the Production of Pharmaceutical Granules: the classical
batch concept and the problem of scale-up. Eur. J. Pharm. Biopharm., Theme Issue
Granulation 2001.
20. Leuenberger H., New Trends in the production of pharmaceutical granules: batch versus
continuous processing. Eur. J. Pharm. Biopharm., Theme Issue Granulation 2001.
170 Leuenberger
7
Batch Size Increase in Fluid Bed
Granulation
Dilip M. Parikh
APACE Pharma Inc., Westminster, Maryland
I. INTRODUCTION
The size enlargement of primary particles has been carried out in the pharmaceutical
industry in a variety of ways. One of the most common unit operations used
in the pharmaceutical industry is fluid bed processing. Batch size increase using
fluid bed granulation requires a good understanding of equipment functionality,
the theoretical aspects of fluidization, excipient interactions, and, most of all,
identifying the critical variables that affect the process of agglomeration.
This chapter* will provide an essential understanding of fluidization theory,
describe the system that makes up the fluid bed processor, and discuss the critical
variables associated with the equipment, the product, and the process. Upon gaining
this basic understanding, one can design scale-up protocols. These protocols
should be able to ensure successful transition from R&D batch sizes to pilot-size
batches and ultimately to the commercial scale. As in any unit operation that requires
batch size increase, the fluid bed process must undergo process qualification
to establish its robustness. If these process variables are identified at an early
stage of product development and then extrapolated, these variables, based on a
knowledge of equipment variables and tolerances and material handling considerations,
will provide a trouble-free batch size increase.
171
*Reprinted in part, with revisions and updates, from Ref. 98.
A. Fluidization Theory
A fluidized bed is a bed of solid particles with a stream of air or gas passing upward
through the particles at a rate great enough to set them in motion, this velocity, according
to Kulling and Simon [1], is higher than the incipient fluidizing velocity but
lower than the entrainment velocity. When the rate of flow of gas increases, the pressure
drop across the bed also increases until, at a certain rate of flow, the frictional
drag on the particles equals the effective weight of the bed. These conditions, and
the velocity of gas corresponding to it, are termed incipient fluidization and incipient
velocity, respectively. The relationship between air velocity and pressure drop is
as shown in Figure 1 [2]. At low gas velocities, the bed of particles is practically a
packed bed, and the pressure drop is proportional to the superficial velocity. As the
gas velocity is increased, a point is reached at which the bed behavior changes from
fixed particles to suspended particles. The superficial velocity required to first suspend
the bed particles is known as minimum fluidization velocity (umf). The minimum
fluidization velocity sets the lower limit of possible operating velocities, and
the approximate pressure drop can be used to approximate the pumping energy requirements.
Air velocity required for the agglomeration process in the fluid bed processor
is normally five to six times the minimum fluidization velocity.
At the incipient point of fluidization, the pressure drop of the bed will be
very close to the weight of the particles divided by the cross-sectional area of the
bed (W/A). For the normal gas fluidized bed, the density of the gas is much less
than the density of the solids and the balance of forces can be shown as
Pmf 
 W/A
where
W 
 (1  *mf)p  g/gc
p 
 pressure drop
*mf 
 minimum fluidization void fraction
A 
 cross-sectional area,
W 
 weight of the particles
p 
 density of particles
g/gc 
 ratio of gravitational acceleration and gravitational conversion factor.
As the velocity of the gas is increased further, the bed continues to expand and its
height increases with only slight increase in the pressure drop. As the velocity of
the gas is further increased, the bed continues to expand and its height increases,
whereas the concentration of particles per unit volume of the bed decreases. At a
certain velocity of the fluidizing medium, known as the entrainment velocity, particles
are carried over by the gas. This phenomenon is called entrainment. When
the volumetric concentration of solid particles is uniform throughout the bed at all
times, the fluidization is termed particular. When the concentration of solids is
172 Parikh
Batch Size Increase in Fluid Bed Granulation 173
Figure 1 Typical pressure drop as a function of gas velocity. (From Ref. 2.)
not uniform throughout the bed, and if the concentration keeps fluctuating with
time, the fluidization is called aggregative fluidization. A slugging bed is a fluid
bed in which the gas bubbles occupy entire cross sections of the product container
and divide the bed into layers. A boiling bed is a fluid bed in which the gas bubbles
are approximately the same size as the solid particles. A channeling bed is a
fluid bed in which the gas forms channels in the bed through which most of the air
passes. A spouting bed is a fluid bed in which the gas forms a single opening
through which some particles flow and fall on the outside. Figure 2 shows various
types of fluid beds [3].
The mechanisms by which air affects fluidization have been discussed by
various researchers [4–9]. When the fluidizing velocity is greater than the incipi-
174 Parikh
Figure 2 Various types of fluid beds. (From Ref. 3.)
ent velocity, bubbles of air rise through the bed, causing mixing of particles. Mixing
does not generally occur when the bed is fluidized at very low or zero excess
gas velocities, because insufficient bubbles are formed to cause bulk displacement
of particles. It is the gas passing through the bed in the form of bubbles that determines
the degree of mixing. The extent of mixing appears to vary with particle
size. Mixing of particles having a mean particle size of less than approximately
150 m decreases as the mean size approaches zero. Different types of beds, described
earlier, are formed depending upon the movement of bubbles through the
bed. The pattern of movement of the gas phase in and out of bubbles depends upon
several factors, including minimum fluidization velocity and particle size. These
movements affect heat transfer between air bubbles and particles. The air distributor
at the bottom of the container has a controlling influence on the uniform distribution
of gas, minimization of dead areas, and maximization of particle movement.
The most common reason for mixing problems such as segregation in the
fluid bed are the particle density differences. The extent of segregation can be controlled
in part by maintaining high fluidizing velocities and a high bowl-height-tobowl-
diameter ratio. There are standard air velocities for various processes that
can be used as guidelines.
The standard velocities are based upon the cross-sectional area at the bottom
of the product container. This is calculated by using the following formula for
calculating air velocity:
velocity (m/sec) 
 air flow {cubic meters per hour (CMH)}
+ area (square meters)  3600
where
air flow in cubic meters per hour (CMH) 
 air flow (CFM)  1.696
Standard air velocities are based on the application. Low air velocities, such as
0.8–1.4 meters/second, are required for drying. The velocities are higher during
the early stages of drying because of the wet mass present in the bowl, but will be
reduced when the product loses its moisture. The objective is to have good particle
movement but to keep the material out of filters. Particle movement and quick
drying are important during the agglomeration process. Air flow velocities are
normally 1.0–2.0 meters/second.
An indication of good fluidization is a free downward flow of the granulation
at the sight glass of the drying container. However, improper fluidization can
also be detected by monitoring the outlet air temperature. Every product has a
unique constant rate of drying in which the bed temperature remains relatively
constant for a significant length of time. Therefore, if the outlet temperature rises
more rapidly than anticipated, it will indicate an improper fluidization and the process
may have to be stopped and manual or mechanical intervention may be required
to assist the fluidization.
Batch Size Increase in Fluid Bed Granulation 175
B. Fluidization and Fluid Bed Granulation
Fluidization is the operation by which fine solids are transformed into a fluidlike
state through contact with a gas. At certain gas velocities, the fluid will support the
particles, giving them freedom of mobility without entrainment. Such a fluidized
bed resembles a vigorously boiling fluid with solid particles undergoing extremely
turbulent motion, which increases with gas velocity.
Fluidized bed granulation is a process by which granules are produced in a
single piece of equipment by spraying a binder solution onto a fluidized powder
bed. This process is sometimes classified as the one-pot system. The fluid bed
granulation process has received considerable attention within the pharmaceutical
industry. However, other process industries, such as food, agrochemical,
dyestuffs, and other chemical industries, have adopted the fluid bed granulation
process to address particle agglomeration, dust containment, and material handling.
The fluidization technique as it is known today began with the work of the
Standard Oil Company (now known as Exxon in the United States) and M. W.
Kellogg Company in an effort to produce the first catalytic cracking plant on a
commercial scale in 1942 [10].
The fluid bed processing of pharmaceuticals was first reported by Dale
Wurster, who used the air suspension technique to coat tablets [11,12]. In 1960,
he reported on granulating and drying a pharmaceutical granulation, suitable for
the preparation of compressed tablets, using the air suspension technique. In
1964 Scott et al. [13] and Rankell et al. [14] reported on the theory and design
considerations of the process using a fundamental engineering approach and employing
mass and thermal energy balances. They expanded this application to
the 30-kg-capacity pilot model designed for both batch and continuous operations.
Process variables such as air flow rate, process air temperature, and liquid
flow rate were studied. Contini and Atasoy [15] later reported the processing details
and advantages of the fluidized bed process in one continuous step. Wolf
[16] discussed the essential construction features of the various fluid bed components,
and Liske and Mobus [17] compared the fluidized bed and traditional
granulation process. The overall results indicated that the material processed by
fluid bed granulator was finer and more free flowing, and had homogeneous
granules, which after compression produced stronger and faster disintegration of
tablets than the materials processed by conventional wet granulation. Reviews
by Sherrington and Oliver [18] and Pietch [19] and a series published on the
topic of “Fluidization in the Pharmaceutical Industry” [20–25] provide an indepth
background on the fundamental aspects of the fluidized bed and other
granulating technologies. The fluidized bed was used only for drying the pharmaceutical
granulation efficiently in the early days, but now it is employed routinely
for drying, agglomerating, pelletizing, and producing modified-release
dosage forms using air suspension coating. Because of this, these units are normally
called multiprocessor fluid bed units.
176 Parikh
II. SYSTEM DESCRIPTION
A fluid bed processor is a system of unit operations involving heating process air,
directing it through the material to be processed, and having the same air (usually
laden with moisture) exit the unit, void of the product. Figure 3 shows a typical
fluid bed processor with all the components. These components and their utility
for the granulation will be reviewed.
At the downstream end of the fluid bed processor, an exhaust blower or
fan is situated to draw the air through the entire unit. This arrangement provides
negative pressure in the fluid bed, which is necessary to facilitate material loading,
maintain safe operation, prevent material escape, and carry out the process
under good manufacturing practices guidelines, all of which will be discussed
later in the chapter.
A. Air Handling Unit (AHU)
A typical air preparation system includes sections for air filtering, air heating, air
cooling, and humidity removal. Generally, outside air is used as the fluidizing
medium in a fluid bed processor. For the air to be used for pharmaceutical products,
it must be free of dust and contaminants. This is achieved by placing coarsedust
filters (30–85%) in the AHU. Figure 4 shows the typical air handling unit.
Batch Size Increase in Fluid Bed Granulation 177
Figure 3 Typical components of a fluid bed processor.
After installation of the filters, distinct heating or cooling sections are installed
in the air handler, depending upon the geographical location of the plant.
In a extremely cold climate, where cooling coils (needed in summer months for
maintaining a uniform dew point) can freeze in winter, a preheating section is
placed ahead of the cooling coils. A typical range for the air after pretreatment that
one should aim at achieving is 15–30°C dry bulb and 3–5°C wet bulb. If the unit
is located in a tropical or humid climate, the humidity removal section is employed
first. The dehumidification of the air is extremely important where the outside air
moisture varies over a wide range. In summer, when the outside humidity is high,
dehumidification of the process air is required to maintain a specific dew point of
the incoming process air. Rehumidification may be necessary during the winter
months in some regions. A steam injector is used for rehumidifying the dry air.
Generally, the lower the process-air dew point, the higher the affinity to entrain
moisture and the shorter the process time. When granulating extremely fine powders,
inlet-air dew point of 15°C is beneficial to reduce static charges and facilitate
uniform fluidization. In many processes, when preheating is required, a bypass
loop can be used for preconditioning the air. This loop allows the required
process temperature and humidity to be attained within the system ducts before
the product is subjected to fluidization. After the conditioned air leaves the humidification/
dehumidification section of the AHU, it is finally heated to the desired
process-air temperature and then passed through a high-efficiency particulate
air (HEPA) filter of about 99.90–99.99% capacity. As the process air is treated
and filtered, it is transported by the inlet duct. The air is thus brought into the process
vessel in the lower plenum.
B. Product Container and Air Distributor
With the air at the desired humidity and temperature, it is ready to be passed
through the bed of solids. Figure 5 shows a typical product container with the air
178 Parikh
Figure 4 Typical Air Handling Unit for the fluid bed processor.
distributor. The air must be introduced evenly at the bottom of the product container
through an inlet-air plenum. Proper air flow in the inlet-air plenum is critical
to ensure that equal air flow velocities occur at every point on the air distributor
plate. If the air is not properly distributed before it reaches the bottom of the
container, uneven fluidization can occur.
To properly fluidize and mix the material in the container, the correct choice
of container and air distributor must be made. The container volume should be
chosen such that the bowl is filled to at least 35–40% of its total volume and no
more than 90% of its total volume. The correct choice of air distributor is important.
These distributors are made of stainless steel and are available with a 2–30%
open area. Typically, the distributor should be chosen so that the pressure drop
across the product bed and air distributor is 200–300 mm of water column. A fine
screen of 60–325 mesh normally covers the air distributor and retains the product
in the container. This type of sandwiched construction has been used for the last
30 years in the fluid bed processors. The classic air distributor with the fine-product-
retaining screen is shown in Figure 5.
Batch Size Increase in Fluid Bed Granulation 179
Figure 5 Typical product container with air distributor.
Keeping the screen and air distributors clean has been challenging. Partially
to address the cleaning problems and partially to provide the efficient processing,
a new overlap gill plate, shown in Figures 6a and b, was introduced in 1990 [26].
These new overlap gill air distributors eliminate the need for a fine screen and perform
dual functions as the efficient air distributor and product retainer. Other advantages
claimed by the manufacturer are validatable clean-in-place (CIP), controlled
fluidization and directional flow of air to discharge the processed product
from the container.
C. Spray Nozzle
A spray is a zone of liquid drops in a gas, and spraying is the act of breaking up a
liquid into a multitude of these droplets. The general purpose of spraying is to increase
the surface area of a given mass of liquid to disperse it over the product
area. The two-fluid (binary) nozzle, in which the binder solution (one fluid) is atomized
by compressed air or gas (second fluid), is the most commonly used nozzle
for fluid bed granulation (Fig. 7a). These nozzles are available as a single-port
or multiple-port design. Generally, the single-port nozzles are adequate for a batch
of up to 100 kg, but for larger-sized batches a multiport (either three- or six-port)
nozzle is required. When these nozzles are air-atomized, the spray undergoes three
distinct phases. In the first, the compressed air (or gas) expands, essentially adiabatically,
from the high pressure at the nozzle to that of the fluid bed chamber. The
gas undergoes a Joule-Thomson effect, and its temperature falls. In the second, the
liquid forms into discrete drops. During this atomization, the liquid’s specific surface
usually increases 1000 times. In the third, the drops travel, after being
formed, until they become completely dry or impinge on the product particles.
During this phase, the solvent evaporates, and the diameter of the drop increases.
The energy required to form a drop is the product of the surface tension
and the new surface area. About 0.1 cal/g is needed to subdivide 1 g of water into
1-m droplets. The air pressure required to atomize the binder liquid is set by
means of a pressure regulator. The spray pattern and spray angle are adjusted by
adjusting the air cap.
The binder solution is delivered to the nozzle port through a spray lance and
tubing (Fig. 7b). The peristaltic, or positive displacement, pump is commonly
used to pump the binder solution. The pneumatically controlled nozzle needle prevents
the binder liquid from dripping when fluid flow is stopped. Nozzle port
openings 0.8 and 2.8 mm in diameter are most common and are interchangeable.
D. Disengagement Area and Process Filters
Once the air leaves the product bed, fine particles need to be separated from the
air stream; two zones are used in the fluid bed for this process: the disengagement
area and the exhaust filters. In the disengagement area, larger particles lose mo-
180 Parikh
Batch Size Increase in Fluid Bed Granulation 181
(a)
(b)
Figure 6 (a) Schematic of an overlap gill air distributor. (b) Container with the overlap
air distributor and side discharge opening.
182 Parikh
Figure 7 (a) Schematic of a nozzle showing different parts.
mentum and fall back into the bed. The velocity of the process air is highest at the
center of the processor and approaches zero at the side walls. A process air filter
system removes the particles from the exhaust air. The process air is filtered by
using bags or cartridges. The bags can be constructed out of nylon, polyester,
polypropylene, and/or polytetrafluroethylene- (PTFE) lined materials. To dissipate
the potential static charges from the product particles, conductive fabrics are
also available and are recommended. Cartridge filters lined with PTFE were introduced
to the industry in 1980s [27]. Recently, cartridges made of stainless steel
suitable for CIP have been introduced [28]. These process filters are cleaned during
the granulation process by mechanical means or by using a low-pressure blowback
system. Figure 8 shows various filters used in the fluid bed processors.
E. Exhaust Blower or Fan
Once the air leaves the exhaust filters, it travels to the fan. The fan is on the outlet
side of the system, which keeps the system at a lower pressure than the surround-
Batch Size Increase in Fluid Bed Granulation 183
Figure 7 (b) Schematic of a two-fluid nozzle showing liquid and air pathways.
ing atmosphere. The air flow is controlled by a valve or damper installed just ahead
of or after the fan. The selection of the fan is normally done by the manufacturer
based upon the layout and complexity of the system. Fan size is determined by calculating
the pressure drop (P) created by all the components that make up the fluid
bed processor, including product at the highest design airflow volume.
F. Control System
A fluid bed granulation process can be controlled by pneumatic analog control devices
or by using state-of-the-art programmable logic controllers (PLCs) or com-
184 Parikh
Figure 8 Various process filters and cleaning mechanisms.
puters. The electronic-based control system offers not only reproducible batches
according to the recipe but a complete record and printout of all the process conditions.
Process control technology has changed very rapidly, and it will continue
to change as advances in computer technology take place and as the cost of control
systems fall.
G. Solution Delivery System
A peristaltic pump capable of delivering binder solution at a controlled rate is
desirable. The liquid is transported from the solution vessel through the tubing
and then atomized, using a two-fluid (binary) nozzle, in the fluid bed processor.
III. PARTICLE AGGLOMERATION AND GRANULE
GROWTH
Agglomeration can be defined as the size enlargement process, in which the starting
material is fine particles and the final product is an aggregate in which primary
particles can still be identified. The granules are held together with bonds formed
by the binder used to agglomerate. Various mechanisms of granule formation
have been described in the literature [29–31]. To summarize, three mechanisms
for granule formation have been suggested by the researchers:
1. Bridges due to immobile liquids form adhesional and cohesional bridging
bonds. Thin adsorption layers are immobile and can contribute to
the bonding of fine particles under certain circumstances.
2. Mobile liquids, where interfacial and capillary forces are present.
3. Solid bridges formed due to crystallization of dissolved substances during
drying.
The type of bonds formed approaches through four transition states, described by
Newitt and Conway-Jones [29] as:
1. Pendular
2. Funicular
3. Capillary
4. Droplet, which normally happens during spray-drying
Most of the fluid bed granulated products require an amount of wetting
much less than the high-shear granulation or spray-dryer-processed product. In the
fluid bed granulation process, the particles are suspended in the hot air stream and
the atomized liquid is sprayed on it. The degree of bonding between these primary
particles to form an agglomerated granule depends on the binder used, physicochemical
characteristics of the primary particles being agglomerated, and process
parameters.
Batch Size Increase in Fluid Bed Granulation 185
186 Parikh
Figure 9 Mechanism of granulation in fluid bed. (Adapted from Ref. 36.)
Schaefer and Worts [32] and Smith and Nienow [33] have reported a description
of the growth mechanisms in the fluid bed, where the bed particles are
wetted by liquid droplets in the spray zone. Atomized liquid from the nozzle tends
to spread over the particle surface as long as there is a adequate wettability of the
particle by the fluid [34]. Wet particles, on impact, form a liquid bridge and solidify
as the agglomerate circulates throughout the remainder of the bed. Solid
bridges then hold the particles together. The strength of the binder determines
whether these particles stay as agglomerates. These binding forces should be
larger than the breakup forces and this in turn depends on the size of the solid
bridge. The breakup forces arise from movement of the randomized particles colliding
with each other and are related to the excess gas velocity and particle size.
If the binding forces are in excess of the breakup forces, either in the wet
state or in the dry state, uncontrolled growth will proceed to an overwetted bed or
production of excessive fines, respectively. If a more reasonable balance of forces
is present, controlled agglomeration will occur, growth of which can be controlled.
Maroglou and Nienow presented a granule growth mechanism in the fluid
bed by the use of model materials and scanning electron microscope [35]. Figure
9 shows the various paths a liquid droplet can take and the consequences on particle
growth.
The mechanism of formation of a granule and subsequent growth progresses
primarily through three stages:
1. Nucleation
2. Transition
3. Ball growth
Figure 10 shows the growth of the granule relative to the liquid added. In the beginning
of the spraying stage, primary particles form nuclei and are held together
by liquid bridges in a pendular state. The size of these nuclei depends upon the
droplet size of the binder solution. As the liquid addition continues, more and
more nuclei agglomerate and continue the transition from the pendular state to the
capillary state.
Batch Size Increase in Fluid Bed Granulation 187
Figure 10 States of liquid saturation.
The uniqueness of the fluid bed agglomeration process is how the liquid addition
and drying (evaporation) steps are concurrently carried out. When the granulation
liquid is sprayed into a fluidized bed, the primary particles are wetted and
form, together with the binder, relatively loose and very porous agglomerates.
Densification of these agglomerates is brought about solely by the capillary forces
present in the liquid bridges. It is therefore important that the quantity of liquid
sprayed into the bed be relatively large compared with that used in high-shear
granulation.
Drying a wet product in a fluid bed is a separate topic, but during the granulation
process it becomes an integral part of the process, hence understanding
fluid bed drying is important before we review the agglomeration process.
IV. FLUID-BED DRYING
Drying is usually understood to be removal of moisture or solvent. Drying involves
heat transfer and mass transfer. Heat is transferred to the product to evaporate
liquid, and mass is transferred as a vapor in the surrounding gas; hence these
two phenomenon are interdependent. The drying rate is determined by the factors
affecting the heat and mass transfer. The transfer of heat in the fluid bed takes
place by convection. Convection is the transfer of heat from one point to another
within a fluid (gas, solid, liquid) by the mixing of one portion of the fluid with another.
The removal of moisture from a product granulated in the fluid bed granulator
or in other equipment essentially removes the added water or solvent. This
free moisture content is the amount of moisture that can be removed from the material
by drying at a specified temperature and humidity. The amount of moisture
that remains associated with the material under the drying conditions specified is
called the equilibrium moisture content, or EMC. The rate of evaporation of liquid
film surrounding the granule being dried is related to the rate of heat transfer
by the following equation:
dw/dt 
 hA/HT
where
dw/dt is the mass transfer rate (drying rate)
h is the heat transfer coefficient
A is the surface area
H is the latent heat of evaporation
T is the temperature difference between the air and the material surface
Because fluid bed processing involves drying of a product in suspended hot
188 Parikh
air, the heat transfer is extremely rapid. In a properly fluidized processor, product
temperature and the exhaust air temperatures should reach equilibrium.
Improper air distribution, hence poor heat transfer in fluidized bed, causes
numerous problems, such as caking, channeling, and sticking. The capacity of the
air (gas) stream to absorb and carry away moisture determines the drying rate and
establishes the duration of the drying cycle. Controlling this capacity is the key to
controlling the drying process. The two elements essential to this control are inlet-
air temperature and air flow. The higher the temperature of the drying air, the
greater its vapor-holding capacity. Since the temperature of the wet granules in a
hot gas depends on the rate of evaporation, the key to analyzing the drying process
is psychometry [37–39].
Psychometry is defined as the study of the relationships between the material
and energy balances of water vapor–air mixture. Psychometric charts (Fig. 11)
simplify the crucial calculations of how much heat must be added and how much
moisture can be added to the air. The process of drying involves both heat and
mass transfer. For drying to occur, a concentration gradient must exist between the
moist granule and the surrounding environment. As in heat transfer, the maximum
rate of mass transfer that occurs during drying is proportional to the surface area,
the turbulence of the drying air, the driving force between the solid and the air, and
the drying rate. Because the heat of vaporization must be supplied to evaporate the
moisture, the driving force for mass transfer is the same driving force required for
heat transfer, which is the temperature difference between the air and the solid.
Schaefer and Worts [40] have shown that the higher the temperature difference
between incoming air and the product, the faster the drying rate. Therefore,
product temperature should be monitored closely to control the fluidized-bed drying
process. During fluid bed drying, the product passes through three distinct
temperature phases (Fig. 12). At the beginning of the drying process, the material
heats up from the ambient temperature to approximately the wet bulb temperature
of the air in the dryer. This temperature is maintained until the granule moisture
content is reduced to the critical level. At this point, the material holds no free surface
water, and the temperature starts to rise further.
The drying capacity of the air depends upon the relative humidity (RH) of
the incoming air. At 100% RH, the air is holding the maximum amount of water
possible at a given temperature. But if the temperature of the air is raised, the relative
humidity drops and the air can hold more moisture. If air is saturated with
water vapor at a given temperature, a drop in temperature will force the air mass
to relinquish some of its moisture through condensation. The temperature at which
moisture condenses is the dew point temperature. Thus, the drying capacity of the
air varies significantly during processing. By dehumidifying the air to a preset
dew point, incoming air can be maintained at a constant drying capacity (dew
point) and hence provide reproducible process times.
Batch Size Increase in Fluid Bed Granulation 189
190 Parikh
Figure 11 Psychrometric chart.
V. PROCESS AND VARIABLES IN GRANULATION
A. Process
As with any granulating system, in fluid bed granulation processing the goal is to
form agglomerated particles through the use of binder bridges between the particles.
To achieve a good granulation, particles must be uniformly mixed, and liquid
bridges between the particles must be strong and easy to dry. Therefore, this
system is sensitive to the particle movement of the product in the unit, the addition
of the liquid binder, and the drying capacity of the air. The granulation process
in the fluid bed requires a binary nozzle, a solution delivery system, and compressed
air to atomize the liquid binder. Figure 13 shows the equipment set up for
granulation using the fluid bed processor.
Thurn [41], in a 1970 thesis, investigated details of the mixing, agglomerating,
and drying operations that take place in the fluid bed process. Results indicated
that the mixing stage was particularly influenced by air flow rate and air volume.
It was suggested that the physical properties of the raw materials, such as
hydrophobicity, may exert a strong influence upon the mixing stage. At the granulation
stage, particular attention was paid to the nozzle and it was concluded that
a binary-design (two-fluid) nozzle gave a wide droplet size distribution, yielding
a homogeneous granule. The need for strong binders was recommended to aid
granule formation and it was suggested that the wettability of the raw materials required
particular attention. Several research papers have been published on the influence
of raw material [40–57], binder type [14,17,40,41,51,53,58–68], binder
concentration, and binder quantity [17,44,49,53,55,58,60–62,65–67,69–85].
Batch Size Increase in Fluid Bed Granulation 191
Figure 12 Product temperature changes during drying in a fluid bed processor. (From
Ref. 20.)
Each phase of the granulation process must be controlled carefully to
achieve process reproducibility. When binder liquid is sprayed into a fluidized
bed, the primary particles are wetted and form, together with the binder, relatively
loose and very porous agglomerates. Densification of these agglomerates is
brought about almost solely by the capillary forces present in the liquid bridges. It
is therefore important that the liquid binder sprayed into the bed be relatively large
in quantity compared with that used in high- or low-shear granulation process.
During spraying, a portion of the liquid is immediately lost by evaporation, so the
192 Parikh
Figure 13 Typical fluid bed processor set up for the fluid bed granulation process.
system has little tendency to pass beyond the liquid bridge phase. The particle size
of the resulting granule can be controlled to some extent by adjusting the quantity
of binder liquid and the rate at which it is fed, i.e., the droplet size. The mechanical
strength of the particles depends principally on the composition of the primary
product being granulated and the type of the binder used. Aulton et al. [75] found
that lower fluidizing air temperature, a dilute solution of binder fluid, and a greater
spray rate produced better granulation for tableting.
B. Variables
The factors affecting the fluid bed granulation process can be divided into three
broad categories:
1. Formulation-related variables
2. Equipment-related variables
3. Process-related variables
1. Formulation-Related Variables
a. Properties of Primary Material. Ideally, the particle properties desired
in the starting material include a low particle density, a small particle size, a
narrow particle size range, the particle shape approaching spherical, a lack of particle
cohesiveness, and a lack of stickiness during the processing. Properties such
as cohesiveness, static charge, particle size distribution, crystalline vs. amorphous
nature, and wettability are some of the properties that have an impact on the properties
of granules formed. The cohesiveness and static charges on particles present
fluidization difficulty. The same difficulties were observed when the formulation
contained hydrophobic material or a mixture of hydrophilic and hydrophobic materials.
The influence of hydrophobicity of primary particles has been shown by
Aulton and Banks [25]. They demonstrated that the mean particle size of the product
was directly related to the wettability of the primary particles, expressed as cos
 (where  is the contact angle of the particles). It was also reported that as the hydrophobicity
of the mix is increased, a decrease in granule growth is observed.
Aulton et al., in a later publication, showed that addition of a surface-active agent
such as sodium laurel sulfate improves the fluidized bed granulation [56]. In a
mixture containing hydrophobic and hydrophilic primary particles, granule
growth of hydrophilic materials takes place selectively, creating content uniformity
problems. Formulating a controlled-release granulation can be accomplished
by using fluid bed granulation. A controlled-release matrix formulation of
naproxin was successfully developed using fluid bed granulation [86].
b. Low-Dose Drug Content. Wan et al. [87] studied various methods of
incorporating a low-dose drug such as chlorphenarmine maleate in lactose formu-
Batch Size Increase in Fluid Bed Granulation 193
lation with PVP as the granulating solution. They concluded that the randomized
movement of particles in the fluid bed may cause segregation of the drug and that
uniform drug distribution was best achieved by dissolving the drug in granulating
solution. The mixing efficiency of drug particles with the bulk material was found
to increase in proportion with the granulating liquid used to dissolve the drug. The
optimum nozzle atomizing pressure was deemed to be important to avoid spraydrying
the drug particles or overwetting, which creates uneven drug distribution.
Higashide et al. [88] studied the fluidized bed granulation using 5-fluorouracil in
concentration of 0.3% in 1:1 mixture of starch and lactose. Hydroxy propyl cellulose
(HPC) was used as the binder. The ratios of starch and lactose contained in
the granules were measured gravimetrically. The researchers found that a bigger
amount of the drug and starch was found in larger granules than in smaller granules.
The results were attributed to the hydrophobicity of the 5-fluorouracil,
starch, and the hydrophilicity of lactose.
c. Binder. A more general discussion on the types of binders used in the
pharmaceutical granulations and their influence on the final granule properties
was presented in Ref. 88a. Different binders have different binding properties, and
the concentration of individual binder may have to be changed to obtain similar
binding of primary particles. Thus the type of binder, the binder content in the formulation,
and the concentration of the binder have a major influence on granule
properties. These properties include friability, flow, bulk density, porosity, and
size distribution.
Davies and Gloor [89,90] reported that the types of binder, such as povidone,
acacia, gelatin, and hydroxypropyl cellulose (HPC), all have different binding
properties that affect the final granule properties just mentioned. Hontz [83]
investigated the effects of microcrystalline cellulose concentration, inlet-air temperature,
binder (PVP) concentration, and binder solution concentration on tablet
properties. Binder and microcrystalline cellulose concentration were found to
have a significant effect on tablet properties. Alkan et al. [68] studied binder
(PVP) addition in solution and as a dry powder in the powder mix. They found a
larger mean granule size when the dry binder was granulated with ethanol. However,
when the binder was in solution, the granules produced were less friable and
more free-flowing. This same finding was confirmed by other researchers [84,85].
Binder temperature affects the viscosity of the solution, which in turn affects the
droplet size. Increased temperature of the binder solution reduces the viscosity of
the solution, reducing the droplet size and hence producing smaller mean granule
size. Binder solution viscosity and concentration affect the droplet size of the
binder. Polymers, starches, and high-molecular-weight PVP cause increased viscosity,
which in turn creates larger droplet size and subsequently larger mean
granule particle size [60].
Diluted binders are preferred because they facilitate finer atomization of the
binder solution, provide the control of the particle size, reduce friability, and in-
194 Parikh
crease the bulk density even though the tackiness or binding strength may suffer
[17,61,71,75,90].
d. Binder Solvent. In most instances water is used as a solvent. The selection
of solvent, such as aqueous or organic, depends upon the solubility of the
binder and the compatibility of product being granulated. Generally organic solvents,
due to their rapid vaporization from the process, produce smaller granules
than the aqueous solution. Different solvents have different heats of vaporization
as shown in Table 1. Requirement of solvent for the binder can be eliminated by
incorporating binder or a mixture of binders of low melting point and incorporating
it with the drug substance in the dry form. The temperature of the incoming air
is sufficient to melt the binder and form the granules.
2. Equipment-Related Variables
a. Design. The various fluid bed processors available from different
equipment suppliers are essentially similar. The differences in design sometimes
engender difficulty in scaling up from the laboratory units to production units in a
linear scale.
To fluidize and thus granulate and dry the product, a certain quantity of process
air is required. The volume of air required will vary based upon the amount
of material that needs to be processed. The ratio of drying capacity of the process
air to quantity of the product needs to be maintained constant throughout the scaling-
up process. However, some equipment suppliers provide higher drying capacity
for their laboratory unit but cannot maintain the same ratio for the production
units. This lack of proportionality reduces the drying capacity per unit volume
of process air, resulting in a longer process time in the production units. The current
design of the fluid bed is a modular one, where multiple processes, such as
drying, granulating, coating, and rotoprocessing, can be carried out by simply
changing the container specially designed for the process.
b. Air Distributor Plate. The process of agglomeration and attrition due
to random fluidization requires control of the particle during the granulation pro-
Batch Size Increase in Fluid Bed Granulation 195
Table 1 Heat of Vaporization for Commonly Used Solvents
Boiling point Density Heat of vaporization
Solvent ()C) (g/mL) (kcal/g)
Methylene chloride 40.0 1.327 77.0
Acetone 56.2 0.790 123.5
Methanol 65.0 0.791 262.8
Ethanol 78.5 0.789 204.3
Isopropanol 82.4 0.786 175.0
Water 100.0 1.000 540.0
cess. Optimization of the process requires control over fluidized particles. This is
a complex phenomenon due to the prevailing fluidizing conditions and a particle
size distribution that undergoes changes during the process. As the conditioned air
is introduced through the lower plenum of the batch fluid bed, the fluidizing velocity
of a given volume of air determines how fluidization will be achieved.
Perforated air distributor plates covered with the 60-325 mesh fine stainless
steel screen, described previously, provide an appropriate means of supplying air
to the product. These plates are identified by their percentage of open area. Air distributors
plates that have 4–30% open area are normally available. These interchangeable
plates provide a range of loading capacities so that batches of various
sizes can be produced efficiently and with uniform quality. To prevent channeling,
an operator can select a plate with optimum lift properties. For example, a
product with low bulk density requires low fluidizing velocity. A distributor plate
having a small open area to give a large enough pressure drop may provide uniform
fluidization of such a product without reaching entraining velocity and impinging
the process filters. Alternatively, a product with higher bulk density can
be fluidized and processed using a plate with a larger open area. The air distributor
plate consists of a perforated plate and a fine-mesh screen. This arrangement
sometimes causes problems, like product leakage due to a torn screen, and difficulty
in cleaning without separating the perforated plate and the fine-mesh screen.
To overcome these deficiencies, an overlap gill plate has recently been introduced.
These plate designs were discussed earlier in the chapter.
c. Pressure Drop. Flow of air through the fluid bed processor is created
by the blower or a fan located downstream from the process chamber. This fan imparts
motion and pressure to air using a paddle-wheel action. The moving air acquires
a force or pressure component in its direction of motion because of its
weight and inertia. This force, called velocity pressure, is measured in inches or
millimeters of water column. In operating duct systems, a second pressure that is
independent of air velocity or movement is always present. Known as static pressure,
it acts equally in all directions. In exhaust systems such as fluid bed processors,
a negative static pressure exists on the inlet side of the fan. Total pressure is
thus a combination of static and velocity pressures. Blower size is determined by
calculating the pressure drop (P) created by all the components of the fluid bed
processing system. Proper selection of blower is essential in fluid bed design. A
blower with appropriate P will fluidize the process material adequately. However,
a blower without enough P will not allow proper fluidization of the product, resulting
in longer process time and improper granulation. A similar effect can be
seen when a product with unusually high bulk density is processed in place of normal
pharmaceutical materials or when there is an air distributor plate offering high
resistance due to its construction. This creates a pressure drop that the blower was
not designed to handle. A proper-sized blower or fan should develop sufficient P
so that the exhaust damper can be used in the 30–60% open position.
196 Parikh
Any additional components, such as scrubbers, exhaust HEPA, police filters or
other components in the air handling unit, would require a larger blower/static
pressure, which can be recommended by the supplier of the fluid bed processor.
d. Shaker/Blow-Back Cycle Mechanism. To retain entrained particles of
a process material, process filters are used. To maintain these filters from building
up layers of fine process material and causing higher pressure drop and thus
improper fluidization; these filters are cleaned during the granulation process.
When bag filters are used, mechanical means are used to clean them. This mechanical
cleaning of the bag filters requires a cessation of air flow, and thus of the
fluidization, during the filter cleaning process. In units with a single bag house,
this results in a momentary dead bed, where no fluidization takes place. This interruption
in the process extends the process time. To avoid process interruptions,
a multishaking filter bag arrangement is desired, where granulation process is continuous.
The continuous process is also achieved by using bag filters with a blowback
or using stainless steel filter bags where air under pressure is pulsed through
the filters. Generally, filters should be cleaned frequently during the granulation
step so as to incorporate the fines in the granulation. This is possible if the cleaning
frequency is high and the period between the filter cleaning short. Rawley [91]
reported the effect of bag-shake/interval cycle. He discussed the possibility of improving
particle size distribution by optimizing the shake time and the corresponding
interval between bag shakes.
The following general guidelines for filter cleaning frequency and duration
are recommended.
Single-shaker unit: Frequency of 2–10 minutes between filter cleaning,
5–10 seconds for shaking. This may vary because the fine powders form
granules, and the frequency between the shakes or the duration of the
shaking interval can be extended. In any case, the dead bed time should
be kept at a minimum in a single-shaker unit.
Multiple-shaker unit: Since this is a continuous process, the frequency of
shaking for each section is approximately 15–30 seconds between filter
cleanings and about 5 seconds for shaking the filters. If a low-pressure
blow-back system is used for the bags, the frequency of cleaning is about
10–30 seconds.
Cartridge filters: These offer continuous processing and require cleaning
frequency of 10–30 seconds.
The cleaning frequency and cleaning duration is now offered as an automated
system where instead of having base the cleaning frequency on time, the
trigger point for filter cleaning is the buildup of a pressure drop across the filters.
This automates the process and eliminates operator input.
e. Other Miscellaneous Equipment Factors. Granulator bowl geometry
is considered to be a factor that may have an impact on the agglomeration process.
Batch Size Increase in Fluid Bed Granulation 197
The fluidization velocity must drop from the bottom to the top rim of the bowl by
more than half to prevent smaller, lighter particles from being impinged into the
filter, creating segregation from heavier product components in the bowl. Generally,
a conical shape of the container and expansion chamber is preferred, where
the ratio of the cross-sectional diameter of the distributor plate to the top of the
vessel is 1:2. Most of the suppliers of this equipment offer units with a multiprocessor
concept, where a single unit can be used for drying, agglomerating, air suspension
coating, or rotoprocessing by changing the processing container while the
rest of the unit is common. This approach does eliminate the concerns about the
geometry of the processor because of the way these units are constructed.
3. Process-Related Variables
The agglomeration process is a dynamic process where a droplet is created by a
two-fluid nozzle and deposited on the randomly fluidized particle. The binder solvent
evaporates, leaving behind the binder. Before all of the solvent is evaporated,
other randomized particles form bonds on the wet site. This process is repeated numerous
times to produce the desired agglomerated product. There are a number of
process variables that control the agglomeration. The process variables most important
to consider are:
Process inlet-air temperature
Atomization-air pressure
Fluidization-air velocity and volume
Liquid spray rate
Nozzle position and number of spray heads
Product and exhaust-air temperature
Filter porosity and cleaning frequency
Bowl capacity
These process parameters are interdependent and can produce desirable
product if this interdependency is understood. Inlet-process-air temperature is determined
by the choice of binder vehicle, whether it is aqueous or organic, and the
heat sensitivity of the product being agglomerated. Generally, aqueous vehicles
will enable the use of temperatures between 60 and 100°C. On the other hand, organic
vehicles will require the use of temperatures from 50°C to below room temperature.
Higher temperatures will produce rapid evaporation of the binder solution
and will produce smaller, friable granules. On the other hand, lower
temperatures will produce larger and fluffier and denser granules. Figure 14
shows the relationship of inlet-air and product-air temperature and outlet air humidity
during the granulation process.
The process of drying while applying spraying solution is a critical unit
operation. This mass transfer step was previously discussed. The temperature,
humidity, and volume of the process air determines the drying capacity. If the
198 Parikh
drying capacity of the air is fixed from one batch to the next, then the spray rate
can also be fixed. If the drying capacity of the air is too high, the binder solution
will have a tendency to spray-dry before it can effectively form bridges between
the primary particles. If, on the other hand, the drying capacity of the air
is too low, the bed moisture level will become too high and particle growth may
become uncontrollable. This will result in unacceptable movement of the product
bed.
As previously discussed, the appropriate process-air volume, inlet-air temperature,
and binder spray rate are critical to achieving proper and consistent particle
size distribution and granule characteristics. There are many ways to arrive
at the proper operating parameters. The following procedure was found by the authors
to be one of the ways one can set the operating parameters when granulating
with fluid bed processors.
1. Determine the proper volume of air to achieve adequate mixing and
particle movement in the bowl. Avoid excessive volumetric air flow so
as to entrain the particles into the filters.
Batch Size Increase in Fluid Bed Granulation 199
Figure 14 Temperature and humidity changes during the granulation process.
2. Choose an inlet-air temperature that is high enough to negate weather
effects (outside-air humidity or inside-room conditions). The air temperature
should not be detrimental to the product being granulated. (To
achieve consistent process year round, a dehumidification/humidification
system is necessary, which provides the process air with a constant
dew point and hence a constant drying capacity).
3. Achieve a binder solution spray rate that will not dry while spraying
(spray-drying) and will not overwet the bed. This rate should also allow
the nozzle to atomize the binder solution to the required droplet size.
4. As stated earlier, a typical air velocity used for spray granulation is
from 1.0 to 2.0 meters/second. Table 2, which is based upon the psychometric
chart, gives a first guess at determining the proper spray rate
for a spray granulation process in a fluid bed processor.
The variables in the fluid bed granulation process and its impact on the final
granulation were summarized by Davies and Gloor Jr. [92]; they state that the
200 Parikh
Table 2 Calculation of Fluid Bed Spray Rate
Given process data
Air volume range:
Minimum (1.2 m/sec) m3/hr
Maximum (1.8 m/sec) m3/hr
Inlet-air temperature and humidity to be used: )C % RH
% solids in sprayed solution % solids
From psychrometric chart
Air density at point where air volume is measured: m3/kg air
Inlet air absolute humidity (H): g H2O/kg air
Maximum outlet air absolute humidity (H): g H2O/kg air
(follow line of constant adiabatic conditions)
Use 100% outlet RH for spray granulator or 30–90% (as required) for column coating
Calculations for spray rate
Step 1. Convert air volumetric rate to air mass rate:
Minimum m3/hr + (60  m3/kg air) 
 kg air/min
Maximum m3/hr + (60  m3/kg air) 
 kg air/min
Step 2. Subract inlet-air humidity from outlet-air humidity:
(g H2O/kg air) H out  (g H2O/kg air) H in 

g H2O removed/kg air
Step 3. Calculate (minimum and maximum) spray rate of solution:
(This will provide a range of generally acceptable spray rates based on the airflow
used in the unit.)
Step 1 (minimum)  Step 2 + [1  ( % solids +
100)] 
 spray rate (g/min) at minimum airflow
Step 1 (maximum)  Step 2 + [1  ( % solids +
100)] 
 spray rate (g/min) at minimum airflow
physical properties of granulation are dependent upon both the individual formulations
and the various operational variables associated with the process. The solution
spray rate increase and subsequent increase in average granule size resulted
in a less friable granulation, higher bulk density, and a better flow property for a
lactose/corn starch granulation. Similar results were obtained by an enhancing the
binder solution, decreasing the nozzle air pressure, or lowering the inlet-air temperature
during the granulation cycle. The position of the binary nozzle with respect
to the fluidized powders was also studied. It was concluded that by lowering
the nozzle, binder efficiency is enhanced, resulting in average granule size and
a corresponding decrease in granule friability. The significant process parameters
and their effect on the granule properties are summarized in the Table 3.
Batch Size Increase in Fluid Bed Granulation 201
Table 3 Effect of Process Parameters on Granular Properties
Process
parameter Effect on process Refs.
Inlet-air
temperature
Humidity
Fluidizing air
flow
Nozzle and
nozzle height
Atomization air
volume and
pressure
Binder spray
rate
Higher inlet temperature produces finer granules, and
lower temperature produces larger, stronger granules.
Increase in air humidity causes larger granule size,
longer drying times.
Proper air flow should fluidize the bed without clogging
the filters. Higher air flow will cause attrition
and rapid evaporation, generating smaller granules
and fines.
A binary nozzle produces finest droplets and is preferred.
The size of the orifice has an insignificant
effect except when binder suspensions are to be
sprayed. Optimum nozzle height should cover the
bed surface. Too close to the bed will wet the bed
faster, producing larger granules, whereas too high
a position will spray-dry the binder, create finer
granules, and increase granulation time.
Liquid is atomized by the compressed air. This
mass/liquid ratio must be kept constant to control
the droplet size and, hence, the granule size. Higher
liquid flow rate will produce larger droplet and
larger granules and the reverse will produce
smaller granules. At a given pressure, an increase
in orifice size will increase droplet size and liquid
throughput.
Droplet size is affected by liquid flow rate, binder viscosity,
and atomizing air pressure and volume. The
finer the droplet, the smaller the resulting average
granules.
75, 94
40
3, 75
60
40, 60, 92, 95
57, 74, 75, 95
Maroglou and Nienow [36] listed various parameters affecting the type and
rate of growth in batch fluidized granulation (Table 4) and showed the influence
of the process parameters and the material parameters on the product.
VI. PROCESS CONTROLS AND AUTOMATION
The agglomeration process is a batch process, and accurate repeatable control of
all critical process parameters is necessary for a robust system. Earlier designs of
202 Parikh
Table 4 Granulation Parameters Affecting the Type and Rate of Growth in Batch
Fluidized Granulation
Operating parameters
Droplet size NARa
Atomization air velocity
Rheology
Surface tension
Nozzle position
Nozzle type
Bed moisture content Solution type and feed rate
Bed temperature
Fluidization velocity
Attrition Fluidization velocity
Aspect ratio
Nozzle position and atomization air velocity
Distributor design
Jet grinding
Solution (binder) concentration Bridge strength and size
Rheology
Material parameters
Solution (binder) concentration Bridge strength and size
Rheology
Type of binder & wettability Molecularlength and weight
Particle–solvent interaction
Surface tension
Viscosity
Material to be granulated Average size
Size distributionb
Shape
Porosity
Drying characteristics
Density and density differenceb
a NAR is the ratio of air to liquid flow rates through the nozzle of a twin-fluid atomizer, expressed
either in mass units or in volume units (air at STP).
b Especially important relative to elutriation and segregation.
the fluid bed processor used pneumatic control, which provided safe operation in
hazardous areas but relied heavily on human actions to achieve repeatable product
quality and accurate data acquisition. Current designs use programmable logic controllers
(PLCs) and personal computers (PCs) to achieve sophisticated control and
data acquisition. The operating conditions are controlled to satisfy parameters of
multiple user-configured recipes, and critical data is collected at selected time intervals
for inclusion in an end-of-batch report. Access to all user-configured data
is protected by security levels, with passwords permitting access only to selected
functions. With the appropriate security level, not only are operating conditions
configured, but also identification of each valid recipe and operator is entered. The
identification is verified before any operator actions are permitted and is included
with the end-of-run report. The use of computer-related hardware requires some
additional validation; but with coordination between the control system provider
and the end user, the validation of software can be managed. Figure 15a shows a
PLC-based control panel; and Figure 15b shows a typical operation screen.
The most important sensors for control of the drying process are those for
inlet-air and exhaust-air temperature and the sensor for air flow measurement, located
in the air transport system. Other sensors for the spray agglomeration process
include those for atomization air pressure and volume, pressure drops (across
Batch Size Increase in Fluid Bed Granulation 203
(a)
Figure 15 (a) PLC-based control panel. (continues)
204 Parikh
Figure 15 Continued. (b) PLC-based screen providing graphic representation of a process. (Courtesy of Atlantic Pharmaceutical
Services Inc.)
(b)
the inlet filter, the product container with the product being processed and outlet
process air filter), inlet-air humidity or dew point, process filter cleaning frequency
and duration, spray rate for the binder solution, and total process time. All
of these sensors provide constant feedback information to the computer. These
electronic signals may be stored in the computer’s memory and then recalled as a
batch report. With this ability to recall data analysis, a greater insight can be
gained into the process.
VII. PROCESS SCALE-UP
A. Regulatory
Scale-up is normally identified with an incremental increase in batch size until a
desired level of production is obtained. In 1991, the American Association of
Pharmaceutical Scientists (AAPS), along with the U.S. FDA held, a workshop on
scale-up [93]. Several speakers presented scale-up issues from the industrial and
regulatory perspectives. For example, Shangraw divided scale-up problems in two
general categories: those related to raw materials or formulation and those related
to processing equipment. He also indicated that it is essential to ascertain whether
or not changes in raw materials have occurred before one looks at
processing/equipment changes as a source of any problem. The workshop report
as it pertains to the process and equipment is reproduced here.
It is generally recognized that many NDAs and ANDAs contain provision for
multiple manufacturers of the drug substance(s), and that not all drug substance
suppliers, a priori, produce equivalent material. There is then a need for
material quality control to assure the performance and reproducibility of the
finished product. Particle size and distribution, morphology, and intrinsic dissolution
of the drug substance are important considerations. Polymorphism,
hygroscopicity, surface area, wettability, density (bulk and tapped), compressibility
(for dry blending), and powder flow effects should be controlled.
Additionally, the process should be controlled by employment of a validation
protocol, which defines the critical parameters and also establishes the acceptance
criteria for the granulation or blend; which may include sieve analysis,
flow, density, uniformity, and compressibility, moisture content, etc. In
the milling, blending, granulating, and/or drying processes, the operating
principles of the equipment employed should be defined and the variables determined.
The impact and mechanism of measurement on in-process variables
should be defined. Time, temperature, work input of equipment, blend/granulation
volume, and granulating rate should be determined. . . . The parameters
selected should be appropriate for the process. . . . In those cases where
the manufacturing process has been controlled and validated as specified in
the foregoing discussion; batch scale-up, changes in site of manufacture, allowance
for equipment change (where the operating principle is the same),
Batch Size Increase in Fluid Bed Granulation 205
minor formulation changes, etc., should be determined on the basis of the
comparability of both the blend/granulation and the final product, as assured
by: (a) appropriate tests; (b) specifications; (c) process validation; and (d)
comparative accelerated stability.
B. Scale-Up and Equipment Design
The scale-up from laboratory equipment to production-size units is dependent on
equipment design, which may or may not have been scalable as far as its selected
dimensional features or components is concerned. The importance of scalability
is well understood and accepted by the manufacturers of fluid bed processors.
Various sizes in their product line are logically designated and manufactured. Air
flow in the fluid bed process is a critical parameter. The design and selection of
the processor is very important for the laboratory and the production unit. Because
air flow is one of the components of the drying capacity of a fluid bed system, the
ratio of air volume per kg or liter of the product is very critical to achieve scaleup
that is linear. The other critical design feature is the cross-sectional area of the
product container and how it has been designed throughout the various sizes that
a manufacturer supplies. The relationship between various sizes of the process
containers can be utilized to calculate the scale-up of binder spray rate; if the
cross-sectional area is designed linearly, then the spray rate scale-up can be linear.
C. Scale-Up and Process Factors
The fluid bed agglomeration process is a combination of three steps: dry mixing,
spray agglomeration, and drying to a desired moisture level. These process steps
are equally important. But the quality of the granules is really determined during
the spraying stage, the process where constant building of granules and evaporation
of binder solvent is taking place. Granule size is directly proportional to the
bed humidity during granulation [40]; hence, control of this humidity during
scale-up is essential.
Gore et al. [94] studied the factors affecting the fluid bed process during
scale-up. The authors found that the processing factors that most affected granule
characteristics were process-air temperature, height of the spray nozzle from the
bed, rate of binder addition, and degree of atomization of the binder liquid.
The atomizing air pressure and the wetness of the bed are two of the most important
elements of fluid bed granulation. A higher atomizing air pressure yields a
finer droplet of binder solution. Therefore granule growth, as described earlier in
this section, will be affected by the atomizing air pressure. A major factor that must
be considered during the scale-up of a fluid bed granulation process is maintaining
the same droplet size of the binder for ensuring successful scale-up. A more recent
study [95] confirmed the influence of the spray nozzle setup parameters and the
drying capacity of the air. The study concluded that more attention should be given
206 Parikh
to the easily overlooked nozzle atomizing air pressure and volume. When considering
the atomizing air pressure, attention must be paid to ensure that enough air is
delivered to the nozzle tip. This can be ensured by placing air pressure and volume
measurement devices at the nozzle. The data also show that the drying capacity of
the process air influences the final granulated particle size. Jones [96] has suggested
the following process-related factors that should be considered during the
scale-up of fluid bed processing: Due to the higher degree of attrition in the larger
unit as compared to the smaller unit, the bulk density of the granulation from the
larger fluid bed is approximately 20% higher than that of the smaller unit. He also
reemphasized the importance of keeping the bed moisture level below a critical
moisture level to prevent the formation of larger agglomerates. Since the higher air
flow, along with the temperature (drying capacity) in a larger unit, provides a
higher evaporation rate, one must maintain the drying capacity in the larger unit
such that the bed temperature is similar to the smaller unit’s bed temperature. This
can be accomplished either by increased spray rate, increased air temperature, increased
air flow, or a combination of these variables to obtain suitable results. Since
the ratio of bed depth to the air distributor increases with the size of the equipment,
the fluidization air velocity is kept constant by increasing the air volume.
In the past, scale-up was carried out by selecting best-guess process parameters.
The recent trend is to employ the factorial and modified factorial designs
and search methods. These statistically designed experimental plans can generate
mathematical relationships between the independent variables, such as process
factors, and the dependent variables, such as product properties. This approach
still requires an effective laboratory/pilot-scale development program and an understanding
of the variables that affect the product properties.
In summary, when scaling up, the following processing conditions should
be similar to those in the pilot-scale studies.
Fluidization velocity of the process air through the system
Ratio of granulation spray rate to the drying capacity of the fluidization air
volume
Droplet size of the binder spray liquid
Each of these values must be calculated based on the results of the operation of the
pilot-size unit. Pilot-size equipment studies should also be conducted in a wide
range to determine the allowable operating range for the process.
VIII. CASE STUDY
The following case study illustrates how a product is scaled up from 15 kg to 150
kg in equipment supplied by Aeromatic when one understands the critical process
parameters used when scaling up.
Batch Size Increase in Fluid Bed Granulation 207
A spray granulation process was developed for a common pharmaceutical
compound. The granulation process involved spraying a 5% w/w binder solution
onto the fluidized powder. Table 5 shows the data from the 15-kg run and the resulting
successful 150-kg run condition for a spray agglomeration process [97].
A. Air Flow Calculations
To maintain the same fluidization velocity, the air volume in a larger unit must be
increased, based upon the cross-sectional area of the product bowl. In this case,
the cross-sectional area of the base of the larger container was 0.77 m2 and the
smaller was 0.06 m2. The correct air flow should be calculated as
300  (0.77/0.06) 
 3850 CMH
This number was further modified, after considering the increase in bed depth in
a larger unit, to 4000 CMH.
B. Spray Rate Calculations
To maintain the same particle size, the triple-headed nozzle could spray three
times the pilot-unit spray rate at a 2.5 atomization air pressure. However, this
could result in a longer process time. Another approach to maintain a similar
droplet size is to maintain the mass balance of spray rate and the atomization pressure.
Thus by increasing the atomization pressure to 5 bar, the spray rate was increased
to 800 grams per minute, keeping the same droplet size and hence obtaining
granulation with desired characteristics.
C. Temperature Calculations
Finally, the required inlet temperature was recalculated based upon the change
in the ratio of air volume to spray rate. Because the air volume was increased
over 13 times but the spray rate was increased only 8 times, the inlet tempera-
208 Parikh
Table 5 Scale-Up of Fluid Bed Granulation Process Parameters
Process parameter 15 kg 150 kg
Airflow (m3h1) 300 4000
Inlet-air temperature ()C) 55 50
Spray rate (g min1) 100 800
Nozzle air pressure (bar) 2.5 5
Container cross-sectional 0.06 0.77
area of the base (m2)
Numbers of nozzles 1 3
ture was reduced to 50°C. This adjustment in drying capacity was necessary to
avoid spray-drying the spray solution. (A three-headed nozzle used in this scaleup
can be replaced by a six-headed nozzle. This would have resulted in the ability
to increase the spraying rate 13 times above the pilot-size unit to match the
air flow. The maintenance of droplet size and temperature could have been
achieved with the six-headed nozzle. The end result would be reduced process
time.) Figure 16 shows the particle size distribution produced using the 15-kg
unit and the 150-kg unit.
IX. MATERIAL HANDLING
The transfer of materials to and from a fluid bed processor is an important consideration.
The loading and unloading of the processing bowl can be accomplished
by manual mode or by automated methods.
A. Loading
The contemporary method for loading the unit is to remove the product bowl from
the unit, charge the material into the bowl, and then place the bowl back into the
unit. This loading is simple and cost effective. Unfortunately, it has the potential
of exposing the operators to the product and contaminating the working area. To
avoid making the product a dust and cleaning hazard, a system should be installed
Batch Size Increase in Fluid Bed Granulation 209
Figure 16 Scale-up case study and resultant particle size distribution.
to collect the dust before it spreads. A manual process also depends on the batch
size and on the operator’s physical ability to handle the material and the containerful
of product. Furthermore, this can be time consuming, since the material must
be added to the product container one material at a time.
The loading process can be automated and isolated to avoid worker exposure,
minimize dust generation, and reduce loading time. There are two main types
of loading systems, which are similar because both use the fluid bed’s capability
to create a vacuum inside the unit. Here the product enters the fluid bed through a
product in-feed port on the side of the unit. This is done by having the fan running
and the inlet-air control flap set so that minimum air flow may pass through the
product container and the outlet flap is almost fully open. Once the material has
210 Parikh
Figure 17 Loading the fluid bed through the product in-feed port and unloading through
the bottom of the fluid bed processor. (Courtesy of Niro Pharma Systems.)
been charged to the fluid bed, the product in-feed valve is closed and the granulating
process started. This transfer method uses some amount of air to help the
material move through the tube. Figure 17 shows the setup for loading the fluid
bed. Loading can be done either vertically, from an overhead bin, or from the
ground. Less air is required through the transfer pipe when the material is transferred
vertically, because gravity is working to help the process. Vertical transfer
methods do require greater available height in the process area. Loading by this
method has the advantages of limiting operator exposure to the product, allowing
the product to be fluidized as it enters the processor, and reducing the loading
time. The disadvantage of this type of system is that cleaning is required between
different products.
B. Unloading
As with loading, the standard method for unloading is to remove the product bowl
from the unit. Once the bowl is removed, the operator may scoop the material from
the bowl, which is the most time-consuming and impractical method, because of the
potential for exposure to the product. Alternatively, the product can be vacuum-transferred
to a secondary container or unloaded by placing the product bowl into a bowl
dumping device, as shown in Figure 18. This hydraulic device is installed in the pro-
Batch Size Increase in Fluid Bed Granulation 211
(a)
Figure 18 (a) Product discharge with a bowl dumping device. (continues)
cessing area. The mobile product container of the fluid bed processor is pushed under
the cone of the bowl dumper and coupled together by engaging the toggle locks.
Subsequently, the container is lifted hydraulically, pivoted around the lifting column,
and rotated 180° for discharging. Use of the bowl dumping device or vacuum unloading
device still requires the product bowl to be removed from the unit.
There are contained and automated methods for unloading the product while
the product bowl is still in the fluid bed processor. The product may be unloaded
either out of the bottom of the product container or from the side. Until recently,
212 Parikh
(b)
Figure 18 Continued. (b) Mechanism of bowl lifting, raising, inverting, and bringing it
down for discharging. (Courtesy of Atlantic Pharmaceutical Services Inc.).
the most common contained method was to unload the material from the bottom
of the unit. This requires a ceiling high enough to accommodate the operation, or
the installation becomes a multistoried installation. There are two types of bottom
discharge options: gravity and pneumatic (Fig. 19). Gravity discharge allows for
collection of the product into a container, which is located below the lower
plenum. If the overall ceiling height limitation prevents discharge by gravity, a
gravity/pneumatic transfer combination can be considered. Gravity discharge
poses cleaning problems, since the process air and the product discharge follow
the same path; assurance of cleanliness is always of prime concern.
The desire to limit the processing area, and the development of the overlap
gill air distributor mentioned earlier in the chapter, has prompted the consideration
of side discharge as an option. The product bowl is fitted with the discharge
gate as shown in Figure 20. Most of the product, being free-flowing granules,
Batch Size Increase in Fluid Bed Granulation 213
Figure 19 Product discharge through the bottom (pneumatic or gravity). (Courtesy of
Niro Pharma Systems.)
214 Parikh
Figure 20 Product discharge through the side, showing closed and open discharge with
overlap gill air distributor. (Courtesy of Atlantic Pharmaceutical Services Inc.)
flows through the side discharge into a container. The remainder of the product is
then discharged by manipulation of the air flow through the overlap gill air distributor.
The discharged product can be pneumatically transported to an overhead
bin if dry milling of the granulation is desired.
The contained system for unloading the product helps to isolate the operator
from the product. The isolation feature also prevents the product from being
contaminated via exposure to the work environment. Material handling must be
thought of early in the equipment procurement process. With fluid bed processing,
whether it’s an integral part of a high-shear mixer/fluid bed dryer or a granulating
equipment option, production efficiency and eventual automation can be
enhanced by considering these loading and unloading options.
X. SUMMARY
The fluid bed process, similar to other granulation techniques, requires an understanding
of the importance of characterizing the raw materials (especially for a active
pharmaceutical ingredient), the process equipment, the limitations of the selected
process, the establishment of an in-process control specifications, the
characterization of the finished product, and cleaning and process validation. It is
equally important that the formulation and development scientists not lose sight of
the fact that the process being developed in the pilot plant must be transferred to
the production floor. The scientists should spend enough time in the production
department to understand the scale of operation that the desired process is being
developed to.
Process scale-up can become very challenging if issues other than the fluid
bed process are not addressed as one scales up. The selection of the solution delivery
system could have significant impact on the process scale-up. For example,
as you scale up the solution preparation step, the ingredient addition sequence and
its impact, if any, need to be evaluated; the size and type of the impeller could determine
if the homogenous binder solution is prepared to provide uniform binder
concentration. Sometimes the length of the tubing from the solution tank to the
processor creates problems, such as settlement of particles (where suspension is
being sprayed as a binder) and possible breakage or back pressure developed from
the clogged nozzle port. The control of spray rate to deliver the adequate quantity
of solution can depend on the selection of the pump, the size of the liquid transfer
lines, the size of the nozzle orifice, etc.
Similarly, scientists must think through how the material will be added and
taken away from the processor. Without this forethought, processes that come to
production can wind up very labor intensive. If the development scientists work
with the production and engineering departments from early on, such difficulties
can be avoided.
Batch Size Increase in Fluid Bed Granulation 215
REFERENCES
1. Kulling, W., and Simon. Fluid bed technology applied to pharmaceuticals. Pharm.
Technol. 4(1), 1980.
2. Gomezplata, A., and Kugelman, A. M. Processing systems. Chapter 4, In: Gas–Solid
Handling in the Process Industries. Joseph M. Marchello & Albert Gomezplata, eds.
New York: Marcel Dekker, 1976, Chap 4.
3. Parikh, D. M. Airflow in batch fluid bed processing. Pharm. Technol. 15(3):100–110,
1991.
4. Thiel, W. J. Solids mixing in gas fluidized beds. Int. J. Pharm. Tech. Prod. Manuf.
2(9):1981.
5. Row, P. N., et al. Trans. Inst. Chem. Eng. 32T:271, 1965.
6. Davis, L., et al. Trans. Inst. Chem. Eng. 44T:293, 1966.
7. Gorrodnichev, V. I., et al. Pharm. Chem. J. (USSR) (English translation) 8:298, 1974.
8. Thiel, W. J. The theory of fluidization and application to the industrial processing of
pharmaceutical products. Int. J. Pharm. Tech. Prod. Manuf. 2(5):1981.
9. Kirk-Othmer, Fluidization. In: Encyclopedia of Chemical Technology. Vol. 10. 3rd
ed. New York: Wiley-Interscience, pp. 548–581.
10. Kunii, D., and Lvenspiel, O. Fluidization Engineering. Wiley, 1968.
11. Wurster, D. E. J. Am. Pharm. Assoc. (Sci. Edi.) 49:82, 1960.
12. Wurster, D. E. J. Am. Pharm. Assoc. (Sci. Edi.) 48(8):451–454, 1959.
13. Scott, M. W. Liberman, H. A., Rankell, A. S., and Battista, J. V. J. Pharm. Sci.
53(3):314–319, 1964.
14. Rankell, A. S., Scott, M. W., Liberman, H. A., Chow, F. S., and Battista, J. V. J.
Pharma. Sci. 53(3):320, 1964.
15. Contini, S., and Atasoy, K. Pharm. Ind. 28:144–146, 1966.
16. Wolf, G. Drugs Made in Germany 11:172–180, 1968.
17. Liske, T., and Mobus, W. The manufacture and comparative aspects of fluidized layer
spray granulation. Drugs Made in Germany 11:182–189, 1968.
18. Sherrington, P. J., and Oliver, R. Granulation. (chapter 3) In: Goldberg, A. S., ed.
Powder Science and Technology. London: Heyden, 1981.
19. Pietch, W. B. In: Fayed, M. E., and Otten, L., eds. Handbook of Powder Science and
Technology. New York: Van Nostrand Reinhold, 1984.
20. Hersey, J. A. Fluidized bed technology—an overview. Int. J. Pharm. Tech. Prod.
Manuf. 2(3):, 1981.
21. Thiel, W. J. The theory of fluidization and application to the industrial processing of
pharmaceutical products. Int. J. Pharm. Tech. Prod. Manuf. 2(5):1981.
22. Littman, H. An overview of flow in fluidized Beds. Pharm. Technol. 9(3):48, 1985.
23. Whitehead, A. B. Behavior of fluidized bed systems. Pharm. Technol. 2(13):1981.
24. Story, M. J. Granulation and film coating in the fluidized bed. Pharm. Technol.
2(19):1981.
25. Aulton, M. J., and Banks, M. Fluidized bed granulation, factors influencing the quality
of the product. Pharm. Technol. 2(24), 1981.
26. US Patent 5,392,531, 1991; European Patent 0507038A1, 1991.
27. Japanese Patent Application 61-259696, 1986.
216 Parikh
28. Swiss Patent 0176/93, 1993; US Patent 5,444,892, 1995, European Patent
0572356A1.
29. Newitt, D. M., and Conway-Jones, J. M., A Contribution to the theory and practice of
granulation. Int. J. Pharm. Tech. Prod. Manuf., 36:422, 1958.
30. Record, P. C. A Review of pharmaceutical granulation technology. Int. J. Pharm.
Tech. Prod. Manuf. 1 32, 1980.
31. Rumpf, Agglomeration. In: W. Krepper, ed., New York: Interscience, 1962, p. 374.
32. Schaefer, T., and Worts, O. Control of fluidized bed granulation. I. Effects of spray
angle, nozzle height and starting materials on granule size and size distribution. Arch.
Pharm. Chemi. Sci. Ed. 5:51–60, 1977.
33. Smith, P. J., and Nienow, A. W. Chem. Eng. Sci. 38(8):1223–1231, 1323–1240,
1983.
34. Aulton, M. E., and Banks, M., Int. J. Pharm. Tech. Prod. Manuf. 2(4):24–29, 1981.
35. Maroglou, A., and Nienow, A. W. 4th Symposium on Agglomeration, Toronto, June
1985, pp. 465–470.
36. Maroglou, A., and Nienow, A. W. Fluidized bed Granulation Technology and its application
to tungsten carbide. Powder Metallurgy 29(4):1986.
37. McCabe, W. L., and Smith, J. C. Unit Operations of Chemical Engineering. New
York: McGraw-Hill, 1956.
38. Green, D. W., ed. Perry’s Chemical Engineer’s Handbook. Section 20. New York:
McGraw-Hill, 1984.
39. Rankell, R. S., Liberman, H. A., and Schiffman, R. F. Drying. In: The Theory and
Practice of Industrial Pharmacy. 3rd ed. Philadelphia: Lea & Feabiger, 1986, pp.
40. Schaefer, T., and Worts, O. Control of fluidized granulation. III. Effects of the inlet
air temperature and liquid flow rate on granule size and size distribution. Arch.
Pharm. Chemi. Sci. Ed. 6:1–13, 1978.
41. Thurn, U. Dissertation no. 4511. Eidgenossischen Technischen, Hochschule, Zurich,
1970.
42. Liske, T., and Mobus, W. Drugs Made in Germany 11(4):182–189, 1968.
43. Schaefer, T., and Worts, O. Control of fluidized bed granulation. I. Effects of spray
angle, nozzle height and starting materials on granule size and size distribution. Arch.
Pharm. Chemi. Sci. Ed. 5:51–60, 1977.
44. Schaefer, T., and Worts, O. Control of fluidized bed granulation. V. Factors affecting
granule growth. Arch. Pharm. Chemi. Sci. Ed. 6:69–82, 1978.
45. Ormos, Z., and Pataki, K. Hung. J. Indust. Chem. 7:89–103, 1979.
46. Ormos, Z., and Pataki, K. Hung. J. Indust. Chem. 7:105–117, 1979.
47. Banks, M. C.N.A.A. Ph.D. dissertation, Leicester Polytechnic, 1981.
48. Galmen, M. J., and Greer, W. Fluid Technol. Pharm. Manuf. International Conference,
Paper 2, Poroder Advisory Center, London, 1982.
49. Aulton, M. E. Fluid Technol. Pharm. Manuf. International Conference, Paper 3, Powder
Advisory Center, London, 1982.
50. Veillard, M., et al. Int. J. Pharm. Tech. Prod. Mfg. 3(4):100–107, 1982.
51. Georgakopoulos, P. P., et al. Pharmazie 38(4):240–243, 1983.
52. Jinot, J. C., et al. S.T.P. Pharma 2(13):126–131, 1986.
53. Shinoda, A., et al. Yakuzaigaku 36(2):83–88, 1976.
Batch Size Increase in Fluid Bed Granulation 217
54. Aulton, M. E., et al. J. Pharm. Pharmacol. Suppl. 59P, 1977.
55. Schepky, G. Acta. Pharm. Technol. 24(3):185–212, 1978.
56. Aulton, M. E., et al. Proc. Int. Conf. Powder Technol. in Pharmacy, Powder Advisory
Center, Basel, Switzerland, June 1979, pp.
57. Kocova, El-Arini, S., et al. Drugs Made in Germany 26(4):205–211, 1983.
58. Davies, W. L., and Gloor, W. T. J. Pharm. Sci. 61(4):618–622, 1972.
59. Rouiller, M., et al. Acta. Pharm. Technol. 21(2):129–138, 1975.
60. Schaefer, T., and Worts, O. Control of Fluidized bed granulation. II. Estimation of
droplet size of atomized binder solution. Arch. Pharm. Chemi. Sci. Ed. 5:178–193,
1977.
61. Ormos, Z., et al. Hung. J. Indust. Chem. 7:131–140, 1979.
62. Ormos, Z., et al. Hung. J. Indust. Chem. 7:141–151, 1979.
63. Ormos, Z., et al. Hung. J. Indust. Chem. 7:153–163, 1979.
64. Ormos, Z., et al. Hung. J. Indust. Chem. 7:221–235, 1979.
65. Kocova El-Arini S. Pharm Ind. 43(7):674–679, 1981.
66. Jager, K. F., and Bauer, K. H. Acta Pharmaceutica Technologica 30(1):85–92, 1984.
67. Nouh, A. T. I. Pharm Ind. 48(6):670–673, 1986.
68. Alkan, H., et al. Doga. Tu. J. Med. Pharm. 11(1):1–7, 1987.
69. Bank, A., et al. Proc. 2nd Conf. Appl. Physic. Chem. 2:687–692, 1971.
70. Davies, W. L., and Gloor, W. T. J. Pharm. Sci. 62(1):170–172, 1973.
71. Ormos, Z., et al. Hung. J. Indust. Chem. 1:307–328, 1973.
72. Ormos, Z. et al. Hung. J. Indust. Chem. 1:463–474, 1973.
73. Johnson, M. C. R., et al. J. Pharm. Pharmacol. Suppl. 80P, 1975.
74. Schaefer, T., and Worts, O. Control of fluidized bed Granulation IV. Effects of binder
solution and atomization on granule size and size distribution. Arch. Pharm. Chemi.
Sci. Ed. 6:14–25, 1978.
75. Aulton, M. E., et al. Mfg. Chem. Aerosol News 12:50–56, 1978.
76. Gorodnichev, V. I., et al. Pharm. Chem. J. (USSR) 14(10):72–77, 1980.
77. Ceschel, G. C., et al. Il Farmaco Ed. Prat. 36(6):281–293, 1981.
78. Rangnarsson, G., et al. Int. J. Pharmaceut. 12:163–171, 1982.
79. Meshali, M., El-Banna, H. M., El-Sabbagh, H. Pharmazie 38(5):323–325, 1983.
80. Hajdu, R., and Ormos, Z. Hung. J. Ind. Chem. 12:425–430, 1983.
81. Devay, A., et al. Acta Pharmaceutica Technologica 30(3):239–242, 1984.
82. Alkan, M. H., and Yuksel, A. Drug. Dev. Ind. Pharm. 12(10):1529–1543, 1986.
83. Hontz, J. Assessment of Selected formulation and processing variables in fluid bed
granulation. Ph.D. dissertation, University of Maryland at Baltimore, 1987.
84. Wan, L. S. C., and Lim, K. S. S.T.P. Pharm. 4(7):560–571, 1988.
85. Wan, L. S. C., and Lim, K. S. S.T.P. Pharm. 5(4):244–250, 1989.
86. Dahl, T. C., and Bormeth, A. P. Naproxen controlled release matrix tablets: fluid bed
granulation feasibility. Drug. Dev. Ind. Pharm. 16(4):581–590, 1990.
87. Wan, Lucy S. C., Heng, Paul W. S., and Muhuri, G. Incorporation and distribution of
a low-dose drug in granules. Int. J. Pharmaceutics 88:159–163, 1992.
88. Higashide, F., Miki Y., Nozawa, Y., and Ishibashi, K. Dependence of drug content
uniformity on particle sizes in fluidized bed granulation. Pharm. Ind.
47(11):1202–1205, 1985.
218 Parikh
88a. Khankari R, Hontz J. Binders and solvents. In: Parikh D, ed. Handbook of Pharmaceutical
Granulation Theory. New York: Marcel Dekker, 1997, pp 54–73.
89. Davies, W. L., and Gloor Jr., W. T. Batch production of pharmaceutical granulation
in fluidized bed II: effects of various binders and their concentrations on granulations
and compressed tablets. J. Pharm. Sci. 61:618, 1972.
90. Davies, W. L., and Gloor Jr., W. T. Batch production of pharmaceutical granulation
in fluidized bed III: binder dilution effects on granulation. J. Pharm. Sci. 62:170,
1973.
91. Rawley, F. A. Effects of the bag shaking cycle on the particle size distribution of
granulation. Pharm. Technol. 13(9):78–82, 1989.
92. Davies, W. L., and Gloor Jr., W. T. Batch production of pharmaceutical granulation
in fluidized bed I: effects of process variables on physical properties of final granulation.
J. Pharm. Sci. 60(12):1869–1874, 1971.
93. AAPS/FDA. Scale-Up of Oral Solid Dosage Forms. December 11–13, 1991.
94. Gore, A. Y., McFarland, D. W., Batuyios, N. H. Fluid bed granulation: factors affecting
the process in laboratory development and production scale-up. Pharm. Technol.
9(9):114, 1985.
95. Bonck, J. A., Spray granulation. Presented at the AIChE Annual Meeting, November
1993, pp.
96. Jones, D. M. Factors to consider in fluid bed processing. Pharm. Technol. 9(4):50,
1985.
97. Unpublished data, Niro Inc., Aeromatic-Fielder Division.
98. Parikh DM, Bonck JA, Mogavero M. Batch fluid bed granulation. In: Handbook of
Pharmaceutical Granulation Technology. New York: Marcel Dekker, 1997, pp
227–331.
Batch Size Increase in Fluid Bed Granulation 219

8 (1)
Scale-Up of the Compaction and
Tableting Process
Joseph B. Schwartz
Philadelphia College of Pharmacy, Philadelphia, Pennsylvania
I. INTRODUCTION
A pharmaceutical tablet is a solid compact in any shape, containing drug and/or
excipients, prepared from powder by the application of compressional force, and
exhibiting some degree of strength. Compaction is the pharmaceutical unit operation
of applying pressure or force to the powder to densify it and generate the
physical bonds between the powder particles to create this strength.
To consider the subject of scale-up of the compaction and tableting process,
one must consider the production of one tablet in 30 minutes, if one were a new
graduate student using the Carver Hydraulic Laboratory Press for the first time, to
a single-stroke Model E or Model F press at 60 tablets per minute, to a full-scale
rotary tablet press at more than 2000 tablets per minute.
The principles of compaction/compression are the same. The critical parameters
are (1) the material properties of the particles being compacted and (2)
the equipment used for the compaction operation. Some general compaction concepts
should be kept in mind.
1. Tablet presses fill by volume. This volume is controlled by the position
of the lower punch in the die. This, in turn, controls tablet weight and,
therefore, dose.
2. Tablet shape is fixed by the shape of the die cavity and the punch faces.
3. On all presses, the upper punch is set to come down to a specific point
in the die cavity; this position, which is set by the operator, controls
tablet thickness. More specifically, this setting controls the compaction
force (pressure) and, in turn, tablet hardness.
221
The only real test to determine that the scale-up batch will run well on the
selected tablet press in production is a “use test”; i.e., the batch must be run. Although
there is no completely accurate prediction of compaction behavior during
scale-up, there are many excellent test methods that can provide an evaluation of
specific material properties (flow, lubrication, etc.) and provide an understanding
of the material properties of one’s formulation. If proper science is applied, these
measurements and approaches can provide assurance that scale-up can occur with
a minimum of problems.
II. COMPACTION
The basic mechanical unit of compaction/compression consists of three parts: (1)
an upper punch, (2) a lower punch, and (3) a die. Producing a finished tablet involves
the compaction of a powdered solid between two punches and within the
confines of a die, with the application of an external force [1].
There are three definitions needed to accurately describe this process. (1)
Compaction is the compression and consolidation of a two-phase (particulate
solid/gas) system by the application of an external force; (2) compression causes
an increase in the apparent density (or a reduction in volume) by the displacement
of air; and (3) consolidation is defined as an increase in mechanical strength due
to particle–particle interaction [1,2].
When the external force is applied to the powder in the die cavity, the bulk
volume will decrease through the following mechanism: (1) initially it occurs
through repacking of the particles (this effect is limited because the mass will
quickly become more like a single body); (2) with an additional load, densification
occurs through elastic deformation (a reversible process); and (3) if the elastic
limit of the material is exceeded, then “plastic deformation” and/or “brittle
fracture” will occur. The exact type and mechanism of the material deformation
will be dependent on its viscoelastic properties. It should be noted that when the
upper punch moves away to release the applied load and allow ejection from the
die, the viscoelastic behavior of the material, i.e., the relaxation of the compacted
material combined with the forces necessary for ejection, can determine whether
the tablet will survive intact or whether lamination or capping might occur. It is
generally accepted that this decompression behavior is equally as important as the
compression behavior. (Note that if ejection of the tablet represents a problem in
production, the use of tapered dies sometimes alleviates the problem.)
As discussed later, compression and densification during compaction can be
followed by monitoring and measuring density and porosity. The monitoring of
the consolidation, i.e., the bonding process to create the tablet strength, is more
difficult. It should be clear, and can be emphasized again, that the important parameters
in this operation are the physicochemical properties of the powder and
the equipment used to perform this operation.
222 Schwartz
III. MATERIAL PREPARATION
The required material properties for compression/compaction are that the material
be:
Free-flowing (so that the powder flows uniformly into the die cavity)
Cohesive, i.e., that it possess binding properties so the powder will hold together
when it is compressed
Lubricated (to prevents the powder/granulation and the tablet from sticking
to punches and die, and to enable the formed tablet to be ejected from the
die wall and released cleanly from the punch faces)
There are other desirable properties for the powder, such as exhibiting a hydrophilic
surface, but these are related to tablet performance, to product stability
(antioxidant), or to esthetic characteristics (e.g., colors, flavors).
One should consider desirable tablet characteristics from the very first
stages of formulation to the final stage of process scale-up. These might include:
Physical strength
Pharmaceutical elegance
Biologically available drug substance(s)
Stability (chemical and physical)
Reproducibility (uniformity)
It should be noted that a good formulator will also consider scale-up parameters
from the first stages of a project. One must keep in mind the large-scale requirements
for each operation required by the formula he or she is developing.
As for the three required properties for manufacture (i.e., flowability, cohesiveness,
and lubrication), most of the drug substance in the pharmaceutical industry
do not exhibit them. The two methods by which one may impart these characteristics
to the final powder mixture are:
1. Formulation (selection of excipients)
2. Processing (selection of method of manufacture)
A discussion of formulation is beyond the scope and objectives of this chapter. A
description of the three methods of manufacture is well summarized elsewhere
[3–6]. As a summary, here are the methods of preparation/manufacture for tablets:
Wet granulation method
Dry granulation method
Direct compression (or simple blending)
Although there may be other reasons for selecting a method/process (such
as economics), the manufacturing dictates can be summarized as follows:
1. If a material or mixture flows and is compressible, one can use direct
compression.
Scale-Up for Compaction and Tableting 223
2. If a material or mixture is compressible (but exhibits poor flow), one
can use dry granulation.
3. If a material or mixture neither flows nor is compressible, one must use
wet granulation.
Remember that the first category can be accomplished by prudent selection of direct
compression diluents and that wet granulation need not be aqueous (note for
drugs that might be labile).
A final list should be kept in mind from the first formulation attempts
through the production stage, i.e., the list of important tablet characteristics from
a performance point of view. These, of course, are the specifications one sets on
the final product, and they include:
Tablet weight
Tablet hardness (or tensile strength)
Tablet thickness
Disintegration time
Friability
Assay
Uniformity of dosage units
Content uniformity
Weight variation
Dissolution
IV. FORMULA PROPERTIES
The most important characteristics of the final formulation to be compacted are
particle size and particle size distribution, density and/or porosity, powder flow,
cohesiveness, and lubrication. Particle size, particle size distribution, and density
and porosity of the formula will not be addressed here because they are the result
of other operations in the scale-up sequence, such as granulation and milling.
They should be evaluated as part of those specific operations. It should be noted,
however, that the influence of particle size on powder flow and, therefore, on uniform
die fill is very important to the compaction operation, but is not a result of it.
The one consideration to keep in mind during scale-up is the speed of the press,
which will directly affect the time available for the die filling to occur. This is an
important parameter to observe carefully.
Although there are laboratory tests that one can perform to quantitate the
flow of a final lubricated granulation, such as angle of repose and flow time
through a funnel [7], they are best used as comparison techniques to choose between
two or more formulations. If one considers the many different tablet
presses available, the use of force feeders on most modern presses, and the fine-
224 Schwartz
tuning an operator can perform with the press, these laboratory tests provide no
predictive quantitation. Again the real test will be performed on the specific production
press selected.
Cohesiveness, compactibility, and lubrication can be evaluated on research
instrumented tablet presses, as discussed later. Such measurements should give a
degree of assurance that the material will compress and eject properly. Only highspeed
compaction simulators or other equipment that controls dwell time, however,
will give any indication of potential problems with high-speed presses.
V. MATERIAL PROPERTIES
The specific material properties of most import to the compaction operation are
elastic deformation behavior, plastic deformation behavior, and viscoelastic properties.
These are also referred to as mechanisms of deformation. As mentioned
earlier, they are equally important during compression and decompression; i.e.,
the application of the compressional load to form the tablet, and the removal of the
compressional load to allow tablet ejection. Elastic recovery during this decompression
stage can result in tablet capping and lamination.
There are several important things to note. The first is that elastic deformation
is a reversible process, but plastic deformation and brittle fracture are not. More
importantly, plastic deformation and viscoelastic behavior are kinetic phenomena;
time is important, and they can be affected by press speed. In reality, most materials
exhibit both plastic and brittle behavior, but specific materials can be classified
as “primarily plastic” or “primarily brittle.” For example, microcrystalline cellulose
deforms primarily by a plastic deformation mechanism; calcium phosphate deforms
primarily by a brittle fracture mechanism; lactose is in the middle [8].
Obviously, each material in a formulation can be characterized in this way
by use of instrumented press studies and “Heckel” plot analysis in research and
development. This approach can be of use to formulators in selecting specific excipients
for specific drug entities. However, the characterization and performance
of the final formulation are the critical measurements in the scale-up/production
compaction operation.
VI. TABLET PRESSES
The equipment used to perform the compaction operation is a tablet press. The
small-scale equipment from which one might scale up would include:
Carver Laboratory hydraulic press
Single-stroke Stokes or Manesty model “E” or model “F” presses
Three- to six-station rotary tablet press (e.g., Korsch)
Scale-Up for Compaction and Tableting 225
The most common rotary production tablet presses to which one would
scale up the compaction operation include:
Stokes/Pennwalt
Manesty
Fette
Hata
Kilian
Kikusui
Korsch
Courtoy
These rotary tablet presses range from machines with 16–90 or more stations of
matched tooling. Specific details for each manufacturer would be best obtained
from the supplier’s literature.
Some models of these tablet presses are equipped with a precompression
station. This is an additional set of pressure wheels that can apply force to the material
in the die prior to the final (normal) compaction step; i.e., the tablet is compressed
twice. When used, the force applied is usually lower than that in the final
compaction. A precompression step can densify the material, allow more time for
plastic deformation, and allow air to escape rather than being trapped inside the
compact.
The original concept was that precompression would allow a more gradual
escape of air from the granulation or direct compression mixture. It was believed
by some that the entrapment of air in the compact, due to the rapid and forceful
compaction, would result in capping and lamination of the tablet. Although this
might be a minor consideration, it does not seem to be the most important reason
for such tablet defects.
It does seem reasonable that because plastic deformation is a kinetic phenomenon,
the extra time occupied by precompression allows the proper bonds to
be formed in a timely manner. Another consideration may be that the relaxation
of the compact is also provided more time and then a final compaction step occurs.
VII. INSTRUMENTED PRESSES AND SIMULATORS
Much of the information about compaction can be attributed to the early work in
tablet press instrumentation and publications in the general area identified as the
physics of tablet compression. For the interested reader, a review of the early history
of that work has been published elsewhere [2].
The current uses of instrumented presses and simulators can be separated
into three distinct areas: research and development, pilot plant (scale-up), and pro-
226 Schwartz
duction (operations). Although the major focus of this chapter is scale-up and production,
the R&D applications will be discussed briefly.
In general, one should be aware that tablet press instrumentation involves
the use of strain gauges or piezoelectric transducers to provide a voltage signal
proportional to the force applied for the compaction operation. Let us say we can
measure forces, such as those applied to the granulation by the punches, that applied
to the die wall, that required for tablet ejection, etc. With the use of other
transducers we can also measure distance. With the measurement of force and distance,
we can calculate work, energy, etc.
The details of instrumentation for tablet presses is thoroughly described in
several texts and review papers [1,2,9,10] and will not be repeated here. The concepts,
however, are important. The first and most important result of the instrumentation
results in a plot of force vs. time (see Fig. 1). This shows the maximum
force (or pressure) used for compaction of a tablet; and such plots become even
more important on a rotary press, when this measurement can be made on each
tablet produced.
Scale-Up for Compaction and Tableting 227
Figure 1 Schematic representation of a compaction force vs. time curve. On a singlestroke
tablet press, the time represents approximately one-tenth of the time between tablets.
The most common parameter is the compaction force represented by the peak height.
A. Uses in Research and Development
From these simple data on a single-stroke research press, a formulator can begin
to generate relationships between tablet properties and the compressional forces
used to compact them. Thus, one could plot tablet hardness as a function of compaction
force or pressure (see Fig. 2). The same would be true for disintegration
time, thickness, a dissolution number, etc. In fact, any dependent variable (tablet
property) can be related to the independent variable (compaction force.) It is important
to remember that force is the parameter one can control and, therefore, the
independent variable.
Powder densification can be followed with measurements of porosity and
force by means of the Heckel or Athy/Heckel equation [1]:
log 1/E 
 KyP  Kr
where:
E is porosity
P is applied pressure
Ky is a material-dependent constant inversely proportional to yield
strength
Kr is a constant related to initial repacking
The appropriate calculations, of course, require the measurement of the “true”
density of the materials being compacted.
One can analyze the data from this type of work to classify materials with
respect to their brittle fracture or plastic deformation tendencies or behavior
[1,10]. Examples of Heckel plots are shown in Figure 3. This technique has also
been used to follow bead compaction with modifications of the Heckel equation
to account for rheological behavior [8].
More recently, Heckel analysis was expanded in an attempt to analyze the
various sections of the plot to more precisely differentiate the densification behavior
of various materials [11] (see Fig. 4).
The most common analyses in compaction research include:
Compaction force vs. time curves to obtain a peak force on which to base
the tablet property relationships and to measure functional dwell time (the
time over which the maximum force is applied, most often defined as the
time where the compaction force is at 90% of the maximum value)
Ejection force vs. time curves to observe shape and peak force to evaluate
lubrication efficacy
Tablet porosity vs. force curve to visualize the densification process
Heckel plots to quantitate the densification process and characterize materials
with respect to the deformation mechanism
228 Schwartz
Scale-Up for Compaction and Tableting 229
Figure 2 Tablet hardness as a function compaction force for an experimental
formulation.
230 Schwartz
Figure 3 Heckel plots for (A) microcrystalline cellulose and (B) an MCC/lactose mixture.
Compaction profiles, which are plots of radial (die wall) pressure vs. axial
(compaction) pressure to determine compression and decompression
behavior
Force–displacement plots to determine the work of compaction and the energy
involved
Some of these measurements can also be performed on compaction simulators,
which are single-stroke presses specifically designed to evaluate individual
materials and/or full formulations [12]. The simulation of short dwell times and of
many different profiles for punch movement in real time are the advantages of this
type of measurement. Recent work with a compaction simulator has even included
a thermodynamic analysis of compaction [13,14].
B. Uses in Production
The major use of the instrumented press in the operations or production area is
for tablet weight monitoring and control. Early research in this field was able to
show that the measured force of compression was proportional to the mass of
material in the die cavity. This, of course, led to systems that could monitor the
uniformity of the peak heights measure, send a signal to a servo motor on the
press to adjust the weight control if necessary, and finally turn off the press or
Scale-Up for Compaction and Tableting 231
Figure 4 A full-cycle Heckel plot for an experimental material, with densification, compression,
and decompression phases noted.
divert off-weight tablets if adjustments could not be made in a timely manner
(seconds). The fully computerized tablet presses available today perform these
and other operations.
Other uses in production might include tooling care and maintenance. It is
important to note that because of the way in which the force is set on production
presses, the punch lengths must be matched exactly, or the force signal will vary.
Therefore, if one observes one station of tooling with a force value different from
the others, it probably indicates an incorrect punch length.
C. Uses in Scale-Up
There are several uses of tablet press instrumentation in the scale-up process itself.
One of these involves obtaining a sample of the scale-up batch and compacting
that sample on the pilot-plant or research instrumented tablet press on which the
formulation has been previously evaluated. Similarity of the fingerprint or the various
research plots (Heckel, force-displacement, radial vs. axial plots) is evidence
that the scale-up batch is similar to the previously evaluated research batch [2].
Larger-scale instrumented equipment, such as the Presster
, can also give
an indication of compaction characteristics of a scale-up batch with respect to
tablet hardness vs. compaction force measurements [15].
If the tablet presses in production are instrumented and if they provide a
force reading, then one can perform many of the analyses already discussed to
evaluate the scale-up formulation, i.e., compaction force (and/or precompression
force) vs. time, ejection force vs. time, or displacement information to provide
densification information. It is the author’s experience, however, that most production
presses are not used in this way, though many in the pilot plant are. Although
many production presses are instrumented, the force readings are used
only for tablet weight control by monitoring the uniformity of the peak heights;
i.e., one does not collect actual force readings or traces. Automatic systems with
servo motors then adjust tablet weight (die fill).
The alternative would be to obtain a portion of the formulation, take it back
to the instrumented press used in the pilot plant or in R&D, and perform the same
evaluation as was performed on the smaller batches. By this technique, one can
evaluate the scale-up process for all the other operations and then note any differences
in performance on the production press.
VIII. TABLET PROPERTIES
Although there are many tablet properties to be evaluated, the most important to
observe during the scale-up process are tablet hardness (or tensile strength) and
tablet dissolution. The former could be affected significantly by press speed (if the
232 Schwartz
formulation deforms primarily by a plastic deformation mechanism). Both hardness
and dissolution are most often a function of compaction force; they are, of
course, related to each other, and both must be monitored carefully. With a proper
developmental experimental plan or by the use of appropriate experimental design
and/or optimization studies in R&D or in the pilot plant, the product development
scientist should already know the effects of “force” on tablet hardness and dissolution
and the relationship between the two.
For dissolution testing, it is no longer sufficient to show that the product
meets specifications—i.e., to use the USP Q-value acceptance table and singlepoint
testing—a profile is required. To determine whether the dissolution profile
from the scale-up lot is “the same as” that for the research or clinical or “bio”-
batches, one uses the relationship given in the SUPAC document (see Appendix)
for immediate-release dosage forms [16]. This equation determines a similarity
factor for two products (test and reference). The SUPAC document actually addresses
many variations in the scale-up or site transfer of a product, including
components and composition, site changes, changes in batch size, and manufacturing
changes. Equation (1) determines a similarity factor (?2) based on the dissolution
points on two curves, one for each of two products/batches. Rt and Tt are
the percent dissolved at each time point, where at least 12 tablets (individual
dosage units) are tested. A similarity factor [an ?2 value] between 50 and 100 indicates
that the two profiles are similar.
?2 
 50 log 
1  N
1
?
n
t
1
(Rt  Tt)20.5
 100	 (1)
IX. SPECIAL CONSIDERATIONS IN SCALE-UP
It is obvious that most of the effects of scale-up are seen in the unit operations that
occur before compressing, especially blending, granulation, milling, and drying.
These operations impart the important physical properties to the mixture to be
compressed. For example, separation of particle sizes in the hopper would be a
function of the choice of excipients or the processing steps to get to the final granulation
or direct compression mixture.
There are, however, several special concerns in the scale-up of compaction
that relate exclusively to the compaction step and that cannot be determined on a
smaller scale. The list might include:
Press speed for materials that compact by plastic deformation
Overmixing of the lubricant by the force feeder
Heat build-up over a long run
Abrasive materials
Tooling care—unmatched sets of tooling
Scale-Up for Compaction and Tableting 233
A. Press Speed
Strain rate sensitivity of (or the effect of press speed on) the formulation is of primary
concern in scale-up. Whether the product development work was performed
on a single-stroke press or a smaller rotary press, the objective in operations will
be to increase efficiency, in this case the tablet output rate and, therefore, the speed
of the press. For a material that deforms exclusively by brittle fracture, there will
be no concern. Materials that exhibit plastic deformation, which is a kinetic phenomenon,
do exhibit strain rate sensitivity, and the effect of press speed will be
significant. One must be aware that although specific ingredients (such as calcium
phosphate and lactose) may exhibit predominately brittle fracture behavior, almost
everything has some plastic deformation component, and for some materials
(such as microcrystalline cellulose) plastic deformation is the predominant behavior.
The usual parameter indication is that target tablet hardness cannot be
achieved at the faster press speed. Slowing the press may be the only option to correct
the problem.
B. Lubrication
The effects of lubrication, especially with magnesium stearate, are not only
a function of the ingredient level, but also a function of the blending time. It is well
known that overmixing causes a spreading of the particles and an increase in
the hydrophobicity of this material. The resulting effects on dissolution are
well known. Less well known, however, is the effect of this type of overlubrication/
overmixing on tablet hardness or tensile strength. Lubricants, and especially
magnesium stearate, can coat the surface of other ingredients or granules and, by
preventing particle contact and bonding, can result in a softer tablet.
It is the authors’ experience that with a formulation compressed without a
forced feeder in R&D, the scale-up in a different country, but by gravity feed
and without a forced feeder, was perfect. In a second country, however, all production
presses operated with forced feeders, and the target tablet hardness was
not achieved. It was possible to conclude that press speed was not the cause of
the problem; but it was much later (and based on laboratory experiments) that it
was possible to conclude that the lubricant was overmixed on the tablet press,
resulting in a softer tablet. Fortunately, the drug was very soluble and no dissolution
problem resulted, but slower dissolution could be a problem with a drug
of low solubility.
C. Batch Size/Length of the Compaction Run
No matter what type of tablet press was used in R&D or in the pilot plant, there is
no possible way to experience the phenomenon on a full-size batch and the associated
time of the compaction run. One must be aware of the possible build-up of
234 Schwartz
heat due to the length of the compaction operation, i.e., the operation of the press.
Formulators should be aware of and attentive to the effects of a possible temperature
increase on the stability/degradation of the active compound (or any heat-labile
ingredient) or the softening of any low-melting ingredients. Abrasive materials
in the formula can produce such a heat build-up even without the tablet
machine effects.
D. Tooling Care
It is a fundamental assumption for the use of instrumented presses for tablet
weight control in production that the sets of tooling on the press are perfectly
matched. These systems work on the basis that a low fill wight (low powder mass)
in the die cavity results in a low force signal and that a high fill weight results in
a high force signal. Although the forces are not recorded, the uniformity of the
peak heights is, and weight adjustments are made accordingly.
The force signals, however, can also be affected by a change or variation in
the length of the punches. If any one punch is slightly shorter than the others, less
force will be applied to the powder mass, and the signal will be low. These weight
control systems would then assume that the tablet weight is low. Therefore, tooling
maintenance is extremely important in the scale-up operation.
X. OTHER PARAMETERS TO MEASURE DURING
SCALE-UP
As already noted, the most important parameters or characteristics to observe during
scale-up of the compaction process are tablet hardness (or tensile strength) and
tablet dissolution. However, the following might also provide useful information.
A. Tablet Weight Uniformity
Tablet weight uniformity will provide a measure of the efficiency of the powder
flow, the force feeder, or the automated weight control system. Weight monitoring
by the press operator is usually the weight of a 5- or 10-tablet sample.
Uniformity of individual tablets, which after all does relate to dose, will be
more informative. The powder flow may not be sufficiently good, even with
forced feeders.
B. Tablet Hardness Uniformity
Tablet hardness uniformity will monitor the same parameters, but could also be an
indication of matched or unmatched punches on the tablet press. It may also be
Scale-Up for Compaction and Tableting 235
useful to observe the tablet behavior during hardness testing. Sometimes, capping
or lamination that does not appear during compaction but does appear during
hardness testing may indicate that one is operating in a borderline force area. One
can observe this with a plot of hardness or tensile strength vs. force; a parabolic
shape is produced [17]. If the hardness is lower at higher forces, it could be an indication
of weak bonds of lamination that show up as a softer tablet during the
hardness testing. This may be the one case where lower compaction force could
produce a harder tablet.
C. Tablet Hardness vs. Dissolution Data
Although this information should have been generated during the development of
the formulation, it is often useful to confirm the relationship between these two
dependent variables on tablets compacted on the production press during scale-up.
Such information becomes invaluable for troubleshooting.
D. Instrumented Press Data
If the tablet presses are instrumented and if they provide force readings or, more
importantly, if they provide force vs. time curves, then the following parameters
should be measured:
Dwell time (which is most often defined as the time where the compaction
force is at 90% of the maximum value)
Compressional force
Ejection force
Displacement
(See Sec. VII.A on Instrumented Presses in Research for discussion.)
REFERENCES
1. K. Marshall. Compression and consolidation of pharmaceutical powders. In: H. A.
Lieberman, L. Lachman, and J. L. Kanig, eds. The Theory and Practice of Industrial
Pharmacy. 3rd ed. Lea & Febiger, Philadelphia, 1986, Chap 4, p 66.
2. J. B. Schwartz. The Instrumented Tablet Press: Uses in Research and Production.
Pharm. Technology 5(9):102, 1981.
3. E. M. Rudnic and J. B. Schwartz. Oral solid dosage forms. In: A. Gennaro, ed. Remington:
The Science and Practice of Pharmacy. 19th ed. Mack, Easton, PA, 1995,
Chap 92, pp 1615–1649. [E. M. Rudnic and J. B. Schwartz. Oral solid dosage forms,
Chapter 45 In: A. Gennaro, ed. Remington: The Science and Practice of Pharmacy.
20th ed. 2000, Chap 45, in press.]
236 Schwartz
4. H. A. Lieberman, L. Lachman, and J. B. Schwartz, eds. Pharmaceutical Dosage
Forms: Tablets. 2nd ed. Marcel Dekker, New York, Vol. 1, 1989; Vol. 2, 1990; Vol.
3, 1990.
5. G. S. Banker and N. R. Anderson. Tablets. In: H. A. Lieberman, L. Lachman, and J.
L. Kanig, eds. The Theory and Practice of Industrial Pharmacy. 3rd ed. Lea &
Febiger, Philadelphia, 1986, Chap 11, p 293.
6. E. M. Rudnic and M. K. Kottke. Tablet dosage forms. Chapter 10 In: Banker and
Rhodes, eds. Modern Pharmaceutics. 3rd ed. Marcel Dekker, New York, 1995, pp
333–394.
7. R. J. Lantz and J. B. Schwartz. Mixing. Chapter 1 In: H. A. Lieberman, L. Lachman,
and J. B. Schwartz, eds. Pharmaceutical Dosage Forms: Tablets. Vol. 2. 2nd ed. Marcel
Dekker, New York, 1990, pp 1–71.
8. J. B. Schwartz, N. H. Nguyen, and R. L. Schnaare. Compaction studies on beads:
compression and consolidation parameters. Drug Dev. Ind. Pharm. 20(20):
3105–3129, 1994.
9. K. Marshall. Instrumentation of tablet and capsule filling machines. Pharm. Tech.
9(3):68–82, 1983.
10. E. L. Parrott. Compression. In: H. A. Lieberman, L. Lachman, and J. B. Schwartz,
eds. Pharmaceutical Dosage Forms: Tablets. Vol. 2. 2nd ed. Marcel Dekker, New
York, Chap 4, 1990, p 201.
11. L. E. Morris and J. B. Schwartz. Isolation and densification regions during powder
compression. Drug Dev. Ind. Pharm. 12(4):427–446, 1995.
12. M. Celik and K. Marshall. Use of a compaction simulator system in tabletting research
I. Introduction to and initial experiments with the system. Drug Dev. Ind.
Pharm. 15:759–800, 1989.
13. M. T. DeCrosta. Thermodynamic analysis of compact formation: compaction, unloading
and ejection. Ph.D. dissertation, Philadelphia College of Pharmacy & Science,
March 25, 1998.
14. M. T. DeCrosta, J. B. Schwartz, R. J. Wigent, and K. Marshall. Thermodynamic analysis
of compact formation: compaction, unloading, and ejection. I. Design and development
of a compaction calorimeter. Int. J. Pharmaceutics 198:113–134, 2000.
15. M. Levin. Use of the Presster
 for Tableting. AAPS 34th Annual Pharmaceutical
Technologies Conference at Arden House, January 1999.
16. [SUPAC] FDA Guidance for Industry. Immediate Release Solid Oral Dosage Forms,
Scale-Up and Post Approval Changes, CDER, November 1995.
17. Lisa E. Morris, Jeffrey C. Moore, and Joseph B. Schwartz. Characterization and performance
of a new direct compression excipient for chewable tablets: Xylitab. Drug
Dev. Ind. Pharm. 22:925–932, 1996.
Scale-Up for Compaction and Tableting 237

8 (2)
Practical Aspects of Tableting
Scale-Up
Walter A. Strathy and Adolfo L. Gomez
I.D.E.A.S., Inc., Wilson, North Carolina
The key to scaling up a tableting process is to consider it during the entire development
process. From the inception of a development project, the formulation scientist
must consider scale-up. It should not be a process removed from development.
A formulation scientist should begin a development project with the end in
mind. Just as a builder, prior to nailing boards, planks, and plywood together, has
a blueprint of what the structure is supposed to look like, a formulator should
know what the goals of the delivery system are.
Some questions a formulator needs to address up front are: What are the
marketing plans? What are the potential obstacles to uniformity? Is the active raw
material physically and chemically consistent? What are the physical plant constraints?
Addressing these and other questions in the early stages of development
could aid in avoiding many scale-up nightmares. Additionally, the identification
of potential scale-up issues forces the formulator to consider commercialization of
the drug delivery system. Too often, formulation scientists develop tablet formulations
in a bubble, only to be later handed off to some poor process development
person who has to make it work.
Although the focus of this chapter is on the scale-up of the tableting process,
one cannot ignore the significance of upstream (precompaction) processing.
A pragmatic formulator approaches a development project as a computer
programmer would approach the development of a program. A programmer defines
the input (the independent variables) and output (the dependent variables)
prior to tackling the program. The formulator should do the same in the early
stages of formulation development. Independent variables of a tablet formulation
include the active drug substance, clinical data, marketing demands, manu-
239
facturing constraints, and sales forecasts. Additional inputs are the location of
manufacturing (if known) and available manufacturing techniques. Dependent
variables a formulator must consider during early stages of development of a
tablet formula include marketing issues such as the color, shape, and size of the
tablet, final product specifications (dissolution, etc.), bioavailability, run rates,
patient/consumer acceptance, and stability (shelf life). A successful development
project is one that delivers the desired output for the given independent variables.
Characterization of the active drug substance early in the development process
is paramount in avoiding scale-up issues downstream. Characterization exercises
should include determining physical, chemical, and functional attributes.
Physical characterization of the drug substance includes measuring particle size,
density, surface area, etc. Some chemical characterization should focus on solubility,
stability, and reactivity. In tablet formulation development, functionality
could play an important role in the successful scale-up. Functional testing should
include measuring parameters such as compactabilty and flow. Characterization
activities should be performed while considering the defined delivery system output.
What is the definition of success for the formulation project? For example,
characterization activities carried out for a low-dose tablet will be vastly different
than characterization of a compound to be used in a tablet formula that is made up
mostly of active ingredients.
It is important that the formulation scientist also define other independent
variables (inputs). One additional given input is the drug’s clinical characteristics.
Formulators inherit clinical requirements, such as dose, route of administration,
area of adsorption, and metabolism. The formulation of a tablet and its subsequent
scale-up depend on marketing inputs, such as color, flavor, size, shape, and target
patient. Manufacturing constraints must also be considered prior to scaling up a
tablet formulation. What are the equipment or facility constraints? What are the
personnel capabilities? What is the desired manufacturing rate (tied to marketing
forecasts)? Regulatory issues are also important to consider during scale-up activities
of a tablet process. Understanding one’s limitations within the various regulations
(SUPAC, etc.) aids the formulator in scaling up a process that the FDA
will find equivalent to the one by which the clinical batches were produced. A formulator
needs to understand that some flexibility exists in the current regulatory
environment when scaling up from a laboratory to a pilot plant and from a pilot
plant to manufacturing environments. Clinical batch size versus allowable scaleup
batch size is an important relationship to understand early in the development
project. Formulation composition and an understanding of what changes to composition
can be made will aid the formulator in scale-up. Defining processing
equipment operating principles during development and their relationship to the
available equipment in the scale-up facility will also aid in the successful scale-up
of a tableting process.
240 Strathy and Gomez
After most of the independent variables have been defined (or characterized),
the formulator must consider what the criteria for success are. What are the
dependent variables, or output, of the formulation? It’s simple: input  formulation

output. The formulator’s job is to develop a system that takes all of the project’s
input into consideration and to produce a product that meets the criteria for
success (output). Some output, or dependent, variables include the specifications
that the dosage form must meet and the bioavailability. Run rates in manufacturing
need to satisfy market demands. Reliability and consistency in manufacturing
should be a goal in any process. Another dependent development variable is consumer
(or patient) acceptance of the dosage form.
Once the formulation scientist gets a handle on the formulation input (dependent
variables) and the formulation output (dependent variables), a set of experiments
needs to be designed to determine how to take the given and get the
desired. Upon execution of the experiments, the formulator should gather an understanding
of how the input relates to the output. For example, if marketing
wants a 300-mg tablet and the dose has been set at 0.1 mg, a formulator will take
all necessary precautions to ensure dose uniformity. It is obvious that experimentation
in the latter case would focus on the preparation of tablets that are 300
mg (output) containing 0.1 mg of drug (input). If, in contrast, marketing desires
a 300-mg tablet containing 250 mg of drug, the formulator might shift the focus
of the experiments from obtaining dose uniformity to the compactability of the
active drug.
After all the preformulation and characterization activities have been executed
and formulation excipents rationalized, a formulator needs to begin the
building of early tablet prototypes. During the early stages of development, the
formulator will decide how the precompressed material will be prepared. If a formulation
scientist is developing a formulation for eventual commercialization, he
or she will evaluate the early blends in an effort to identify potential downstream
(scale-up) processing issues. A direct compression formulation is usually where
the formulator begins to evaluate formulation issues. If, during the compression of
the formulator’s first 100 tablets on a single-punch tablet press, segregation and
capping are observed, adjustments obviously need to be made. In this example,
one can only imagine what the results would be for a lot scaled up with that formula.
Based on the results of the first (DC) attempt, most formulators would evaluate
the need to additionally process their formula. Some considerations could be
particle size distribution adjustments, wet granulation, addition of compression
aids, and roller compaction.
Early data collection of prototype-blend experiments could be an invaluable
tool to successful scale-up. Physical characteristics such as particle size distribution,
bulk and tapped density, and flowability and functional characteristics
(mainly compactability) are key indicators of possible downsteam scale-up problems.
If, for example, the active drug substance has a mean particle diameter
Practical Aspects of Tableting Scale-Up 241
nowhere near that of the excipients, one is begging for segregation upon scale-up.
Bulk and tapped density data will aid in determining blender loads. Flowability is
an important consideration when transferring a process from the laboratory to a
manufacturing environment. Not only does the precompacted blend need to flow
out of the blender, but the material may need to be able to quickly (and uniformly)
fill the dies of a high-speed tablet press. Compactability characteristics are obviously
the most important functional consideration in the production of a tablet.
Compactability, for the purposes of this chapter, is defined as the ability to
consolidate the particles of a blend to result in increased apparent density and a
unit that has some physical strength. Often called compressibility, compactability
needs to be characterized and optimized early in the development process. Characterizing
compactability requires the collection of data related to many aspects of
tableting. Consider how a tablet is formed: (1) A mixture of powders flows into a
die cavity; (2) an adjustment in a critically important volume is made; (3) the
blend is subjected to a great deal of stress, strain, and shear (hopefully resulting in
a consolidated compact); (4) the compact (tablet) must be pushed out of the die
cavity; (5) the tablet must be pulled, pushed, or knocked off the surface of the
lower punch face; and finally, (6) the tablet must safely travel into a container
where it will be stored for further processing. The characterization and optimization
of the compactability would therefore include flow measurements, force vs.
compactability measurements, ejection force measurements, punch face release
measurements, and resulting tablet attrition data collection. The earlier these parameters
are defined in the development process, the better the chances are for a
successful scale-up.
Flowability is important to the successful scale-up of a tableting process.
The rate at which the precompacted blend flows into the hoppers of the tablet press
and subsequently into the die cavity could be crucial to dose uniformity. Three
measurements are most commonly used to measure flow:
Angle of repose—a blend is poured through a funnel into a pile and the angle
at the base of the cone is measured.
Dynamic flow—an instrument is used to measure the time it takes a constant
volume of material to flow through a fixed orifice (these instruments usually
have mechanical vibrators on them).
Funnel flow—a glass funnel of fixed volume and angle is filled and the time
it takes to empty is measured.
The third method of flow measurement enables the formulator to characterize
the flow as well. Is the flow a mass flow or a funnel flow? Does it rathole
or bridge?
Compactability exercises are probably the single most important set of experiments
a formulator carries out early in the development of a tablet formula.
Proper execution of compaction studies could avoid a host of potential scale-up
242 Strathy and Gomez
difficulties. Compaction studies are carried out on various types of tablet presses.
The presses are equipped with instrumentation able to measure various forces and
an output device able to interpret these forces. The type(s) of forces measured can
vary. Some scientists measure the force applied to the blend, while other formulators
choose to measure the force transmitted through the blend. These studies are
generally carried out by compacting a blend at various levels of force at a constant
rate.
Various measurements are made on the resulting tablets. Useful information
used to optimize a formula include: force versus hardness, force versus friability,
and hardness versus dissolution. One could also compare hardness with thickness
and/or friability. Numerous comparisons can be made using the data in an effort to
optimize the formulation. Force versus tablet hardness plots are the most common
compaction profiles used. Force versus these hardness plots are extremely valuable
when designing early tablet prototypes. The guesswork is removed when rationalizing
excipients and levels. Several formulations containing various levels of excipients
can be compacted at different forces and the hardness of the resulting tablets
measured. A formulation scientist can use the data to compare different prototypes.
An optimal formula is one that results in the hardest tablet given the lowest amount
of force applied (see Fig. 1) while meeting all other success criteria. These measurements
should be used for comparison/optimization purposes. The rate at which
a tablet is formed needs to be addressed as a part of the scale-up process.
Other force measurements valuable in the development of a tablet formula
relate to the ejection of the tablet out of the die. The goal of the formulator should
be to optimize compactability (a hard tablet using low force) while minimizing
forces related to tablet ejection. If ejection forces are too high, the stress caused
can result in capping, lamination, chipping, cracking, and/or breaking. Two predominant
forces related to the ejection of a tablet should be examined. The force
required to remove the tablet from the die (ejection) and the force it takes to remove
the tablet from the lower punch face (knock-off force). When examining
and optimizing ejection force, the formulator should focus on minimizing peak
height. (For examples of ejection data generated by an instrumented press see
Figs. 2 and 3.) Optimizing lubricant levels, thus reducing ejection forces, is often
done at the expense of compactability. In general, the excipients (or processes)
used to reduce ejection forces inevitably increase the force required for compaction.
The rate of the compaction process is another variable that should be considered
throughout development, including scale-up. Typically, the development of a
tablet formulation takes place on tablet presses that are relatively slow. The tableting
rate is important to consider for several reasons. Blend flow is important to ensure
bulk blend transfer into the tablet press (hopper) and consistent die fill. Variation
or difficulty in the bulk flow and die fill can contribute to tablet weight
variation. As the compaction rate increases, the blended material must be able to
Practical Aspects of Tableting Scale-Up 243
244 Strathy and Gomez
Figure 1 Force vs. hardness compaction profile.
Practical Aspects of Tableting Scale-Up 245
Figure 2 Ejection force curve.
Figure 3 Take-off force trace.
keep up with flow requirements. Optimal blend flow can only be defined upon scaleup.
The optimal flow of a blended material depends on dose, tablet size and shape,
the type of tablet press being used, and a host of other variables. As the tableting rate
increases, formulators often find the need to incorporate die-induced feed frames
onto the tablet press being used for the scale-up work. An overzealous feed frame
speed can wreck havoc on a blend susceptible to overmixing. Overmixing in a feed
frame could lead to a reduction in lubrication effectiveness, increase the hydrophobicity
of the blend, and/or a modification of particle size distribution.
In addition to the blend flow/movement characteristics, the tableting rate affects
the time that the blend is subjected to compaction forces. The two major elements
in the formation of a tablet are the forces applied to the blend and the length
of time those forces are applied (time when compression wheel is in contact with the
flat portion of punch head is called dwell time). Dwell times significantly differ upon
scale-up. Dwell times also differ between presses within a manufacturing area.
Dwell times on typical development tablet presses run from 0.080 to 0.500 seconds.
Production scale presses can go as low as 0.005 seconds per compaction event. The
difference in dwell time affects the maximum peak height of a compaction event
(see Figs. 4 and 5). In this example, the same blend was subjected to compaction at
two different rates. The peak height for the compaction event with a shorter dwell
time is usually significantly higher then the peak height resulting from the longer
dwell time. The significance of compaction peak height is important in scale-up.
Larger peak forces can affect the operation of a high-speed (production-scale) tablet
246 Strathy and Gomez
Figure 4 Example of a short dwell time.
press. Tooling, cams, and pressure roll wheels will wear faster as compaction forces
increase. The tablet stresses strain and shear also increase as dwell times decrease
and compaction force increases. These stresses can cause several scale-up nightmares,
such as capping, lamination, and die binding. The most common cure for
these scale-up issues is slowing the press down, thus increasing dwell time.
In an effort to overcome the dwell time/scale-up issues, Metropolitan Computer
Corporation (MCC) has developed a single-station development tablet press
that reproduces the compaction event time of manufacturing-scale tablet presses.
The PressterTM (see Fig. 6) can be set up to match the rate, roll wheel configuration,
and tooling of any manufacturing-scale tablet press. This enables the formulator
to eliminate compaction rate as a variable upon scale-up. It does require that
early in development the formulation scientist identify the tablet press that the
commercialized product will run on. This is in keeping with the theme of this
chapter—begin a development project with the end in mind.
In summary, scale-up of a tablet formulation should not be a process separate
from the development of the initial formulation. Scale-up should be a consideration
from the onset of the development of the early prototypes. The formulation
scientist should begin a project with the end (commercialization) in mind. The
task a formulator is assigned is one where the input (independent variables) and
output (dependent variables) are clearly defined at the beginning of a development
project. The formulator fills the gap between the input and the output. The solid-
Practical Aspects of Tableting Scale-Up 247
Figure 5 Example of a long dwell time.
dose formulation scientist receives reams of information from groups such as
pharmacokinetics, toxicology, clinical science, and synthesis, together with a bottle,
bucket, or drum of active substance. The formulator ultimately must deliver a
dosage form that passes predetermined specifications, can pass a validation exercise,
is stable, can be consistently and efficiently manufactured, and is acceptable
to the consumer.
I. SCALE-UP CASE STUDIES
A. Example 1: Blend Feed Segregation
1. Formulation/Process Background
This particular formulation was a direct compression formula containing two active
ingredients: Active A, 60 mg, and Active B, 4 mg per tablet. The actives made
248 Strathy and Gomez
Figure 6 The MCC Presster™.
up about 50% of the total tablet mass. Active A was a crystalline material with a
mean particle diameter of approximately 180 microns. Active B was an amorphous
powder with a mean particle diameter of approximately 120 microns. The
tablet matrix comprised microcrystalline cellulose, spray-dried lactose, disintegrant,
and lubricant.
The process to prepare the blend was relatively straightforward. Active A
was milled through a 0.075,-opening conical mill. All the other components were
screened through a #20 mesh (840-micron) screen. All materials except the lubricant
were blended in a diffusion blender. The lubricant was blended for a short
time at the end.
2. Laboratory Work Through Scale-Up
The initial lab batch was prepared using small, pilot-scale equipment. The first
batch was 8 kg (prepared in a 16-quart V-blender). No blend testing was performed
on the first lab-blend batch. The compaction was performed on a 16-station
gravity-feed tablet press. Extensive tablet uniformity testing was carried out
on the tablets generated from the initial 8 kg. A total of 120 tablets were assayed
for both actives. The tablets tested were from a composite sample taken throughout
the compaction process. The uniformity of both active ingredients in the
tablets produced from the laboratory batch was excellent. Both active ingredients
assayed between 96% and 106% of label strength, with a %RSD of less
than 2.
Based on the success of the laboratory batch, an intermediate-scale batch
was prepared. The lot size was approximately 65 kg. The blend was prepared in a
5-cubic-foot diffusion blender. Several unit dose samples of the blend were withdrawn
from the drum containing the blend discharged from the blender using a
single compartment thief. All the unit dose blend samples met acceptance criteria
for both actives. This blend was compacted on a 30-station force-fed tablet press.
Samples were taken throughout the compaction process. A composite sample was
made, and 120 tablets were assayed for dose uniformity. Uniformity of both active
ingredients in the tablets was excellent. Both active ingredients assayed between
97% and 105% of label strength, with a %RSD under 2.
Again, based on the success of the intermediate-size batch, a decision was
made to prepare a manufacturing-scale batch. The manufacturing lot size was approximately
200 kg. The blend was prepared in a 16-cubic-foot diffusion blender.
Using a single-compartment thief, several unit dose samples of the blend were
withdrawn from all the drums containing the blend discharged from the blender.
All the unit dose blend samples met acceptance criteria for both actives. This
blend was compacted on a 30-station force-fed tablet press. Samples were taken
throughout the compaction process. A composite sample was made, and 240
tablets were tested for dose uniformity. Uniformity of both active ingredients con-
Practical Aspects of Tableting Scale-Up 249
tained in the tablets was outside the limits of the acceptance criteria. Both active
ingredients varied in assay between 80% and 122% of label strength, with a
%RSD of more than 9.
3. Cause of the Issue
After an exhaustive investigation, it was determined that the cause of the nonuniform
tablets was segregation in the tote/overhead feeding system used in the manufacturing
operation. The laboratory- and intermediate-size batches were handscooped
into the hopper of the tablet press. The overhead-feed duct acted as a
classifier. The differences in cohesion and adhesion of the two actives, coupled
with the length and angle of the ductwork, fostered segregation.
4. Addressing the Problem
There were two possible approaches to addressing the segregation issue. The
first was to modify the blend (granulation, etc.). The second was to modify the
blend feed system. The latter was chosen in an effort to prevent recurrence in
other, similar formulations. After the modification of the tablet press overheadfeed
system, all subsequent batches passed uniformity testing and eventually a
validation exercise.
5. Lessons Learned
Consider the systems between major steps of the process as sources of process
influence.
B. Example 2: Cracked Dies
1. Formulation/Process Background
The formulation was a chewable antibiotic for children. The active substance was
fluid-bed granulated in a sucrose base. The granulation was blended in a diffusion
blender with additional amounts of sucrose, flavors, colors, and other excipients.
2. Laboratory Work Through Scale-Up
Due to the limited availability of the active component, several small (approximately
5-kg) granulations and blends were prepared. All prototype-formulation
work was compacted on a singe-station tablet press. The material compacted
during the lab-trial work met predetermined acceptance criteria physically
and chemically.
Upon compaction scale-up of the formula to a higher-speed rotary tablet
press, die cracking was noticed.
250 Strathy and Gomez
3. Cause of the Issue
The dies cracked due to the inordinate amount of force required to compact the
tablet, coupled with a poorly designed tablet shape (kids/fun shapes). As the tablet
press speed was increased, the dwell time of the compaction event decreased, thus
increasing the amount of peak force required for compaction.
4. Addressing the Problem
Several adjustments were made to the formula and process to improve the compactibility
of this product. The moisture specification was adjusted, additional dry
binder was added to the formula, and the tooling design was re-engineered.
5. Lessons Learned
Compaction dwell time must be a consideration when scaling up.
Practical Aspects of Tableting Scale-Up 251

8 (3)
Dimensional Analysis of the
Tableting Process
Michael Levin
Metropolitan Computing Corporation, East Hanover, New Jersey
Marko Zlokarnik
Graz, Austria
I. INTRODUCTION
Scale-up of the tableting process in the pharmaceutical industry is still an empirical
process. Dimensional analysis, a powerful method that has been successfully
used in other applications, can provide a solid scientific basis for tableting scaleup.
It is a method for producing dimensionless numbers that completely describe
the process. The analysis should be carried out before the measurements are made,
because dimensionless numbers essentially condense the frame in which the measurements
are performed and evaluated. It can be applied even when the equations
governing the process are not known.
II. DIMENSIONAL ANALYSIS—RELEVANCE LIST
With the basic dimensions of mass, length, and time denoted as [M], [L], and [T],
respectively, the relevance list for the target quantity H [ML1T2] (mechanical
tensile strength of the tablet) included:
Depth of fill, or loading depth of the powder bed h [L]
Final (out-of-die) tablet thickness ht [L]
Compression roll diameter Dcr [L]
Maximum applied compression pressure pm [ML1T2]
253
Compression rate n [T1]
Powder compressibility parameter - [M1LT2] 
 V/(pVt) (where V
and p are the changes in tablet volume V and applied pressure p, respectively,
and Vt is the final tablet volume)
Geometric dwell time  [T]
Geometric dwell time is an indicator of a linear speed, sort of a yardstick that allows
one to compare speeds of different tablet presses. It is defined here as the time
required for a punch to traverse a horizontal distance of 9.5 mm (when the flat portion
of the IPT Type B punch head is in contact with the compression wheel).
III. DIMENSIONAL ANALYSIS—DIMENSIONAL MATRIX
The dimensional matrix consists of a (square) core matrix and a residual matrix.
Based on our relevance list, the dimensional matrix representing a tableting process
can be written as shown in Table 1.
By a simple linear transformation, the core matrix becomes a unity matrix
(Table 2).
The dimensionless numbers are formed as fractions, where each physical
quantity indicated in the residual matrix represents the numerator, while a product
of all quantities of the core matrix (with the exponents indicated in the residual
matrix) constitutes the denominator. This standard procedure yielded the following
	 set:
{H-, h/ht, Dcr /ht, pm-, n}
254 Levin and Zlokarnik
Table 1 Core and Residual Matrices
Core matrix Residual matrix
Dimension - ht n H h Dcr pm 
Mass [M] 1 0 0 1 0 0 1 0
Length [L] 1 1 0 1 1 1 1 0
Time [T] 2 0 1 2 0 0 2 1
Table 2 Unity Matrix
Unity matrix Residual matrix
Dimension - ht n H h Dcr pm 
[M] 1 0 0 1 0 0 1 0
[L]  [M] 0 1 0 0 1 1 0 0
([T]  2[M]) 0 0 1 0 0 0 0 1
The target dimensionless quantity (H-) can be expressed in terms of all other dimensionless
quantities.
IV. EXPERIMENTAL RESULTS
To test the foregoing dimensionless relationship, two powders (Avicel PH101, a ductile,
viscoelastic material, and Emcompress, a brittle material, blended with 0.5%
magnesium stearate) were compressed on the Presster™, a single-station mechanical
replicator of rotary tablet presses. In the first set of experiments, a 16-station Manesty
Betapress (a research-scale press) was simulated at two speeds, 60 and 100 rpm. In
the second set, a 36-station Fette P2090 (a medium-scale production press) was simulated
at two speeds, 55.8 and 70 rpm. It should be noted that 100 rpm of the Betapress
corresponds to 55.8 rpm of the Fette 2090 in terms of the linear speed of the turret.
Basic parameters for the two tablet presses are presented in Table 3.
A standard IPT Type B tooling was used with a 
8
3
, round flat tool tip. Tablets
were made one at a time, and the compression force as well as the upper punch
displacement and lower punch displacement were recorded. Tablet weight, thickness,
and breaking hardness were measured for each tablet.
The Presster™ is a single-station press that can mimic the load profile of
any production press. The Presster™ uses mechanical means to achieve geometric
similarity with different tablet presses. Kinematic and dynamic similarities are
achieved by matching the speed and force of compression. The process parameters
for both press simulations are indicated in Table 4.
Multiple regression of the target quantity (H-) on a combined data set (including
data for two materials, two presses, two speed levels for each press, and a
Dimensional Analysis of the Tableting Process 255
Table 3 Tablet Press Parameters
Compression
Number of roll diameter
Tablet press stations Dcr (mm)
Manesty Betapress 16 177.8
Fette 2090 36 300
Table 4 Process Parameters
Measured
Compression force (kN)
compression speed (RPM) Avicel Emcompress
Manesty Betapress 57.7 to 111.6 2.0 to 11.5 5.1 to 26.3
Fette 2090 53.3 to 88.5 4.8 to 6.8 6.9 to 31.1
range of compression forces) in a log-log domain yielded a multiple regression coefficient
of 0.9788. Regression coefficients for each of the dimensionless variables
of the 	 set were found to be highly significant (p-level of less than
0.00001).
The resulting regression equation was
ln(H-) 
 ln{a(h/ht)b1(Dcr /ht)b2( pm-)b3(n)b4}
256 Levin and Zlokarnik
Table 5 Regression Table (N 
 61)
Standard
bi error of bi t (56) p-level
Intercept 49.7966 2.4245 20.5387 0.0000
ln(h/ht) 9.0029 0.3925 22.9383 0.0000
ln(Dcr/ht) 5.7702 0.5174 11.1502 0.0000
ln(pm · -) 5.7195 0.5225 10.9463 0.0000
ln(n · ) 0.7234 0.1193 6.0654 0.0000
Multiple R 
 0.9788, F (4,56) 
 320.32, p  .00000, Std. error of estimate 
 0.28708
Figure 1 Observed vs. predicted data.
The relevant statistics are summarized in Table 5. The regression plot is presented
in Figure 1.
V. CONCLUSION
It was demonstrated that dimensional analysis of the tableting process can produce a
scientifically reliable way of predicting tablet properties across the range of materials
and with diverse compaction mechanisms. A theoretically sound scale-up method
is thus readily available for tableting equipment of different capacity. The method can
be readily expanded to include other materials and tablet presses and other target
quantities, such as tablet stability (disintegration) and bioavailability (dissolution).
VI. CALCULATIONS AND FORMULAE
Tensile strength H of a tablet was calculated as
H 
 2C/(pdht)
where
C 
 crushing force
d 
 die diameter
Loading depth h was calculated as
h 
 V0 /A
where
V0 
 initial powder volume (V0 
 Wd )
W 
 tablet weight
d 
 bulk density (0.468 g/cc and 0.962 g/cc for Avicel and Emcompress,
respectively)
A 
 punch tip area (A 
 pd2/4)
Applied maximum pressure p was calculated as
p 
 Fm/A
where
Fm 
 peak compression force
Dimensional Analysis of the Tableting Process 257
The powder compressibility parameter - was calculated as defined,
-
 V/(pVt)
where
V 
 change in tablet volume (V 
 V0  Vt)
Vt 
 final tablet volume (Vt 
 Aht)
p 
 change in compression pressure (p 
 pm)
For the purpose of this study, the average powder compressibility parameter
- was calculated as shown in Table 6.
258 Levin and Zlokarnik
Table 6 Powder Compressibility Parameter
Powder compressibility
Material parameter - (mm2/N)
Avicel PH101 2.450E-02
Encompress 7.582E-03
9
Scale-Up of Film Coating
Stuart C. Porter
Pharmaceutical Technologies International, Inc.,
Belle Mead, New Jersey
I. INTRODUCTION
A. Overview of Coating Processes
A comprehensive overview of pharmaceutical coating (materials, formulations,
and processes) has been given by Porter and Bruno [1]. It should be noted that
there has been a steady transition in the pharmaceutical industry, beginning with
sugar coating, moving to film coating, and finally arriving at aqueous film coating.
Sugar coating can be characterized as a relatively complex but noncritical
process. Complexity stems from the multiplicity of coating formulations used during
one process and the sequencing (dosing, distributing, and drying) that must
take place for each application of coating liquid; noncriticality is associated with
the fact that precise control over process parameters (air volumes, temperatures,
spray rates, etc.) is not a prerequisite for success in the process. In contrast, film
coating is relatively simple but critical process. In this case, simplicity relates to
the need to use fewer (and sometimes only one) coating formulations during the
process, which are usually applied in a continuous but controlled manner; criticality
is manifest by the need to identify and control a range of key processing factors,
especially when applying water-based coating formulations.
Although both sugar coating and film coating are utilized by a significant
number of pharmaceutical companies worldwide, the film-coating process is the
one most often preferred today. Film coating was formally introduced into the
pharmaceutical industry in the middle of the last century. Initially intended to provide
a means for more rapidly applying coatings to pharmaceutical tablets, it has
readily been adapted for coating other types of products (such as pellets, granules,
powders, and capsules). In general terms, film coating is a process whereby a
259
polymer-based coating is applied to the substrate such that:
The rate of application of the coating fluid and the drying rate are carefully
controlled.
The coating material is uniformly applied to the surface of the substrate.
The quality and functionality of the applied coating are both maximized and
reproducible.
Although film coatings are most often applied for their aesthetic qualities, they
have a important role to play in improving product stability and robustness, as
well as enhancing flavor attributes, facilitating ingestion, and modifying drug release
characteristics.
Film-coating formulations encompass those that are expected to allow a
drug to be rapidly released from the dosage form, those that may possess special
barrier properties (with respect to, for example, moisture or oxygen), and those designed
to modify drug release characteristics and facilitate drug targeting. As
such, these coating formulations are exemplified by:
Organic solvent–based solutions of polymers [1]
Aqueous solutions or dispersions of polymers [2]
Hot-melt systems [3]
Powder coatings [3]
Despite the apparent variety expressed by these options, aqueous systems hold a
dominant position in the pharmaceutical industry at this time. As a consequence,
serious constraints are often imposed on the products being coated, the coating
formulations used, and the coating processes that are adopted, with the result that
scaling up the coating process can present serious challenges.
It is one of the intriguing contradictions of film coating, especially when
considering aqueous processes, that, in order to create a more robust product, the
initial product has to be designed to survive a process that becomes progressively
more stressful the larger the scale of process employed. Such stress is associated
with both the environmental conditions within the process and the attritional effects
to which the product being coated is subjected. It is often a failure to appreciate
these issues that reduces the likelihood of achieving complete success during
the scale-up process. It is also worth remembering that process scale-up is not
a one-time event; rather, it can be an ongoing process that is driven by the need to
increase capacity and cut operating costs throughout the product life cycle. Under
these circumstances, the need to modify a less-than-optimal process to accommodate
ongoing scale-up issues may face regulatory constraints that prevent total
success from being achieved. There is no substitute, therefore, for taking great
steps to confirm the robustness of both formulations (core and coating) and coating
processes, especially since critical decisions may have been made on the ba-
260 Porter
sis of laboratory-scale trials conducted early on in the development process. More
on this subject will be discussed later in this chapter.
1. Film Coating—Equipment Concepts
At the heart of any coating process is the coating vessel, which can take one of two
forms:
Coating pans
Fluid-bed coating equipment
In the beginning, film-coating equipment was commonly derived from that used
in the sugar-coating process, namely, conventional coating pans. The early days
of film coating, however, coincided with the introduction of a fluid bed coating
process developed by Dale Wurster [4], and this quickly became adopted for
many film-coating operations. The growing demand, however, to find alternatives
to the use of organic solvents, together with the introduction of the sidevented
coating pan (initially in the form of the Accela-Cota), has resulted in
coating pans being preferred for coating tablets, whereas fluid bed processes are
more commonly employed for coating multiparticulates [5]. While a veritable
plethora of coating equipment is available in the industry today (especially since
generic versions of many of the pioneering developments are now available), the
basic concepts of panning equipment are shown in Figure 1 and those of fluid
bed equipment in Figure 2.
The availability of such a variety of equipment often adds an extra degree
of complexity to the scale-up process. Geographical preferences in equipment
Scale-Up of Film Coating 261
Figure 1 Schematic diagram highlighting the basic concepts of pan-coating equipment.
selection (often as the result of a desire to source locally and take advantage of
vendor support programs) often means that the manufacturing-scale equipment
available may differ from the equipment used during process development, even
when the equipment design is essentially based on the “same operating principles.”
2. Thermodynamics of the Film-Coating Process
Since the majority of film-coating operations around the world utilize aqueous
coating processes, it is often useful to apply thermodynamic models to the process.
In this way, the development-scale process can be fundamentally characterized,
based on application of the first law of thermodynamics, as suggested by
Ebey [6], allowing more accurate predictions for operating the production-scale
process in a manner so that the two processes are essentially equivalent.
Ideally, of course, it would be desirable to operate all processes under constant
conditions. Such an ideal is often beyond the practical capabilities of many
film-coating operations. Application of the concepts proposed by Ebey, however,
usually permit predictive processing adjustments to be made in order to allow for
natural variation in the coating process. For example, for a process where the
262 Porter
Figure 2 Schematic diagram highlighting the basic concepts of fluid bed coating equipment.
moisture content of the processing air varies from day to day, season to season,
etc., it is possible to determine what changes, for example, in spray rates, inlet-air
temperatures, or inlet-air volumes are required to maintain the product temperature
at the predetermined set point. By way of example, the initial process conditions
outlined in Table 1 represent process conditions for an aqueous film-coating
process conducted in a laboratory-scale coating pan where the moisture content of
the inlet air is such that its dew point is 4.5°C. The modified conditions in the same
table exemplify how the process can be adjusted by changing the spray rate to
maintain an equivalent process when the moisture content of the inlet air has increased
(to where the dew point is now 15.5°C).
Though mathematical tools such as those described by Ebey are useful for
predicting adjustments in order to maintain the equivalency of two processes, it
must be remembered that these tools are evaluating the macroenvironment
within those processes. The changes that may, however, be taking place at the
microscopic level (as, for example, that which exists at the precise moment
when droplets of coating liquid make contact and begin to interact with the surface
of tablets, pellets, etc.) are much more complex and much less predictable.
Mathematical models as suggested here, however, still have value in making
predictions that can often reduce the actual number of coating trials that need to
be performed, even though they cannot be used to predict empirical results, such
as coated tablet aesthetics.
Scale-Up of Film Coating 263
Table 1 Example of Application of Thermodynamic Model to
Predict Adjustments in Process Conditions When the Inlet-Air
Moisture Content Is Increased
Initial Modified
Process parameter process process
Spray rate (g min1) 75 72
Coating solution solids 15.0 15.0
content (% w/w)
Inlet-air temperature ()C) 70 70
Inlet-air dew point ()C) 4.5 15.5
Process-air volume:
(cfm) 200 200
(m3h1) 350 350
Exhaust-air 43 44
temperature ()C)
Environmental equivalency 1.761 1.761
factor, EE
3. Boundaries of the Film-Coating Process
Unlike the processes described elsewhere in this book, the film-coating process is
inherently much more complex, since the list of parameters that contribute to
overall success is potentially exhaustive. Thus the complexities of the scale-up
process are potentially more challenging. In basic terms, these three components
of the film-coating process all contribute, in a very much interactive manner, to
the overall success of the process:
The core (ingredients, size, shape, surface chemistry, physical attributes,
etc.)
The coating (ingredients, solvents, surface chemistry, rheology, tackiness,
etc.)
The coating process (equipment design, process parameters employed,
maintenance and calibration programs, etc.)
The inherent complexities of this process are well illustrated by the process
operational boundaries highlighted in Figure 3. Although this diagram specifically
references tablet coating in a side-vented pan, the concepts are applicable to the
film coating of all types of products in a wide variety of coating machines.
264 Porter
Figure 3 Outline of the operational boundaries of a film-coating process.
II. SCALING UP THE COATING PROCESS
A. General Factors to Consider
The introductory section has provided the reader with some idea of the complexities
of pharmaceutical coating processes, especially those relating to the
now predominant aqueous film-coating process. These complexities can be
transformed into serious challenges that face the scientists and engineers
charged with the responsibility for scaling up the coating process. Unlike that
associated with many other unit operations, scale-up of the coating process involves
much more than just dealing with larger batch sizes and faster throughputs.
Application of coatings, often being the penultimate step to packaging, can
leave a long-lasting impression in terms of product appearance and product performance
(both in terms of functionality and stability). Additionally, once the
coating stage is reached, there has already been much investment (time and
money) in that batch of product.
In a somewhat simplistic way, scale-up of a coating process typically
involves:
Taking a laboratory-scale process (hopefully one that has been appropriately
optimized) and transferring the processing technology first to the pilot
scale and ultimately to full production scale
Further optimizing the process on the larger scale to take into account issues
whose influence could not easily be predicted during earlier process development
activities
Irrespective of the type of coating process used, the potential process
changes that commonly occur on scale-up include:
Increased batch sizes
Increased attritional effects
Increased spray rates
Increased number of spray guns (or change from a single- to a multiple-head
nozzle)
Increased drying air volumes
Increased processing times (per batch)
Many of these parameters are quite predictable, especially when applying
some of the thermodynamic concepts described earlier. The increased processing
time, which brings with it increased exposure to stressful conditions (both
mechanical and as a result of environmental conditions used in the process, especially
when that process is aqueous based) is much more unpredictable, and is
often the root cause of much angst during the preparation of early commercial
batches.
Scale-Up of Film Coating 265
1. The Robustness Factor
In spite of the issues outlined in the previous section, all too often the amount of
time spent on formulation and process design is inconsistent with the impact that
is felt when performance in the coating operation fails to meet expectations. More
attention in this regard is usually paid when the applied coating has some specialized
functionality (such as improving product shelf life or modifying drug release
characteristics); however, even when the purpose of the coating is primarily for
aesthetics and product identification (in which cases, poor coated product quality
is unlikely to impact product efficacy), failure to meet certain visual standards all
too often results in batch rejection, leading to:
Discarding the batch (often determined on the basis of balancing recovery
costs with the inherent value of the batch)
Reprocessing the batch
Sorting the batch to remove defective material
In each of these cases, there is a certain financial cost associated with potential
product loss, reprocessing, and work in process.
Clearly, therefore, there is a strong incentive to ensure that:
The formulations (core and coating) are sufficiently robust to meet the needs
of the operation. This requirement is all the more important when viewed
in terms of the increased (but often ill-defined) stresses to which the product
is subjected on scale-up.
Critical elements of the coating process and their impact on final product
quality (in the broadest sense) have been determined and taken into account
during process optimization.
While these requirements seem obvious, they are often ignored. Critical decisions
with respect to the design of coating formulations and processes are frequently
made on the basis of data produced from small-scale processing trials. The
consequences of such decisions only become apparent after product approval, thus
resulting in the fact that the changes required to rectify matters are often very
much constrained by regulatory issues (although these may be diminished to a degree
as a result of the issue of the SUPAC Guidances).
One of the elements of film coating that attracts much attention at technical
symposia is that dealing with troubleshooting. This very fact is a clear indication
of how poorly the matters described here are considered. Although it is certainly
important to understand the issues that can potentially lead to problems and to explore
recovery options, the very idea that troubleshooting needs to be considered
is clearly an admission of failure during critical stages of product and process development.
The photographs shown in Figure 4 provide typical examples of problems
that crop up all too often under the troubleshooting banner and usually relate
to some aspect of the coating process employed.
266 Porter
2. Opportunities for Process Optimization and Use of Expert
Systems
A lot of the data developed during product and process development are often empirically
derived and, as such, reflect the relative experience and preferences of
those responsible for that development process. Although application of such experience
can be of tremendous value, it is not unusual to find that each new product
that is being developed, or process refinement being employed, has inherent
idiosyncrasies that reduce the relevance of prior experience. In order to create a
“robust” product and process, personal bias has to be removed, and, instead, decisions
must be made based on scientific validity. All too often, the phrase “we have
fully optimized the product and process” is used to describe a situation where decisions
have been made on the basis of an iterative process where process (and formulation)
variables have been studied in a “trial and error” manner, changing one
parameter at a time. This process, often called one of “successive approximation,”
is followed until an acceptable process has been achieved. The problems associated
with employing such techniques include:
A truly optimal process (or product) is rarely achieved.
A comprehensive database that relates to the critical features of that process
is rarely obtained,
Subsequent decisions that demand further process modifications (for example,
on the basis of meeting operational requirements to improve process
productivity or reduce process costs) often confound the “optimization”
process.
Scale-Up of Film Coating 267
Figure 4 Common examples of film-coating problems that trigger troubleshooting exercises.
The answer to these concerns involves the employment, during the development
process, of techniques that utilize a design of experiments (DOE) approach.
The application of such techniques has been well documented in the published
literature. For example, Porter et al. [7], in examining a side-vented pan
process, were able to produce unambiguous quantitative results that defined how,
inter alia, uniformity of distribution of the coating and coating process efficiency
could be maximized while meeting other objectives with respect to coated product
quality (for example, gloss, smoothness, and residual moisture content).
Turkoglu and Sakr [8], in studying the application of a modified-release coating
to pellets in a rotary fluidized-bed process, determined that coating temperature
and atomizing air pressure were key factors that influenced drug release from the
pellets when applying an aqueous ethylcellulose dispersion. Finally, Rodriguez et
al. [9] employed similar techniques when studying the thermodynamics of an
aqueous film-coating process performed in a GS Coating Systems pan.
Ultimately, the real advantage of utilizing a DOE approach during process
development and optimization is that:
All critical process parameters can be identified in a way that removes personal
bias.
A truly optimized process can be developed that has a sufficiently sound scientific
basis to satisfy queries from regulatory agencies.
Further process refinements, particularly during scale-up, can be made in a
much more predictable manner when faced with the need to meet specific
operational constraints.
Clearly then, adopting a formal, scientifically valid approach to designing
and optimizing a particular coating process provides a good foundation ultimately
for scaling up that process. That having been said, in these days of globalization,
the scale-up process can involve technology transfer from one department to another
that may be geographically remote from one another. In such a situation, the
department on the receiving end of the transfer process may be in a technical void
with respect to critical knowledge about that process. Under these circumstances,
ready access to such technical information (on a 24-hour basis) is often of
paramount importance if success in the scale-up process is to be achieved and
maintained. Considering such knowledge may reside with only a few key people,
the challenge is thus how to provide the necessary access.
Conventional wisdom is to prepare exhaustive technical reports, either in
hard copy or electronic form, that can be distributed as need requires. In the present
environment, however, instant access to information, utilizing a user-friendly
approach, is often demanded. One such approach that is gaining more attention in
the pharmaceutical industry involves the application of expert systems.
Fundamentally, these systems consist essentially of a computer program
that makes decisions or recommendations based on knowledge gained from experts
in the field. Such programs are usually customized to fit a given situation and
268 Porter
can utilize tools such as artificial neural networks, rule-based systems, and decision
trees. The application of expert systems to pharmaceutical processes (including
film coating) has been described by Rowe [10], and the commercial availability
of such systems has been demonstrated [11].
So far, the discussion has centered on providing a description of the basis
for typical film-coating processes, outlining some of the critical issues that need
to be considered when contemplating process scale-up, and identifying some useful
tools that may be employed to facilitate that process. Clearly there is no substitute
for careful preparation, and the benefits of doing so can best be illustrated
by reference to case studies that exemplify scale-up studies that have been successfully
concluded. In this regard, the case studies that will be discussed involve
scaling up a process that includes:
Coating of tablets in a pan process
Coating pellets in a fluid bed process
B. Scaling Up a Pan-Coating Process
1. Introduction
It should be quite clear now that time and money spent designing a robust process
(where all of the critical process factors have been defined and their impact well
documented) has the potential to save time and money later on, especially during
the time leading up to and immediately after product launch. Designing an optimal
process also has great benefit in the training of process operators so that they
become well informed about the critical constraints of that process.
If a particular process is going to be used for a range of products that have
similar characteristics, then time spent optimizing that process provides benefit
many times over. There will, however, be times when a particular product has special
needs that will mean that a well-optimized process may have to be further refined
to meet those needs. Such a requirement is particularly evident when a coating
process that has been designed for the application of conventional coatings
(where aesthetics may be high on the list of attributes defining product quality) is
now required to be adapted for the application of highly functional coatings, such
as modified-release coatings (in which case, drug release characteristics will assume
a much greater degree of importance).
Some key attributes of coated products and coating processes that may well
be used to set objectives for optimizing a coating process are shown in Table 2. In
many cases, the attributes as listed are very subjective and thus must be defined in
clearly measurable terms if they are to be used as the basis for process optimization.
Additionally, meeting defined objectives may equally be dependent on the
existence of certain coating and tablet formulation attributes as well. Nonetheless,
although the information listed in Table 2 is not meant to be all-inclusive, it does
provide an idea of the types of response that could be used as a basis for optimizing
a coating process.
Scale-Up of Film Coating 269
When optimizing a coating process, however, a major challenge that must
be faced involves selecting the appropriate process variables that must be examined.
Reference to the operating boundaries of a typical coating process shown in
Figure 3 clearly indicates that the list of potential variables to be studied is quite
extensive. In order to create a manageable design of experiments program, the list
of variables to be studied should not typically exceed four or five; otherwise the
number of coating trials to be undertaken becomes prohibitive. Thus attention
should be focused only on those variables that have a critical role to play. Reducing
the number of variables to a manageable level can be accomplished in a number
of ways, including:
Fixing as constants those variables that are not open to change (for example,
selecting a particular type of coating pan, spray gun, mixing baffle
design, pan loading, etc.).
Applying a preliminary screening technique, where a larger number of variables
can be studied in a much more superficial manner. This approach
enables the critical variables to be identified and then used as the basis for
a more comprehensive evaluation.
Earlier reference was made to published articles that described the use of
optimization techniques for coating processes. In particular, the one presented by
Porter et al. [7] provides a useful example of how aesthetic, functional, and processing
issues can be dealt with. The key elements of the study that formed the basis
for this article are listed in Table 3; typical results obtained in this study are
summarized in Table 4. From these data, it is possible to optimize the coating pro-
270 Porter
Table 2 Coated Product Attributes and Coating Process Characteristics That May Be
Used as Objectives to Develop an Optimal Process
Coated tablet attributes
Coating process
Aesthetic Functional characteristics
1. High gloss
2. Smooth coating
3. Good color uniformity
4. Absence of edge
chipping
5. Absence of film
cracking
6. Absence of logo
bridging
7. Absence of twinning
8. Absence of picking
1. Drug release
characteristics meet target
requirements
2. Coated product meets
stability requirements
3. Effective taste masking is
achieved (if required)
4. Coated tablet meets target
strength requirements
1. High (and
reproducible) process
coating efficiency
2. High uniformity of
distribution (on a
weight basis) of
coating from tablet to
tablet
3. High productivity
Scale-Up of Film Coating 271
Table 3 Process Parameters Examined in a Study Designed to Optimize a Coating
Process Based on the Use of a 24, Laboratory Side-Vented Coating Pan
Coating process variable Variable range setting
A. Fixed operating parameters
1. Pan loading (kg) 15.0
2. Drying air (cfm) Inlet: 250; exhaust: 300
3. Coating system Opadry II
4. Quantity of coating applied (% w/w) 3.0 (theoretical)
5. Pattern air pressure
(psi) 30.0
(bar) 2.1
B. Variable operating parameters
1. Solids content of coating suspension (% w/w) 10–20
2. Inlet-air temperature ()C) 60–90
3. Spray rate (g min1) 35–75
4. Atomizing air pressure
(psi) 22–60
(bar) 1.5–4.1
5. Pan speed (rpm) 8–20
6. Number of spray guns used 1 or 2
Table 4 Typical Results Obtained in Optimization Study
Response measured Response units Response ranges
Uniformity of distribution of % RSD 11.88–59.59
coating material
Coating process efficiency % 26.23–99.37
Roughness value of applied Rz, m 7.76–15.90
coatinga
Gloss value of applied coatingb Gu at 60) angle 2.60–3.78
Final moisture content of % w/w 0.10–5.33
coated tabletc
Exhaust temperature of coating )C 32.8–57.3
process
a The higher the value, the rougher the coating.
b The higher the value, the glossier the tablets.
c Initial uncoated tablet moisture content was 3.0% w/w.
cess with respect to:
Aesthetic qualities (gloss and coating smoothness) of the final coated tablet
Potential impact on final tablet stability (as this relates to product temperatures
experienced in the process and residual coated tablet moisture content)
Process efficiencies (with respect to actual vs. theoretical amount of coating
applied, and uniformity of distribution of the coating)
An important fact to be recognized, however, is that an extensive database
relating to the coating process in question has been established, and key process
variables (including their interactive effects) have been identified, providing a
sound platform from which to begin the scale-up process.
2. Predicting Scale-Up Issues
Once an appropriate laboratory-scale process has been established, many of the
key elements of the process should have been determined. Some operating parameters
(such as inlet-air temperature, coating formulation to be used, and solids
content of the coating solution/suspension) can be directly translated to the largerscale
process. Others, however, will have to change, and these include:
Drying-air volume
Pan speed
Pan loading
Number of spray guns to be used
Gun-to-tablet-bed distance
Spray rate
Spray gun dynamics
a. Drying-Air Volume. Drying-air volume, although potentially variable,
is often selected based either on the recommendations of the vendor of the
equipment to be used or on the basis of the optimum conditions designed for the
air-handling system that has been installed. The supply- and exhaust-air fan
speeds should be set, based on the equipment used, to meet the negative pressure
pan settings that are usually recommended. Once the appropriate drying-air volume
has been established, this setting becomes a driver for other key processing
variables, such as spray rate (see later discussion).
b. Pan Speed. Selecting appropriate pan speeds often becomes more of
a challenge than is really necessary. Clearly tablet motion, a factor influenced
greatly by pan speed, can be a major issue when it comes to potential tablet breakage,
edge wear, and surface erosion. On the other hand, according to data established
by Porter et al. [7], the uniformity of distribution of the applied coating is
also greatly influenced by pan speed, with the higher pan speeds being better in
272 Porter
this regard. Consequently, there is a great incentive to design tablet cores so that
they can withstand high pan speeds in order to allow coating uniformity to be fully
maximized.
Typically, those pan speeds that are selected on scale-up are often lower
than are truly optimal, in recognition of the fact that attritional effects do increase
with increasing scale of process. Nonetheless, a good rule of thumb, based on pan
speeds used on the laboratory scale and dimensions of the laboratory-scale equipment,
is to calculate the linear velocity of the tablets in the coating pan and then
to determine the pan speed on the larger scale that will give an equivalent linear
velocity. In this way, tablet dwell time in the spray zone on the larger scale will be
equivalent to that achieved on the smaller scale, and full benefit can be taken of
the optimization strategies used on the smaller scale to maximize uniformity of
distribution of the coating. An example of how pan speed can be determined on
scale-up is shown Table 5.
c. Pan Loading. In general, defining appropriate pan loading should not
be a troublesome issue. A coating pan of given dimensions is designed to hold a
certain charge of tablets. Unfortunately, pan loadings are usually defined in terms
of volume fill, rather than by weight. Thus, the optimum pan loading by weight
will vary from product to product depending on the apparent density (which takes
into account the mass/volume ratio of an individual tablet as well as the shape and
size of that tablet) of that product. Even allowing for such product variation, calculating
optimal pan loadings should not be a serious challenge. The difficulty
Scale-Up of Film Coating 273
Table 5 Estimating Pan Speed on Scale-Up
Parameter Pan size
Pan diameter 24 in. 36 in. 48 in. 60 in.
(60 cm) (90 cm) (120 cm) (150 cm)
Typical pan rotational 5–20 3–17 2–15 2–11
speed ranges (rpm)
Pan circumference 75 in. 115 in. 150 in. 190 in.
(190 cm) (290 cm) (380 cm) (480 cm)
Peripheral pan 12.5 in. sec1 19.2 in. sec1 25.0 in. sec1 31.5 in. sec1
speed at 10 rpm (31.8 cm (48.8 cm (63.5 cm (80.0 cm
sec1) sec1) sec1) sec1)
Projected pan rotational 10 6.5 5.0 4.0
speed at a peripheral
speed of 12.5 in sec1
(31.8 cm sec1)a
a This example is based on the rotational speed of 10 rpm used in a laboratory-scale coating pan.
arises, however, for these reasons:
On the laboratory scale, it is not too difficult to ensure that a pan is appropriately
loaded. Even when only a very small amount of product is available,
this problem can be dealt with by bulking up active tablets with
placebos to make a full charge.
On the production scale, pan loading often has nothing to do with the ideal
loading for the pan, but rather with the total batch weight of the compressed
tablets and how evenly these can be divided into a whole number
of pan loads. For example, if the total batch weight is 500 kg and these
tablets are to be coated in a pan that optimally holds 120 kg per run, then
the instructions will call for five pan loads of 100 kg each to be coated.
The result is that each coating run will have each pan underloaded by
about 16%.
In the example shown, a 16% underloading may not seem to be too much of
a problem, but potentially critical issues that may arise (especially if the degree to
which the pan is underloaded is even greater than the amount shown in the example)
include:
The possibility that, in a side-vented coating pan, there may not be enough
tablets in the pan to ensure that the exhaust-air plenum is completely covered
(in which case, drying air will take the path of least resistance and
flow directly toward the air plenum rather than passing through the tablet
bed). With some designs of coating pan, this potential problem may be
obviated by the placement of a sliding damper in the exhaust-air plenum
so that the exposed part can be sealed off.
The potential that the side walls of the coating pan, or even baffles, become
more exposed to the spray, causing coating liquid to build up on exposed
metal surfaces, often with the results that tablets will stick to these surfaces.
Again, with some foresight, changing the gun-to-bed distances,
gun spacing, or, indeed, the number of guns used can minimize this problem.
These solutions are likely to be utilized if, for a particular product,
the pan loadings are relatively constant. In situations where compression
batch weights frequently vary, then such corrective measures are less
likely to be employed.
The likelihood that when the pan is significantly underloaded, as baffles
move through the tablet bed as the pan rotates, the surface of the tablet
bed moves sufficiently to change the gun-to-bed distance. This situation,
as will be seen later, could potentially change the characteristics of the
spray droplets that are impinging on the surfaces of the tablets.
As baffles become more exposed and as pan speeds are constantly adjusted
to keep the tablets in motion (more of a challenge in an underloaded pan),
there is increased risk that tablets will become damaged.
274 Porter
Thus during product and process development, even though compression
batch weights are often defined in terms of the capacities of blenders, granulators,
dryers, etc., there is sufficient justification, when the product is to be coated, to
keep in mind the capacities of the coating pans that will be used.
d. Number of Spray Guns to be Used. In any film-coating process, it is
critical to ensure that the spray zone is optimized with respect to these key criteria:
Making sure that the full width of the tablet bed is covered so that few, if
any, tablets on the surface pass through the spray zone without receiving
some coating
Setting up each gun (in terms of atomizing and pattern air) so that maximum
coverage is achieved without compromising the quality (in terms of
droplet size, size distribution, droplet density, and relative “wetness”) of
the atomized coating liquid
Avoiding overspray on to the pan side walls
This being the case, a major decision that has to be faced is how many
spray guns should be used. The answer may well depend on the type of spray
guns available. As will be seen in later discussion, some spray guns have greater
capabilities than others in achieving broader coverage without compromising
spray quality.
Sight should not be lost of the possibility that, on scale-up, the type of spray
guns available on the production-sized equipment may be different that those used
on the lab scale. This situation may arise because:
The spray guns used on the laboratory scale are not capable of achieving the
spray rates required or of maintaining effective atomization at those
higher spray rates on the larger scale.
Scale-up may involve transfer to a manufacturing site that is geographically
remote from that where process development was undertaken, and preference
may have been shown for locally sourced spray guns.
Unfortunately, scant attention is often paid to the need to minimize the number
of changes that take place on scale-up, and this may be especially true in the
case of spray-gun selection, where, all too often, one type of spray gun is assumed
to be very much equivalent to another. Again, as will be seen later, such equivalency
may be far from true.
Concluding, therefore, that the main objective is to maximize bed coverage,
issues that greatly influence the choice in number of spray guns used will be those
as shown in Figure 5, where broader coverage per gun may well reduce the number
of guns required, while more restricted coverage, often chosen in attempts to
produce better coated tablet quality (in terms of coating gloss and smoothness),
will necessitate the use of a larger number of guns. The data listed in Table 6 illustrate
how spray pattern can influence coated tablet quality, with round spray
Scale-Up of Film Coating 275
patterns tending to produce smoother coated tablets, although with the increased
risk that localized overwetting can occur, resulting in greater likelihood of sticking
and picking. Clearly, the main objective is to avoid problems like those shown
in Figure 6, where ineffective bed coverage leads to increased opportunities for
tablets to pass through the spray zone without receiving any coating.
276 Porter
Figure 5 Influence of typical spray patterns on the number of spray guns used.
Table 6 Influence of Spray Pattern Used on Tablet Quality
Polymer Mean coating % Tablets
concentration Atomizing Spray pattern roughness, showing defects
(% w/w) air pressure shape Ra (m) (picking or sticking)
9 40 psi Elliptical 2.72 24.0
(2.8 bar) Round 1.68 26.0
9 60 psi Elliptical 2.53 4.5
(4.1 bar) Round 1.44 35.0
9 80 psi Elliptical 2.29 2.5
(5.5 bar) Round 1.29 35.0
12 60 psi Elliptical 3.51 2.0
(4.1 bar) Round 2.07 9.0
e. Gun-to-Tablet-Bed Distance. There are very few examples of where
a truly scientific approach is taken to establish appropriate positioning of spray
guns inside coating pans (unlike with fluid bed coating machines, where gun location
is more often predetermined). Typically, with the help of rudimentary positioning
tools, such as a ruler, the operator is often left to set up gun position by
eye. It is quite surprising that this feature of equipment setup often receives scant
attention, considering that gun positioning needs to be optimized to:
Ensure that optimal and reproducible bed coverage is achieved.
Facilitate broad coverage while providing maximum surface drying time
(before tablets on the surface of the bed “fold under” and get mixed into
the tablet mass)
Achieve reproducible (from run-to-run) spray droplet characteristics as they
arrive at the tablet surface (see later discussion)
It is also interesting to note that spray-gun-to-tablet-bed distances are often
different in production-scale equipment than they are in equipment used in the
laboratory. Fundamentally, if this parameter has been optimized appropriately
during process development, then there is no reason not to believe that these distances
should be the same, irrespective of the scale of the process used. Nonethe-
Scale-Up of Film Coating 277
Figure 6 Example of how using too few spray guns leads to poor bed coverage.
less, the rationale for the existence of differences includes:
On the laboratory scale, because of geometric constraints, there is often very
little opportunity to optimize the gun-to-bed distance, and thus this parameter
takes on a fixed setting often defined by personal preference.
Once a move is made to the production scale, there is more opportunity
to reconsider gun positioning (although logic does not always prevail).
On the production scale, only a suboptimal number of guns may be available,
with the result that the guns are moved further back to ensure that
appropriate bed coverage is achieved. This requirement may also be dictated
by use of different types of spray guns on the larger scale that also
necessitates repositioning to gain good bed coverage.
The spray rate per gun on the production scale can be substantially higher,
requiring that the guns be moved further away to prevent localized overwetting.
Clearly, therefore, greater attention should be paid to how spray guns are set
up. In reality, unless spray gun positioning is optimized during process development,
the same type of guns are to be used in both the laboratory and the manufacturing
plant, and the spray rate per gun can be maintained (within reasonable
ranges) in both cases, it is futile to expect to be able to fix gun-to-bed distances no
matter the scale of process used. Even so, greater consideration should be given to
achieving these ideals.
Pragmatically, therefore, it is quite normal to find that gun-to-bed distances
will be 50–60% greater on the production scale than those used on the typical laboratory
scale (for a 24-in.), or 60-cm-, diameter coating pan holding 10–15 kg of
tablets).
f. Spray Rate. Assuming there are no major climatic differences to be
faced during technology transfer, then predicting typical spray rates to be adopted
during scale-up is a relatively simple task. As a simple guideline, calculations
should be based on the relative airflows used for each scale of process, as shown
in Eq. (1):
S2 
 (S1  V2)/V1 (1)
where:
S1 
 spray rate used on the scale used in process development
V1 
 air volume used on the scale used in process development
V2 
 air volume used on the larger-scale process
S2 
 prediction for the spray rate to be used
If substantial changes in other parameters are expected (environmental humidity,
processing temperatures as a result of heater capabilities, etc.), then better predictions
can be made using the thermodynamic principles outlined in Sec. I.A.2.
278 Porter
For a side-vented pan-coating process, the processing data shown in Table
7 exemplify some spray rates that may well be used during process scale-up. It is
interesting to note from these data that the drying- (and exhaust-) air volumes used
in the production-scale Hi-Coaters are somewhat lower than those seen in an
equivalent scale Accela-Cota or, indeed, as might be predicted from studies conducted
in a laboratory-scale Hi-Coater. These differences reflect design considerations
that suggest that, in the Hi-Coater, incoming air has essentially no place to
go except out through the exhaust plenum and thus must pass through the coating
pan (and, thus, the tablet bed). In other types of side-vented coating pans, particularly
those that are completely perforated, incoming air is often introduced into
a cabinet that surrounds the outside of the coating pan itself and that must pass
through the perforated section of the pan in order to gain access to the inside the
pan (and thus effectively dry the tablets). As a consequence, fully perforated pans
are often operated with higher drying-air volumes. These different requirements
do not pose any problems unless a pharmaceutical manufacturer decides to switch
from one type of coating pan to another and contracts with an independent vendor
to provide the air handling equipment. In this situation, it is critical that recommended
specifications (from the coating pan vendor) be obtained in order to ensure
that the independent contractor provides an appropriately sized system.
These idiosyncrasies, in terms of air flow requirements, do complicate
matters, however, when scaling up from one type of coating pan to another.
Scale-Up of Film Coating 279
Table 7 Example of Operating Parameter Ranges Used When Scaling Up an Aqueous
Film-Coating Process
Pan type (and size or model)
Accela-Cota Hi-Coater
Parameter 24, 48, 60, HCT 60 HC 130 HC 170
Inlet-air volumea:
(a) cfm 250 1800 3800 260 900 1300
(b) m3 hr1 440 3200 6700 450 1600 2300
Exhaust-air volumea:
(a) cfm 300 2000 4000 280 1300 2100
(b) m3 hr1 525 3500 7000 500 2300 3700
Inlet 60–80 60–80 60–80 60–80 60–80 60–80
temperature ()C)
Exhaust 40–45 40–45 40–45 40–45 40–45 40–45
temperature ()C)
Spray rate (g min1) 40–70 250–500 500–1000 40–70 300–600 500–900
Pan speed (rpm) 12–14 4–7 3–6 12–14 4–7 3–6
a These are nominal air volumes, since actual values may be different depending on the installation and
on whether the coating pan vendor or an independent supplier supplied the air handling equipment.
These complications arise when applying the simple predictions [based on Eq.
(1)] for spray rates. If the scale-up process involves switching from a laboratoryscale
fully perforated pan to a production-scale Hi-Coater, there is a risk that the
predicted spray rates will be understated. For the sake of the calculation, a useful
rule of thumb is to double the value for the actual air volume that will be employed
in the larger-scale Hi-Coater and to use that value solely for the purposes
of the calculation.
g. Spray Gun Dynamics. Earlier in this section, frequent reference was
made to the importance of establishing spraying conditions that are consistent
from the development scale right up to that used in the manufacturing plant. Similarly,
mention was also made of the scant attention typically paid to spraying dynamics
and the lack of a strong understanding of what actually happens when
droplets of coating fluid emerge from a nozzle, move toward the tablet bed, and
impinge upon the surfaces of tablets.
All too often, an overly simplistic view is taken of the role that spray gun
design (namely, brand of gun and features of the fluid nozzles and air caps used)
can play in achieving good, reproducible coated tablet quality. The fact that spray
gun design may differ (from laboratory to production setting) is often considered
to have little relevance, and accommodations for such differences are routinely
made based on prior experience and, often, instinct, without benefit of reference
to scientific data. A commonly held assumption, therefore, is that guns made by
one manufacturer are essentially the same in terms of gun performance as those
from another and that differences that exist are purely in the features presented
and, ultimately, the cost.
Quality attributes of film-coated tablets that can be associated with spray
gun performance include:
Appearance:
Coating gloss
Coating roughness
Existence of defects (“picking,” edge chipping/edgewear, filling in of logos)
Color uniformity
Functional:
Uniformity of distribution of coating
Coating porosity (which influences film permeability)
Solvent (water) penetration into the tablet cores and, hence, product stability
Clearly, there is thus a great incentive to gain a better understanding of those factors
that influence gun performance as well as those differences that exist between
guns supplied from different manufacturers.
280 Porter
In a recent presentation, Cunningham [12] has described some of the factors
that can influence spray gun performance and has compared the performance of
spray guns from different vendors. As can be seen from the results shown in Figure
7 (where the performance of a Schlick spray gun is compared to a Spraying
Systems spray gun), the influence of gun-to-bed distance and coating suspension
solids content on mean droplet size is quite different for each type of spray gun.
In both cases, droplet size tends to increase the further away from the nozzle one
goes (probably due to droplet collisions, causing size enlargement). The influence
of coating suspension solids content on mean droplet size is much more pronounced,
however, in the case of the Schlick gun (producing results in the range
of approximately 25–275 m, compared to the Spraying Systems gun, which
yields droplet sizes in the range of 30–60 m under the same conditions).
These results clearly have implications for situations where the type of gun
may be changed on scale-up but also where gun-to-bed distance may also be
changed in the same process. Comparing the data shown in Figure 8, the differences
are even more pronounced when observing the influences of spray rate and
atomizing air pressure on mean droplet size. Since these two parameters are commonly
increased during the scale-up process, it can clearly be seen that little
change would occur when using a Schlick gun, but the change would, indeed, be
substantial if a Spraying Systems VAU gun were used.
Scale-Up of Film Coating 281
Figure 7 Example of how the type of spray gun used, gun-to-bed distance, and solids
content of the coating fluid can influence the size of droplets generated.
An argument might be made that, when coating tablets, such changes in
mean droplet may be of no consequence, since the ranges of droplet sizes achieved
are still quite small when compared to that of the tablets being coated. This viewpoint
is overly simplistic, since the size of droplets formed can have an influence
on coating smoothness and gloss as well an impact on how rapidly the liquid dries
during flight from the spray nozzle to the tablet surface.
Further comparisons between these two types of spray guns indicate that
there are differences in droplet velocity produced (see Fig. 9) as well as in the
breadth of coverage on the surface of the tablet be (see Fig. 10). Droplet velocity,
especially for those droplets arriving at the tablet surface, can potentially influence:
Wetting (velocity at impact can influence the advancing contact angle
formed between the tablet surface and the droplet and the degree to
which the droplet spreads immediately after contact) and, ultimately,
film adhesion
Overspray, where the velocity of impact may cause droplets to be reflected
from the tablet surface
The breadth of coverage can influence the number of spray guns that will be
needed, and the likelihood that overspray onto the side walls of the pan will occur.
Clearly the results shown in Figure 10 suggest that fewer spray guns of the Schlick
type will be required to give equivalent coverage to that obtained when using
Spraying Systems guns.
282 Porter
Figure 8 Example of how the type of spray gun used, atomizing air pressure, and spray
rate can influence the size of droplets generated.
Scale-Up of Film Coating 283
Figure 9 Example of how the type of spray gun used, atomizing air pressure, and gunto-
bed distance can influence droplet velocity.
Figure 10 Example of how the type of spray gun used, gun-to-bed distance, and pattern
air pressure can influence bed coverage.
In summary, the results shown in Figures 7–10, though only representing
data for two distinct types of spray guns, provide clear warning of the potential
problems that can occur if, during the scale-up process, commonly seen differences
in spray gun performance are ignored. Appreciation for this situation is of
paramount importance when one considers that there is a very real possibility that
the types of spray guns used may be changed, especially if scale-up involves technology
transfer from a development site to a manufacturing one that is geographically
remote, quite a common occurrence in these days of globalization.
3. Scale-Up of Pan-Coating Processes: A Case Study
From the foregoing discussion, there are clearly many issues to be confronted
when scaling up the pan-coating process. Evidently, the more definitive the data
that are developed early on, the less likely that major problems will occur later on,
especially problems that could inevitably delay a product launch and cost much in
the way of lost revenues, particularly when dealing with a potentially “blockbuster”
drug product.
This case study will summarize the development of a pan-coating process
designed for the application of an enteric coating to a tablet product, provide insight
into some of the early process optimization studies that were undertaken, and
show how these ultimately facilitated the development of production-scale manufacturing
processes.
a. Initial Process Development. Early development studies were carried
out using a laboratory-scale 24, Accela-Cota and employing a statistical design of
experiments technique in which the operational variables were as shown in Table
8. Although several response variables were examined in this study, the principal
issues concerned themselves with providing good functional enteric performance.
Recognizing that enteric products are often potentially known for their lack of robustness
(manifested as inherent brittleness of the coating, which is likely to cause
enteric failures during subsequent handling, such as emptying the coating pan,
284 Porter
Table 8 Ranges of Process Variables Used During Optimization of
the Enteric Film-Coating Process
Parameter studied Ranges examined
Solids content of coating suspension 10–25
(based on Sureteric® YAE-6-18108)
(% w/w)
Inlet-air temperature ()C) 50–70
Spray rate (g min1) 50–90
Quantity of coating applied (% w/w) 5–10
Atomizing air pressure (psi) 25–55
Atomizing air pressure (bar) 1.75–3.75
printing, and packaging), an extra challenge was imposed in the form of a stress
test (see later discussion) to confirm appropriate robustness of the final dosage
form. The two criteria used to measure enteric performance, therefore, were:
Enteric test (ET): One hundred tablets were exposed to artificial gastric
juice (0.1 N hydrochloric acid solution) for two hours using a modified
disintegration tester. Performance was expressed in terms of percent failure,
which was represented by the percentage of tablets showing any sign
of enteric failure (such as premature disintegration, swelling, or even
slight softening).
Stressed enteric test (SET ): Essentially the same test as the enteric test, but
in this case the 100 tablets were placed in a friability tester for four minutes
at 25 rpm prior to being submitted for the enteric disintegration test
in artificial gastric juice.
From this initial study, and referring to the data shown in Figure 11, it is evident
that good functional enteric performance can be achieved when the coating
Scale-Up of Film Coating 285
Figure 11 Influence of inlet-air temperature and solids content of the coating suspension
on enteric test performance of enteric-coated tablets.
process is operated under conditions where:
The inlet-air temperature is greater than 60°C
The coating suspension solids content is in the range of 10–15% w/w.
The data represented by the stressed enteric results (SET), however, tell a slightly
different story (see Fig. 12A). Clearly, the process operating ranges where acceptable
performance can be achieved are quite limited. However, if the level of
applied enteric coating is fixed at a minimum of 10% w/w and the coating suspension
solids content is reduced to 15% w/w, then the process operating ranges
become quite broad (see Fig. 12B).
b. Scaling Up the Optimized Enteric-Coating Process. Based on the results
described in the previous section, an optimized coating procedure was designed
and used as a platform for scaling up the enteric-coating process. Details
of this optimized laboratory process, as well as the conditions used in the scale-up
study, are shown in Table 9. In addition, the results for the enteric tests performed
on tablets coated in these coating trials are shown in Table 10. The fact that these
results clearly meet (and in most cases, surpass) the specifications designated for
the enteric testing of aspirin tablets provides sufficient confirmation for the validity
of the optimization and scale-up procedures used in this case study.
C. Scaling Up Fluid Bed Coating Processes
1. Introduction
Fluid bed coating processes, although applicable for coating the full range of
pharmaceutical product types, are more likely to be reserved for the coating of
multiparticulates, usually with some kind of functional coating (taste masking, enteric,
sustained release). The nature of the substrate and the purpose of the applied
coating clearly provide additional challenges during both initial process development
and the scale-up process. This situation is made even more complex by the
fact that with the current preference for aqueous coating formulations, such highly
functional coatings often demand the use of latex or polymer dispersion coating
systems. These systems have certain idiosyncrasies in terms of film formation that
place extra demands when optimizing the coating process in order to ensure that
stable, reproducible applied coatings are obtained.
Much has been said in the discussion so far as it relates to scaling-up the
pan-coating processes. Philosophically, many of the issues already described are
equally applicable to the fluid bed process. There are, however, some important
differences that must be appreciated during the development of fluid bed coating
processes. For the most part, although there is a plethora of pan-coating equipment
currently available and each brand has its specific characteristics and features, the
operating principles are essentially the same for most types of equipment that are
in common usage in the pharmaceutical industry today. In contrast, when it comes
286 Porter
Scale-Up of Film Coating 287
Figure 12 Example of how process conditions can influence the enteric performance of tablets that have been submitted to a
stress test prior to undertaking the enteric test.
to fluid bed coating, there are three distinct processing concepts commonly used,
as illustrated in Figure 2. To summarize, these are:
The top-spray process, which is a manifestation of the fluid bed granulation
process that has long been used in the pharmaceutical industry
The bottom-spray process, commonly called the Wurster process and the
only one specifically designed as a coating process
288 Porter
Table 9 Coating Process Details Used in Scaling Up an Aqueous Enteric-Coating
Process Using an Accela-Cota Process
Coating process conditions for scale indicated
24, 48, 60,
Process parameter Accela-Cota Accela-Cota Accela-Cota
Inlet-air volume:
(cfm) 250 1800–2000 2300–2700
(m3 hr1) 425 3100–3400 3900–4600
Exhaust-air volume:
(cfm) 300 1900–2100 2400–2800
(m3 hr1) 500 3200–3600 4100–4800
Inlet-air temperature ()C) 75–84 70–80 70–80
Exhaust-air temperature ()C) 38–41 40–45 40–45
Spray rate (g min1) 60–70 400–500 650–700
Number of spray guns 2 3 5
(Binks 605; fluid nozzle
66SS; air cap 66SH)
Gun-tablet-bed distance:
(inches) 5–7 8–12 10–12
(cm) 12–18 20–30 25–30
Atomizing air pressure:
(psi) 35–40 60–80 50–70
(bar) 2.4–2.7 4.1–5.5 3.5–4.8
Pan loading (kg) of aspirin 12.0 135 300
325 mg tablets
Tablet bed prewarm 45–50 45–48 45–48
temperature ()C)
Pan speed (rpm) 14 6 4
Enteric-coating suspension 15.0 15.0 15.0
solids content (% w/w)
Quantity of coating applied 10.0 10.0 10.0
(% w/w)a
Coating process time (hr)a 2.00 3.00–3.75 4.75–5.10
a This only refers to the enteric-coating layer; in addition, a subcoating [based on Opadry] applied to
a level of 2.0% w/w, and a colored top coating [based on Opadry II] applied to a level of 3.0% w/w
were also used.
The tangential-spray, or rotor, process, originally designed as a granulator
for producing spheronized granulates
Each of these processing concepts, which can all be supplied by each of the
major vendors of fluid bed coating equipment, has special characteristics that
makes it suitable for certain tasks, as shown in Table 11. Although the concepts
Scale-Up of Film Coating 289
Table 10 Enteric Test Results for Aspirin (325 mg) Tablets Coated in Scale-Up
Processing Studies
Disintegration test
% Failures in 0.1 Dissolution test
N HCl solution
% Drug % Drug
Batch Enteric Stressed Disintegration released after released after
size test enteric test time in buffer, 2 hours in 90 min in buffer
(kg) (ET) (SET) pH 
 6.8 0.1 N HCl (a) pH 
 6.8 (a)
12 0 0 8:05  0:32 0 104.5
135 0 0 7:04  0:52 0 91.5
300 0 0 6:32  1:00 0 105.2
a Compendial specification calls for: 10% dissolved in 0.1 N HCl after 2 hours and 80%
dissolved in buffer, pH 
 6.8, after 90 minutes.
Table 11 Features and Uses of the Three Concepts for Fluid Bed Film Coating
Process Advantages Disadvantages Uses
Top spray Larger batches Limited batch weight Application of:
Easy nozzle access flexibility Aqueous coatings
Relatively simple Limited weight gains Taste mask coatings
setup Greater risk of spray Hot-melt coatings
Good mixing drying
Bottom spray Moderate batch Poor nozzle access Application of:
sizes during coating Aqueous coatings
Uniform distribution Requires tallest Taste mask coatings
of coatings expansion chamber Modified-release
Wide range of coatings
applications Drug-layer coatings
Tangential Relatively easy setup High mechanical Application of:
spray Easy nozzle access stress on product Drug layer coatings
Shortest processing being coated Modified-release
chamber coatings
Fast spray rates
Wide batch weight
flexibility
outlined in this table represent those that are frequently used in the industry today,
some specialized fluid bed processes, the operating principles of which fall outside
those of the three listed, are also worthy of note. Examples would be the
“Kugelcoater” (which is manufactured by BWI Manesty in Europe), and the “Precision
Coater” (manufactured by GEA).
In contrast to pan-coating processes, some characteristics of fluid bed processes
that may feature strongly in the scale-up process include the facts that:
Nozzle positions (with the possible exception of the top-spray process) are
somewhat fixed, and the distances between the nozzle tips and product
being coated are often quite small and unlikely to change on scale-up.
Spray patterns are always round, and thus pattern air is not a factor in the atomizing
process or in defining the spray characteristics.
Although fluid bed machines have optimal operating capacities, they often
have much more flexibility in accommodating a range of batch sizes
within a given process, especially those based on the tangential-spray
concept. Although there is a certain minimum requirement in order to facilitate
appropriate fluidization of the product, this flexibility is often a requirement
when one considers that the amount of coating material that is
often applied may range from 1 to 50% (and even broader if one includes
the drug-layering process). Such extremes are rarely required in typical
pan-coating operations.
Nozzle (atomizing) air can contribute significantly to product movement
and can also be a source of a significant increase in product attrition.
Drying air is also the main source of “power” for creating product movement.
Thus the needs of the drying process and that required to create motion
are interdependent, adding complexity in terms of meeting (and optimizing)
the requirements of each. For example, when a significant
amount of coating material is being applied, the batch mass will increase,
requiring more air volume to maintain motion; at the same time, the requirements
for drying remain little changed.
2. Predicting Scale-Up Issues
As with pan coating, the key to successfully scaling up the fluid bed process involves
the design of a completely optimized laboratory-scale process on which
key decisions can be based. As discussed earlier, Turkoglu and Sakr [8] have provided
an appropriately relevant example of how such an optimized fluid bed process
(in this case, a tangential-spray process) may be designed.
It is not unexpected to assume that certain features of the process will again
remain unchanged throughout the scale-up process. These features include:
Product and coating formulations
Solids content of the coating liquid
290 Porter
Inlet-air and product temperatures (although these may be adjusted to accommodate
other limitations that may arise, such as uncontrollable
changes in drying-air humidity and limitations on heater capacity)
Key processing parameters on which much attention will have to be focused
include primarily:
Batch size
Drying-/fluidizing air volumes
Spray nozzle dynamics
Spray/evaporation rate
The photographs shown in Figure 13 provide a useful example of the kinds of
equipment changes that can take place when scaling up a fluid bed process. In this
case, reference is made to the Wurster process, which possesses some useful characteristics.
Once the pilot scale (in this case, the 18, Wurster process) is reached,
larger machines are based on multiples of the 18, concept, thus somewhat simplifying
further scale-up. Thus, with this type of process, many of the challenges occur
when scaling up from the laboratory to pilot scale, rather than from pilot to full
production scale.
a. Considerations for Batch Size. Mention was made earlier in this
chapter, and much has been said in pharmaceutical publications, about the batchsize
flexibility that is often associated with the fluid bed process. It is perhaps
more appropriate, however, to talk in terms of the flexibility of such equipment to
accommodate ranges in starting batch weight. Any fluid bed process that is involved
in a coating application will always have an optimum batch fill weight that,
as with pan-coating processes, will be defined by the interior volume of that particular
machine. Each will also have an upper capacity limit that is defined by the
operating needs of that process.
It is critical, during initial process development, to give serious consideration
to the amount of material that will be applied (especially for processes involving
drug layering or those involved with the application of modified-release
coatings to fine particle products, where required coating levels in excess of 50%
are not uncommon). Key factors to be established are:
What are the minimum and maximum limits for batch capacity in a particular
machine?
How much coating material is to be applied?
Answering these questions provides suitable guidelines for deciding on which
particular type of process is appropriate. Selection of the wrong process may require
that, part way through processing, the batch may have to be divided in order
to allow the full process to be completed. Such a necessity is more likely when using
the bottom-spray (Wurster) process and least likely when using the tangential-
Scale-Up of Film Coating 291
292 Porter
Figure 13 Photographs illustrating equipment used during the scale-up of the Wurster process.
spray process. Dividing batches in this manner is rarely troublesome on the laboratory
scale but becomes much more of a issue when going to large, productionscale
processes, which is something that may prove to be a potentially costly oversight
during the initial stages of process development. Since batch size constraints
may be more significant in the Wurster process, this processing concept will be
used primarily as the basis for further discussion on the subject of defining appropriate
batch sizes.
For fluid bed processes, a useful limit to consider is working capacity,
which essentially refers to the final batch weight. In the case of the Wurster process,
this term refers to the volume outside the inner partitions. The minimum
starting batch size for the Wurster process is usually approximately 40% of its
working capacity. This loading is essentially a guideline, since a critical element
of this process is to ensure that there will ultimately be enough material in the upbed
region [that is, that region inside the partition(s) when the process is in operation]
to capture all of the material that is being sprayed, thereby avoiding low
process coating efficiencies as a result of either material that will be deposited on
the side walls of the inner partition(s) or material that is not captured by the product
being coated and that passes all the way up into the filter system. Using the
40% guideline is only suitable when the amount of coating (or drug to be layered)
is substantial. When the coating level is low (less than 10% w/w), then the starting
batch weight should be more in the range of 60–70% of working capacity.
For the Wurster process, calculating batch volume on scale-up can be calculated
using Eq. (2):
B 
 (2)
where:
B 
 batch volume, or working capacity (liters)
r2 
 radius of the product (Wurster) chamber (cm)
r2 
 radius of each inner partition (cm)
n 
 number of inner partitions
L 
 length of each inner partition (cm)
If the batch volume is multiplied by the bulk density of the product to be coated,
then the batch load, by weight, can be determined.
Although these examples are more specific to the Wurster process, similar
guidelines can be applied to the top-spray process, in which case the definition for
working capacity will be different. When dealing with the tangential-spray process,
the quantity of product that is sufficient to ensure that the spray nozzles are
completely immersed when the product is in motion will define the minimum
starting batch weight.
r21
L  n(r22
L)
 1000
Scale-Up of Film Coating 293
b. Drying/Fluidizing Air Volumes. As stated earlier, unlike the case of a
coating pan, the air that passes through a fluid bed machine serves two purposes:
drying and imparting motion. The key objectives in each case need not be mutually
inclusive. Keeping the product moving in an appropriate manner and maintaining
the volume of air required to do that may well depend on:
The mass of material inside the machine. This requirement is confounded
by the fact that as more coating is applied, the mass increases, as does the
requirement for fluidizing air.
The tackiness of the coating being applied. Tacky coatings can increase both
the “drag” on coated particles and also the potential for agglomeration to
occur. In either case, an increase in fluidizing air may well be required to
offset these two problems. Tackiness is often associated with the nature
of the polymer(s) used in the coating system, the presence of other additives
(such as plasticizers), excessive levels of residual solvents present
as a result of ineffective drying, and, especially, with the use of latex coating
systems. When ineffective drying is the cause of tackiness, an increase
in air volume may well be a suitable remedy. When this problem
is caused by the other factors, an increase in air flow may act as a doubleedged
sword: Increasing air flow, by improving motion, may well alleviate
the problem; however, increased air flow, by increasing the level of
heat in the product, may well result in increased tackiness.
In each of these scenarios, though a change in air flow will presumably improve
product movement, unless spray rates (or process temperatures) are changed appropriately,
the associated increase in drying capacity may well be detrimental to
the process.
In general terms, the top- and tangential-spray processes may be less demanding
in their requirements with respect to air flow. In the former, the fluidization
pattern is quite random; in the latter, much of the burden for creating motion
falls on the spinning disk so that the incoming air is required only to:
Create lift at the walls of the processing chamber
Prevent product from dropping below the spinning disk
Facilitate drying
Again, it is the Wurster process that presents the greatest challenge in optimizing
air flows, where it is desirable to ensure that product rapidly accelerates up
through the inner partition while maintaining a smooth, even flow in the downbed
(and essentially maintaining product in the down-bed in a near-weightless
condition). Considering the range in particle sizes of the products that may be
coated in this process, some accommodation can be made in terms of specific
product requirements by changing the orifice plate [which determines the relative
amounts of air passing upward through the region of the inner partition(s) and also
that meeting the downward-moving product in the down-bed region of the pro-
294 Porter
cessing chamber] at the bottom of the processing chamber as well as the relative
height of the inner partition.
When scaling up the fluid bed process, a major requirement is to produce
fluidization behavior on the larger machines equivalent to that used on the scale
that provided the basis for process development. To achieve this goal and to minimize
attritional effects, the same air velocities for each scale of equipment are required.
Thus the overall increase in air volume required during scale-up will be related
to the increase in area of the perforated base plate and, in the case of the
Wurster process, the open area of the partition plate immediately beneath each of
the inner partitions. Such calculations are simplified when scaling up from an 18,
pilot-scale machine to, say, a 32, machine, since the latter represents a three-multiple
of the former and thus would require a threefold increase in air flow.
c. Spray Nozzle Dynamics. Spray nozzle dynamics often prove to be a
more challenging subject when dealing with fluid bed processes, because:
Often the product being coated is a multiparticulate ranging in size from approximately
50 m up to about 2–3 mm in size.
In order to coat each particle in a discrete manner and avoid agglomeration,
the coating fluid must often be atomized more finely and in a more controlled
manner than in the case where tablets are coated in a typical pan
process.
In order to maintain fineness of atomization at the higher spray rates typically
required in the larger-scale processes, atomizing air pressures may
often have to be increased to levels where atomization air velocity can seriously
increase product attrition.
In order to meet the atomization constraints required, it is almost always
necessary to change the model of spray gun used in order to achieve the
effective levels of atomization at the increased spray rates required during
the scale-up process.
With the possible exception of the top-spray process, the issue of nozzle-tobed
differences becomes a nonissue in the fluid bed process, since this distance is
extremely small and, to all intents and purposes, fixed. Indeed, the close proximity
between the nozzle and the product being coated can be problematic in some
cases, since the velocity gradient created between the fluidizing air and the atomizing
air can cause product to be drawn into the wettest part of the spray, increasing
the chances of localized overwetting and agglomeration.
With the substantial interest in use of aqueous coating systems, an added
burden is placed on the atomizing process. This burden results from the relatively
high viscosities and surface tensions of aqueous systems. Fortunately, in applications
using modified-release coatings, aqueous versions of such coating systems
are typically in the form of latexes, or polymer dispersions, which have relatively
low viscosities for the solids content of the coating system, and the presence of
Scale-Up of Film Coating 295
surfactants (as dispersion stabilizers) facilitates a reduction in what would otherwise
be high surface tension values.
The data displayed in Figure 14 clearly indicate the dilemma with which one
is faced when trying to achieve an increase in spray rate for a given type of nozzle.
In the examples shown, the Schlick 970 series gun is typical of what is used
on the laboratory scale, whereas the 940 series gun is more suitable for pilot- and
production-scale operations. Clearly, the 940 series gun has serious limitations
when scaling up to full production requirements, since if, for example, it is desirable
to achieve a mean droplet size of 15 m, this objective can be achieved (by
increasing the atomizing air pressure as spray rate is increased) as long as the required
spray rate does not exceed 250 mL min1. For all practical purposes, 6 bar
represents a practical upper limit for atomizing air pressure in this type of coating
process in order to prevent serious product damage due to attrition. Under these
circumstances, if effective atomization cannot be achieved, use of specialized
nozzle setups, such as those employed in the Glatt HS system, offers a potential
solution. These types of nozzle allow higher spray rates to be achieved (see Fig.
15), since:
The higher atomizing air velocities produce smaller droplets, even at high
spray rates.
296 Porter
Figure 14 Influence of spray nozzle type and atomizing air pressure on the mean droplet
size of water sprayed from guns used in a Wurster process.
A special nozzle surround keeps product further away from the nozzle tip,
thus preventing that product from being drawn into the “wet” area of the
spray zone, and also limits the attritional effects that normally accompany
the use of high atomizing air pressures and velocities.
d. Spray/Evaporation Rate. As described when discussing scaling up
the spray application rates used in pan-coating operations, application of simple
models [as represented by Eq. (1)] can prove to be extremely useful also for fluid
bed processes. Further refinements, in terms of fully optimizing the process in this
regard, can be achieved by applying appropriate thermodynamic principles. Jones
[13] has provided a good example of how such an approach can be applied to a
fluid bed coating process.
The spray rate that can be achieved in a given process is related to the volume
of air that passes through the machine and to the temperature and humidity
of that air. Clearly, therefore, spray rate will be governed to some extent by the
rate at which the solvent (aqueous or otherwise) can be removed. Spray rate will
also be influenced by:
The behavior of the coating fluid.
The inherent tackiness of the coating, especially during the critical time immediately
after deposition onto the surface of the substrate.
Scale-Up of Film Coating 297
Figure 15 Example showing how a highly specialized nozzle (HS nozzle) can achieve
equivalent atomization at high spray rates to that obtained in a more conventional nozzle
when used at lower spray rates.
The rate at which the product being coated moves through the spray zone.
Generally, the faster that product moves through the spray zone, the lower
is the “dwell time,” the less coating that is captured during that time, resulting
in a faster dry time for the coating. As the rate at which the applied
coating dries (so that particle-to-particle contact no longer carries the risk
of interparticulate adhesion, resulting in agglomeration) has a direct influence
on the ultimate spray rate that can be achieved, rapid particle
movement through the spray zone increases the potential to spray faster.
e. Summary of Scale-Up Issues. Scaling up the fluid bed process clearly
faces many hurdles that are both similar and, at the same time, different to those
faced with pan-coating processes. Additional complexity stems from the nature of
the substrate that is likely to be coated in the fluid bed process as well as from the
fact that, very often, the applied coating has a very important role to play in drug
delivery.
That said, the task should not be overcomplicated, and many good instances
exist to illustrate successful conclusions to such efforts. For example, the data
shown in Table 12 illustrate the scaling up of the Wurster process in which an
aqueous latex coating has been applied to drug-loaded pellets in order to prepare
a modified-release product. It is appropriate to point out that since the 32, Wurster
essentially comprises three 18, Wurster units, the air flow used in the former represents
approximately a threefold increase over that of the latter, with the result
that the spray rate is scaled up by the same factor. This situation illustrates the relative
simplicity of scaling up from the pilot-scale unit.
The functional characteristics (in terms of drug release) for the pellets
coated in this particular study are shown in Figure 16. Statistical comparison of
these data (using the ?2 factor) confirm that these drug release profiles are essen-
298 Porter
Table 12 Coating Process Conditions Used in the Scaling Up of the Wurster Process
for Application of an Aqueous Latex Coating to Drug-Loaded Pellets
Process parameter settings
Process parameter 7, Wurster 18, Wurster 32, Wurster
Inlet temperature ()C) 70 70 64
Inlet dew point ()C) 20 15 11
Product temperature ()C) 34 34 33
Fluidizing air volume (m3 hr1) 270 1225 3740
Atomizing air pressure (bar) 2.0 2.0 3.0
Spray rate (g min1) 50 300 850
Exit air RH (%) 85.4 73.7 64.5
Yield (5%) 99.0 96.7 98.4
tially equivalent, although the best comparison, as is evident by simple visual inspection,
is illustrated by the results for the coating trials performed on the pilot
and production scales. This observation should not be all that surprising, since the
processing conditions used in both these cases showed closer agreement.
3. Scale-Up of Fluid Bed Coating Processes: A Case Study
Effective product and process optimization play a prominent role in any successful
scale-up study. As an illustration, this case study summarizes the initial development
and subsequent scale-up of a Wurster process designed to facilitate the application
of an aqueous ethylcellulose dispersion to drug-loaded pellets. At the
same time, it was intended to deal, up front, with some of the idiosyncrasies of such
a coating system that often influence the functionality of the final dosage form.
a. Initial Process Development. A preliminary study was established to
examine the potential influence of processing parameters on some critical performance
attributes of the final product, especially those associated with ultimate
drug release rate and the reproducibility of the same.
Making certain assumptions about formulation issues (with regard to both
the substrate being coated and the coating system being applied), the ultimate
influence of the applied coating on drug release rate can be reduced to two
Scale-Up of Film Coating 299
Figure 16 Comparison of drug release characteristics of pellets coated with an aqueous
ethylcellulose dispersion using a laboratory-, pilot-, and production-scale Wurster process.
key elements:
The thickness of the coating applied
The structure of that coating
Having fixed the amount of coating to be applied and controlling the surface area
to be covered by selection of a specific size fraction of pellets to be coated, the one
significant processing factor that can affect coating thickness is the relative coating
efficiency achieved (that is, the actual quantity of coating deposited relative to
the theoretical amount applied). At the same time, coating structure will be influenced
by:
The effectiveness of coalescence of the latex coating
The incidences of defects such as “pick marks” or “cracks”
Consequently, in this study, the critical factors that were examined during process
development involved establishing the influence of process conditions on:
Coating process efficiency
Coalescence of the film coating (determined by means of assessing drug release
characteristics before and after imposition of a “curing” step)
Evaluating the impact of processing conditions on film structure (by means
of visual analysis using scanning electron microscopy)
Initial process development and ultimate process optimization were conducted
as described by Vesey and Porter [14]. Basically, the study was performed
300 Porter
Table 13 Process Variables Used in the Development
and Optimization of a Coating Process Designed for the
Application of a Modified-Release Film Coating to Drug-
Loaded Pellets
Variable ranges
Process variable evaluated
Solids content of aqueous 10.0–25.0
ethylcellulose dispersion
(% w/w)
Inlet-air temperature ()C)a 50–70
Spray rate (g min1) 15–45
Atomizing air pressure (bar) 1–3
Oven curing time at 60)C (hr) 0 or 24
a The fluidizing-air volume was adjusted during each run to
maintain a constant fluidization pattern; the volume of air
required to achieve this was recorded in each case.
in a Glatt GPCG-3 unit fitted with a Wurster insert. The process variables that
were evaluated are as shown in Table 13.
In order to assess the influence of process conditions on the coalescence efficiency
of the latex coating, dissolution profiles (for samples from each coating
run) were compared before and after being subjected to a curing step. Statistical
analysis was undertaken using the ?2 fit factor, which is based on a logarithmic
transformation of the sum of the squared error when comparing two dissolution
profiles. The ultimate fit factor, expressed in terms of numerical values between 0
and 100, suggests that statistically equivalent dissolution profiles are achieved
when the numeric values exceed 50.
A summary of the response variables obtained in this preliminary study are
shown in Table 14, and the order ranking for the influence of process variables on
the critical responses associated with coating process efficiency and drug release
are provided in Table 15. As can be seen from the summary provided in Table 14,
there is clearly an influence of the processing conditions used on ultimate drug release
characteristics. On further examination, it was concluded that the major
causes of the magnitude of differences in drug release characteristics were primarily
due to:
Variation in coating process efficiency, which resulted in a significant variation
in the actual amount of coating applied.
Overwetting that occurred for the coating runs where product temperature
fell substantially below those typically observed (38–42°C) for this type
of process. Such overwetting induced a significant degree of drug leaching,
as confirmed using elemental analysis employed during the application
of scanning electron microscopy.
On the basis of the results obtained, an optimized procedure was designed that was
intended both to maximize the coating process efficiencies and to ensure that the
?2 fit factor values were in excess of 70.
Scale-Up of Film Coating 301
Table 14 Summary of Ranges Obtained for Response
Variables Studied
Response variable Variable ranges
Product temperature ()C) 22–58
Process air flow (m3 hr1)a 61–142
Coating process efficiency (%) 79.1–97.9
T50, before curing (min) 75–340
T50, after curing (min) 90–320
?2 value 56.6–95.6
a These ranges were used simply to maintain equivalent
fluidization patterns for each coating run.
b. Scaling Up the Optimized Process. Using the optimized coating process
as a basis, procedures were developed that enabled the process to be scaled
up from the 3-kg laboratory scale to a 70-kg pilot scale and ultimately to a 200-
kg production scale. The details of the coating process conditions that were designed
for each of these processes are shown in Table 16. As is readily evident
from the table, the objectives set for coating process efficiencies were easily
met. Data representing drug release characteristics are illustrated in Figure 17,
with clear indication that the equivalent coating process profiles were obtained
for each scale of process. With respect to ensuring good coalescence of the latex
coating, the ?2 fit factor values were 73.3, 70.6, and 75.4 (for the drug release
characteristics obtained before and after implementation of an oven-curing
step) for the laboratory, pilot, and production coating processes respectively,
confirming that the objectives set in this area were also attained. Hence, once
again the value of taking a systematic, sound scientific approach (and one that
excludes personal bias) to process development as the basis for scale-up strategies
has been confirmed.
302 Porter
Table 15 Rank Order Summary of Process Variables Influencing Coating Process
Efficiencies and Drug Release Characteristics (T50)
Coating process Drug release (T50) Drug release (T50)
efficiency before curing after curing
Variable Ranking Variable Ranking Variable Ranking
Inlet temperature 17% Spray rate 40% Spray rate 38%
Spray rate  17% Coating 28% Inlet temperature 21%
atomizing air suspended  spray rate
pressure solids
Coating 17% Inlet 20% Coating 19%
suspension temperature suspension
solids solids
Inlet temperature 17% Atomizing air 12% Inlet temperature 13%
 spray rate pressure
Spray rate  11% (Coating 9%
coating suspension
suspension solids)2
solids
Atomizing air 11%
pressure
(Atomizing air 10%
pressure)2
III. ALTERNATIVE CONSIDERATIONS TO SCALING UP
COATING PROCESSES
Up to this point, the issue of process scale-up has been dealt with in terms of technology
transfer from a small- to intermediate- to full production-scale processes.
In each case, the coating process is a batch process that gets progressively larger.
During the last decade of the 20th century, new processing concepts were introduced
that potentially facilitate a paradigm shift as far as pharmaceutical coating
process technologies are concerned and also in terms of how the issue of scale-up
may be dealt with.
Scale-Up of Film Coating 303
Table 16 Details of Coating Procedures Used in Scaling Up the Wurster Process
Coating process conditions
Glatt Glatt Glatt
Process parameter used GPCG-3 GPCG-60 GPCG-200
Batch size (kg) 3 70 200
Fluidizing-air volume
(cfm) 83–107 800–900 N/Aa
(m3 hr1) 140–180 1360–1530
Inlet-air temperature ()C) 64–67 60–66 72–75
Exhaust-air 40–45 39–41 47–51
temperature ()C)
Product 41–47 40–46 43–46
temperature ()C)
Atomizing-air 1.5 2.0 2.0
pressure (bar)
Number of nozzles One (Schlick One (HS, Three (Schlick
used 970, 1.2-mm 1.5-mm 940, 1.5-mm
orifice) orifice) orifice)
Solids content of 15.0 15.0 15.0
coating dispersionb
(% w/w)
Theoretical quantity 10.0 10.0 10.0
of coating applied
(% w/w)
Spray rate (g min1) 25–28 210–306 500–650
Coating process 99.3 99.6 99.6
efficiency (%)
a Machine did not have a device monitoring air flow; fluidizing air was adjusted to maintain a
fluidization pattern equivalent to those used on other scales.
b Surelease E-7-19010.
One approach, fundamentally based on existing processing concepts, involves
the adoption of continuous processing technologies. Another introduces a
totally different approach to the application of film coatings and, in doing so, totally
changes and essentially eliminates most issues as they relate to preparing
larger and larger batches of coated products.
A. Continuous Coating Processes Based on Existing Film-
Coating Technologies
The concept of continuous processing, in terms of oral solid dosage forms, is not
new to the pharmaceutical industry. Indeed, the tableting process is a continuous
one. Some companies will also lay claim to having introduced continuous coating
processes decades ago. But in each case, these processes have been fundamentally
batch/continuous processes where material handling times (involved with unloading
and loading the coating vessel between batches) has simply been reduced
to a minimum.
The present concept of continuous coating is one in which uncoated product
is constantly fed in at one end and completely coated product comes out at the
other end. Processes of this type had their origins in other industries (especially
the food and agriculture, where batch sizes are routinely much larger than those
dealt with in the pharmaceutical industry).
304 Porter
Figure 17 Drug release characteristics of pellets coated on various scales of the Wurster
process when the laboratory-scale process, used as the basis for scale-up, has been fully optimized.
Mancoff [15] and Pentecost [16] have both described continuous filmcoating
processes that have been designed primarily for pharmaceutical applications.
The fundamental basis of such processes is as shown in the schematic outline
described in Figure 18. The inherent advantages exhibited by these
processes are that:
Dwell time in the coating vessel is short (approximately 5–15 minutes).
Throughput, on a continuous basis, is typically 500–2000 kg hr1.
The bed depth is much shallower than typically seen in a more conventional
pan.
Coating uniformity is significantly improved, and typically, when applying
a colored coating, a 2.0% weight gain in the continuous pan provides
equivalent coverage to that which can be achieved with a 3.0–4.0%
weight gain in a more conventional batch process.
Stress on the product being coated is substantially reduced as a result of the
shorter residence times (in the process) and the shallower bed depths
used.
To date, use of such continuous processes has been restricted primarily to
the manufacture of large-volume products, an application for which continuous
processes potentially have a major advantage. Nonetheless, continuous coating
processes provide a potentially viable alternative for the scale-up of any film-coating
process, where many of the tasks potentially become much simpler, since they
would always be the same irrespective of whether the production batch size is 250
kg or 5000 kg. Simplification arises from reducing or eliminating tasks that would
Scale-Up of Film Coating 305
Figure 18 Schematic diagram of a continuous pan-coating process.
otherwise involve:
Deciding appropriate pan loadings
Defining the appropriate number of spray guns to be used
Determining spray application rates
Determining air flow volumes
Defining appropriate gun-to-bed distances
As they currently exist, continuous processes do have their limitations, which include
the facts that:
Material produced during start-up and shutdown of the process may have to
be either scrapped or reworked, since it is likely to have received less than
the targeted levels of coating as a result of reduced exposure to the spray
application process.
Laboratory-scale continuous processes are essentially nonexistent, thus
making process development on the laboratory scale more challenging,
since processes have to be developed on the basis of a small-batch process
and then transferred to a continuous process.
The quantity of coating that can be applied in one pass is limited to about a
2.0% weight gain, thus providing a challenge when applying modifiedrelease
coatings, where weight gains on the order of 2–10% may be required
(unless the use of multiple passes is acceptable). This disadvantage
can be offset to some extent when the sprayable solids content of the
coating liquid can be increased beyond typical levels of 10–15% w/w. For
example, spraying a latex coating at 30% w/w solids would facilitate an
increase in the amount of coating deposited to about 4–5%.
It is likely, however, that future developments in this area will allow the advantages
of this type of process to be fully realized while addressing and eliminating
current disadvantages.
In order to assess what the potential advantages of the continuous process
might be, as an alternative to more traditional ones in the scale-up process, it is
necessary to determine what the potential throughout rates might be for the continuous
process. There are two elements to making such a determination, one
based on the thermodynamic limitations of the process, the other on geometric
limitations. Throughout (TTh), in kg hr1, based on thermodynamic limitations is
essentially given by:
TTh 

(SR) 
W
(SC)  0.06 (3)
where:
SR 
 spray rate (g min1)
306 Porter
SC 
 the solids content of the coating system (expressed as a decimal
fraction, where, for example, 10% becomes 0.10)
W 
 weight gain to be achieved (again expressed as a decimal fraction)
Throughput (Tgeom), in kg hr1, based on geometric limitations, is given by:
Tgeom 

(A)  (L
r
)  ()
  0.06 (4)
where:
A 
 cross-sectional area of the tablet bed (cm2)
L 
 length of the pan (cm)
 
 bulk density of the tablets (g cm3)
r 
 tablet residence time in the process (min)
There is a link between the two calculations in terms of residence time, r, which
is influenced by thermodynamic factors.
B. Continuous Processes Based on Electrostatic Powder
Deposition
Discussion to this point has focused on processes involving:
Spraying of liquid coating systems
“Solidifying” the coating through a solvent removal (drying) process
Coating tablets en masse
Using constant tablet motion, together with other appropriate mixing devices,
to facilitate uniform distribution of the coating.
These fundamentals provide the basis for many of the difficulties that are encountered
as the process is scaled up.
A more recently introduced concept, described by Staniforth et al. [17] involves
the use of electrophotographic principles (essentially those used in the photocopying
process) as a basis for the application of dry powder coatings to pharmaceutical
tablets. This concept is illustrated in Figure 19. Although representing
an early prototype, the essential principles of the process are clearly outlined. The
salient features of this process are:
It is continuous.
Tablets are handled and coated individually, irrespective of whether the
batch size is one tablet or 1 million tablets.
Tablets are coated first on one side and then on the other, thus allowing different
coatings (in terms of color, functionality, or both) to be deposited
on each side.
Scale-Up of Film Coating 307
The coating zone is defined by the needs of an individual tablet, and the
quantity of coating applied is controlled by the magnitude of the electrical
field that is created and the electrostatic properties of the powder that
is to be deposited.
Deposition of the coating is much more precise than is typically achieved
using current spray application processes, leading to substantial improvements
in coating uniformity both from tablet to tablet and across the
surface of each individual tablet.
Heat fusion takes the place of solvent removal as the means of creating a
dry, continuous coating.
Absence of both a drying step and direct tablet-to-tablet contact essentially
eliminates those stress factors that are an ever-present feature of the scaleup
of more traditional coating processes.
Considering the processing fundamentals of this dry process, almost all of
the issues associated with the scale-up of more traditional film-coating processes
are eliminated, and the key objective is to feed tablets directly from the tablet press
into the electrostatic coating operation and thence on to packaging. Thus once the
process is defined in terms of coating one tablet, it is replicated an appropriate
number of times in order to coat all of the tablets in the batch.
IV. SCALE-UP OF COATING PROCESSES:
OVERALL SUMMARY
The characteristics of pharmaceutical coating processes sets them apart form
most, if not all, other pharmaceutical unit operations, not only in terms of issues
308 Porter
Figure 19 Schematic diagram of a continuous electrostatic powder coating process.
that need to be understood during process development, but also when it comes to
scaling up those processes. This is especially true when dealing with the number
of process variables that have to be considered. If coating processes are subdivided
into pan and fluid bed processes, then for those specific types of processes
that are routinely employed in the pharmaceutical industry today, it is valid to
summarize these processes as belonging to two or three fundamental operating
principles. Even if this simplistic view, however, is taken, process scale-up is
much more complex than just considering it a case of geometric enlargement.
Spraying of coating liquids, ensuring that effective and consistent drying
takes place, achieving appropriate uniformity of distribution of the coating, and
enabling final coating structure and functionality to remain consistent with the
intended purpose of that coating are all events that must well defined if successful
process scale-up is to be accomplished. Coming to grips with the multiplicity
of parameters that commonly define such a process is clearly facilitated
when employing statistical techniques exemplified by the design of experiments
approach. Technology transfer on a global scale is equally well facilitated by access
to expert systems that capture all of the relevant process and formulation
events that have been used to define the final coated dosage form. Finally, in the
long run, the best approach to troubleshooting such a complex process to avoid
trouble altogether.
REFERENCES
1. S. C. Porter, C. H. Bruno. In: H. A. Lieberman, L. Lachman, J. B. Schwartz, ed. Pharmaceutical
Dosage Forms: Tablets. Vol 3, 2nd ed. New York: Marcel Dekker, 1990,
pp 77–160.
2. J. W. McGinity, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms.
2nd ed. New York: Marcel Dekker, 1997, pp 1–582.
3. S. C. Porter. A review of trends in film-coating technology. Am. Pharm. Rev.
2:32–41, 1999.
4. D. E. Wurster. U.S. Patent #2,648,609, 1953.
5. S. C. Porter, I. Ghebre-Sellassie. In I. Ghebre-Sellassie, ed. Multiparticulate Oral
Drug Delivery. New York: Marcel Dekker, 1994, pp 217–284.
6. G. C. Ebey. A thermodynamic model for aqueous film coating. Pharm. Technol.
11(4):40, 1987.
7. S. C. Porter, R. V. Verseput, C. R. Cunningham. Process optimization using design
of experiments. Pharm. Technol. 21(10):60–80, 1997.
8. M. Turkoglu, A. Sakr. Mathematical modelling and optimization of a rotary fluidized-
bed coating process. Int. J. Pharm. 88:75–87, 1992.
9. L. Rodriguez, R. Greechi, M. Cini, N. Passerini, O. Caputo, C. Vecchio. Variation of
operational parameters and optimization in aqueous film coating. Pharm. Technol.
20(4):76–86, 1986.
10. R. C. Rowe. Expert systems in solid dosage development. Pharm. Ind. 55(11):
1040–1045, 1993.
Scale-Up of Film Coating 309
11. Information Obtained from PTI website (www.pt-int.com).
12. C. R. Cunningham. Spray gun optimization for aqueous film-coating processes. Proceedings
of TechSource® Coating Technology 99, Atlantic City, NJ, October 12–13,
1999.
13. D. M. Jones. Effect of process air dew point on a top-spray fluidized bed-coating process.
Presented in Session 265; Coating in the pharmaceutical industry. Proceedings
of AIChE Annual Meeting, 1998.
14. C. F. Vesey, S. C. Porter. Modified-release coating of pellets with an aqueous ethylcellulose-
based coating formulation: coating process considerations. Proceedings of
the 13th Annual Meeting and Exposition of AAPS, San Francisco, 1998.
15. W. O. Mancoff. Film coating compressed tablets in a continuous process. Pharm.
Technol. Yearbook, pp 12–18, October 1998.
16. B. Pentecost. Continuous coating process. Proceedings of TechSource® Coating
Technology 99, Atlantic City, NJ, October 12–13, 1999.
17. J. N. Staniforth, L. A. Reeves, T. Page. Electrostatic powder coating of tablets I: design
and characteristics of a continuous coater prototype. Proceedings of the 13th Annual
Meeting & Exposition of AAPS, San Francisco, 1998.
310 Porter
10
Engineering Aspects of Process
Scale-Up and Pilot Plant Design
Adolfo L. Gomez and Walter A. Strathy
I.D.E.A.S., Inc., Wilson, North Carolina
I. INTRODUCTION
This chapter deals with the design of a pilot plant facility. Although this chapter
discusses many aspects of pilot plant scale-up considerations, it is not meant as a
treatise on process scale-up. Many other authors in this book discuss this subject
more thoroughly. All discussions on process scale-up in this chapter are presented
to serve as examples of the thought process that must be considered when engaged
in the design of a facility.
Although all types of manufacturing processes will be discussed throughout
this chapter, solid-dose manufacturing will be used as the primary example. We
will go through the design of a solid-dose manufacturing facility and take it
through the different stages of the process.
There are four general steps in the design of a pilot plant: planning, design,
construction, and qualification. We will discuss the first two in detail by breaking
them up further into more specific areas of consideration. There is also a brief
overview of the last two phases of the project.
During the planning phase, a series of basic questions must be answered.
What is the ultimate goal for the facility? What type of production will the facility
be used for? What quantities of materials will be typically manufactured? To
answer these questions and the many more that come up, a team must be assembled.
This team should be made up of professionals in the field that are qualified
and empowered to ask questions and make decisions that will ultimately lead to
the successful completion of the facility.
During the design phase, the process flow must be mapped out thoroughly.
311
Decisions on room qualifications and controls must be made. The utilities and process
equipment must be described. In this section of the chapter, we will describe
a typical process for solid-dose manufacturing and use it as an example. This illustration
will allow us to view a specific design and watch it take form. Security
issues must also be addressed during the design of the facility. Will there be controlled
substances in the facility?
During the construction phase of the project, we will make decisions on coordination
options and permit requirements. We will discuss the various options
available for the tracking of the project to ensure timelines are kept. Additionally,
it is at this time when staffing requirements must be finalized. And a consideration
of protocols, production records, and quality assurance documentation must
be formalized.
Finally, during the qualification of the facility, all systems are tested, calibrated,
and cleaned. The mechanical and service infrastructure must be qualified.
The operational qualification will involve practice runs. All documentation must
be finalized. This includes standard operating procedures, batch records, and
equipment logs.
II. PHASE 1—PLANNING
As discussed earlier, all phases can be broken down into more specific areas. In
this chapter the planning phase is broken down into process characterization, manufacturing
projections, and manufacturing philosophy. However, before any activity
begins, a team that will spearhead the project must be assembled. This team
should be comprised of individuals experienced in the following fields, process
engineering, process development, project management, and operations management.
Additional team members may include professionals in regulatory affairs,
purchasing, and quality assurance. Upper management should empower this team
to make critical decisions and move ahead in a timely manner. Open and frequent
communication is vital for this team. Frequent meetings should be scheduled to
monitor progress and react to any problems that may arise.
A. Project Management
Good project management is a key to completing this project on schedule. During
the first meetings of the team, clear goals must be set. The paths towards these
goals must be mapped out and critical steps identified. A baseline schedule should
be clearly described. As part of the project management setup phase, all resources
should be identified, both those within the organization as well as those that need
to be contracted out. Because, at this stage, process requirements have not been
assessed, the project management schedule should be in broad terms, allowing for
312 Gomez and Strathy
different types of processes to be built into the facility design. Later on in the design
phase a review of the project is conducted to focus the activities on more specific
tasks.
B. Process Characterization
How does the team characterize the process for which the pilot plant is to be
manufactured? The first question that needs to be answered is “What is the ultimate
goal for the facility?” Is it to support development for solid dosage forms,
liquid products, or biologically derived products? Or does it have to serve multiple
functions? The answer to this question will allow us to focus and generate
more accurate plans. Until later on in the design phase, this process characterization
should be kept broad and not very detailed. Included in the evaluation
should be the ancillary service equipment and support services, such as electrical
and air handling requirements.
C. Solid Dosage Forms
Solid dosage forms include tablets and capsules. The manufacturing of solid
dosage forms involves extensive powder handling. The powder must be blended
for uniformity and converted into the dosage form either through compression or
encapsulation. Typical requirements include weighing, blending, mixing/granulation
areas, compression/encapsulation areas, and coating areas.
D. Liquids and Ointments
Liquids and ointments include syrups, elixirs, solutions, creams, and ointments.
Typically, they require extensive mixing and bottle filling capacities. Purified water
is essential for the manufacture of these products as well as on-site packaging
capabilities (filling).
E. Biologically Derived Products
Biologically derived products include fermentation products and genetically engineered
materials. These products typically require sterile manufacturing areas.
They require extensive air handling equipment and environmental controls. Sterilization/
sanitation must be easily carried out.
F. Manufacturing Projections
Preliminary manufacturing projections are critical at this stage of planning. What
type of batches will be manufactured at this facility? A pilot plant can, by design,
Engineering Aspects of Pilot Plant Design 313
serve a wide array of batch sizes and purposes. It can be used to manufacture small
development batches of one kilogram or less. And it can serve to manufacture
large scale-up batches of as much as 120 kg. To cover this broad range of batch
sizes, many different sizes of equipment must be available.
G. Types of Products to Be Manufactured
As already described, there are a variety of reasons for the manufacture of batches
in the pilot plant facility. First, the batch may be manufacture as a development
batch. In other words, it could be the first attempt at manufacturing a product. This
type of experimental manufacturing could be the result of a design of experiments
analysis. These experiments are usually carried out at very small sizes, possibly 1
kg or less. However, many of these batches could be made as part of one experiment.
For these batches it is important that the equipment can easily be used for
many runs in as little time as possible. It is also important that manpower requirements
remain as low as possible for manufacturing these small-scale batches as
well as for the cleaning the equipment.
Another type of batch to be manufactured could be larger-scale development
batches. These batches are typically 5–20 kg kilograms in size and are
used for a variety of reasons. They could be used for clinical studies, analytical
development, process development, stability testing, and formulation optimization,
among other purposes. For many of these types of batches, it is important
that current good manufacturing practices (cGMP) are followed. It may also be
critical at this time that the process used for manufacturing is one that can be duplicated,
albeit on a larger scale, on the factory floor. If batches are to be used
for stability studies, special consideration must be given to the packaging capabilities
of this facility.
H. Full-Scale Scenarios
Larger-scale batches may also be planned for this facility. Many pilot plants can
manufacture 120 kg or more of material. These batches may be used as prevalidation
batches, scale-up batches, as well as full-scale production batches. For successful
manufacture of these types of batches, the equipment must be of the same
operating principle as that found in the manufacturing facility. Maintenance of the
pilot plant must be exactly as that of the full-scale manufacturing facility. In fact,
they should share documentation, batch records, SOPs, logbooks, etc. Additionally,
quality assurance (QA) must play a significant role in a pilot plant with these
capabilities. Quality assurance must maintain a presence during the manufacturing
of the batches. They will ultimately be responsible for the release of the product
for either clinical studies or commercialization. The requirements of QA must
be accounted for in the design of the facility. These include testing areas, proper
314 Gomez and Strathy
product containment areas (quarantine), work-in-process (WIP) areas as well as
released material areas. Additionally, consideration must be given for the handling
of larger quantities of materials. Overhead feeding systems may be incorporated
into the design of the facility. Perhaps in situ cleaning capabilities (clean in
place) may also be investigated.
For the manufacture of products that will be used for human consumption,
either by clinical studies or through marketing, a facility must be operated under
Good Manufacturing Practices (cGMP). The Code of Federal Regulations, Section
21, part 211, describes the conditions required for maintaining cGMP compliance.
Compliance of cGMP guidelines is enforced by the Food and Drug Administration
(FDA). Compliance to these guidelines must be built into the design
of the facility.
In our example of a solid dosage pilot facility, we have decided that our
plant will be used for a variety of batches. We will develop novel formulations and
prepare samples for marketing evaluation, we will support manufacturing, and we
will occasionally manufacture a full-scale production batch as required by the
market demands.
I. Manufacturing Philosophy
Once the manufacturing projection questions have been answered, a manufacturing
philosophy must be decided on. This includes deciding on documentation requirements,
special materials handling, controlled substance security, cleaning
validation criteria, and equipment and facility qualification requirements. Now
that we know what types of batches are to be manufactured, we can be more detailed
in the description of the requirements of the facility. These requirements
may be based on internal as well as regulatory requirements. In fact, if a full-scale
facility is already in place, this step can be completed fairly easily and quickly.
Many of the policies and systems may be transferred directly into the pilot facility.
And others may be transferred with only slight modifications.
J. Documentation Requirements
Documentation requirements are predicated on the types of batches to be manufactured
at the pilot facility. For the development of novel formulations, laboratory
notebooks are the primary source of documentation. Room and equipment
logbooks should be maintained. Personnel training records and SOPs must also be
maintained. Once the facility is used for the larger-scale batches described earlier,
what was recommended now becomes required. Manufacturing runs need to be
documented accurately, preferably in batch records. Logbooks should maintain an
accurate record of the product history in rooms and equipment. At this level of
manufacturing, it is also important that personnel training records be kept. These
Engineering Aspects of Pilot Plant Design 315
should document the employees training in general safety issues, cGMP issues,
equipment operation, and material handling. All documentation should be catalogued
and easily accessible for review by either internal quality functions or by
external auditing groups, such as customers or the FDA.
K. Special Materials Handling
Now that we know what types of batches will be manufactured, we can think
about special materials handling. Although the design team can not be 100% sure
what types of raw materials will be introduced into the facility, it can make provisions
for special handling. What types of materials require special handling?
First, let’s answer the question “Why does a material need special handling?” Special
handling may be needed to protect the user from detrimental effects from exposure
to the compound. Secondly, the compound may need special handling to
protect it against the environment.
In the first case, the operator may be working with toxic materials. Toxicity
may be expressed either acutely or chronically. Each of these types of materials
has different types of controls, which are required for the protection of the user.
For toxic products, there are a variety of levels of controls that may be enacted.
Many of these controls can be separated from the design of the facility itself, for
example, portable respirators and gowns. Others may need to be incorporated into
the design. For highly toxic products, we may need to supply the operator with a
source of clean air.
There are many cases where the compound needs to be protected from the
environment. Some material may be sensitive to light, in which case we may need
to control the wavelength of the light during certain operations. Other materials
may be sensitive to moisture, in which case controls of temperature and humidity
are essential.
In general, however, the question of how much control to design into the facility
needs to be answered. It is possible to design a facility without many of the
special materials handling scenarios addressed and allow for a case-by-case analysis
later on during the actual handling.
L. Controlled Substance Security
Similar to special material handling is the issue of controlled substance security.
If it is decided to allow for this type of material handling, special considerations
need to be made for legal issues involved. Security areas must be built into the design
if these special classes of materials are to be handled. In 1970, the Controlled
Substances Act (CSA), Title II of the Comprehensive Drug Abuse Prevention and
Control Act, was enacted into law. This law deals with the regulation of narcotics,
stimulants, depressants, hallucinogens, and anabolic steroids. All of these com-
316 Gomez and Strathy
pounds are categorized into five schedules. The criteria used to categorize each
drug are the drug’s medicinal value, harmfulness, and potential for abuse or addiction.
Schedule I is the most highly regulated one, while schedule V is the least
controlled. Facilities that are to manufacture these controlled substances need to
register with the Drug Enforcement Agency under section 823 of the CSA. Once
licensed, the facility must maintain strict documentation of all controlled substance
activities, such as purchasing, storage, manufacturing, distribution, and destruction.
Additionally, areas of secure storage must be designed and maintained.
M. Cleaning Validation Criteria
Although we will deal with cleaning issues later in this chapter, it is necessary
to consider the issues involved with cleaning validation in the planning part of
the process. If the facility is to be operated under cGMP guidelines, a master
plan for cleaning validation must be set in place. Of particular concern is ensuring
that the cleaning procedures to be used are appropriate and effective. To
fully evaluate a cleaning protocol’s efficiency, we must consider the types of
materials the facility will be exposed to. Along with the master plan for cleaning
validation, feasibility of clean-in-place (CIP) systems should be evaluated.
Many of the tanks used in the manufacture of liquids and ointments as well as
biological products are available with these CIP systems incorporated into their
design. Additionally, the facility must be designed to allow for thorough cleaning
of the rooms as well as the equipment. Floor drains should be included. The
floors and walls should be made of materials that are easy to clean, water and
chemical resistant, and impervious.
N. Equipment and Facility Qualification Requirements
As part of the planning part of the project, an evaluation of the cleaning requirements
for both the equipment and the facility must be done. An overall plan
must be outlined for the evaluation of the success of the team. This success may
be measured by the results of the equipment and facility qualification. What criteria
will we use to qualify our construction and installation? The answer to this
question will allow us to tailor our activities so that we can remain focused on
the task at hand.
III. PHASE 2—DESIGN
Now that we have completed the planning phase, we can move into the design
phase. As described earlier, the design phase is when the process flow is mapped
out in detail. The utilities and process equipment required are described and in-
Engineering Aspects of Pilot Plant Design 317
corporated into the plan. In this section we will first discuss the facilities. More
specifically, we will go through a process flow for a solid-dosage pilot plant. Then
the room classifications will be mapped out. In other words, we will decide on
dedicated areas, multifunctional areas, and common areas. Secondly, the utility
requirements will be discussed. What will our requirements for electricity, steam,
water, communications, and air be? The process equipment will be described;
scale-up factors and operating plans will also be analyzed. And finally, requirements
for physical and analytical testing will be evaluated.
A. Facilities
Now that we have decided what types of batches will be manufactured in the pilot
plant, we need to map out the process. In a solid dosage form facility there are
a few process flows that can be followed. Some processes that can be used are dry
blending, wet granulation, and dry granulation (see Fig. 1). Either compaction into
318 Gomez and Strathy
Figure 1 Process flow diagram.
tablet form or encapsulation then converts the resulting material into a dosage
form. And lastly, for a variety of reasons, the tablets can be coated and imprinted.
Because our facility will not be a full-scale production facility primarily, we will
not use automated material handling. The design team must allow for easy and efficient
material flow. However, automation may not allow us to manufacture
small batches. It may also interfere with our ability to stay flexible throughout the
manufacturing process, as is required by the nature of the manufacture of experimental
batches.
B. Sizing
Sizing allows us to control the particle size of the incoming raw material. It serves
the purpose of aiding in material flow and efficiency of blending. Additionally,
through the control of the particle size of the raw material, the effect of lot-to-lot
variability can be reduced. Typically for small-scale batches, sizing can be done
in the blending room. However, as we increase the batch size, we may find it necessary
to isolate sizing. During sizing, significant quantities of dust may be generated.
It is important that dust control systems be built in the design of the room.
C. Blending
For the production of acceptable dosage forms, the powder must be uniform in
its content of the drug substance as well as in its content of the excipients.
Blending may be achieved in many different types of equipment. These different
types of equipment may use different principles of mixing. A review of the
blending equipment is presented shortly. For small-scale batches, blenders may
be loaded with material by hand. However, as the batch size is increased, more
automated ways of loading should be looked at. Typically, there is dust generated
only during loading and during discharge. For larger-scale production, positioning
of the blenders should allow for direct discharge into containers for
transfer to the next unit operation.
D. Wet Granulation
Wet granulation can be used to improve the flow of the material to be processed.
Additionally, it is used to improve the uniformity of the material. It may also be
used to increase the density of the materials to allow for better processing downstream.
Wet granulation processes require the handling of solutions. Typically,
there is minimal dust generation. Additionally, processes involve the use of alcohol
or water. Facilities should include drying capabilities either built into the granulators
or as a separate functional area. Utilities required include electricity, compressed
air, and steam.
Engineering Aspects of Pilot Plant Design 319
E. Compaction
Compaction, also known as compression, is the operation by which the blend is
compressed into a tablet. For high-volume operations, an overhead feeding system
is usually used. There is some dust generation in this process. Typical utilities
required are compressed air and electrical service.
F. Coating
Tablet coating is done for a variety of reasons. The tablet core may contain an
active substance that imparts undesirable organoleptic qualities to the tablet. The
active moiety of the tablet may be unstable to specific environmental conditions
and may need protection. The core may need to be coated to meet marketing requirements.
The coating may be needed to impart enteric properties or sustained-
release characteristics to the active release profile. Typical coating processes
require a solvent, organic or aqueous. Utilities required include
compressed air, steam, and electrical service. Provisions should be made for air
handling. The exhaust system used must be capable of handling the solvent used
in this process.
G. Room Classification
As part of the design of the facility, we may determine the appropriateness of using
dedicated areas, multifunctional areas, as well as common areas. For large
clinical and production batches, all unit operations are usually maintained in dedicated
areas. This helps minimize the possibilities of cross-contamination as well
as allow for many different products to be manufactured simultaneously. For the
small-scale experimental batches, multifunctional areas may be used. For example,
sizing and blending may be done in one room. Common areas may also be incorporated
into the facility. Typical uses for these areas include work-in-process
areas and in-process testing areas.
H. Space and Security
When allocating the areas for production, attention must be given to the space requirements
of the equipment—not only the footprint of the equipment, but also the
working area. This includes the ancillary equipment, i.e., controls, materials inprocess,
as well as operator working areas. In other words, there should be enough
space for the operator to bring in the material to be processed, operate the machinery,
and record the process in a batch record.
Security issues include the control of DEA scheduled compounds. For the
less controlled substances, locked cages provide sufficient security; however, the
320 Gomez and Strathy
more controlled substances require the use of vaults for storing raw material, inprocess
as well as finished goods. Additionally, processing rooms may require
locking when a controlled substance is in process.
I. Utilities
Now that we have determined what processes the facility will be used for, we can
finalize utility requirements. The following utilities are required for our solid-dose
facility: heating, ventilation, and air conditioning (HVAC), hot and cold water,
steam, electrical service, compressed air, vacuum systems, dust collection,
chillers, effluent stream, and purified water. For the more specialized processes or
special material handling, we may need specialized gases and breathing air. Purified
water is one of the more difficult utilities to maintain the quality of. From a
source of potable water, a series of treatments must be performed to control microbiological
quality. Typical treatment options include carbon filters, reverse osmosis,
and UV radiation.
Heating, ventilation, and air conditioning (HVAC) is a very expensive utility.
However, it is essential and serves a variety of purposes. Not only is it important
to maintain constant temperature and humidity, it is also important to balance
the pressure in the processing areas to minimize cross-contamination opportunities.
Dust collection, as mentioned earlier, is very important when handling powders.
The dust generated during some processes may be toxic and may pose an explosion
hazard. This system is typically very closely associated with the HVAC
system.
Compressed air is required for the operation of some of the processing
equipment we have described earlier. Typically, this service is supplied by an inhouse
compressor unit equipped with a filtration unit.
J. Process Equipment
We have already briefly discussed the manufacturing process. We will now discuss
the equipment used in the unit operations for our solid-dose pilot plant. The
following is presented to serve as an example of what the design team considers
when involved in the design of a solid-dose pilot facility. Because we are designing
a facility to be used to make small-scale batches using processes that
will eventually be transferred to a large-scale manufacturing facility, in this section
we will briefly discuss scale-up issues with each of the processes discussed.
The following section discusses equipment operating principles. For the sake of
clarity, these classifications are as designated by the Manufacturing Equipment
Addendum of the Guidance for Industry document describing SUPAC-IR/MR:
Immediate-Release and Modified-Release Solid Dosage Forms published January
1999.
Engineering Aspects of Pilot Plant Design 321
K. Sizing
In solid-dose manufacturing, sizing plays a key role in helping ensure that uniformity
is achieved. There are two ways in which sizing is performed, through particle
size reduction and through particle separation. Particle size reduction is performed
through one of the following mechanisms: impact, attrition, compression,
and cutting. The operating equipment includes the following: fluid energy mills,
impact milling, cutting, compression milling, screening, tumble milling.
In general, considerations for the scale-up of a sizing operation are just a
few. Of course, our main interest is in maintaining the same particle size distribution
as in the small-scale process. A major factor, assuming that equivalent screen
sizes are used, is the feed rate of the material into the equipment. As the feed rate
is increased, so is residence time within the chamber of the equipment. This results
in a finer distribution. To successfully mimic large-scale conditions, we may
want to design an overhead feeding mechanism into our sizing equipment.
L. Blending
There are two main operating principles for blending: diffusion blending and convection
blending. Diffusion blenders are very common in solid-dose manufacturing.
They include the V-blender, double-cone blenders, slant-cone blenders, and
bin blenders. Scale-up considerations for processes involving these types of
blenders include time of blending, blender loading, and size of blender. Mathematical
relationships can be established between blending time and diameter of
rotation.
Convection mixers use a different principle for blending. These mixers have
an impeller. This class includes ribbon blenders, orbiting screw blenders, vertical
and horizontal high-intensity mixers, as well as diffusion blenders with an intensifier
bar. Scale-up considerations are similar to those for the tumble blenders.
M. Granulation
There is a variety of operating principles for granulation processes. These include
dry granulation, wet high-shear granulation, wet low-shear granulation, and fluidbed
granulation. Dry granulation is accomplished through either slugging or roller
compaction. Wet high-shear granulation equipment uses high-energy impellers
during the addition of the granulation solvent. These can be either vertically or
horizontally driven. Wet low-shear granulators can use either a rotating impeller,
reciprocal kneading, or a screw-type mechanism to induce the granulation.
Fluid-bed granulation is accomplished by fluidizing the material to be granulated
in a chamber while spraying the granulation solution into the fluidized
powder. Scale-up of granulation processes is very complex and has been covered
322 Gomez and Strathy
extensively in previous chapters. The successful scale-up of a granulation process
can be measured by the compaction properties of the resulting material as well as
by the drug uniformity found in the blend and finished product.
N. Compaction
Compaction, also known as tableting, involves the compression of the blend into
a unit dose. The mechanism for this type of processing has remained unchanged
for quite some time. The main components of the compression cycle are: pressure
rolls, weight adjustment cam, ejection cam, and feed frame. The main considerations
when scaling up is compression speed. Compression speed effects dwell
time and feed rate. As you go from a small development compression machine to
a high-speed production machine, the powder is processed much more rapidly.
O. Encapsulation
There are three main systems for filling capsules with powder: gravity, tamping,
and dosator. Typically for small-scale batches, gravity systems are adequate.
However, as speed of processing becomes an issue, force filling becomes more
important. For consideration when scaling up is the ability of the powder to fill at
the higher speeds required. Also important is the flow of the material from the
hopper into the mechanism of the encapsulator.
P. Coating
Coating is accomplished by atomizing the coating material into a fine mist that is
then sprayed onto a rotating bed of tablets on a perforated pan. Throughout this
process, there is a fine balance between the process air coming into the system and
the process air leaving the system. Additionally, special attention is paid to the degree
of atomization of the solution as well as to the rate of application of the solution.
The main issues for consideration of scaling up in a coating process are: the
tablet loading of the coating pan, the spray rate of the coating solution, the quantity
of solution required, as well as the volume of air used during coating. As mentioned
earlier, coating systems require extensive air handling utilities. They require
very strict temperature and humidity controls.
Q. In-Process Testing
In-process testing is especially critical, if the material being produced is to be used
for human consumption. The types of in-process testing requirements will vary
with the process. However, following is a brief description of the types of the inprocess
testing requirements of a solid-dose manufacturing process.
Engineering Aspects of Pilot Plant Design 323
During the screening step, an in-process particle size analysis may be done.
This may give us an indication of the control of the sizing operation. After the
completion of blending, samples are taken for blend uniformity analysis. If the
process includes wet granulation, a sample is taken for moisture content determination.
If the granulation process used any organic solvents, then a sample must
be taken to test for residual solvents. Throughout the compaction process, samples
must be taken regularly for measurement of weight, hardness, thickness, and friability.
Similarly, during the encapsulation process, samples are taken regularly
for weight determination.
During the design of the facility, provisions must be made for the areas for
in-process testing to be carried out. Much of the testing may be done in common
areas, i.e., tablet and capsule testing. However, some must be done in specialized
areas, i.e., uniformity testing.
IV. CONCLUSION
At this point in the project, we are ready to begin the construction phase. At which
point, the project management function becomes paramount in importance. All
tasks must be identified and tracked properly. Coordination of this phase can be
kept in-house or be turned over to contractors. It is important that if the bulk of
this phase is contracted out, strict goals are identified so that the progress of the
project can be tracked closely. It is also at this point that we will need to obtain
building permits, emission permits, drug licenses, as well as controlled drug licenses.
Upon the conclusion of the construction phase, qualification of the facility,
utilities, and equipment is carried out. Protocols outlining the acceptance criteria
need to be written and approved. These protocols set standards required for the acceptance
of the facility and equipment as completed.
324 Gomez and Strathy
11
A Collaborative Search for Efficient
Methods of Ensuring Unchanged
Product Quality and Performance
During Scale-Up of Immediate-
Release Solid Oral Dosage Forms
Ajaz S. Hussain
U.S. Food and Drug Administration, Rockville, Maryland
I. BACKGROUND
Quality and performance attributes of pharmaceutical products are a function of
several formulation and manufacturing factors. To develop drug products with optimal
performance characteristics (for use in clinical testing), certain physical,
chemical, and biological attributes of a drug are characterized in preformulation
and preclinical programs. The effects of manufacturing factors on product quality
and performance are evaluated during product development. These important steps
are essential for minimizing the likelihood that product quality problems will confound
the pivotal safety and efficacy databases. Generally, after establishment of
an acceptable safety and efficacy profile of a drug (using a high-quality clinical trial
product), the manufacturing processes are scaled up to provided sufficient volume
of product to meet market needs. Manufacturing process and formulation changes
needed for scale-up should not adversely affect the safety or efficacy of a product.
Two fundamental product quality questions posed during drug development
are:
How do we build quality into products that are tested in the clinic to establish
safety and efficacy?
How do we utilize product development and clinical data/experience to establish
appropriate specifications for the “to-be-marketed” product?
325
These questions are at the core of the basic principles of quality assurance.
These principles may be stated as follows [1]:
1. Quality, safety, and effectiveness must be designed and built into the
product.
2. Quality cannot be inspected or tested into the finished product.
3. Each step of the manufacturing process must be controlled to maximize
the probability that the finished product meets all quality and design
specifications.
In Figure 1, the two fundamental product quality questions are positioned
within the well-recognized stages or phases of the drug development process.
During product development, a set of formulation and manufacturing factors and
their target values or acceptable ranges are identified, generally through extensive
experimentation, and manufacturing processes validated to ensure acceptable and
reproducible quality and performance. Product specifications are developed to
confirm product quality and focus on attributes that impact product performance.
Specifications establish a set of criteria to which a product should conform to be
considered acceptable for its intended use; regulatory authorities require these as
conditions of approval [2]. Unchanged product quality and performance, batch to
batch, is assured via adherence to Current Good Manufacturing Practices
(CGMPs), conformance with established raw material specifications, in-process
controls, and finished-product specifications. It is through careful design and validation
of both the process and process controls that a manufacturer establishes a
high degree of confidence that all manufactured units from successive lots will be
326 Hussain
Figure 1 Connecting-the-dots: Discovery–development–marketing.
acceptable [1]. Data generated during these various stages of drug development
provide information and knowledge about the safety and efficacy of a drug candidate.
These data are then reviewed by regulatory agencies to ensure an acceptable
benefit-to-risk profile prior to granting approval for marketing. Additional testing
sometimes is necessary after approval (Phase IV). Postmarketing surveillance and
compliance programs are utilized to monitor product quality and performance
(e.g., adverse event reports, AERs) after regulatory approval.
Manufacturing changes have the potential for altering the safety and efficacy
profile of a product. A demonstration of bioequivalence and acceptable stability
of postchange product is therefore needed to qualify significant manufacturing
changes. Bioequivalence assessments and chemistry requirements are also
used, in place of clinical safety and efficacy evaluation, for approval of generic
drug products and postapproval changes to these products. Maintaining and documenting
consistent quality and performance in the presence of change is a challenge
to both industry and regulatory agencies. Ideally, product quality and performance
specifications are developed and validated based on a mechanistic
understanding on how formulation and manufacturing factors affect product performance.
However, in some instances both scientific and resource (time) challenges
may not permit development of a mechanistic framework for quality/performance
specifications. In the absence of a clear understanding on how
manufacturing changes impact product performance, changes are discouraged or
extensive testing recommended by regulatory agencies. Under these conditions
significant resources may have to be expended to qualify even minor changes,
and the introduction of new and/or more efficient manufacturing technology
may be hindered.
II. INTRODUCTION
Since the late 1980s, several scientific workshops and symposia have been held
on topics of manufacturing changes and approaches for ensuring unchanged product
quality and performance. These public debate opportunities initiated the process
of building scientific consensus on how critical formulation and manufacturing
variables should be identified, optimized, and controlled. These proceedings
have provided tangible results [3,4]; an excellent example is the Food and Drug
Administration’s (FDA) Scale-Up and Post Approval Changes guidance document
for immediate-release solid oral dosage forms (SUPAC-IR) [5]. (For this
and other SUPAC documents, see Appendices.) This plus other similar results
provided a stage for building enduring collaborative relationships between
industry, academia, and the FDA for the worthy purpose of enhancing the
scientific foundations of regulatory policies related to product quality. The
Product Quality Research Institute, Inc. (PQRI) is an ensuing vehicle for this collabor-
ation [6]. It is a virtual research institute founded in 1999 by several
Quality Control for IR Solid Oral Dosage Forms 327
pharmaceutical trades and professional associations and the Center for Drug Evaluation
and Research (CDER) FDA. The American Association of Pharmaceutical
Scientists (AAPS) administers it. The United States Pharmacopoeia (USP) recently
joined this institute.
The SUPAC-IR guidance document is generally regarded as a significant
initial milestone on the path to building scientific consensus on approaches for
qualifying manufacturing changes. It also provides a benchmark to chart the
progress of future collaborative projects being developed on this topic in the
PQRI. These projects propose to further improve the scientific foundations of industrial
practices and regulatory policies related to conventional or immediate-release
(IR) solid oral dosage forms. Initial focus on IR products was based on their
market prevalence, long (~100 years) manufacturing history, and the recognition
of scientific and technical advances in the establishment of causal links between
critical manufacturing variables and product performance.
For the past several years, scientific debates within the pharmaceutical community
on the topic of manufacturing changes have centered on the question of additional
tests and reporting requirements needed to document unchanged quality
and performance. The SUPAC approach focused this debate on the definitions of
significant changes and what constitutes sufficient characterization.
In PQRI, this debate served as a focal point for discussions, and for this purpose
it was framed as: “Adherence to CGMP’s plus conformance with appropriate
process controls and product specifications are sufficient to qualify manufacturing
changes to IR products.” The counterargument in this debate is that the
primary objectives of in-process controls and product specifications are to ensure
that validated processes remains under control to yield products that conform with
established specifications and that, when significant changes occur, specifications
may not provide sufficient characterization to ensure unchanged performance.
The PQRI programs offer a means for transforming these debates into opportunities
for enhancing the science of minimize risks of unacceptable deviations in
product performance when manufacturing changes are implemented.
Clearly, significant progress has been made during the past four decades
in moving the practice of pharmaceutical product development from art to science.
The debate on manufacturing changes could also have been farmed as an
art vs. science debate. The term art as used in this discussion stands for “the
power of performing certain actions, especially as acquired by experience,
study, or observation” [7]. It is distinguished from the term science, which “signifies
accumulated and accepted knowledge that has been systematized and formulated
with reference to the discovery of general thruths or the operation of
general laws” [7]. Acceptance of established knowledge by several scientific
disciplines and the public is often a prerequisite for its application in public policy
decisions, especially when such decisions can have a broad and significant
impact on public health.
328 Hussain
The objective of this chapter is to illustrate some key elements of the scientific
debate on the value of established specifications for qualifying manufacturing
changes. For this purpose an example of the scale-up of a capsule product and
the associated formulation and equipment changes was selected and evaluated
within the framework of current regulatory recommendations. Many pharmaceutical
scientists may consider adherence to CGMPs plus conformance with product
specifications sufficient to qualify changes encountered in this example as opposed
to the current regulatory recommendations of additional bioequivalence and
stability testing and the prior-approval supplement process.
III. MANUFACTURING CHANGES
Manufacturing changes are often necessary for reasons such as scale-up, introduction
of new manufacturing technology, and company mergers. In these situations
formulation and manufacturing process conditions are identified that allow
the product to satisfy established specification for the prechange product and the
modified process validated in accordance with CGMPs. For accomplishing this
task, several changes in manufacturing equipment, processing conditions, and/or
formulation may be necessary due to the multifactorial nature of the pharmaceutical
products. This scenario and certain elements of the SUPAC debate are examined
using a scale-up example selected from the literature [8]. The information
used in this chapter was derived from the literature and other public sources.
Manufacturing changes: Scale-up of a developmental product using encapsulation
equipment of different design.
Development product: Capsule product containing x mg of drug y (“freely
water soluble”) and 1% magnesium stearate was developed using a
Zanasi LZ-64 capsule-filling machine. Initial development experiments
identified a causal link between blend time and dissolution rate. Capsules
prepared with powders blended for 5 minutes exhibited a more rapid dissolution
rate (~95% dissolved in 10 minutes) compared to powders
blended for 40 minutes (~90% dissolved in 45 minutes). A 10-kg lot was
blended for 15 minutes in a V-blender. Under these conditions the resulting
capsules conformed to an in vitro dissolution acceptance criteria of
Q75% in 45 minutes (in 900 mL water at 37°C, USP Basket 100 rpm).
Scale-up product: Initial trial for scale-up utilized a batch size of 570 kg,
a Hoflinger & Karg GFK-1500 capsule-filling machine (H&K), and a
V-blender, with the mixing time set to 15 minutes. Capsules resulting
from this batch did not conform to the dissolution specification (only
about 40% dissolved in 45 minutes). To rule out “overblending” with
magnesium stearate, a blend time of 5 minutes in the V-blender was uti-
Quality Control for IR Solid Oral Dosage Forms 329
lized and another batch manufactured. This step failed to resolve the observed
dissolution problem, suggesting that “overblending” may not be
occurring in the V-blender. Further analysis of the problem indicated
that during encapsulation on the H&K machine, powder was being
sheared (during the tamping steps, not during the auger-feeding process),
resulting in an unacceptable dissolution rate. Using a shear simulation
approach, the optimal level of magnesium stearate of 0.3% was
identified for the H&K machine, which satisfied encapsulation (e.g.,
content uniformity) and dissolution criteria. The full production batch
(1100 kg) was produced on the H&K machine using 0.3% magnesium
stearate and a blend time of 15 minutes.
Formulation attributes for optimal encapsulation on machines of different
design can vary. Changing Zanasi to H&K may require a reduction in the amount
of magnesium stearate, even for a formulation without a pronounced drug–lubricant–
mixing interaction. With respect to formulation requirements for the Zanasi
and H&K machines, the following observations have been made [9]:
1. Powder flow requirements vary with equipment design. To maintain a
low weight variation, optimum values of Carr’s index (CI) is in the 25
to 35 range for Zanasi and 18  CI  30 for H&K. (Note: Carr’s Index
is calculated from the loose bulk density (LBD) and tapped bulk density
(TBD) of powders. CI 
 100[(TBD  LBD)/TBD]
2. Zanasi: Powders with high Cl (30) produce stronger plugs with lower
weight variation; for powders with a low Cl (20), higher compression
forces may be needed (150–200 N) to improve powder retention in
dosator tube.
H&K: Formulations with high Cl (30) tend to flood near the ejection
station.
3. Based on plug ejection forces, a relatively lower level of lubricant
(about 
1
2
) is sufficient for H&K machines as compared to Zanasi.
A recent survey of capsule formulation practices in industry reported that a
majority of companies (64%) use equipment of the same design and operating
principles for development/pilot and production batches, and about 18% develop
pilot formulations on equipment of different design from the production machines.
The choice of encapsulation equipment design, dosing disc vs. dosator
type machines, is about equally divided, with about 18% of companies using both
types of machines; i.e., about 40% of companies use only one type (design) of machine
[9]. In today’s global economy, developing capsule formulations that can be
encapsulated using equipment of different design can be advantageous. The survey
estimated that only about 18% of companies use both types of machines (both
dosator and dosing disc types) in their facilities, suggesting that many current for-
330 Hussain
mulations may not be tailored for equipment of different design. With the increasing
number of mergers and the consolidation of manufacturing operations,
plus a trend for outsourcing certain manufacturing operations, it could be anticipated
that the selected example represents a class of SUPAC that may be relevant
for a number of companies. The other critical aspect of this case deals with
changes in the amount of magnesium stearate, the most widely used excipient in
tablet and capsule formulations. Therefore, information developed in this analysis
should be useful beyond this particular case study.
IV. REGULATORY RECOMMENDATIONS ON
MANUFACTURING CHANGES
A. A Note on Regulatory Recommendations
It is important to note that the FDA guidance documents reflect that agency’s
current thinking on a given issue. These documents do not create or confer any
rights for or on any person and do not operate to bind the FDA or the public. An
alternative approach may be used if such approach satisfies the requirements of
the applicable statutes, regulations, or both. These guidance documents assist in
clarifying regulatory decisions and thereby eliminate or reduce unanticipated decisions.
The SUPAC-IR guidance was issued in November 1995 to provide recommendations
on tests and filing documentation to sponsors of new and abbreviated
drug applications on the following types of postapproval changes in the manufacture
of immediate-release oral solid products: (1) components and composition,
(2) site of manufacture, (3) scale-up/scale-down of manufacture, and/or (4) manufacturing
process and equipment. The guidance defines: levels of change, recommended
chemistry, manufacturing, and controls tests for each level of change,
in vitro dissolution tests and/or in vivo bioequivalence tests for each level of
change, and documentation that should support the change. Prior to SUPAC-IR,
all postapproval changes were considered together and generally required extensive
stability and bioequivalence documentation. SUPAC-IR changed this by creating
a multitiered system for both stability and bioequivalence documentation
that was based on the estimated likelihood that a specific manufacturing change
would adversely affect product performance.
The Food and Drug Administration Modernization Act (1997), section 116,
amended the Food, Drug, and Cosmetic Act by adding section 506A (21 U.S.C.
356a), which provides requirements for making and reporting manufacturing
changes to an approved application and for distributing a drug product made with
such changes. The Center for Drug Evaluation and Research (CDER) of the FDA
issued a new guidance to provide recommendations on postapproval changes in
accordance with section 506A [10]. Note that this guidance supercedes the SUQuality
Control for IR Solid Oral Dosage Forms 331
PAC-IR on recommendations for reporting categories. Another guidance was issued
recently that discusses waiver of in vivo bioequivalence studies for IR products
during both pre- and postapproval phases [11].
The discussion to follow examines the SUPAC-IR guidance recommendations
for the manufacturing changes encountered in the selected example. Although
this guidance did not provide recommendations on multiple related
changes, the new guidance [10] does address this issue as follows:
For multiple related changes where the recommended reporting categories for
the individual changes differ, CDER recommends that the filing be in accordance
with the most restrictive of those recommended for the individual
changes. When the multiple related changes all have the same recommended
reporting category, CDER recommends that the filing be in accordance with
the reporting category for the individual changes.
After identifying the regulatory recommendation, a brief scientific/regulatory
risk analysis is conducted within the framework of the two fundamental product
quality questions posed earlier.
B. Batch Size (10 kg to 1100 kg)
Changes in batch size are categorized in two levels. The Level 1 change in batch
size is up to and including 10 times the size of the pilot or bio batch that is accomplished
using equipment of the same design and operating principles and
without changing its manufacturing procedures and formulation. Changes in batch
size beyond 10 times the size of pilot batch is accomplished using equipment of
the same design and operating principles, and its manufacturing procedures and
formulation are considered Level 2 change.
The SUPAC-IR guidance suggests that a pilot-scale batch be, at minimum,
one-tenth that of full production scale or 100,000 dose units (tablets or capsules),
whichever is larger. If the dose of drug Y was 100 mg, a 10-kg batch will,
in theory, produce 100,000 units but will not meet the 
1
1
0
 production-scale criteria.
The origin of the 
1
1
0
 production-scale criterion was intended primarily to ensure
that the pilot batch was manufactured by a procedure fully representative of
and simulating that used for full manufacturing scale (e.g., heat and mass transfer
efficiency).
If the development formulation were considered a pilot batch, then increasing
batch size from 10 kg to 1100 kg using equipment of the same design and operating
principles (see later) would be considered a Level 2 change. Additional
tests recommended include stability (three months’ accelerated stability and longterm
stability data on one batch) and multipoint dissolution profile comparison in
the application or compendial medium (Case B).
332 Hussain
C. Manufacturing (Equipment and Process) Changes
In the SUPAC-IR guidance, changes in equipment and/or process are considered
separately under the section on manufacturing changes. Three levels of process
changes are defined. Level 1 is limited to changes in processing times and operating
speeds within application/validation ranges, Level 2 is when these changes are
outside of application/validation ranges, and Level 3 is for change in process (unit
operation), such as wet granulation to direct compression.
Two change levels are defined for equipment changes. Level 1 for changes
to alternative equipment of the same design and operating principles (same or different
capacity) and Level 2 for equipment of different design and different operating
principles. A companion guidance document is provided that describes and
classifies pharmaceutical equipment on the basis of operating principles and design
[12]. The operating principle is used to define an equipment class, and equipment
design is used to create a subclass. For example, a change from one type of
diffusion mixer (such as a V-blender from manufacturer A) to another diffusion
mixer (a V-blender from manufacturer B) generally would not represent a change
in operating principle. However, a change from a V-blender to a ribbon blender
demonstrates a change in the operating principle from diffusion blending to convection
blending.
For equipment changes, this guidance [12] provides the following recommendations:
Applicants should carefully consider and evaluate on a case-by-case basis
changes in equipment that are in the same class but different subclass. In
many situations, this type of change in equipment would be considered similar.
For example, within the Blending and Mixing section, under the Diffusion
Mixers Class, a change from a V-blender (subclass) to a Bin tumbler (subclass)
represents a change within a class and between subclasses. Provided the
manufacturing process with the new equipment is validated, this change
would likely not need a preapproval supplement. The applicant should have
available at the time of the change the scientific data and rationale used to
make this determination. This information is subject to FDA review at its discretion.
It is up to the applicant to determine the filing requirement.
1. Equipment and Process Change (V-Blender, Capacity)
Change in V-blender capacity (Level 1 Equipment Change) may be qualified by
conforming to CGMPs, application/compendial release requirements, and a commitment
to place one batch of postapproval product on long-term stability. In this
example, the mixing time was 15 minutes for both pre- and postchange products.
Note: A more appropriate control for this unit operation might be the number of
revolutions, not time.
Quality Control for IR Solid Oral Dosage Forms 333
2. Equipment Change (Encapsulation Machine, Zanasi LZ64 to
Hoflinger & Karg GFK-1500)
The operating principle encapsulation is the division of material into a hard
gelatin capsules. Encapsulator subclasses are distinguished from one another primarily
by the method used for introducing material into the capsule. Encapsulators
can deliver materials with a rotating auger, vacuum, vibration of perforated
plate, tamping into a bored disk (dosing disk), or cylindrical tubes fitted with pistons
(dosator).
The Zanasi LZ64 fills capsules by dipping a dosator into powder bed and
compacting the powder bed into cylindrical plugs. The Hoflinger & Karg GFK-
1500 delivers the powder from a feed hopper onto a dosing disk by means of a vertical
auger. The powder falls into cavities in the dosing disk and is successively
forced by a set of tamping pins to form cylindrical plugs that are then inserted into
bodies of capsule shell [8].
This change (Zanasi to H&K) represents a change in subclass. A conservative
approach would be to classify this as a Level 2 equipment change. If so classified,
SUPAC-IR guidance recommends the following additional tests:
Stability testing: Recommendation based on the availability of a significant
body of information on the stability of the drug product that is
“likely to exist after five years of commercial experience for new
molecular entities, or three years of commercial experience for new
dosage forms.”
Significant body of information available: One batch with three months’ accelerated
stability data reported in supplement; one batch on long-term
stability data reported in annual report.
Significant body of information not available: Up to three batches with three
months accelerated stability data reported in supplement; up to three
batches on long-term stability data reported in annual report.
Dissolution documentation: Case C dissolution profile. Multipoint dissolution
profiles performed in water, 0.1N HCl, and USP buffer media at pH
4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently accepted
formulations. Adequate sampling should be performed at 15, 30,
45, 60, and 120 minutes until either 90% of drug from the drug product is
dissolved or an asymptote is reached. A surfactant may be used with appropriate
justification.
D. Composition Change (Magnesium Stearate 1% to 0.3%)
Changes in the qualitative or quantitative formulation, including inactive ingredients,
as provided in the approved application, are considered major changes
334 Hussain
and should be filed in a prior-approval supplement, unless exempted by regulation
or guidance (Food, Drug, and Cosmetic Act; 506A(c)(2)(A)). With respect
to magnesium stearate in IR products, SUPAC-IR guidance recommends
a quantitative change to the following extent: 0.25% be considered Level 1,
and changes within 0.5% are considered Level 2. In this example, the target
amount of magnesium stearate was 1%, which was changed to 0.3%
(i.e., 0.7%), which exceeds the recommended range for Level 2. Therefore,
this change may be considered Level 3, with the following recommended additional
tests:
Stability tests:
Significant body of information available: One batch with three months’ accelerated
stability data reported in supplement; one batch on long-term
stability data reported in annual report.
Significant body of information not available: Up to three batches with three
months’ accelerated stability data reported in supplement; one batch on
long-term stability data reported in annual report.
Dissolution documentation: Case B dissolution profile.
In vivo bioequivalence documentation: Full bioequivalence study.
E. Multiple Related Changes
For multiple related changes where the recommended reporting categories for the
individual changes differ, the new guidance [10] recommends that the filing be in
accordance with the most restrictive of those recommended for individual
changes. For the selected example this appears to be Level 3 component and composition
change category (earlier). Based on this change level, to justify changes
in the selected example, an in vivo bioequivalence study along with stability (accelerated
and long-term) studies are recommended. The filing mechanism recommended
is the prior-approval supplement. Note that a waiver of in vivo bioequivalence
study may be justified if the drug in this example exhibits high solubility,
high permeability, and wide therapeutic index; and both the pre- and postchange
products exhibit rapid dissolution in vitro [11].
The selected example [8] represents a relatively straightforward formulation
development project with a well-recognized interaction between drug, excipient,
and process conditions that, when not managed properly, can have an adverse impact
on product quality (content uniformity and dissolution). It offers a means to
exemplify; (1) the relationship between the two product quality questions stated
in the introductory section, and (2) challenges and debates associated with the development
of regulatory policy for addressing manufacturing changes to products
that are multifactorial in their design.
Quality Control for IR Solid Oral Dosage Forms 335
V. PERSPECTIVES ON ENSURING UNCHANGED QUALITY
AND PERFORMANCE
Pharmaceutical products must demonstrate and maintain established public standards
for attributes that relate to their safety or effectiveness. In the United States
these attributes are expressed as identity (e.g., chemical structure), strength (e.g.,
assay, content uniformity), quality (e.g., combination of certain physical, chemical,
and biological attributes), purity (e.g., limits on impurities and degradation
products), and potency (e.g., biological activity, bioavailability, bioequivalence)
[10]. Public standards serve as one of several mechanisms for minimizing the risk
of product-related injuries. In principle these standards should reflect the current
state of scientific understanding and ensure and promote the development of highquality
products.
A. Building Quality into Products
During the development of a pharmaceutical product, the impact of several factors
(e.g., formulation, process, packaging, and storage conditions) on product
quality and performance should be characterized and optimized. Preformulation
programs evolved in the late 1950s; prior to this the general emphasis in product
development was on producing elegant dosage forms based on organoleptic considerations
[13]. The goals of modern preformulation programs are to develop analytical
methods and (1) to characterize the necessary physical, chemical, and permeability
attributes of a new drug substance, (2) to determine the degradation
mechanisms and establish its kinetic rate profile, and (3) to establish compatibility
with the excipient to be used in a formulation. In the discussion to follow it is
assumed that the selected formulation was developed following sufficient preformulation
characterization to ensure compatibility between the formulation ingredients.
Also note that the concept of “building quality in” during the product development
phase is equally relevant for postapproval changes.
The selected formulation example is a binary powder mixture (drug Y and
magnesium stearate) that is encapsulated in hard gelatin capsules [8]. In this formulation,
magnesium stearate (a hydrophobic lubricant) is included to assist in the
manufacturability of the product (i.e., ensure content uniformity and uninterrupted
machine operations). Suboptimal levels can bring about content uniformity problems.
However, physical interaction between drug particles, hydrophobic lubricants,
and processing conditions (e.g., shear forces exerted on the powder during
mixing and encapsulation processes) can decrease the wettability of drug particles
and retard dissolution. This phenomenon was recognized over 30 years ago and
has since been investigated extensively; these research efforts have provided
mechanistic explanations and also proposed formulation strategies to overcome
adverse effects of this interaction on drug dissolution [14–31].
336 Hussain
To implement change in capsule filling equipment in this case, several
change management strategies could be adopted: (a) reduce shear on the powder
by adjusting the pin settings on the H&K machine, (b) optimize (reduce) the level
of magnesium stearate to satisfy the content uniformity and dissolution acceptance
criteria, and (c) change the formulation to facilitate plug formation and/or
minimize undesirable effects of magnesium stearate (e.g., addition of a wetting
agent such as sodium lauryl sulfate). Use of a less hydrophobic lubricant is also an
option [18,20], but this approach is seldom practiced (see up coming Fig. 2). The
selection of a change management strategy is likely to be based on a number of
technical and economic factors. An important consideration for this decision
should be an understanding of the impact on product performance and the risk of
product failure (i.e., failure to meet established dissolution and other specifications)
during routine production. It is postulated that the risk of product failure
during routine manufacturing is likely to be in the order (a)  (b)  (c).
The first strategy, adjustments of pin settings, was rejected by the authors
because they concluded that this strategy would only reduce, not eliminate, the
problem and that this strategy may be appropriate for a formulation that is less
sensitive to the effect of shearing [8]. This decision was in line with the concept
of “building quality in.” It is rationalized later why this equipment adjustment
strategy for the selected example was postulated to be a high-risk practice. Although
this discussion is focused on the adverse impact on dissolution due to
shear observed during the encapsulation process, this could also have occurred
during the mixing process if a V-blender equipped with a high-speed intensifier
bar was used [20].
Even if machine adjustments could have been made, to reduce this dissolution
problem to an undetectable level for a given lot of magnesium stearate there
would exist a (significant) chance of product failure with different lots of magnesium
stearate. Additional control strategies may also be needed to ensure that machines
were set correctly and that the settings did not change during a production
run. The physical properties of magnesium stearate from different commercial
sources as well as lot–lot variations from a single source can be problematic [32].
If this strategy were adopted, would the risk of failure become apparent during
process validation? Perhaps, if different lots of magnesium stearate were used during
process validation and (predictive) functionality tests developed/adopted to
qualify vendors and lots. The final step in process validation, i.e., the demonstration
of repeatability, is predicated on quality being “built into” products. If this
were not so, one would expect to encounter problems during routine manufacturing,
when some differences in compendial materials may be unavoidable. This
may be a reason why Harwood and Molnar [33] characterized process validations
as a “well-rehearsed demonstration that manufacturing formula can work three
successive times,” and that “validation exercise precedes a trouble-free time period
in the manufacturing area only to be followed by many hours (possibly days
Quality Control for IR Solid Oral Dosage Forms 337
or weeks) of troubleshooting and experimental work after a batch or two of product
fails to meet specifications. This becomes a never-ending task.”
A survey of formulation practices, conducted in 1993, provides some insight
on how variability associated with magnesium stearate is currently being
managed [34]. In this survey, when asked whether their company specified an exclusive
source and type of magnesium stearate, 80% of respondents said yes. Others
indicated that they utilized a functionality test (particle size testing and/or bulk
density test) or simply relied on compendial standards [34]. The USP/NF monograph
on magnesium stearate does not include tests for its lubricant functionality
[35].
In spite of the problems associated with magnesium stearate, 54 of 58 formulators
identified magnesium stearate as their first choice [34]. This popularity
was also evident in a spur-of-the-moment survey of the FDA’s Inactive Ingredient
Guide, conducted by this author, of excipients used in formulations of capsule
dosage forms (see Fig. 2; note that gelatin and other materials, such as colors, were
not included in this figure and that titanium dioxide is probably a component of
both the gelatin shell and the encapsulated material). This popularity suggests that
that lot–lot variability and other problems associated with magnesium stearate
variability are being successfully managed by industry.
The other two possible strategies rely on adjusting or changing the formula.
Reducing the amount of magnesium stearate from 1% to 0.3% was determined to
be optimum and adopted by the authors [8]. Another option could have been to include
a wetting agent to make this formulation insensitive to equipment and pro-
338 Hussain
Figure 2 Common excipients in oral capsules.
cessing conditions. The latter approach may be preferred if drug Y was poorly soluble.
From Figure 2 it appears that about half the submissions on oral capsule formulation
to the FDA utilize a wetting agent (sodium lauryl sulfate), suggesting
that the lubricant plus wetting agent combination is a fairly common formulation
design strategy.
In an FDA-sponsored study it was found that the impact of magnesium
stearate on drug dissolution and the bioavailability of piroxicam (a low-solubility
drug) from capsule formulations (encapsulated on Zanasi LZ-64) containing a
wetting agent was negligible. Sodium lauryl sulfate level and piroxicam particle
size were the most important main effects affecting dissolution. Lubricant levels
(range studied 0.5–1.5%) and lubricant blending times (2–18 minutes in a Vblender)
either were not significant or were among the lowest-ranking factors affecting
dissolution. Changes in equipment, e.g., Zanasi to H&K, were not evaluated
in this study [36].
B. Do Specifications Ensure Unchanged Product
Performance?
The desired goal of a manufacturing change-management system is generally to
maintain an unchanged safety and efficacy profile of a product. Two primary attributes
utilized for most drug products are bioequivalence and unchanged stability
profile or expiration date (shelf life).
1. Bioavailability and Bioequivalence
In the selected example, critical formulation factors with respect to dissolution
(and bioequivalence) are the ones that affect the ability of the dissolution medium
to gain access to the drug particle surface (wettability) and drug particle size/surface
area (ignoring dissolution of the gelatin shell). The criticality of these factors
is likely to be a function of drug properties such as its aqueous solubility. These
critical factors are controlled by establishing standard operating procedures
(SOPs), in-process controls for blending and encapsulation operations, specifications
for drug (and possibly magnesium stearate) particle size (not discussed in
this chapter), content uniformity, and dissolution (which also serves as a functionality
test for drug–lubricant-blending interaction). Information derived from
several biopharmaceutical and pharmacokinetic studies conducted during drug
development are generally utilized to justify a proposed dissolution specification
(also see decision tree #7 in Ref. 2). The one-point dissolution test acceptance criterion,
in this case Q75% in 45 minutes, is designed to guard against poor dissolution.
By reducing the amount of magnesium stearate, the likelihood of slow dissolution
is further reduced. Based on this developmental experience, one could
argue that conformance with established controls and specifications should be suf-
Quality Control for IR Solid Oral Dosage Forms 339
ficient to ensure bioequivalence between pre- and postchange product, especially
since the drug is freely soluble in water.
In the discussion so far it was assumed that the dissolution specification developed
for this formulation of drug Y, Q75% in 45 minutes (in 900 mL water at
37°C, USP Basket 100 rpm), was appropriate for ensuring bioequivalence between
different lots of clinical products as well as the scaled-up formulation. In
many cases dissolution specifications are based only on observed variability information
of different lots of a product used in clinical trials. Information on critical
formulation variables is generally not developed or provided for regulatory review.
Therefore, the value of dissolution specifications established in this manner
is unknown for managing changes. If the postchange product were not characterized
in vivo, can we assume with confidence that the specifications developed or
justified using data obtained on prechange product lots would ensure bioequivalence
of postchange product?
Since in this study in vitro dissolution served as the response or objective
function for optimizing the level of magnesium stearate, it would appear that the
authors of Ref. 8 had a high degree of confidence in this method. The dissolution
test method and acceptance criterion in the selected example is fairly common. Its
in vivo relevance is assumed by many with a fair degree of confidence, as exemplified
by the following perspective expressed in the USP [35]:
1. There is no known medically significant bioinequivalence problem with
articles where 75% of an article is dissolved in water or acid at 37°C in
45 minutes in the official basket or paddle apparatus operated at the usual
speed, that is, USP First Case.
2. A majority of monographs have such requirements.
3. USP First Case performance is recognized as a reliable formulation objective
in the United States and bears attention worldwide for product development
where in vivo bioavailability testing is not readily available.
4. It obviates wasteful biostudies.
5. Medically significant cases of bioinequivalence rest mainly on four
causal factors: inappropriate particle size of an active ingredient; magnesium
stearate in excess as a lubricant-glidant; coatings, especially shellac;
and inadequate disintegrant. Each of these factors is reactive to dissolution
testing.
These generalizations appear to be based primarily on accumulated experiences,
and it is difficult to define the term medically significant bioinequivalence.
Critical analyses of data supporting such generalizations are needed to establish
multidisciplinary consensus. Current regulatory policies and practices are designed
to ensure the introduction of bioequivalent products on the U.S. market.
For most IR products of a drug with demonstrated bioequivalence, the same dissolution
specification generally gets adopted in the USP. However, conformance
only to the same dissolution specification may not ensure bioequivalence [37].
340 Hussain
The rate and extent of absorption of drug Y will be a function of its solubility,
intestinal permeability, and stability in the gastrointestinal fluids and dissolution
rate. Differences in the absorption of two pharmaceutically equivalent products
should then primarily be a function of their in vivo dissolution rate
differences, assuming the excipients used do not alter bioavailability [38]. Therefore,
the key question here is: Does an in vitro dissolution test emulate in vivo drug
dissolution?
To further explore some complexities associated with decisions on the value
of dissolution tests, it is postulated that for the selected formulation, in vitro dissolution
is likely to be a more sensitive tool for studying formulation differences
than in vivo bioequivalence studies. The following arguments can be made to support
this postulate.
(1) For most IR products (and especially those of water-soluble drugs),
dissolution in vivo is not likely to be rate-determining step and /or
(2) The surface tension of in vitro dissolution media without added surfactants
is significantly greater than what is likely to be observed for
human gastric and intestinal fluids [39].
In the absence of an established in vitro–in vivo correlation (IVIVC) or association
it is difficult to substantiate the assumptions inherent in these arguments.
And IVIVCs for IR formulations (such as Level A or C) are rare (since dissolution
in vivo is often not the rate-determining step). But when such correlations are
reported (e.g., for poorly soluble drugs), these tend to be formulation specific; i.e.,
an established IVIVC may not accurately predict the performance of a product
with significant changes or differences in formulation [37]. In this case study, the
risk of bioinequivalence is present due to an increased potential for a higher rate
of in vivo dissolution/absorption as a result of reduced magnesium stearate level.
If a relative bioavailability study comparing the prechange product to a simple
aqueous solution of drug Y was conducted during drug development and the two
found to be bioequivalent, these data could support the first argument [40].
The second argument is appealing form a mechanistic perspective. If this
argument can be substantiated, it would provide additional support for the postulate
stated earlier, now restated as follows: Demonstration of similar in vitro
dissolution of the scaled-up product on an H&K machine would minimize the
risk of bioinequivalence. Lowering the surface tension of the dissolution
medium (water; 72 dynes/cm) by about 50% (to the approximate surface tension
of gastric fluid) should enhance the dissolution rate. If drug Y were lithium carbonate
(low-solubility drug), an experiment that was conducted in 1974 [19]
provides useful insight on this issue. In this experiment it was found that a 50%
reduction in the surface tension of dissolution medium, by the addition of 0.02%
sodium lauryl sulfate to the medium, had no effect on the dissolution rate. However,
increasing the amount of sodium lauryl sulfate to 0.5% (i.e., greater than
Quality Control for IR Solid Oral Dosage Forms 341
the critical micelle concentration) did have a pronounced effect on the dissolution
rate of lithium carbonate. This partially supports the postulate stated earlier,
but raises other questions, such as the similarity (e.g., solubilization mechanism)
of sodium lauryl sulfate to biological surfactants. Questions related to in vivo
relevance (or similarity) of the hydrodynamic conditions in the dissolution vessel
are also raised.
In the study with lithium carbonate capsule formulations [19] it was observed
that the addition of 0.002% sodium lauryl sulfate in the capsule formulation
was more effective in improving dissolution than when dissolution medium
contained very large quantities of sodium lauryl sulfate. With respect to this
drug–lubricant-mixing interaction, it has been suggested that the (sodium lauryl
sulfate) surfactant affects drug dissolution by interacting with magnesium stearate
during the mixing process [31], presumably by reducing drug–lubricant bonds or
by creating hydrophilic channels in the hydrophobic lubricant film formed on drug
particles during (prolonged) mixing. A higher impact of a small amount of surfactant
incorporated within a dosage form on the fluid microenvironment (due to
high local concentrations) surrounding the particles undergoing dissolution is also
a possible explanation. Also note that it has been reported that the hydrophobic nature
of different batches of magnesium stearate can vary depending on the presence
of water-soluble, surface-active impurities such as sodium stearate. Batches
containing a very low concentration of these impurities have been shown to retard
drug dissolution to a greater extent than when using batches that contain higher
levels of impurities [41]. Inferences that may be drawn from these observations—
incorporating a wetting agent in a formulation with drug–lubricant-mixing interaction:
(a) reduces the adverse effect of this interaction on drug dissolution (i.e.,
reduces lot–lot variability and the likelihood that a product will fail to meet specifications)
and (b) reduces the dependency of the in vitro dissolution rate on the
composition (presence or absence of a surfactant) of the dissolution medium.
Does the latter inference help to reduce the concern with respect to the appropriateness
of the dissolution medium (and hydrodynamics)?
In the piroxicam capsules study discussed earlier [36], the sodium lauryl
sulfate level (formulation studied in vivo contained 0, 0.5, 1.0% for slow-,
medium-, and fast-dissolving products, respectively) and drug particle size were
the most important main factors affecting dissolution (in USP apparatus T, 50
rpm, 900 mL of simulated gastric fluid without enzymes). Products with a dissolution
of 66 (slow), 80 (medium), and 95% (fast) in 45 minutes were bioequivalent.
In vitro dissolution tests were more sensitive to formulation differences, suggesting
that these formulation differences did not influence the in vivo
dissolution/absorption processes and/or the differences could not be observed in
vivo because physiologic factors, such as gastric emptying, contributed to the observed
variability in blood levels (also note that piroxicam exhibits a relatively
long elimination half-life).
342 Hussain
Reported in vitro dissolution failures due to cross-linking of gelatin shells
that did not result in bioinequivalence [42,45] serve as another set of examples, although
based on a different mechanism, that suggests that significant in vitro differences
do not necessarily translate to in vivo differences.
A high degree of sensitivity of in vitro dissolution tests to formulation differences
raises questions about the appropriate acceptance criteria—how similar
should two in vitro dissolution profiles be to be considered similar? The SUPACIR
introduced to the regulatory decision-making process a metric referred to as
“f2” [43] for profile comparison. Application of this criterion to the examples
cited in this report (e.g., piroxicam formulations) would have resulted in a recommendation
for the in vivo bioequivalence study.
2. Expiration Date or Shelf Life
Stability is an essential quality attribute of a drug product that can also have a significant
clinical consequence. The time during which a batch may be expected to
remain within specifications depends not only on the rate of physical, chemical,
or microbiological changes, but also on the initial average value for the batch.
During drug development, stability studies are conducted to establish an expiration-
dating period that would be applicable to all future batches of the product
manufactured under similar circumstances. This approach assumes that an inference
drawn from these studies extends to all future batches. Therefore, tested
batches should be representative of the population of future production batches.
Generally, an expiration date is determined based on the statistical analysis of observed
long-term stability data under the storage conditions recommended in the
labeling [44].
For the selected example one could argue that the likelihood of observing a
change in the expiration date of this product following changes is minimal, since,
(a) there was a quantitative change only in the level of magnesium stearate, and
(b) the manufacturing process is dry and did not involve heat transfer. In the
postapproval phase further support for this risk estimate can be derived from the
knowledge of the acceptable stability profile of the prechange product. The SUPAC-
IR guidance recognizes this link by utilizing the “significant body of information”
approach. Causal links between preformulation characterization (including
compatibility evaluation) and product stability would be another source of
information, which could be brought to bear on such decisions. This approach is
not currently utilized in SUPAC-IR guidance but probably is being practiced in industry
when go/no-go decisions are made to implement certain changes.
The drug dissolution profiles from capsules have been documented to
change with time due to changes in the gelatin capsule shell properties, interaction
between gelatin and an encapsulated ingredient such as anionic compounds (e.g.,
substituted benzoic and sulfonic acid dyes), and compounds with keto groups. The
Quality Control for IR Solid Oral Dosage Forms 343
moisture content of a hard gelatin capsule (and its performance) may change depending
on the sorption isotherms of the fill material. The disintegration time of
plugs filled in capsule and/or drug particle size or morphic form may also change
with time [45].
A significant fraction of observed stability problems involve physical
changes in the product without accompanying chemical changes (e.g., dissolution
failures). A survey of market withdrawals for the year 1998 identified 154 recalls
(all categories), the lowest number in 12 years [46]. For solid oral dosage forms
(including modified-release), the product quality problems that led to these recalls
are listed in Table 1. For several years, failing to meet dissolution specifications
has occupied a prominent spot on this list. In 1997, 26 recalls were due to dissolution
failures. The recall information is provided only to bring attention to the issue
of ensuring stability, including physical (dissolution) stability. This report
does not intend to suggest or discuss the root cause for these recalls, it only suggests
that the current scientific understanding of time-dependent physical changes
in pharmaceutical dosage forms is limited.
When one takes into account the large number of solid oral products on
the market, these recall numbers represent a very small fraction; however, recalls
are undesirable and further efforts are needed to prevent them. Accelerated
tests have been very useful in predicting chemical changes, but their value for
predicting physical changes (e.g., dissolution shelf life) under ambient conditions
is difficult to ascertain. With respect to physical stability, data obtained under
accelerated conditions are useful for assessing the “ruggedness” of the product
and its ability to withstand the varied climatic conditions during shipping
and storage [47]. To ensure an unchanged stability profile and expiration date
following manufacturing changes, in addition to accelerated stability testing an
344 Hussain
Table 1 Product Quality Problems That Led to Recall
of Solid Oral Dosage Forms in 1998
Number of
Problem recalls
Potency/content uniformity 15
Dissolution 8 (4 cap.)
Other specifications 3
Contamination 5
(microbial and other)
Noncompliance with 5
NDA/monograph requirements
Manufacturing/testing method 1
deficiencies
evaluation of long-term stability data under the storage conditions recommended
in the labeling is necessary.
C. “Connecting-the-Dots”: Art–Science–Regulatory
Policies
The uncertainties or lack of scientific consensus presented in the previous section
contribute to the conservative structures of regulatory recommendations (e.g.,
multimedia dissolution profile comparisons and in vivo bioequivalence studies).
Regulatory decisions are essentially risk management decisions. When developing
regulatory recommendations on manufacturing changes, one needs to: (a) estimate
the risk of adverse effects on quality and performance—the likelihood of
occurrence and the severity of the consequences; (b) identify optimal regulatory
approaches (additional tests and reporting mechanisms) to mitigate an unacceptable
level of risk; and (c) ensure that regulatory recommendations are acceptable
to society (i.e., consistent with its statutes).
The risk of bioinequivalence between pre- and postchange products is due
to (a) the potential for a different (higher) rate of in vivo dissolution between preand
postchange products due to a lower amount of magnesium stearate in the latter
and and/or (b) a reliance on the in vitro dissolution test (similar dissolution) to
ensure unchanged bioavailability. The former risk factor is complex; it essentially
manifests as a physical interaction between drug, lubricant, and processing conditions.
Drug attributes (e.g., solubility, particle size), the physical and chemical attributes
of magnesium stearate (surface area, level of impurities such as sodium
stearate, etc.), the mechanism and duration of shearing during processing are all
likely to modulate this risk factor. Published reports on this topic are predominantly
in vitro studies, with very few linkages to in vivo evaluations.
To mitigate the risks associated with the use of dissolution tests, the BCS
was adopted in the SUPAC-IR guidance and more recently its regulatory applications
expanded in the BCS-based biowaiver guidance [11]. This new guidance
document provides a means for justifying biowaivers for rapidly dissolving products
(85% in 30 minutes in 900 mL of 0.1 N HCl, 4.5 pH and 6.8 pH media, in
USP I or II) of highly soluble (highest dose strength soluble in 250 mL in pH 1–7.5
range) and highly permeable (extent of absorption equal to or greater than 90%)
drugs [11]. Such waivers are not recommended for drugs with a narrow therapeutic
range (NTR). The high-permeability plus high-solubility attributes are utilized
to minimize risk of bioinequivalence due to solubility- or permeability-limited absorption
processes. Low-permeability drugs exhibit incomplete absorption from
the small intestine, and therefore the small intestinal residence time of these drugs
(dissolved) is considered critical. Relatively minor differences in the time needed
for complete in vivo dissolution of low-permeability drugs can potentially reduce
the time available for their absorption during small intestinal transit. The rapid dis-
Quality Control for IR Solid Oral Dosage Forms 345
solution (in three different pH conditions) and built-in profile similarity criteria
are to ensure that dissolution in vivo is not likely to be rate limiting and that minimal
differences in product disintegration time (to minimize the likelihood of differences
in gastric emptying) are observed between the pre- and postchange products.
It could be argued that rapid dissolution in fluid representing gastric fluid pH
should be sufficient, since it is unlikely that rapidly dissolving products will be exposed
in solid form to a pH of 6.8, reflecting the lower portion of the small intestine.
The multimedia dissolution is recommended to account for the observed
physiologic (and pathologic) variability in gastric fluid pH and gastric emptying
process. Since the time of drug administration (during bioequivalence studies and
use by patients) is not synchronized (and should not be for practical reasons) with
the gastric motility pattern, gastric emptying in some subjects could occur almost
immediately after administration. In such cases dissolution would occur in the
small intestine following emptying. If one of the two products being compared exhibits
a different dissolution rate (compared to the other product) in intestinal pH,
then the effect of variable gastric emptying on in vivo dissolution may not be a
truly random phenomenon. This may increase the likelihood of bioinequivalence
when only a single in vitro dissolution condition (e.g., 0.1 N HCl) is used to compare
two products. The multimedia dissolution criteria are intended to minimize
this possibility. The permeability attribute of drugs plays a significant role in the
request for biowaivers. In addition to the reasons stated earlier, permeability contributes
to the development of “sink condition” for in vivo drug dissolution. Drug
dissolution in vitro in a relatively large volume, 900 mL, is likely to be a better
emulation of the in vivo dissolution process of a highly permeable drug. High permeability
also reduces the probability that the excipient will affect bioavailability
due to an effect on gastrointestinal membranes and/or motility [48].
In the previous section it was postulated that reduction in the magnesium
stearate level and inclusion of sodium lauryl sulfate were preferred strategies over
machine adjustment (pin settings on H&K) to implement the desired equipment
changes in the selected example. The BCS-based biowaiver guidance makes it
possible to adopt such strategies without the need for in vivo bioequivalence studies.
However, in vivo bioequivalence evaluation is currently recommended for:
(a) drugs that are not highly soluble or permeable, (b) drugs considered to have a
NTR, and (c) drug products that do not conform to the rapid dissolution criteria.
If a company decides to add sodium lauryl sulfate to counteract the effects of
drug–lubricant-processing interaction for their capsule product of a low-permeability
or low-solubility drug, they would need to conduct an in vivo bioequivalence
study to qualify this change. From Figure 2 it is apparent that a large number
(~50%) of marketed capsule products contain sodium lauryl sulfate. This
information suggests that this excipient (in amounts used in tablets and capsules)
is not likely to alter intestinal permeability. However, the in vivo evidence supporting
this assumption is scattered among different submissions and is currently
not considered sufficient for broad generalization.
346 Hussain
To further expand the use of dissolution tests for ensuring bioequivalence,
two major concerns will need to be addressed: (a) the impact of excipients on
bioavailability, and (b) the ability of dissolution tests to emulate critical in vivo
dissolution processes as these relate to differences in the two formulations. For the
latter, an evaluation of failed bioequivalence studies would be a good starting
point. It was estimated from NDA submissions that about 20–30% of in vivo bioequivalence
studies fail to demonstrate bioequivalence for products that conform to
established dissolution specifications. Of these only a fraction appear to be truly
bioinequivalent products that require reformulation. A pattern that seems to repeat
in some of these failures is a combination of pH (dissolution medium), drug ionization
behavior (pKa in a 3–6 range), and certain product attributes (particle size
and disintegration time differences). For example, similar or even identical dissolution
in 0.1 N HCl (USP I or II, usual rpm settings) may not ensure bioequivalence
for two IR drug products of a weak base differing in particle size, disintegration
time, and/or amount of dicalcium phosphate in a formulation (changes
commonly encountered when a manufacturing process is changed from wet granulation
to direct compression) [48].
In 1997, the SUPAC approach was estimated to provided substantial cost
savings to industry. These savings were realized primarily from (a) revenues from
previously unmarketable stability test batches, (b) more rapid implementation of
site changes (reduced overhead expenses for maintaining two sites), and (c) reduced
stability testing costs. With long regulatory lead times, stability batches often
become “short-dated”; i.e., the remaining shelf life is not sufficient for the
batches to be marketable. One company estimated that it saved $4 million from
being able to sell stability batches of a product that otherwise would have been lost
[49]. Moving away from a prior approval process for low-risk manufacturing
changes can provide significant cost savings for industry and allow the FDA to focus
its limited resources on high-risk issues and practices. An opportunity that has
not yet been realized is the establishment of causal links between preformulation
information and stability (shelf life). Such causal links will provide a means for
identifying risk factors for stability and allow further development of risk-based
regulatory testing and reporting recommendations. Recently the FDA/CDER presented
its initial thoughts on a Risk-Based Chemistry Review program [50] that
intends to further down-regulate chemistry requirements for postapproval
changes. The risk-based review, the planned revision of SUPAC-IR, and PQRI
projects are all designed to enhance the scientific basis of regulatory polices while
reducing regulatory burden on industry.
VI. CONCLUSION
The different perspectives presented in this chapter were inspired by many discussions
and debates (e.g., at the FDA, PQRI, the University of Maryland, and nu-
Quality Control for IR Solid Oral Dosage Forms 347
merous national and international workshops) the author was privileged to participate
in over the last five years. An attempt was made to define and focus these debates
by selecting a real-life example of scale-up and pharmaceutical literature utilized
to examine the scientific basis underlying some of these arguments. This
analysis served to reinforce (at least for the author) that these debates are indeed
art vs. science debates. It is hoped that consensus on this understanding within the
pharmaceutical community will provide a shared vision and strategies (industry,
academia, and regulatory authorities) for moving the science of product development
forward.
In the last three decades the science and practice of biopharmaceutics has
evolved from a mostly empirical study of factors that affect drug absorption to a
more rigorous mechanistic study of drug absorption at the cellular level. This new
understanding is providing novel opportunities in every aspect of the drug development
process, such as;
1. In the drug discovery process, increased emphasis is being placed on
the biopharmaceutical attributes of new chemical entities to identify the
most promising candidates for development, and new tools are being
developed for the rapid assessment of such attributes.
2. In product development, new strategies are being utilized for improving
oral drug absorption.
3. In clinical practice, the likely impact of drug–drug and drug–food interactions
on bioavailability can now be anticipated with some confidence.
4. In regulatory assessment of bioavailability/bioequivalence, increased
emphasis is being directed toward in vitro methods.
The characterization of the biopharmaceutical attributes of a drug substance
early in the drug development process provides valuable information for: (a) design
and development of products with optimal bioavailability, (b) development
of meaningful in vitro dissolution test specifications (methods and acceptance criteria)
for quality assurance, and (c) development of in vitro tests for ensuring
bioequivalence when changes in product formulation are necessary. The Biopharmaceutics
Classification System (BCS) serves as an example of how preformulation
information can be utilized not only for product development but also for
bioequivalence assessment. This approach offers significant opportunities for
“building quality in” and thereby reducing unnecessary testing in humans. A similar
approach for stability, i.e., for predicting and/or ensuring shelf life (chemical,
physical, and microbiological), will be very valuable.
The SUPAC and other related regulatory guidance documents have, for the
first time, provided an opportunity to reduce the regulatory constraints based on
the pharmaceutical sciences. The FDA’s participation in PQRI reflects its desire
to enhance the scientific basis of its policies, thus creating numerous regulatory
opportunities. It is hoped that the pharmaceutical community will recognize these
348 Hussain
opportunities and work together to overcome the many challenges that exist—
pharmaceutical dosage forms are complex multifactorial systems, and data underlying
a publicly available pharmaceutical knowledge base have been derived from
traditional trial-and-error and one-factor-at-a-time experiments. Estimating the
limits of generalization of, and strategies for filling gaps in, this accumulated
knowledge may be difficult without additional prospective experimentation
and/or sharing of proprietary data in a suitably blinded manner to ensure their confidentiality.
With the focus on combinatorial chemistry and high-throughput screening
in drug discovery, it is likely that product development activities (have?) may become
“rate-limiting” in the drug development process. This challenge could be
considered as an industrial opportunity for developing new (predictive) product
development systems that can improve the efficiency of the process for identifying
optimally performing formulations and process conditions. The regulatory opportunity
provides a means for reducing regulatory burden and hence is also an industrial
opportunity. The economic and public benefits that will be derived form
these opportunities can potentially pave the way for additional public and private
support for research in this area. Both regulatory and industrial opportunities can
turn in to academic opportunities. PQRI provides a win–win–win opportunity for
the public, industry, and the agency.
ACKNOWLEDGMENTS
The author wishes to acknowledge the contributions of Professors L. Augsburger
(University of Maryland) and G. L. Amidon (University of Michigan), members
of the Drug Product and Biopharmaceutics Technical Committees of the PQRI,
and several FDA colleagues, especially those on the Biopharmaceutics Coordinating
Committee (BCS Working Group), the Chemistry Manufacturing Controls
Coordination Committees (SUPAC-IR Revision Working Group), and the participants
of various workshops on this topic. The concept of PQRI was envisioned
and championed by Dr. Roger Williams during his tenure at the FDA.
The opinions expressed in this chapter are those of the author and do not
necessarily reflect the views or policies of the FDA.
REFERENCES
1. Guideline on General Principles of Process Validation, May 1987. Center for Drug
Evaluation and Research, Food and Drug Administration. http://www.fda.gov/cder/
guidance/pv.htm.
Quality Control for IR Solid Oral Dosage Forms 349
2. ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances. Issued 11/1997, Posted
11/25/1997. 
3. Skelly, J. P., Van Buskrik, G. A., Savello, D. R., et al. Workshop report: scale-up of
immediate release oral solid dosage forms. Pharm. Res. 10:313–316, 1993.
4. Augsburger, L. L., Shangraw, R., Lesko, L. J., and Williams, R. W. An approach toward
establishing a scientific foundation for interpreting regulations and workshop
reports on scale-up and post approval changes. Pharm. Res. 11(10):S-143, 1994.
5. SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval
Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing,
and In Vivo Bioequivalence Documentation. November 1995. Center for Drug
Evaluation and Research, Food and Drug Administration. http://www.fda.gov/cder/g
uidance/index.htm.
6. The Product Quality Research Institute, Inc. www.pqri.org
7. Webster’s Third New International Dictionary of the English Language. G. & C.
Merriam Company, Springfield, MA, 1976.
8. Ullah, I., Wiley, G. J., and Agharkar, S. N. Analysis and simulation of capsule dissolution
problem encountered during product scale-up. Drug. Dev. Ind. Pharm. 18(8):
895–910, 1992.
9. Heda, P. K. A comparative study of the formulation requirements of dosator and dosing
disc encapsulators, simulation of plug formation, and creation of rules for an expert
system for formulation design. Ph.D. Dissertation, University of Maryland,
School of Pharmacy, 1998.
10. Guidance for Industry. Changes to an Approved NDA or ANDA. U.S. Department of
Health and Human Services, Food and Drug Administration Center for Drug Evaluation
and Research (CDER), November 1999. http://www.fda.gov/cder/guidance/2
766fnl.htm.
11. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Optional
Format: PDF. Issued 8/2000, Posted 8/31/2000. http://www.fda.gov/cder/guidance/
index.htm.
12. SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms
Manufacturing Equipment Addendum. Issued 1/1999, Posted 2/25/1999. http://
www.fda.gov/cder/guidance/index.htm.
13. Carstensen, J. T. Preformulation. In: J. T. Carstensen and C. T. Rhodes, eds. Drug Stability:
Principles and Practices. Third Eds Marcel Dekker, New York, 2000, Chap 9, p 237.
14. Samyn, J. C., and Jung, W. Y. In vitro dissolution from several experimental capsule
formulations. J. Pharm. Sci. 59:169–175, 1970.
15. Rowley, G., and Newton, J. M. Limitations of liquid penetration in predicting the release
of drugs from hard gelatin capsules. J. Pharm. Pharmacol. 22:966–967, 1970.
16. Newton, J. M., Rowley, G., and Tornblom, J. F. Effect of additives on the release of
drug from hard gelatin capsules. J. Pharm. Pharmacol. 23:452–453, 1971.
17. Khalil, S. A., and Ali, M. M. Some formulation factors affecting disintegration and
dissolution of chloramphenicol capsules. Acta. Pharm. Suec. 9:563–572, 1972.
18. Caldwell, H. C., and Westlake, W. J. Magnesium lauryl sulfate–soluble lubricant. J.
Pharm. Sci. 61:984–985, 1972.
350 Hussain
19. Caldwell, H. C. Dissolution of lithium and magnesium from lithium carbonate capsules
containing magnesium stearate. J. Pharm. Sci. 63:770–773, 1974.
20. Murthy, K. S., and Samyn, J. C. Effect of shear mixing on in vitro drug release of capsule
formulations containing lubricants. J. Pharm. Sci. 66:1215–1219, 1977.
21. Newton, J. M., and Razzo, F. N. Influence of additives on the presentation of a drug
in hard gelatin capsules. J. Pharm. Pharmacol. 29:294–297, 1977.
22. Shah, A. C., and Mlodozeniec, A. R. Mechanism of surface lubrication: influence of
duration of lubricant–excipient mixing on processing characteristics of powders and
properties of compressed tablets. J. Pharm. Sci. 66:1377–1382, 1977.
23. Stewart, A. G., Grant, D. J. W., and Newton, J. M. Release of a model low dose drug
(riboflavin) from hard gelatin capsule formulations. J. Pharm. Pharmacol. 31:1–6,
1979.
24. Ahmed, M., and Enever, R. P. Influence of magnesium stearate on physical properties
and biological availability of sulfadiazine tablet formulations. Pharm. Acta. Helv.
53:358–364, 1978.
25. Mehta, A. M., and Augsburger, L. L. Preliminary study of the effect of slug hardness
on drug dissolution from hard gelatin capsules filled on an automatic capsule filling
machine. Int. J. Pharm. 7:327–334, 1981.
26. Johansson, M. E., and Nicklasson, M. Investigation of the film formation of magnesium
stearate by applying a flow through dissolution technique. J. Pharm. Pharmacol.
38:51–54, 1986.
27. Chowhan, Z. T., and Chi, L. H. Drug-excipient interactions resulting from powder
mixing. Part 3. Solid-state properties and their effect on drug dissolution. J. Pharm.
Sci. 75:534–541, 1986.
28. Chowhan, Z. T., and Chi, L. H. Drug–excipient interactions resulting from powder
mixing. Part 4. Role of lubricants and their effect on in vitro dissolution. J. Pharm.
Sci. 75:542–545, 1986.
29. Wang, L. H., and Chowhan, Z. T. Drug–excipient interactions resulting from powder
mixing. Part 5. Role of sodium lauryl sulfate. Int. J. Pharm. 60:61–78, 1990.
30. Desai, D. S., Rubitski, B. A., Varia, S. A., and Newman, A. W. Physical interactions
of magnesium stearate with starch-derived disintegrants and their effects on capsule
and tablet dissolution. Int. J. Pharm. 91:217–226, 1993.
31. Ong, J. T., Chowhan, Z. T., and Samuels, G. J. Drug–excipient interactions resulting
from powder mixing. Part 6. Role of various surfactants. Int. J. Pharm. 96:231–242,
1993.
32. Barra, J., and Somma, R. Influence of the physicochemical variability of magnesium
stearate on its lubricant properties: possible solutions. Drug. Dev. Ind. Pharm.
22:1105–1120, 1996.
33. Harwood, R. J., and Molnar, S. A. Using design of experiments (DOE) techniques to
avoid process problems. Pharm. Dev. Tech. 3:577–578, 1998.
34. Shangraw, R. F., and Demarest, D. Survey of current industrial practice in the formulation
and manufacture of tablets and capsules. Pharm. Tech. 17(1):32–44, 1993.
35. USP 24-NF 19. United States Pharmacopoeia Convention, Inc. Rockville, MD, 2000.
36. Piscitelli, D. A., Bigora, S., Propst, C., Goskonda, S., Young, D., et al. Impact of formulation
process changes on in vitro dissolution and the bioequivalence of piroxicam
capsules. Pharm. Dev. Technol. 3:443–452, 1998.
Quality Control for IR Solid Oral Dosage Forms 351
37. Hussain, A. S., Lesko, L. J., Lo, H, Y., Shah, V. P., Volpe, D., and Williams, R. L.
The Biopharmaceutics Classification System: Highlights of the FDA’s Draft Guidance.
Dissolution Technol. 6:5–9, 1999.
38. Amidon, G. L., Lennernas, H., Shah, V. P., et al. A theoretical basis for a biopharmaceutics
drug classification system: the correlation of in vitro drug product dissolution
and in vivo bioavailability. Pharm. Res. 12:413–420, 1995.
39. Lindahl, A., Ungell, A. L., Knutson, L., and Lennernas, H. Characterization of fluids
from the stomach and proximal jejunum in men and women. Pharm. Res. 14:
497–502, 1997.
40. Kaus, L. C., Gillespie, W. R., Hussain, A. S., and Amidon, G. A. The effect of in vivo
dissolution, gastric emptying rate, and intestinal transit time on the peak concentration
and area-under-the-curve of drugs with different gastrointestinal permeabilities.
Pharm. Res. 16:272–280, 1999.
41. Billany, M. R., and Richards, J. H. Batch variation of magnesium stearate and its effect
on the dissolution rate of salicylic acid from solid dosage forms. Drug. Dev. Ind.
Pharm. 8:497–511, 1982.
42. Meyer, M. C., Straughn, A. B., Mhatre, R. M., et al. The effect of gelatin cross-linking
on the bioequivalence of hard and soft gelatin acetaminophen capsules. Pharm.
Res. 17:962–966, 2000.
43. Moore, J. W., and Flanner, H. H. Mathematical comparison of dissolution profiles.
Pharm. Technol. 20:54–75, 1996.
44. Draft Guidance for Industry. Stability Testing of Drug Substances and Drug Products,
1998. http://www.fda.gov/cder/guidance/1707dft.pdf.
45. Carstensen, J. T. Physical Testing. In: J. T. Carstensen and C. T. Rhodes, eds. Drug
Stability: Principles and Practices. Third Edition, Marcel Dekker, New York, 2000,
Chap 10, p 261.
46. Drug Recalls Declined for 1998. The Gold Sheets. Vol. 33. February 1999.
47. Murthy, K. S., and Ghebere-Sellassie, I. Current perspectives on the dissolution stability
of solid dosage forms. J. Pharm. Sci. 82:113–26, 1993.
48. Hussain, A. S. Biopharmaceutics Classifications System. Advisory Committee for
Pharmaceutical Science meeting, 11 December 1997. Food and Drug Administration.
http://www/fda.gov/ohrms/dockets/ac/97/transcpts/335 0.pdf.
49. Pharmaceutical Industry Cost Savings Through Use of the Scale-up and Post-Approval
Change Guidance for Immediate Release Solid Oral Dosage Forms (SUPACIR).
Office of Planning and Evaluation, Food and Drug Administration, 1998.
http://www.fda.gov/ope/supac5.pdf.
50. Chiu, Y. Y. Risk-Based Chemistry Review. Advisory Committee for Pharmaceutical
Science. Center for Drug Evaluation and Research, Food and Drug Administration.
November 2000. (The Gold Sheet also reported on this discussion. Risk-Based CMC
Review Plan Unveiled by FDA’s Drug Center. November 2000.)
352 Hussain
Appendix A
Guidance for Industry1—Immediate
Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes:
Chemisty, Manufacturing, and Controls,
In Vitro Dissolution Testing, and In Vivo
Bioequivalence Documentation
I. PURPOSE OF GUIDANCE
This guidance provides recommendations to sponsors of new drug applications
(NDA’s), abbreviated new drug applications (ANDA’s), and abbreviated antibiotic
applications (AADA’s) who intend, during the postapproval period, to
change: 1) the components or composition; 2) the site of manufacture; 3) the
scale-up/scale-down of manufacture; and/or 4) the manufacturing (process and
equipment) of an immediate release oral formulation.
This guidance is the result of: 1) a workshop on the scale-up of immediate
release drug products conducted by the American Association of Pharmaceutical
Scientists in conjunction with the United States Pharmacopoeial
353
1 This guidance has been prepared by the Immediate Release Scale-up and Post Approval Change (SUPAC)
Expert Working Group of the Chemistry Manufacturing Controls Coordinating Committee
(CMC CC) of the Center for Drug Evaluation and Research at the Food and Drug Administration.
This guidance is an informal communication under 21 CFR 10.90(b)(9) that reflects the best judgment
of CDER employees at this time. It does not create or confer any rights, privileges or benefits
for or on any person, nor does it operate to bind or obligate FDA in any way. For additional copies
of this guidance contact the Consumer Affairs Branch (formerly the Executive Secretariat Staff),
HFD-8, Center for Drug Evaluation and Research, 7500 Standish Place, Rockville, MD 20855
(Phone: 301-594-1012). An electronic version of this guidance is also available via Internet by connecting
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).
Convention and the Food and Drug Administration (FDA); 2) research conducted
by the University of Maryland at Baltimore on the chemistry, manufacturing
and controls of immediate release drug products under the FDA/University
of Maryland Manufacturing Research Contract; 3) the drug categorization
research conducted at the University of Michigan and the University of Uppsala
on the permeability of drug substances; and 4) the Scale- Up and Post Approval
Changes (SUPAC) Task Force which was established by the Center for Drug
Evaluation and Research (CDER) Chemistry, Manufacturing and Controls Coordinating
Committee to develop guidance on scale-up and other postapproval
changes.
The guidance defines: 1) levels of change; 2) recommended chemistry,
manufacturing, and controls tests for each level of change; 3) in vitro dissolution
tests and/or in vivo bioequivalence tests for each level of change; and 4) documentation
that should support the change. For those changes filed in a “changes
being effected supplement” [21 CFR 314.70(c)], the FDA may, after a review of
the supplemental information, decide that the changes are not approvable. This
guidance thus sets forth application information that should be provided to CDER
to assure continuing product quality and performance characteristics of an immediate
release solid oral dose formulation for specified postapproval changes. This
guidance does not comment on or otherwise affect compliance/inspection documentation
that has been defined by CDER’s Office of Compliance or FDA’s Office
of Regulatory Affairs. This guidance does not affect any postapproval
changes other than the ones specified. For changes not addressed in this guidance,
or for multiple changes submitted at one time or over a short period of time, or
where the number of batches needed for stability testing is not specified, sponsors
should contact the appropriate CDER review division or consult other CDER
guidances/guidelines to obtain information about tests and application documentation.
21 CFR 314.70(a) provides that applicants may make changes to an
approved application in accordance with a guideline, notice, or regulation
published in the FEDERAL REGISTER that provides for a less burdensome
notification of the change (for example, by notification at the time a supplement
is submitted or in the next annual report). This guidance permits less
burdensome notice of certain postapproval changes within the meaning of §
314.70(a).
For postapproval changes for immediate release dosage forms that affect
components and composition, scale-up, site change, and manufacturing process or
equipment changes, this guidance supersedes the recommendations in section 4.G
of the Office of Generic Drugs Policy and Procedure Guide 22–90 (September 11,
1990). For all other dosage forms and changes, this guidance does not affect the
recommendations in Guide 22–90.
354 Appendix A
II. DEFINITION OF TERMS2
A. Batch
A specific quantity of a drug or other material produced according to a single manufacturing
order during the same cycle of manufacture and intended to have uniform
character and quality, within specified limits [21 CFR 210.3(b)(2)].
B. Contiguous Campus
Continuous or unbroken site or a set of buildings in adjacent city blocks.
C. Dissolution Testing
Case A: Dissolution of Q 
 85% in 15 minutes in 900 milliliters (mL) of 0.1N
hydrochloride (HCl), using the United States Pharmacopeia (USP) 711 Apparatus
1 at 100 revolutions per minute (rpm) or Apparatus 2 at 50 rpm.
Case B: Multi-point dissolution profile in the application/compendial
medium at 15, 30, 45, 60, and 120 minutes or until an asymptote is reached for the
proposed and currently accepted formulation.
Case C: Multi-point dissolution profiles performed in water, 0.1N HCl,
and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the
proposed and currently accepted formulations. Adequate sampling should be performed
at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug
product is dissolved or an asymptote is reached. A surfactant may be used with appropriate
justification.
D. Drug Product
A drug product is a finished dosage form (e.g., tablet, capsule, or solution) that
contains a drug substance, generally, but not necessarily, in association with one
or more other ingredients [21 CFR 314.3(b)]. A solid oral dosage form includes
tablets, chewable tablets, capsules, and soft gelatin capsules.
E. Drug Substance
An active ingredient that is intended to furnish pharmacological activity or other
direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a dis-
Appendix A 355
2 See Workshop Report: Scale-up of Immediate Release Oral Solid Dosage Forms, Pharmaceutical
Research, 10 (2): 313–316, Skelly et al; and Federal Register. Vol. 59, No. 183, Thursday, September
22, 1994, pages 48754–59.
ease, or to affect the structure of any function of the human body, but does not include
intermediates used in the synthesis of such ingredient [21 CFR 314.3(b)].
F. Equipment
Automated or non-automated, mechanical or non-mechanical equipment used to
produce the drug product, including equipment used to package the drug product.
G. Formulation
A listing of the ingredients and composition of the dosage form.
H. Justification
Reports containing scientific data and expert professional judgment to substantiate
decisions.
I. New Drug Substance
Any substance that, when used in the manufacture, processing, or packing of a
drug, causes that drug to be a new drug, but does not include intermediates used
in the synthesis of such substance [21 CFR 310.3(g)].
J. Operating Principle
Rules or concepts governing the operation of the system.
K. Pilot Scale
The manufacture of either drug substance or drug product by a procedure fully
representative of and simulating that used for full manufacturing scale.
For solid oral dosage forms this is generally taken to be, at a minimum, onetenth
that of full production, or 100,000 tablets or capsules, whichever is larger (see
the FEDERAL REGISTER of Thursday, September 22, 1994, 59 FR 48754-59).
L. Process
A series of operations and/or actions used to produce a desired result.
M. Ranges
The extent to which or the limits between which acceptable variation exists.
356 Appendix A
N. Same
Agreeing in kind, amount; unchanged in character or condition.
O. Scale-Up
The process of increasing the batch size.
P. Scale-Down
The process of decreasing the batch size.
Q. Similar
Having a general likeness.
R. Significant Body of Information
A significant body of information on the stability of the drug product is likely to
exist after five years of commercial experience for new molecular entities, or three
years of commercial experience for new dosage forms.
S. Validation
Establishing through documented evidence a high degree of assurance that a specific
process will consistently produce a product that meets its predetermined
specifications and quality attributes. A validated manufacturing process is one that
has been proven to do what it purports or is represented to do. The proof of validation
is obtained through collection and evaluation of data, preferably beginning
from the process development phase and continuing through the production phase.
Validation necessarily includes process qualification (the qualification of materials,
equipment, systems, buildings, and personnel), but it also includes the control
of the entire processes for repeated batches or runs.
III. COMPONENTS AND COMPOSITION
This section of the guidance focuses on changes in excipients in the drug product.
Changes in the amount of drug substance are not addressed by this guidance.
Changes in components or composition that have the effect of adding a new excipient
or deleting an excipient are defined at Level 3 (defined below), except as
described below.
Appendix A 357
A. Level 1 Changes
1. Definition of Level
Level 1 changes are those that are unlikely to have any detectable impact on formulation
quality and performance.
Examples:
a. Deletion or partial deletion of an ingredient intended to affect the color
or flavor of the drug product; or change in the ingredient of the printing
ink to another approved ingredient.
b. Changes in excipients, expressed as percentage (w/w) of total formulation,
less than or equal to the following percent ranges:
Percent excipient (w/w) out of total
Excipient target dosage form weight
Filler 5
Disintegrant
Starch 3
Other 1
Binder 0.5
Lubricant
Calcium (Ca) or
Magnesium (Mg) Stearate 0.25
Other 1
Glidant
Talc 1
Other 0.1
Film Coat 1
These percentages are based on the assumption that the drug substance in
the product is formulated to 100% of label/potency. The total additive effect of all
excipient changes should not be more than 5%. (Example: In a product consisting
of active ingredient A, lactose, microcrystalline cellulose and magnesium stearate,
the lactose and microcrystalline cellulose should not vary by more than an absolute
total of 5% (e.g. lactose increases 2.5% and microcrystalline cellulose decreases
by 2.5%) relative to the target dosage form weight if it is to stay within the
Level 1 range).
The components (active and excipients) in the formulation should have numerical
targets which represent the nominal composition of the drug product on
which any future changes in the composition of the product are to be based. Allowable
changes in the composition should be based on the approved target composition
and not on previous Level 1 changes in the composition.
358 Appendix A
2. Test Documentation
a. Chemistry Documentation
Application/compendial release requirements and stability testing.
Stability testing: one batch on long-term stability data reported in annual
report.
b. Dissolution Documentation
None beyond application/compendial requirements.
c. In Vivo Bioequivalence Documentation
None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Changes
1. Definition of Level
Level 2 changes are those that could have a significant impact on formulation
quality and performance. Tests and filing documentation for a Level 2 change
vary depending on three factors: therapeutic range, solubility, and permeability.
Therapeutic range is defined as either narrow or non-narrow. A list of narrow
therapeutic range drugs is provided in Appendix A. Drug solubility and drug permeability
are defined as either low or high. Solubility is calculated based on the
minimum concentration of drug, milligram/milliliter (mg/mL), in the largest
dosage strength, determined in the physiological pH range (pH 1 to 8) and temperature
(37  0.5 C). High solubility drugs are those with a dose/solubility volume
of less than or equal to 250 mL. (Example: Compound A has as its lowest solubility
at 37  0.5 C, 1.0 mg/mL at pH 7, and is available in 100 mg, 200 mg and
400 mg strengths. This drug would be considered a low solubility drug as its
dose/solubility volume is greater than 250 mL (400 mg/1.0 mg/mL
400 mL).
Permeability (P, centimeter per second) is defined as the effective human jejunal
wall permeability of a drug and includes an apparent resistance to mass transport
to the intestinal membrane. High permeability drugs are generally those with an
extent of absorption greater than 90% in the absence of documented instability in
the gastrointestinal tract, or those whose permeability attributes have been determined
experimentally).
Examples:
a. Change in the technical grade of an excipient. (Example: Avicel PH102
vs. Avicel PH200.)
b. Changes in excipients, expressed as percent (w/w) of total formulation,
greater than those listed above for a Level 1 change but less than or
Appendix A 359
equal to the following percent ranges (which represent a two fold increase
over Level 1 changes):
Percent excipient (w/w) out of total
Excipient target dosage form weight
Filler 10
Disintegrant
Starch 6
Other 2.10
Binder 1
Lubricant
Ca or Mg Stearate 0.5
Other 2
Glidant
Talc 2
Other 0.2
Film Coat 2
These percentages are based on the assumption that the drug substance in
the drug product is formulated to 100% of label/potency. The total additive effect
of all excipient changes should not change by more than 10%.
The components (active and excipients) in the formulation should have numerical
targets that represent the nominal composition of the product on which
any future changes in the composition of the product are to be based. Allowable
changes in the composition should be based on the approved target composition
and not on the composition based on previous Level 1 or Level 2 changes.
2. Test Documentation
a. Chemistry Documentation. Application/compendial release requirements
and batch records.
Stability testing: 1 batch with 3 months accelerated stability data in supplement
and 1 batch on long-term stability.
b. Dissolution Documentation.
Case A: High Permeability, High Solubility Drugs
Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl. If
a drug product fails to meet this criterion, the applicant
should perform the tests described for Case B or C (below).
Case B: Low Permeability, High Solubility Drugs
Multi-point dissolution profile should be performed in the
360 Appendix A
application/compendial medium at 15, 30, 45, 60 and 120
minutes or until an asymptote is reached. The dissolution
profile of the proposed and currently used product formulations
should be similar.
Case C: High Permeability, Low Solubility Drugs
Multi-point dissolution profiles should be performed in water,
0.1 N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5
(five separate profiles) for the proposed and currently accepted
formulations. Adequate sampling should be performed
at 15, 30, 45, 60, and 120 minutes until either 90% of
drug from the drug product is dissolved or an asymptote is
reached. A surfactant may be used, but only with appropriate
justification. The dissolution profile of the proposed and currently
used product formulations should be similar.
c. In Vivo Bioequivalence Documentation. None: if the situation does
not meet the description in Case A, Case B or Case C, refer to Level 3 changes.
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
C. Level 3 Changes
1. Definition of Level
Level 3 changes are those that are likely to have a significant impact on formulation
quality and performance. Tests and filing documentation vary depending on
the following three factors: therapeutic range, solubility, and permeability.
Examples:
a. Any qualitative and quantitative excipient changes to a narrow therapeutic
drug beyond the ranges noted in Section III.A.1.b.
b. All other drugs not meeting the dissolution criteria under Section
III.B.2.b.
c. Changes in the excipient ranges of low solubility, low permeability
drugs beyond those listed in Section III.A.1.b.
d. Changes in the excipient ranges of all drugs beyond those listed in Section
III.B.1.b.
2. Test Documentation
a. Chemistry Documentation. Application/compendial release requirements
and batch records.
Appendix A 361
SIGNIFICANT BODY OF INFORMATION AVAILABLE. One batch with three
months accelerated stability data reported in supplement; one batch on long-term
stability data reported in annual report.
SIGNIFICANT BODY OF INFORMATION NOT AVAILABLE. Up to three batches
with three months accelerated stability data reported in supplement; one batch on
long-term stability data reported in annual report.
b. Dissolution Documentation. Case B dissolution profile as described
in Section III.B.2.b.
c. In Vivo Bioequivalence Documentation. Full bioequivalence study.
The bioequivalence study may be waived with an acceptable in vivo/in vitro correlation
has been verified.
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
IV. SITE CHANGES
Site changes consist of changes in location of the site of manufacture for both
company-owned and contract manufacturing facilities and do not include any
scale-up changes, changes in manufacturing (including process and/or equipment),
or changes in components or composition. Scale-up is addressed in Section
V of this guidance. New manufacturing locations should have a satisfactory current
Good Manufacturing Practice (CGMP) inspection.
A. Level 1 Changes
1. Definition of Level
Level 1 changes consist of site changes within a single facility where the same
equipment, standard operating procedures (SOP’s), environmental conditions
(e.g., temperature and humidity) and controls, and personnel common to both
manufacturing sites are used, and where no changes are made to the manufacturing
batch records, except for administrative information and the location of the facility.
Common is defined as employees already working on the campus who have
suitable experience with the manufacturing process.
2. Test Documentation
a. Chemistry Documentation. None beyond application/compendial release
requirements.
362 Appendix A
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Annual report.
B. Level 2 Changes
1. Definition of Level
Level 2 changes consist of site changes within a contiguous campus, or between
facilities in adjacent city blocks, where the same equipment, SOP’s, environmental
conditions (e.g., temperature and humidity) and controls, and personnel common
to both manufacturing sites are used, and where no changes are made to the
manufacturing batch records, except for administrative information and the location
of the facility.
2. Test Documentation
a. Chemistry Documentation. Location of new site and updated batch
records. None beyond application/compendial release requirements. One batch on
long-term stability data reported in annual report.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement; annual report (long-term stability test data).
C. Level 3 Changes
1. Definition of Level
Level 3 changes consist of a change in manufacturing site to a different campus.
A different campus is defined as one that is not on the same original contiguous
site or where the facilities are not in adjacent city blocks. To qualify as a Level 3
change, the same equipment, SOP’s, environmental conditions, and controls
should be used in the manufacturing process at the new site, and no changes may
be made to the manufacturing batch records except for administrative information,
location and language translation, where needed.
Appendix A 363
2. Test Documentation
a. Chemistry Documentation. Location of new site and updated batch
records. Application/compendial release requirements
Stability:
SIGNIFICANT BODY OF DATA AVAILABLE. One batch with three months accelerated
stability data reported in supplement; one batch on long-term stability
data reported in annual report.
SIGNIFICANT BODY OF DATA NOT AVAILABLE. Up to three batches with
three months accelerated stability data reported in supplement; up to three batches
on long- term stability data reported in annual report.
b. Dissolution Documentation.
Case B: Multi-point dissolution profile should be performed in the
application/compendial medium at 15, 30, 45, 60 and 120
minutes or until an asymptote is reached. The dissolution
profile of the drug product at the current and proposed site
should be similar.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement; annual report (long-term stability data).
V. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)
Postapproval changes in the size of a batch from the pivotal/pilot scale biobatch
material to larger or smaller production batches call for submission of additional
information in the application. Scale-down below 100,000 dosage units is not covered
by this guidance. All scale-up changes should be properly validated and,
where needed, inspected by appropriate agency personnel.
A. Level 1 Changes
1. Definition of Level
Change in batch size, up to and including a factor of 10 times the size of the
pilot/biobatch, where: 1) the equipment used to produce the test batch(es) is
of the same design and operating principles; 2) the batch(es) is (are) manufactured
in full compliance with CGMP’s; and 3) the same standard operating
364 Appendix A
procedures (SOP’s) and controls, as well as the same formulation and manufacturing
procedures, are used on the test batch(es) and on the full-scale production
batch(es).
2. Test Documentation
a. Chemistry Documentation. Application/compendial release requirements.
Notification of change and submission of updated batch records in annual
report.
One batch on long-term stability reported in annual report.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. In Vivo Bioequivalence. None.
3. Filing Documentation
Annual report (long-term stability data).
B. Level 2 Changes
1. Definition of Level
Changes in batch size beyond a factor of ten times the size of the pilot/biobatch,
where: 1) the equipment used to produce the test batch(es) is of the same design
and operating principles; 2) the batch(es) is (are) manufactured in full compliance
with CGMP’S; and 3) the same SOP’s and controls as well as the same formulation
and manufacturing procedures are used on the test batch(es) and on the fullscale
production batch(es).
2. Test Documentation
a. Chemistry Documentation. Application/compendial release requirements.
Notification of change and submission of updated batch records. Stability
testing: One batch with three months accelerated stability data and one batch on
long-term stability.
b. Dissolution Documentation. Case B testing.
c. In Vivo Bioequivalence. None.
d. Filing Documentation. Changes being effected supplement; annual
report (long-term stability data).
Appendix A 365
VI. MANUFACTURING
Manufacturing changes may affect both equipment used in the manufacturing process
and the process itself.
A. Equipment
1. Level 1 Changes
a. Definition of Change. This category consists of: 1) change from nonautomated
or non-mechanical equipment to automated or mechanical equipment
to move ingredients; and 2) change to alternative equipment of the same design
and operating principles of the same or of a different capacity.
b. Test Documentation.
i. Chemistry Documentation
Application/compendial release requirements. Notification of
change and submission of updated batch records.
Stability testing: One batch on long-term stability.
ii. Dissolution Documentation
None beyond application/compendial release requirements.
iii. In Vivo Bioequivalence Documentation
None.
c. Filing Documentation. Annual report (long-term stability data).
2. Level 2 Changes
a. Definition of Level. Change in equipment to a different design and
different operating principles.
b. Test Documentation.
i. Chemistry Documentation
Application/compendial release requirements.
Notification of change and submission of updated batch records.
Stability testing:
SIGNIFICANT BODY OF DATA AVAILABLE. One batch with three months accelerated
stability data reported in supplement; one batch on long-term stability
data reported in annual report.
SIGNIFICANT BODY OF DATA NOT AVAILABLE. Up to three batches with
three months accelerated stability data reported in supplement; up to three batches
on long-term stability data reported in annual report.
366 Appendix A
ii. Dissolution Documentation
Case C dissolution profile.
iii. In Vivo Bioequivalence Documentation
None.
c. Filing Documentation. Prior approval supplement with justification
for change; annual report (long-term stability data).
B. Process
1. Level 1 Changes
a. Definition of Level. This category includes process changes including
changes such as mixing times and operating speeds within application/validation
ranges.
b. Test Documentation.
i. Chemistry Documentation
None beyond application/compendial release requirements.
ii. Dissolution Documentation
None beyond application/compendial release requirements.
iii. In Vivo Bioequivalence Documentation
None.
c. Filing Documentation. Annual report.
2. Level 2 Changes
a. Definition of Level. This category includes process changes including
changes such as mixing times and operating speeds outside of application/validation
ranges.
b. Test Documentation.
i. Chemistry Documentation
Application/compendial release requirements. Notification of
change and submission of updated batch records.
Stability testing: One batch on long-term stability.
ii. Dissolution Documentation
Case B dissolution profile.
iii. In Vivo Bioequivalence Documentation
None.
c. Filing Documentation. Changes being effected supplement; annual
report (long-term stability data).
Appendix A 367
3. Level 3 Changes
a. Definition of Level. This category includes change in the type of process
used in the manufacture of the product, such as a change from wet granulation
to direct compression of dry powder.
b. Test Documentation.
i. Chemistry Documentation
Application/compendial release requirements. Notification of
change and submission of updated batch records.
Stability testing:
SIGNIFICANT BODY OF DATA AVAILABLE. One batch with three months accelerated
stability data reported in supplement; one batch on long-term stability
data reported in annual report.
SIGNIFICANT BODY OF DATA NOT AVAILABLE. Up to three batches with
three months accelerated stability data reported in supplement; up to three batches
on long-term stability data reported in annual report.
ii. Dissolution Documentation
Case B dissolution.
iii. In Vivo Bioequivalence Documentation
In vivo bioequivalence study. The bioequivalence study may be
waived if a suitable in vivo/in vitro correlation has been verified.
c. Filing Documentation. Prior approval supplement with justification;
annual report (long-term stability data).
VII. IN VITRO DISSOLUTION
See current United States Pharmacopeia/National Formulary, section 711, for
general dissolution specifications. All profiles should be conducted on at least 12
individual dosage units.
Dissolution profiles may be compared using the following equation that defines
a similarity factor (f2):
f2 
 50 LOG {[1  1/n ?nt

1 (Rt  Tt)2]0.5  100}2
where R and T are the percent dissolved at each time point. An f2 value between
50 and 100 suggests the two dissolution profiles are similar.
368 Appendix A
VIII. IN VIVO BIOEQUIVALENCE STUDIES
Below is a general outline of an in vivo bioequivalence study. It is intended as a
guide and the design of the actual study may vary depending on the drug and
dosage form.
A. Objective
To compare the rate and extent of absorption of the drug product for which the
manufacture has been changed, as defined in this guidance, to the drug product
manufactured prior to the change.
B. Design
The study design should be a single dose, two-treatment, two-period crossover
with adequate washout period between the two phases of the study. Equal numbers
of subjects should be randomly assigned to each of the two dosing sequences.
C. Selection of Subjects
The number of subjects enrolled in the bioequivalence study should be determined
statistically to account for the intrasubject variability and to meet the current bioequivalence
interval.
D. Procedure
Each subject should receive the following two treatments:
Treatment 1: Product manufactured with the proposed change.
Treatment 2: Product manufactured prior to the proposed change.
Following an overnight fast of at least 10 hours, subjects should receive
either Treatments 1 or 2 above with 240 mL water. Food should not be allowed
until 4 hours after dosing. Water may be allowed after the first hour. Subjects
should be served standardized meals beginning at 4 hours during the study.
E. Restrictions
Prior to and during each study phase, water may be allowed ad libitum except for
1 hour before and after drug administration. The subject should be served standardized
meals and beverages at specified times. No alcohol or xanthine- or caffeine-
containing foods and beverages should be consumed for 48 hours prior to
each study period and until after the last blood sample is collected.
Appendix A 369
F. Blood Sampling
Blood samples should be collected in sufficient volume for analysis of parent drug
and active metabolite(s), if any. The sampling times should be such that it should
be able to capture the C and T during the max max absorption period. Sampling
should be carried out for at least three terminal elimination half-lives for both
parent drug and active metabolite(s). Whole blood, plasma or serum, whichever is
appropriate for the analytes, should be harvested promptly and samples should be
frozen at 20 C or 70 C to maintain sample stability.
G. Analytical Method
The assay methodology selected should ensure specificity, accuracy, interday and
intraday precision, linearity of standard curves, and adequate sensitivity, recovery,
and stability of the samples under the storage and handling conditions associated
with the analytical method.
H. Pharmacokinetic Analysis
From the plasma drug concentration-time data, AUC0-t, AUC0-inf, Cmax, Tmax, Kel
and t1/2 should be estimated.
I. Statistical Analysis
Analysis of variance appropriate for a crossover design on the pharmacokinetic
parameters using the general linear models procedures of SAS or an equivalent
program should be performed, with examination of period, sequence and treatment
effects. The 90% confidence intervals for the estimates of the difference between
the test and reference least squares means for the pharmacokinetic parameters
(AUC0-t, AUC0-inf, Cmax should be calculated, using the two one-sided t-test
procedure).
REFERENCES
A. Code of Federal Regulations 210.3(b)(2) and (10), 310.3(b) and (g), and 320.1(a) and
(e).
B. FDA/University of Maryland Manufacturing Research Contract Summary.
C. Federal Register. Vol. 59, No. 183, Thursday, September 22, 1994, pages 48754–59.
D. “Guideline for Industry: Stability Testing of New Drug Substances and Products,”
U.S. Department of Health and Human Services, Food and Drug Administration,
September 1994.
370 Appendix A
E. “Guideline for Submitting Documentation for the Manufacture of and Controls for
Drug Products,” U.S. Department of Health and Human Services, Food and Drug Administration,
February 1987.
F. Policy and Procedure Guide #22–90: “Interim Policy on Exceptions to the Batch-Size
and Production Condition Requirements for Non-Antibiotic, Solid, Oral-Dosage Form
Drug Products Supporting Proposed ANDA’s”, U.S. Department of Health and Human
Services, Center for Drug Evaluation and Research, Office of Generic Drugs,
September 13, 1990.
G. Workshop Report: Scale up of Immediate Release Oral Solid Dosage Forms, Pharmaceutical
Research, 10 (2): 313–16, Skelly et al.
NARROW THERAPEUTIC RANGE DRUGS
Aminophylline Tablets, ER Tablets
Carbamazepine Tablets, Oral Suspension
Clindamycin Hydrochloride Capsules
Clonidine Hydrochloride Tablets
Clonidine Transdermal Patches
Dyphylline Tablets
Ethinyl Estradiol/Progestin Oral Contraceptive Tablets
Guanethidine Sulfate Tablets
Isoetharine Mesylate Inhalation Aerosol
Isoproterenol Sulfate Tablets
Lithium Carbonate Capsules, Tablets, ER Tablets
Metaproterenol Sulfate Tablets
Minoxidil Tablets
Oxtriphylline Tablets, DR Tablets, ER Tablets
Phenytoin, Sodium Capsules (Prompt or Extended), Oral Suspension
Prazosin Hydrochloride Capsules
Primidone Tablets, Oral Suspension
Procainamide Hydrochloride, Capsules, Tablets, ER Tablets
Quinidine Sulfate Capsules, Tablets, ER Tablets
Quinidine Gluconate Tablets, ER Tablets
Theophylline Capsules, ER Capsules, Tablets, ER Tablets
Valproic Acid Capsules, Syrup
Divalproex, Sodium DR Capsules, DR Tablets
Warfarin, Sodium Tablets
ER - Extended Release
DR - Delayed Release
Appendix A 371

Appendix B
Guidance for Industry1—
SUPAC-MR: Modified Release
Solid Oral Dosage Forms
Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls;
In Vitro Dissolution Testing and In Vivo
Bioequivalence Documentation
I. INTRODUCTION
This guidance provides recommendations to pharmaceutical sponsors of new
drug applications (NDAs), abbreviated new drug applications (ANDAs), and abbreviated
antibiotic drug applications (AADAs) who intend to change (1) the
components or composition, (2) the site of manufacture, (3) the scale-up/scaledown
of manufacture, and/or (4) the manufacturing (process and equipment) of
a modified release solid oral dosage form during the postapproval period. The
guidance defines (1) levels of change, (2) recommended chemistry, manufacturing,
and controls (CMC) tests for each level of change, (3) recommended in
vitro dissolution tests and/or in vivo bioequivalence tests for each level of
373
1 This guidance has been prepared by the Scale-up and Postapproval Change Modified Release (SUPAC-
MR) Working Group operating under the direction of the Chemistry Manufacturing Controls
Coordinating Committee (CMC CC) and the Biopharmaceutics Coordinating Committee (BCC) in
the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA).
This guidance represents the Agency’s current thinking on modified release solid oral dosage forms
scale-up and postapproval changes. It does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. An alternative approach may be used if such approach
satisfies the requirement of the applicable statute, regulations, or both.
change; and (4) documentation that should support the change. This guidance
specifies application information that should be provided to the Center for Drug
Evaluation and Research (CDER) to ensure continuing product quality and performance
characteristics of a modified release solid oral dose formulation for
specified postapproval changes.
This guidance does not comment on or otherwise affect compliance/inspection
documentation that has been defined by CDER’s Office of Compliance or
FDA’s Office of Regulatory Affairs. This guidance does not affect any postapproval
changes other than the ones specified. For those changes filed in a Changes
Being Effected (CBE) supplement (21 CFR 314.70(c)), the FDA may, after a review
of the supplemental information, decide that the changes are not approvable.
For changes not addressed in this guidance, or for multiple changes submitted at
one time or over a short period of time, sponsors should contact the appropriate
CDER review division or consult other CDER guidances to obtain information
about tests and application documentation. FDA regulations at 21 CFR 314.70(a)
provide that applicants may make changes to an approved application in accordance
with a guidance, notice, or regulation published in the Federal Register that
provides for a less burdensome notification of the change (for example, by notification
at the time a supplement is submitted or in the next annual report). This guidance
permits less burdensome notice of certain postapproval changes within the
meaning of § 314.70(a). For postapproval changes for modified release solid oral
dosage forms that affect components and composition, scale-up/scale-down, site
change, and manufacturing process or equipment changes, this guidance supersedes
the recommendations in section 4.G of the Office of Generic Drugs (OGD)
Policy and Procedure Guide 22–90 (September 11, 1990). For all other dosage
forms and changes, this guidance does not affect the recommendations in Guide
22–90.
II. GENERAL STABILITY CONSIDERATIONS
The effect SUPAC-type changes have on the stability of the drug product should
be evaluated. For general guidance on conducting stability studies, applicants are
referred to the FDA Guideline for Submitting Documentation for the Stability of
Human Drugs and Biologics (02/87). For SUPAC submissions, the following
points also should be considered:
• In most cases (except those involving scale up), stability data from pilot
scale batches will be acceptable to support the proposed change.
• Where stability data show a trend toward potency loss or degradant increase
under accelerated conditions, it is recommended that historical
accelerated stability data from a representative prechange batch be sub-
374 Appendix B
mitted for comparison. It is also recommended that under these circumstances,
all available long-term data on test batches from ongoing studies
be provided in the supplement. Submission of historical accelerated and
available long-term data would facilitate review and approval of the
supplement.
• A commitment should be included to conduct long-term stability studies
through the expiration dating period, according to the approved protocol,
on the first or first three (see text for details) production batches and to report
the results in the annual reports.
III. COMPONENTS AND COMPOSITION—NONRELEASE
CONTROLLING EXCIPIENT
This section of the guidance focuses on changes in nonrelease controlling excipients
in the drug product. For modified release solid oral dosage forms, consideration
should be given as to whether the excipient is critical or not critical
to drug release. The sponsor should provide appropriate justifications for claiming
any excipient(s) as a nonrelease controlling excipient in the formulation of
the modified release solid oral dosage form. The functionality of each excipient
should be identified. Changes in the amount of the drug substance are not addressed
by this guidance. Changes in components or composition that have the
effect of adding a new excipient or deleting an excipient are defined at level 3
(defined below), except as described below in Section III.A.1.a. Waiver of bioequivalence
testing for a change in composition which involves only a different
color, flavor or preservative may be permissible as described in 21 CFR
320.22(d)(4).
A. Level 1 Change
1. Definition of Level
Level 1 changes are those that are unlikely to have any detectable impact on formulation
quality and performance.
Examples:
a. Deletion or partial deletion of an ingredient intended to affect the color
or flavor of the drug product; or change in the ingredient of the printing
ink to another approved ingredient.
b. Changes in nonrelease controlling excipients, expressed as percentage
(w/w) of total formulation, less than or equal to the following percent
ranges:
Appendix B 375
Nonrelease controlling Percent excipient (w/w) out of total
excipient target dosage from weight
Filler 5
Disintegrant
Starch 3
Other 1
Binder 0.5
Lubricant
Ca or Mg Stearate 0.25
Other 1
Glidant
Talc 1
Other 0.1
Film Coat 1
These percentages are based on the assumption that the drug substance in
the product is formulated to 100% of label/potency. The total additive effect of all
nonrelease controlling excipient changes should not be more than 5%.2 The total
weight of the dosage form should still be within the original approved application
range.
The components (active and excipients) in the formulation should have numerical
targets that represent the nominal composition of the drug product on
which any future changes in the composition of the product are to be based.
Allowable changes in the composition should be based on the original approved
target composition and not on previous level 1 changes in the composition. For
products approved with only a range for excipients, the target value may be assumed
to be the midpoint of the original approved application range.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements.
Stability: First production batch on long-term stability data reported in annual
report.
b. Dissolution Documentation. None beyond application/compendial
requirements.
c. Bioequivalence Documentation. None.
376 Appendix B
2 Example: In a product consisting of active ingredient A, lactose, microcrystalline cellulose, and magnesium
stearate, the lactose and microcrystalline cellulose should not vary by more than an absolute
total of 5% (e.g., lactose increases by 2.5% and microcrystalline cellulose decreases by 2.5%) relative
to the target dosage form weight if it is to stay within the level 1 range.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Level 2 changes are those that could have a significant impact on formulation
quality and performance.
Examples:
a. A change in the technical grade and/or specifications of a nonrelease
controlling excipient3
b. Changes in nonrelease controlling excipients, expressed as percentage
(w/w) of total formulation, greater than those listed above for a level 1
change, but less than or equal to the following percent ranges (which
represent a two-fold increase over level 1 changes):
Nonrelease controlling Percent excipient (w/w) out of total
excipient target dosage from weight
Filler 10
Disintegrant
Starch 6
Other 2
Binder 1
Lubricant
Ca or Mg Stearate 0.5
Other 2
Glidant
Talc 2
Other 0.2
Film Coat 2
These percentages are based on the assumption that the drug substance in
the drug product is formulated to 100% of label/potency. The total additive effect
of all nonrelease controlling excipient changes should not change by more than
10%. The total weight of the dosage form could still be within or outside the original
approved application range.
Appendix B 377
3 Example: Avicel PH102 vs. Avicel PH200.
The components (active and excipients) in the formulation should have numerical
targets that represent the nominal composition of the product on which
any future changes in the composition of the product are to be based. Allowable
changes in the composition are based on the original approved target composition
and not on the composition based on previous level 1 or level 2 changes. For products
approved with only a range for excipients, the target value may be assumed
to be the midpoint of the original approved application range.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and updated executed batch records.
Stability: One batch with three months accelerated stability data reported in
prior approval supplement and long-term stability data of first production batch
reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, multipoint dissolution profiles should be
obtained in three other media, for example, in water, 0.1N HCl, and USP buffer
media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed
batch (unchanged drug product). Adequate sampling should be performed,
for example, at 1, 2, and 4 hours and every two hours thereafter until either 80%
of the drug from the drug product is released or an asymptote is reached. A surfactant
may be used with appropriate justification.
Delayed release: In addition to application/compendial release requirements,
dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage)
followed by testing in USP buffer media, in the range of pH 4.5–7.5 (buffer stage)
under standard (application/compendial) test conditions and two additional agitation
speeds using the application/ compendial test apparatus (three additional test
conditions). If the application/compendial test apparatus is the rotating basket
method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and
if the application/compendial test apparatus is the rotating paddle method (Apparatus
2), a rotation speed of 50, 75, and 100 rpm may be used. Multipoint dissolution
profiles should be obtained during the buffer stage of testing. Adequate sampling
should be performed, for example, at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
The above dissolution testing should be performed using the changed drug product
and the biobatch or marketed batch (unchanged drug product).
All modified release solid oral dosage forms: In the presence of an established
in vitro/in vivo correlation (6), only application/compendial dissolution
testing need be performed (i.e., only in vitro release data by the correlating method
378 Appendix B
need to be submitted). The dissolution profiles of the changed drug product and
the biobatch or marketed batch (unchanged drug product) should be similar. The
sponsor should apply appropriate statistical testing with justifications (e.g., the f
equation) for comparing 2 dissolution profiles (5). Similarity testing for the two
dissolution profiles (i.e., for the unchanged drug product and the changed drug
product) obtained in each individual medium is appropriate.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
C. Level 3 Change
1. Definition of Level
Level 3 changes are those that are likely to have a significant impact on formulation
quality and performance.
Example:
a. Changes in the nonrelease controlling excipient range beyond those
listed in Section III.B.1.b. The total weight of the dosage form may be
within or outside the approved original application range.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and updated executed batch records.
Stability: Significant body of information available: One batch with three
months’ accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report..
Significant body of information not available: Three batches with three
months’ accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, a multipoint dissolution profile should be
obtained using the application/compendial test conditions for the changed drug
product and the biobatch or marketed batch (unchanged drug product). Adequate
sampling should be performed, for example, at 1, 2, and 4 hours and every two
hours thereafter, until either 80% of the drug from the drug product is released or
an asymptote is reached.
Delayed release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained during the buffer stage
Appendix B 379
of testing using the application/compendial test conditions for the changed drug
product and the biobatch or marketed batch (unchanged drug product). Adequate
sampling should be performed, for example at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
c. Bioequivalence Documentation. A single-dose bioequivalence study
(3). The bioequivalence study may be waived in the presence of an established in
vitro/in vivo correlation (6).
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
IV. COMPONENTS AND COMPOSITION—RELEASE
CONTROLLING EXCIPIENT
This section of the guidance focuses on changes in release controlling excipients
in the drug product. For modified release solid oral dosage forms, consideration
should be given as to whether or not the excipient is critical to drug release. The
sponsor should provide appropriate justifications (i.e., mechanism of drug release
and manufacturing process) for claiming any excipient(s) as a release controlling
excipient in the formulation of the modified release solid oral dosage form. The
functionality of each excipient should be identified. Changes in the amount of the
drug substance are not addressed by this guidance. Changes exceeding the ranges
defined in each of the levels below may be allowed if considered to be within
normal batch-to-batch variation and contained within an approved original application.
In such situations, sponsors should contact the appropriate CDER review
division for further guidance.
A. Level 1 Change
1. Definition of Level
Level 1 changes are those that are unlikely to have any detectable impact on formulation
quality and performance.
Example:
a. Changes in the release controlling excipient(s), expressed as percentage
(w/w) of total release controlling excipient(s) in the formulation less
than or equal to 5% w/w of total release controlling excipient content in
the modified release solid oral dosage form.
380 Appendix B
The drug substance in the product is formulated to 100% of label/potency.
The total additive effect of all release controlling excipient changes should not be
more than 5% w/w of the total release controlling excipients in the original approved
formulation.4 The total weight of the dosage form should still be within the
4 approved original application range.
The components (active and excipients) in the formulation should have numerical
targets that represent the nominal composition of the product on which
any future changes in the composition of the product are to be based. Allowable
changes in the composition should be based on the original approved target composition
and not on previous level 1 changes in the composition. For products approved
with only a range for excipients, the target value may be assumed to be the
midpoint of the original approved application range.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements.
Stability: First production batch on long-term stability data reported in annual
report.
b. Dissolution Documentation. None beyond application/compendial
requirements.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Level 2 changes are those that could have a significant impact on formulation
quality and performance. Test documentation for a level 2 change would vary de-
Appendix B 381
4 Example: In a product consisting of active ingredient A, ethylcellulose and a plasticizer, the ethylcellulose
and plasticizer content should not vary by more than an absolute total of 5% w/w of the total
release controlling excipients (e.g., ethylcellulose content increases by 2.5% and plasticizer content
increases by 2.5%) relative to the original approved total release controlling excipient content
weight in the modified release solid oral dosage form if it is to stay within the given range allowed
for level 1.
pending on whether the product could be considered to have a narrow therapeutic
range.5
Examples:
a. Change in the technical grade and/or specifications of the release controlling
excipient(s).6
b. Changes in the release controlling excipient(s), expressed as percentage
(w/w) of total release controlling excipient(s) in the formulation,
greater than those listed above for a level 1 change, but less than or
equal to 10% w/w of total release controlling excipient content in the
modified release solid oral dosage form.
The drug substance in the drug product is formulated to 100% of label/potency.
The total additive effect of all release controlling excipient changes should
not be more than 10% w/w of the total release controlling excipient(s) in the original
approved formulation. The total weight of the dosage form could still be
within or outside the approved original application range.
The components (active and excipients) in the formulation should have numerical
targets that represent the nominal composition of the product on which
any future changes in the composition of the product are to be based. Allowable
changes in the composition are based on the original approved target composition
and not on the composition based on previous level 1 or level 2 changes. For products
approved with only a range for excipients, the target value may be assumed
to be the midpoint of the original approved application range.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and updated executed batch records.
Stability:
• Nonnarrow therapeutic range drugs: One batch with three months’ accelerated
stability data reported in prior approval supplement and long-term
stability data of first production batch reported in annual report.
382 Appendix B
5 At present, there is no official CDER list of narrow therapeutic range drugs. A list was developed
earlier in a preliminary attempt to identify drugs where there was greater concern that deviation from
the specifications and potential changes in bioavailability could raise clinical issues. This preliminary
list was not based solely on 21 CFR 320.33(c) which is contained in a section of the regulations
related to criteria and evidence to assess actual or potential bioequivalence problems, nor does it accurately
reflect the Agency’s opinion on narrow therapeutic range drugs. Currently, the issue of narrow
therapeutic range drugs is under discussion within CDER. If unsure about the classification of a
drug as a narrow therapeutic range drug, sponsors should contact the appropriate CDER review division.
6 Example: Eudragit RS-100 vs. Eudragit RL-100.
• Narrow therapeutic range drugs: Three batches with three months’ accelerated
stability data reported in prior approval supplement and long-term
stability data of first three production batches reported in annual report.
b. Dissolution Documentation.
• Nonnarrow therapeutic range drugs
Extended release: In addition to application/compendial release requirements,
multipoint dissolution profiles should be obtained in three other media, for
example, in water, 0.1N HCl, and USP buffer media at pH 4.5, and 6.8 for the
changed drug product and the biobatch or marketed batch (unchanged drug product).
Adequate sampling should be performed, for example, at 1, 2, and 4 hours
and every two hours thereafter until either 80% of the drug from the drug product
is released or an asymptote is reached. A surfactant may be used with appropriate
justification.
Delayed release: In addition to application/compendial release requirements,
dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage)
followed by testing in USP buffer media in the range of pH 4.5–7.5 (buffer stage)
under standard (application/compendial) test conditions and two additional agitation
speeds using the application/compendial test apparatus (three additional test
conditions). If the application/compendial test apparatus is the rotating basket
method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and
if the application/compendial test apparatus is the rotating paddle method (Apparatus
2), a rotation speed of 50, 75, and 100 rpm may be used. Multipoint dissolution
profiles should be obtained during the buffer stage of testing. Adequate sampling
should be performed, for example, at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
The above dissolution testing should be performed using the changed drug product
and the biobatch or marketed batch (unchanged drug product).
All modified release solid oral dosage forms: In the presence of an established
in vitro/in vivo correlation (6), only application/compendial dissolution
testing should be performed (i.e., only in vitro release data by the correlating
method should be submitted). The dissolution profiles of the changed drug product
and the biobatch or marketed batch (unchanged drug product) should be similar.
The sponsor should apply appropriate statistical testing with justifications
(e.g., the f equation) for comparing dissolution profiles (5). Similarity testing for
the two dissolution profiles (i.e., for the unchanged drug product and the changed
drug product) obtained in each individual medium is appropriate.
• Narrow therapeutic range drugs
Extended release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained in application/compen-
Appendix B 383
dial medium for the changed drug product and the biobatch or marketed batch (unchanged
drug product). Adequate sampling should be performed, for example at
1, 2, and 4 hours and every two hours thereafter until either 80% of the drug from
the drug product is released or an asymptote is reached.
Delayed release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained during the buffer stage
of testing using the application/compendial medium for the changed drug product
and the biobatch or marketed batch (unchanged drug product). Adequate sampling
should be performed, for example, at 15, 30, 45, 60, and 120 minutes (following
the time from which the dosage form is placed in the buffer) until either 80% of
the drug from the drug product is released or an asymptote is reached.
c. Bioequivalence Documentation.
• Nonnarrow therapeutic range drugs: None.
• Narrow therapeutic range drugs: A single-dose bioequivalence study (3).
The bioequivalence study may be waived in the presence of an established
in vitro/in vivo correlation (6). Changes in release controlling excipients
in the formulation should be within the range of release controlling
excipients of the established correlation.
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
C. Level 3 Change
1. Definition of Level
Level 3 changes are those that are likely to have a significant impact on formulation
quality and performance affecting all therapeutic ranges of the drug.
Examples:
a. Addition or deletion of release controlling excipient(s) (e.g., release
controlling polymer/plasticizer).
b. Changes in the release controlling excipient(s), expressed as percentage
(w/w) of total release controlling excipient(s) in the formulation,
greater than those listed above for a level 2 change (i.e., greater than
10% w/w of total release controlling excipient content in the modified
release solid oral dosage form). Total weight of the dosage form may be
within or outside the original approved application range.
384 Appendix B
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and updated executed batch records.
Stability: Three batches with three months’ accelerated stability data reported
in prior approval supplement and long-term stability data of first three production
batches reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, a multipoint dissolution profile should be
obtained using application/compendial test conditions for the changed drug
product and the biobatch or marketed batch (unchanged drug product). Adequate
sampling should be performed, for example at 1, 2, and 4 hours and every two
hours thereafter until either 80% of the drug from the drug product is released or
an asymptote is reached.
Delayed release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained during the buffer stage
of testing using the application/compendial test conditions for the changed drug
product and the biobatch or marketed batch (unchanged drug product). Adequate
sampling should be performed, for example at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
c. Bioequivalence Documentation. A single-dose bioequivalence study
(3). The bioequivalence study may be waived in the presence of an established in
vitro/in vivo correlation (6). Changes in release controlling excipients in the formulation
should be within the range of release controlling excipients of the established
correlation.
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
V. SITE CHANGES
Site changes consist of changes in location of the site of manufacture, packaging
operations, and/or analytical testing laboratory for both company-owned and contract
manufacturing facilities. They do not include any scale-up changes, changes
in manufacturing (including process and/or equipment), or changes in components
or composition. New manufacturing locations should have had a satisfactory
current good manufacturing practice (cGMP) inspection.
Appendix B 385
A stand-alone packaging operations site change, using container(s)/closure(
s) in the approved application, may be submitted as a Changes Being Effected
supplement. The facility should also have a current and satisfactory cGMP
compliance profile with the FDA for the type of packaging operation in question
before submitting the supplement. If the facility has not received a satisfactory
cGMP inspection for the type of packaging operation in question, a prior approval
supplement is recommended. The supplement should contain a written certification
from the packaging facility stating that it is in conformance with cGMPs. It
should also contain a commitment to place the first production batch of the product,
and annual batches thereafter, on long-term stability studies using the approved
protocol in the application and to submit the resulting data in annual reports.
Where the product is available in more than one strength, size, or
container/closure system, one lot of each combination should be placed on longterm
stability studies. Bracketing or matrixing is allowed only if it has been approved
previously by the FDA. Any changes to an approved stability protocol
should have a supplemental approval prior to the initiation of the stability study.
A stand-alone analytical testing laboratory site change may be submitted as
a Changes Being Effected supplement if the new facility has a current and satisfactory
cGMP compliance profile with the FDA for the type of testing operation
in question. The supplement should contain a commitment to use the same test
methods employed in the approved application, written certification from the
testing laboratory stating that they are in conformance with cGMPs, and a full description
of the testing to be performed by the testing lab. If the facility has not
received a satisfactory cGMP inspection for the type of testing involved, a prior
approval supplement is recommended.
A. Level 1 Change
1. Definition of Level
Level 1 changes consist of site changes within a single facility where the same
equipment, standard operating procedures (SOPs), environmental conditions
(e.g., temperature and humidity) and controls, and personnel common to both7
manufacturing sites are used and where no changes are made to the executed batch
records, except for administrative information and the location of the facility.
2. Test Documentation
a. Chemistry Documentation. None beyond application/compendial
product release requirements.
386 Appendix B
7 Common is defined as employees already working on the campus who have suitable experience with
the manufacturing process.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Annual report.
B. Level 2 Change
1. Definition of Level
Level 2 changes consist of site changes within a contiguous campus, or between
facilities in adjacent city blocks, where the same equipment, SOPs, environmental
conditions (e.g., temperature and humidity) and controls, and personnel
common7 to both manufacturing sites are used and where no changes are made to
the executed batch records, except for administrative information and the location
of the facility.
2. Test Documentation
a. Chemistry Documentation. Notification of location of new site and
updated executed batch records. None beyond application/compendial product release
requirements. Stability: One batch with three months accelerated stability
data reported in Changes Being Effected supplement and long-term stability data
of first production batch reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, multipoint dissolution profiles should be
obtained in three other media, for example, in water, 0.1N HCl, and USP buffer
media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed
batch (unchanged drug product). Adequate sampling should be performed,
for example at 1, 2, and 4 hours and every two hours thereafter until either 80% of
the drug from the drug product is released or an asymptote is reached. A surfactant
may be used with appropriate justification. Delayed release: In addition to application/
compendial release requirements, dissolution tests should be performed
in 0.1 N HCl for 2 hours (acid stage) followed by testing in USP buffer media, in
the range of pH 4.5–7.5 (buffer stage) under standard (application/compendial)
test conditions and two additional agitation speeds using the application/ compendial
test apparatus (three additional test conditions). If the application/compendial
test apparatus is the rotating basket method (Apparatus 1), a rotation speed
of 50, 100, and 150 rpm may be used, and if the application/compendial test apparatus
is the rotating paddle method (Apparatus 2), a rotation speed of 50, 75, and
100 rpm may be used.
Appendix B 387
Multipoint dissolution profiles should be obtained during the buffer stage
of testing. Adequate sampling should be performed, for example, at 15, 30, 45,
60, and 120 minutes (following the time from which the dosage form is placed in
the buffer) until either 80% of the drug from the drug product is released or
an asymptote is reached. The above dissolution testing should be performed using
the changed drug product and the biobatch or marketed batch (unchanged
drug product).
All modified release solid oral dosage forms: In the presence of an established
in vitro/in vivo correlation (6), only application/compendial dissolution
testing should be performed (i.e., only in vitro release data by the correlating
method should be submitted). The dissolution profiles of the changed drug product
and the biobatch or marketed batch (unchanged drug product) should be similar.
The sponsor should apply appropriate statistical testing with justifications
(e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity testing for
the two dissolution profiles (i.e., for the unchanged drug product and the changed
drug product) obtained in each individual medium is appropriate.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Changes Being Effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
C. Level 3 Change
1. Definition of Level
Level 3 changes consist of a change in manufacturing site to a different campus.
A different campus is defined as one that is not on the same original contiguous
site or where the facilities are not in adjacent city blocks. To qualify as a level 3
change, the same equipment, SOPs, environmental conditions, and controls
should be used in the manufacturing process at the new site, and no changes may
be made to the executed batch records except for administrative information, location
and language translation, where needed.
2. Test Documentation
a. Chemistry Documentation. Notification of location of new site and
updated executed batch records. Application/compendial product release
requirements.
Stability: Significant body of information available: One batch with three
months’ accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report.
388 Appendix B
Significant body of information not available: Three batches with three
months’ accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, a multipoint dissolution profile should be
obtained using application/compendial test conditions for the changed drug product
and the biobatch or marketed batch (unchanged drug product). Adequate sampling
should be performed, for example at 1, 2, and 4 hours and every two hours
thereafter until either 80% of the drug from the drug product is released or an
asymptote is reached.
Delayed release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained during the buffer stage
of testing using the application/compendial test conditions for the changed drug
product and the biobatch or marketed batch (unchanged drug product). Adequate
sampling should be performed, for example, at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
c. Bioequivalence Documentation. A single-dose bioequivalence study
(3). The bioequivalence study may be waived in the presence of an established in
vitro/in vivo correlation (6).
3. Filing Documentation
Prior approval supplement (all information including accelerated stability test
data); annual report (long-term stability data).
VI. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-DOWN)
Postapproval changes in the size of a batch from the pivotal/pilot scale biobatch
material to larger or smaller production batches call for submission of additional
information to the application. Scale-down below 100,000 dosage units is not covered
by this guidance. Adjustments in parameters such as mixing times and speeds
may be made to tailor the process to the characteristics of larger or smaller scale
equipment. All scale-up changes should be properly validated and, where needed,
inspected by appropriate Agency personnel.
A. Level 1 Change
1. Definition of Level
Change in batch size, up to and including a factor of ten times the size of the
pilot/biobatch, where (1) the equipment used to produce the test batch(es) may
Appendix B 389
vary in capacity, but are of the same design and operating principles; (2) the
batch(es) is manufactured in full compliance with cGMPs; and (3) the same standard
operating procedures (SOPs) and controls, as well as the same formulation
and manufacturing procedures, are used on the test batch(es) and on the full-scale
production batch(es).
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records in annual report. Stability: First production batch on long-term stability
data reported in annual report.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Changes in batch size beyond a factor of ten times the size of the pilot/biobatch
where (1) the equipment used to produce the test batch(es) is of the same design
and operating principles; (2) the batch(es) is manufactured in full compliance with
cGMPs; and (3) the same SOPs and controls as well as the same formulation and
manufacturing procedures are used on the test batch(es) and on the full-scale production
batch(es).
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated batch records.
Stability: One batch with three months’ accelerated stability data reported
in Changes Being Effected supplement and long-term stability data of first production
batch reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, multipoint dissolution profiles should be
obtained in three other media, for example, in water, 0.1N HCl, and USP buffer
media at pH 4.5, and 6.8 for the changed drug product and the biobatch or mar-
390 Appendix B
keted batch (unchanged drug product). Adequate sampling should be performed,
for example, at 1, 2, and 4 hours, and every two hours thereafter until either 80%
of the drug from the drug product is released or an asymptote is reached. A surfactant
may be used with appropriate justification.
Delayed release: In addition to application/compendial release requirements,
dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage)
followed by testing in USP buffer media in the range of pH 4.5–7.5 (buffer stage)
under standard (application/compendial) test conditions and two additional agitation
speeds using the application/ compendial test apparatus (three additional
test conditions). If the application/compendial test apparatus is the rotating basket
method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and
if the application/compendial test apparatus is the rotating paddle method
(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used. Multipoint
dissolution profiles should be obtained during the buffer stage of testing. Adequate
sampling should be performed, for example, at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until
either 80% of the drug from the drug product is released or an asymptote is
reached. The above dissolution testing should be performed using the changed
drug product and the biobatch or marketed batch (unchanged drug product).
All modified release solid oral dosage forms: In the presence of an established
in vitro/in vivo correlation (6), only application/compendial dissolution
testing should be performed (i.e., only in vitro release data by the correlating
method should be submitted). The dissolution profiles of the changed drug product
and the biobatch or marketed batch (unchanged drug product) should be similar.
The sponsor should apply appropriate statistical testing with justifications
(e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity testing for
the two dissolution profiles (i.e., for the unchanged drug product and the changed
drug product) obtained in each individual medium is appropriate.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Changes Being Effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
VII. MANUFACTURING EQUIPMENT CHANGES
Manufacturing changes may involve the equipment used in the manufacturing
process (critical manufacturing variable). If a manufacturer wishes to use manufacturing
equipment that is not identical in every respect to the original manufacturing
equipment used in the approved application, appropriate validation studies
Appendix B 391
should be conducted to demonstrate that the new equipment is similar to the original
equipment. For modified release solid oral dosage forms, consideration
should be given as to whether or not the change in manufacturing equipment is
critical to drug release (critical equipment variable).
A. Level 1 Change
1. Definition of Level
This category consists of (1) change from nonautomated or nonmechanical equipment
to automated or mechanical equipment to move ingredients and (2) change
to alternative equipment of the same design and operating principles of the same
or of a different capacity.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records.
Stability: First production batch on long-term stability data reported in annual
report.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Change in equipment to a different design and different operating principles.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records.
Stability:
Significant body of information available: One batch with three months’ accelerated
stability data reported in prior approval supplement and long-term stability
data of first three production batches reported in annual report.
392 Appendix B
Significant body of information not available: Three batches with three
months’ accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, multipoint dissolution profiles should be
obtained in three other media, for example, in water, 0.1N HCl, and USP buffer
media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed
batch (unchanged drug product). Adequate sampling should be performed,
for example, at 1, 2, and 4 hours and every two hours thereafter until either 80%
of the drug from the drug product is released or an asymptote is reached. A surfactant
may be used with appropriate justification.
Delayed release: In addition to application/compendial release requirements,
dissolution tests should be performed in 0.1 N HCl for 2 hours (acid stage)
followed by testing in USP buffer media, in the range of pH 4.5–7.5 (buffer stage)
under standard (application/compendial) test conditions and two additional agitation
speeds using the application/ compendial test apparatus (three additional test
conditions). If the application/compendial test apparatus is the rotating basket
method (Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and
if the application/compendial test apparatus is the rotating paddle method (Apparatus
2), a rotation speed of 50, 75, and 100 rpm may be used. Multipoint dissolution
profiles should be obtained during the buffer stage of testing. Adequate sampling
should be performed, for example, at 15, 30, 45, 60, and 120 minutes
(following the time from which the dosage form is placed in the buffer) until either
80% of the drug from the drug product is released or an asymptote is reached.
The above dissolution testing should be performed using the changed drug product
and the biobatch or marketed batch (unchanged drug product).
All modified release solid oral dosage forms: In the presence of an established
in vitro/in vivo correlation (6), only application/compendial dissolution
testing should be performed (i.e., only in vitro release data by the correlating
method should be submitted). The dissolution profiles of the changed drug product
and the biobatch or marketed batch (unchanged drug product) should be similar.
The sponsor should apply appropriate statistical testing with justifications
(e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity testing for
the two dissolution profiles (i.e., for the unchanged drug product and the changed
drug product) obtained in each individual medium is appropriate.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Prior approval supplement with justification for change (all information including
accelerated stability data); annual report (long-term stability data).
Appendix B 393
VIII. MANUFACTURING PROCESS CHANGES
Manufacturing changes may involve the manufacturing process itself (critical
manufacturing variable). If a manufacturer wishes to use a manufacturing process
that is not identical in every respect to the original manufacturing process used in
the approved application, appropriate validation studies should be conducted to
demonstrate that the new process is similar to the original process. For modified
release solid oral dosage forms, consideration should be given as to whether or not
the change in manufacturing process is critical to drug release (critical processing
variable). For purposes of categorizing the level of changes, process change may
be considered only to affect a release controlling excipient when both types of excipients
(i.e., nonrelease and release controlling) are present during the unit operation
undergoing a change.
A. Level 1 Change
1. Definition of Level
Process changes involving adjustment of equipment operating conditions such as
mixing times and operating speeds within original approved application ranges affecting
the nonrelease controlling and/or release controlling excipient(s). The
sponsor should provide appropriate justifications for claiming any excipient(s) as
a nonrelease controlling or a release controlling excipient in the formulation of the
modified release solid oral dosage form.
2. Test Documentation
a. Chemistry Documentation. None beyond application/compendial
product release requirements. Notification of the change and submission of the
updated executed batch records.
b. Dissolution Documentation. None beyond application/compendial
release requirements.
c. Bioequivalence Documentation. None.
3. Filing Documentation
Annual report.
B. Level 2 Change
1. Definition of Level
This category includes process changes involving adjustment of equipment operating
conditions such as mixing times and operating speeds outside of original approved
application ranges.
394 Appendix B
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records. Stability: One batch with three months’ accelerated stability data reported
in Changes Being Effected supplement and long-term stability data of first production
batch reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, multipoint dissolution profiles should be
obtained in three other media, for example, in water, 0.1N HCl, and USP buffer
media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed
batch (unchanged drug product). Adequate sampling should be performed,
for example at 1, 2, and 4 hours and every two hours thereafter until either 80% of
the drug from the drug product is released or an asymptote is reached. A surfactant
may be used with appropriate justification.
Delayed release: In addition to application/compendial release requirements,
dissolution tests should be performed in 0.1 N HCl for 2 hours (acid
stage) followed by testing in USP buffer media, in the range of pH 4.5–7.5
(buffer stage) under standard (application/compendial) test conditions and two
additional agitation speeds using the application/ compendial test apparatus
(three additional test conditions). If the application/compendial test apparatus is
the rotating basket method (Apparatus 1), a rotation speed of 50, 100, and 150
rpm may be used, and if the application/compendial test apparatus is the rotating
paddle method (Apparatus 2), a rotation speed of 50, 75, and 100 rpm may
be used. Multipoint dissolution profiles should be obtained during the buffer
stage of testing. Adequate sampling should be performed, for example, at 15, 30,
45, 60, and 120 minutes (following the time from which the dosage form is
placed in the buffer) until either 80% of the drug from the drug product is released
or an asymptote is reached. The above dissolution testing should be performed
using the changed drug product and the biobatch or marketed batch (unchanged
drug product).
All modified release solid oral dosage forms: In the presence of an
established in vitro/in vivo correlation (6), only application/compendial dissolution
testing should be performed (i.e., only in vitro release data by the correlating
method should be submitted). The dissolution profiles of the changed
drug product and the biobatch or marketed batch (unchanged drug product)
should be similar. The sponsor should apply appropriate statistical testing with
justifications (e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity
testing for the two dissolution profiles (i.e., for the unchanged drug product
and the changed drug product) obtained in each individual medium is
appropriate.
c. Bioequivalence Documentation. None.
Appendix B 395
3. Filing Documentation
Changes Being Effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
C. Level 3 Change
1. Definition of Level
This category includes change in the type of process used in the manufacture of
the product, such as a change from wet granulation to direct compression of dry
powder.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records.
Stability: Three batches with three months’ accelerated stability data reported
in prior approval supplement and long-term stability data of first three production
batches reported in annual report.
b. Dissolution Documentation. Extended release: In addition to application/
compendial release requirements, a multipoint dissolution profile should be
obtained using application/compendial test conditions for the changed drug product
and the biobatch or marketed batch (unchanged drug product). Adequate sampling
should be performed, for example at 1, 2, and 4 hours and every two hours
thereafter until either 80% of the drug from the drug product is released or an
asymptote is reached.
Delayed release: In addition to application/compendial release requirements,
a multipoint dissolution profile should be obtained during the buffer stage of testing
using the application/compendial test conditions for the changed drug product
and the biobatch or marketed batch (unchanged drug product). Adequate sampling
should be performed, for example at 15, 30, 45, 60, and 120 minutes (following the
time from which the dosage form is placed in the buffer) until either 80% of the
drug from the drug product is released or an asymptote is reached.
c. Bioequivalence Documentation. A single-dose bioequivalence study
(3). The bioequivalence study may be waived in the presence of an established in
vitro/in vivo correlation (6).
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
396 Appendix B
GLOSSARY OF TERMS
The following terms and their definitions (9) are being provided to assist the
reader in using this guidance document.
Batch: A specific quantity of a drug or other material produced according to a
single manufacturing order during the same cycle of manufacture and intended to
have uniform character and quality, within specified limits (21 CFR 210.3(b)(2)).
Batch Formula (Composition): A complete list of the ingredients and their
amounts to be used for the manufacture of a representative batch of the drug product.
All ingredients should be included in the batch formula whether or not they
remain in the finished product (1).
Biobatch: The lot of drug product formulated for purposes of pharmacokinetic
evaluation in a bioavailability/bioequivalency study. For modified release solid
oral, this batch should be 10% or greater than the proposed commercial production
batch or at least 100,000 units, whichever is greater.
Bioequivalence Studies for Modified Release Drug Product: Refer to the
OGD Guidance (3). The bioequivalence study should be conducted using the
reference listed drug (RLD) product and/or the innovator drug product as the reference
and the test product should be the product (generic or innovator) which has
undergone postapproval change.
Contiguous Campus: Continuous or unbroken site or a set of buildings in
adjacent city blocks.
Critical Equipment Variable: A specific design, operating principle, or automation
of equipment that can affect a specific performance variable critical to
the ultimate and predictable performance of the dosage form and its drug.
Critical Manufacturing Variable: Includes those manufacturing materials
(critical composition variable), methods, equipment, and processes that significantly
affect drug release, from the formulation (e.g., coating thickness, particle
size, crystal form, excipient type, concentrations and distribution, and tablet
hardness).
Critical Processing Variable: A specific step, unit process, or condition of a
unit process that can affect a specific performance variable critical to the ultimate
and predictable performance of the dosage form and its drug.
Delayed Release: Release of a drug (or drugs) at a time other than immediately
following oral administration.
Dissolution Testing: Extended release: Dissolution testing should be conducted
on 12 individual dosage units for the changed drug product and the biobatch
or marketed batch (unchanged drug product). The potential for pH dependence
of drug release from a modified release drug product is well recognized.
Multipoint dissolution profiles should be obtained using discriminating agitation
speed and medium. A surfactant may be used with appropriate justification. Early
Appendix B 397
sampling times of 1, 2, and 4 hours should be included in the sampling schedule
to provide assurance against premature release of the drug (dose dumping) from
the formulation. Differing sampling times should be justified to prevent premature
drug release. See current USP 23 NF 18, sections 711 and 724, for general
dissolution requirements. The general dissolution conditions to be followed
are shown below:
1. Apparatus: USP 23 Apparatus 1 (rotating basket)
USP 23 Apparatus 2 (rotating paddle)
USP 23 Apparatus 3 (reciprocating cylinder) *
USP 23 Apparatus 4 (flow-through cell) *
USP 23 Apparatus 7 (reciprocating disk) *
2. Rotation Speed: 50, 100, and 150 rpm (basket)
50, 75 and 100 rpm (paddle)
3. Temperature: 37  0.5 C°
4. Units To Be Tested: 12
5. Dissolution Volume: 500–1000 mL
6. Dissolution Medium: Aqueous media of various pH.
7. Sampling Schedule: Adequate sampling should be performed, for example
at 1, 2, and 4 hours, and every two hours thereafter until either
80% of the drug is released or an asymptote is reached.
8. Tolerances: As established.
9. Content Uniformity: Content uniformity testing of the proposed product
lot should be performed as described in USP 23.
When using USP 23 Apparatus 3 (reciprocating cylinder), USP 23 Apparatus
4 (flow- * through cell), or USP 23 Apparatus 7 (reciprocating
disk) the above dissolution testing conditions should be modified accordingly.
Delayed release: For enteric coated drug products, drug release procedures
described in USP 23 NF 18, sections 711 and 724 should be followed.
When the guidance refers to dissolution testing in addition to application/compendial
release requirements, the dissolution test should be performed in 0.1N
HCl for 2 hours (acid stage) followed by testing in USP buffer media, in the range
of pH 4.5–7.5 (buffer stage) under standard (application/compendial) test conditions
and increased agitation speeds using the application/ compendial test apparatus.
For the rotating basket method (Apparatus 1), a rotation speed of 50, 100,
and 150 rpm may be used and for the rotating paddle method (Apparatus 2), a
rotation speed of 50, 75, and 100 rpm may be studied. Multipoint dissolution profiles
should be obtained during the buffer stage of testing. Adequate sampling
should be performed, for example, at 15, 30, 45, 60, and 120 minutes (following
the time from which the dosage form is placed in the buffer) until either 80% of
the drug is released or an asymptote is reached. The above dissolution testing
398 Appendix B
should be performed using the changed drug product and the biobatch or marketed
batch (unchanged drug product).
Drug Product: A drug product is a finished dosage form (e.g., tablet and capsule)
that contains a drug substance, generally, but not necessarily, in association
with one or more other ingredients (21 CFR 314.3(b)). A solid oral dosage form
includes but is not limited to tablets, chewable tablets, enteric coated tablets, capsules,
caplets, encapsulated beads, and gelcaps.
Drug Substance: An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of a disease, or to affect the structure of any function of the human
body, but does not include intermediates used in the synthesis of such ingredient
(21 CFR 314.3(b)).
Enteric Coated: Intended to delay the release of the drug (or drugs) until the
dosage form has passed through the stomach. Enteric coated products are delayed
release dosage forms.
Equipment: Automated or nonautomated, mechanical or nonmechanical
equipment used to produce the drug product, including equipment used to package
the drug product.
Extended Release: Extended release products are formulated to make the drug
available over an extended period after ingestion. This allows a reduction in dosing
frequency compared to a drug presented as a conventional dosage form (e.g.,
as a solution or an immediate release dosage form).
Formulation: A listing of the ingredients and composition of the dosage form.
Immediate Release: Allows the drug to dissolve in the gastrointestinal contents,
with no intention of delaying or prolonging the dissolution or absorption of the drug.
In Vitro Dissolution Profile Comparison: Model Independent Approach Using
Similarity Factor: Dissolution profiles may be compared using the following
equation that defines a similarity factor (f2):
f2 
 50 LOG {[11/n ?nt

1 (Rt Tt)2 ]0.5  100}
where LOG 
 logarithm to base 10, n 
 number of sampling time points, ? 

summation over all time points, Rt 
 dissolution at time point t of the reference
(unchanged drug product, i.e., pre- change batch), Tt 
 dissolution at time point t
of the test (changed drug product, i.e., post-change batch) (5 and 8).
For comparison of multipoint dissolution profiles obtained in multiple media,
similarity testing should be performed using pairwise dissolution profiles
(i.e., for the unchanged and changed product) obtained in each individual medium.
It is recommended that only one point past the plateau of the profiles be used in
calculating the f2 value. A correction for a lag time prior to similarity testing
should not be performed unless justified.
An f value between 50 and 100 suggests the two dissolution profiles are
similar. Also, the 2 average difference at any dissolution sampling time point
Appendix B 399
should not be greater than 15% between the changed drug product and the biobatch
or marketed batch (unchanged drug product) dissolution profiles. An appropriate
reference for this comparison should represent an average dissolution
profile derived from at least three consecutive recent batches of the unchanged
drug product (biobatch or marketed batch). Finally, the dissolution data obtained
under the application/compendial dissolution testing conditions (media, agitation,
etc.), on both the changed drug product and the biobatch or marketed batch
(unchanged drug product) should be within the application/compendial specifications.
An f2 value less than 50 does not necessarily indicate lack of similarity. If
the sponsor is of the opinion that the differences observed related to this calculation
of f2 are typical for the drug product involved in this SUPAC situation, an
appropriate justification can be submitted, but only as part of a prior approval supplement.
This justification should include additional data to support the claim
of similarity, as well as supporting statistical analysis (e.g. 90% confidence interval
analysis). If this justification is not found acceptable, the potential effect of
the proposed change on the differences in dissolution on bioavailability should
be determined.
Dissolution profiles can also be compared using other model independent or
model dependent methods (5).
In Vitro–In Vivo Correlation: A predictive mathematical model
describing the relationship between an in vitro property of an oral dosage form
(usually the rate or extent of drug dissolution or release) and a relevant in vivo response
(e.g., plasma drug concentration or amount of drug absorbed).
For modified release dosage forms, changes in release controlling excipients
in the formulation should be within the range of release controlling excipients
of the established correlation. In the presence of an established in vitro/in vivo correlation
(6), only application/ compendial dissolution testing need be performed.
Also, an established in vitro/in vivo correlation can be used for any level of
changes described in this guidance.
Justification: Reports containing scientific data and expert professional judgment
to substantiate decisions.
Lot: A batch or a specific identified portion of a batch, having uniform character
and quality within specified limits or, in the case of a drug product produced
by continuous process, a specific identified amount produced in a unit of time or
quantity in a manner that assures its having uniform character and quality within
specified limits (21 CFR 210.3(b)(10)).
Modified Release Dosage Forms: Dosage forms whose drug-release characteristics
of time course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by conventional dosage forms such as a solution
or an immediate release dosage form. Modified release solid oral dosage
forms include both delayed and extended release drug products.
400 Appendix B
Nonrelease Controlling Excipient (Non-Critical Composition Variable: An
excipient in the final dosage form whose primary function does not include modifying
the duration of release of the active drug substance from the dosage form.
Operating Principles: Rules or concepts governing the operation of the system.
Pilot Scale: The manufacture of either drug substance or drug product by a procedure
fully representative of and simulating that used for full manufacturing scale.
For solid oral dosage forms this is generally taken to be, at a minimum, one tenth
that of full production, or 100,000 tablets or capsules, whichever is larger (4).
Process: A series of operations, actions and controls used to manufacture a drug
product.
Ranges: The extent to which or the limits between which acceptable variation
exists.
Release Controlling Excipient (Critical Composition Variable): An excipient
in the final dosage form whose primary function is to modify the duration of
release of the active drug substance from the dosage form.
Release Mechanism: The process by which the drug substance is released from
the dosage form. Typically the definition contains the energy source or pictorially
describes the way the drug is released.
Representative: Corresponding to or replacing some other species or the like;
exemplifying a group or kind; typical.
Same: Agreeing in kind, amount; unchanged in character or condition.
Satisfactory Current Good Manufacturing Practice (cGMP) Inspection: A
satisfactory cGMP inspection is one during which (1) no objectionable conditions
or practices were found during an inspection or (2) objectionable conditions
were found, however, corrective action is left to the firm to take voluntarily
and the objectionable conditions do not justify further administrative or
regulatory actions.
Scale-up: The process of increasing the batch size.
Scale-down: The process of decreasing the batch size.
Significant Body of Information:
• Immediate Release Solid Oral Dosage Forms: A significant body of information
on the stability of the drug product is likely to exist after five
years of commercial experience for new molecular entities, or three years
of commercial experience for new dosage forms.
• Modified Release Solid Oral Dosage Forms: A significant body of information
should include, for “Modified Release Solid Oral Dosage Forms,”
a product-specific body of information. This product-specific body of information
is likely to exist after five years of commercial experience for
the original modified release solid oral drug product, or three years of
commercial experience for any subsequent modified release solid oral
drug product utilizing similar drug release mechanism.
Appendix B 401
Similar: Having a general likeness.
Technical Grade: Technical grades of excipients may differ in (1) specifications
and/or functionality, (2) impurities, and (3) impurity profiles.
Validation: Establishing through documented evidence a high degree of assurance
that a specific process will consistently produce a product that meets its predetermined
specifications and quality attributes. A validated manufacturing process
is one that has been proven to do what it purports or is represented to do. The
proof of validation is obtained through collection and evaluation of data, preferably
beginning from the process development phase and continuing through into
the production phase. Validation necessarily includes process qualification (the
qualification of materials, equipment, systems, buildings, and personnel), but it
also includes the control of entire processes for repeated batches or runs.
REFERENCES
1. FDA, Guideline for Submitting Documentation for the Manufacture of and Controls
for Drug Products, February 1987.
2. FDA, “Interim Policy on Exceptions to the Batch-Size and Production Condition Requirements
for Non-Antibiotic, Solid, Oral-Dosage Form Drug Products Supporting
Proposed ANDA’s” Policy and Procedure Guide #22–90, September 13, 1990.
Office of Generic Drugs, CDER, September 13, 1990.
3. FDA, Oral Extended (Controlled) Release Dosage Forms In Vivo Bioequivalence and
In Vitro Dissolution Testing, September 1993.
4. FDA, Stability Testing of New Drug Substances and Products; ICH Guideline, Federal
Register, Vol. 59, No. 183, 48754–48759, September 1994.
5. FDA, Guidance for Dissolution Testing of Immediate Release Solid Oral Products,
1997.
6. FDA, Guidance for the Development, Evaluation and Application of In Vitro/In Vivo
Correlations for Extended Release Solid Oral Dosage Forms, 1997.
7. FDA/University of Maryland Manufacturing Research Contract Summary.
8. Moore, J. W. and H. H. Flanner, “Mathematical Comparison of Dissolution Profiles,”
Pharmaceutical Technology, 6:64–74, 1996.
9. Skelly, J. P., et al., “Workshop Report: Scaleup of Oral Extended-Release Dosage
Forms,” Pharmaceutical Research, 10(12): 1800–1805, 1993.
402 Appendix B
Appendix B 403
A-1 Extended Release Solid Oral Dosage Forms Non-release Controlling Components
and Composition
Therapeutic Filing
Level Classification range Test documentation documentation
I -Complete or partial All drugs -Stability -Annual report
deletion of color/ -Application/ compendial
flavor requirements
-Change in inks, imprints -No biostudy
-Up to SUPAC- IR level 1
excipient ranges
-No other changes
II -Change in technical All drugs -Notification & updated batch -Prior approval
grade and/ or record supplement
specifications -Stability
-Higher than SUPAC- IR -Application/ compendial
level 1 but less than requirements plus multilevel
2 excipient ranges point dissolution profiles
-No other changes in three other media (e. g.,
water, 0.1N HCL, and USP
buffer media at pH 4.5 and
6.8) until 
 80% of drug
released or an asymptote is
reached1
-Apply some statistical test
(f2 test) for comparing
dissolution profiles2
-No biostudy
III -Higher than SUPAC- IR All drugs -Updated batch record -Prior approval
level 2 excipient ranges -Stability supplement
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
404 Appendix B
A-2 Extended Release Solid Oral Dosage Forms Release Controlling Components and
Composition
Therapeutic Filing
Level Classification range Test documentation documentation
I -
 5% w/ w change All drugs -Stability -Annual report
based on total release -Application/ compendial
controlling excipient requirements
(e.g., controlled -No biostudy
release polymer,
plasticizer) content
-No other changes
II -Change in technical Non- narrow -Notification & updated -Prior approval
grade and/ or batch record supplement
specifications -Stability
-
 10% w/ w change -Application/ compendial
based on total release requirements plus
controlling excipient multi- point
(e.g., controlled dissolution profiles in
release polymer, three other media
plasticizer) content (e.g., water, 0.1N
-No other changes HCL, and USP buffer
media at pH 4.5 and
6.8) until 
 80% of
drug released or an
asymptote is reached1
-Apply some statistical
test (F2 test) for
comparing dissolution
profiles2
-No biostudy
Narrow -Updated batch record -Prior approval
-Stability supplement
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
III - 10% w/ w change All drugs -Updated batch record -Prior approval
based on all drugs -Stability supplement
total release -Application/ compendial
controlling excipient (profile) requirements
(e.g., controlled -Biostudy or IVIVC1
release polymer,
plasticizer) content
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix B 405
A-3 Extended Release Solid Oral Dosage Forms Site Change
Therapeutic Filing
Level Classification range Test documentation documentation
I
II
III
-Single facility
-Common personnel
-No other changes
-Same contiguous campus
-Common personnel
-No other changes
-Different campus
-Different personnel
All drugs
All drugs
All drugs
-Application/ compendial
requirements
-No biostudy
-Identification and
description of site change,
and updated batch record
-Notification of site change
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in three other media (e.g.,
water, 0.1N HCL, and USP
buffer media at pH 4.5 and
6.8) until 
 80% of drug
released or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Notification of site change
-Updated batch record
-Stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Changes being
effected
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
406 Appendix B
A-4 Extended Release Solid Oral Dosage Forms Scale-up/ Scale-down
Filing
Level Classification Change Test documentation documentation
I
II
-Scale- up of bio-batch(s)
or pivotal clinical
batch(s)
-No other changes
-Scale- up of bio-batch(s)
or pivotal clinical
batch(s)
-No other changes

 10X
(All drugs)
 10X
(All drugs)
-Updated batch record
-Stability
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in three other media (e.g.,
water, 0.1N HCL, and USP
buffer media at pH 4.5 and
6.8) until 
 80% of drug
released or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Annual report
-Changes being
effected
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix B 407
A-5 Extended Release Solid Oral Dosage Forms Manufacturing—Equipment
Filing
Level Classification Change Test documentation documentation
I
II
-Equipment changes
-No other changes
(all drugs)
-Equipment changes
-No other changes
(All drugs)
-Alternate
equipment of
same design
and principle
-Automated
equipment
-Change to
equipment of a
different
design and
operating
principle
-Updated batch record
-Stability
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in three other media (e.g.,
water, 0.1N HCL, and USP
buffer media at pH 4.5 and
6.8) until 
 80% of drug
released or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Annual report
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
408 Appendix B
A-6 Extended Release Solid Oral Dosage Forms Manufacturing—Processing
Filing
Level Classification Change Test documentation documentation
I
II
III
-Processing
changes affecting
the non- release
controlling
excipients and/
or the release
conrolling
excipients
-No other changes
-Processing
changes affecting
the non- release
controlling
excipients and/
or the release
controlling
excipients
-No other changes
-processing changes
affecting the
non- release
controlling
excipients and/
or the release
controlling
excipients
-Adjustment of
equipment
operating
conditions
(e.g. mixing
times,
operating
speeds, etc.)
-Within approved
application
ranges
-Adjustment of
equipment
operating
conditions
(e.g. mixing
times,
operating
speeds, etc.)
-Beyond
approved
application
ranges
-Change in the
type of process
used (e.g.
from wet
granulation to
direct
compression)
-Updated batch record
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in three other media (e.g.,
water, 0.1N HCL, and USP
buffer media at pH 4.5 and
6.8) until 
 80% of drug
released or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Changes being
effected
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix B 409
B-1 Delayed Release Solid Oral Dosage Forms Non-release Controlling Components
and Composition
Therapeutic Filing
Level Classification range Test documentation documentation
I
II
III
-Complete or partial
deletion of color/
flavor
-Change in inks, imprints
-Up to SUPAC- IR level
1 excipient ranges
-No other changes
-Change in technical
grade and/ or
specifications
-Higher than SUPAC- IR
level 1 but less than
level 2 excipient
ranges
-No other changes
-Higher than SUPAC- IR
level 2 excipient
ranges
All drugs
All drugs
All drugs
-Stability
-Application/ compendial
requirements
-No biostudy
-Notification & updated
batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in additional buffer stage
testing (e.g., USP buffer
media at pH 4.5–7.5) under
standard and increased
agitation conditions until

 80% of drug released
or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Prior approval
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
410 Appendix B
B-2 Delayed Release Solid Oral Dosage Forms Release Controlling Components
and Composition
Therapeutic Filing
Level Classification range Test documentation documentation
I
II
III
-
 5% w/ w change
based on total release
controlling excipient
(e.g., controlled
release polymer,
plasticizer) content
-No other changes
-Change in technical
grade and/ or
specifications
-
 10% w/ w change
based on total release
controlling excipient
(e.g., controlled
release polymer,
plasticizer) content
-No other changes
-10% w/ w change
based on total release
controlling excipient
(e. g., controlled
release polymer,
plasticizer) content
All drugs
Non-narrow
Narrow
All drugs
-Stability
-Application/ compendial
requirements
-No biostudy
-Notification & updated
batch record
-Stability
-Application/ compendial
requirements plus
multi- point dissolution
profiles in additional
buffer stage testing (e.g.,
USP buffer media at pH
4.5–7.5) under standard
and increased agitation
conditions until 
 80%
of drug released or an
asymptote is reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Updated batch record &
stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Prior approval
supplement
-Prior approval
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix B 411
B-3 Delayed Release Solid Oral Dosage Forms Site Change
Therapeutic Filing
Level Classification range Test documentation documentation
I
II
III
-Single facility
-Common personnel
-No other changes
-Same contiguous campus
-Common personnel
-No other changes
-Different campus
-Different personnel
All drugs
All drugs
All drugs
-Application/ compendial
requirements
-No biostudy
-Identification and
description of site change,
and updated batch record
-Notification of site change
-Stability
-Application/ compendial
requirements plus
multi- point dissolution
profiles in additional
buffer stage testing (e.g.,
USP buffer media at pH
4.5–7.5) under standard
and increased agitation
conditions until 
 80%
of drug released or an
asymptote is reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Notification of site change
-Updated batch record
stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Changes being
effected
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
412 Appendix B
B-4 Delayed Release Solid Oral Dosage Forms Scale-up/ Scale-down
Filing
Level Classification Change Test documentation documentation
I
II
-Scale- up of
bio-batch(s) or pivotal
clinical batch(s)
-No other changes
-Scale- up of biobatch(
s) or pivotal
clinical batch(s)
-No other changes

 10X
(All drugs)
 10X
(All drugs)
-Updated batch record
-Stability
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in additional buffer stage
testing (e.g., USP buffer
media at pH 4.5–7.5) under
standard and increased
agitation conditions until

 80% of drug released
or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Annual report
-Changes being
effected
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix B 413
B-5 Delayed Release Solid Oral Dosage Forms Manufacturing—Equipment
Filing
Level Classification Change Test documentation documentation
I
II
-Equipment changes
-No other changes
(All drugs)
-Equipment changes
-No other changes
(All drugs)
-Alternate
equipment of
same design
and principle
-Automated
equipment
-Change to
equipment of a
different
design and
operating
principle
-Updated batch record
-Stability
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in additional buffer stage
testing (e.g., USP buffer
media at pH 4.5–7.5) under
standard and increased
agitation conditions until

 80% of drug released
or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Annual report
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
414 Appendix B
B-6 Delayed Release Solid Oral Dosage Forms Manufacturing—Processing
Filing
Level Classification Change Test documentation documentation
I
II
III
-Processing
changes affecting
the non- release
controlling
excipients and/
or the release
conrolling
excipients
-No other changes
-Processing
changes affecting
the non- release
controlling
excipients and/
or the release
controlling
excipients
-No other changes
-Processing
changes affecting
the non- release
controlling
excipients and/
or the release
controlling
excipients
-Adjustment of
equipment
operating
conditions
(e.g., mixing
times,
operating
speeds, etc.)
-Within
approved
application
ranges
-Adjustment of
equipment
operating
conditions
(e.g., mixing
times,
operating
speeds, etc.)
-Beyond
approved
application
ranges
-Change in the
type of process
used (e.g.,
from wet
granulation to
direct
compression)
-Updated batch record
-Application/ compendial
requirements
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
requirements plus multipoint
dissolution profiles
in additional buffer stage
testing (e.g., USP buffer
media at pH 4.5–7.5) under
standard and increased
agitation conditions until

 80% of drug released
or an asymptote is
reached1
-Apply some statistical test
(F2 test) for comparing
dissolution profiles2
-No biostudy
-Updated batch record
-Stability
-Application/ compendial
(profile) requirements
-Biostudy or IVIVC1
-Annual report
-Changes being
effected
supplement
-Prior approval
supplement
1 In the presence of an established in vitro/in vivo correlation only application/ compendial dissolution testing
should be performed.
2 In the absence of an established in vitro/in vivo correlation.
Appendix C
Guidance for Industry1—
SUPAC-IR/MR: Immediate Release
and Modified Release Solid Oral
Dosage Forms
Manufacturing Equipment Addendum
I. INTRODUCTION
The purpose of this guidance is to provide recommendations to pharmaceutical
manufacturers using the Center for Drug Evaluation and Research’s Guidance for
Industry: Immediate Release Solid Oral Dosage Forms—Scale-Up and Post-Approval
Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation (SUPAC-IR), which published
in November 1995, and Guidance for Industry: SUPAC-MR: Modified
Release Solid Oral Dosage Forms Scale-Up and Post-Approval Changes: Chemistry,
Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence
Documentation, which published in October 1997. This document was
developed by the U.S. Food and Drug Administration (FDA) with the assistance
of the International Society of Pharmaceutical Engineering (ISPE). This docu-
415
1 This guidance has been prepared by the Immediate Release Scale-up and Post Approval Change (SUPAC)
Expert Working Group of the Chemistry Manufacturing Controls Coordinating Committee
(CMC CC) of the Center for Drug Evaluation and Research at the Food and Drug Administration.
This guidance is an informal communication under 21 CFR 10.90(b)(9) that reflects the best judgment
of CDER employees at this time. It does not create or confer any rights, privileges or benefits
for or on any person, nor does it operate to bind or obligate FDA in any way. For additional copies
of this guidance contact the Consumer Affairs Branch (formerly the Executive Secretariat Staff),
HFD-8, Center for Drug Evaluation and Research, 7500 Standish Place, Rockville, MD 20855
(Phone: 301-594-1012). An electronic version of this guidance is also available via Internet by connecting
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).
ment extends and supersedes the Manufacturing Equipment Addendum published
in October 1997 that covered only immediate release solid oral dosage forms. The
scope of this document is limited to only changes of equipment. If changes in
components and composition, site, scale, or process occur in addition to the equipment
change, then this should be considered a multiple change under SUPAC-IR
and SUPAC-MR. For modified release solid oral dosage forms, consideration
should be given as to whether or not the change in manufacturing equipment is
critical to drug release (critical equipment variable).
The document should be used in conjunction with the SUPAC-IR and
SUPAC-MR guidance documents in determining what documentation should be
submitted to FDA regarding equipment changes made in accordance with the
recommendations in these guidance documents. The SUPAC guidance documents
define (1) levels of change; (2) recommended chemistry, manufacturing, and controls
tests for each level of change; (3) in vitro dissolution tests and/or in vivo
bioequivalence tests for each level of change; and (4) documentation that should
support the change for new drug applications (NDAs) and abbreviated new drug
applications (ANDAs). This document is only an aid and, in some cases, specific
equipment may not be listed. It does, however, include a representative list of
equipment commonly used in the industry. The guidance does not address equipment
that has been modified by a pharmaceutical manufacturer to fit its specific
needs. If questions arise in using this guidance document please contact the appropriate
reviewing office at CDER.
Although this guidance does not discuss validation, any equipment
changes should be validated in accordance with current good manufacturing
practices (cGMPs) and the resulting data will be subject to examination by field
investigators during routine GMP inspections. The information is presented in
broad categories of unit operation (blending and mixing, drying, particle size reduction/
separation, granulation, unit dosage, coating and printing, soft gelatin
capsule encapsulation). Definitions and classification are provided. For each operation,
a table is presented that categorizes equipment by class (operating principle)
and subclass (design characteristic). Examples are given within the
subclasses.
Equipment within the same class and subclass would be considered to have
the same design and operating principle under SUPAC-IR and SUPAC-MR.
Therefore, for example, a change from one type of diffusion mixer (e.g, V-blender
from manufacturer A) to another diffusion mixer (e.g., V-blender from manufacturer
B) generally would not represent a change in operating principle and would,
therefore, be considered to be the same under either SUPAC-IR or SUPAC-MR.
A change from equipment in one class to equipment in a different class
would usually be considered a change in design and operating principle. For example,
a change from a V-blender to a ribbon blender demonstrates a change in
the operating principle from diffusion blending to convection blending and would
be considered to be different under either SUPAC-IR or SUPAC-MR.
416 Appendix C
Applicants should carefully consider and evaluate on a case-by-case basis
changes in equipment that are in the same class, but different subclass. In many
situations, this type of change in equipment would be considered similar. For example,
within the Blending and Mixing section, under the Diffusion Mixers Class,
a change from a V-blender (sub-class) to a Bin tumbler (sub-class) represents a
change within a class and between sub-classes. Provided the manufacturing process
with the new equipment is validated, this change would likely not need a preapproval
supplement. The applicant should have available at the time of the
change the scientific data and rationale used to make this determination. This information
is subject to FDA review at its discretion. It is up to the applicant to determine
the filing requirement.
This guidance will be updated as needed to reflect the introduction and discontinuation
of specific types of manufacturing equipment. Manufacturers of
equipment are encouraged to help keep the document current by communicating
changes to the Agency and by making suggestions regarding what equipment
should be considered to be within the same class or subclass. The submitted information
will be reviewed by FDA and incorporated in an updated guidance document
as appropriate.
II. PARTICLE SIZE REDUCTION/SEPARATION
A. Definitions
1. Unit Operations
a. Particle Size Reduction. The mechanical process of breaking particles
into smaller pieces via one or more particle size reduction mechanisms. The
mechanical process used generally is referred to as milling.
i. Particle - Refers to either a discrete particle or a grouping of particles,
generally known as an agglomerate.
ii. Particle Size Reduction Mechanisms
• Impact - Particle size reduction by applying an instantaneous force
perpendicular to the particle/agglomerate surface. The force can result
from particle-to-particle or particle-to-mill surface collision.
• Attrition - Particle size reduction by applying a force in a direction
parallel to the particle surface.
• Compression - Particle size reduction by applying a force slowly (as
compared to Impact) to the particle surface in a direction toward the
center of the particle.
• Cutting - Particle size reduction by applying a shearing force to a material.
b. Particle Separation. Particle size classification according to particle
size alone.
Appendix C 417
Table 1 Unit Operation—Particle Size Reduction
Class Subclass Examples
Fluid Energy Mills Tangential Jet Alpine (Hosokawa)
Fluid Energy Aljet
Jetpharma
Sturtevant
Loop/Oval Fluid Energy Aljet
Opposed Jet Garlock
Opposed Jet with Dynamic Fluid Energy Aljet
Classifier Alpine (Hosokawa)
Fluidized Bed None Identified
Fixed Target None Identified
Moving Target None Identified
Impact Mills Hammer Air Swept Alpine (Hosokawa)
Bepex (Hosokawa)
Sturtevant
Hammer Conventional Alpine (Hosokawa)
Fitzpatrick
Fluid Air
Mikro (Hosokawa)
Rietz (Hosokawa)
Stokes-Merrill
Pin/Disc Alpine (Hosokawa)
Kemutec
Sturtevant
Cage Stedman
Cutting Mills None Identified Alpine (Hosokawa)
Fitzpatrick
Urschel
Compression Mills None Identified MCA International
Screening Mills Rotating Impeller Bepex (Hosokawa)
Fitzpatrick
Fluid Air
Jetpharma
Kemutec
Quadro
Stokes-Merrill
Zanchetta (Romaco)
Rotating Screen Glatt
Oscillating Bar Bepex (Hosokawa)
Frewitt
Jackson-Crockatt
Stokes-Merrill
Vector
Tumbling Mills Ball Media US Stoneware
Rod Media None Identified
Vibrating Sweco
418
2. Operating Principles
a. Fluid Energy Milling. Particles are reduced in size as a result of highspeed
particle-to-particle impact and/or attrition; also known as micronizing.
b. Impact Milling. Particles are reduced in size by high-speed mechanical
impact or impact with other particles; also known as milling, pulverizing, or
comminuting.
c. Cutting. Particles are reduced in size by mechanical shearing.
d. Compression Milling. Particles are reduced in sized by compression
stress and shear between two surfaces.
e. Screening. Particles are reduced in size by mechanically induced attrition
through a screen. This process commonly is referred to as milling or deagglomeration.
f. Tumble Milling. Particles are reduced in size by attrition utilizing
grinding media.
g. Separating. Particles are segregated based upon particle size alone
and without any significant particle size reduction. This process commonly is referred
to as screening or bolting.
B. Equipment Classifications
1. Fluid Energy Mills
Fluid energy mill subclasses have no moving parts and primarily are distinguished
from one another by the configuration and/or shape of their chambers, nozzles,
and classifiers.
• Tangential Jet
• Loop/Oval
• Opposed Jet
• Opposed Jet with Dynamic Classifier
• Fluidized Bed
• Fixed Target
• Moving Target
2. Impact Mills
Impact mill subclasses primarily are distinguished from one another by the configuration
of the grinding heads, chamber grinding liners (if any), and classifiers.
• Hammer Air Swept
• Hammer Conventional
Appendix C 419
• Pin/Disc
• Cage
3. Cutting Mills
Although cutting mills may differ from one another in whether the knives are
movable or fixed and in the classifier configuration, no cutting mill subclasses
have been identified.
4. Compression Mills
Although compression mills may differ from one another in whether one or both
surfaces are moving, no compression mill subclasses have been identified.
5. Screening Mills
Screening mill subclasses primarily are distinguished from one another by the rotating
element.
• Rotating Impeller
• Rotating Screen
• Oscillating Bar
6. Tumbling Mills
Tumbling mill subclasses primarily are distinguished from one another by the
grinding media used and by whether the mill is vibrated.
• Ball Media
• Rod Media
• Vibrating.
420 Appendix C
Table 2 Unit Operation—Separation
Class Subclass Examples
Separators Vibratory/Shaker Allgaier
McLanahan
Rotex
Russell Finex
Sweco
VortiSiv
Centrifugal AZO
Kason
Kemutec
Sweco
7. Separators
Separator subclasses primarily are distinguished from one another by the mechanical
means used to induce particle movement.
• Vibratory/Shaker
• Centrifugal
III. BLENDING AND MIXING
A. Definitions
1. Unit Operations
Blending and Mixing: The reorientation of particles relative to one another in order
to achieve uniformity.
2. Operating Principles
a. Diffusion Blending (Tumble). Particles are reoriented in relation to
one another when they are placed in random motion and interparticular friction is
reduced as the result of bed expansion (usually within a rotating container); also
known as tumble blending.
b. Convection Mixing. Particles are reoriented in relation to one another
as a result of mechanical movement; also known as paddle or plow mixing.
c. Pneumatic Mixing. Particles are reoriented in relation to one another
as a result of the expansion of a powder bed by gas.
B. Equipment Classifications
1. Diffusion Mixers (Tumble)
Diffusion mixer subclasses primarily are distinguished by geometric shape and
the positioning of the axis of rotation.
• V-blenders
• Double Cone Blenders
• Slant Cone Blenders
• Cube Blenders
• Bin Blenders
• Horizontal/Vertical/Drum Blenders
• Static Continuous Blenders
• Dynamic Continuous Blenders
Appendix C 421
422 Appendix C
Table 3 Unit Operation—Blending and Mixing
Class Subclass Examples
Diffusion Mixers V-Blenders Aaron
(Tumble) Paul O. Abbe
Gemco
Jaygo
Kemutec
Lleal
Lowe
O’Hara
Patterson-Kelley
Pneuvac
Zanchetta (Romaco)
Double Cone Blenders Aaron
Paul O. Abbe
Gemco
Jaygo
Kemutec
Lleal
Lowe
MO Industries
Patterson- Kelley
Pneuvac
ServoLift
Zanchetta (Romaco)
Slant Cone Blenders Gemco
Lleal
Patterson-Kelley
Cube Blenders Lightnin
ServoLift
Zanchetta (Romaco)
Bin Blenders Paul O. Abbe
L. B. Bohle
Cora International
CONSEP
Creative Design & Machine
Custom Metal Craft
GEI-Gallay (GEI
International/Patriot)
Gemco
Glatt
Jenike & Johanson
Kemutec
Matcon, USA
Appendix C 423
Table 3 Continued.
Class Subclass Examples
Scholl (MO Industries)
ServoLift
Tote Systems
Zanchetta (Romaco)
Horizontal/Vertical/Drum Munson Mill Machinery
Blenders
Static Continuous Blenders Ross
Dynamic Continuous Patterson-Kelley
Blenders
Convection Mixers Ribbon Blenders Aaron
Paul O. Abbe
Automatic Industry Machines
Azo-Ruberg
Custom Metal Craft
Jaygo
Kemutec
Lowe
Pneuvac
Ross
Vrieco-Nauta (Hosokawa)
Orbiting Screw Blenders Aaron
Jaygo
Littleford Day
Ross
Vrieco-Nauta (Hosokawa)
Planetary Blenders Aaron
Aeschbach
AMF
GEI-Collette (GEI
International)
Hobart
Jaygo
Littleford Day
Ross
Vrieco
Forberg Blenders Paul O. Abbe
Dynamic Air
Horizontal Double Arm Aaron
Blenders Paul O. Abbe
Custom Metal Craft
Dynamic Air
(Continued)
2. Convection Mixers
Convection blender subclasses primarily are distinguished by vessel shape ad impeller
geometry:
• Ribbon Blenders
• Orbiting Screw Blenders
• Planetary Blenders
• Forberg Blenders
• Horizontal Double Arm Blenders
424 Appendix C
Table 3 Continued.
Class Subclass Examples
Jaygo
Kemutec
Littleford Day
Ross
Sigma
Teledyne Readco
Horizontal High Intensity Littleford Day
Mixers (Side Driven) Lodige
Processall
Vertical High Intensity Aeromatic-Fielder
Mixers (Top or Bottom (GEA-Niro)
Driven) APV
Baker-Perkins
L.B. Bohle
Dierks & Shone
Diosna (Fluid Air)
GEI-Collette (GEI
International)
Key International
Littleford Day
Lodige
Powrex (Glatt)
Processall
Werner & Pfeiderer
Zanchetta (Romaco)
Diffusion Mixers (Tumble) Paul O. Abbe
with Intensifier/Agitator Gemco
Patterson-Kelley
Pneumatic Mixers None Identified Dynamic Air
Reimelt.
• Horizontal High Intensity Mixers
• Vertical High Intensity Mixers
• Diffusion Mixers (Tumble) with Intensifier/Agitator
3. Pneumatic Mixers
Although pneumatic mixers may differ from one another in vessel geometry, air
nozzle type, and air nozzle configuration, no pneumatic mixer subclasses have
been identified.
IV. GRANULATION
A. Definitions
1. Unit Operations
Granulation: The process of creating granules. The powder morphology is modified
through the use of either a liquid that causes particles to bind through capillary
forces or dry compaction forces. The process will result in one or more of
the following powder properties: enhanced flow; increased compressibility; densification;
alteration of physical appearance to more spherical, uniform, or larger
particles; and/or enhanced hydrophilic surface properties.
2. Operating Principles
a. Dry Granulation. Dry powder densification and/or agglomeration by
direct physical compaction.
b. Wet High-Shear Granulation. Powder densification and/or agglomeration
by the incorporation of a granulation fluid into the powder with high-powerper-
unit mass, through rotating high-shear forces.
c. Wet Low-Shear Granulation. Powder densification and/or agglomeration
by the incorporation of a granulation fluid into the powder with low-powerper-
unit mass, through rotating low-shear forces.
d. Low-Shear Tumble Granulation. Powder densification and/or agglomeration
by the incorporation of a granulation fluid into the powder with lowpower-
per-unit mass, through rotation of the container vessel and/or intensifier bar.
e. Extrusion Granulation. Plasticization of solids or wetted mass of
solids and granulation fluid with linear shear through a sized orifice using a pressure
gradient.
f. Rotary Granulation. Spheronization, agglomeration, and/or densification
of a wetted or non-wetted powder or extruded material. This is accom-
Appendix C 425
426 Appendix C
Table 4 Unit Operation—Granulation
Class Subclass Examples
Dry Granulator Slugging Various
Roller Compaction Alexanderwerk
Bepex (Hosokawa)
Fitzpatrick
Freund
Vector
Wet High-Shear Horizontal (Side Driven) Littleford Day
Granulator Lodige
Processall
Vertical (Top or Aeromatic-Fielder
Bottom Driven) (GEA-Niro)
APV
Baker-Perkins
L.B. Bohle
Dierks & Shone
Diosna (Fluid Air)
GEI-Collette
(GEI International)
Key International
Littleford Day
Lodige
Powrex (Glatt)
Processall
Werner & Pfeiderer
Zanchetta (Romaco)
Wet Low-Shear Planetary Aaron
Granulator Aeschbach
AMF
GEI-Collette
(GEI International)
Hobart
Jaygo
Littleford Day
Ross
Vrieco
Kneading Aaron
Paul O. Abbe
Custom Metal Craft
Dynamic Air
Jaygo
Kemutec
Littleford Day
Table 4 Continued.
Class Subclass Examples
Processall
Ross
Sigma
Teledyne Readco
Screw Vrieco-Nauta (Hosokawa)
Low-Shear Tumble Slant Cone, or Double Paul O. Abbe
Granulator Cone, or V-Blender Gemco
Patterson-Kelley
Extrusion Granulator Radial or Basket Alexanderwerk
GEA Niro
LCI
Luwa
Ross
Axial Bepex (Hosokawa)
Gabler
LCI
Ram LCI
Roller, Gear, or Alexanderwerk
Pelletizer Bepex (Hosokawa)
Rotary Granulator Open Freund (Vector)
GEA Niro
LCI
Luwa
Closed Aeromatic-Fielder
(GEA Niro)
Glatt
LCI
Processall
Vector
Fluid Bed Granulator None Identified Aeromatic-Fielder
(GEA Niro)
APV
BWI Huttlin (Thomas
Engineering)
Diosna
Fitzpatrick
Fluid Air
Glatt
Heinen
Vector
Spray Dry Granulator None Identified Allgaier
GEA Niro
Glatt
Heinen
427
plished by centrifugal or rotational forces from a central rotating disk, rotating
walls, or both. The process may include the incorporation and/or drying of a
granulation fluid.
g. Fluid Bed Granulation. Powder densification and/or agglomeration
with little or no shear by direct granulation fluid atomization and impingement on
solids, while suspended by a controlled gas stream, with simultaneous drying.
h. Spray Dry Granulation. A pumpable granulating liquid containing
solids (in solution or suspension) is atomized in a drying chamber and rapidly
dried by a controlled gas stream, producing a dry powder.
B. Equipment Classification
1. Dry Granulator
Dry granulator subclasses primarily are distinguished by the densification force
application mechanism.
• Slugging
• Roller Compaction
2. Wet High-Shear Granulator
Wet high-shear granulator subclasses primarily are distinguished by the geometric
positioning of the primary impellers; impellers can be top, bottom, or side
driven.
• Vertical (Top or Bottom Driven)
• Horizontal (Side Driven)
3. Wet Low-Shear Granulator
Wet low-shear granulator subclasses primarily are distinguished by the geometry
and design of the shear inducing components; shear can be induced by rotating impeller,
reciprocal kneading action, or convection screw action.
• Planetary
• Kneading
• Screw
4. Low-Shear Tumble Granulator
Although low-shear tumble granulators may differ from one another in vessel geometry
and type of dispersion or intensifier bar, no low-shear tumble granulator
subclasses have been identified.
428 Appendix C
5. Extrusion Granulator
Extrusion granulator subclasses primarily are distinguished by the orientation of
extrusion surfaces and driving pressure production mechanism.
• Radial or Basket
• Axial
• Ram
• Roller, Gear, or Pelletizer
6. Rotary Granulator
Rotary granulator subclasses primarily are distinguished by their structural architecture.
They have either open top architecture, such as a vertical centrifugal
spheronizer, or closed top architecture, such as a closed top fluid bed dryer.
• Open
• Closed
7. Fluid Bed Granulator
Although fluid bed granulators may differ from one another in geometry, operating
pressures, and other conditions, no fluid bed granulator subclasses have been
identified.
8. Spray Dry Granulator
Although spray dry granulators may differ from one another in geometry, operating
pressures, and other conditions, no spray dry granulator subclasses have been
identified.
Note: If a single piece of equipment is capable of performing multiple discrete
unit operations (mixing, granulating, drying), the unit was evaluated solely
for its ability to granulate. If multifunctional units were incapable of discrete steps
(fluid bed granulator/drier), the unit was evaluated as an integrated unit.
V. DRYING
A. Definitions
1. Unit Operation
Drying: The removal of a liquid from a solid by evaporation.
2. Operating Principles
a. Direct Heating, Static Solids Bed. Heat transfer is accomplished by
direct contact between the wet solids and hot gases. The vaporized liquid is car-
Appendix C 429
430 Appendix C
Table 5 Unit Operation—Drying
Class Subclass Examples
Direct Heating, Static Tray and Truck Colton
Solids Bed Despatch
Gruenberg
Hot Pack
Lydon
O’Hara
Proctor & Schwartz
Trent
Belt Despatch
Proctor & Schwartz
Direct Heating, Rotating Tray Krauss Maffei
Moving Solids Bed Wyssmont
Horizontal Vibrating Carrier
Conveyor Witte
Direct Heating, None Identified Aeromatic-Fielder
Fluidized Solids Bed (GEA-Niro)
(Fluid Bed Dryer) APV
BWI Huttlin (Thomas
Engineering)
Diosna
Fitzpatrick
Fluid Air
Glatt
Heinen
Vector
Direct Heating, Dilute None Identified Allgaier
Solids Bed, Spray APV
Dryer BWI Huttlin (Thomas
Engineering)
GEA-Niro
Glatt
Direct Heating, Dilute None Identified Allgaier
Solids Bed, Flash APV
Dryer GEA-Niro
Micron (Hosokawa)
Indirect Conduction, Paddle Bepex (Hosokawa)
Moving Solids Bed Jaygo
Littleford Day
Processall
Rotary (Tumble) Paul O. Abbe
Gemco
Glatt
ried away by the drying gases. There is no relative motion among solid particles.
The solids bed exists as a dense bed, with the particles resting upon one another.
b. Direct Heating, Moving Solids Bed. Heat transfer is accomplished by
direct contact between the wet solids and hot gases. The vaporized liquid is
carried away by the drying gases. Solids motion is achieved by either mechanical
agitation or gravity force, which slightly expands the bed enough to flow one particle
over another.
Appendix C 431
Table 5 Continued.
Class Subclass Examples
Littleford Day
Patterson-Kelley
Processall
Zanchetta (Romaco)
Agitation L. B. Bohle
Diosna
GEI-Collette
(GEI International)
Krauss-Maffei
Processall
Vrieco-Nauta (Hosokawa)
Zanchetta (Romaco)
Indirect Conduction, None Identified Hull
Static Solids Bed
Indirect Conduction, None Identified Amsco
Lyophilization Hull
Serail
Stokes
Gas Stripping None Identified Aeromatic-Fielder
(GEA-Niro)
L.B. Bohle
Diosna (Fluid Air)
GEI-Collette
(GEI International)
Processall
Zanchetta (Romaco)
Indirect Radiant Heating, None Identified Aeromatic-Fielder
Moving Solids Bed (GEA-Niro)
(Microwave Dryer) L. B. Bohle
Diosna
GEI-Collette
(GEI International)
c. Direct Heating, Fluidized Solids Bed. Heat transfer is accomplished
by direct contact between the wet solids and hot gases. The vaporized liquid is carried
away by the drying gases. The solids are in an expanded condition, with the
particles supported by drag forces caused by the gas phase. The solids and gases
intermix and behave like a boiling liquid. This process commonly is referred to as
fluid bed drying.
d. Direct Heating, Dilute Solids Bed, Spray Drying. Heat transfer is accomplished
by direct contact between a highly dispersed liquid and hot gases. The
feed liquid may be a solution, slurry, emulsion, gel or paste, provided it is
pumpable and capable of being atomized. The fluid is dispersed as fine droplets
into a moving stream of hot gases, where they evaporate rapidly before reaching
the wall of the drying chamber. The vaporized liquid is carried away by the drying
gases. The solids are fully expanded and so widely separated that they exert
essentially no influence on one another.
e. Direct Heating, Dilute Solids Bed, Flash Drying. Heat transfer is accomplished
by direct contact between wet solids and hot gases. The solid mass is
suspended in a finely divided state in a high-velocity and high-temperature gas
stream. The vaporized liquid is carried away by the drying gases.
f. Indirect Conduction, Moving Solids Bed. Heat transfer to the wet solid
is through a retaining wall. The vaporized liquid is removed independently from
the heating medium. Solids motion is achieved by either mechanical agitation or
gravity force, which slightly expands the bed enough to flow one particle over another.
g. Indirect Conduction, Static Solids Bed. Heat transfer to the wet solid
is through a retaining wall. The vaporized liquid is removed independently from
the heating medium. There is no relative motion among solid particles. The solids
bed exists as a dense bed, with the particles resting upon one another.
h. Indirect Conduction, Lyophilization. Drying in which the water vapor
sublimes from the product after freezing.
i. Gas Stripping. Heat transfer is a combination of direct and indirect
heating. The solids motion is achieved by agitation and the bed is partially fluidized.
j. Indirect Radiant, Moving Solids Bed. Heat transfer is accomplished
with varying wavelengths of energy. Vaporized liquid is removed independently
from the solids bed. The solids motion is achieved by mechanical agitation, which
slightly expands the bed enough to flow one particle over one another. This process
commonly is referred to as microwave drying.
432 Appendix C
B. Equipment Classifications
1. Direct Heating, Static Solids Bed
Static solids bed subclasses primarily are distinguished by the method of moving
the solids into the dryer.
• Tray and Truck
• Belt
2. Direct Heating, Moving Solids Bed
Moving solids bed subclasses primarily are distinguished by the method or technology
for moving the solids bed.
• Rotating Tray
• Horizontal Vibrating Conveyor
3. Direct Heating, Fluidized Solids Bed (Fluid Bed Dryer)
Although fluid bed dryers may differ from one another in geometry, operating
pressures, and other conditions, no fluidized solids bed dryer subclasses have been
identified.
4. Direct Heating, Dilute Solids Bed, Spray Dryer
Although spray dryers may differ from one another in geometry, operating pressures,
and other conditions, no spray dryer subclasses have been identified.
5. Direct Heating, Dilute Solids Bed, Flash Dryer
Although flash dryers may differ from one another in geometry, operating pressures,
and other conditions, no flash dryer subclasses have been identified.
6. Indirect Conduction Heating, Moving Solids Bed
Moving solids bed subclasses primarily are distinguished by the method or technology
for moving the solids bed.
• Paddle
• Rotary (Tumble)
• Agitation
7. Indirect Conduction Heating, Static Solids Beds
No indirect heating, static solids bed shelf dryer subclasses have been identified.
Appendix C 433
8. Indirect Conduction, Lyophilization
No lyophilizer subclasses have been identified.
9. Gas Stripping
Although gas stripping dryers may differ from one another in geometry, shape of
agitator, and how fluidizing gas is moved through the bed, no gas stripping dryer
subclasses have been identified.
10. Indirect Radiant Heating, Moving Solids Bed (Microwave
Dryer)
Although microwave dryers may differ from one another in vessel geometry and
the way microwaves are directed into the solids, no indirect radiant heating, moving
solids bed dryer subclasses have been identified.
Note: If a single piece of equipment is capable of performing multiple discrete
unit operations (mixing, granulating, drying), the unit was evaluated solely
for its ability to dry. The drying equipment was sorted into similar classes of
equipment, based upon the method of heat transfer and the dynamics of the solids
bed.
VI. UNIT DOSING
A. Definitions
1. Unit Operation
Unit Dosing: The division of a powder blend into uniform single portions for delivery
to patients.
2. Operating Principles
a. Tabletting. The division of a powder blend in which compression
force is applied to form a single unit dose.
b. Encapsulating. The division of material into a hard gelatin capsule.
Encapsulators should all have the following operating principles in common: rectification
(orientation of the hard gelatin capsules), separation of capsule caps
from bodies, dosing of fill material/formulation, rejoining of caps and bodies, and
ejection of filled capsules.
c. Powder Filling. Division of a powder blend into a container closure
system.
434 Appendix C
B. Equipment Classifications
1. Tablet Press
Tablet press subclasses primarily are distinguished from one another by the
method that the powder blend is delivered to the die cavity. Tablet presses can
deliver powders without mechanical assistance (gravity), with mechanical assistance
(power assisted), by rotational forces (centrifugal), and in two different locations
where a tablet core is formed and subsequently an outer layer of coating
material is applied (compression coating).
• Gravity
• Power Assisted
Appendix C 435
Table 6 Unit Dosing
Class Subclass Examples
Tablet Press Gravity Colton (Vector)
Manesty (Thomas Engineering)
Stokes
Power Assisted Colton (Vector)
Courtoy (AC Compacting)
Fette
Hata (Elizabeth Carbide)
Kikusui
Kilian
Manesty (Thomas Engineering)
Centrifugal Comprima (IMA)
Compression Coating Manesty (Thomas Engineering)
Kikusui
Kilian
Encapsulator Auger Capsugel Type B
Elanco No. 8
Vacuum Perry
Vibratory Osaka (Sharpley-Stokes)
Dosing Disk H&K/ Bosch
Index
Dosator Macofar (Romaco)
MG2
Zanasi/Pharmatic/IMA
Powder Filler Vacuum Bosch
Perry
Zanasi
Auger All-Fill
Calumatic
• Centrifugal
• Compression Coating
2. Encapsulator
Encapsulator subclasses primarily are distinguished from one another by the
method that is used for introducing material into the capsule.
Encapsulators can deliver materials with a rotating auger, vacuum, vibration
of perforated plate, tamping into a bored disk (dosing disk), or cylindrical tubes
fitted with pistons (dosator).
• Auger
• Vacuum
• Vibratory
• Dosing Disk
• Dosator
3. Powder Filler
Subclasses of powder fillers primarily are distinguished by the method used to deliver
the predetermined amount for container fill.
• Vacuum
• Auger
VII. SOFT GELATIN CAPSULES
A. Definitions
1. Unit Operations
a. Gel Mass Preparation. The manufacture of a homogeneous, degassed
liquid mass (solution) of gelatin, plasticizer, water, and other additives, either in
solution or suspension, such as colorants, pigments, flavors, preservatives, etc.,
that comprise a unique functional gel shell formation. The operation may be performed
in discreet steps or by continuous processing. Minor components can be
added after the liquid gel mass is made.
b. Fill Mixing. The mixing of either liquids or solids with other liquids
to form a solution; blending of limited solubility solid(s) with a liquid carrier and
suspending agents used to stabilize the blend to form a suspension; or the uniform
combination of dry inert and drug active substances to form a dry powder fill suitable
for encapsulation. The reader should refer to the other sections of this document
for dry fill manufacture.
436 Appendix C
Appendix C 437
Table 7 Unit—Soft Gelatin Capsules
Class Subclass Examples
Mixers and Mixing Low Energy GEI-Collette
Vessels (GEI International)
GEI-Kreiger
(GEI International)
Hobart
Koruma (Romaco)
Lightnin
Moorhouse-Cowles
Quadro
High Energy Cowles
GEI-Collette
(GEI International)
Koruma (Romaco)
Planetary Aaron
Aeschbach
AMF
GEI-Collette
(GEI International)
Hobart
Jaygo
Littleford Day
Ross
Vrieco
Jacketed with and Becomix
without Vacuum Fryma
GEI-Kreiger
(GEI International)
Hicks
Lee Industries
Paul Mueller Co.
Ross
Koruma (Romaco)
Conventional Lee Industries
Deaggregators Rotor Stator Barinco
Greerco
Koruma (Romaco)
Roller Stokes-Merrill
Cutting Mills Alpine(Hosokawa)
Fitzpatrick
Urschel
Stone Mills Fryma
Koruma (Romaco)
(Continued)
c. Core Enrobing. The gelatin coating of gravity or force fed pre-formed
tablets or caplets.
d. Encapsulation. The continuous casting of gel ribbons, with liquid fill
material being injected between the gel ribbons using a positive displacement
438 Appendix C
Table 7 Continued.
Class Subclass Examples
Tumbling Mills Paul O. Abbe
Fryma
Premier Corp.
U.S. Stoneware
Deaerators Vacuum Vessel Fryma
GEI-Kreiger
(GEI International)
Koruma (Romaco)
Lee Industries
Paul Mueller Co.
Processall
Off Line/In Line The Cornell Machine Co.
Fryma
Koruma (Romaco)
Holding Vessels Jacketed Vessel with GEI-Kreiger
and without Mixing (GEI International)
System Koruma (Romaco)
Lee Industries
Encapsulators Positive Displacement Chang Sung
Pump Gaberino International
Consultants
Higuchi, Inc. USA
Hypak Industries
In House Construction
J.B. Engineering
Technopar Equipment
& Svcs., Ltd
Gravity or Force Feed Accogel® (Stern Machine)
Inspection/Sorting Belt Lakso
Merrill
Vibratory Stokes
Roller Maschimpex
Rotary Table Lakso
Merrill
ElectroMechanical Mocon
pump or, for dry materials being gravity or force fed with capsule formation
using a rotary die.
e. Washing. The continuous removal of a lubricant material from the
outside of the formed capsule. The washing operation is unique to each manufacturer’s
operation and generally uses in-house fabricated equipment. This equipment
will not be discussed in this guidance document.
f. Drying. The removal of the majority of water from the capsule’s gel
shell by tumbling and subsequent tray drying using conditioned air, which
enhances the size, shape, and shell physical properties of the final product. The
drying operation is unique to each manufacturer’s operation and generally uses inhouse
fabricated equipment. This equipment will not be discussed in this guidance
document.
g. Inspection/Sorting. The process wherein undesirable capsules are removed,
including misshapen, leaking, and unfilled capsules as well as agglomerates
of capsules.
h. Printing. The marking of a capsule surface for the purpose of product
identification, using a suitable printing media or method.
2. Operating Principles
a. Mixing. The combination of solid and liquid components, including
suspending aid(s) at either ambient or elevated temperatures to form a solution,
suspension, or dry powder blend for the manufacture of gel mass or fill material.
Mixing also includes the incorporation of minor components into the liquid
gel mass.
b. Deaggregation. The removal of aggregates using a suitable homogenizer/
mill to provide a pumpable fill material. The procedure has minimal effect
on the particle size distribution of the initial solid component(s), and is viewed as
a processing aid.2
c. Deaeration. The removal of entrapped air from either the gel mass or
fill material, solution or suspension. This process can take place in either the mixing
vessel, through the application of vacuum, or a separate off-line step.
d. Holding. The storage of liquid gel mass or fill material in a vessel,
with a mixer or without, prior to encapsulation, which also may be equipped with
a jacket for either heating or cooling.
Appendix C 439
2 Carstensen, J. T., “Theory of Pharmaceutical Systems, Volume 11 Heterogeneous Systems,” Academic
Press, New York, NY, 1973, p 51.
e. Encapsulation. The formation of capsules using a rotary die machine.
3
f. Inspection/Sorting. The physical removal of misshapen, leaking, or
agglomerated capsules, using either a manual or automatic operation.
g. Printing. The user of this document is asked to refer to the
coating/printing section, in which the use of various pieces of equipment are defined
and categorized.
B. Equipment Classifications
1. Mixers and Mixing Vessels
Mixer and mixing vessel subclasses primarily are distinguished by the mixing energy,
mixer type, and whether a jacketed vessel with vacuum capabilities is used
in conjunction with a specific mixer.
• Low Energy Mixer
• High Energy Mixer
• Planetary
• Jacketed Vessel With and Without Vacuum
• Conventional
2. Deaggregators
Deaggregator subclasses primarily are distinguished by the type of mechanical action
imparted to the material.
• Rotor/Stator
• Roller
• Cutting Mills
• Stone Mills
• Tumbling Mills
3. Deaerators
Deaerator subclasses primarily are distinguished by the air removal path, either
through the bulk or through a thin film, and whether it is a batch or in-line process.
440 Appendix C
3 Lachman, L., H. A. Lieberman, and J. L. Kanig (Eds.), The Theory and Practice of Industrial Pharmacy,
Chapter 3, p. 359 (Stanley, J. P.), Philadelphia: Lea & Febiger, 1971.
Tyle, P. (Ed.), Specialized Drug Delivery Systems, Manufacturing and Production Technology, Chapter
10, p. 409 (Wilkinson, P.K.and F.S. Hom), New York: M. Dekker, 1990.
Porter, S., Remington’s Pharmaceutical Sciences, Edition 18, Chapter 89, pp. 1662–1665, Easton,
Penn.: Mack Publishing Co.
• Vacuum Vessel
• Off Line/In Line
4. Holding Vessels
Although holding vessels may differ from one another, based upon whether they
are jacketed, with and without integrated mixing capabilities, no holding vessel
subclasses have beeen identified.
5. Encapsulators
Encapsulator subclasses primarily are distinguished by the method used to inject
the fill material.
• Positive Displacement Pump
• Gravity or Force Fed
6. Inspection/Sorting
Inspection/sorting equipment subclasses primarily are distinguished by the
method used to present the capsule for viewing and mechanical method of separation.
• Belt
• Vibratory
• Roller
• Rotary Table
• Electromechanical
VIII. COATING/PRINTING/DRILLING
A. Definitions
1. Unit Operation
a. Coating. The uniform deposition of a layer of material on or around a
solid dosage form, or component thereof, to:
• protect the drug from its surrounding environment (air, moisture, and
light), with a view to improving stability.
• mask unpleasant taste, odor, or color of the drug.
• increase the ease of ingesting the product for the patient.
• impart a characteristic appearance to the tablets, which facilitates product
identification and aids patient compliance.
• provide physical protection to facilitate handling. This includes minimizing
dust generation in subsequent unit operations.
Appendix C 441
442 Appendix C
Table 8 Unit Operation—Coating Equipment
Class Subclass Examples
Pan Coating Conventional Coating Bruck
System O’Hara
Pellegrini
Stokes-Merrill
Perforated Coating System BWI Huttlin
(Thomas Engineering)
Driam
Glatt
GS Coating Systems
Nicomac
O’Hara
Raymond
Strunck
Thomas Engineering
Vector
Gas Suspension Fluidized Bed Aeromatic-Fielder
(GEA Niro)
BWI Huttlin
(Thomas Engineering)
Fluid Air
Glatt
Vector
Spray Congealing/Drying Allgaier
APV
BWI Huttlin
(Thomas Engineering)
GEA-Niro
Glatt
Vacuum Film Coating None Identified Glatt
Dip Coating None Identified None Identified
Electrostatic Coating None Identified None Identified
Ink-Based Printing Off Set Ackley
Hartnett
Markem
Takeda
Ink Jet Image
Linx
Laser Etching (Printing) None Identified Lumonics
• reduce the risk of interaction between incompatible components. This
would be achieved by coating one or more of the offending ingredients.
• modify the release of drug from the dosage form. This includes delaying,
extending, and sustaining drug substance release.
The coating material deposition typically is accomplished through one of
four major techniques:
1. Sugar Coating - Deposition of coating material onto the substrate from
aqueous solution/suspension of coatings, based predominately upon sucrose
as a raw material.
2. Film Coating - The deposition of polymeric film onto the solid dosage
form.
3. Microencapsulation - The deposition of a coating material onto a particle,
pellet, granule, or bead core. The substrate in this application ranges
in size from submicron to several millimeters. It is this size range that
differentiates it from the standard coating described in 1 and 2 above.
4. Compression Coating (This topic is addressed in the Unit Dosing section.)
b. Printing. The marking of a capsule or tablet surface for the purpose
of product identification. Printing may be accomplished by either the application
of a contrasting colored polymer (ink) onto the surface of a capsule or tablet, or by
the use of laser etching.
The method of application, provided the ink formulation is not altered, is of
no consequence to the physical-chemical properties of the product.
c. Drilling. The drilling or ablating of a hole or holes through the polymeric
film coating shell on the surfaces of a solid oral dosage form using a laser.
The polymeric film shell is not soluble in vivo. The hole or holes allow for the
modified release of the drug from the core of the dosage form.
2. Operating Principles
a. Pan Coating. The uniform deposition of coating material onto the
surface of a solid dosage form, or component thereof, while being translated via a
rotating vessel.
Appendix C 443
Table 9 Unit Operation—Drilling Equipment
Class Subclass Examples
Laser Drilling None Identified Convergent Energies
Coherent
The Automation Partner
Lumonics
b. Gas Suspension. The application of a coating material onto a solid
dosage form, or component thereof, while being entrained in a process gas stream.
Alternatively, this may be accomplished simultaneously by spraying the coating
material and substrate into a process gas stream.
c. Vacuum Film Coating. This technique uses a jacketed pan equipped
with a baffle system. Tablets are placed into the sealed pan, an inert gas (i.e., nitrogen)
is used to displace the air and then a vacuum is drawn.
d. Dip Coating. Coating is applied to the substrate by dipping it into the
coating material. Drying is accomplished using pan coating equipment.
e. Electrostatic Coating. A strong electrostatic charge is applied to the
surface of the substrate. The coating material containing oppositely charged ionic
species is sprayed onto the substrate.
f. Compression Coating. Refer to the Unit Dosing section of this document.
g. Ink-Based Printing. The application of contrasting colored polymer
(ink) onto the surface of a tablet or capsule.
h. Laser Etching. The application of identifying markings onto the surface
of a tablet or capsule using laser-based technology.
i. Drilling. A drilling system typically is a custom built unit consisting
of a material handling system to orient and hold the solid dosage form, a laser (or
lasers), and optics (lenses, mirrors, deflectors, etc.) to ablate the hole or holes, and
controls. The drilling unit may include debris extraction and inspection systems as
well. The sorting, orienting, and holding equipment commonly is provided by
dosage form printing equipment manufacturers, and is considered ancillary in this
use.
B. Equipment Classification
1. Pan Coating
Pan coating subclasses primarily are distinguished by the pan configuration, the
pan perforations, and/or the perforated device used to introduce process air for
drying purposes. Perforated coating systems include both batch and continuous
coating processes.
• Conventional Coating System
• Perforated Coating System
444 Appendix C
2. Gas Suspension
Gas suspension subclasses primarily are distinguished by the method by which the
coating is applied to the substrate.
• Fluidized Bed
• Spray Congealing/Drying
3. Vacuum Film Coating
Although there may be differences in the jacketed pan, baffle system, or vacuum
source, no vacuum film coating subclasses have been identified.
4. Dip Coating
Because of the custom design associated with this class of coating, no dip coating
subclasses or examples have been identified.
5. Electrostatic Coating
Because of the custom design associated with this class of coating, no electrostatic
coating subclasses or examples have been identified.
6. Compression Coating
Refer to the Unit Dosing section of this document.
7. Ink-Based Printing
Ink-based printing subclasses primarily are distinguished by the method by which
the marking is applied to a capsule or tablet surface.
• Offset
• Ink Jet
8. Laser Etching (Printing)
Although laser etching systems may differ from one another, no laser etching subclasses
have been identified.
9. Drilling
The method of producing the laser pulse that ablates the hole(s) is of no consequence
to the physical-chemical properties of the product. Therefore, no dosage
form drilling equipment subclasses have been identified.
Appendix C 445

Appendix D
Guidance for Industry1—Extended
Release Oral Dosage Forms
Development, Evaluation,
and Application of In Vitro/In Vivo
Correlations
I. INTRODUCTION
This guidance provides recommendations to pharmaceutical sponsors who intend
to develop documentation in support of an in vitro/in vivo correlation (IVIVC)
for an oral extended release (ER) drug product for submission in a new drug application
(NDA), abbreviated new drug application (ANDA), or antibiotic drug
application (AADA). The guidance presents a comprehensive perspective on (1)
methods of developing an IVIVC and evaluating its predictability; (2) using an
IVIVC to set dissolution specifications; and (3) applying an IVIVC as a surrogate
for in vivo bioequivalence when it is necessary to document bioequivalence during
the initial approval process or because of certain pre- or postapproval changes
(e.g., formulation, equipment, process, and manufacturing site changes).
II. BACKGROUND
The concept of IVIVC, particularly for ER drug products, has been extensively
discussed by pharmaceutical scientists. The ability to predict, accurately and pre-
447
1 This guidance has been prepared by the Extended Release Dissolution Working Group of the Biopharmaceutics
Coordinating Committee (BCC) in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA). This guidance represents the Agency’s current
thinking on in vitro/in vivo correlations for extended release oral dosage forms. It does not create or
confer any rights for or on any person and does not operate to bind FDA or the public. An alternative
approach may be used if such approach satisfies the applicable statute, regulations, or both.
cisely, expected bioavailability characteristics for an ER product from dissolution
profile characteristics is a long sought after goal. Several workshops and publications
have provided information in support of this goal.
These are discussed briefly as follows:
• A report from a 1987 ASCPT/DIA/APS/FDA-sponsored workshop entitled
Report of the Workshop on CR Dosage Forms: Issues and Controversies
(1987) indicated that the state of science and technology at that
time did not permit consistently meaningful IVIVC for ER dosage forms
and encouraged IVIVC as a future objective. Dissolution testing was considered
useful only for process control, stability, minor formulation
changes, and manufacturing site changes.
• A USP PF Stimuli Article in July 1988 established the classification of
IVIVC into Levels A, B and C, which are currently in use.
• A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled
In vitro/In vivo Testing and Correlation for Oral Controlled/Modified
Release Dosage Forms (1990) concluded that, while the science and technology
may not always permit meaningful IVIVC, the development of an
IVIVC was an important objective on a product-by-product basis. Procedures
for development, evaluation, and application of an IVIVC were
described. Validation of dissolution specifications by a bioequivalence
study involving two batches of product with dissolution profiles at the upper
and lower dissolution specifications was suggested.
• USP Chapter 1088 similarly describes techniques appropriate for Level
A, B, and C correlations and methods for establishing dissolution specifications.
• Further information related to IVIVCs was developed in a USP/AAPS/
FDA-sponsored workshop, which resulted in a report entitled Workshop
II Report: Scale-up of Oral Extended Release Dosage Forms (1993). This
report identified the objectives of an IVIVC to be the use of dissolution as
a surrogate for bioequivalency testing, as well as an aid in setting dissolution
specifications. The report concluded that dissolution may be used
as a sensitive, reliable, and reproducible surrogate for bioequivalence testing.
The report gave support to the concepts of USP Chapter 1088 and further
found that an IVIVC may be useful for changes other than minor
changes in formulation, equipment, process, manufacturing site, and
batch size.
These reports document increasing confidence in IVIVC to estimate the in
vivo bioavailability characteristics for an ER drug product. In this regard, increased
IVIVC activity in NDA submissions has been apparent. Still, the complete
process of developing an IVIVC with high quality and predictability and identifying
specific applications for such correlations has not been well defined.
448 Appendix D
As part of the process of developing this guidance, the Agency conducted
several surveys of NDA submissions for ER drug products to find out the number
of times that IVIVCs were developed. The first survey included NDA submissions
from 1982–1992 and found 9 IVIVCs in 60 submissions. A more recent survey included
NDA submissions from October 1994 to October 1995 and found 9
IVIVCs in 12 submissions.
This guidance is based on these prior deliberations and publications as well
as on current understanding at the FDA and elsewhere on approaches to developing
reliable and useful IVIVCs. This guidance describes the levels of correlations
that can be established with varying degrees of usefulness, important considerations
for in vivo and in vitro experimentation, evaluation of the correlation by
focusing on the critical feature of predictability, and practical applications that can
be achieved using the IVIVC. With the availability of this guidance, sponsors
are encouraged to develop IVIVCs for ER products in the expectation that the
information will be useful in establishing dissolution specifications and will
permit certain formulation and manufacturing changes without an in vivo bioequivalence
study.
III. CATEGORIES OF IN VITRO/IN VIVO CORRELATIONS
A. Level A
A Level A correlation2 is usually estimated by a two-stage procedure: deconvolution
2 followed by comparison of the fraction of drug absorbed to the fraction of
drug dissolved. A correlation of this type is generally linear and represents a pointto-
point relationship between in vitro dissolution and the in vivo input rate (e.g.,
the in vivo dissolution of the drug from the dosage form). In a linear correlation,
the in vitro dissolution and in vivo input curves may be directly superimposable
or may be made to be superimposable by the use of a scaling factor. Nonlinear correlations,
while uncommon, may also be appropriate. Alternative approaches to
developing a Level A IVIVC are possible. One alternative is based on a convolution
procedure that models the relationship between in vitro dissolution and
plasma concentration in a single step. Plasma concentrations predicted from the
model and those observed are compared directly. For these methods, a reference
treatment is desirable, but the lack of one does not preclude the ability to develop
an IVIVC.
Whatever the method used to establish a Level A IVIVC, the model should
predict the entire in vivo time course from the in vitro data. In this context, the
Appendix D 449
2 Level A correlations are the most common type of correlation developed in NDAs submitted to the
FDA. Level B correlations are rarely seen in NDAs; multiple Level C correlations are seen infrequently.
model refers to the relationship between in vitro dissolution of an ER dosage
form and an in vivo response such as plasma drug concentration or amount of
drug absorbed.
B. Level B
A Level B IVIVC uses the principles of statistical moment analysis. The mean in
vitro dissolution time is compared either to the mean residence time or to the mean
in vivo dissolution time. A Level B correlation, like a Level A, uses all of the in
vitro and in vivo data, but is not considered to be a point-to-point correlation. A
Level B correlation does not uniquely reflect the actual in vivo plasma level curve,
because a number of different in vivo curves will produce similar mean residence
time values.
C. Level C
A Level C IVIVC establishes a single point relationship between a dissolution
parameter, for example, t50%, percent dissolved in 4 hours and a pharmacokinetic
parameter (e.g., AUC, Cmax, Tmax). A Level C correlation does not reflect the complete
shape of the plasma concentration time curve, which is the critical factor that
defines the performance of ER products.
D. Multiple Level C
A multiple Level C correlation relates one or several pharmacokinetic parameters
of interest to the amount of drug dissolved at several time points of the dissolution
profile.
IV. GENERAL CONSIDERATIONS:
The following general statements apply in the development of an IVIVC in an
NDA or ANDA/AADA:
• Human data should be supplied for regulatory consideration of an IVIVC.
• Bioavailability studies for IVIVC development should be performed with
enough subjects to characterize adequately the performance of the drug
product under study. In prior acceptable data sets, the number of subjects
has ranged from 6 to 36. Although crossover studies are preferred, parallel
studies or cross-study analyses may be acceptable. The latter may
involve normalization with a common reference treatment. The reference
product in developing an IVIVC may be an intravenous solution, an aqueous
oral solution, or an immediate release product.
450 Appendix D
• IVIVCs are usually developed in the fasted state. When a drug is not tolerated
in the fasted state, studies may be conducted in the fed state.
• Any in vitro dissolution method may be used to obtain the dissolution
characteristics of the ER dosage form. The same system should be used
for all formulations tested.
• The preferred dissolution apparatus is USP apparatus I (basket) or II (paddle),
used at compendially recognized rotation speeds (e.g., 100 rpm for
the basket and 50–75 rpm for the paddle). In other cases, the dissolution
properties of some ER formulations may be determined with USP apparatus
III (reciprocating cylinder) or IV (flow through cell).
Appropriate review staff in CDER should be consulted before using any
other type of apparatus.
• An aqueous medium, either water or a buffered solution preferably not
exceeding pH 6.8, is recommended as the initial medium for development
of an IVIVC. Sufficient data should be submitted to justify pH greater
than 6.8. For poorly soluble drugs, addition of surfactant (e.g., 1% sodium
lauryl sulfate) may be appropriate. In general, nonaqueous and hydroalcoholic
systems are discouraged unless all attempts with aqueous media
are unsuccessful. Appropriate review staff in CDER should be consulted
before using any other media.
• The dissolution profiles of at least 12 individual dosage units from each
lot should be determined. A suitable distribution of sampling points
should be selected to define adequately the profiles. The coefficient of
variation (CV) for mean dissolution profiles of a single batch should be
less than 10%.
• A Level A IVIVC is considered to be the most informative and is recommended,
if possible.
• Multiple Level C correlations can be as useful as Level A correlations.
However, if a multiple Level C correlation is possible, then a Level A correlation
is also likely and is preferred.
• Level C correlations can be useful in the early stages of formulation development
when pilot formulations are being selected.
• Level B correlations are least useful for regulatory purposes.
• Rank order correlations are qualitative and are not considered useful for
regulatory purposes.
V. DEVELOPMENT AND EVALUATION OF A LEVEL A
IN VITRO/IN VIVO CORRELATION
A. Developing the Correlation
The most commonly seen process for developing a Level A IVIVC is to (1) develop
formulations with different release rates, such as slow, medium, fast, or a
Appendix D 451
single release rate if dissolution is condition independent; (2) obtain in vitro dissolution
profiles and in vivo plasma concentration profiles for these formulations;
(3) estimate the in vivo absorption or dissolution time course using an appropriate
deconvolution technique for each formulation and subject (e.g., Wagner-Nelson,
numerical deconvolution). These three steps establish the IVIVC model. Alternative
approaches to developing Level A IVIVCs are possible. Further general
information follows:
• The IVIVC relationship should be demonstrated consistently with two or
more formulations with different release rates to result in corresponding
differences in absorption profiles. Although an IVIVC can be defined
with a minimum of two formulations with different release rates, three or
more formulations with different release rates are recommended. Exceptions
to this approach (i.e., use of only one formulation) may be considered
for formulations for which in vitro dissolution is independent of the
dissolution test conditions (e.g., medium, agitation, pH).
• Ideally, formulations should be compared in a single study with a
crossover design.
• If one or more of the formulations (highest or lowest release rate formulations)
does not show the same relationship between in vitro dissolution
and in vivo performance compared with the other formulations, the correlation
may still be used within the range of release rates encompassed
by the remaining formulations.
• The in vitro dissolution methodology should adequately discriminate
among formulations. Dissolution testing can be carried out during the formulation
screening stage using several methods. Once a discriminating
system is developed, dissolution conditions should be the same for all formulations
tested in the biostudy for development of the correlation and
should be fixed before further steps towards correlation evaluation are undertaken.
• During the early stages of correlation development, dissolution conditions
may be altered to attempt to develop a 1-to-1 correlation between the in
vitro dissolution profile and the in vivo dissolution profile.
• Time scaling may be used as long as the time scaling factor is the same
for all formulations. Different time scales for each formulation indicate
absence of an IVIVC.
B. Evaluating the Predictability of a Level A Correlation
An IVIVC should be evaluated to demonstrate that predictability of in vivo performance
of a drug product from its in vitro dissolution characteristics is maintained
over a range of in vitro dissolution release rates and manufacturing
changes. Since the objective of developing an IVIVC is to establish a predictive
452 Appendix D
mathematical model describing the relationship between an in vitro property and
a relevant in vivo response, the proposed evaluation approaches focus on the estimation
of predictive performance or, conversely, prediction error. Depending on
the intended application of an IVIVC and the therapeutic index of the drug, evaluation
of prediction error internally and/or externally may be appropriate. Evaluation
of internal predictability is based on the initial data used to define the IVIVC
model. Evaluation of external predictability is based on additional test data sets.
Application of one or more of these procedures to the IVIVC modeling process
constitutes evaluation of predictability.
An important concept is that the less data available for initial IVIVC development
and evaluation of predictability, the more additional data may be needed
to define completely the IVIVC’s predictability. Some combination of three or
more formulations with different release rates is considered optimal.
Another significant factor is the range of release rates studied. The release
rates, as measured by percent dissolved, for each formulation studied, should differ
adequately (e.g., by 10%). This should result in in vivo profiles that show a
comparable difference, for example, a 10% difference in the pharmacokinetic parameters
of interest (Cmax or AUC) between each formulation.
Methodology for the evaluation of IVIVC predictability is an active area of
investigation and a variety of methods are possible and potentially acceptable. A
correlation should predict in vivo performance accurately and consistently. Once
this relationship has been achieved, in vitro dissolution can be used confidently as
a surrogate for in vivo bioequivalence of ER drug products in the situations
described below.
1. Experimental Data Considerations
a. Dosage Form Properties: Dependence of In Vitro Release on Experimental
Conditions.
CONDITION INDEPENDENT DISSOLUTION. If in vitro dissolution is shown to
be independent of dissolution conditions (e.g., pH and agitation) and if the in vitro
dissolution profile is shown to be equal to the in vivo absorption or in vivo dissolution
profile, then the results for a single formulation (one release rate) may be
sufficient. Evaluation of data for this formulation and evaluation of additional test
data sets, as appropriate, for the purpose of estimation of internal and/or external
predictability are recommended.
CONDITION DEPENDENT DISSOLUTION. In all other instances where an
IVIVC model is presented, results from a single formulation (one release rate)
should be considered insufficient. To estimate internal and/or external predictability,
evaluation of data from two or more formulations with different
release rates is recommended.
Appendix D 453
b. Internal and External Predictability. Two distinct aspects of predictability
can be considered. However, both aspects are not recommended in all
instances.
ESTIMATION OF PREDICTION ERROR INTERNALLY. The first aspect relates to
evaluating how well the model describes the data used to define the IVIVC and is
appropriate in all instances.
If formulations with three or more release rates are used to develop the
IVIVC model, no further evaluation beyond this initial estimation of prediction error
may be necessary for non-narrow therapeutic index drugs (Category 2 a and b
applications, see page 12). However, depending on the results of this internal
prediction error calculation, determination of prediction error externally may
be appropriate.
If only two formulations with different release rates are used, the application
of the IVIVC is further limited to Category 2a applications (see page 12). In
this circumstance, determination of prediction error externally is recommended
for complete evaluation and subsequent full application of the IVIVC.
ESTIMATION OF PREDICTION ERROR EXTERNALLY. The second aspect relates
to how well the model predicts data when one or more additional test data
sets are used that differ from those used to define the correlation. This is appropriate
in some situations, particularly when only two formulations with different
release rates are used to develop the IVIVC model, when calculation of prediction
error internally is inconclusive, or when a narrow therapeutic index drug is
studied.
The additional test data sets used for external prediction error calculation
may have several differing characteristics compared to the data sets used in IVIVC
development. Although formulations with different release rates provide the optimal
test of an IVIVC’s predictability, a formulation need not be prepared solely
for this purpose. In the absence of such a formulation, data from other types of formulations
may be considered. In each case, bioavailability data should be available
for the data set under consideration.
The following represent, in decreasing order of preference, formulations
that may be used to estimate prediction error externally:
• A formulation with a different release rate than those used in IVIVC development.
The release rate of the test formulation may be either within
or outside the range used to define the IVIVC relationship.
• A formulation with the same or similar release rate, but involving some
change in manufacture of this batch (e.g., composition, process, equipment,
manufacturing site).
• A formulation with the same or similar release rate obtained from another
batch/lot with no changes in manufacturing.
454 Appendix D
c. Pharmacologic Properties of the Drug (Therapeutic Index).
NARROW THERAPEUTIC INDEX DRUGS. If an IVIVC model is to be used in
estimating the in vivo performance of formulations of narrow therapeutic index
drugs, the model’s predictability should be tested further with a data set that
differs from those data sets used to define the correlation. In other words, the external
predictability of the correlation should be evaluated.
NON-NARROW THERAPEUTIC INDEX DRUGS. If an IVIVC model is to be
used in estimating the in vivo performance of formulations of non-narrow therapeutic
index drugs, testing the model’s predictability with a data set that differs
from those data sets used to define the correlation may be desirable, but is not considered
as important as for a narrow therapeutic index drug.
Note—If the classification of a drug as a narrow therapeutic index drug is
uncertain, appropriate review staff in CDER should be consulted.
2. Methods for Evaluation of Predictability
The objective of IVIVC evaluation is to estimate the magnitude of the error in
predicting the in vivo bioavailability results from in vitro dissolution data. This
objective should guide the choice and interpretation of evaluation methods.
Any appropriate approach related to this objective may be used for evaluation
of predictability.
a. Internal Predictability. All IVIVCs should be studied regarding internal
predictability. One recommended approach involves the use of the IVIVC
model to predict each formulation’s plasma concentration profile (or Cmax
and/or AUC for a multiple Level C IVIVC) from each respective formulation’s
dissolution data. This is performed for each formulation used to develop the
IVIVC model. The predicted bioavailability is then compared to the observed
bioavailability for each formulation and a determination of prediction error is
made.
CRITERIA.
• Average absolute percent prediction error (% PE) of 10% or less for Cmax
and AUC establishes the predictability of the IVIVC. In addition, the %
PE for each formulation should not exceed 15%.
• If these criteria are not met, that is, if the internal predictability of the
IVIVC is inconclusive, evaluation of external predictability of the IVIVC
should be performed as a final determination of the ability of the IVIVC
to be used as a surrogate for bioequivalence.
b. External Predictability. Most important when using an IVIVC as a
surrogate for bioequivalence is confidence that the IVIVC can predict in vivo per-
Appendix D 455
formance of subsequent lots of the drug product. Therefore, it may be important
to establish the external predictability of the IVIVC. This involves using the
IVIVC to predict the in vivo performance for a formulation with known bioavailability
that was not used in developing the IVIVC model.
CRITERIA.
• % PE of 10% or less for C and AUC establishes the external max predictability
of an IVIVC.
• % PE between 10–20% indicates inconclusive predictability and the
need for further study using additional data sets. Results of estimation
of PE from all such data sets should be evaluated for consistency of predictability.
• % PE greater than 20% generally indicates inadequate predictability, unless
otherwise justified.
With the exception of narrow therapeutic index drugs, the external predictability
step in the IVIVC evaluation process may be omitted if the evaluation
of internal predictability indicates acceptable % PE. However, when the evaluation
of internal predictability is inconclusive, evaluation of external predictability
is recommended.
VI. DEVELOPMENT AND EVALUATION OF A LEVEL C
IN VITRO/IN VIVO CORRELATION
A single point Level C correlation allows a dissolution specification to be set at
the specified time point. While the information may be useful in formulation development,
waiver of an in vivo bioequivalence study (biowaiver) is generally not
possible if only a single point correlation is available. A multiple point Level C
correlation may be used to justify a biowaiver, provided that the correlation has
been established over the entire dissolution profile with one or more pharmacokinetic
parameters of interest. This could be achieved by correlating the amount
dissolved at various time points with Cmax, AUC, or any other suitable parameter.
A relationship should be demonstrated at each time point with the same parameter
such that the effect on the in vivo performance of any change in dissolution can
be assessed. If such a multiple Level C correlation is achievable, then the development
of a Level A correlation is likely. A multiple Level C correlation should
be based on at least three dissolution time points covering the early, middle, and
late stages of the dissolution profile. The recommendations for assessing the predictability
of Level C correlations will depend on the type of application for which
the correlation is to be used. These methods and criteria are the same as those for
a Level A correlation (see Section V B2).
456 Appendix D
VII. APPLICATIONS OF AN IVIVC
In vitro dissolution testing is important for (1) providing process control and quality
assurance; (2) determining stable release characteristics of the product over
time; and (3) facilitating certain regulatory determinations (e.g., absence of effect
of minor formulation changes or of change in manufacturing site on performance).
In certain cases, especially for ER formulations, the dissolution test can serve not
only as a quality control for the manufacturing process but also as an indicator of
how the formulation will perform in vivo. Thus, a main objective of developing and
evaluating an IVIVC is to establish the dissolution test as a surrogate for human
bioequivalence studies, which may reduce the number of bioequivalence studies
performed during the initial approval process as well as with certain scale-up and
postapproval changes. However, for the applications outlined below, the adequacy
of the in vitro dissolution method to act as a surrogate for in vivo testing should be
shown through an IVIVC for which predictability has been established.
A. Biowaivers for Changes in the Manufacturing of a Drug
Product
1. Category 1: Biowaivers Without an IVIVC
For formulations consisting of beads in capsules, with the only difference between
strengths being the number of beads, approval of lower strengths without an
IVIVC is possible, provided bioavailability data are available for the highest
strength.
Where the guidance for industry SUPAC-MR: Modified Release Solid Oral
Dosage Forms; Scale-Up and Postapproval changes: Chemistry, Manufacturing,
and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation
recommends a biostudy, biowaivers for the same changes made on lower
strengths are possible without an IVIVC if (1) all strengths are compositionally proportional
or qualitatively the same, (2) in vitro dissolution profiles of all strengths
are similar, (3) all strengths have the same release mechanism, (4) bioequivalence
has been demonstrated on the highest strength (comparing changed and unchanged
drug product), and (5) dose proportionality has been demonstrated for this ER drug
product. In the last circumstance (5), documentation of dose proportionality may
not be necessary if bioequivalence has been demonstrated on the highest and lowest
strengths of the drug product, comparing changed and unchanged drug product
for both strengths, as recommended in SUPAC-MR.
For the above situations, waivers can be granted without an IVIVC if dissolution
data are submitted in the application/compendial medium and in three other
media (e.g., water, 0.1N HCl, and USP buffer at pH 6.8, comparing the drug product
after the change to the drug product before the change).
Appendix D 457
Biowaivers, as defined in SUPAC-MR, that do not necessitate either bioequivalence
testing or an IVIVC will likely be granted in preapproval situations for
both narrow and non-narrow therapeutic index ER drug products if dissolution
data, as described in SUPAC-MR, are submitted.
a. Comparison of Dissolution Profiles. Dissolution profiles can be compared
using model independent or model dependent methods. A model independent
approach using a similarity factor, and comparison criteria are described in
SUPAC-MR.
2. Category 2: Biowaivers Using an IVIVC: Non-Narrow
Therapeutic Index Drugs
a. Two Formulations/Release Rates. A biowaiver will likely be granted
for an ER drug product using an IVIVC developed with two formulations/release
rates for (1) Level 3 manufacturing site changes as defined in SUPAC-MR; (2)
Level 3 nonrelease controlling excipient changes as defined in SUPAC-MR, with
the exception of complete removal or replacement of excipients (see below).
b. Three Formulations/Release Rates. A biowaiver will likely be
granted for an ER drug product using an IVIVC developed with three formulations/
release rates (or developed with two formulations/release rates with establishment
of external predictability) for (1) Level 3 process changes as defined in
SUPAC-MR; (2) complete removal of or replacement of nonrelease controlling
excipients as defined in SUPAC-MR; and (3) Level 3 changes in the release controlling
excipients as defined in SUPAC-MR.
c. Biowaivers for Lower Strengths. If an IVIVC is developed with the
highest strength, waivers for changes made on the highest strength and any lower
strengths may be granted if these strengths are compositionally proportional or
qualitatively the same, the in vitro dissolution profiles of all the strengths are similar,
and all strengths have the same release mechanism.
d. Approval of New Strengths. This biowaiver is applicable to strengths
lower than the highest strength, within the dosing range that has been established
to be safe and effective, if the new strengths are compositionally proportional or
qualitatively the same; have the same release mechanism; have similar in vitro
dissolution profiles; and are manufactured using the same type of equipment and
the same process at the same site as other strengths that have bioavailability data
available.
For generic products to qualify for this biowaiver, one of the following situations
should exist:
• Bioequivalence has been established for all strengths of the reference
listed product.
458 Appendix D
• Dose proportionality has been established for the reference listed product,
and all reference product strengths are compositionally proportional or
qualitatively the same, have the same release mechanism, and the in vitro
dissolution profiles of all strengths are similar.
• Bioequivalence is established between the generic product and the reference
listed product at the highest and lowest strengths and, for the reference
listed product, all strengths are compositionally proportional or qualitatively
the same, have the same release mechanism, and the in vitro
dissolution profiles are similar.
OBTAINING CATEGORY 2D BIOWAIVERS: The difference in predicted means
of Cmax and AUC should be no more than 10%, based on dissolution profiles of
the highest strength and the lower strength product.
e. Changes in Release Controlling Excipients. Changes in release
controlling excipients in the formulation should be within the range of release
controlling excipients of the established correlation.
f. Obtaining Category 2a, 2b, and 2c Biowaivers. The difference in predicted
means of Cmax and AUC should be no more than 20% from that of the reference
product and, where appropriate, the new formulation should meet the application/
compendial dissolution specifications.
3. Category 3: Biowaivers Using an IVIVC: Narrow Therapeutic
Index Drugs
If external predictability of an IVIVC is established, the following waivers will
likely be granted if at least two formulations/release rates have been studied for
the development of the IVIVC.
a. Situations in Which Biowaivers May be Granted. A biowaiver will
likely be granted for an ER drug product using an IVIVC for (1) Level 3 process
changes as defined in SUPAC-MR; (2) complete removal of or replacement of
non-release controlling excipients as defined in SUPAC-MR; and (3) Level 3
changes in the release controlling excipients as defined in SUPAC-MR.
b. Biowaivers for Lower Strengths. If an IVIVC is developed with the
highest strength, waivers for changes made on the highest strength and any lower
strengths may be granted, if these strengths are compositionally proportional or
qualitatively the same, the in vitro dissolution profiles of all the strengths are similar,
and all strengths have the same release mechanism.
c. Approval of New Strengths. This biowaiver is applicable to strengths
lower than the highest strength, within the dosing range that has been established
to be safe and effective, provided that the new strengths are compositionally proportional
or qualitatively the same, have the same release mechanism, have simi-
Appendix D 459
lar in vitro dissolution profiles, and are manufactured using the same type of
equipment, and the same process at the same site as other strengths that have
bioavailability data available.
For generic products to qualify for this biowaiver, one of the following situations
should exist:
• Bioequivalence has been established for all strengths of the reference
listed product.
• Dose proportionality has been established for the reference listed product,
all reference product strengths are compositionally proportional or qualitatively
the same and have the same release mechanism, and the in vitro
dissolution profiles of all strengths are similar.
• Bioequivalence is established between the generic product and the reference
listed product at the highest and lowest strengths and, for the
reference listed product, all strengths are compositionally proportional or
qualitatively the same and have the same release mechanism, and the in
vitro dissolution profiles are similar.
OBTAINING CATEGORY 3C BIOWAIVERS. The difference in predicted means
of Cmax and AUC should be no more than 10%, based on dissolution profiles of
the highest strength and the lower strength product.
d. Changes in Release Controlling Excipients. Changes in release controlling
excipients in the formulation should be within the range of release controlling
excipients of the established correlation.
e. Obtaining Category 3a and 3b Biowaivers. The difference in predicted
means of Cmax and AUC should be no more than 20% from that of the
reference product and, where appropriate, the new formulation meets the application/
compendial dissolution specifications.
4. Category 4: Biowaivers When In Vitro Dissolution Is
Independent of Dissolution Test Conditions
Situations in which biowaivers are likely to be granted for both narrow and nonnarrow
therapeutic index drugs:
a. Category 2 and Category 3 Biowaivers are Likely to be Granted with
an IVIVC Established with One Formulation/Release Rate. Biowaivers may be
granted if dissolution data are submitted in application/compendial medium and
in three other media (e.g., water, 0.1 N HCl, USP buffer at pH 6.8) and the following
conditions apply:
• In vitro dissolution should be shown to be independent of dissolution test
conditions after change is made in drug product manufacturing.
• Comparison of dissolution profiles
460 Appendix D
Dissolution profiles can be compared using model independent or model dependent
methods. A model independent approach using a similarity factor and
comparison criteria is described in SUPAC-MR.
b. Obtaining Category 4 Biowaivers. The difference in predicted means
of Cmax and AUC should be no more than 20% from that of the reference product
and, where appropriate, the new formulation should meet the application/compendial
dissolution specifications.
5. Category 5: Situations for Which an IVIVC Is Not
Recommended
a. Approval of a New Formulation of an Approved ER Drug Product
When the New Formulation has a Different Release Mechanism.
b. Approval of a Dosage Strength Higher or Lower Than the Doses That
Have Been Shown to be Safe and Effective in Clinical Trials.
c. Approval of Another Sponsor’s ER Product Even with the Same Release
Controlling Mechanism.
d. Approval of a Formulation Change Involving a Nonrelease Controlling
Excipient in the Drug Product That May Significantly Affect Drug Absorption.
B. Setting Dissolution Specifications
In vitro dissolution specifications should generally be based on the performance
of the clinical/bioavailability lots. These specifications may sometimes be
widened so that scale-up lots, as well as stability lots, meet the specifications associated
with the clinical/bioavailability lots. This approach is based on the use of
the in vitro dissolution test as a quality control test without any in vivo significance,
even though in certain cases (e.g., ER formulations), the rate limiting step
in the absorption of the drug is the dissolution of the drug from the formulation.
An IVIVC adds in vivo relevance to in vitro dissolution specifications, beyond
batch-to-batch quality control. In this approach, the in vitro dissolution test becomes
a meaningful predictor of in vivo performance of the formulation, and dissolution
specifications may be used to minimize the possibility of releasing lots
that would be different in in vivo performance.
1. Setting Dissolution Specifications Without an IVIVC
• The recommended range at any dissolution time point specification is 
10% deviation from the mean dissolution profile obtained from the clinical/
bioavailability lots.
• In certain cases, reasonable deviations from the  10 % range can be accepted
provided that the range at any time point does not exceed 25%.
Appendix D 461
Specifications greater than 25% may be acceptable based on evidence that
lots (side batches) with mean dissolution profiles that are allowed by the
upper and lower limit of the specifications are bioequivalent.
• Specifications should be established on clinical/bioavailability lots.
Widening specifications based on scale-up, stability, or other lots for which
bioavailability data are unavailable is not recommended.
• A minimum of three time points is recommended to set the specifications.
These time points should cover the early, middle, and late stages of the dissolution
profile. The last time point should be the time point where at least
80% of drug has dissolved. If the maximum amount dissolved is less than
80%, the last time point should be the time when the plateau of the dissolution
profile has been reached.
• Specifications should be established based on average dissolution data for
each lot under study, equivalent to USP Stage 2 testing. Specifications allow
that all lots to pass at Stage 1 of testing may result in lots with less than
optimal in vivo performance passing these specifications at USP Stage 2 or
Stage 3.
• USP acceptance criteria for dissolution testing are recommended unless alternate
acceptance criteria are specified in the ANDA/NDA.
2. Setting Dissolution Specifications Where an IVIVC Has Been
Established
Optimally, specifications should be established such that all lots that have dissolution
profiles within the upper and lower limits of the specifications are bioequivalent.
Less optimally but still possible, lots exhibiting dissolution profiles at
the upper and lower dissolution limits should be bioequivalent to the
clinical/bioavailability lots or to an appropriate reference standard.
a. Level A Correlation Established.
• Specifications should be established based on average data.
• A minimum of three time points is recommended to establish the
specifications. These time points should cover the early, middle and
late stages of the dissolution profile. The last time point should be the
time point where at least 80% of drug has dissolved. If the maximum
amount dissolved is less than 80%, then the last time point should be
the time where the plateau of the dissolution profile has been reached.
• Calculate the plasma concentration time profile using convolution
techniques or other appropriate modeling techniques and determine
whether the lots with the fastest and slowest release rates that are allowed
by the dissolution specifications result in a maximal difference
of 20% in the predicted Cmax and AUC.
462 Appendix D
• An established IVIVC may allow setting wider dissolution specifications.
This would be dependent on the predictions of the IVIVC (i.e.,
20% differences in the predicted Cmax and AUC).
• USP acceptance criteria for dissolution testing are recommended unless
alternate acceptance criteria are specified in the ANDA/NDA.
b. Multiple Level C Correlation Established.
• If a multiple point Level C correlation has been established, establish
the specifications at each time point such that there is a maximal difference
of 20% in the predicted Cmax and AUC.
• Additionally, the last time point should be the time point where at
least 80% of drug has dissolved.
c. Level C Correlation Based on Single Time Point Established. This
one time point may be used to establish the specification such that there is not
more than a 20% difference in the predicted AUC and Cmax. At other time points,
the maximum recommended range at any dissolution time point specification
should be  10% of label claim deviation from the mean dissolution profile obtained
from the clinical/bioavailability lots. Reasonable deviations from  10%
may be acceptable if the range at any time point does not exceed 25%.
3. Setting Specifications Based on Release Rate
If the release characteristics of the formulation can be described by a zero-order
process for some period of time (e.g., 5%/hr from 4 to 12 hours), and the dissolution
profile appears to fit a linear function for that period of time, a release rate
specification may be established to describe the dissolution characteristics of that
formulation. A release rate specification may be an addition to the specifications
established on the cumulative amount dissolved at the selected time points. Alternatively,
a release the rate specification may be the only specification except for
the specification for time when at least 80% of drug has dissolved.
DEFINITION OF TERMS
Batch: A specific quantity of a drug or other material produced according to a
single manufacturing order during the same cycle of manufacture and intended to
have uniform character and quality, within specified limits (21 CFR 210.3(b)(2)).
Batch Formula (Composition): A complete list of the ingredients and their
amounts to be used for the manufacture of a representative batch of the drug product.
All ingredients should be included in the batch formula whether or not they
remain in the finished product (Guideline for Submitting Documentation for the
Manufacture of and Controls for Drug Products, FDA, February 1987).
Appendix D 463
Bioavailability: The rate and extent to which the active drug ingredient or therapeutic
moiety is absorbed from a drug product and becomes available at the site
of drug action (21 CFR 320.1(a)).
Biobatch: A lot of drug product formulated for purposes of pharmacokinetic
evaluation in a bioavailability/bioequivalency study. This lot should be 10% or
greater than the proposed commercial production batch or at least 100,000 units,
whichever is greater.
Bioequivalent Drug Products: Pharmaceutical equivalents or pharmaceutical
alternatives whose rate and extent of absorption do not show a significant difference
when administered at the same molar dose of the therapeutic moiety under
similar experimental conditions, either single dose or multiple dose. Some pharmaceutical
equivalents or pharmaceutical alternatives may be equivalent in the
extent of their absorption but not in their rate of absorption and yet may be considered
bioequivalent because such differences in the rate of absorption are intentional
and are reflected in the labeling, are not essential to the attainment of effective
body drug concentrations on chronic use, or are considered medically
insignificant for the particular drug product studied (21 CFR 320.1(e)).
Convolution: Prediction of plasma drug concentrations using a mathematical
model based on the convolution integral. For example, the following convolution
integral equation may be used to predict the plasma concentration (c(t)) resulting
from the absorption rate time course (rabs):
c(t) 
 0
t c (t  u) rabs (u) du
The function c represents the concentration time course that would result from
the instantaneous absorption of a unit amount of drug and can be estimated from
either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo) immediate
release dosage forms.
Correlation: As used in this guidance, a relationship between in vitro dissolution
rate and in vivo input (absorption) rate.
Deconvolution: Estimation of the time course of drug input (usually in vivo absorption
or dissolution) using a mathematical model based on the convolution integral.
For example, the absorption rate time course (rabs) that resulted in the
plasma concentrations (c(t)) may be estimated by solving the following convolution
integral equation for r : abs
c(t) 
 0
t c (t  u) rabs (u) du
The function c represents the concentration time course that would result from
the instantaneous absorption of a unit amount of drug and is typically estimated
from either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo)
immediate release dosage forms.
Development: Establishing an in vitro/in vivo correlation.
Drug Product: A finished dosage form, e.g., tablet, capsule, or solution, that
464 Appendix D
contains a drug substance, generally, but not necessarily, in association with one
or more other ingredients (21 CFR 314.3(b)).
Extended Release Dosage Form: A dosage form that allows a reduction in dosing
frequency as compared to that presented by a conventional dosage form, e.g.,
a solution or an immediate release dosage form.
Evaluation: In the context of in vitro/in vivo correlation, a broad term encompassing
experimental and statistical techniques used during development and
evaluation of a correlation which aid in determining the predictability of the correlation.
Formulation: A listing of the ingredients and composition of the dosage form.
In Vitro/In Vivo Correlation: A predictive mathematical model describing the
relationship between an in vitro property of an extended release dosage form (usually
the rate or extent of drug dissolution or release) and a relevant in vivo response,
e.g., plasma drug concentration or amount of drug absorbed.
In Vivo Dissolution: The process of dissolution of drug in the gastro-intestinal
tract.
In Vitro Release: Drug dissolution (release) from a dosage form as measured
in an in vitro dissolution apparatus.
In Vivo Release: In vivo dissolution of drug from a dosage form as determined
by deconvolution of data obtained from pharmacokinetic studies in humans (patients
or healthy volunteers).
Level A Correlation: A predictive mathematical model for the relationship between
the entire in vitro dissolution/release time course and the entire in vivo response
time course, e.g., the time course of plasma drug concentration or amount
of drug absorbed.
Level B Correlation: A predictive mathematical model for the relationship
between summary parameters that characterize the in vitro and in vivo time
courses, e.g., models that relate the mean in vitro dissolution time to the mean
in vivo dissolution time, the mean in vitro dissolution time to the mean residence
time in vivo, or the in vitro dissolution rate constant to the absorption rate
constant.
Level C Correlation: A predictive mathematical model of the relationship between
the amount dissolved in vitro at a particular time (or the time required for
in vitro dissolution of a fixed percent of the dose, e.g., T50 %) and a summary parameter
that characterizes the in vivo time course (e.g., Cmax or AUC).
Lot: A batch, or a specific identified portion of a batch, having uniform character
and quality within specified limits or, in the case of a drug product produced
by continuous process, a specific identified amount produced in a unit of time or
quantity in a manner that assures its having uniform character and quality within
specified limits (21 CFR 210.3(b)(10)).
Mean Absorption Time: The mean time required for drug to reach systemic
circulation from the time of drug administration. This term commonly refers to the
Appendix D 465
mean time involved in the in vivo release and absorption processes as they occur
in the input compartment and is estimated as MAT 
 MRToral  MRTi.v.
Mean In Vitro Dissolution Time: The mean time for the drug to dissolve under
in vitro dissolution conditions. This is calculated using the following equation:
MDTvitro 

 0
. (M.
M

.
M(t))dt

Mean In Vivo Dissolution Time: For a solid dosage form: MDTsolid 
 MRTsolid
 MRTsolution. This reflects the mean time for drug to dissolve in vivo.
Mean Residence Time: The mean time that the drug resides in the body. MRT
may also be the mean transit time. MRT 
 AUMC/AUC.
Narrow Therapeutic Index Drugs: Drugs having, for example, less than a
two-fold difference in the minimum toxic concentrations and the minimum effective
concentrations (21 CFR 320.33 (c)).
Nonrelease Controlling Excipient (Noncritical Compositional Variable):
An inactive ingredient in the final dosage form that does not significantly affect
the release of the active drug substance from the dosage form.
Predictability: Verification of the model’s ability to describe in vivo bioavailability
results from a test set of in vitro data (external predictability) as well as
from the data that was used to develop the correlation (internal predictability).
Percent Prediction Error: % PE 
 [(Observed value  Predicted value) / Observed
value]  100
Release Controlling Excipient (Critical Compositional Variable): An inactive
ingredient in the final dosage form that functions primarily to extend the release
of the active drug substance from the dosage form.
Release Mechanism: The process by which the drug substance is released from
the dosage form.
Release Rate: Amount of drug released per unit of time as defined by in vitro
or in vivo testing.
Statistical Moments: Parameters that describe the characteristics of the time
courses of plasma concentration (area, mean residence time, and variance of mean
residence time) and of urinary excretion rate.
REFERENCES
1. Gillespie, W. R., Office of Clinical Pharmacology and Biopharmaceutics, FDA, “Convolution-
Based Approaches for In Vivo-In Vitro Correlation Modeling.”
2. FDA, September 1997, Guidance for Industry: SUPAC-MR: Modified Release Solid
Oral Dosage Forms; Scale-Up and Post-Approval Changes: Chemistry, Manufacturing
and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.
466 Appendix D
3. Moore, J. W., and H. H. Flanner, November 1994, “Mathematical Comparison of
Curves with an Emphasis on Dissolution Profiles,” presented at the AAPS National
Meeting, Personal Communication from AAI Inc., Wilmington, NC 28405.
4. Skelly, J. P., et al., 1987, “Report of the Workshop on CR Dosage Forms: Issues and
Controversies,” Pharmaceutical Research, 4(1):75–78.
5. United States Pharmacopeial Convention, Inc., July 1988, “In Vitro-In Vivo Correlation
for Extended Release Oral Dosage Forms,” Pharmacopeial Forum Stimuli Article,
4160–4161.
6. Skelly, J. P., et al., September 1990, “Report of Workshop on In Vitro and In Vivo
Testing and Correlation for Oral Controlled/Modified-Release Dosage Forms,” Journal
of Pharmaceutical Sciences, 79(9):849–854.
7. United States Pharmacopeial Convention, Inc., “In Vitro In Vivo Evaluation of Dosage
Forms”, USP XXIII1088, 1927–1929.
8. Skelly, J. P., et al., 1993, Workshop II Report “Scale-up of Oral Extended Release
Dosage Forms,” Pharmaceutical Research, 10(12):1800–1805.
Appendix D 467

Appendix E
Guidance for Industry1—
Nonsterile Semisolid Dosage Forms
Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls;
In Vitro Release Testing and In Vivo
Bioequivalence Documentation
SUPAC-SS
I. INTRODUCTION
This guidance provides recommendations to pharmaceutical sponsors of new
drug applications (NDAs), abbreviated new drug applications (ANDAs), and abbreviated
antibiotic drug applications (AADAs) who intend to change (1) the
components or composition, (2) the manufacturing (process and equipment), (3)
the scale-up/scale-down of manufacture, and/or (4) the site of manufacture of a
semisolid formulation during the postapproval period. This guidance addresses
nonsterile semisolid preparations (e.g., creams, gels, lotions, and ointments) intended
for topical routes of administration. The guidance defines (1) the levels
of change; (2) recommended chemistry, manufacturing, and controls (CMC)
tests to support each level of change; (3) recommended in vitro release tests
469
1 This guidance has been prepared by the Scale-Up and Post Approval Change Semisolids (SUPACSS)
Working Group operating under the direction of the Chemistry Manufacturing Controls Coordinating
Committee (CMC CC) and the Biopharmaceutics Coordinating Committee (BCC) in the Center
for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance
document represents the Agency’s current thinking on semisolid dosage forms scale-up and postapproval
changes. It does not create or confer any rights for or on any person and does not operate to
bind FDA or the public. An alternative approach may be used if such approach satisfies the requirement
of the applicable statute, regulations, or both.
and/or in vivo bioequivalence tests to support each level of change; and (4) documentation
to support the change.
The guidance specifies the application information that should be provided
to the Center for Drug Evaluation and Research (CDER) to ensure continuing
product quality and performance chacteristics of the semisolid topical formulation
for specified changes. The guidance does not comment on or otherwise affect
compliance/inspection documentation defined by the Office of Compliance in
CDER or the Office of Regulatory Affairs at FDA.
The guidance provides recommendations on application documentation for
the following multiple changes, provided appropriate test and filing documents are
submitted (1) multiple level 1 changes with level 1 test and filing documentation;
(2) multiple level 1 changes; one level 2 change with level 2 test and filing documentation;
(3) multiple level 2 changes with level 2 test documentation and a prior
approval supplement (PAS) and (4) level 3 manufacturing site change and any
other level 1 change with level 3 manufacturing site change test and filing documentation.
The documentation to support the changes varies depending on the type
and the complexity of the semisolid dosage form. For those changes filed in a
Changes Being Effected (CBE) Supplement (21 CFR 314.70(c)), the FDA may review
the supplemental information and decide that the changes are not approvable.
Sponsors should contact the appropriate CDER review division and staff for information
about tests and application documentation for changes not addressed in
this guidance, or for successive level 2 or 3 changes submitted over a short period.
The regulations provide that applicants may make changes to an approved
application in accordance with a guidance, notice, or regulation published in the
Federal Register that provides for a less burdensome notification of the change
(e.g., by notification at the time a supplement is submitted or in the next annual report)
(21 CFR 314.70(a)). This guidance permits less burdensome notice of certain
postapproval changes within the meaning of § 314.70(a).
II. GENERAL BACKGROUND
In general, semisolid dosage forms are complex formulations having complex
structural elements. Often they are composed of two phases (oil and water), one
of which is a continuous (external) phase, and the other of which is a dispersed (internal)
phase. The active ingredient is often dissolved in one phase, although occasionally
the drug is not fully soluble in the system and is dispersed in one or both
phases, thus creating a three-phase system. The physical properties of the dosage
form depend upon various factors, including the size of the dispersed particles, the
interfacial tension between the phases, the partition coefficient of the active ingredient
between the phases, and the product rheology. These factors combine to
determine the release characteristics of the drug, as well as other characteristics,
such as viscosity.
470 Appendix E
A. Critical Manufacturing Parameters
For a true solution, the order in which solutes are added to the solvent is usually
unimportant. The same cannot be said for dispersed formulations, however, because
dispersed matter can distribute differently depending on to which phase a
particulate substance is added. In a typical manufacturing process, the critical
points are generally the initial separation of a one-phase system into two phases
and the point at which the active ingredient is added. Because the solubility of
each added ingredient is important for determining whether a mixture is visually
a single homogeneous phase, such data, possibly supported by optical microscopy,
should usually be available for review. This is particularly important
for solutes added to the formulation at a concentration near or exceeding that of
their solubility at any temperature to which the product may be exposed. Variations
in the manufacturing procedure that occur after either of these events are
likely to be critical to the characteristics of the finished product. This is especially
true of any process intended to increase the degree of dispersion through
reducing droplet or particle size (e.g., homogenization). Aging of the finished
bulk formulation prior to packaging is critical and should be specifically addressed
in process validation studies.
B. General Stability Considerations
The effect that SUPAC changes may have on the stability of the drug product
should be evaluated. For general guidance on conducting stability studies, see the
FDA Guideline for Submitting Documentation for the Stability of Human Drugs
and Biologics. For SUPAC submissions, the following points should also be considered:
1. In most cases, except those involving scale-up, stability data from pilot
scale batches will be acceptable to support the proposed change.
2. Where stability data show a trend towards potency loss or degradant increase
under accelerated conditions, it is recommended that historical
accelerated stability data from a representative prechange batch be submitted
for comparison. It is also recommended that under these circumstances,
all available long-term data on test batches from ongoing
studies be provided in the supplement. Submission of historical accelerated
and available long-term data would facilitate review and approval
of the supplement.
3. A commitment should be included to conduct long-term stability
studies through the expiration dating period, according to the approved
protocol, on either the first or first three (see section III-VI for details)
production batches, and to report the results in subsequent annual
reports.
Appendix E 471
C. The Role of In Vitro Release Testing
The key parameter for any drug product is its efficacy as demonstrated in controlled
clinical trials. The time and expense associated with such trials make them
unsuitable as routine quality control methods. Therefore, in vitro surrogate tests
are often used to assure that product quality and performance are maintained over
time and in the presence of change. A variety of physical and chemical tests commonly
performed on semisolid products and their components (e.g., solubility,
particle size and crystalline form of the active component, viscosity, and homogeneity
of the product) have historically provided reasonable evidence of consistent
performance. More recently, in vitro release testing has shown promise as a
means to comprehensively assure consistent delivery of the active component(s)
from semisolid products.
An in vitro release rate can reflect the combined effect of several physical
and chemical parameters, including solubility and particle size of the active ingredient
and rheological properties of the dosage form. In most cases, in vitro release
rate is a useful test to assess product sameness between prechange and
postchange products. However, there may be instances where it is not suitable for
this purpose. In such cases, other physical and chemical tests to be used as measures
of sameness should be proposed and discussed with the Agency. With any
test, the metrics and statistical approaches to documentation of “sameness” in
quality attributes should be considered.
The evidence available at this time for the in vitro-in vivo correlation of release
tests for semisolid dosage forms is not as convincing as that for in vitro dissolution
as a surrogate for in vivo bioavailability of solid oral dosage forms. Therefore,
the Center’s current position concerning in vitro release testing is as follows:
1. In vitro release testing is a useful test to assess product “sameness” under
certain scale-up and postapproval changes for semisolid products.
2. The development and validation of an in vitro release test are not required
for approval of an NDA, ANDA or AADA nor is the in vitro release
test required as a routine batch-to-batch quality control test.
3. In vitro release testing, alone, is not a surrogate test for in vivo bioavailability
or bioequivalence.
4. The in vitro release rate should not be used for comparing different formulations
across manufacturers.
III. COMPONENTS AND COMPOSITION
This section of the guidance focuses on changes in excipients in the drug product.
Qualitative changes in excipients should include only those excipients which are
472 Appendix E
present in approved drug products for the specific route of administration. Quantitative
changes in excipients should not exceed the amount previously approved
in products with the same specific route of administration.2 The chronology of
changes in components and composition should be provided. Changes in components
or composition that have the effect of adding a new excipient or deleting an
existing excipient are defined as level 3 changes (see section III.C below), except
as described below. These changes generally result in the need to change the labeling.
Compositional changes in preservatives are considered separately and are
not included as part of the total additive effect under sections III.A, B and C.
A. Level 1 Change
1. Definition of Level
Level 1 changes are those that are unlikely to have any detectable impact on formulation
quality and performance.
Examples:
• Deletion or partial deletion of an ingredient intended to affect the color,
fragrance, or flavor of the drug product.
• Any change in an excipient up to 5% of approved amount of that excipient.
The total additive effect of all excipient changes should not be more
than 5%. Changes in the composition should be based on the approved
target composition and not on previous level 1 changes in the composition.
A change in diluent (q.s. excipient) due to component and composition
changes in excipient may be made and is excluded from the 5%
change limit.
• Change in a supplier of a structure forming excipient that is primarily a
single chemical entity (purity$95%) or change in a supplier or technical
grade of any other excipient.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and stability testing. Stability testing: First production batch on
long-term stability reported in annual report.
b. In Vitro Release Documentation. None.
c. In Vivo Bioequivalence Documentation. None.
Appendix E 473
2 FDA, CDER, Inactive Ingredient Guide, 1996, Division of Drug Information Resources.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Level 2 changes are those that could have a significant impact on formulation
quality and performance.
Examples:
• Changes of 5% and 
10% of approved amount of an individual excipient.
The total additive effect of all excipient changes should not be
more than 10%. Changes in the composition should be based on the approved
target composition and not on previous level 1 or level 2 changes
in the composition. Changes in diluent (q.s. excipient) due to component
and composition changes in excipients are acceptable and are excluded
from the 10% change limit.
• Change in supplier of a structure forming excipient not covered under
level 1.
• Change in the technical grade of structure forming excipient.
• Change in particle size distribution of the drug substance, if the drug is
in suspension.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and executed batch records.
Stability testing: One batch with three months accelerated stability data reported
in changes being effected supplement and long-term stability data of first
production batch reported in annual report.
b. In Vitro Release Documentation. The in vitro release rate of a lot of the
new/modified formulation should be compared with that of a recent lot of comparable
age of the pre-change formulation of the product. The median in vitro release
rates (as estimated by the estimated slope from each cell, see section VII) of the two
formulations should be demonstrated to be within acceptable limits using the testing
procedure described in section VII (IN VITRO RELEASE TEST) below.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
474 Appendix E
C. Level 3 Change
1. Definition of Level
Level 3 changes are those that are likely to have a significant impact on formulation
quality and performance.
Examples:
• Any qualitative and quantitative changes in an excipient beyond the
ranges noted in level 2 change.
• Change in crystalline form of the drug substance, if the drug is in suspension.
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements and executed batch records.Significant body of information
available: One batch with three months accelerated stability data reported in prior
approval supplement and long-term stability data of first three production batches
reported in annual report.
Significant body of information not available: Three batches with three
months accelerated stability data reported in prior approval supplement and longterm
stability data of first three production batches reported in annual report.
b. In Vitro Release Documentation. The in vitro release rate of the
new/modified formulation should be established as a point of reference. Under
this level 3 change, in vitro release documentation is not required, but sponsors are
encouraged to develop this information for use in subsequent changes under this
guidance.
c. In Vivo Bioequivalence Documentation. Full bioequivalence study on
the highest strength, with in vitro release/other approach on the lower strength(s).
3. Filing Documentation
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
D. Preservative
For semisolid products, any change in the preservative may affect the quality
of the product. If any quantitative or qualitative changes are made in the
formulation, additional testing should be performed. No in vitro release documentation
or in vivo bioequivalence documentation is needed for preservative
changes.
Appendix E 475
1. Level 1 Change
a. Definition of Level. Quantitatively 10% or less change in the approved
amount of preservative.
b. Test Documentation.
• Application/compendial product release requirements.
• Preservative Effectiveness Test carried out at lowest specified
preservative level.
c. Filing Documentation. Annual report
2. Level 2 Change
a. Definition of Level. Quantitatively greater than 10% and up to 20%
change in the approved amount of preservative.
b. Test Documentation.
• Application/compendial product release requirements.
• Preservative Effectiveness Test at lowest specified preservative
level.
c. Filing Documentation. Changes being effected supplement.
3. Level 3 Change
a. Definition of Level. Quantitatively greater than 20% change in the approved
amount of preservative (including deletion) or use of a different preservative.
b. Test Documentation.
• Application/compendial product release requirements.
• Preservative Effectiveness Test at lowest specified preservative
level.
• Analytical method for identification and assay for new preservative.
• Validation studies to show that the new preservative does not interfere
with application/compendial test.
• Executed batch records.
• Stability testing: One batch with three months accelerated stability
data reported in prior approval supplement and long-term stability
data of first production batch reported in annual report.
c. Filing Documentation. Prior approval supplement (all information including
accelerated stability data); annual report (long-term stability data).
476 Appendix E
IV. MANUFACTURING
Manufacturing changes may affect both equipment used in the manufacturing process
and the process itself.
A. Equipment
1. Level 1 Change
a. Definition of Level. Change from nonautomated or nonmechanical
equipment to automated or mechanical equipment to transfer ingredients. Change
to alternative equipment of the same design and operating principles.
b. Test Documentation.
I. CHEMISTRY DOCUMENTATION. Application/compendial product release
requirements. Notification of change and submission of updated executed
batch records. Stability testing: First production batch on long-term stability reported
in annual report.
II. IN VITRO RELEASE DOCUMENTATION. None.
III. IN VIVO BIOEQUIVALENCE DOCUMENTATION. None.
c. Filing Documentation. Annual report (all information including longterm
stability data).
2. Level 2 Change
a. Definition of Level. Change in equipment to a different design or different
operating principles. Change in type of mixing equipment, such as high
shear to low shear and vice versa.
b. Test Documentation.
I. CHEMISTRY DOCUMENTATION. Application/compendial product release
requirements. Notification of change and submission of updated executed
batch records. Significant body of information available: One batch with three
months accelerated stability data reported in changes being effected supplement
and long-term stability data of first production batch reported in annual report.
Significant body of information not available: Three batches with three
months accelerated stability data reported in changes being effected supplement
and long-term stability data of first three production batches reported in annual
report.
II. IN VITRO RELEASE DOCUMENTATION. The in vitro release rate of a lot
of the dosage form prepared in new equipment should be compared with the re-
Appendix E 477
lease rate of a recent lot of comparable age of the product prepared using original
equipment. The median in vitro release rates (as estimated by the estimated slope
from each cell, see section VII) of the two formulations should be demonstrated
to be within acceptable limits, using the testing procedure described in section VII
(IN VITRO RELEASE TEST) below.
III. IN VIVO BIOEQUIVALENCE DOCUMENTATION. None.
c. Filing Documentation. Changes being effected supplement (all information
including accelerated stability data); annual report (long-term stability
data).
3. Level 3 Change
No level 3 changes are anticipated in this category.
B. Process
1. Level 1 Change
a. Definition of Level. Process changes, including changes such as rate
of mixing, mixing times, operating speeds, and holding times within approved
application ranges. Also, order of addition of components (excluding actives) to
either oil or water phase.
b. Test Documentation.
I. CHEMISTRY DOCUMENTATION. None beyond application/compendial
product release requirements.
II. IN VITRO RELEASE DOCUMENTATION. None.
III. IN VIVO BIOEQUIVALENCE DOCUMENTATION. None.
c. Filing Documentation. Annual report.
2. Level 2 Change
a. Definition of Level. Process changes, including changes such as rate
of mixing, mixing times, rate of cooling, operating speeds, and holding times outside
approved application ranges for all dosage forms. Also, any changes in the
process of combining the phases.
b. Test Documentation.
I. CHEMISTRY DOCUMENTATION. Application/compendial product release
requirements. Notification of change and submission of updated executed
batch records. Significant body of information available: One batch with three
478 Appendix E
months accelerated stability data reported in changes being effected supplement
and long-term stability data of first production batch reported in annual report.
Significant body of information not available: Three batches with three
months accelerated stability data reported in changes being effected supplement
and long-term stability data of first three production batches reported in annual
report.
II. IN VITRO RELEASE DOCUMENTATION. The in vitro release rate of a lot
of the dosage form prepared by the new/modified process should be compared
with the in vitro release rate of a recent lot of comparable age of the dosage form
prepared by the prechange process. The median in vitro release rates (as estimated
by the estimated slope from each cell, see VII) of the lots prepared by the two processes
should be demonstrated to be within acceptable limits, using the testing
procedure described in section VII (IN VITRO RELEASE TEST) below.
III. IN VIVO BIOEQUIVALENCE DOCUMENTATION. None.
c. Filing Documentation. Changes being effected supplement (all information
including accelerated stability data); annual report (long-term stability
data).
3. Level 3 Change
No level 3 changes are anticipated in this category.
V. BATCH SIZE (SCALE-UP/SCALE-DOWN)
This guidance recommends that the minimum batch size for the NDA pivotal clinical
trial batch or the ANDA/AADA biobatch be at least 100 kg or 10% of a production
batch, whichever is larger. Deviations from this recommendation should
be discussed with the appropriate agency review division. All scale changes should
be properly validated and may be inspected by appropriate agency personnel.
A. Level 1 Change
1. Definition of Level
Change in batch size, up to and including a factor of ten times the size of the pivotal
clinical trial/biobatch, where: (1) the equipment used to produce the test
batch(es) are of the same design and operating principles; (2) the batch(es) is manufactured
in full compliance with cGMPs; and (3) the same standard operating
procedures (SOPs) and controls, as well as the same formulation and manufacturing
procedures, are used on the test batch(es) and on the full-scale production
batch(es).
Appendix E 479
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records in annual report. Stability testing: First production batch on long-term stability
reported in annual report.
b. In Vitro Release Documentation. None.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Annual report (all information including long-term stability data).
B. Level 2 Change
1. Definition of Level
Changes in batch size from beyond a factor of ten times the size of the pivotal clinical
trial/biobatch, where: (1) the equipment used to produce the test batch(es) are
of the same design and operating principles; (2) the batch(es) is manufactured in
full compliance with cGMPs; and (3) the same standard operating procedures
(SOPs) and controls, as well as the same formulation and manufacturing procedures,
are used on the test batch(es) and on the full-scale production batch(es).
2. Test Documentation
a. Chemistry Documentation. Application/compendial product release
requirements. Notification of change and submission of updated executed batch
records. Stability testing: One batch with three months accelerated stability data
reported in changes being effected supplement and long-term stability data of first
production batch reported in annual report.
b. In Vitro Release Documentation. The in vitro release rate of a lot of
the scaled-up batch should be compared with the in vitro release rate of a recent
lot, of comparable age, of the prechange scale. The median in vitro release rates
(as estimated by the estimated slope from each cell, see section VII) of the lots of
the two scales should be demonstrated to be within acceptable limits, using the
testing procedure described in section VII (IN VITRO RELEASE TEST) below.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
480 Appendix E
C. Level 3 Change
No level 3 changes are anticipated in this category.
VI. MANUFACTURING SITE
Manufacturing site changes consist of changes in location in the site of manufacture,
packaging/filling operations, and/or testing for both company owned and
contract manufacturing facilities and do not include any other level 2 or 3 changes,
e.g., changes in scale, manufacturing (including process and/or equipment), and
components or composition. New manufacturing locations should have had a satisfactory
cGMP inspection within the past two years.
A stand-alone analytical testing laboratory site change may be submitted as
a changes being effected supplement if the new facility has a current and satisfactory
cGMP compliance profile with FDA for the type of testing operation in question.
The supplement should contain a commitment to use the same test methods
employed in the approved application, written certification from the testing laboratory
stating that they are in conformance with cGMPs, and a full description of
the testing to be performed by the testing lab. If the facility has not received a satisfactory
cGMP inspection for the type of testing involved, a prior approval supplement
is recommended. No stability data are needed for a change in a stand
alone analytical facility.
A. Level 1 Change
1. Definition of Level
Level 1 changes consist of site changes within a single facility where the same
equipment, standard operating procedures (SOPs), environmental conditions
(e.g., temperature and humidity) and controls, and personnel common to both
manufacturing sites are used, and where no changes are made to the manufacturing
batch records, except for administrative information and the location of the
facility. Common is defined as employees already working on the campus who
have suitable experience with the manufacturing process.
2. Test Documentation
a. Chemistry Documentation. None beyond application/compendial
product release requirements.
b. In Vitro Release Documentation. None.
c. In Vivo Bioequivalence Documentation. None.
Appendix E 481
3. Filing Documentation
Annual report.
B. Level 2 Change
1. Definition of Level
Level 2 changes consist of site changes within a contiguous campus, or
between facilities in adjacent city blocks, where similar equipment, standard
operating procedures, (SOPs), environmental conditions (e.g., temperature and
humidity) and controls, and personnel common to both manufacturing sites are
used, and where no changes are made to the manufacturing batch records, except
for administrative information and the location of the facility.
2. Test Documentation
a. Chemistry Documentation. Location of new site and updated
executed batch records. None beyond application/compendial product release
requirements. Stability testing: First production batch on long-term stability reported
in annual report.
b. In Vitro Release Documentation. None.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement; annual report (long-term stability
data).
C. Level 3 Change
1. Definition of Level
Level 3 changes consist of a site change in manufacturing site to a different campus.
A different campus is defined as one that is not on the same original contiguous
site or where the facilities are not in adjacent city blocks. To qualify as a Level
3 change, similar equipment, SOPs, environmental conditions, and controls
should be used in the manufacturing process at the new site. Changes should not
be made to the manufacturing batch records except when consistent with other
level 1 changes. Administrative information, location, and language translation
may be revised as needed. Any change to a new contract manufacturer also constitutes
a level 3 change.
482 Appendix E
2. Test Documentation
a. Chemistry Documentation. Location of new site and updated executed
batch records. Application/compendial product release requirements.
Significant body of information available: One batch with three months accelerated
stability data reported in changes being effected supplement and longterm
stability data of first three production batches reported in annual report.
Significant body of information not available: Three batches with three
months accelerated stability data reported in changes being effected supplement
and long-term stability data of first three production batches reported in annual
report.
b. In Vitro Release Documentation. The in vitro release rate of a lot of
the dosage form from the new manufacturing site should be compared with the in
vitro release rate of a recent lot of comparable age of the dosage form manufactured
at the prior site. The median in vitro release rates (as estimated by the estimated
slope from each cell, see section VII) of the lots from the two sites should
be demonstrated to be within acceptable limits, using the testing procedure described
in section VII (IN VITRO RELEASE TEST) below.
c. In Vivo Bioequivalence Documentation. None.
3. Filing Documentation
Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
VII. IN VITRO RELEASE TEST
In vitro release is one of several standard methods which can be used to characterize
performance characteristics of a finished topical dosage form, i.e.,
semisolids such as creams, gels, and ointments. Important changes in the characteristics
of a drug product formula or the thermodynamic properties of the drug(s)
it contains should show up as a difference in drug release. Release is theoretically
proportional to the square root of time (/t) when the formulation in question is in
control of the release process because the release is from a receding boundary. In
vitro release method for topical dosage forms is based on an open chamber diffusion
cell system such as a Franz cell system, fitted usually with a synthetic membrane.
The test product is placed on the upper side of the membrane in the open
donor chamber of the diffusion cell and a sampling fluid is placed on the other side
of the membrane in a receptor cell. Diffusion of drug from the topical product to
and across the membrane is monitored by assay of sequentially collected samples
Appendix E 483
of the receptor fluid. The in vitro release methodology should be appropriately
validated. Sample collection can be automated.
Aliquots removed from the receptor phase can be analyzed for drug content
by high pressure liquid chromatography (HPLC) or other analytical methodology.
A plot of the amount of drug released per unit area (mcg/cm ) against the square
root of time yields a straight line, the slope of 2 which represents the release rate.
This release rate measure is formulation-specific and can be used to monitor product
quality. The release rate of the biobatch or currently manufactured batch
should be compared with the release rate of the product prepared after a change as
defined in this guidance.
One possible in vitro release study design is summarized below. Sponsors
are encouraged to review the reference articles listed here.
Diffusion Cell System: A diffusion cell system with a standard open cap
ground glass surface with 15 mm diameter orifice and total diameter of 25 mm.
Synthetic Membrane: Appropriate inert and commercially available synthetic
membranes such as polysulfone, cellulose acetate/nitrate mixed ester, or
Polytetrafluoroethylene 70 Fm membrane of appropriate size to fit the diffusion
cell diameter (e.g., 25 mm in above case).
Receptor Medium: Appropriate receptor medium such as aqueous buffer for
water soluble drugs or a hydro-alcoholic medium for sparingly water soluble
drugs or another medium with proper justification.
Number of Samples: Multiple replicates (six samples are recommended) to
determine the release rate (profile) of the topical dermatological product.
Sample Applications: About 300 mg of the semisolid preparation is placed
uniformly on the membrane and kept occluded to prevent solvent evaporation and
compositional changes. This corresponds to an infinite dose condition.
Sampling Time: Multiple sampling times (at least 5 times) over an appropriate
time period to generate an adequate release profile and to determine the
drug release rate (a 6-hour study period with not less than five samples, i.e., at 30
minutes, 1, 2, 4 and 6 hours) are suggested. The sampling times may have to be
varied depending on the formulation. An aliquot of the receptor phase is removed
at each sampling interval and replaced with fresh aliquot, so that the lower surface
of the membrane remains in contact with the receptor phase over the experimental
time period.
Sample Analysis: Appropriate validated specific and sensitive analytical
procedure should be used to analyze the samples and to determine the drug concentration
and the amount of drug released.
In Vitro Release Rate: A plot of the amount of drug released per unit membrane
area (mcg/cm ) versus square 2 root of time should yield a straight line. The
slope of the line (regression) represents the release rate of the product. An X intercept
typically corresponding to a small fraction of an hour is a normal characteristic
of such plots.
484 Appendix E
Design of the Rate (Profile) Comparison Study: The typical in vitro release
testing apparatus has six cells. For each run of the apparatus, the two products being
compared should be assigned to the six cells as follows:
where T represents the Postchange Lot (Test product) and R represents the
Prechange Lot (Reference product). This approach of including both products in
each run of the in vitro apparatus will help ensure an unbiased comparison in the
event of a systematic difference between runs.
• The choice of the assignment of products to cells (i.e., whether the
prechange lot or the postchange lot is assigned to the “upper left corner
cell” of the apparatus) may either be made systematically (i.e., alternate
the pattern for each successive run) or randomly (i.e., flip a coin or use
some other random mechanism).
• For the case of a nonstandard apparatus, with other than six cells, the
principle of including both the prechange lot and the postchange lot in
the same run should still be used. If the apparatus has only a single cell,
the runs on the prechange and postchange lots should be intermixed,
rather than obtaining all observations on one product followed by all observations
on the other product.
Details of the In Vitro Release Comparison Test
The in vitro release comparison should be carried out as a two-stage test. At the
first stage, two runs of the (six cells) in vitro apparatus should be carried out,
yielding six slopes (estimated in vitro release rates) for the prechange lot (R) and
six slopes for the postchange lot (T). A 90% confidence interval (to be described
below) for the ratio of the median in vitro release rate (in the population) for the
postchange lot over the median in vitro release rate (in the population) for the
Appendix E 485
1.1331 1.1842 1.0824 1.3049 1.0410 1.2419
1.3390 1.1817 1.1307 1.2371 1.0261 1.2863 1.0782
1.3496 1.1911 1.1397 1.2469 1.0343 1.2964 1.0867
1.4946 1.3190 1.2621 1.3808 1.1454 1.4357 1.2035
1.4668 1.2945 1.2386 1.3551 1.1241 1.4090 1.1811
1.1911 1.0512 1.0058 1.1004 0.9128 1.1442 0.9591
1.2210 1.0776 1.0311 1.1280 0.9357 1.1729 0.9832
prechange lot should be computed, expressed in percentage terms. If, at the first
stage, this 90% confidence interval falls within the limits of 75% to 133.33%, no
further in vitro testing is necessary. If the test is not passed at the first stage, 4 additional
runs of the (six cells) in vitro apparatus should be carried out, yielding 12
additional slopes for each product, or 18 in all (including the first-stage results).
The 90% confidence interval (to be described below) should be computed using
all 18 slopes for each product, including the first-stage results. At the second stage,
this 90% confidence interval should fall within the limits of 75% to 133.33%.
Computation of Confidence Interval—an Example
Because outliers are expected to occur on occasion with this testing (for example,
due to an air bubble between the product sample and the membrane), a nonparametric
method is proposed, whose performance tends to be resistant to the presence
of outliers.
The computations are illustrated in the following example:
Suppose that the slope data obtained at the first stage are as follows:
486 Appendix E
Postchange Prechange
Lot (T) Lot (R)
1.3390 1.1331
1.3496 1.1842
1.4946 1.0824
1.4668 1.3049
1.1911 1.0410
1.2210 1.2419
The first step in the computation of the confidence interval is to form the 36
(
 6  6) individual T/R ratios. This is illustrated in the following table, where
the prechange lot slopes (R) are listed across the top of the table, the postchange
lot slopes (T) are listed down the left margin of the table, and the individual T/R
ratios are the entries in the body of the table:
The second step in the computation of the confidence interval is to order
these individual T/R ratios from lowest to highest:
0.9128 0.9357 0.9591 0.9832 1.0058 1.0261 1.0311 1.0343. . .1.2863 1.2945
1.2964 1.3190 1.3551 1.3808 1.4090 1.4357.
In the third step, the 8th and 29th ordered individual ratios are the lower and
upper limits, respectively, of the 90% confidence interval for the ratio of the median
in vitro release rate (slope) for T over the median in vitro release rate for R.
In the example, this confidence interval is 1.0343 to 1.2863, or in percentage
terms, 103.43% to 128.63%.
Because this confidence interval falls within the limits of 75% to 133.33%,
the product passes at the first stage.
If the product had not passed at the first stage, an additional 4 runs would
have been carried out, yielding 12 additional slopes per lot, for a total of 18 slopes
per lot altogether (including the first-stage slopes).
All 324 ( 
 18  18) individual T/R ratios would be obtained, and these
would be ranked from lowest to highest. It should be evident that even the computations
at the first stage would be tedious to do by hand, and doing the computations
at the second stage by hand is infeasible. A computer should be used.
At the second stage, the 110th and the 215th ordered individual ratios are
the lower and upper limits, respectively, of the 90% confidence interval for the ratio
of the median in vitro release rate (slope) for T over the median in vitro release
rate for R. If this confidence interval falls within the limits of 75% to 133.33%, the
product passes the test at the second stage.
Further Remarks on the In Vitro Release Comparison Test
The statistical test described above is based on a standard confidence interval procedure
related to the Wilcoxon Rank Sum/Mann-Whitney rank test, applied to the
log slopes. References to this confidence interval procedure include:
Conover, W.J., Practical Nonparametric Statistics (Second Edition), John Wiley
& Sons, page 223ff, 1980.
Hollander, M. and D.A.Wolfe, Nonparametric Statistical Methods, John Wiley &
Sons, page 78ff, 1973.
However, as was seen in the example, it is not necessary to actually compute logs
in order to carry out the test.
• The example illustrates the case of full data, i.e., where there are 6 slopes
per lot at the first stage and, if the second stage is necessary, 18 slopes
per lot at the second stage. If slopes are missing, the computations will
need to be modified. For example, if a single slope were missing from
one of the lots (it does not matter if it is the prechange lot or the
postchange lot) at the first stage, there would only be 30 (
 5  6) indi-
Appendix E 487
vidual T/R ratios, and the limits of the 90% confidence interval would no
longer be the eighth and twenty-ninth ordered individual T/R ratio, but
rather would be the sixth and twenty-fifth ordered individual T/R ratio.
If data are missing at either stage of the test, the correct computation
should be determined either by reference to a statistical text or consultant,
or by consultation with CDER staff.
• The statistical procedure as described above does not take the block
structure of the test (i.e., the fact that data are obtained in runs of six
slopes at a time, rather than all at once) into account. This is justified by
the following:
1. In vitro release data available to the Center at this time show no evidence
of an important run-to-run effect.
2. The proposed experimental design, in which both products are included
in each run, will help to ensure unbiasedness if a run-to-run
effect should occur.
VIII. IN VIVO BIOEQUIVALENCE STUDIES
The design of in vivo bioequivalence studies for semisolid dosage forms varies
depending on the pharmacological activity of the drug and dosage form. A brief
general discussion of such tests follows.
Objective
To document the bioequivalence of the drug product for which the manufacture
has been changed, as defined in this guidance, compared to the drug product manufactured
prior to the change or compared to the reference listed drug (RLD).
Design
The study design is dependent on the nature of the active drug. The bioequivalence
study can be a comparative skin blanching study as in glucocorticoids (FDA, Topical
Dermatological Corticosteroids: In Vivo Bioequivalence, June 2, 1995.) or a
comparative clinical trial or any other appropriate validated bioequivalence study
(e.g., dermatopharmacokinetic study) for the topical dermatological drug product.
Analytical Method
The assay methodology selected should ensure specificity, accuracy, interday and
intraday precision, linearity of standard curves, and adequate sensitivity, recovery,
and stability of the samples under the storage and handling conditions associated
with the analytical method.
488 Appendix E
GLOSSARY OF TERMS3
Approved Target Composition: The components and amount of each ingredient
for a drug product used in an approved pivotal clinical study or bioequivalence
study.
Batch: A specific quantity of a drug or other material produced according to a
single manufacturing order during the same cycle of manufacture and intended to
have uniform character and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in adjacent
city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended
drug substances for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making
up volume and/or weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or
ointment) in its marketed package. It also can be a finished dosage form (e.g.,
tablet, capsule, or solution) that contains a drug substance, generally, but not necessarily,
in association with one or more other ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing
the drug to be distributed into the skin or be absorbed into the body where it
may exert its pharmacological effect.
Drug Substance: An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of a disease, or to affect the structure or any function of the human
body, but does not include intermediates used in the synthesis of such ingredient
(21 CFR 314.3(b)).
Emulsion: Emulsions are two phase systems in which an immiscible liquid
(dispersed phase) is dispersed throughout another liquid (continuous phase or external
phase) as small droplets. Where oil is the dispersed phase and an aqueous
solution is the continuous phase, the system is designated as an oil-in-water emulsion.
Conversely, where water or an aqueous solution is the dispersed phase and
oil or oleaginous material is the continuous phase, the system is designated as a
water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent
coalescence, the merging of small droplets into larger droplets and, ultimately,
into a single separated phase. Emulsifying agents (surfactants) do this by
concentration in the interface between the droplet and external phase and by providing
a physical barrier around the particle to coalesce. Surfactants also reduce
the interfacial tension between the phases, thus increasing the ease of emulsification
upon mixing. Emulsifying agents substantially prevent or delay the time
needed for emulsion droplets to coalesce. Emulsification is the act of forming an
Appendix E 489
3 See Workshop Report: Scale-up of liquid and semisolids disperse systems. G.A. Van Buskirk, V.P.
Shah, D. Adair, et al. Pharm. Res. 11:1216–1220, 1994.
emulsion. Emulsification can involve the incorporation of a liquid within another
liquid to form an emulsion or a gas in a liquid to form a foam.
Formulation: A listing of the ingredients and quantitative composition of the
dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three dimensional,
cross-linked matrix. The drug substance may be either dissolved or
suspended within the liquid phase.
Homogenization: A method of atomization and thereby emulsification of one
liquid in another in which the liquids are pressed between a finely ground valve
and seat under high pressure (e.g., up to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion comprises
the droplets that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation,
generally expressed as amount/unit area/time0.5.
Ointment: An unctuous semisolid for topical application. Typical ointments
are based on petrolatum. An ointment does not contain sufficient water to separate
into a second phase at room temperature. Water soluble ointments may be formulated
with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully representative
of and simulating that intended to be used for full manufacturing scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation
to which it has been added.
Process: A series of operations, actions and controls used to manufacture a drug
product.
Scale-down: The process of decreasing the batch size.
Scale-up: The process of increasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous
parts of a body to slide relative to one another in direction parallel to their
plane of contact. In emulsification and suspensions, the strain produced upon
passing a system through a homogenizer or other milling device.
Low shear: Processing in which the strain produced through mixing and/or
emulsifying shear is modest.
High shear: Forceful processes which, at point of mixing or emulsification
place a great strain on the product. Homogenization, by its very nature, is a high
shear process which leads to a small and relatively uniform emulsion droplet size.
Depending on their operation, mills and mixers are categorized as either high
shear or low shear devices.
Significant Body of Information: A significant body of information on the stability
of the product is likely to exist after five years of commercial experience for
new molecular entities, or three years of commercial experience for new dosage
forms.
Strength: Strength is the concentration of the drug substance (for example,
weight/weight, weight/volume, or unit dose/volume basis), and/or the potency,
490 Appendix E
that is, the therapeutic activity of the drug product as indicated by appropriate laboratory
tests or by adequately developed and controlled clinical data (expressed,
for example, in terms of units by reference to a standard) (21 CFR 210.3(b)(16)).
For semisolid dosage forms the strength is usually stated as a weight/weight (w/w)
or weight/volume (w/v) percentage.
Structure Forming Excipient: An excipient which participates in the formation
of the structural matrix which gives an ointment, cream or gel etc., its
semisolid character. Examples are gel forming polymers, petrolatum, certain colloidal
inorganic solids (e.g., bentonite), waxy solids (e.g., cetyl alcohol, stearic
acid), and emulsifiers used in creams.
Suspending Agent: An excipient added to a suspension to control the rate of
sedimentation of the active ingredients.
Technical Grade: Technical grades of excipients differ in their specifications
and intended use. Technical grades may differ in: (1) specifications and/or functionality,
(2) impurities, and (3) impurity profiles.
Validation: A procedure to establish documented evidence that provides a high
degree of assurance that a specific process or test will consistently produce a product
or test outcome meeting its predetermined specifications and quality attributes.
A validated manufacturing process or test is one that has been proven to do what
it purports or is represented to do. The proof of process validation is obtained
through collection and evaluation of data, preferably beginning with the process
development phase and continuing through the production phase. Process validation
necessarily includes process qualification (the qualification of materials,
equipment, systems, building, personnel), but it also includes the control of the entire
processes for repeated batches or runs.
REFERENCES
1. Shah, V. P., J. Elkins, J. Hanus, C. Noorizadeh, and J. P. Skelly,”In Vitro Release of
Hydrocortisone from Topical Preparations and Automated Procedure,” Pharmaceutical
Research, 8:55–59, 1991.
2. Shah, V. P., J. S. Elkins, and R. L. Williams, “In Vitro Drug Release Measurement of
Topical Glucocorticoid Creams,” Pharmacopeial Forum, 19, 5048–5059, 1993.
3. Corbo, M., T. W. Schultz, G. K. Wong, and G. A. Van Buskirk, “Development and
Validation of In Vitro Release Testing Methods for Semisolid Formulations,” Pharmaceutical
Technology 17(9):112–128, 1993.
4. Li, J. B. and P. C. Rahn, “Automated Dissolution Testing of Topical Drug Formulations
Using Franz Cells and HPLC Analysis,” Pharmaceutical Technology
17(7):44–52, 1993.
5. Shah, V. P. and J. S. Elkins, “In Vitro Release from Corticosteroid Ointments,” Journal
of Pharmaceutical Sciences, 84:1139–1140, 1995.
6. Zatz, J.L., “Drug Release from Semisolids: Effect of Membrane Permeability on Sensitivity
to Product Parameters,” Pharmaceutical Research 2:787–789, 1995.
Appendix E 491
492 Appendix E
Table 1 Components and Composition
Level Change Test documentation Filing documentation
1
2
• Deletion or partial
deletion of color,
fragrance, or flavor
• Up to 5% change in
approved amount of an
excipient with the total
additive effect of all
excipient changes

5%
• Supplier of structure
forming excipient that
is primarily a single
chemical entity (purity

95%) or change in
supplier or technical
grade of any other
excipient
• Change of 5% and

10% of approved
amount of an excipient
with the total additive
effect of all excipient
changes 
10%
• Change in supplier of
a structure forming
excipient (not covered
under level 1)
• Change in technical
grade of a structure
forming excipient
• Change in particle size
distribution of the drug
substance, if the drug
is in suspension
• Application/compendial
product release
requirements
• Stability: First production
batch on long-term
stability
• Application/compendial
product release
requirements
• Executed batch records
• Stability: One batch with
three months accelerated
stability data and first
production batch on longterm
stability
• In vitro release test
• Annual report
(all information
including longterm
stability
data)
• Changes being
effected
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Appendix E 493
Table 1 Continued.
Level Change Test documentation Filing documentation
3 • Any qualitative and
quantitative changes in
an excipient beyond
the ranges noted in
level 2 change
• Change in crystalline
form of the drug
substance, if the drug
is in suspension
• Application/compendial
product release
requirements
• Executed batch records
• Stability:
Significant body of
information available:
One batch with three
months accelerated
stability data and first
three production batches
on long-term stability.
Significant body of
information not available:
Three batches with three
months accelerated
stability data and first
three production batches
on long-term stability.
• In vitro release test
(encouraged only)
• In vivo bioequivalence
test
• Prior approval
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
494 Appendix E
Table 2 Components and Composition—Preservative
Level Change Test documentation Filing documentation
1
2
3
• Quantitatively 10% or
less change in the
approved amount of
preservative
• Quantitatively greater
than 10% and up to
20% change in the
approved amount of
preservative
• Quantitatively greater
than 20% change in
the approved amount
of preservative
(including deletion) or
use of a different
preservative
• Application/compendial
product release
requirements
• Preservative
effectiveness test at
lowest specified
preservative level
• Application/compendial
product release
requirements
• Preservative
effectiveness test at
lowest specified
preservative level
• Application/compendial
product release
requirements
• Executed batch records
• Preservative
effectiveness test at
lowest specified
preservative level
• For new preservative:
analytical method for
identification and assay;
validation studies
showing new
preservative does not
interfere with
application/compendial
tests
• Stability: One batch
with three months
accelerated stability
data and first
production batch on
long-term stability
• Annual report
• Changes being
effected
supplement
• Prior approval
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
Appendix E 495
Table 3 Manufacturing Equipment
Level Change Test documentation Filing documentation
1
2
• Nonautomated or
nonmechanical
equipment to
automated or
mechanical equipment
to transfer ingredients
• Alternative equipment
of same design and
operating principles
• Equipment of a
different design or
different operating
principles
• Type of mixing
equipment: e.g., high
shear to low shear or
vice versa.
• Application/compendial
product release
requirements
• Stability: First
production batch on
long-term stability
• Application/compendial
product release
requirements
• Executed batch records
• Stability:
Significant body of
information available:
One batch with three
months accelerated
stability data and first
production batch on
long-term stability.
Significant body of
information not
available: Three batches
with three months
accelerated stability
data and first three
production batches on
long-term stability.
• In vitro release test
• Annual report (all
information
including longterm
stability)
• Changes being
effected
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
496 Appendix E
Table 4 Manufacturing Process
Level Change Test documentation Filing documentation
1
2
• Process changes
within approved
applications ranges
requirements
• Order of addition of
components
(excluding actives)
• Process changes
outside approved
application ranges
• Process of combining
phases
• Application/compendial
product release
requirements
• Application/compendial
product release
requirements
• Executed batch records
• Stability:
Significant body of
information available:
One batch with three
months accelerated
stability data and first
production batch on
long-term stability.
Significant body of
information not
available: Three batches
with three months
accelerated stability
data and first three
production batches on
long-term stability.
• In vitro release test
• Annual report
• Changes being
effected
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
Appendix E 497
Table 5 Batch Size
Level Change Test documentation Filing documentation
1
2
• Change in batch size
up to and including ten
times the size of the
pivotal clinical
trial/biobatch
• Change in batch size
beyond a factor of ten
times the size of the
pivotal clinical
trial/biobatch
• Application/compendial
product release
requirements
• Executed batch records
• Stability: First
production batch on
long-term stability
• Application/compendial
product release
requirements
• Executed batch records
• Stability: One batch
with three months
accelerated stability
data and first
production batch on
long-term stability
• In vitro release test
• Annual report (all
information
including longterm
stability)
• Changes being
effected
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
498 Appendix E
Table 6 Manufacturing Site Change
Level Change Test documentation Filing documentation
1
2
3
• Within a single facility
• Within the same
contiguous campus or
between facilities in
adjacent city blocks
• Different campus
• Contract manufacturer
• Application/compendial
product release
requirements
• Application/compendial
product release
requirements
• Executed batch records
• Location of new site
• Stability: First
production batch on
long-term stability
• Application/compendial
product release
requirements
• Executed batch records
• Location of new site
• Stability:
Significant body of
information available:
One batch with three
months accelerated
stability data and first
three production
batches on long-term
stability.
Significant body of
information not
available: Three batches
with three months
accelerated stability
data and first three
production batches on
long-term stability.
• In vitro release test
• Annual report
• Changes being
effected
supplement
• Annual report
(long-term
stability data)
• Changes being
effected
supplement (all
information
including
accelerated
stability data)
• Annual report
(long-term
stability data)
Note: See text for additional information.
Appendix F
Guidance for Industry1—
SUPAC-SS: Nonsterile Semisolid
Dosage Forms
Manufacturing Equipment Addendum
Draft—Not for Implementation
I. INTRODUCTION
This guidance is intended to provide recommendations to pharmaceutical manufacturers
using the Center for Drug Evaluation and Research’s guidance for
industry, SUPAC-SS: Nonsterile Semisolid Dosage Forms, Scale-Up and Post
Approval Changes: Chemistry Manufacturing and Controls; In Vitro Release
Testing and In Vivo Bioequivalence Documentation (SUPAC-SS), which published
in June 1997. This document should be used in conjunction with the
SUPAC-SS guidance document in determining what documentation should be submitted
to the Food and Drug Administration (FDA) on equipment changes made in
accordance with the recommendations of the SUPAC-SS guidance document. The
earlier SUPAC guidance document defines (1) levels of change; (2) recommended
chemistry, manufacturing, and controls tests for each level of change; (3) recommended
in vitro release tests and/or in vivo bioequivalence tests to support each
level of change; and (4) documentation that should support the change for new drug
applications (NDAs) and abbreviated new drug applications (ANDAs).
This document is only an aid and, in some cases, specific equipment may not
499
1 This guidance has been prepared under the auspices of the Chemistry, Manufacturing, and Controls
Coordinating Committee in the Center for Drug Evaluation and Research (CDER) and the Office of
Regulatory Affairs (ORA) at the Food and Drug Administration, with the assistance of the International
Society of Pharmaceutical Engineering (ISPE). This guidance represents the Agency’s current
thinking on equipment changes under SUPAC-SS. It does not create or confer any rights for or on
any person and does not operate to bind the FDA or the public. An alternative approach may be used
if such approach satisfies the requirements of the applicable statute, regulations or both.
be listed. It does, however, include a representative list of equipment commonly
used in the industry. This guidance does not address equipment that has been modified
by a pharmaceutical manufacturer to fit its specific needs. If questions arise
in using this guidance, please contact the appropriate reviewing office at CDER.
Although this guidance does not discuss validation, any equipment changes
should be validated in accordance with current good manufacturing practices
(CGMPs). The resulting data will be subject to examination by field investigators
during routine GMP inspections. The information here is presented in broad
categories of unit operation (particle size reduction and/or separation, mixing,
emulsification, deaeration, transfer, and packaging). Definitions and classifications
are provided. For each operation, a table categorizes equipment by class
(operating principle) and subclass (design characteristic). Examples are given
within the subclasses.
Under SUPAC-SS, equipment within the same class and subclass are considered
to have the same design and operating principle. For example, a change
from a planetary mixer from manufacturer A to another planetary mixer from
manufacturer B would not represent a change in design or operating principle and
would be considered the same.
A change from equipment in one class to equipment in a different class
would usually be considered a change in design and operating principle. For example,
a change from a planetary mixer to a dispersator mixer demonstrates a
change in operating principle from low-shear convection mixing to high-shear
convection mixing. These types of equipment would be considered different under
SUPAC-SS.
Applicants should carefully consider and evaluate on a case-by-case basis
changes in equipment that are in the same class, but different subclasses.2 In many
situations, these changes in equipment would be considered similar. For example,
in Section III, Mixing, under the convection mixers, low shear, a change from an
impeller mixer (subclass) to a planetary mixer (subclass) represents a change
within a class and between subclasses. Provided the manufacturing process with
the new equipment is validated, this change would likely not need a changes being
effected (CBE) supplement. At the time of such a change the applicant should
have available the scientific data and rationale used to make this determination. It
is up to the applicant to determine the filing category.
This guidance will be updated as needed to reflect the introduction and discontinuation
of specific types of manufacturing equipment. Manufacturers are en-
500 Appendix F
2 In the guidance for industry, SUPAC-SS Nonsterile Semisolid Dosage Forms, Scale-Up and Post Approval
Changes: Chemistry Manufacturing and Controls; In Vitro Release Testing and In Vivo Bioequivalence
Documentation (SUPAC-SS), a changes being effected (CBE) supplement is recommended
for a change in equipment to a “different design or operating principle.” On further review,
CDER has determined this should state “different design and operating principle.” The SUPAC-SS
guidance will be revised to make this change after the comment period closes on this Addendum and
it is finalized.
couraged to help keep the document current by communicating changes to the
Agency and by making suggestions on what equipment should be put in the same
class or subclass. The information submitted will be reviewed by FDA and incorporated
in an updated guidance document, as appropriate.
On November 21, 1997, the President signed the Food and Drug Administration
Modernization Act (FDAMA).3 Section 116 of FDAMA amended the
Food, Drug, and Cosmetic Act by adding section 506A (21 U.S.C. 356a), which
provides requirements for making and reporting manufacturing changes to an approved
human and animal drug application and for distributing a drug product
made with such change. The FDA is currently preparing a proposed rule to amend
its regulations (21 CFR 314.70 and 21 CFR 514.8) for supplements and other
changes to approved applications to implement the manufacturing changes provision
of FDAMA. This draft guidance will be revised as and when appropriate to
take into consideration the revised regulations in 21 CFR 314.70 and 21 CFR
514.8 when they are finalized.
II. PARTICLE SIZE REDUCTION/SEPARATION
A. Definitions
1. Unit Operations
a. Particle Size Reduction. The mechanical process of breaking particles
into smaller pieces via one or more size reduction mechanisms. The mechanical
process used is generally referred to as milling.
i. Particle - Either a discrete crystal or a grouping of crystals, generally
known as an agglomerate
ii. Particle Size Reduction Mechanisms
• Impact - Particle size reduction by applying an instantaneous force
perpendicular to the particle and/or agglomerate surface. The force
can result from particle-to-particle or particle-to-mill surface collision.
• Attrition - Particle size reduction by applying force parallel to the
particle surface
• Compression - Particle size reduction by applying a force slowly (as
compared to impact) to the particle surface toward the center of the
particle
• Cutting - Particle size reduction by applying a shearing force to a
material
b. Particle Separation. Particle size classification according to particle
size alone
Appendix F 501
3 Pub. L. 105–115
Table 1 Unit Operation—Particle Size Reduction
Class Subclass Examples
Fluid Energy Mills Fixed Target None Identified
Fluidized Bed None Identified
Loop/Oval Fluid Energy Aljet
Moving Target None Identified
Opposed Jet Garlock
Opposed Jet with Alpine (Hosokawa)
Dynamic Classifier Fluid Energy Aljet
Tangential Jet Alpine (Hosokawa)
Fluid Energy Aljet
Sturtevant
Impact Mills Cage Stedman
Hammer Air Swept Alpine (Hosokawa)
Bepex (Hosowaka)
Sturtevant
Hammer Conventional Alpine (Hosokawa)
Fitzpatrick
Fluid Air
Mikro (Hosokawa)
Rietz (Hosokawa)
Stokes-Merrill
Pin/Disc Alpine (Hosokawa)
Kemutec
Sturtevant
Cutting Mills None Identified Alpine (Hosokawa)
Fitzpatrick
Urschel
Compression Mills None Identified MCA International
Ross
Stokes-Merrill
Screening Mills Oscillating Bar Bepex (Hosokawa)
Frewitt
Jackson-Crockatt
Stokes-Merrill
Vector
Rotating Impeller Bepex (Hosokawa)
Fitzpatrick
Fluid Air
Kemutec
Quadro
Stokes-Merrill
Zanchetta (Romaco)
Rotating Screen Glatt
Tumbling Mills Ball Media US Stoneware
Rod Media None Identified
Vibrating Sweco
2. Operating Principles
a. Fluid Energy Milling: Particle size reduction by high-speed particle-toparticle
impact and/or attrition (also known as micronizing)
b. Impact Milling: Particle size reduction by high-speed mechanical impact
or impact with other particles (also known as milling, pulverizing,
or comminuting)
c. Cutting: Particle size reduction by mechanical shearing
d. Compression Milling: Particle size reduction by compression stress and
shear between two surfaces
e. Screening: Particle size reduction by mechanically-induced attrition
through a screen (commonly referred to as milling or deagglomeration)
f. Tumble Milling: Particle size reduction by attrition, using grinding media
g. Separating: Particle segregation based on size alone, without any significant
particle size reduction (commonly referred to as screening or
bolting)
B. Equipment Classifications
1. Fluid Energy Mills
Fluid energy mill subclasses have no moving parts and primarily differ in the configuration
and/or shape of their chambers, nozzles, and classifiers.
• Fixed target
• Fluidized bed
• Loop and/or oval
• Moving target
• Opposed jet
• Opposed jet with dynamic classifier
• Tangential jet
2. Impact Mills
Impact mill subclasses primarily differ in the configuration of the grinding heads,
chamber grinding liners (if any), and classifiers.
• Cage
• Hammer air swept
• Hammer conventional
• Pin or disc
3. Cutting Mills
Although cutting mills can differ in whether the knives are movable or fixed, and
in classifier configuration, no cutting mill subclasses have been identified.
Appendix F 503
4. Compression Mills
Although compression mills, also known as roller mills, can differ in whether one
or both surfaces move, no compression mill subclasses have been identified.
5. Screening Mills
Screening mill subclasses primarily differ in the rotating element.
• Oscillating bar
• Rotating impeller
• Rotating screen
6. Tumbling Mills
Tumbling mill subclasses primarily differ in the grinding media used and whether
the mill is vibrated.
• Ball media
• Rod media
• Vibrating
7. Separators
Separator subclasses primarily differ in the mechanical means used to induce particle
movement.
• Centrifugal
• Vibratory or shaker
Note: If a single piece of equipment is capable of performing multiple discrete
unit operations, it has been evaluated solely for its ability to impact particle
size or separation.
504 Appendix F
Table 2 Unit Operation—Separation
Class Subclass Examples
Separators Centrifugal AZO
Kason
Kemutec
Sweco
Vibratory/Shaker Allgaier
McLanahan
Rotex
Russell Finex
Sweco
Vortisiv
III. MIXING
A. Definitions
1. Unit Operation
Mixing: The reorientation of particles relative to one another to achieve uniformity
or randomness. This process can include wetting of solids by a liquid phase,
dispersion of discrete particles, or deagglomeration into a continuous phase. Heating
and cooling via indirect conduction may be used in this operation to facilitate
phase mixing or stabilization.
2. Operating Principles
a. Convection Mixing, Low Shear. Mixing process with a repeated pattern
of cycling material from top to bottom, in which dispersion occurs under low
power per unit mass through rotating low shear forces
b. Convection Mixing, High Shear. Mixing process with a repeated pattern
of cycling material from top to bottom, in which dispersion occurs under high
power per unit mass through rotating high shear forces
c. Roller Mixing (Milling). Mixing process by high mechanical shearing
action where compression stress is achieved by passing material between a series
of rotating rolls. This is commonly referred to as compression or roller milling.
d. Static Mixing. Mixing process in which material passes through a
tube with stationary baffles. The mixer is generally used in conjunction with an inline
pump.
B. Equipment Classification
1. Convection Mixers, Low Shear
This group normally operates under low shear conditions and is broken down by
impeller design and movement. Design can also include a jacketed vessel to facilitate
heat transfer.
• Anchor or sweepgate
• Impeller
• Planetary
2. Convection Mixers, High Shear
This group normally operates only under high shear conditions. Subclasses are
differentiated by how the high shear is introduced into the material, such as by a
dispersator with serrated blades or homogenizer with rotor stator.
Appendix F 505
506 Appendix F
Table 3 Unit Operation—Mixing
Class Subclass Examples
Convection Mixers, Anchor/Sweepgate Brogli
Low Shear Fryma
GEI Krieger (GEI
North America)
Groen
Koruma (Romaco)
Lee Industries
Ross
Waukesha Cherry Burrell
Impeller Bematek
Chemineer
Gate
IKA
Lightnin
Moorhouse-Cowles
Quadro
Ross
Planetary Aaron
Aeschbach
AMF
GEI-Collette (GEI North
America/Vector)
Hobart
Jaygo
Littleford Day
Ross
Vrieco
Convection Mixers, Dispersator Chemineer
High Shear Cowles
Gate
IKA
Koruma (Romaco)
Lightnin
Ross
Roto Stator Arde-Barinco
Bematek
Fryma
Gaulin
Greerco
Koruma (Romaco)
Manton Gaulin
Appendix F 507
Table 3 Continued.
Class Subclass Examples
Moorhouse-Cowles
Premier
Ross
Silverson
Tri-Homo
Ultra Turex
Urschel
Roller Mixers (Mills) None Identified MCA International
Ross
Stokes Merrill
Static Mixers None Identified Ross
• Dispersator
• Rotor stator
3. Roller Mixers (Mills)
No roller mixer subclasses have been identified.
4. Static Mixers
No static mixer subclasses have been identified.
Note: If a single piece of equipment is capable of performing multiple discrete
unit operations, it has been evaluated solely for its ability to mix materials.
IV. EMULSIFICATION
A. Definitions
1. Unit Operation
Emulsification: The application of physical energy to a liquid system consisting
of at least two immiscible phases, causing one phase to be dispersed into the other.
2. Operating Principles
a. Low Shear Emulsification. Use of low shear energy using mechanical
mixing with an impeller to achieve a dispersion of the mixture. The effectiveness
of this operation is especially dependent on proper formulation.
b. High Shear Emulsification. Use of high shear energy to achieve a dispersion
of the immiscible phases. High shear can be achieved by the following
means:
i. Stirring the mixture with a high speed chopper or saw-tooth dispersator
ii. Passing the mixture through the gap between a high-speed rotor and a
stationary stator
iii. Passing the mixture through a small orifice at high pressure (valvetype
homogenizer) or through a small orifice at high pressure followed
by impact against a hard surface or opposing stream (valve-impactor
type homogenizer), causing sudden changes of pressure
508 Appendix F
Table 4 Unit Operation—Emulsification
Class Subclass Examples
Low Shear Emulsifiers None Identified Bematek
Lightnin
Moorhouse-Cowles
Ross
High Shear Emulsifiers Dispersator Chemineer
Cowles
Gate
IKA
Koruma (Romaco)
Lightnin
Ross
Rotor Stator Arde-Barinco
Bematek
Fryma
Gaulin
Greerco
Koruma (Romaco)
Manton Gaulin
Moorhouse-Cowles
Premier
Ross
Silverson
Tri-Homo
Ultra Turex
Urschel
Valve or Pressure Manton Gaulin
Homogenizer Microfluidics
B. Equipment Classification
1. Low Shear Emulsifiers
Although low shear emulsification equipment (mechanical stirrers or impellers)
can differ in the type of fluid flow imparted to the mixture (axial-flow propeller or
radial-flow turbines), no subclasses have been defined.
2. High Shear Emulsifiers
Subclasses of high shear emulsification equipment differ in the method used to
generate high shear.
• Dispersator
• Rotor stator
• Valve or pressure homogenizer
Note: If a single piece of equipment is capable of performing multiple discrete
unit operations, the unit has been evaluated solely for its ability to emulsify
materials.
V. DEAERATION
A. Definitions
1. Unit Operation
Deaeration: The elimination of trapped gases to provide more accurate volumetric
measurements and remove potentially reactive gases
Appendix F 509
Table 5 Unit of Operation—Deaeration
Class Subclass Examples
Deaerators Off Line/In Line Cornell Machine Co.
Fryma
Jaygo
Koruma (Romaco)
Vacuum Vessel Fryma
GEI-Kreiger (GEI
North America)
Groen
Koruma (Romaco)
Lee Industries
Paul Mueller Co.
2. Operating Principles
The use of vacuum or negative pressure, alone or in combination with mechanical
intervention or assistance
B. Equipment Classification
1. Deaerators
Deaerator subclasses differ primarily in their air removal paths, either through the
bulk material or through a thin film, and in whether they use a batch or in-line process.
• Off-Line or in-line
• Vacuum vessel
Note: If a single piece of equipment is capable of performing multiple
discrete unit operations, it has been evaluated solely for its ability to deaerate
materials.
VI. TRANSFER
A. Definition
1. Unit Operation
Transfer: The controlled movement or transfer of materials from one location to
another
2. Operating Principles
a. Passive. The movement of materials across a non-mechanicallyinduced
pressure gradient, usually through conduit or pipe
b. Active. The movement of materials across a mechanically-induced
pressure gradient, usually through conduit or pipe
B. Equipment Classification
1. Low Shear
Active or passive material transfer, with a low degree of induced shear
• Diaphragm
• Gravity
• Peristaltic
510 Appendix F
Table 6 Unit Operation—Transfer
Class Subclass Examples
Low Shear Diaphragm APV
Pulsafeeder
TL Systems
Tri-Clover
Wilden
Gravity None Identified
Peristaltic Barnant Co
Cole Palmer
Pulsafeeder
Vanton
Watson-Marlow
Piston APV
Graco
National
Nordson
Waukesha
Wilden
Pneumatic None Identified
Rotating Lobe Flowteck
Fristam
Sine
Tri-Clover
Viking
Waukesha
Screw or Helical Screw Moyno
High Shear Centrifugal or Turbine APV
BMS
Fristam
Pulsafeeder
Tri-Clover
Vanton
Waukesha
Piston APV
Graco
National Instrument
Nordson
Waukesha
Wilden
Rotating Gear APV
BSM
Ertel Engineering
Pulsafeeder
Viking
Waukesha
511
• Piston
• Pneumatic
• Rotating lobe
• Screw or helical screw
2. High Shear
Active or mechanical material transfer with a high degree of induced shear
• Centrifugal or turbine
• Piston
• Rotating gear
Note: This section is intended to deal with the transfer of shear sensitive materials,
including product or partially manufactured product. A single piece of
equipment can be placed in either a low or high shear class, depending on its operating
parameters. If a single piece of equipment is capable of performing multiple
discrete unit operations, the unit has been evaluated solely for its ability to
transfer materials.
VII. PACKAGING
A. Definitions
1. Unit Operation
a. Holding. The process of storing product after completion of manufacturing
process and prior to filling final primary packs
b. Transfer. The process of relocating bulk finished product from
holding to filling equipment using pipe, hose, pumps and/or other associated
components
c. Filling. The delivery of target weight or volume of bulk finished
product to primary pack containers
d. Sealing. A device or process for closing and/or sealing primary pack
containers following the filling process
2. Operating Principles
a. Holding. The storage of liquid, semi-solids, or product materials in a
vessel that may or may not have temperature control and/or agitation
b. Transfer. The controlled movement or transfer of materials from one
location to another
512 Appendix F
c. Filling. Filling operating principles involve several associated subprinciples.
The primary package can be precleaned to remove particulates or other
materials by the use of ionized air, vacuum, or inversion. A holding vessel
equipped with an auger, gravity, or pressure material feeding system should be
used. The vessel may or may not be able to control temperature and/or agitation.
Actual filling of the dosage form into primary containers can involve a metering
system based on an auger, gear, orifice, peristaltic, or piston pump. A head-space
blanketing system can also be used.
d. Sealing. Primary packages can be sealed using a variety of methods,
including conducted heat and electromagnetic (induction or microwave) or mechanical
manipulation (crimping or torquing).
Appendix F 513
Table 7 Unit Operation—Holding
Class Subclass Examples
Holders Auger Bonafacci
Bosch
Cozzoli Machine
Erweka
Fryma-Maschinenbau
Inova
Loeb Equipment
Sarong
Young Industries
Gravity Bonafacci
Bosch
Cozzoli Machine
Erweka
Fryma-Maschinenbau
Inova
Loeb Equipment
Sarong
Young Industries
Pneumatic (nitrogen, Bonafacci
air, etc.) Bosch
Cozzoli Machine
Erweka
Fryma-Maschinenbau
Inova
Loeb Equipment
Sarong
Young Industries
Table 8 Unit Operation—Filling
Class Subclass Examples
Fillers Auger Bonafacci
Bosch
Erweka
Fryma-Maschinenbau
IWKA
Kalish
Norden
Sarong
Gear pump APV
BMS
Bonafacci
Bosch
Ertel Engineering
Erweka
Fryma-Maschinenbau
IWKA
Kalish
Norden
Pulsafeeder
Sarong
Viking
Waukesha
Orifice Bonafacci
Bosch
Erweka
Fryma-Maschinenbau
IWKA
Kalish
Norden
Sarong
Peristaltic pump Barnant Co.
Bonafacci
Bosch
Cole-Parmer
Erweka
Fryma-Maschinenbau
IWKA
Kalish
Norden
Pulsafeeder
Sarong
Vanton
Watson-Marlow
514 Appendix F
Appendix F 515
Table 8 Continued.
Class Subclass Examples
Piston APV
Bonafacci
Bosch
Erweka
Fryma-Maschinenbau
Graco
IWKA
Kalish
National
Norden
Sarong
Waukesha
Wilden
Table 9 Unit Operation—Sealing
Class Subclass Examples
Sealers Heat Harro Hofliger Packaging
Hutchins and Hutchins
Loeb Equipment
Prodo-Pak
Romaco
VWR Scientific Products
Induction Pillar
Microwave None Identified
Mechanical/Crimping Austin Reed
Bishop International
Chase-Logeman
Cozzoli Machine
Integrated Packaging System
Loeb Equipment
Romaco
VWR Scientific Products
Torque Bausch and Stroebel Machine
Cozzoli Machine
Electronic Liquid Filler
Madison Equipment
Sure Torque
B. Equipment Classification
1. Holders
Although holding vessels can differ in their geometry and ability to control temperature
or agitation, their primary differences are based on how materials are fed.
• Auger
• Gravity
• Pneumatic (nitrogen, air, etc.)
2. Fillers
The primary differences in filling equipment are based on how materials are metered.
• Auger
• Gear pump
• Orifice
• Peristaltic pump
• Piston
3. Sealers
The differences in primary container sealing are based on how energy is transferred
or applied.
• Heat
• Induction
• Microwave
• Mechanical or crimping
• Torque
516 Appendix F
Appendix G
Guidance for Industry1—
Changes to an Approved
NDA or ANDA
I. INTRODUCTION
On November 21, 1997, the President signed the Food and Drug Administration
Modernization Act (the Modernization Act).2 Section 116 of the Modernization
Act amended the Food, Drug, and Cosmetic Act (the Act) by adding section 506A
(21 U.S.C. 356a), which provides requirements for making and reporting manufacturing
changes to an approved application and for distributing a drug product
made with such changes.
The purpose of this guidance is to provide recommendations to holders of
new drug applications (NDAs) and abbreviated new drug applications (ANDAs)
who intend to make postapproval changes in accordance with Section 506A. The
guidance covers recommended reporting categories for postapproval changes for
drugs, other than specified biotechnology and specified synthetic biological products.
Recommendations are provided for postapproval changes in (1) components
and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications,
(5) package, (6) labeling, (7) miscellaneous changes, and (8) multiple
related changes.
Recommendations on reporting categories for changes relating to specified
biotechnology and specified synthetic biological products regulated by CDER
are found in the guidance for industry entitled Changes to an Approved Appli-
517
1 This guidance has been prepared under the direction of the Chemistry, Manufacturing and Controls
Coordinating Committee in the Center for Drug Evaluation and Research (CDER) at the Food and
Drug Administration. This guidance represents the Agency’s current thinking on how it will apply the
requirements of section 506A of the Act for NDA and ANDA products. It does not create or confer
any rights for or on any person and does not operate to bind FDA or the public. An alternative approach
may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both.
2 Pub. L. 105–115.
cation for Specified Biotechnology and Specified Synthetic Biological Products
(July 1997).3
This guidance does not provide recommendations on the specific information
that should be developed by an applicant to assess the effect of the change on
the identity, strength (e.g., assay, content uniformity), quality (e.g., physical,
chemical, and biological properties), purity (e.g., impurities and degradation products),
or potency (e.g., biological activity, bioavailability, bioequivalence) of a
product as they may relate to the safety or effectiveness of the product. An applicant
should consider all relevant CDER guidance documents for recommendations
on the information that should be submitted to support a given change.4
CDER has published guidances, including the SUPAC (scale-up and
postapproval changes) guidances, that provide recommendations on reporting
categories. To the extent that the recommendations on reporting categories in this
guidance are found to be inconsistent with guidances published before this
guidance was finalized, the recommended reporting categories in such previously
published guidances are superseded by this guidance. This guidance does not
provide extensive recommendations on reporting categories for components and
composition changes (see section V). Therefore, recommended reporting categories
for components and composition changes provided in previously published
guidances, such as the SUPAC guidances, still apply. Section 506A of the Act
provides for two types of changes being effected supplements (see section II)
while previously there was only one type. It is important for applicants to use this
guidance to determine which type of changes being effected supplement is recommended.
CDER intends to update the previously published guidances to make
them consistent with this guidance.
If guidance for either recommended filing categories and/or information that
should be submitted to support a particular change is not available, the appropriate
CDER chemistry or microbiology review staff can be consulted for advice.
II. REPORTING CATEGORIES
Section 506A of the Act provides for four reporting categories that are distinguished
in the following paragraphs.
A major change is a change that has a substantial potential to have an adverse
effect on the identity, strength, quality, purity, or potency of a product as
they may relate to the safety or effectiveness of the product (506A(c)(2)). A ma-
518 Appendix G
3 FDA is currently revising the 1997 guidance and intends to issue it in draft for public comment.
4 A list of CDER guidances is available on the Internet at http://www.fda.gov/cder/guidance/
index.htm.
jor change requires the submission of a supplement and approval by FDA prior to
distribution of the product made using the change (506A(c)(1)). This type of supplement
is called, and should be clearly labeled, a Prior Approval Supplement.
An applicant may ask FDA to expedite its review of a prior approval supplement
for public health reasons (e.g., drug shortage) or if a delay in making the change
described in it would impose an extraordinary hardship on the applicant. This type
of supplement is called, and should be clearly labeled, a Prior Approval Supplement—
Expedited Review Requested.5 Requests for expedited review based on
extraordinary hardship should be reserved for manufacturing changes made necessary
by catastrophic events (e.g., fire) or by events that could not be reasonably
foreseen and for which the applicant could not plan.
A moderate change is a change that has a moderate potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the product as
they may relate to the safety or effectiveness of the product. There are two types
of moderate change. One type of moderate change requires the submission of a
supplement to FDA at least 30 days before the distribution of the product made using
the change (506A(d)(3)(B)(i)). This type of supplement is called, and should
be clearly labeled, a Supplement—Changes Being Effected in 30 Days. The
product made using a moderate change cannot be distributed if FDA informs the
applicant within 30 days of receipt of the supplement that a prior approval supplement
is required (506A(d)(3)(B)(i)). For each change, the supplement must
contain information determined by FDA to be appropriate and must include the
information developed by the applicant in assessing the effects of the change
(506A(b)). If FDA informs the applicant within 30 days of receipt of the supplement
that information is missing, distribution must be delayed until the supplement
has been amended with the missing information.
FDA may identify certain moderate changes for which distribution can occur
when FDA receives the supplement (506A(d)(3)(B)(ii)). This type of supplement
is called, and should be clearly labeled, a Supplement—Changes Being Effected.
If, after review, FDA disapproves a changes being effected in 30 days
supplement or changes being effected supplement, FDA may order the manufacturer
to cease distribution of the drugs that have been made using the disapproved
change (506A(d)(3)(B)(iii)).
A minor change is a change that has minimal potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product. The applicant must describe
minor changes in its next Annual Report (506A(d)(1)(A) and (d)(2)).
Appendix G 519
5 Internal Agency policies and procedures relating to processing requests for expedited review of supplements
to approved ANDAs and NDAs are documented in CDER’s Manual of Policies and Procedures
(MAPP) at 5240.1 and 5310.3, respectively. MAPPs can be located on the Internet at
http://www.fda.gov/cder/mapp.htm.
An applicant can submit one or more protocols (i.e., comparability protocols)
describing tests, validation studies, and acceptable limits to be achieved to
demonstrate the absence of an adverse effect from specified types of changes. A
comparability protocol can be used to reduce the reporting category for specified
changes. A proposed comparability protocol should be submitted as a prior
approval supplement, if not approved as part of the original application. FDA intends
to issue separate guidance on comparability protocols.
III. GENERAL REQUIREMENTS
Other than for editorial changes in previously submitted information (e.g., correction
of spelling or typographical errors, reformatting of batch records), an
applicant must notify FDA about each change in each condition established in an
approved application beyond the variations already provided for in the application
(506A(a)).
An applicant making a change to an approved application under section
506A of the Act must also conform to other applicable laws and regulations, including
current good manufacturing practice (CGMP) requirements of the Act (21
U.S.C. 351(a)(2)(B)) and applicable regulations in Title 21 of the Code of Federal
Regulations (e.g., 21 CFR parts 210, 211, 314). For example, manufacturers must
comply with relevant CGMP validation and recordkeeping requirements and
ensure that relevant records are readily available for examination by authorized
FDA personnel during an inspection. A changes being effected supplement for labeling
changes must include 12 copies of the final printed labeling (21 CFR
314.50(e)(2)(ii)).
Except for a supplemental application providing for a change in labeling, an applicant
should include a statement in a supplemental application or amendment
certifying that the required field copy (21 CFR 314.50) of the supplement or
amendment has been provided.6
IV. ASSESSING THE EFFECT OF MANUFACTURING
CHANGES
A. Assessment of the Effects of the Change
A drug made with a manufacturing change, whether a major manufacturing
change or otherwise, may be distributed only after the holder validates (i.e., as-
520 Appendix G
6 Mailing information for field copies is provided in 21 CFR 314.440(a)(4). FDA recommends that the
applicant’s home FDA district office referred to in the regulations be the district office where the applicant’s
headquarters is located.
sesses) the effects of the change on the identity, strength, quality, purity, and
potency of the product as these factors may relate to the safety or effectiveness of
the product (506A(b)).7 For each change, the supplement or annual report must
contain information determined by FDA to be appropriate and must include the information
developed by the applicant in assessing the effects of the change
(506A(b), (c)(1), (d)(2)(A), and (d)(3)(A)). Recommendations on the type of information
that should be included in a supplemental application or annual report
is available in guidance documents. If no guidance is available on the type of
information that should be submitted to support a change, the applicant is encouraged
to contact the appropriate chemistry or microbiology review staff.
1. Conformance to Specifications
An assessment of the effect of a change on the identity, strength, quality, purity,
or potency of the drug product should include a determination that the drug substance
intermediates, drug substance, in-process materials, and/or drug product
affected by the change conform to the approved specifications.8 A specification is
a quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided
in an approved application to confirm the quality of drug substances, drug
products, intermediates, raw materials, reagents, and other components, including
container closure systems and their components and in-process materials. For the
purpose of defining specifications, acceptance criteria are numerical limits,
ranges, or other criteria for the tests described. Conformance to a specification
means that the material, when tested according to the analytical procedures listed
in the specification, will meet the listed acceptance criteria.
2. Additional Testing
In addition to confirmation that the material affected by manufacturing changes
continues to meet its specification, the applicant should perform additional testing,
when appropriate, to assess whether the identity, strength, quality, purity, or
potency of the product as they may relate to the safety or effectiveness of the product
have been or will be affected. The assessment should include, as appropriate,
Appendix G 521
7 Validate the effects of the change means to assess the effect of a manufacturing change on the identity,
strength, quality, purity, or potency of a drug as these factors relate to the safety or effectiveness
of the drug. The term assess or assessment, as used in this guidance, is not the same as CGMP validation.
Unless otherwise specified by FDA, CGMP validation (e.g., process, equipment) data need
not be filed in the application but should be retained at the facility and be available for review by FDA
at the Agency’s discretion. For example, in addition to the information assessing the effects of the
change specified in 506A(b) of the Act, validation information on sterilization processes should be
submitted in an NDA or ANDA.
8 If a specification needs to be revised as a result of the change, this would be considered a multiple
change (See sections VIII and XII).
evaluation of any changes in the chemical, physical, microbiological, biological,
bioavailability, and/or stability profiles. This additional assessment could involve
testing of the postchange drug product itself or, if appropriate, the component directly
affected by the change. The type of additional testing that an applicant
should perform would depend on the type of manufacturing change, the type of
drug substance and/or drug product, and the effect of the change on the quality of
the product. For example:
• Evaluation of changes in the impurity or degradant profile could first involve
profiling using appropriate chromatographic techniques and then,
depending on the observed changes in the impurity profile, toxicology
tests to qualify a new impurity or degradant or to qualify an impurity that
is above a previously qualified level.9
• Evaluation of the hardness or friability of a tablet after certain changes.
• Assessment of the effect of a change on bioequivalence when required
under 21 CFR part 320 could include, for example, multipoint and/or
multimedia dissolution profiling and/or an in vivo bioequivalence study.
• Evaluation of extractables from new packaging components or moisture
permeability of a new container closure system.
An applicant should refer to all relevant CDER guidance documents for
recommendations on the information that should be submitted to support a given
change. If guidance for information that should be submitted to support a particular
change is not available, applicants can consult the appropriate CDER chemistry
or microbiology review staff for advice.
B. Equivalence
When testing is performed, the applicant should usually assess the extent to which
the manufacturing change has affected the identity, strength, quality, purity, or potency
of the drug product. Typically this is accomplished by comparing test results
from pre- and postchange material and determining if the test results are equivalent.
Simply stated: Is the product made after the change equivalent to the product
made before the change? An exception to this general approach is that when bioequivalence
should be redocumented for certain ANDA postapproval changes, the
comparator should be the reference listed drug. Equivalence comparisons
frequently require a criterion for comparison with calculation of confidence intervals
relative to a predetermined equivalence interval. For this, as well as for other
reasons, equivalent does not necessarily mean identical. Equivalence may also re-
522 Appendix G
9 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant guidances
(e.g., ICH Q3B Impurities in New Drug Products (November 1996)).
late to maintenance of a quality characteristic (e.g., stability) rather than a single
performance of a test.
C. Adverse Effect
Sometimes manufacturing changes have an adverse effect on the identity,
strength, quality, purity, or potency of the drug product. In many cases, the applicant
chooses not to implement these manufacturing changes, but sometimes the
applicant wishes to do so. If an assessment concludes that a change has adversely
affected the identity, strength, quality, purity, or potency of the drug product, the
change should be filed in a prior approval supplement, regardless of the recommended
reporting category for the change. For example, a type of process
change with a recommended filing category of a supplement—changes being
effected in 30 days, could cause a new degradant to be formed that requires qualification
and/or identification.10 However, the applicant’s degradation qualification
procedures may indicate that there are no safety concerns relating to the new
degradant. The applicant should submit this change in a prior approval supplement
with appropriate information to support the continued safety and effectiveness
of the product. During the review of the prior approval supplement, the FDA
will assess the impact of any adverse effect on the product as it may relate to the
safety or effectiveness of the product.
Applicants are encouraged to consult with the appropriate CDER chemistry
or microbiology review staff if there are any questions on whether a change in a
characteristic would be viewed by CDER as adversely affecting the identity,
strength, quality, purity, or potency of the product.
V. COMPONENTS AND COMPOSITION
Changes in the qualitative or quantitative formulation, including inactive ingredients,
as provided in the approved application, are considered major changes and
should be filed in a prior approval supplement, unless exempted by regulation or
guidance (506A(c)(2)(A)). The deletion or reduction of an ingredient intended to
affect only the color of a product may be reported in an annual report. Guidance
on changes in components and composition that may be filed in a changes being
effected supplement or annual report is not included in this document because of
the complexity of these recommendations, but may be covered in one or more
guidance documents describing postapproval changes (e.g., SUPAC documents).
Appendix G 523
10 Recommendations on identifying, qualifying, and reporting impurities can be found in relevant
guidances.
VI. MANUFACTURING SITES 11
A. General Considerations
CDER should be notified about a change to a different manufacturing site used by
an applicant to (1) manufacture or process drug products,12 in-process materials,
drug substances, or drug substance intermediates, (2) package drug products, (3)
label drug products, and (4) test components, drug product containers, closures,
packaging materials, in-process materials, or drug products. Sites include those
owned by the applicant or contract sites used by an applicant. Testing sites include
those performing physical, chemical, biological, and microbiological testing to
monitor, accept, or reject materials, as well as those performing stability testing.
Sites used to label drug products are considered those that perform labeling of the
drug product’s primary or secondary packaging components. Sites performing
operations that place identifying information on the dosage form itself (e.g., ink
imprint on a filled capsule) are considered to be facilities that manufacture or process
the drug product. The supplement or annual report should identify whether
the proposed manufacturing site is an alternative or replacement to those provided
for in the approved application.
A move to a different manufacturing site, when it is a type of site routinely
subject to FDA inspection, should be filed as a prior approval supplement if the
site does not have a satisfactory CGMP inspection13 for the type of operation14
being moved (see sections VI.B.1 and 2).
For labeling, secondary packaging, and testing site changes, the potential for
adverse effect on the identity, strength, quality, purity, or potency of a product as
they may relate to the safety or effectiveness of the product is considered to be independent
of the type of drug product dosage form or specific type of operation being
performed. Therefore, the recommended reporting category for any one of these
manufacturing site changes will be the same for all types of drug products and operations.
For manufacturing sites used to (1) manufacture or process drug products,
in-process materials, drug substances, or drug substance intermediates or (2) perform
primary packaging operations, the potential for adverse impact and, consequently,
the recommended reporting category depends on various factors such as the
type of product and operation being performed. For this reason, recommended reporting
categories may differ depending on the type of drug product and operations.
524 Appendix G
11 See Attachment A for a discussion of the definition of same manufacturing site and different manufacturing
site.
12 Manufacturing or processing drug product would also include the preparation (e.g., sterilization, depyrogenation,
irradiation, washing) by the applicant or applicant’s contractor of container closure
systems or packaging components.
13 See Glossary for a definition of satisfactory CGMP inspection.
14 See Attachment B for a discussion of the term type of operation.
Except for those situations described in sections VI.B.4, VI.C.1.b, and
VI.D.5, moving production operations between buildings at the same manufacturing
site or within a building, or construction activities occurring at a
manufacturing site, do not have to be reported to CDER. A move to a different
manufacturing site that involves other changes (e.g., process, equipment) should
be evaluated as a multiple related change (see section XII) to determine the appropriate
reporting category.
B. Major Changes (Prior Approval Supplement)
The following are examples of changes that are considered to have a substantial
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. A move to a different manufacturing site, except one used to manufacture
or process a drug substance intermediate, when the new manufacturing
site has never been inspected by FDA for the type of operation
that is being moved or the move results in a restart at the new manufacturing
site of a type of operation that has been discontinued for more
than two years.
2. A move to a different manufacturing site, except those used to manufacture
or process a drug substance intermediate, when the new manufacturing
site does not have a satisfactory CGMP inspection for the type
of operation being moved.
3. A move to a different manufacturing site for (1) the manufacture, processing,
or primary packaging of drug products when the primary
packaging components control the dose delivered to the patient or the
formulation modifies the rate or extent of availability of the drug, or (2)
the manufacture or processing of in-process materials with modifiedrelease
characteristics. Examples of these types of drug products
include modified-release solid oral dosage forms,15 transdermal systems,
liposomal products, depot products, oral and nasal metered-dose
inhalers (MDIs), dry powder inhalers (DPIs), and nasal spray pumps.
4. Transfer of manufacturing of an aseptically processed sterile drug
substance or aseptically processed sterile drug product to (1) a newly
constructed or refurbished aseptic processing facility or area or (2) an
existing aseptic processing facility or area that does not manufacture
similar (including container types and sizes) approved products. For
Appendix G 525
15 Certain operations relating to the manufacture, processing, or primary packaging of modified-release
solid oral dosage form products need not be reported in a prior approval supplement (see sections
VI.C.1.c and VI.D.6).
example, transferring the manufacture of a lyophilized product to an
existing aseptic process area where no approved lyophilized products
are manufactured or the approved lyophilized products being manufactured
have dissimilar container types and/or sizes to the product being
transferred. See section VI.C.1.b for recommendations for other manufacturing
site changes relating to aseptically processed sterile drug
substance or aseptically processed sterile drug product.
5. Transfer of the manufacture of a finished product sterilized by terminal
processes to a newly constructed facility at a different manufacturing
site. Once this change has been approved, subsequent site changes to
the facility for similar product types and processes may be filed as a
supplement—changes being effected in 30 days (see section VI.C.1.a).
C. Moderate Changes (Supplement—Changes Being
Effected)
The following are examples of changes that are considered to have a moderate potential
to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
The following manufacturing site changes (excluding changes relating to
drug substance intermediate manufacturing sites) should be filed in a prior approval
supplement if the new site does not have a satisfactory CGMP inspection
for the type of operation being moved (see sections VI.B.1 and 2).
1. Supplement—Changes Being Effected in 30 Days
a. A move to a different manufacturing site for the manufacture or processing
of any drug product, in-process material, or drug substance that
is not otherwise provided for in this guidance.
b. For aseptically processed sterile drug substance or aseptically processed
sterile drug product, a move to an aseptic processing facility or
area at the same or different manufacturing site, except as provided for
in section VI.B.4.
c. A move to a different manufacturing site for the primary packaging of
(1) any drug product that is not otherwise listed as a major change and
(2) modified-release solid oral dosage form products.
d. A move to a different manufacturing site for testing if (1) the test procedures
approved in the application or procedures that have been
implemented via an annual report are used, (2) all postapproval commitments
made by the applicant relating to the test procedures have
been fulfilled (e.g., providing methods validation samples), and (3) the
new testing facility has the capability to perform the intended testing.
526 Appendix G
2. Supplement—Changes Being Effected
a. A move to a different manufacturing site for the manufacture or processing
of the final intermediate.
D. Minor Changes (Annual Report)
The following are examples of changes that are considered to have a minimal
potential to have an adverse effect on the identity, strength, quality, purity, or
potency of a product as they may relate to the safety or effectiveness of the
product.
The following manufacturing site changes (excluding changes relating to
drug substance intermediate manufacturing sites) should be filed in a prior approval
supplement if the new site does not have a satisfactory CGMP inspection
for the type of operation being moved (see sections VI.B.1 and 2).
1. A move to a different manufacturing site for secondary packaging.
2. A move to a different manufacturing site for labeling.
3. A move to a different manufacturing site for the manufacture or processing
of drug substance intermediates, other than the final intermediate.
4. A change in the contract sterilization site for packaging components
when the process is not materially different from that provided for in the
approved application and the facility has a satisfactory CGMP inspection
for the type of operation being performed.
5. A transfer of the manufacture of a finished product sterilized by terminal
processes to a newly constructed building or existing building at the
same manufacturing site.
6. A move to a different manufacturing site for the ink imprinting of solid
oral dosage form products.
VII. MANUFACTURING PROCESS
A. General Considerations
The potential for adverse effects on the identity, strength, quality, purity, or potency
of a drug product as they may relate to the safety or effectiveness of the
product depends on the type of manufacturing process and the changes being instituted
for the drug substance or drug product.
In some cases there may be a substantial potential for adverse effect, regardless
of direct testing of the drug substance or drug product for conformance
with the approved specification. When there is a substantial potential for adverse
effects, a change should be filed in a prior approval supplement.
Appendix G 527
B. Major Changes (Prior Approval Supplement)
The following are examples of changes that are considered to have a substantial
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. Changes that may affect the controlled (or modified) release, metering
or other characteristics (e.g., particle size) of the dose delivered to the
patient, including the addition or deletion of a code imprint by embossing,
debossing, or engraving on a modified-release solid oral dosage
form.
2. Changes that may affect product sterility assurance including, where
appropriate, process changes for sterile drug substances and sterile
packaging components. These include:
• Changes in the sterilization method (e.g., gas, dry heat, irradiation).
These include changes from sterile filtered or aseptic processing to
terminal sterilization, or vice versa.
• Addition, deletion, or substitution of sterilization steps or procedures
for handling sterile materials in an aseptic processing operation.
• Replacing sterilizers that operate by one set of principles with sterilizers
that operate by another principle (e.g., substituting a gravity
displacement steam process with a process using superheated water
spray).
• Addition to an aseptic processing line of new equipment made of
different materials (e.g., stainless steel versus glass, changes
between plastics) that will come in contact with sterilized bulk solution
or sterile drug components, or deletion of equipment from an
aseptic processing line.
• Replacing a Class 100 aseptic fill area with a barrier system or
isolator for aseptic filling. Once this change has been approved, subsequent
process changes for similar product types in the same
barrier system or isolator may be filed as a Supplement—changes
being effected in 30 days.
• Replacement or addition of lyophilization equipment of a different
size that uses different operating parameters or lengthens the overall
process time.
• Changes from bioburden-based terminal sterilization to the use of an
overkill process, and vice versa.
• Changes to aseptic processing methods, including scale, that extend
the total processing, including bulk storage time, by more than 50
percent beyond the validated limits in the approved application.
528 Appendix G
• Changes in sterilizer load configurations that are outside the range
of previously validated loads.
• Changes in materials or pore size rating of filters used in aseptic processing.
3. The following changes for a natural product:16
• Changes in the virus or adventitious agent removal or inactivation
methods. This is applicable to any material where such procedures
are necessary, including drug substance, drug product, reagents, and
excipients.
• For drug substance and drug product, changes in the source material
(e.g., microorganism, plant) or cell line.
• For drug substance and drug product, establishment of a new master
cell bank or seed.
4. Any fundamental change in the manufacturing process or technology
from that currently used by the applicant. For example:
a. Drug product
• Dry to wet granulation or vice versa.
• Change from one type of drying process to another (e.g., oven
tray, fluid bed, microwave).
b. Drug substance
• Filtration to centrifugation or vice versa.
• Change in the route of synthesis of a drug substance.
5. The following changes for drug substance
• Any process change made after the final intermediate processing
step in drug substance manufacture.
• Changes in the synthesis or manufacture of the drug substance that
may affect its impurity profile and/or the physical, chemical, or biological
properties.
6. Addition of an ink code imprint or change to or in the ink used for an existing
imprint code for a solid oral dosage form drug product when the
ink as changed is not currently used on CDER-approved products.17
7. Establishing a new procedure for reprocessing a batch of drug substance
or drug product that fails to meet the approved specification.
Appendix G 529
16 For the purposes of this guidance, natural product refers to materials (e.g., drug substance, excipients)
that are derived from plants, animals, or microorganisms. The specific recommendations for
natural products are not applicable to inorganic compounds (e.g., salts, minerals).
17 See Attachment C for a discussion of CDER-approved.
C. Moderate Changes (Supplement—Changes Being
Effected)
The following are examples of changes that are considered to have a moderate
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. Supplement—Changes Being Effected in 30 Days
a. For drug products, any change in the process, process parameters
and/or equipment, except as otherwise provided for in this guidance.
b. For drug substances, any change in process and/or process parameters,
except as otherwise provided for in this guidance.
c. For natural protein drug substances and drug products:
• Any change in the process, process parameters, and/or equipment,
except as otherwise provided for in this guidance.
• An increase or decrease in production scale during finishing steps
that involves new or different equipment.
• Replacement of equipment with that of similar, but not identical, design
and operating principle that does not affect the process methodology
or process operating parameters.
d. For sterile products, drug substances, and components, as appropriate:
• Changes in dry heat depyrogenation processes for glass container
systems for products that are produced by terminal sterilization processes
or aseptic processing.
• Changes to filtration parameters for aseptic processing (including
flow rate, pressure, time, or volume, but not filter materials or pore
size rating) that require additional validation studies for the new parameters.
• Filtration process changes that provide for a change from single to
dual product sterilizing filters in series, or for repeated filtration of
a bulk.
• Changes from one qualified sterilization chamber to another for inprocess
or terminal sterilization that results in changes to validated
operating parameters (time, temperature, F, and 0 others).
• Changes in scale of manufacturing for terminally sterilized products
that increase the bulk solution storage time by more than 50 percent
beyond the validated limits in the approved application when
bioburden limits are unchanged.
e. For drug substances, redefinition of an intermediate, excluding the final
intermediate, as a starting material.
530 Appendix G
2. Supplement—Changes Being Effected
a. A change in methods or controls that provides increased assurance that
the drug substance or drug product will have the characteristics of identity,
strength, purity, or potency that it purports or is represented to possess.
b. For sterile drug products, elimination of in-process filtration performed
as part of the manufacture of a terminally sterilized product.
D. Minor Changes (Annual Report)
The following are examples of changes that are considered to have a minimal
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. For drug products and protein drug substances, changes to equipment
of the same design and operating principle and/or changes in scale,
except as otherwise provided for in this guidance (e.g., section
VII.C.1.c).
2. A minor change in an existing code imprint for a dosage form. For
example, changing from a numeric to alphanumeric code.
3. Addition of an ink code imprint or a change in the ink used in an existing
code imprint for a solid oral dosage form drug product when the ink
is currently used on CDER-approved products.
4. Addition or deletion of a code imprint by embossing, debossing, or
engraving on a solid dosage form drug product other than a modifiedrelease
dosage form.
5. A change in the order of addition of ingredients for solution dosage
forms or solutions used in unit operations (e.g., granulation solutions).
6. Changes in scale of manufacturing for terminally sterilized products
that increase the bulk solution storage time by no more than 50 percent
beyond the validated limits in the approved application when bioburden
limits are unchanged.
VIII. SPECIFICATIONS
A. General Considerations
All changes in specifications from those in the approved application must be submitted
in a prior approval supplement unless otherwise exempted by regulation or
guidance (506A(c)(2)(A)). Specifications (i.e., tests, analytical procedures, and
acceptance criteria) are the quality standards provided in an approved application
to confirm the quality of drug substances, drug products, intermediates, raw ma-
Appendix G 531
terials, reagents, and other components, including container and closure systems
and in-process materials. For the purpose of defining specifications, acceptance
criteria are numerical limits, ranges, or other criteria for the tests described. An
example of a test, analytical procedure, and acceptance criteria is: assay, a specific
fully described high pressure liquid chromatography (HPLC) procedure, and
98.0–102.0 percent. The recommendations in this section also apply to specifications
associated with sterility assurance that are included in NDA and ANDA submissions.
18
A regulatory analytical procedure is the analytical procedure used to evaluate
a defined characteristic of the drug substance or drug product. The analytical
procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those
legally recognized under section 501(b) of the Act as the regulatory analytical procedures
for compendial items.
The applicant may include in its application alternative analytical procedures
to the approved regulatory procedure for testing the drug substance and drug
product. However, for purposes of determining compliance with the Act, the regulatory
analytical procedure is used.
In sections B-D below, the use of the term analytical procedure without a
qualifier such as regulatory or alternative refers to analytical procedures used to
test materials other than the drug substance or drug product.
B. Major Changes (Prior Approval Supplement)
The following are examples of changes in specifications that are considered to
have a substantial potential to have an adverse effect on the identity, strength,
quality, purity, or potency of a product as they may relate to the safety or effectiveness
of the product.
1. Relaxing an acceptance criterion, except as otherwise provided for in
this guidance (e.g., section VIII.C.1.b).
2. Deleting any part of a specification, except as otherwise provided for in
this guidance (e.g., section VIII.D.2).
3. Establishing a new regulatory analytical procedure.
4. A change in a regulatory analytical procedure that does not provide the
same or increased assurance of the identity, strength, quality, purity, or
potency of the material being tested as the regulatory analytical procedure
described in the approved application.
5. A change in an analytical procedure used for testing components, packaging
components, the final intermediate, in-process materials after the
final intermediate, or starting materials introduced after the final inter-
532 Appendix G
18 See FDA guidance for industry on the Submission of Documentation for Sterilization Process Validation
in Applications for Human and Veterinary Drug Products (November 1994).
mediate that does not provide the same or increased assurance of the
identity, strength, quality, purity, or potency of the material being tested
as the analytical procedure described in the approved application,
except as otherwise noted. For example, a change from an HPLC procedure
that distinguishes impurities to (1) one that does not, (2) another
type of analytical procedure (e.g., titrimetric) that does not, or (3) one
that distinguishes impurities but the limit of detection and/or limit of
quantitation is higher.
6. Relating to testing of raw materials for viruses or adventitious
agents:19(1) relaxing an acceptance criteria, (2) deleting a test, or (3) a
change in the analytical procedure that does not provide the same or increased
assurance of the identity, strength, quality, purity, or potency of
the material being tested as the analytical procedure described in the approved
application.
C. Moderate Changes (Supplement—Changes Being
Effected)
The following are examples of changes in specifications that are considered to
have a moderate potential to have an adverse effect on the identity, strength, quality,
purity, or potency of a product as they may relate to the safety or effectiveness
of the product.
1. Supplement—Changes Being Effected in 30 Days
a. Any change in a regulatory analytical procedure other than editorial or
those identified as major changes.
b. Relaxing an acceptance criterion or deleting a test for raw materials
used in drug substance manufacturing, in-process materials prior to the
final intermediate, starting materials introduced prior to the final drug
substance intermediate, or drug substance intermediates (excluding final
intermediate), except as provided for in section VIII.B.6.
c. A change in an analytical procedure used for testing raw materials used
in drug substance manufacturing, in-process materials prior to the intermediate,
starting materials introduced prior to the final drug substance
intermediate, or drug substance intermediates (excluding final
intermediate) that does not provide the same or increased assurance of
the identity, strength, quality, purity, or potency of the material being
tested as the analytical procedure described in the approved application,
except as provided for in section VIII.B.6.
Appendix G 533
19 In this context, testing for adventitious agents is not considered to include tests that are found in an
official compendium (e.g., USP 61).
d. Relaxing an in-process acceptance criterion associated with microbiological
monitoring of the production environment, materials, and
components that are included in NDA and ANDA submissions. For
example, increasing the microbiological alert or action limits for critical
processing environments in an aseptic fill facility or increasing the
acceptance limit for bioburden in bulk solution intended for filtration
and aseptic filling.
2. Supplement—Changes Being Effected
a. An addition to a specification that provides increased assurance that the
drug substance or drug product will have the characteristics of identity,
strength, purity, or potency that it purports or is represented to possess.
For example, adding a new test and associated analytical procedure and
acceptance criterion.
b. A change in an analytical procedure used for testing components, packaging
components, the final intermediate, in-process materials after the
final intermediate, or starting materials introduced after the final intermediate
that provides the same or increased assurance of the identity,
strength, quality, purity, or potency of the material being tested as the
analytical procedure described in the approved application.
D. Minor Changes (Annual Report)
The following are examples of changes in specifications that are considered to
have a minimal potential to have an adverse effect on the identity, strength, quality,
purity, or potency of a product as they may relate to the safety or effectiveness
of the product.
1. Any change in a specification made to comply with an official compendium.
2. For drug substance and drug product, the addition, deletion or revision
of an alternative analytical procedure that provides the same or greater
level of assurance of the identity, strength, quality, purity, or potency of
the material being tested as the analytical procedure described in the approved
application.
3. Tightening of acceptance criteria.
4. A change in an analytical procedure used for testing raw materials used
in drug substance synthesis, starting materials introduced prior to the final
drug substance intermediate, in-process materials prior to the final
intermediate, or drug substance intermediates (excluding final intermediate)
that provides the same or increased assurance of the identity,
strength, quality, purity, or potency of the material being tested as the
analytical procedure described in the approved application.
534 Appendix G
IX. PACKAGE
A. General Considerations
The potential for adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product
when making a change to or in the container closure system is generally dependent
on the route of administration of the drug product, performance of the
container closure system, and the likelihood of interaction between the packaging
component and the dosage form. In some cases there may be a substantial potential
for adverse effect, regardless of direct product testing for conformance with
the approved specification.
A change to or in a packaging component will often result in a new or revised
specification for the packaging component. This situation does not have to
be considered a multiple related change. Only the reporting category for the packaging
change needs to be considered.
B. Major Changes (Prior Approval Supplement)
The following are examples of changes that are considered to have a substantial
potential to have an adverse effect on the identity, strength, quality, purity, or
potency of a product as they may relate to the safety or effectiveness of the
product.
1. For liquid (e.g., solution, suspension, elixir) and semisolid (e.g.,
creams, ointments) dosage forms, a change to or in polymeric materials
(e.g., plastic, rubber) of primary packaging components, when the composition
of the component as changed has never been used in a CDERapproved
product of the same dosage form and same route of administration.
For example, a polymeric material that has been used in a
CDER-approved topical ointment would not be considered CDER-approved
for use with an ophthalmic ointment.
2. For liquid (e.g., solution, suspension, elixir) and semisolid (e.g.,
creams, ointments) dosage forms in permeable or semipermeable container
closure systems, a change to an ink and/or adhesive used on the
permeable or semipermeable packaging component to one that has
never been used in a CDER-approved product of the same dosage form,
same route of administration, and same type of permeable or semipermeable
packaging component (e.g., low density polyethylene, polyvinyl
chloride).
3. A change in the primary packaging components for any product when
the primary packaging components control the dose delivered to the patient
(e.g., the valve or actuator of a metered-dose inhaler).
Appendix G 535
4. For sterile products, any other change that may affect product sterility
assurance such as:20
• A change from a glass ampule to a glass vial with an elastomeric
closure.
• A change to a flexible container system (bag) from another container
system.
• A change to a prefilled syringe dosage form from another container
system.
• A change from a single unit dose container to a multiple dose container
system.
• Changes that add or delete silicone treatments to container closure
systems (such as elastomeric closures or syringe barrels).
• Changes in the size and/or shape of a container for a sterile drug
product.
5. Deletion of a secondary packaging component intended to provide additional
protection to the drug product (e.g., carton to protect from light,
overwrap to limit transmission of moisture or gases).
6. A change to a new container closure system if the new container closure
system does not provide the same or better protective properties
than the approved container closure system.
C. Moderate Changes (Supplement—Changes Being
Effected)
The following are examples of changes that are considered to have a moderate potential
to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. Supplement—Changes Being Effected in 30 Days
a. A change to or in a container closure system, except as otherwise provided
for in this guidance.
b. Changes in the size or shape of a container for a sterile drug substance.
2. Supplement—Changes Being Effected
a. A change in the size and/or shape of a container for a nonsterile drug
product, except for solid dosage forms (see section IX.D.2 regarding
solid dosage forms).
b. A change in or addition or deletion of a desiccant.
536 Appendix G
20 Some of these identified changes, depending on the circumstances, may have to be filed as new
NDAs or ANDAs instead of as supplements. Applicants can consult the appropriate CDER chemistry
division/office if there are questions.
D. Minor Changes (Annual Report)
The following are examples of changes that are considered to have a minimal potential
to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. A change in the container closure system for a nonsterile drug product,
based on a showing of equivalency to the approved system under a protocol
approved in the application or published in an official compendium.
2. A change in the size and/or shape of a container containing the same
number of dose units, for a nonsterile solid dosage form.
3. The following changes in the container closure system of solid oral
dosage form products as long as the new package provides the same or
better protective properties (e.g., light, moisture) and any new primary
packaging component materials have been used in and been in contact
with CDER-approved solid oral dosage form products:21
• Adding or changing a child-resistant closure, changing from a metal
to plastic screw cap, or changing from a plastic to metal screw cap.
• Changing from one plastic container to another of the same type of
plastic (e.g., high density polyethylene (HDPE) container to another
HDPE container).
• Changes in packaging materials used to control odor (e.g., charcoal
packets).
• Changes in bottle filler (e.g., change in weight of cotton or amount
used) without changes in the type of filler (e.g., cotton to rayon).
• Increasing the wall thickness of the container.
• A change in or addition of a cap liner.
• A change in or addition of a seal (e.g., heat induction seal).
• A change in an antioxidant, colorant, stabilizer, or mold releasing
agent for production of the container and/or closure to one that is
used at similar levels in the packaging of CDER-approved solid oral
dosage form products.
• A change to a new container closure system when the container closure
system is already approved in the NDA or ANDA for other
strengths of the product.
4. The following changes in the container closure system of nonsterile liquid
products, as long as the new package provides the same or better
Appendix G 537
21 For sections IX.D.3 to 6, changes in the container closure system that result in product contact with
a component material that has never been used in any CDER-approved product of the same type
should be filed as a supplement—changes being effected in 30 days (IX.C.1) or prior approval supplement
(IX.B.1).
protective properties and any new primary packaging component materials
have been used in and been in contact with CDER-approved liquid
products with the same route of administration (i.e., the material in contact
with a liquid topical should already have been used with other
CDER-approved liquid topical products):
• Adding or changing a child-resistant closure, changing from a metal
to plastic screw cap, or changing from a plastic to metal screw cap.
• Increasing the wall thickness of the container.
• A change in or addition of a cap liner.
• A change in or addition of a seal (e.g., heat induction seal).
5. A change in the container closure system of unit dose packaging (e.g.,
blister packs) for nonsterile solid dosage form products, as long as the
new package provides the same or better protective properties and any
new primary packaging component materials have been used in and
been in contact with CDER-approved products of the same type (e.g.,
solid oral dosage form, rectal suppository).
6. The following changes in the container closure system of nonsterile
semisolid products, as long as the new package provides the same or
better protective properties and any new primary packaging component
materials have been used in and been in contact with CDER-approved
semisolid products:
• Changes in the closure or cap.
• Increasing the wall thickness of the container.
• A change in or addition of a cap liner.
• A change in or addition of a seal.
• A change in the crimp sealant.
7. A change in the flip seal cap color, as long as the cap color is consistent
with any established color coding system for that class of drug
products.
X. LABELING
A. General Considerations
A drug product labeling change includes changes in the package insert, package
labeling, or container label. An applicant should promptly revise all promotional
labeling and drug advertising to make it consistent with any labeling change implemented
in accordance with the regulations. All labeling changes for ANDA
products must be consistent with section 505(j) of the Act.
538 Appendix G
B. Major Changes (Prior Approval Supplement)
Any proposed change in the labeling, except those that are designated as
moderate or minor changes by regulation or guidance, should be submitted as
a prior approval supplement. The following list contains some examples
of changes that are currently considered by CDER to fall into this reporting
category.
1. Changes based on postmarketing study results, including, but not limited
to, labeling changes associated with new indications and usage.
2. Change in, or addition of, pharmacoeconomic claims based on clinical
studies.
3. Changes to the clinical pharmacology or the clinical study section reflecting
new or modified data.
4. Changes based on data from preclinical studies.
5. Revision (expansion or contraction) of population based on data.
6. Claims of superiority to another product.
7. Change in the labeled storage conditions, unless exempted by regulation
or guidance.
C. Moderate Changes (Supplement—Changes Being
Effected)
A changes being effected supplement should be submitted for any labeling
change that (1) adds or strengthens a contraindication, warning, precaution, or
adverse reaction, (2) adds or strengthens a statement about drug abuse, dependence,
psychological effect, or overdosage, (3) adds or strengthens an instruction
about dosage and administration that is intended to increase the safe use of
the product, (4) deletes false, misleading, or unsupported indications for use or
claims for effectiveness, or (5) is specifically requested by FDA. The submission
should include 12 copies of final printed labeling. The following list includes
some examples of changes that are currently considered by CDER to fall
into this reporting category.
1. Addition of an adverse event due to information reported to the applicant
or Agency.
2. Addition of a precaution arising out of a postmarketing study.
3. Clarification of the administration statement to ensure proper administration
of the product.
4. Labeling changes, normally classified as major changes, that FDA
specifically requests be implemented using a changes being effected
supplement.
Appendix G 539
D. Minor Changes (Annual Report)
Labeling with editorial or similar minor changes or with a change in the information
concerning the description of the drug product or information about how the
drug is supplied that does not involve a change in the dosage strength or dosage
form should be described in an annual report. The following list includes some examples
that are currently considered by CDER to fall into this reporting category.
1. Changes in the layout of the package or container label that are consistent
with FDA regulations (e.g., 21 CFR part 201), without a change in
the content of the labeling.
2. Editorial changes, such as adding a distributor’s name.
3. Foreign language versions of the labeling, if no change is made to the
content of the approved labeling and a certified translation is included.
4. Labeling changes made to comply with an official compendium.
XI. MISCELLANEOUS CHANGES
A. Major Changes (Prior Approval Supplement)
The following are examples of changes that are considered to have a substantial
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. Changes requiring completion of studies in accordance with 21
CFR part 320 to demonstrate equivalence of the drug to the drug as
manufactured without the change or to a reference listed drug
(506A(c)(2)(B)).
2. Addition of a stability protocol or comparability protocol.
3. Changes to an approved stability protocol or comparability protocol unless
otherwise provided for in this guidance (e.g., VIII.C, VIII.D,
XI.C.2).
4. An extension of an expiration dating period based on (1) data obtained
under a new or revised stability testing protocol that has not been approved
in the application or (2) full shelf life data on pilot scale batches
using an approved protocol.
B. Moderate Changes (Supplement—Changes Being
Effected)
The following are examples of changes that are considered to have a moderate
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
540 Appendix G
1. Supplement—Changes Being Effected in 30 Days
a. Reduction of an expiration dating period to provide increased assurance
of the identity, strength, quality, purity, or potency of the drug product.
Extension of an expiration date that has previously been reduced under
this provision should be filed in a supplement—changes being effected
in 30 days even if it is based on data obtained under a protocol approved
in the application.
2. Supplement—Changes Being Effected
No changes have been identified.
C. Minor Changes (Annual Report)
The following are examples of changes that are considered to have a minimal
potential to have an adverse effect on the identity, strength, quality, purity, or potency
of a product as they may relate to the safety or effectiveness of the product.
1. An extension of an expiration dating period based on full shelf life data
on full production batches obtained under a protocol approved in the
application.
2. Addition of time points to the stability protocol or deletion of time
points beyond the approved expiration dating period.
3. A change from previously approved stability storage conditions to storage
conditions recommended in International Conference on Harmonisation
(ICH) guidances.
4. Non-USP reference standards:
• Replacement of an in-house reference standard or reference panel
(or panel member) according to procedures in an approved application.
• Tightening of acceptance criteria for existing reference standards to
provide greater assurance of product purity and potency.
XII. MULTIPLE RELATED CHANGES
Multiple related changes involve various combinations of individual changes. For
example, a site change may also involve equipment and manufacturing process
changes or a components and composition change may necessitate a change in a
specification. For multiple related changes where the recommended reporting categories
for the individual changes differ, CDER recommends that the filing be in
accordance with the most restrictive of those recommended for the individual
Appendix G 541
changes. When the multiple related changes all have the same recommended
reporting category, CDER recommends that the filing be in accordance with the
reporting category for the individual changes.
ATTACHMENT A: MANUFACTURING SITES
All owners or operators of all drug establishments (not exempt by regulation) that
engage in the manufacture, preparation, propagation, compounding, or processing
of a drug or drugs are required to register with the FDA (21 CFR 207.20). An establishment
means a place of business under one management at one general
physical location (21 CFR 207.3(a)(7)). A general physical location is reasonably
construed to include separate buildings within the same city if the activities in
them are closely related to the same business enterprise, under the supervision of
the same local management, and all inspected at the same time (ORA Field Management
Directive No. 132).
For the purposes of determining the reporting category for moves between
buildings, the terms different manufacturing site and same manufacturing site
mean:
A. Domestic Establishments
1. Same Manufacturing Site
• The new and old building are included under the same drug establishment
registration number22
and
• The same FDA district office is responsible for inspecting the operations
in both the new and old building.
2. Different Manufacturing Site
• The new and old building have different drug establishment registration
numbers
or
• Different FDA district offices are responsible for inspecting operations
in the new and old building.
542 Appendix G
22 The registration number is the number assigned to the establishment by the district (ORA Field Management
Directive No. 92). Currently, the registration number is the seven digit central file number
(CFN).
For domestic establishments, the terms same and different manufacturing
site supersede the terms contiguous campus, same campus, and different campus
as used in the SUPAC guidances.
B. Foreign Establishments
Foreign establishments are not currently required to register with the FDA. On
May 14, 1999 FDA published a proposed rule to require registration of foreign establishments
(64 FR 26330). Until the time registration of foreign establishments
is required, same and different manufacturing sites mean:
1. Same Manufacturing Site
• A contiguous or unbroken site or a set of buildings in adjacent city
blocks.
2. Different Manufacturing Site:
• New and old building not on a contiguous site or not in adjacent city
blocks.
ATTACHMENT B: TYPE OF OPERATION AND CGMP
INSPECTIONS
Section VI states that a change to a different manufacturing site should be filed in
a prior approval supplement when (1) the new manufacturing site has never been
inspected by FDA for the type of operation being moved, (2) the move results in
a restart at the new manufacturing site of a type of operation that has been discontinued
for more than two years, or (3) the new manufacturing site does not
have a satisfactory current good manufacturing practice (CGMP) inspection for
the type of operation being moved.
A profile class system is used by FDA to assist in (1) managing the
CGMP inspection process, (2) evaluating the findings and the compliance follow-
up needed, and (3) communicating the results of inspections. A profile class
can relate to the manufacture of a particular dosage form (e.g., large volume
parenterals, oral liquids), type of drug substance (e.g., sterile bulk by chemical
synthesis), or specific function performed at a site (e.g., control testing laboratory).
There are profile class codes for major categories of drug substance
processes, dosage forms, and manufacturing functions (see table below).
Appendix G 543
However, the system is not comprehensive for all operations performed in
the pharmaceutical industry (see not elsewhere classified (NEC) profile class
code).
The term type of operation refers to the specialized or even unique conditions
and practices which are employed to manufacture a class or category of drug
substance or drug product or to perform a limited segment of the manufacturing
process. These conditions and practices exist and are performed within the framework
of CGMPs, along with general conditions and practices that contribute to the
manufacture of all products at a given manufacturing site. Both the general and the
specific conditions and practices are inspected to evaluate the CGMP acceptability
of a manufacturing site. A wide variety of classes or categories of drug substances
and products may be produced at a manufacturing site or the manufacturing
site may only produce a single class of drug substance and/or drug product or
perform a limited segment of a manufacturing process. Each type of operation is
represented by a profile class code.
Generally, a satisfactory CGMP rating for a profile class code is used
to communicate a satisfactory CGMP clearance for all of the products and
for all of the operations included within the category that code represents. Thus
the profile class code for a particular dosage form or type of drug substance
is used to communicate the CGMP status for all aspects of manufacturing,
processing, packing, or holding that are performed at the specific manufacturing
site relating to that particular dosage form or type of drug substance,
including packaging and labeling operations, testing, and quality control. The
profile class code for a particular dosage form or type of drug substance is also
used |to communicate the CGMP status for manufacturing sites that produce
in-process material (e.g., controlled-release beads), package drug products,
or label drug products, even if these are stand-alone (e.g., contractor)
operations.
A few profile class codes that describe certain types of operations (see items
in boldface in table) are provided to report the CGMP status for contractor firms
whose only function in the manufacturing process is to perform this operation. If
one of these operations (e.g., steam sterilization process) is performed at the manufacturing
site involved in producing the drug product/drug substance, the CGMP
status for that operation is reported as part of the profile class code for the particular
dosage form or type of drug substance. For example, a manufacturing site
producing a terminally sterilized small volume parenteral product would be reported
with the profile class code for the dosage form (SVT), not by the profile
code for the sterilization process (SSP).
Certain inspections may be required by program priorities even if a profile
class code indicates an acceptable CGMP status. The current profile codes/classes
for human drugs are:
544 Appendix G
Appendix G 545
ADM Aerosol dispensed medication NEC Not elsewhere classified (when
using this class, tinctures)
CBI Biotechnology crude drug OIN Ointment, nonsterile
(includes cream, jelly, paste)
CEX Plant/animal extraction POW Powders (includes oral
crude drug and topical)
CFS Sterile bulk by fermentation RAD Radiopharmaceutical
crude drug
CFN Nonsterile bulk by fermentation RSP Radiation sterilization process
crude drug
CHG Capsule, prompt release SNI Sterile noninjectable
CRU Crude bulk drugs-nonsynthesized SOP Soap
CSG Capsules, soft gelatin SSP Steam sterilization process
CSN Nonsterile bulk by SUP Suppositories
chemical synthesis
CSP Chemical sterilization process SVL Small volume parenterals
(lyophilized)
CSS Sterile bulk by chemical synthesis SVS Sterile-filled small volume
parenterals
CTL Control testing laboratories SVT Terminally sterilized small
volume parenteral
CTR Capsules, modified-release TCM Tablets, prompt-release
GAS Medical gas (includes liquid TCT Tablets, delayed-release
oxygen and other)
GSP Gas sterilization process TDP Transdermal patches
HSP Dry heat sterilization process TSP Fractional (tyndallization)
sterilization process
LIQ Liquid (includes solutions, TTR Tablets, extended-release
suspension, elixirs,
and tinctures)
LVP Large volume parenterals WSP Water sterilization process
CGMP inspectional status, based on the profile class, is available through
FDA’s Freedom of Information (FOI) Office. (See Glossary under Satisfactory
Current Good Manufacturing Practice (CGMP) Inspection for more information
regarding FOI requests.)
Examples of postapproval manufacturing site changes and filing consequences:
• An applicant wants to move the manufacture of an immediate-release
tablet (TCM) to a different manufacturing site that currently manufactures,
and has satisfactory CGMP status for, capsules (CHG) and powders
for oral solution (POW). This manufacturing site change should be
filed in a prior approval supplement because the new manufacturing site
doesn’t have a satisfactory CGMP inspection for immediate-release
tablets.
• An applicant wants to contract out their packaging operations for immediate-
release tablets (TCM) and capsules (CHG), and modified-release
capsules (CTR). The potential contract packager has a satisfactory
CGMP status for immediate-release and modified-release capsules but
has never packaged immediate-release tablets. The packaging site
change for the immediate-release tablet products should be filed in a
prior approval supplement. The packaging site change for the capsule
products should be filed as recommended in section VI of this guidance
for packaging sites with a satisfactory CGMP inspection.
• An applicant wishes to consolidate their product testing to a single
analytical laboratory at a manufacturing site. This manufacturing site
produces various solid oral dosage form products, has an operational analytical
laboratory currently at the site, and satisfactory CGMP inspections
for the manufacturing occurring at the facility. Some of the products
that will be tested at the analytical laboratory when the consolidation occurs
are not solid oral dosage form products. Unlike most other production
operations, testing laboratories (and other operations in boldface in
the table) are not inspected on a dosage form/type of drug substance specific
basis. The satisfactory CGMP inspection of the analytical laboratory,
which was performed as part of the CGMP inspection for manufacture
of the solid oral dosage form products, is considered to apply to all
dosage forms, including those not actually produced at the site.
ATTACHMENT C: CDER-APPROVED
In several places throughout the guidance, different reporting categories are proposed
for changes to or the addition of certain components based on whether the
546 Appendix G
component/material has been used in and has been in contact with CDER-approved
products. Different reporting categories are recommended once CDER has
reviewed certain components/materials in association with a product approval because
similar subsequent changes then have a reduced potential to have an adverse
effect on the identity, strength, quality, purity, or potency of a product as they may
relate to the safety or effectiveness of the product. For example, certain changes
in the container closure systems of solid oral dosage form products may be included
in the annual report, as long as the new package provides the same or better
protective properties and any new primary packaging component materials
have been used in and been in contact with CDER-approved solid oral dosage
form products (see section IX.D.3). If the primary packaging component material
has not been used in or has not been in contact with CDER-approved solid oral
dosage form products, then submission of the change in an annual report is not
recommended.
CDER-approved products are considered those subject to an approved NDA
or ANDA. Some information on which components/materials are used in CDERapproved
products is available from the Agency (e.g., FDA, CDER, Inactive Ingredient
Guide, 1996, Division of Drug Information Resources). When information
is not available, an applicant should use reliable sources of information to
determine that the component or material has been used in and has been in contact
with a CDER-approved product of the same dosage form and route of administration,
as appropriate. The applicant should identify in the supplement or annual report
the basis for the conclusion that the component or material is used in a CDERapproved
product.
If an applicant cannot confirm that a component or material has been used
in and has been in contact with a CDER-approved product of the same dosage
form and route of administration, the applicant has the option of filing the change
for a single NDA or ANDA using the higher recommended reporting category
and, after approval, filing similar subsequent changes for other NDAs and ANDAs
using the lower recommended reporting category.
GLOSSARY
Acceptance Criteria: Numerical limits, ranges, or other criteria for the tests described.
Active Ingredient/Drug Substance: Any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of a disease, or to affect the structure or any function of
the human body, but does not include intermediates used in the synthesis of such
ingredient. The term includes those components that may undergo chemical
change in the manufacture of the drug product and are present in the drug product
Appendix G 547
in a modified form intended to furnish the specified activity or effect (21 CFR
210.3(b)(7) and 314.3).
Component: Any ingredient intended for use in the manufacture of a drug product,
including those that may not appear in such drug product (21 CFR
210.3(b)(3)).
Container Closure System: The sum of packaging components that together
contain and protect the dosage form. This includes primary packaging components
and secondary packaging components, if the latter are intended to provide
additional protection to the drug product.
Drug Product: A finished dosage form, for example, tablet, capsule, or solution,
that contains an active ingredient, generally, but not necessarily, in association
with inactive ingredients (21 CFR 210.3(b)(4)).
Final Intermediate: The last compound synthesized before the reaction that
produces the drug substance. The final step forming the drug substance must involve
covalent bond formation or breakage; ionic bond formation (i.e., making the
salt of a compound) does not qualify. Consequently, when the drug substance is a
salt, the precursors to the organic acid or base, rather than the acid or base itself,
should be considered the final intermediate.
Inactive Ingredients: Any intended component of the drug product other than
an active ingredient.
In-process Material: Any material fabricated, compounded, blended, or derived
by chemical reaction that is produced for, and used in, the preparation of the
drug product (21 CFR 210.3(b)(9)). For drug substance, in-process materials are
considered those materials that are undergoing change (e.g., molecular, physical).
Intermediate: A material produced during steps of the synthesis of a drug substance
that must undergo further molecular change before it becomes a drug substance.
Package: The container closure system and labeling, associated components
(e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons, shrink
wrap).
Packaging Component: Any single part of a container closure system.
Primary Packaging Component: A packaging component that is or may be in
direct contact with the dosage form.
Reference Listed Drug: The listed drug identified by FDA as the drug product
on which an applicant relies in seeking approval of its abbreviated application (21
CFR 314.3).
Satisfactory Current Good Manufacturing Practice (CGMP) Inspection: A
satisfactory CGMP inspection is an FDA inspection during which (1) no objectionable
conditions or practices were found during (No Action Indicated (NAI))
or (2) objectionable conditions were found, but, corrective action is left to the firm
to take voluntarily and the objectionable conditions will not be the subject of further
administrative or regulatory actions (Voluntary Action Indicated (VAI)).
548 Appendix G
Information about the CGMP status of a firm may be obtained by requesting a
copy of the Quality Assurance Profile (QAP) from the FDA’s Freedom of Information
(FOI) Office. The QAP reports information on the CGMP compliance status
of firms that manufacture, package, assemble, repack, relabel, or test human
drugs, devices, biologics, and veterinary drugs. All FOI requests must be in writing
and should follow the instructions found in the reference entitled A Handbook
for Requesting Information and Records from FDA. An electronic version of this
reference is available on the Internet at http://www.fda.gov/opacom/backgrounders/
foiahand.html.
Secondary Packaging Component: A packaging component that is not and
will not be in direct contact with the dosage form.
Specifications: The quality standards (i.e., tests, analytical procedures, and acceptance
criteria) provided in an approved application to confirm the quality of
drug substances, drug products, intermediates, raw materials, reagents, and other
components including container closure systems, and in-process materials.
Validate the Effects of the Change: To assess the effect of a manufacturing
change on the identity, strength, quality, purity, or potency of a drug as these factors
relate to the safety or effectiveness of the drug.
Appendix G 549

Appendix H
Guidance for Industry1—
Waiver of In Vivo Bioavailability
and Bioequivalence Studies
for Immediate-Release Solid
Oral Dosage Forms Based on a
Biopharmaceutics Classification
System
I. INTRODUCTION
This guidance provides recommendations for sponsors of investigational new
drug applications (INDs), new drug applications (NDAs), abbreviated new drug
applications (ANDAs), and supplements to these applications who wish to request
a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies for
immediate release (IR) solid oral dosage forms. These waivers are intended to apply
to (1) subsequent in vivo BA or BE studies of formulations after the initial establishment
of the in vivo BA of IR dosage forms during the IND period, and (2)
in vivo BE studies of IR dosage forms in ANDAs. Regulations at 21 CFR part 320
address the requirements for bioavailability (BA) and BE data for approval of
drug applications and supplemental applications. Provision for waivers of in vivo
BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR
551
1 This guidance has been prepared by the Biopharmaceutics Classification System Working Group of
the Biopharmaceutics Coordinating Committee in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA). This guidance represents the Agency’s current
thinking on the topic. It does not create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such an approach satisfies the
requirements of the applicable statutes, regulations, or both.
320.22. This guidance explains when biowaivers can be requested for IR solid oral
dosage forms based on an approach termed the Biopharmaceutics Classification
System (BCS).
II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM
The BCS is a scientific framework for classifying drug substances based on their
aqueous solubility and intestinal permeability. When combined with the dissolution
of the drug product, the BCS takes into account three major factors that govern
the rate and extent of drug absorption from IR solid oral dosage forms: dissolution,
solubility, and intestinal permeability.2 According to the BCS, drug
substances are classified as follows:
Class 1: High Solubility—High Permeability
Class 2: Low Solubility—High Permeability
Class 3: High Solubility—Low Permeability
Class 4: Low Solubility—Low Permeability
In addition, IR solid oral dosage forms are categorized as having rapid or
slow dissolution. Within this framework, when certain criteria are met, the BCS
can be used as a drug development tool to help sponsors justify requests for
biowaivers.
Observed in vivo differences in the rate and extent of absorption of a drug
from two pharmaceutically equivalent solid oral products may be due to differences
in drug dissolution in vivo.2 However, when the in vivo dissolution of an
IR solid oral dosage form is rapid in relation to gastric emptying and the drug
has high permeability, the rate and extent of drug absorption is unlikely to be
dependent on drug dissolution and/or gastrointestinal transit time. Under such
circumstances, demonstration of in vivo BA or BE may not be necessary for
drug products containing Class 1 drug substances, as long as the inactive ingredients
used in the dosage form do not significantly affect absorption of the active
ingredients. The BCS approach outlined in this guidance can be used to justify
biowaivers for highly soluble and highly permeable drug substances (i.e.,
Class 1) in IR solid oral dosage forms that exhibit rapid in vitro dissolution using
the recommended test methods (21 CFR 320.22(e)). The recommended
methods for determining solubility, permeability, and in vitro dissolution are
discussed below.
552 Appendix H
2 Amidon, G. L., H. Lennernas, V. P. Shah, and J. R. Crison, AA Theoretical Basis For a Biopharmaceutics
Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo
Bioavailability,@ Pharmaceutical Research, 12: 413–420 (1995).
A. Solubility
The solubility class boundary is based on the highest dose strength of an IR product
that is the subject of a biowaiver request. A drug substance is considered
highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous
media over the pH range of 1–7.5. The volume estimate of 250 ml is derived
from typical BE study protocols that prescribe administration of a drug product to
fasting human volunteers with a glass (about 8 ounces) of water.
B. Permeability
The permeability class boundary is based indirectly on the extent of absorption
(fraction of dose absorbed, not systemic BA) of a drug substance in humans and
directly on measurements of the rate of mass transfer across human intestinal
membrane. Alternatively, nonhuman systems capable of predicting the extent of
drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods).
In the absence of evidence suggesting instability in the gastrointestinal
tract, a drug substance is considered to be highly permeable when the extent of
absorption in humans is determined to be 90% or more of an administered dose
based on a mass balance determination or in comparison to an intravenous reference
dose.
C. Dissolution
In this guidance, an IR drug product is considered rapidly dissolving when no less
than 85% of the labeled amount of the drug substance dissolves within 30 minutes,
using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50
rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl
or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a
pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.
III. METHODOLOGY FOR CLASSIFYING A DRUG
SUBSTANCE AND FOR DETERMINING
THE DISSOLUTION CHARACTERISTICS
OF A DRUG PRODUCT
The following approaches are recommended for classifying a drug substance and
determining the dissolution characteristics of an IR drug product according to the
BCS:
Appendix H 553
A. Determining Drug Substance Solubility Class
An objective of the BCS approach is to determine the equilibrium solubility of a
drug substance under physiological pH conditions. The pH-solubility profile of
the test drug substance should be determined at 37  1 ° C in aqueous media with
a pH in the range of 1–7.5. A sufficient number of pH conditions should be evaluated
to accurately define the pH-solubility profile. The number of pH conditions
for a solubility determination can be based on the ionization characteristics of the
test drug substance. For example, when the pKa of a drug is in the range of 3–5,
solubility should be determined at pH 
 pKa, pH 
 pKa 1, pH 
 pKa1, and
at pH 
 1 and 7.5. A minimum of three replicate determinations of solubility in
each pH condition is recommended. Depending on study variability, additional
replication may be necessary to provide a reliable estimate of solubility. Standard
buffer solutions described in the USP are considered appropriate for use in solubility
studies. If these buffers are not suitable for physical or chemical reasons,
other buffer solutions can be used. Solution pH should be verified after addition
of the drug substance to a buffer. Methods other than the traditional shake-flask
method, such as acid or base titration methods, can also be used with justification
to support the ability of such methods to predict equilibrium solubility of the test
drug substance. Concentration of the drug substance in selected buffers (or pH
conditions) should be determined using a validated stability-indicating assay that
can distinguish the drug substance from its degradation products.3 If degradation
of the drug substance is observed as a function of buffer composition and/or pH,
it should be reported along with other stability data recommended in section
III.B.3.
The solubility class should be determined by calculating the volume of an
aqueous medium sufficient to dissolve the highest dose strength in the pH range
of 1–7.5. A drug substance should be classified as highly soluble when the highest
dose strength is soluble in  250 ml of aqueous media over the pH range of
1–7.5.
B. Determining Drug Substance Permeability Class
The permeability class of a drug substance can be determined in human subjects
using mass balance, absolute BA, or intestinal perfusion approaches. Recommended
methods not involving human subjects include in vivo or in situ intestinal
perfusion in a suitable animal model (e.g., rats), and/or in vitro permeability methods
using excised intestinal tissues, or monolayers of suitable epithelial cells. In
many cases, a single method may be sufficient (e.g., when the absolute BA is 90%
554 Appendix H
3 See the FDA guidance for industry on Submitting Documentation for the Stability of Human Drugs
and Biologics (February 1987), posted at http://www.fda.gov/guidance/index.htm.
or more, or when 90% or more of the administered drug is recovered in urine).
When a single method fails to conclusively demonstrate a permeability classification,
two different methods may be advisable. Chemical structure and/or certain
physicochemical attributes of a drug substance (e.g., partition coefficient in suitable
systems) can provide useful information about its permeability characteristics.
Sponsors may wish to consider use of such information to further support a
classification.
1. Pharmacokinetic Studies in Humans
a. Mass Balance Studies. Pharmacokinetic mass balance studies using
unlabeled, stable isotopes or a radiolabeled drug substance can be used to document
the extent of absorption of a drug. Depending on the variability of the studies,
a sufficient number of subjects should be enrolled to provide a reliable estimate
of extent of absorption. Because this method can provide highly variable
estimates of drug absorption for many drugs, other methods described below may
be preferable.
b. Absolute Bioavailability Studies. Oral BA determination using intravenous
administration as a reference can be used. Depending on the variability of
the studies, a sufficient number of subjects should be enrolled in a study to provide
a reliable estimate of the extent of absorption. When the absolute BA of a
drug is shown to be 90% or more, additional data to document drug stability in the
gastrointestinal fluid is not necessary.
2. Intestinal Permeability Methods
The following methods can be used to determine the permeability of a drug substance
from the gastrointestinal tract: (1) in vivo intestinal perfusion studies in humans;
(2) in vivo or in situ intestinal perfusion studies using suitable animal models;
(3) in vitro permeation studies using excised human or animal intestinal
tissues; or (4) in vitro permeation studies across a monolayer of cultured epithelial
cells.
In vivo or in situ animal models and in vitro methods, such as those using
cultured monolayers of animal or human epithelial cells, are considered appropriate
for passively transported drugs. The observed low permeability of some drug
substances in humans could be caused by efflux of drugs via membrane transporters
such as P-glycoprotein (P-gp). When the efflux transporters are absent in
these models, or their degree of expression is low compared to that in humans,
there may be a greater likelihood of misclassification of permeability class for a
drug subject to efflux compared to a drug transported passively. Expression of
known transporters in selected study systems should be characterized. Functional
expression of efflux systems (e.g., P-gp) can be demonstrated with techniques
Appendix H 555
such as bidirectional transport studies, demonstrating a higher rate of transport in
the basolateral-to-apical direction as compared to apical-to-basolateral direction
using selected model drugs or chemicals at concentrations that do not saturate the
efflux system (e.g., cyclosporin A, vinblastine, rhodamine 123). An acceptance
criterion for intestinal efflux that should be present in a test system cannot be set
at this time. Instead, this guidance recommends limiting the use of nonhuman permeability
test methods for drug substances that are transported by passive mechanisms.
Pharmacokinetic studies on dose linearity or proportionality may provide
useful information for evaluating the relevance of observed in vitro efflux of a
drug. For example, there may be fewer concerns associated with the use of in vitro
methods for a drug that has a higher rate of transport in the basolateral-to-apical
direction at low drug concentrations but exhibits linear pharmacokinetics in humans.
For application of the BCS, an apparent passive transport mechanism can be
assumed when one of the following conditions is satisfied:
• A linear (pharmacokinetic) relationship between the dose (e.g., relevant
clinical dose range) and measures of BA (area under the concentrationtime
curve) of a drug is demonstrated in humans
• Lack of dependence of the measured in vivo or in situ permeability is
demonstrated in an animal model on initial drug concentration (e.g.,
0.01, 0.1, and 1 times the highest dose strength dissolved in 250 ml) in
the perfusion fluid
• Lack of dependence of the measured in vitro permeability on initial drug
concentration (e.g., 0.01, 0.1, and 1 times the highest dose strength dissolved
in 250 ml) is demonstrated in donor fluid and transport direction
(e.g., no statistically significant difference in the rate of transport between
the apical-to-basolateral and basolateral-to-apical direction for the
drug concentrations selected) using a suitable in vitro cell culture
method that has been shown to express known efflux transporters (e.g.,
P-gp)
To demonstrate suitability of a permeability method intended for application
of the BCS, a rank-order relationship between test permeability values and the
extent of drug absorption data in human subjects should be established using a sufficient
number of model drugs. For in vivo intestinal perfusion studies in humans,
six model drugs are recommended. For in vivo or in situ intestinal perfusion studies
in animals and for in vitro cell culture methods, twenty model drugs are recommended.
Depending on study variability, a sufficient number of subjects, animals,
excised tissue samples, or cell monolayers should be used in a study to
provide a reliable estimate of drug permeability. This relationship should allow
precise differentiation between drug substances of low and high intestinal permeability
attributes.
556 Appendix H
For demonstration of suitability of a method, model drugs should represent
a range of low (e.g.,  50%), moderate (e.g., 50–89%), and high /90%) absorption.
Sponsors may select compounds from the list of drugs and/or chemicals provided
in Attachment A or they may choose to select other drugs for which there is
information available on mechanism of absorption and reliable estimates of the
extent of drug absorption in humans.
After demonstrating suitability of a method and maintaining the same study
protocol, it is not necessary to retest all selected model drugs for subsequent studies
intended to classify a drug substance. Instead, a low and a high permeability
model drug should be used as internal standards (i.e., included in the perfusion
fluid or donor fluid along with the test drug substance). These two internal standards
are in addition to the fluid volume marker (or a zero permeability compound
such as PEG 4000) that is included in certain types of perfusion techniques (e.g.,
closed loop techniques). The choice of internal standards should be based on compatibility
with the test drug substance (i.e., they should not exhibit any significant
physical, chemical, or permeation interactions). When it is not feasible to follow
this protocol, the permeability of internal standards should be determined in the
same subjects, animals, tissues, or monolayers, following evaluation of the test
drug substance. The permeability values of the two internal standards should not
differ significantly between different tests, including those conducted to demonstrate
suitability of the method. At the end of an in situ or in vitro test, the amount
of drug in the membrane should be determined.
For a given test method with set conditions, selection of a high permeability
internal standard with permeability in close proximity to the low/high permeability
class boundary may facilitate classification of a test drug substance. For instance,
a test drug substance may be determined to be highly permeable when its
permeability value is equal to or greater than that of the selected internal standard
with high permeability.
3. Instability in the Gastrointestinal Tract
Determining the extent of absorption in humans based on mass balance studies using
total radioactivity in urine does not take into consideration the extent of degradation
of a drug in the gastrointestinal fluid prior to intestinal membrane permeation.
In addition, some methods for determining permeability could be based on
loss or clearance of a drug from fluids perfused into the human and/or animal gastrointestinal
tract either in vivo or in situ. Documenting the fact that drug loss from
the gastrointestinal tract arises from intestinal membrane permeation, rather than
a degradation process, will help establish permeability. Stability in the gastrointestinal
tract may be documented using gastric and intestinal fluids obtained from
human subjects. Drug solutions in these fluids should be incubated at 37 ° C for a
period that is representative of in vivo drug contact with these fluids; for example,
Appendix H 557
1 hour in gastric fluid and 3 hours in intestinal fluid. Drug concentrations should
then be determined using a validated stability-indicating assay method. Significant
degradation (5%) of a drug in this protocol could suggest potential instability.
Obtaining gastrointestinal fluids from human subjects requires intubation
and may be difficult in some cases. Use of gastrointestinal fluids from suitable animal
models and/or simulated fluids such as Gastric and Intestinal Fluids USP can
be substituted when properly justified.
C. Determining Drug Product Dissolution Characteristics
and Dissolution Profile Similarity 4
Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus
II at 50 rpm using 900 ml of the following dissolution media: (1) 0.1 N HCl
or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a
pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. For capsules
and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with
enzymes) can be used.
Dissolution testing apparatus used in this evaluation should conform to the
requirements in USP (711 Dissolution). Selection of the dissolution testing
apparatus (USP Apparatus I or II) during drug development should be based on a
comparison of in vitro dissolution and in vivo pharmacokinetic data available for
the product. The USP Apparatus I (basket method) is generally preferred for capsules
and products that tend to float, and USP Apparatus II (paddle method) is
generally preferred for tablets. For some tablet dosage forms, in vitro (but not in
vivo) dissolution may be slow due to the manner in which the disintegrated product
settles at the bottom of a dissolution vessel. In such situations, USP Apparatus
I may be preferred over Apparatus II. If the testing conditions need to be modified
to better reflect rapid in vivo dissolution (e.g., use of a different rotating speed),
such modifications can be justified by comparing in vitro dissolution with in vivo
absorption data (e.g., a relative BA study using a simple aqueous solution as the
reference product).
A minimum of 12 dosage units of a drug product should be evaluated to support
a biowaiver request. Samples should be collected at a sufficient number of intervals
to characterize the dissolution profile of the drug product (e.g., 10, 15, 20,
and 30 minutes).
When comparing the test and reference products, dissolution profiles
should be compared using a similarity factor (f2). The similarity factor is a logarithmic
reciprocal square root transformation of the sum of squared error and is
558 Appendix H
4 See the FDA guidance for industry on Dissolution Testing of Immediate Release Solid Oral Dosage
Forms (August 1997).
a measurement of the similarity in the percent (%) of dissolution between the
two curves.
f2 
 50log {[1  (1/n)?nt

1 (Rt  Tt)2]0.5100}2
Two dissolution profiles are considered similar when the f2 value is /50.
To allow the use of mean data, the coefficient of variation should not be more than
20% at the earlier time points (e.g., 10 minutes), and should not be more than 10%
at other time points. Note that when both test and reference products dissolve 85%
or more of the label amount of the drug in !15 minutes using all three dissolution
media recommended above, the profile comparison with an f2 test is unnecessary.
IV. ADDITIONAL CONSIDERATIONS FOR REQUESTING
A BIOWAIVER
When requesting a BCS-based waiver for in vivo BA/BE studies for IR solid oral
dosage forms, applicants should note that the following factors can affect their request
or the documentation of their request:
A. Excipients
Excipients can sometimes affect the rate and extent of drug absorption. In general,
using excipients that are currently in FDA-approved IR solid oral dosage forms
will not affect the rate or extent of absorption of a highly soluble and highly permeable
drug substance that is formulated in a rapidly dissolving IR product. To
support a biowaiver request, the quantity of excipients in the IR drug product
should be consistent with the intended function (e.g., lubricant). When new excipients
or atypically large amounts of commonly used excipients are included in
an IR solid dosage form, additional information documenting the absence of an
impact on BA of the drug may be requested by the Agency. Such information can
be provided with a relative BA study using a simple aqueous solution as the reference
product. Large quantities of certain excipients, such as surfactants (e.g.,
polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic,
and sponsors are encouraged to contact the review division when this is a factor.
B. Prodrugs
Permeability of prodrugs will depend on the mechanism and (anatomical) site of
conversion to the drug substance. When the prodrug-to-drug conversion is shown
to occur predominantly after intestinal membrane permeation, the permeability of
the prodrug should be measured. When this conversion occurs prior to intestinal
permeation, the permeability of the drug should be determined. Dissolution and
Appendix H 559
pH-solubility data on both prodrug and drug can be relevant. Sponsors may wish
to consult with appropriate review staff before applying the BCS approach to IR
products containing prodrugs.
C. Exceptions
BCS-based biowaivers are not applicable for the following:
1. Narrow Therapeutic Range Drugs5
This guidance defines narrow therapeutic range drug products as those containing
certain drug substances that are subject to therapeutic drug concentration or pharmacodynamic
monitoring, and/or where product labeling indicates a narrow therapeutic
range designation. Examples include digoxin, lithium, phenytoin, theophylline,
and warfarin. Because not all drugs subject to therapeutic drug
concentration or pharmacodynamic monitoring are narrow therapeutic range
drugs, sponsors should contact the appropriate review division to determine
whether a drug should be considered to have a narrow therapeutic range.
2. Products Designed to be Absorbed in the Oral Cavity
A request for a waiver of in vivo BA/BE studies based on the BCS is not appropriate
for dosage forms intended for absorption in the oral cavity (e.g., sublingual
or buccal tablets).
V. REGULATORY APPLICATIONS OF THE BCS
A. INDs/NDAs
Evidence demonstrating in vivo BA or information to permit FDA to waive this
evidence must be included in NDAs (21 CFR 320.21(a)). A specific objective is
to establish in vivo performance of the dosage form used in the clinical studies that
provided primary evidence of efficacy and safety. The sponsor may wish to determine
the relative BA of an IR solid oral dosage form by comparison with an
oral solution, suspension, or intravenous injection (21 CFR 320.25 (d)(2) and
320.25 (d)(3)). The BA of the clinical trial dosage form should be optimized during
the IND period.
Once the in vivo BA of a formulation is established during the IND period,
waivers of subsequent in vivo BE studies, following major changes in compo-
560 Appendix H
5 This guidance uses the term narrow therapeutic range instead of narrow therapeutic index, although
the latter is more commonly used.
nents, composition, and/or method of manufacture (e.g., similar to SUPAC-IR
Level 3 changes6) may be possible using the BCS. BCS-based biowaivers are applicable
to the to-be-marketed formulation when changes in components, composition,
and/or method of manufacture occur to the clinical trial formulation, as
long as the dosage forms have rapid and similar in vitro dissolution profiles (see
sections II and III). This approach is useful only when the drug substance is highly
soluble and highly permeable (BCS Class 1), and the formulations pre- and
postchange are pharmaceutical equivalents (under the definition at 21 CFR 320.1
(c)). BCS-based biowaivers are intended only for BE studies. They do not apply
to food effect BA studies or other pharmacokinetic studies.
B. ANDAs
BCS-based biowaivers can be requested for rapidly dissolving IR test products
containing highly soluble and highly permeable drug substances, provided that the
reference listed drug product is also rapidly dissolving and the test product
exhibits similar dissolution profiles to the reference listed drug product (see sections
II and III). This approach is useful when the test and reference dosage forms
are pharmaceutical equivalents. The choice of dissolution apparatus (USP Apparatus
I or II) should be the same as that established for the reference listed drug
product.
C. Postapproval Changes
BCS-based biowaivers can be requested for significant postapproval changes
(e.g., Level 3 changes in components and composition) to a rapidly dissolving IR
product containing a highly soluble, highly permeable drug substance, provided
that dissolution remains rapid for the postchange product and both pre- and
postchange products exhibit similar dissolution profiles (see sections II and III).
This approach is useful only when the drug products pre- and postchange are pharmaceutical
equivalents.
VI. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS
The drug substance for which a waiver is being requested should be highly soluble
and highly permeable. Sponsors requesting biowaivers based on the BCS
should submit the following information to the Agency for review by the Office
Appendix H 561
6 See the FDA guidance for industry on Immediate Release Solid Oral Dosage Forms: Scale-Up and
Post-Approval Changes (November 1995).
of Clinical Pharmacology and Biopharmaceutics (for NDAs) or Office of Generic
Drugs, Division of Bioequivalence (for ANDAs):
A. Data Supporting High Solubility
Data supporting high solubility of the test drug substance should be developed
(see section III.A). The following information should be included in the application:
• A description of test methods, including information on analytical
method and composition of the buffer solutions
• Information on chemical structure, molecular weight, nature of the drug
substance (acid, base, amphoteric, or neutral), and dissociation constants
(pKa(s))
• Test results (mean, standard deviation, and coefficient of variation) summarized
in a table under solution pH, drug solubility (e.g., mg/ml), and
volume of media required to dissolve the highest dose strength
• A graphic representation of mean pH-solubility profile
B. Data Supporting High Permeability
Data supporting high permeability of the test drug substance should be developed
(see section III.B). The following information should be included in the application:
• For human pharmacokinetic studies, information on study design and
methods used along with the pharmacokinetic data
• For direct permeability methods, information supporting the suitability
of a selected method that encompasses a description of the study method,
criteria for selection of human subjects, animals, or epithelial cell line,
drug concentrations in the donor fluid, description of the analytical
method, method used to calculate extent of absorption or permeability,
and where appropriate, information on efflux potential (e.g., bidirectional
transport data)
• A list of selected model drugs along with data on extent of absorption in
humans (mean, standard deviation, coefficient of variation) used to establish
suitability of a method, permeability values for each model drug
(mean, standard deviation, coefficient of variation), permeability class
of each model drug, and a plot of the extent of absorption as a function
of permeability (mean  standard deviation or 95% confidence interval)
with identification of the low/high permeability class boundary and selected
internal standard. Information to support high permeability of a
test drug substance should include permeability data on the test drug
562 Appendix H
substance, the internal standards (mean, standard deviation, coefficient
of variation), stability information, data supporting passive transport
mechanism where appropriate, and methods used to establish high permeability
of the test drug substance.
C. Data Supporting Rapid and Similar Dissolution
For submission of a biowaiver request, an IR product should be rapidly dissolving.
Data supporting rapid dissolution attributes of the test and reference products
should be developed (see section III.C). The following information should be included
in the application:
• A brief description of the IR products used for dissolution testing, including
information on batch or lot number, expiry date, dimensions,
strength, and weight
• Dissolution data obtained with 12 individual units of the test and reference
products using recommended test methods in section III.C. The
percentage of labeled claim dissolved at each specified testing interval
should be reported for each individual dosage unit. The mean percent
dissolved, range (highest and lowest) of dissolution, and coefficient of
variation (relative standard deviation) should be tabulated. A graphic
representation of the mean dissolution profiles for the test and reference
products in the three media should also be included.
• Data supporting similarity in dissolution profiles between the test and
reference products in each of the three media, using the f2 metric
D. Additional Information
The manufacturing process used to make the test product should be described
briefly to provide information on the method of manufacture (e.g., wet granulation
vs. direct compression). A list of excipients used, the amount used, and their
intended functions should be provided. Excipients used in the test product should
have been used previously in FDA-approved IR solid oral dosage forms.
ATTACHMENT A
This attachment includes model drugs suggested for use in establishing suitability
of a permeability method as described in section III. The permeability of these
compounds was determined based on data available to the FDA. Potential internal
standards (IS) and efflux pump substrates (ES) are also identified.
Appendix H 563
564 Appendix H
Drug Permeability class
Antipyrine High (Potential IS candidate)
Caffeine High
Carbamazepine High
Fluvastatin High
Ketoprofen High
Metoprolol High (Potential IS candidate)
Naproxen High
Propranolol High
Theophylline High
Verapamil High (Potential ES candidate)
Amoxicillin Low
Atenolol Low
Furosemide Low
Hydrochlorthiazide Low
Mannitol Low (Potential IS candidate)
•-Methyldopa Low
Polyethylene glycol (400) Low
Polyethylene glycol (1000) Low
Polyethylene glycol (4000) Low (Zero permeability marker)
Ranitidine Low
Index
Bioreactor, 98, 103, 113
CDER (Center for Drug Evaluation and
Research), 237, 328, 331, 332,
347, 350, 353, 354, 374, 380, 382,
402, 415, 416, 447, 451, 455, 469,
470, 473, 487, 500, 517–519,
522–525, 529, 531, 535–541, 546,
547, 551
Chromatography, 100, 107, 110
Compaction, 221–223, 228, 231–234,
237, 243, 251, 320, 323, 426, 428
mechanisms
elastic, 222, 225
plastic, 80, 222, 225, 226, 228, 233,
234
visco-elastic, 222, 225, 255
speed, 233
dwell time, 246, 305
Compression, 167, 222, 223, 226,
236–238, 255, 323, 417–420, 435,
436, 443–445, 501, 503, 504
Design of experiments, 268, 309
Diffusion, 322, 333, 417, 421, 422, 425,
483, 484
565
Dimensional analysis, 2, 20, 34, 83, 92,
100, 120, 170, 253
biotechnology-derived products, 100
dimensional homogeneity, 5
dimensional matrix, 254
dimensional systems, 3
dimensionless groups, 9, 46, 83, 84,
119, 141, 152–155
dry blending and mixing, 120
Froude number, 15, 22, 45, 64, 119,
129
granulation and drying, 152
industrial applications, 1
Newton power number, 12, 13, 30,
154
non-parenteral liquids and semisolids,
83
parenteral drugs, 44
pi theorem, 6, 8, 9, 12
Reynolds number, 12, 16, 19, 30, 45,
46, 47, 49, 50, 51, 62, 64, 65, 67,
75
similarity, 8, 40, 41, 44, 78, 81, 83, 88,
152, 232, 379, 383, 388, 391, 393,
395, 399, 558
tableting, 253
Dissolution, 224, 236, 334, 335, 344,
350–352, 355, 359, 360, 362–368,
373, 376, 378, 379, 381, 383, 385,
387, 389, 390, 392–400, 402, 415,
447, 448, 452, 457, 458, 460–462,
467, 492, 552, 553, 558, 559, 563
Drying, 151, 167, 188, 218, 272, 290,
291, 294, 429, 430, 432, 439, 442,
444, 445
Ejection, 228, 236, 237
Expert systems, 267, 268, 310
Flow
powder, 135, 330
turbulent, 89
Friability, 167, 224
GMP (Good Manufacturing Practices),
43, 55, 96, 315, 326, 416, 500
Granulation, 147, 151, 167, 170, 176,
191, 217–219, 223, 319, 322, 425,
426, 428
Heckel analysis, 225, 228, 232
Particle size, 71, 120, 205, 224, 322, 417,
501, 503
PQRI (Product Quality Research
Institute), 327, 328, 347–350
Precompression, 226
Process optimization, 267, 309
Scale-down, 1, 57, 331, 353, 373, 374, 469
Scale-up, 2, 6, 8, 14, 15, 17, 19, 21–23,
34, 37, 38, 42, 44, 45, 46, 49–51,
53, 55, 58, 61, 66–68, 70, 76–85,
87–90, 96, 98–101, 103–105, 107,
109–112, 116, 118–120, 127, 130,
131, 136, 141, 152, 154–156, 158,
162–164, 170, 205–207, 209, 215,
222–227, 232–236, 239–243, 246,
247, 249, 250, 253, 257, 260, 261,
264–266, 268, 269, 272, 273, 275,
278–281, 284, 286, 290, 291, 293,
295, 299, 302, 303, 305, 306, 308,
309, 311, 314, 318, 321–323, 325,
329, 331, 348, 350, 353, 354, 362,
364, 373, 374, 385, 389, 457, 461,
462, 469, 471, 472, 518
batch size, 95, 105, 171, 291, 332
biotechnology-derived products, 95
dry blending and mixing, 115
film coating, 259
fluid bed granulation, 171
granulation and drying, 151
industrial applications, 1
non-parenteral liquids and semisolids,
57
parenteral drugs, 43
pilot plant design, 311
regulatory aspects, 325
scale-of-agitation, 44, 46–49, 51
tableting, 221, 239, 253
Segregation, 127, 132, 133, 138, 141, 146
Spray Nozzle, 180, 295
Stability, 223, 334, 335, 343, 350, 359,
360, 364–368, 370, 374, 376, 378,
379, 381, 382, 385, 387, 388, 390,
392, 395, 396, 402, 471, 473, 474,
476, 477, 480, 482, 554, 557
SUPAC (Scale-Up and Post-Approval
Changes), 233, 237, 240, 266, 321,
327–329, 331–335, 343, 345,
347–350, 353, 354, 373, 374, 400,
403, 409, 415, 416, 457–459, 461,
467, 469, 471, 499, 500, 518, 523,
543, 561
ER (Extended Release), 447
IR (Immediate Release), 321, 327,
328, 331–335, 343, 345, 347, 349,
350, 415, 416, 561
IR/MR (Immediate Release/Modified
Release), 321, 350, 415
SS (Nonsterile Semisolid), 469
Unit operations, 101
Velocity
fluid, 47, 49
Viscosity
kinematic, 9, 19, 22, 29, 42, 60, 70