PHARMACEUTICAL MANUFACTURING HANDBOOK Production and Processes

SHAYNE COX GAD, PH.D., D.A.B.T. 
Gad Consulting Services 
Cary, North Carolina 



CONTRIBUTORS 
Susanna Abrahms e n - Alami, AstraZeneca R & D Lund, Lund, Sweden, Oral 
Extended - Release Formulations 
James Agalloco, Agalloco & Associates, Belle Mead, New Jersey, Sterile Product 
Manufacturing 
Fakhrul Ahsan, Texas Tech University, Amarillo, Texas, Nasal Delivery of Peptide 
and Nonpeptide Drugs 
James Akers, Akers Kennedy & Associates, Kansas City, Missouri, Sterile Product 
Manufacturing 
Raid G. Alany, The University of Auckland, Auckland, New Zealand, Ocular Drug 
Delivery; Microemulsions as Drug Delivery Systems 
Monique Alric, Universit e d ’ Auvergne, Clermont - Ferrand, France, Recombinant 
Saccharomyces Cerevisiae as New Drug Delivery System to Gut: In Vitro Validation 
and Oral Formulation 
Sacide Alsoy Altinkaya, Izmir Institute of Technology, Urla - Izmir, Turkey, Controlled 
Release of Drugs from Tablet Coatings 
Maria Helena Amaral, University of Porto, Porto, Portugal, Vaginal Drug 
Delivery 
Anil Kumar Anal, Living Cell Technologies (Global) Limited, Auckland, New 
Zealand, Controlled - Release Dosage Forms 
Gavin Andrews, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of 
Grinding in Pharmaceutical Tablet Production 
Sophia G. Antimisiaris, School of Pharmacy, University of Patras, Rio, Greece, 
Liposomes and Drug Delivery 

vi CONTRIBUTORS 
Robert D. Arnold, The University of Georgia, Athens, Georgia, Biotechnology - 
Derived Drug Product Development 
C. Scott Asbill, Samford University, Birmingham, Alabama, Transdermal Drug 
Delivery 
Maria Fernanda Bahia, University of Porto, Porto, Portugal, Vaginal Drug 
Delivery 
Bernard Bataille, University of Montpelier 1, Montpellier, France, Tablet Design 
Gerald W. Becker, SSCI, West Lafayette, Indiana, Biotechnology - Derived Drug 
Product Development; Regulatory Considerations in Approval of Follow - On 
Protein Drug Products 
B. Wayne Bequette, Rensselaer Polytechnic Institute, Troy, New York, From Pilot 
Plant to Manufacturing: Effect of Scale - Up on Operation of Jacketed Reactors 
Erem Bilensoy, Hacettepe University Faculty of Pharmacy, Ankara, Turkey, Cyclodextrin 
- Based Nanomaterials in Pharmaceutical Field 
St e phanie Blanquet, Universit e d ’ Auvergne, Clermont - Ferrand, France, Recombinant 
Saccharomyces Cerevisiae as New Drug Delivery System to Gut: In Vitro 
Validation and Oral Formulation 
Gary W. Bumgarner, Samford University, Birmingham, Alabama, Transdermal 
Drug Delivery 
Isidoro Caraballo, University of Sevilla, Seville, Spain, Tablet Design 
Stephen M. Carl, Purdue University, West Lafayette, Indiana, Biotechnology - 
Derived Drug Product Development; Regulatory Considerations in Approval of 
Follow - On Protein Drug Products 
Sudhir S. Chakravarthi, University of Nebraska Medical Center, College of Pharmacy, 
Omaha, Nebraska, Biodegradable Nanoparticles 
D.F. Chowdhury, University of Oxford, Oxford, United Kingdom, Pharmaceutical 
Nanosystems: Manufacture, Characterization, and Safety 
Barbara R. Conway, Aston University, Birmingham, United Kingdom, Solid Dosage 
Forms 
Jos e das Neves, University of Porto, Porto, Portugal, Vaginal Drug Delivery 
Osama Abu Diak, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects 
of Grinding in Pharmaceutical Tablet Production 
Brit S. Farstad, Instititue for Energy Technology, Isotope Laboratories, Kjeller, 
Norway, Radiopharmaceutical Manufacturing 
Dimitrios G. Fatouros, School of Pharmacy and Biomedical Sciences, Portsmouth, 
England, Liposomes and Drug Delivery 
Jelena Filipovi c - Gr i , Faculty of Pharmacy and Biochemistry, University of 
Zagreb, Zagreb, Croatia, Nasal Powder Drug Delivery 
c c

CONTRIBUTORS vii 
Eddy Castellanos Gil, Center of Pharmaceutical Chemistry and University of 
Havana, Havana, Cuba; University of Sevilla, Seville, Spain; University of Montpelier 
1, Montpellier, France, Tablet Design 
Anita Hafner, Faculty of Pharmacy and Biochemistry, University of Zagreb, 
Zagreb, Croatia, Nasal Powder Drug Delivery 
A. Atilla Hincal, Hacettepe University Faculty of Pharmacy, Ankara, Turkey, 
Cyclodextrin - Based Nanomaterials in Pharmaceutical Field 
Michael Hindle, Virginia Commonwealth University, Richmond, Virginia, Aerosol 
Drug Delviery 
Bhaskara R. Jasti, University of the Pacifi c, Stockton, California, Semisolid Dosages: 
Ointments, Creams, and Gels 
Yiguang Jin, Beijing Institute of Radiation Medicine, Beijing, China, Nanotechnology 
in Pharmaceutical Manufacturing 
David Jones, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of 
Grinding in Pharmaceutical Tablet Production 
Anne Juppo, University of Helsinki, Helsinki, Finland, Oral Extended - Release 
Formulations 
Paraskevi Kallinteri, Medway School of Pharmacy, Universities of Greenwich and 
Kent, England, Liposomes and Drug Delivery 
Gregory T. Knipp, Purdue University, West Lafayette, Indiana, Biotechnology - 
Derived Drug Product Development; Regulatory Considerations in Approval of 
Follow - On Protein Drug Products 
Anette Larsson, Chalmers University of Technology, G o teborg, Sweden, Oral 
Extended - Release Formulations 
Beom - Jin Lee, Kangwon National University, Chuncheon, Korea, Pharmaceutical 
Preformulation: Physiochemical Properties of Excipients and Powders and Tablet 
Characterization 
Xiaoling Li, University of the Pacifi c, Stockton, California, Semisolid Dosages: 
Ointments, Creams, and Gels 
David J. Lindley, Purdue University, West Lafayette, Indiana, Biotechnology - 
Derived Drug Product Development 
Roberto Londono, Washington State University, Pullman, Washington, Liquid 
Dosage Forms 
Ravichandran Mahalingam, University of the Pacifi c, Stockton, California, Semisolid 
Dosages: Ointments, Creams, and Gels 
Kenneth R. Morris, Purdue University, West Lafayette, Indiana, Biotechnology - 
Derived Drug Product Development; Regulatory Considerations in Approval of 
Follow - On Protein Drug Products 
Erin Oliver, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 
Biotechnology - Derived Drug Product Development; Regulatory Considerations 
in Approval of Follow - On Protein Drug Products 

viii CONTRIBUTORS 
Iv a n Pe n uelas, University of Navarra, Pamplona, Spain, Radiopharmaceutical 
Manufacturing 
Omanthanu P. Perumal, South Dakota State University, Brookings, South Dakota, 
Role of Preformulation in Development of Solid Dosage Forms 
Katharina M. Picker - Freyer, Martin - Luther - University Halle - Wittenberg, Institute 
of Pharmaceutics and Biopharmaceutics, Halle/Saale, Germany, Tablet Production 
Systems 
Satheesh K. Podaralla, South Dakota State University, Brookings, South Dakota, 
Role of Preformulation in Development of Solid Dosage Forms 
Dennis H. Robinson, University of Nebraska Medical Center, College of Pharmacy, 
Omaha, Nebraska, Biodegradable Nanoparticles 
Arcesio Rubio, Caracas, Venezuela, Liquid Dosage Forms 
Maria V. Rubio - Bonilla, Research Associate, College of Pharmacy, Washington 
State University, Pullman, Washington, Liquid Dosage Forms 
Ilva D. Rupenthal, The University of Auckland, Auckland, New Zealand, Ocular 
Drug Delivery 
Maria In e s Rocha Miritello Santoro, Department of Pharmacy, Faculty of Pharmaceutical 
Sciences, University of S a o Paulo, S a o Paulo, Brazil, Packaging and 
Labeling 
Helton M.M. Santos, University of Coimbra, Coimbra, Portugal, Tablet 
Compression 
Raymond K. Schneider, Clemson University, Clemson, South Carolina, Clean - 
Facility Design, Construction, and Maintenance Issues 
Anil Kumar Singh, Department of Pharmacy, Faculty of Pharmaceutical Sciences, 
University of S a o Paulo, S a o Paulo, Brazil, Packaging and Labeling 
Jo a o J.M.S. Sousa, University of Coimbra, Coimbra, Portugal, Tablet 
Compression 
Shunmugaperumal Tamilvanan, University of Antwerp, Antwerp, Belgium, Progress 
in Design of Biodegradable Polymer - Based Microspheres for Parenteral 
Controlled Delivery of Therapeutic Peptide/Protein; Oil - in - Water Nanosized 
Emulsions: Medical Applications 
Chandan Thomas, Texas Tech University, Amarillo, Texas, Nasal Delivery of 
Peptide and Nonpeptide Drugs 
Gavin Walker, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of 
Grinding in Pharmaceutical Tablet Production 
Jingyuan Wen, The University of Auckland, Auckland, New Zealand, Microemulsions 
as Drug Delivery Systems 
Hui Zhai, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of Grinding 
in Pharmaceutical Tablet Production 

ix 
CONTENTS 
PREFACE xiii 
SECTION 1 MANUFACTURING SPECIALTIES 1 
1.1 Biotechnology-Derived Drug Product Development 3 
Stephen M. Carl, David J. Lindley, Gregory T. Knipp, Kenneth R. Morris, 
Erin Oliver, Gerald W. Becker, and Robert D. Arnold 
1.2 Regulatory Considerations in Approval on Follow-On Protein 
Drug Products 33 
Erin Oliver, Stephen M. Carl, Kenneth R. Morris, Gerald W. Becker, and 
Gregory T. Knipp 
1.3 Radiopharmaceutical Manufacturing 59 
Brit S. Farstad and Ivan Penuelas 
SECTION 2 ASEPTIC PROCESSING 97 
2.1 Sterile Product Manufacturing 99 
James Agalloco and James Akers 
SECTION 3 FACILITY 137 
3.1 From Pilot Plant to Manufacturing: Effect of Scale-Up on 
Operation of Jacketed Reactors 139 
B. Wayne Bequette

x CONTENTS 
3.2 Packaging and Labeling 159 
Maria Ines Rocha Miritello Santoro and Anil Kumar Singh 
3.3 Clean-Facility Design, Construction, and Maintenance Issues 201 
Raymond K. Schneider 
SECTION 4 NORMAL DOSAGE FORMS 233 
4.1 Solid Dosage Forms 235 
Barbara R. Conway 
4.2 Semisolid Dosages: Ointments, Creams, and Gels 267 
Ravichandran Mahalingam, Xiaoling Li, and Bhaskara R. Jasti 
4.3 Liquid Dosage Forms 313 
Maria V. Rubio-Bonilla, Roberto Londono, and Arcesio Rubio 
SECTION 5 NEW DOSAGE FORMS 345 
5.1 Controlled-Release Dosage Forms 347 
Anil Kumar Anal 
5.2 Progress in the Design of Biodegradable Polymer-Based 
Microspheres for Parenteral Controlled Delivery of Therapeutic 
Peptide/Protein 393 
Shunmugaperumal Tamilvanan 
5.3 Liposomes and Drug Delivery 443 
Sophia G. Antimisiaris, Paraskevi Kallinteri, and Dimitrios G. Fatouros 
5.4 Biodegradable Nanoparticles 535 
Sudhir S. Chakravarthi and Dennis H. Robinson 
5.5 Recombinant Saccharomyces cerevisiae as New Drug Delivery 
System to Gut: In Vitro Validation and Oral Formulation 565 
Stephanie Blanquet and Monique Alric 
5.6 Nasal Delivery of Peptide and Nonpeptide Drugs 591 
Chandan Thomas and Fakhrul Ahsan 
5.7 Nasal Powder Drug Delivery 651 
Jelena Filipovi -Gr i and Anita Hafner 
5.8 Aerosol Drug Delivery 683 
Michael Hindle 
5.9 Ocular Drug Delivery 729 
Ilva D. Rupenthal and Raid G. Alany 
5.10 Microemulsions as Drug Delivery Systems 769 
Raid G. Alany and Jingyuan Wen 
c c c

CONTENTS xi 
5.11 Transdermal Drug Delivery 793 
C. Scott Asbill and Gary W. Bumgarner 
5.12 Vaginal Drug Delivery 809 
Jose das Neves, Maria Helena Amaral, and Maria Fernanda Bahia 
SECTION 6 TABLET PRODUCTION 879 
6.1 Pharmaceutical Preformulation: Physicochemical Properties of 
Excipients and Powers and Tablet Characterization 881 
Beom-Jin Lee 
6.2 Role of Preformulation in Development of Solid Dosage Forms 933 
Omathanu P. Perumal and Satheesh K. Podaralla 
6.3 Tablet Design 977 
Eddy Castellanos Gil, Isidoro Caraballo, and Bernard Bataille 
6.4 Tablet Production Systems 1053 
Katharina M. Picker-Freyer 
6.5 Controlled Release of Drugs from Tablet Coatings 1099 
Sacide Alsoy Altinkaya 
6.6 Tablet Compression 1133 
Helton M. M. Santos and Joao J. M. S. Sousa 
6.7 Effects of Grinding in Pharmaceutical Tablet Production 1165 
Gavin Andrews, David Jones, Hui Zhai, Osama Abu Diak, and 
Gavin Walker 
6.8 Oral Extended-Release Formulations 1191 
Anette Larsson, Susanna Abrahmsen-Alami, and Anne Juppo 
SECTION 7 ROLE OF NANOTECHNOLOGY 1223 
7.1 Cyclodextrin-Based Nanomaterials in Pharmaceutical Field 1225 
Erem Bilensoy and A. Attila Hincal 
7.2 Nanotechnology in Pharmaceutical Manufacturing 1249 
Yiguang Jin 
7.3 Pharmaceutical Nanosystems: Manufacture, Characterization, 
and Safety 1289 
D. F. Chowdhury 
7.4 Oil-in-Water Nanosized Emulsions: Medical Applications 1327 
Shunmugaperumal Tamilvanan 
INDEX 1367


xiii 
PREFACE 
This Handbook of Manufacturing Techniques focuses on a new aspect of the drug 
development challenge: producing and administering the physical drug products 
that we hope are going to provide valuable new pharmacotherapeutic tools in medicine. 
These 34 chapters cover the full range of approaches to developing and producing 
new formulations and new approaches to drug delivery. Also addressed are 
approaches to the issues of producing and packaging these drug products (that is, 
formulations). The area where the most progress is possible in improving therapeutic 
success with new drugs is that of better delivery of active drug molecules to the 
therapeutic target tissue. In this volume, we explore current and new approaches to 
just this issue across the full range of routes (oral, parenteral, topical, anal, nasal, 
aerosol. ocular, vaginal, and transdermal) using all sorts of forms of formulation. 
The current metrics for success of new drugs in development once they enter the 
clinic (estimated at ranging from as low as 2% for oncology drugs to as high as 10% 
for oral drugs) can likely be leveraged in the desired direction most readily by 
improvements in this area of drug delivery. 
The Handbook of Manufacturing Techniques seeks to cover the entire range of 
available approaches to getting a pure drug (as opposed to a combination product) 
into the body and to its therapeutic tissue target. Thanks to the persistent efforts of 
Michael Leventhal, these 34 chapters, which are written by leading practitioners in 
each of these areas, provide coverage of the primary approaches to these fundamental 
problems that stand in the way of so many potentially successful pharmacotherapeutic 
interventions. 


MANUFACTURING SPECIALTIES 
SECTION 1


3 
1.1 
BIOTECHNOLOGY - DERIVED DRUG 
PRODUCT DEVELOPMENT 
Stephen M. Carl, 1 David J. Lindley, 1 Gregory T. Knipp, 1 
Kenneth R. Morris, 1 Erin Oliver, 2 Gerald W. Becker, 3 and 
Robert D. Arnold 4 
1 Purdue University, West Lafayette, Indiana 
2 Rutgers, The State University of New Jersey, Piscataway, New Jersey 
3 SSCI, West Lafayette, Indiana 
4 The University of Georgia, Athens, Georgia 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc. 
Contents 
1.1.1 Introduction 
1.1.2 Formulation Assessment 
1.1.2.1 Route of Administration and Dosage 
1.1.2.2 Pharmacokinetic Implications to Dosage Form Design 
1.1.2.3 Controlled - Release Delivery Systems 
1.1.3 Analytical Method Development 
1.1.3.1 Traditional and Biophysical Analytical Methodologies 
1.1.3.2 Stability - Indicating Methodologies 
1.1.3.3 Method Validation and Transfer 
1.1.4 Formulation Development 
1.1.4.1 Processing Materials and Equipment 
1.1.4.2 Container Closure Systems 
1.1.4.3 Sterility Assurance 
1.1.4.4 Excipient Selection 
1.1.5 Drug Product Stability 
1.1.5.1 Defi ning Drug Product Storage Conditions 
1.1.5.2 Mechanisms of Protein and Peptide Degradation 
1.1.5.3 Photostability 
1.1.5.4 Mechanical Stress 
1.1.5.5 Freeze – Thaw Considerations and Cryopreservation 
1.1.5.6 Use Studies 
1.1.5.7 Container Closure Integrity and Microbiological Assessment 
1.1.5.8 Data Interpretation and Assessment 

4 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
1.1.6 Quality by Design and Scale - Up 
1.1.6.1 Unit Operations 
1.1.6.2 Bioburden Considerations 
1.1.6.3 Scale - Up and Process Changes 
1.1.7 Concluding Remarks 
References 
1.1.1 INTRODUCTION 
Although the origins of the fi rst biological and/or protein therapeutics can be 
traced to insulin in 1922, the fi rst biotechnology - derived pharmaceutical drug 
product approved in the United States was Humulin in 1982. In the early stages 
of pharmaceutical biotechnology, companies that specialized primarily in the development 
of biologicals were the greatest source of research and development in 
this area. Recent advances in molecular and cellular biological techniques and 
the potential clinical benefi ts of biotechnology drug products have led to a substantial 
increase in their development by biotechnology and traditional pharmaceutical 
companies . In terms of pharmaceuticals, the International Conference on 
Harmonization (ICH) loosely defi nes biotechnology - derived products with biological 
origin products as those that are “ well - characterized proteins and polypeptides, 
their derivatives and products of which they are components, and which are 
isolated from tissues, body fl uids, cell cultures, or produced using rDNA technology 
” [1] . In practical terms, biological and biotechnology - derived pharmaceutical 
agents encompass a number of therapeutic classes, including cytokines, 
erythropoietins, plasminogen activators, blood plasma factors, growth hormones 
and growth factors, insulins, monoclonal antibodies, and vaccines [1] . Additionally, 
short interfering and short hairpin ribonucleic acids (siRNA, shRNA) and antisense 
oligonucleotide therapies are generally characterized as biotechnology - 
derived products. 
According to the biotechnology advocacy group, The Biotechnology Industry 
Organization (BIO), pharmaceutical - based biotechnology represents over a $ 30 
billion dollar a year industry and is directly responsible for the production of 
greater than 160 drug therapeutics and vaccines [2] . Furthermore, there are more 
than 370 biotechnology - derived drug products and vaccines currently in clinical 
trials around the world, targeting more than 200 diseases, including various cancers, 
Alzheimer ’ s disease, heart disease, diabetes, multiple sclerosis, acquired immunodefi 
ciency syndrome (AIDS), and arthritis. While the clinical value of these 
products is well recognized, a far greater number of biotechnology - derived drug 
products with therapeutic potential for life - altering diseases have failed in 
development. 
As the appreciation of the clinical importance and commercial potential for biological 
products grows, new challenges are arising based on the many technological 
limitations related to the development and marketing of these complex agents. 
Additionally, the intellectual property protection of an associated agent might not 

provide a suffi cient window to market and regain the costs associated with the discovery, 
research, development, and scale - up of these products. Therefore, to properly 
estimate the potential return on investment, a clear assessment of potential 
therapeutic advantages and disadvantages, such as the technological limitations in 
the rigorous characterization required of these complex therapeutic agents to gain 
Food and Drug Administration (FDA) approval, is needed prior to initiating 
research. Clearly, research focused on developing methodologies to minimize these 
technological limitations is needed. In doing so we hypothesize the attrition rate 
can be reduced and the number of companies engaged in the development of biotechnology 
- derived products and diversity of products will continue to expand. 
Technological limitations have limited the development of follow - on, or generic 
biopharmaceutical products that have lost patent protection. In fact, the potential 
pitfalls associated with developing these compounds are so diverse that regulatory 
guidance concerning follow - on biologics is relatively obscure and essentially notes 
that products will be assessed on a case - by - case basis. The reader is encouraged to 
see Chapter 1.2 for a more detailed discussion concerning regulatory perspectives 
pertaining to follow - on biologics. 
Many of the greatest challenges in producing biotechnology - derived pharmaceuticals 
are encountered in evaluating and validating the chemical and physical nature 
of the host expression system and the subsequent active pharmaceutical ingredient 
(API) as they are transferred from discovery through to the development and marketing 
stages. Although this area is currently a hotbed of research and is progressing 
steadily, limitations in analytical technologies are responsible for a high degree of 
attrition of these compounds. The problem is primarily associated with limited 
resolution of the analytical technologies utilized for product characterization. For 
example, without the ability to resolve small differences in secondary or tertiary 
structure, linking changes to product performance or clinical response is impossible. 
The biological activity of traditional small molecules is related directly to their 
structure and can be determined readily by nuclear magnetic resonance (NMR), 
X - Ray crystallography (X - ray), mass spectrometry (MS), and/or a combination of 
other spectroscopic techniques. However, methodologies utilized for characterizing 
biological agents are limited by resolution and reproducibility. For instance, circular 
dichroism (CD) is generally considered a good method to determine secondary 
structural elements and provides some information on the folding patterns (tertiary 
structure) of proteins. However, CD suffers from several limitations, including a 
lower resolution that is due in part to the sequence libraries used to deconvolute 
the spectra. To improve the reliability of determining the secondary and tertiary 
structural elements, these databases need to be developed further. An additional 
example is the utility of two - dimensional NMR (2D - NMR) for structural determination. 
While combining homonuclear and heteronuclear experimental techniques 
can prove useful in structural determination, there are challenges in that 2D - NMR 
for a protein could potentially generate thousands of signals. The ability to assign 
specifi c signals to each atom and their respective interactions is a daunting task. 
Resolution between the different amino acids in the primary sequence and their 
positioning in the covalent and folded structures become limited with increasing 
molecular weight. Higher dimensional techniques can be used to improve resolution; 
however, the resolution of these methods remains limited as the number of 
amino acids is increased. 
INTRODUCTION 5

6 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
Understanding the limitations of the analytical methodologies utilized for product 
characterization has led to the development of new experimental techniques as well 
as the refi ned application of well - established techniques to this emerging fi eld. Only 
through application of a number of complementary techniques will development 
scientists be able to accurately characterize and develop clinically useful products. 
Unfortunately, much of the technology is still in its infancy and does not allow for 
a more in - depth understanding of the subtleties of peptide and protein processing 
and manufacturing. For instance, many of the analytical techniques utilized for 
characterization will evaluate changes to product conformation on the macroscopic 
level, such as potential denaturation or changes in folding, as observed with CD. 
However, these techniques do not afford the resolution to identify subtle changes 
in conformation that may either induce chemical or physical instabilities or unmask 
antigenic epitopes. 
Further limiting successful product development is a lack of basic understanding 
as to critical manufacturing processes that have the potential to affect the structural 
integrity and activity of biopharmaceuticals. As with traditional small molecules, 
stresses associated with the different unit operations may affect biopharmaceutical 
products differently. In contrast to traditional small molecules, there is considerable 
diffi culty in identifying potentially adverse affects, if any, that a particular unit operation 
may have on the clinically critical structural elements of a drug. Considering 
that many proteins exhibit a greater potential for degradation from shear stress, it 
is particularly important to assess any negative effects of mixing, transport through 
tubing, fi ltration, and fi lling operations. Essentially all unit operations for a given 
manufacturing process could create enough shear stress to induce minor structural 
changes that could lead to product failure. The diffi culty is establishing what degree 
of change will have an impact on the stability, bioactivity, or immunogenic potential 
of the compound. Unfortunately, unless exhaustive formulation development studies 
are conducted, coupled with a comprehensive spectrum of analytical methodologies, 
these effects may not be readily evident until after scale - up of the manufacturing 
process or, worse yet, in the clinical setting. Moreover, modeling shear and stress 
using fl uid dynamic structurally diverse molecules is a foreboding task. Extending 
these models to validate process analytical technologies (PAT) and incorporate 
critical quality by design (QbD) elements in the development process for a collection 
of biopharmaceuticals would be largely hindered by the daunting nature of the 
task at hand. 
The use of biological systems to produce these agents results in additional variability. 
Slight changes in nutrient profi le could affect growth patterns and protein 
expression of cultured cells. Furthermore, microbial contamination in the form of 
viruses, bacteria, fungi, and mycoplasma can be introduced during establishment of 
cell lines, cell culture/fermentation, capture and downstream processing steps, formulation 
and fi lling operations, or drug delivery [3] . Therefore, establishing the 
useful life span of purifi cation media and separation columns remains a critical issue 
for consistently producing intermediates and fi nal products that meet the defi ned 
quality and safety attributes of the product [4] . In short, understanding the proper 
processability and manufacturing controls needed has been a major hurdle that has 
kept broader development of biopharmaceutical products relatively limited. 
Notwithstanding the many technological hurdles to successfully develop a pharmaceutically 
active biotechnology product, they offer many advantages in terms of 

therapeutic potency, specifi city, and target design (not generally limited to a particular 
class or series of compounds). This is an iterative approach, whereby every new 
approved compound, new lessons, and applications to ensure successful product 
development are realized, thereby adding to our knowledge base and facilitating 
the development of future products. This chapter will discuss some of the fundamental 
issues associated with successful biopharmaceutical drug product development 
and aims to provide an understanding of the subtleties associated with their 
characterization, processing, and manufacturing. 
1.1.2 FORMULATION ASSESSMENT 
In order to select the most appropriate formulation and route of administration for 
a drug product, one must fi rst assess the properties of the API, the proposed therapeutic 
indication, and the requirements/limitations of the drug and the target patient 
population. Development teams are interdisciplinary comprised of individuals with 
broad expertise, for example, chemistry, biochemistry, bioengineering, and pharmaceutics, 
that can provide insight into the challenges facing successful product development. 
As such, knowledge gained through refi nement of the API manufacturing 
process through to lead optimization is vital to providing an initial starting point 
for success. Information acquired, for example, in the way of analytical development 
and API characterization, during drug discovery or early preclinical development 
that can be applied to fi nal drug product development may contribute to shorter 
development times of successful products. 
The host system utilized for API production is critical to the production of the 
fi nal product and will determine the basic and higher order physicochemical characteristics 
of the drug. Typically biopharmaceuticals are manufactured in Escherichia 
coli as prokaryotic and yeast and Chinese hamster ovary (CHO) cells as eukaryotic 
expression systems [5] . While general procedures for growth condition optimization 
and processing and purifi cation paradigms have emerged, differences in posttranslational 
modifi cations and host – system related impurities can exist even with relatively 
minor processing changes within a single production cell line [5] . Such changes 
have the potential to alter the biopharmaceutical properties of the active compound, 
its bioactivity , and its potential to elicit adverse events such as immunogenic reactions. 
These properties will be a common theme as they could potentially play a 
major role in both analytical and formulation development activities. 
During the process of lead optimization, characterization work is performed that 
would include a number of parameters that are critical to formulation and analytical 
development scientists. The following information is a minimalist look at what 
information should be available to support product development scientists: 
• Color 
• Particle size and morphology (for solid isolates) 
• Thermoanalytical profi le (e.g., Tg for lyophiles) 
• Hygroscopicity 
• Solubility with respect to pH 
• Apparent solution pH 
FORMULATION ASSESSMENT 7

8 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
• Number and p Ka of ionizable groups 
• Amino acid sequence 
• Secondary and tertiary structural characteristics 
• Some stability parameters with respect to 
 pH 
 Temperature 
 Humidity 
 Light 
 Mechanical stress 
 Oxygen sensitivity 
• Impurity profi le 
 Misfolded/misaligned active 
 Potential isoforms 
 Expression system impurities 
• Potency [median inhibitory concentration (IC 50 )] 
• Animal Pharmacokinetic/Pharmacodynamic (PK/PD) and Tox profi les 
All of the above information will prove invaluable in determining the potential 
methods for rational drug delivery. Particular attention should be paid to the relative 
hygroscopicity of the API, of course, any stability information, as well as the 
impurity profi le and ADMET (absorption, distribution, metabolism, excretion, and 
toxicity) information. In short, the more information that is available when development 
activities are initiated, the easier it is to avoid common pitfalls and make 
development decisions more rationally. 
1.1.2.1 Route of Administration and Dosage 
Biologics are traditionally very potent molecules that may require only picomolar 
blood concentrations to elicit a therapeutic effect. Given that the amount of drug 
required per dosage will be commensurate with the relative potency of the molecule, 
small concentrations are generally required for any unit dose. Biopharmaceuticals 
typically have large molecular weights relative to conventional pharmaceutical 
agents, which may be increased further by posttranslational modifi cations. The pharmacokinetics 
(ADMET) of biotechnology products have been reviewed elsewhere 
[6] , but generally they have short circulating half - lives [7] . As such, biological products 
are most often delivered parenterally and formulated as solutions, suspensions, 
or lyophilized products for reconstitution [8, 9] . However, one must fi rst ascertain 
the potential physiological barriers to drug delivery and effi cacy before assessing 
potential routes of administration. These barriers may include actual physical barriers, 
such as a cell membrane, that could restrict the drug from reaching its site of 
action or chemical barriers, including pH or enzymatic degradation. Based on 
current drug delivery approaches, the proteinaceous nature of biological products 
limits their peroral delivery due to their susceptibility to proteases and peptidases 
present in the gastrointestinal tract as well as size limitations for permeating through 
absorptive enterocytes [10] . 

Diffi culties in peroral delivery have stimulated researchers to explore alternate 
delivery mechanisms for biologics, such as through the lungs or nasal mucosa [11, 
12] . Further, advances in technology and our understanding of the mechanisms 
limiting oral delivery of biotechnology products have led to innovative drug delivery 
approaches to achieve suffi cient oral bioavailability. However, no viable products 
have successfully reached the market [13] . As a result of the technological limitations 
inherent in biopharmaceutical delivery, these compounds are largely delivered 
parenterally through an injection or implant. 
When assessing the potential routes of administration, one must consider the 
physicochemical properties of the drug, its ADMET properties, the therapeutic 
indication, and the patient population, some of which are discussed below. Table 1 
provides a list of some of those factors that must be addressed when determining 
the most favorable route of administration and the subsequent formulation for 
delivery. Ideally the route of administration and subsequent formulation will be 
optimized after identifying critical design parameters to satisfy the needs of patients 
and health care professionals alike while maintaining the safety and effi cacy of the 
product. 
Parenteral administration is the primary route of delivering biopharmaceutical 
agents (e.g., insulin); however, issues associated with patient compliance with administration 
of short - acting molecules are a challenge. Yet, the risk - to - benefi t ratio must 
be weighed when determining such fundamental characteristics of the fi nal dosage 
form. For instance, a number of biopharmaceutical compounds are administered 
subcutaneously, but this route of parenteral administration exhibits the highest 
potential for immunogenic adverse events due to the presence of Langerhans cells 
[14] . A compound ’ s immunogenic potential is related to a host of factors, both 
TABLE 1 Factors That Determine Route of 
Administration 
Site of action 
Therapeutic indication 
Dosage 
Potency/biological activity 
Pharmacokinetic profi le 
Absorption time from tissue vs. IV 
Circulating half - life 
Distribution and elimination kinetics 
Toxicological profi le 
Immunogenic potential 
Patient population characteristics 
Disease state 
Pathophysiology 
Age 
Pharmacodynamic profi le 
Onset and duration of action 
Required clinical effect 
Formulation considerations 
Stability 
Impurity profi le 
FORMULATION ASSESSMENT 9

10 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
patient and treatment related; however, if an alternate, potentially safer route of 
administration is available, it may be prudent to consider it. Other factors, such as 
the frequency of dosing (especially into an immune organ such as the skin) and the 
duration of treatment, can also dramatically increase the potential for immunogenic 
reactions [14] . Many of the factors that contribute to the immunogenic potential of 
biopharmaceuticals, such as impurities, degradation products, and native antigenic 
epitopes, can be mitigated through altering the physicochemical properties of the 
drug (e.g., pegylation [15, 16] , acylation [17, 18] , increased glycosylation to mask 
epitopes [19] ) or changing the characteristics of the formulation [20, 21] . In reality, 
the pharmaceutical industry has done a good job of recognizing the potential implications 
of immunogenic reactions and readily embraced technologies that can either 
mask or eliminate potential antigenic epitopes. However, additional research is 
needed to further identify and remove immunogenic epitopes. 
1.1.2.2 Pharmacokinetic Implications to Dosage Form Design 
Biological agents are generally eliminated by metabolism into di - and tripeptides, 
amino acids, and smaller components for subsequent absorption as nutrients or 
clearance by the kidney, liver, or other routes. Renal elimination of peptides and 
proteins occur primarily via three distinct mechanisms. The fi rst involves the glomerular 
fi ltration of low - molecular - weight proteins followed by reabsorption into 
endocytic vesicles in the proximal tubule and subsequent hydroysis into small peptide 
fragments and amino acids [22] . Interleukin 11 (IL - 11) [23] , IL - 2 [24] , insulin [25] , 
and growth hormone [26] have been shown to be eliminated by this method. The 
second involves hydrolysis of the compound at the brush border of the lumen and 
subsequent reabsorption of the resulting metabolites [6] . This route of elimination 
applies to small linear peptides such as angiotensin I and II, bradykinin, glucagons, 
and leutinizing hormone releasing hormone (LHRH) [6, 27, 28] . The third route of 
renal elimination involves peritubular extraction from postglomerular capillaries 
and intracellular metabolism [6] . Hepatic elimination may also play a major role in 
the metabolism of peptides and proteins; however, reticuloendothelial elimination is 
by far the primary elimination route for large macromolecular compounds [29] . 
Biopharmaceutical drug products are subject to the same principles of pharmacokinetics 
and exposure/response correlations as conventional small molecules [6] . 
However, these products are subject to numerous pitfalls due to their similarity to 
nutrients and endogenous proteins and the evolutionary mechanisms to break them 
down or prevent absorption. The types of pharmacokinetic - related problems that a 
biotechnology drug development team may encounter range from lack of specifi city 
and sensitivity of bioanalytical assays to low bioavailability and rapid drug elimination 
from the system [6] . For example, most peptides have hormone activity and 
usually short elimination half - lives which can be desirable for close regulation of 
their endogenous levels and function. On the other hand, some proteins such as 
albumin or antibodies have half - lives of several days and formulation strategies 
must be designed to account for these extended elimination times [6] . For example, 
the reported terminal half - life for SB209763, a humanized monoclonal antibody 
against respiratory syncytial virus, was reported as 22 – 50 days [30] . Furthermore, 
some peptide and protein products that persist in the bloodstream exhibit the 
potential for idiosyncratic adverse affects as well as increased immunogenic poten

tial. Therefore, the indication and formulation strategy can prove crucial design 
parameters simply based on clearance mechanisms. 
1.1.2.3 Controlled - Release Delivery Systems 
Given that the majority of biopharmaceutical products are indicated for chronic 
conditions and may require repeated administrations, products may be amenable to 
controlled - release drug delivery systems. Examples include Lupron Depot (leuprolide 
acetate), which is delivered subcutaneously in microspheres [31] , and Viadur, 
which is implanted subcutaneously [32] . Various peptide/protein controlled delivery 
systems have been reviewed recently by Degim and Celebi and include biodegradable 
and nondegradable microspheres, microcapsules, nanocapsules, injectable 
implants, diffusion - controlled hydrogels and other hydrophilic systems, microemulsions 
and multiple emulsions, and the use of iontophoresis or electroporation [33] . 
These systems offer specifi c advantages over traditional delivery mechanisms when 
the drug is highly potent and if prolonged administration greater than one week is 
required [5, 33] . However, each of these systems has its own unique processing and 
manufacturing hurdles that must be addressed on a case - by - case basis. These factors, 
coupled with the diffi culties of maintaining product stability, limit the widespread 
application of these technologies. However, the introduction of postapproval 
extended - release formulations may also provide the innovator company extended 
patent/commercial utility life and, as such, remains a viable option for postmarketing 
development. A current example of this is observed in the development of a 
long - acting release formulation of Amylin and Eli Lilly ’ s co - marketed Byetta 
product. 
1.1.3 ANALYTICAL METHOD DEVELOPMENT 
The physical and chemical characterization of any pharmaceutical product is only 
as reliable as the quality of the analytical methodologies utilized to assess it. Without 
question, the role of analytical services to the overall drug product development 
process is invaluable. Good analytical testing with proper controls could mean the 
difference between a marketable product and one that is eliminated from development. 
Analytical methodologies intended for characterization and/or assessment of 
marketed pharmaceutical products must be relevant, validatable, and transferable 
to manufacturing/quality assurance laboratories. 
1.1.3.1 Traditional and Biophysical Analytical Methodologies 
Typically, there are a handful of traditional analytical methodologies that are utilized 
to assess the physical, chemical, and microbiological attributes of small - 
molecule pharmaceutical products. While many of these testing paradigms can still 
be utilized to assess biopharmaceuticals, these molecules require additional biophysical, 
microbiological, and immunogenic characterization as well. In brief, analytical 
methodologies should evaluate the purity and bioactivity of the product and 
must also be suitable to assess potential contaminants from expression systems 
as well as different isoforms and degradation products of the active. Biophysical 
ANALYTICAL METHOD DEVELOPMENT 11

12 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
methodologies allow for assessment of the structural elements of the product with 
respect to its activity. Such assessments include structural elements, such as the 
folding of the molecule, and also encompass potential posttranslational modifi cations 
and their impact on structure. A list of typical analytical parameters and 
methodologies utilized to assess those parameters can be found in Table 2 . 
The impact of a molecule ’ s biophysical characteristics on its clinical effi cacy 
should be readily quantifi able. With respect to rational drug design, it is also 
extremely important to minimize external factors that may infl uence the formation 
of any adverse response. One such factor is the presence of degradation products 
and drug - related impurities that may be responsible for an immune response. One 
such industrial example is granulocyte - macrophage colony - stimulating factor [GM - 
CSF, or Leukine (sargramostim), by Berlex Co.], which is produced as a recombinant 
protein synthesized and purifi ed from a yeast culture, Saccharomyces cerevisiae . As 
expected, the expression system has an impact on the fi nal product: sargramostim, 
manufactured from S. cerevisiae , yields an O - glycosylated protein, while molgramostim 
(Leucomax), synthesized using an E. coli expression system, is nonglycosylated 
[34] . The E. coli – derived product exhibited a higher incidence of adverse reactions 
in clinical trials and never made it to the market. With respect to the drug product, 
the immunogenic reactions included [34, 35] : 
TABLE 2 Analytical Methodologies and Their Utility for API and Drug Product 
Characterization 
Parameter 
Assessed Methodologies Utility 
Appearance Visual appearance, 
colorimetric assays, 
turbidity 
Simple determination of physical 
stability, i.e., are there particles in 
solution, is the solution the correct 
color/turbidity? Is the container 
closure system seemingly intact? 
Purity, 
degradation 
products and 
related 
substances 
GPC/SEC - HPLC, RP - 
HPLC, gel electrophoresis, 
immunoassays, IEF, MS, 
CD, CE 
Gives a general idea of the relative 
purity of the API and the drug 
product. Are there impurities 
related to the expression system? 
Are there alternate API isoforms 
present? Can degradation products 
be distinguished from the active 
component(s)? 
Molecular 
weight 
determination 
GPC/SEC - HPLC, gel 
electrophoresis, multiangle 
laser light scattering 
(MALLS), laser diffraction 
Is the product a single molecular 
weight or polydisperse? Is the 
molecular weight dependent on 
posttranslational modifi cations? 
Potency Biological activity (direct or 
indirect) 
Does the compound have reproducible 
in vitro activity and can this be 
correlated to in vivo? 
pH Potentiometric assays Is the product pH labile or do pH 
changes affect potency is such ways 
that are not evident in other assays, 
i.e., minimal degradation and/or 
unfolding?

ANALYTICAL METHOD DEVELOPMENT 13 
Parameter 
Assessed Methodologies Utility 
Primary 
structural 
elements 
Protein sequencing, N - term 
degradation (Edman 
degradation), peptide 
mapping, amino acid 
composition, 2D - NMR 
Verifi es primary amino acid sequence 
and gives preliminary insight into 
activity. 
Secondary 
structural 
elements 
CD, 2D - NMR, in silico 
modeling from AA 
sequence 
Secondary structural elements result 
from the primary sequence and help 
defi ne the overall conformation 
(3D folding) of the compound. 
Tertiary 
structural 
elements 
Disulfi de content/position, 
CD 
Determines correct folding and overall 
integrity of the 3D product. 
Qualitative determination for 
denaturation potential. Also 
correlates to immunogenic potential. 
Agglomeration/ 
aggregation 
Subvisual and visual Particle 
size analysis, 
immunogenicity 
Indicator of physical instability. Also 
gives an indication of immunogenic 
potential. 
Carbohydrate 
analysis 
RP - HPLC, gel 
electrophoresis, AE - 
HPLC, CE, MALDI - MS, 
ES - MS, enzyme arrays 
Ensures proper posttranslational 
modifi cations and carbohydrate 
content. 
Water content 
(lyophilized 
products) 
Karl Fischer, TGA, NIR Indicator of hydrolytic potential and 
process effi ciency. 
Immunogenic 
potential 
Surface plasmon resonance, 
ELISA, 
immunoprecipitation 
Methodologies generally only give 
positive/negative indicators of 
immunogenic potential. In vitro 
methodologies do not always 
correlate to in vivo. 
Sterility Membrane fi ltration Indicator of microbial contaminants 
from manufacturing operations. 
Bacterial 
endotoxins 
Limulus amebocyte lysate 
(LAL) 
Gives an idea of processing 
contaminants and potentially host 
organism contaminants. 
Container 
closure 
integrity 
Dye immersion, NIR, 
microbial ingress/sterility 
Demonstrates viability of container 
closure system over the life of the 
product. 
Abbreviations : gel permeation chromatography (GPC), size exclusion chromatography (SEC), high - 
performance, or high - pressure, liquid chromatography (HPLC), reverse phase (RP), isoelectric focusing 
(IEF), mass spectrometry (MS), circular dichroism (CD), capillary electrophoresis (CE), nuclear magnetic 
resonance (NMR), anion exchange (AE), matrix - assisted laser desorption ionization (MALDI), 
electrospray ionization (ES), thermogravimetric analysis (TGA), near infrared (NIR), enzyme - linked 
immunosorbent assay (ELISA) 
TABLE 2 Continued

14 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
1. Formation of antibodies which bind and neutralize the GM - CSF 
2. Formation of antibodies which bind but do not affect the effi cacy of 
GM - CSF 
3. Antibody formation against proteins not related to GM - CSF, but to proteins 
from the expression system ( E. coli ) 
4. Antibodies formed against both product - and non - product - related proteins 
5. No antibody formation 
This example clearly illustrates not only the range of clinical manifestations with 
respect to antibody formation to drug therapy but also how the choice of an expression 
system can affect the fi nal product. In this example, the expression system was 
responsible for the adverse events reported. This fi nding is certainly clinically relevant 
considering the homologous product, sargramostim, has been on the U.S. 
market for quite some time. 
The above example also gives an indication of the relative importance of carbohydrate 
analysis. Without question, protein glycosylation is the most complex of all 
posttranslational modifi cations made in eukaryotic cells, the importance of which 
cannot be underestimated. For many compounds, glycosylation can readily affect 
protein solubility (as infl uenced by folding), protease resistance, immunogenicity, 
and pharmacokinetic/pharmacodynamic profi les (i.e., clearance and effi cacy) [36] . 
Typical analytical methodologies used to assess carbohydrate content are also listed 
in Table 2 . 
1.1.3.2 Stability - Indicating Methodologies 
Analytical methodologies that are specifi c to the major analyte that are also capable 
of separating and quantifying potential degradation products and impurities, while 
simultaneously maintaining specifi city and accuracy, are deemed stability indicating. 
Traditional stability - indicating high - performance liquid chromatography (HPLC) 
methodologies for small molecules are developed and validated with relative ease. 
Typically, the stability - indicating nature of an analytical method can be demonstrated 
by subjecting the product to forced degradation in the presence of heat, acid, 
alkali, light, or peroxide [37] . If degradation products are suffi ciently well resolved 
from the active while maintaining specifi city and accuracy, the method is suitable. 
In contrast to small molecules, there is no one “ gold standard ” analytical methodology 
that can be utilized to determine the potential degradation products and impurities 
in the milieu that may constitute a biopharmaceutical drug product. Furthermore, 
a one - dimensional structure assessment (e.g., in terms of an absorption spectrum) 
does not give any indication of the overall activity of the product, as is the case with 
traditional small molecules. Thus, the stability assessment of biopharmaceuticals will 
typically comprise a multitude of methodologies that when taken together give an 
indication of the stability of the product. The overall goal is to assess the structural 
elements of the compound as well as attempt to determine the relative quantities 
of potential degradation products, as well as product isoforms and impurities, that 
are inherent to the expression systems utilized for API manufacture. However, it is 
still advised that bioactivity determinations are made at appropriate intervals 
throughout the stability program, as discussed below. Furthermore, any biopharma

ceutical stability program should also minimally include an evaluation of the in vitro 
immunogenicity profi le of the product with respect to time, temperature, and other 
potential degradative conditions. 
1.1.3.3 Method Validation and Transfer 
Analytical method validation is the process by which scientists prove that the analytical 
method is suitable for its intended use. Guidances available on validation 
procedures for some traditional analytical methodologies [38] can be adapted to 
nontraditional methodologies. The United States Pharmacopeia (USP) and National 
Formulary (NF) do provide some guidance on designing and assessing biological 
assays [39] , as does the U.S. FDA [40] . Essentially, validation determines the acceptable 
working ranges of a method and the limitations of that method. At a minimum 
the robustness, precision, and accuracy of quantitative methodologies should be 
determined during support of API iteration and refi nement, while at the very least 
the robustness of qualitative methodologies should be assessed. Of particular importance 
for successful analytical method validation is ensuring that the proper standards 
and system suitability compounds have been chosen and are representative 
or analogous to the compound to be analyzed and traceable to a known origin 
standard, such as the National Institute of Standards and Technology (NIST) or 
USP/NF. If a reference standard from an “ offi cial ” source is not available, in - house 
standards may be used provided they are of the highest purity that can be reasonably 
obtained and are thoroughly characterized to ensure its identity, strength, 
quality, purity, and potency. 
Methods developed and validated during the product development phase are 
routinely transferred to quality control or contract laboratories to facilitate release 
and in - process testing of production batches. Ensuring that method transfer is executed 
properly, with well - defi ned and reproducible system suitability and acceptance 
criteria, is the responsibility of both laboratories. Experiments should consist 
of all those parameters assessed during method validation and should include an 
evaluation of laboratory - to - laboratory variation. This information will give an idea 
of the reliability of the methodology and equipment used under the rigors of large - 
scale manufacturing. 
1.1.4 FORMULATION DEVELOPMENT 
The previous sections have highlighted some of the limitations and diffi culties in 
developing biotechnology - derived pharmaceuticals. Although there are major technological 
limitations in working with these products, their synthesis and manufacturing 
are signifi cantly more reproducible compared to naturally derived biologics. 
Determining the most appropriate route of administration and subsequent formulation 
is dependent on a number of factors, including the product ’ s indication, duration 
of action, pharmacokinetic parameters, stability profi le, and toxicity. As 
mentioned previously, biopharmaceuticals are typically delivered parenterally, and 
thus we will focus on those studies required to successfully develop a parenteral 
formulation of a biopharmaceutical agent. The goal of formulation development is 
to design a dosage form that ensures the safety and effi cacy of the product through- 
FORMULATION DEVELOPMENT 15

16 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
out its shelf life while simultaneously addressing the clinical needs of both the 
patient and caregivers to ensure compliance. Formulation development is truly a 
balancing act, attempting to emphasize the benefi ts of the therapy and patient compliance 
while maximizing drug effi cacy and minimizing toxicity. As such, a number 
of studies are required to properly design and develop a formulation, many of which 
are discussed below. 
1.1.4.1 Processing Materials and Equipment 
An important factor in the quality and reproducibility of any formulation development 
activity is the materials utilized for formulating and processing studies. In 
addition, the choice of container closure systems for the API and the formulation 
needs to be considered carefully to provide maximum product protection and 
optimal stability. Variability between small - and larger scale development stages 
may also be signifi cant depending on the API and materials involved during process 
scale - up. It is important to conduct process development studies utilizing equipment 
representative of what will be used for large - scale production, if possible. Implementing 
this design approach will enable at least some limited dimensional analysis, 
allowing for early identifi cation of critical design parameters, thereby facilitating 
scale - up or permitting earlier attrition decisions and cost savings. Regardless, it is 
important to consider the chemical composition and material properties of every 
manufacturing component that may contact the drug product. For instance, processing 
vessels may be made of glass, glass - lined steel, or bare steel, while stir paddles 
used to ensure homogeneity made be manufactured of a number of different materials. 
In short, any manufacturing unit that could potentially come into intimate 
contact with either the formulation or the API should be demonstrated to be compatible 
with the product, including sampling instruments, sample vials, analytical and 
processing tubing, and so forth. Material incompatibility could result in something 
as simple as unexplained analytical variability due to a loss of drug through adsorptive 
mechanisms to something as serious as a loss of bioactivity or an increase in 
immunogenic potential. Therefore, equipment design and materials would ideally 
be consistent from formulation development through to scale - up and process validation; 
however, this may not be readily feasible. As such, determining the chemical 
and physical compatibility of each piece of processing equipment with the API is 
critical to maintaining the physical and chemical attributes of the product. Furthermore, 
such studies help eliminate potential sources of experimental variability and 
give a better indicator as to the relative technological hurdles to successful product 
development. 
Material compatibility protocols must be clearly defi ned and require that analytical 
methodologies be suitable for their intended use. Typically, product purity 
methods and cleaning methodologies utilized to determine residual contaminating 
product on processing equipment are used for compatibility studies as they are suf- 
fi ciently sensitive and rugged to accurately determine product content in the presence 
of a multitude of potential confounding factors. This is particularly important 
when assessing potential metal, glass, and tubing compatibilities. Compatibility is a 
function not only of the product ’ s intimate contact with surrounding materials but 
also of the contact time and surface area with these equipment. As such, protocols 
should be designed to incorporate expected real - world conditions the product will 

see when in contact with the material. For instance, temperature, light, and mechanical 
stimulation should mimic usage conditions, although study duration should 
include time intervals that surpass expectations to estimate a potential worst case. 
These factors should all be considered when examining potential process - related 
stability. 
1.1.4.2 Container Closure Systems 
The ICH guideline for pharmaceutical development outlines requirements for container 
closure systems for drugs and biologics [41] . The concept paper prepared for 
this guidance specifi cally states that “ the choice of materials for primary packaging 
should be justifi ed. The discussion should describe studies performed to demonstrate 
the integrity of the container and closure. A possible interaction between 
product and container or label should be considered ” [42] . In essence, this indicates 
that the container closure system should maintain the integrity of the formulation 
throughout the shelf life of the product. In order to maintain integrity, the container 
closure system should be chosen to afford protection from degradation induced by 
external sources, such as light and oxygen. In addition to the primary container, the 
stability of the product should also be examined in the presence of IV administration 
components if the product could be exposed to these conditions (see Section 
1.1.5.6 ). Understanding the potential impact of product - to - container interactions is 
integral to maintaining stability and ensuring a uniform dosage. For example, adsorption 
of insulin and some small molecules has been demonstrated to readily occur 
in polyvinyl chloride (PVC) bags and tubing when these drugs were present as 
additives in intravenous (IV) admixtures [43] . 
In addition to their use in large - volume parenterals and IV sets, thermoplastic 
polymers have also recently found utility as packaging materials for ophthalmic 
solutions and some small - volume parenterals [43] . However, there are many 
potential issues with using these polymers as primary packaging components that 
are not major concerns with traditional glass container closure systems, including 
[44] : 
1. Permeation of vapors and other molecules in either direction through the wall 
of the plastic container 
2. Leaching of constituents from the plastic into the product 
3. Sorption (absorption and/or adsorption) or drug molecules or ions on the 
plastic material 
These concerns largely preclude the utility of thermoplastic polymers as the primary 
choice of container closure system for protein and peptide therapeutics, although 
the formulation scientist should be aware of the potential advantages of these 
systems, such as the ease of manufacturability and their cost. These systems are also 
fi nding greater utility in intranasal and pulmonary delivery systems. 
Parenterally formulated biopharmaceuticals are typically packaged in glass containers 
with rubber/synthetic elastomeric closures. Pharmaceutical glass is composed 
primarily of silicon dioxide tetrahedron which is modifi ed with oxides such 
as sodium, potassium, calcium, magnesium, aluminum, boron, and iron [45] . The USP 
classifi es glass formulations as follows: 
FORMULATION DEVELOPMENT 17

18 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
Type I, a borosilicate glass 
Type II, a soda – lime treated glass 
Type III, a soda – lime glass 
NP, a soda – lime glass not suitable for containers for parenterals 
The tendency of peptides to adsorb onto glass surfaces is well known and a major 
concern in the pharmaceutical industry. This is especially important when the dose 
of the active ingredient is relatively small and a signifi cant amount of drug is 
adsorbed to these surfaces. In addition, the leaching of atoms or elements in the 
glass ’ s silicate network into solution is also a potential issue. This is especially important 
for terminally heat sterilized products where oxide additives included in the 
silicate network are relatively free to migrate/leach, resulting in increased solution 
pH, reaction catalysis, and so on [45] . As such, only type 1 treated glass is traditionally 
used for parenterally administered formulations, where these alkaline - rich 
phases in the glass have been eliminated, thus decreasing the potential for container 
closure system interactions. Additional approaches, including surface treatment with 
silicone (siliconization), have also been developed to minimize the interaction of 
biotechnology products with free silanols (Si – OH) [46] . 
Elastomeric closures are typically used for syringe and vial plungers and closures. 
For vials, elastomers provide a soft and elastic material that can permit the entry of 
a hypodermic needle without loss of the integrity [45] . For syringes, the closures not 
only provide a permeation barrier but also allow for a soft gliding surface facilitating 
plunger movement and drug delivery. Elastomeric polymers, however, are very 
complex materials composed of multiple ingredients in addition to the basic polymers, 
such as vulcanizing agents, accelerators, activators, antioxidants, fi llers, lubricating 
agents, and pigments [45] . As leaching of these components into solution 
is a potential issue, the compatibility of the drug formulation with the closures 
must be studied early during the formulation development process. The choice and 
type of elastomeric closure depends on the pH and buffer, if any preservatives 
are present, the sterilization method, moisture vapor/gas protection, and active 
compatibility [47] . In addition, the problem of the additives in rubber leaching 
into the product can be reduced by the coating with specifi c polymers such as 
Tefl on [48] . 
Container closure systems required for implantable devices are further restricted 
by the fact that they are required to be compatible with the formulation over the 
intended shelf life and therapeutic application time as well as being biocompatible. 
This means that the system not only must afford protection to and contain the formulation 
but also cannot cause any potential adverse effects, such as allergy. Typically, 
implantable systems are composed of biocompatible metals, such as titanium 
or polymers such as polyethylene glycol or polylactic - co - glycolic acid. 
1.1.4.3 Sterility Assurance 
Maintaining the sterility of biopharmaceutical products is especially important due 
to the relative potency and their innate potential for immunogenic reactions. Further, 
the biochemical nature of these compounds enables them to serve as potential 
nutrients for invading organisms. Methods for sterilizing small molecules include 

heat terminal sterilization, terminal fi ltration coupled with aseptic processing techniques, 
ultraviolet (UV) and gamma irradiation, ethylene oxide exposure (for containers 
and packaging only), and electron beam irradiation. While terminal heat 
sterilization is by far the most common sterilization technique, it normally cannot 
readily be utilized for peptide or protein formulations due to the potential effects 
of heat and pressure on the compound ’ s structure [48] . Furthermore, irradiation can 
affect protein stability by cross - linking the sulfur - containing and aromatic residues, 
resulting in protein aggregation [49] . 
To overcome these issues, sterile fi ltration coupled with aseptic processing and 
fi lling is the preferred manufacturing procedure for biopharmaceuticals. Garfi nkle 
et al. refer to aseptic processing as “ those operations performed between the sterilization 
of an object or preparation and the fi nal sealing of its package. These operations 
are, by defi nition, carried out in the complete absence of microorganisms ” [50] . 
This highlights the importance of manufacturing controls and bioburden monitoring 
during aseptic processes. Newer technologies such as isolator technology have been 
developed to reduce human intervention, thereby increasing the sterility assurance. 
These technologies have the added benefi t of facilitating aseptic processing without 
construction of large processing areas, sterile suites, or gowning areas [50] . 
Even the most robust monitoring programs do not ensure the sterility of the fi nal 
formulation. As such, aseptically processed formulations are traditionally fi ltered 
through a retentive fi nal fi lter, which ensures sterility. Coupled with proper component 
sterilization, traditionally by autoclaving, these processes ensure product sterility. 
However, fi ltration is a complex unit operation that can adversely affect the drug 
product through increased pressure, shear, or material incompatibility. Therefore, 
fi ltration compatibility must be assessed thoroughly to demonstrate both product 
compatibility, and suffi cient contaminant retention [51] . Parenteral Drug Association 
(PDA) technical report 26 provides a thorough systematic approach to selecting 
and validating the most appropriate fi lter for a sterilizing fi ltration application 
[51] . 
1.1.4.4 Excipient Selection 
Pharmaceutical products are typically formulated to contain selected nonactive 
ingredients (excipients) whose function is to promote product stability and enable 
delivery of the active pharmaceutical ingredient(s) to the target site. These substances 
include but are not limited to solubilizers, antioxidants, chelating agents, 
buffers, tonicity contributors, antibacterial agents, antifungal agents, hydrolysis 
inhibitors, bulking agents, and antifoaming agents [45] . The ICH states that “ the 
excipients chosen, their concentration, and the characteristics that can infl uence the 
drug product performance (e.g. stability, bioavailability) or manufacturability should 
be discussed relative to the respective function of each excipient ” [42] . Excipients 
must be nontoxic and compatible with the formulation while remaining stable 
throughout the life of the product. Excipients require thorough evaluation and 
optimization studies for compatibility with the other formulation constituents as 
well as the container/closure system [52] . Furthermore, excipient purity may be 
required to be greater than that listed in the pharmacopeial monograph if a specifi c 
impurity is implicated in potential degradation reactions (e.g., presence of trace 
metals) [48] . 
FORMULATION DEVELOPMENT 19

20 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
One of the critical factors in excipient selection and concentration is the effect 
on preferential hydration of the biopharmaceutical product [53, 54] . Preferential 
hydration refers to the hydration layers on the outer surface of the protein and can 
be utilized to thermodynamically explain both stability enhancement and denaturation. 
Typical excipients used in protein formulations include albumin, amino acids, 
carbohydrates, chelating and reducing agents, cyclodextrins, polyhydric alcohols, 
polyethylene glycol, salts, and surfactants. Several of these excipients increase the 
preferential hydration of the protein and thus enhance its stability. Cosolvents need 
to be added in a concentration that will ensure their exclusion from the protein 
surface and enhance stability [54] . A more comprehensive review of excipients utilized 
for biopharmaceutical drug products is available elsewhere [48] . 
Buffer Selection In addition to maintaining solution pH, buffers serve a multitude 
of functions in pharmaceutical formulations, such as contributing toward overall 
isotonicity, preferential hydration of proteins and peptides, and serving as bulking 
agents in lyophilized formulations. The buffer system chosen is especially important 
for peptide and proteins that have sensitive secondary, tertiary, and quaternary 
structures, as the overall mechanisms contributing to conformational stabilization 
are extremely complex [48] . Furthermore, a protein ’ s propensity for deamidation at 
a particular pH can be signifi cant, as illustrated by Wakankar and Borchardt [55] . 
This study illustrated stability concerns with peptides and proteins at physiological 
pH in terms of asparagine (Asn) deamidation and aspartate (Asp) isomerization, 
which can be a major issue with respect to circulating half - life and potential in vivo 
degradation. This study and others also provide insight into predicting potential 
degradative mechanisms based on primary and secondary structural elements allowing 
for formulation design with these pathways in mind. 
Selecting the appropriate buffer primarily depends on the desired pH range and 
buffer capacity required for the individual formulation; however, other factors, 
including concentration, effective range, chemical compatibility, and isotonicity 
contribution, should be considered [56] . Some acceptable buffers include phosphate 
(pH 6.2 – 8.2), acetate (pH 3.8 – 5.8), citrate (pH 2.1 – 6.2, p K 3.15, 4.8, and 6.4), 
succinate (pH 3.2 – 6.6, p K 4.2 and 5.6), histidine (p K 1.8, 6.0, and 9.0), glycine 
(pK 2.35 and 9.8), arginine (p K 2.18 and 9.1), triethanolamine (pH 7.0 – 9.0), tris - 
hydroxymethylaminomethane (THAM, p K 8.1), and maleate buffer [48] . Additionally, 
excipients utilized solely for tonicity adjustment, such as sodium chloride and 
glycerin, may not only differ in ionic strength but also could afford some buffering 
effects that should be considered [52] . 
Preservatives In addition to those processing controls mentioned above (Section 
3.1.4.3 ), the sterility of a product may be maintained through the addition of antimicrobial 
preservatives. Preservation against microbial growth is an important 
aspect of multidose parenteral preparations as well as other formulations that 
require preservatives to minimize the risk of patient infection upon administration, 
such as infusion products [52] . Aqueous liquid products are prone to microbial 
contamination because water in combination with excipients derived from natural 
sources (e.g., polypeptides, carbohydrates) and proteinaceous active ingredients 
may serve as excellent media for the growth [57] . The major criteria for the selection 
of an appropriate preservative include effi ciency against a wide spectrum of micro

organisms, stability (shelf life), toxicity, sensitizing effects, and compatibility with 
other ingredients in the dosage form [57] . Typical antimicrobial preservatives include 
m - cresol, phenol, parabens, thimerosal, sorbic acid, potassium sorbate, benzoic acid, 
chlorocresol, and benzalkonium chloride. Cationic agents such as benzalkonium 
chloride are typically not utilized for peptide and protein formulations because they 
may be inactivated by other formulation components and their respective charges 
may induce conformational changes and lead to physical instability of the API. 
Further, excipients intended for other applications, such as chelating agents, may 
exhibit some antimicrobial activity. For instance, the chelating agent ethylenediaminetetraacetic 
acid (EDTA) may exhibit antimicrobial activity, as calcium is required 
for bacterial growth. 
Identifying an optimal antimicrobial preservative is based largely on the effectiveness 
of that preservative at the concentration chosen. In short, it is not enough to 
assess the compatibility of the preservative of choice with the API and formulation 
and processing components. There also needs to be a determination of whether the 
preservative concentration is suffi cient to kill certain standard test organisms. The 
USP presents standard protocols for assessing the relative effi cacy of a preservative 
in a formulation using the antimicrobial effectiveness test (AET) [58] . Briefl y, by 
comparing the relative kill effi ciency of the formulation containing varying concentrations 
of the preservative, the formulator can determine the minimal concentration 
required for preservative effi cacy and design the formulation accordingly. 
1.1.5 DRUG PRODUCT STABILITY 
1.1.5.1 Defi ning Drug Product Storage Conditions 
From a regulatory standpoint, the primary objective of formulation development is 
to enable the delivery of a safe and effi cacious drug product to treat and/or mitigate 
a disease state throughout its proposed shelf life. The effi cacy and in many cases the 
safety of a product are directly related to the stability of the API, both neat and in 
the proposed formulation under processing, storage, and shipping conditions as well 
as during administration. As such, the concept of drug stability for biotechnology - 
derived products does not change substantially from that of small molecules, 
although the level of complexity increases commensurate with the increased complexity 
of the APIs in question and the formulation systems utilized for their 
delivery. 
Stability study conditions for biotechnology - derived APIs and their respective 
drug products are not substantially different from those studies conducted for small 
molecules. Temperature and humidity conditions under which to conduct said 
studies are outlined in ICH Q1A(R2), which incorporates ICH Q1F, stability study 
conditions for zones III and IV climactic conditions [59] . Additional guidance specifi 
c to conducting stability studies on biopharmaceutical drug products is given in 
ICH Q5C [1] . However, the intention of ICH Q5C is not to outline alternate temperature 
and humidity conditions to conduct primary stability studies; rather it 
provides guidance with respect to the fact that the recommended storage conditions 
and expiration dating for biopharmaceutical products will be different from product 
to product and provides the necessary fl exibility in letting the applicant determine 
DRUG PRODUCT STABILITY 21

22 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
the proper storage conditions for their respective product. Furthermore, this document 
provides general guidance in directing applicants in the types of analytical 
methodologies that may be used and direction on how to properly assess the stability 
of these complex molecules [1] : 
Assays for biological activity, where applicable, should be part of the pivotal stability 
studies. Appropriate physicochemical, biochemical and immunochemical methods for 
the analysis of the molecular entity and the quantitative detection of degradation 
products should also be part of the stability program whenever purity and molecular 
characteristics of the product permit use of these methodologies. 
One recent approach to aid in defi ning the design space for protein and peptide 
therapeutics has been to create empirical phase diagrams indicating the relative 
stability of compounds based on altering conditions and assessing conformational 
changes via a compilation of analytical techniques (Figure 1 ) [60 – 62] . These empirical 
phase diagrams can be generated based on pH, temperature, salt concentration, 
and so on, and, although seemingly laborious at fi rst glance, could provide invaluable 
information in defi ning the extremes to which a compound may be subjected without 
altering its conformation. For instance, if an empirical phase diagram determines 
the safe temperature range for a compound is up to 35 ° C and an excursion occurs 
to 33 ° C, this information would give the stability scientist a guideline as to the 
appropriate course of action. Under the traditional testing paradigm of ICH Q1A, 
where stability testing is limited to 25, 30, and 40 ° C, one may not know the compound 
’ s upper transition temperature to induce conformational changes. If the 
information is not already available, then additional excursion studies may need to 
be conducted to assimilate this information and take the appropriate course of 
action. 
1.1.5.2 Mechanisms of Protein and Peptide Degradation 
The inherent heterogeneity of peptide and protein drug substances results in their 
relative sensitivity to processing, storage, and handling conditions as well as a mul- 
FIGURE 1 Empirical phase diagram for ricin toxin A - chain generated using CD molar 
ellipticity at 208 nm, ANS fl uorescence, and intrinsic Trp fl uorescence intensity data. Labels 
indicate the state of the protein within the same region of color based on evaluation of a 
compilation of data sets. (Reproduced with permission from ref. 62 .) 
20 
40 
60 
80
T 
4 5 6 7 8 9 
pH

titude of other factors. Most importantly, this heterogeneity results in a whole host 
of potential degradative mechanisms, some of which are compiled in Table 3 and 
include chemical instability pathways such as oxidation, hydrolysis of side chains 
and potentially the peptide backbone, and deamidation of Asn and Gln side chains. 
Also, physical instability manifesting in the form of protein unfolding, formation of 
intermediate structures, aggregation, and adsorption to the surfaces of containers 
and other equipment can be a major technical hurdle in developing any biopharmaceutical 
and may or may not be related to chemical instability [63] . Further 
complicating matters is that instability can potentially manifest in various ways and 
may or may not be detectable by any one method. Taken together, however, the 
compilation of methodologies utilized for stability assessment should give a good 
approximation as to the degradative mechanisms of the compound in its respective 
formulation. Further, bioactivity and immunogenicity assays should play integral 
roles in assessing the relative stability of any biopharmaceutical compound. Briefl y 
stated, the chemical and physical stability of products is extraordinarily diffi cult to 
assess and will not be belabored here as good reviews on this topic are readily available 
in the literature [63, 64] . 
1.1.5.3 Photostability 
In certain cases, exposure of pharmaceutical compounds to UV and visible light 
could result in electronic excitation, termed vertical transition, that could ultimately 
result in light - induced degradation. The ICH guideline Q1B [65] is a reference 
on how to conduct photostability stress testing for pharmaceutical compounds. 
In brief, compounds are exposed to an overall illumination of not less than 1.2 
million lux hours and an integrated near - UV energy of not less than 200 Wh/m 2 
[65] . These requirements are in addition to normal stability stress testing and 
require the additional caveat that analytical methodologies are suitable to also 
detect photolytic degradation products, as discussed above. A comprehensive discussion 
of small - molecule photolytic degradative mechanisms is available for 
further review [66] . 
TABLE 3 Potential Degradative Mechanisms of Peptides and Proteins 
Degradative Mechanism Site of Occurrence 
Chemical 
degradative 
mechanisms 
Oxidation Intrachain disulfi de linkages Met, Trp, Tyr 
Peptide bond hydrolysis AA backbone 
N - to - O migration Ser and Thr 
. - to . - Carboxy migration Asp and Asn 
Deamidation Asn and Gln 
Acylation . - Amino and . - amino group 
Esterifi cation/carboxylation Glu, Asp, and C-term 
Physical 
degradative 
mechanisms 
Unfolding Partial unfolding of tertiary structure 
Aggregation Aggregation of subunits could result in 
precipitation 
Adsorption Adsorption to processing equipment and 
container closure systems 
Source : Modifi ed from Crommelin et al. [5] . 
DRUG PRODUCT STABILITY 23

24 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
1.1.5.4 Mechanical Stress 
Regulatory guidance on appropriate methods to evaluate the effect of shear stress 
and process - handling stability studies is not available. However, these studies are 
integral in determining the relative stability of the product with respect to mechanical 
stresses introduced during development and manufacturing. Although not typically 
recognized as a major degradative pathway for most small - molecule dosage 
forms, the introduction of mechanical stress is recognized as a major challenge in 
the formulation of semisolids and can potentially induce physical instability of biopharmaceuticals, 
although the extent of this effect is currently unknown. For example, 
processing shear may infl uence the protein ’ s outer hydration shell, altering the stabilizing 
energy provided from preferential hydration and resulting in the exposure 
of internal, nonpolar residues. This may facilitate aggregation if enough shear force 
is provided. Alternately, the shear energy required to force unfolding has been 
studied but has not been related to the fl uid dynamic shear experienced during 
processing. Therefore, stress studies should include meticulous controls in the form 
of temperature, light and humidity, and fl uid dynamic shear as a function of time. 
Data from these studies could be incorporated into empirical phase diagrams, and/ 
or response surfaces, to help further defi ne the design space for the active and fi nished 
drug product. Understanding the effects of stress introduced during the manufacturing 
processing of biopharmaceutical products could facilitate the selection of 
appropriate PAT tools and QbD incorporation in the development of these products. 
Clearly, there is a considerable need for research in this area, and until the 
extent of the possible effects are understood, this lack of knowledge poses an 
unknown risk and prevents adequate risk assessment for biopharmaceutical development 
activities consistent with ICH Q9. 
1.1.5.5 Freeze – Thaw Considerations and Cryopreservation 
The rapid or continuous freezing and thawing of protein products could contribute 
signifi cantly to instability of the API. Such studies are typically designed to assess 
the implications of potential transport and handling conditions. These conditions 
include not only the manufacturing processing, storage, and shipment to warehouses 
and pharmacies but also subsequent pharmacy storage and patient handling [52] . 
Unpredictable and somewhat modest temperature fl uctuations could easily induce 
degradation or conformational changes that may reduce bioactivity or expose antigenic 
epitopes [5] . These effects could also be a result of altered preferential hydration 
at the surface of the peptide or protein through salting - out effects induced by 
rapid freezing, which could easily denature the product [67] . 
1.1.5.6 Use Studies 
Stability of biopharmaceutical compounds should also be determined under conditions 
that mimic their normal usage. For instance, the stability of reconstituted 
lyophilized products should be assessed with respect to time and temperature and, 
if applicable, light and mechanical stimuli. Likewise, the stability of a compound 
included in implantable devices and controlled - release microsphere formulations 
should be determined over the course of its required use, under conditions which 
mimic the heat, moisture, light, and enzymatic physiological conditions to which it 

will be implanted. Such studies should also determine the release profi le of the 
compound over these specifi ed conditions. 
Drug products intended for IV administration are generally dosed as an initial 
bolus followed by a slow infusion. Consequently, admixture studies of the compound 
in potential IV fl uids, such as 0.9% (w/v) saline, 5% (w/v) dextrose, and Ringer ’ s 
solution, should also be assessed to determine the relative stability of the compound 
in this new environment. These studies are critical as the formulation dynamic that 
protected and stabilized the compound has now been altered dramatically with 
dilution. This environmental change could potentially impact the preferential hydration 
of the compound as well as directly induce conformational changes based on 
the diluent chosen and the compound ’ s potential degradative mechanism(s). Additional 
contributing factors to instability in admixture solutions could be due to 
changes in pH, mechanical mixing of the compound in the IV bag, adsorption of 
the compound to the bag itself (which is typically polymeric), or IV sets used for 
administration, as well as an increased potential for oxidative degradation. The suitability 
of analytical methodologies should also be determined in the presence of 
these additional analytes. 
1.1.5.7 Container Closure Integrity and Microbiological Assessment 
Ensuring that parenteral pharmaceuticals maintain their sterility over the course of 
their shelf life is an integral part of any stability assessment [68] . Parenteral dosage 
forms must be free from microbiological contamination, bacterial endotoxins, and 
foreign particulate matter. Selection of the adequate sterile manufacturing process 
has been briefl y discussed above. Determining the microbiological integrity of the 
product over its shelf life also gives an indication of the relative quality of the container 
closure system chosen for the formulation. Compendial sterility and endotoxin 
testing are often used for this purpose; however, sampling is dependent on a 
statistical evaluation of the batch size, unit fi ll volume, and method of product sterilization 
[68] . Additionally, since these tests are destructive, it would be impossible 
to test an entire stability batch to ensure viability of a container closure system. 
Other nondestructive tests have been developed to determine the integrity of a 
container ’ s closure system [69] . These tests could also serve as a surrogate indicator 
of product manufacturing quality over time. 
1.1.5.8 Data Interpretation and Assessment 
Interpretation of primary stability data for determining expiration dating and 
primary storage conditions has been outlined by ICH Q1E [70] . This guidance document 
delineates broad methodologies for interpreting primary and accelerated stability 
data and extrapolation of said data for determining expiry dating. Of course, 
expiry dating cannot be made without reference to specifi cations for those primary 
stability - indicating parameters assessed, which is discussed below. Traditionally, stability 
assessments performed during preformulation will give an indication of the 
potential storage conditions as well as allow for extrapolation of accelerated stability 
studies to kinetic degradation rates. Typically this is done through Arrhenius 
manipulations. However, as one would expect, these analyses are not readily 
useful for biopharmaceutical products, as there is rarely a linear correlation between 
QUALITY BY DESIGN AND SCALE-UP 25

26 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
temperature and the compound ’ s degradative rate. This is primarily due to the 
complex and often competing degradative mechanisms as well as the potential for 
so - called molten globule intermediate phases. In spite of these limitations, ICH Q5C 
does provide relevant guidance in illustrating the fl exibility required for determining 
storage conditions, as these products usually require a very narrow temperature 
condition to maintain optimal stability. Further guidances may be needed to enhance 
uniformity in testing methodology and enable the utilization of validated PAT 
methodologies. 
1.1.6 QUALITY BY DESIGN AND SCALE - UP 
1.1.6.1 Unit Operations 
Unit operations are defi ned as the individual basic steps in a process that when 
linked together defi ne the process train and result in the fi nal product. In practical 
terms, a unit operation is often defi ned as an individual step that is carried out on 
one piece of equipment. Typical biopharmaceutical API unit operations may include 
fermentation or bioreactor processes, cell separation through centrifugation or 
microfi ltration, virus removal or inactivation, cell lysis and inclusion body precipitation, 
product refolding, and purifi cation steps [71] . Conversely, those unit operations 
for drug product manufacturing procedures would be similar to those seen in the 
manufacture of a small molecule of comparable dosage form, namely mixing, fl uid 
transfer, sterile fi ltration, dose fi lling, lyophilization, and so on. Of course, unit operations 
will be dependent on the manufacturing process for the specifi c dosage form, 
but careful preformulation and characterization studies will enable relatively 
straightforward process design and ease subsequent scale - up activities. Modeling of 
unit operations for both small and large molecules is a recognized gap in our ability 
to achieve QbD. The application of accepted engineering methods to the problem 
is the subject of active research. 
1.1.6.2 Bioburden Considerations 
Bioburden refers to the amount of microbial fl ora that can be detected on an item, 
on a surface, or in a solution [68] . As mentioned previously, microbial contamination 
and bioburden are especially important for biotechnology - derived parenteral products 
since these products are typically capable of supporting microbial growth. 
Special care should be taken to ensure not only that the fi nal packaged product 
does not contain microbial contamination but also that manufacturing equipment 
is also free from contamination. Monitoring bioburden and determining potential 
levels of microbial contamination on equipment surfaces are particularly important 
with respect to the material being evaluated. 
In general, bioburden counts in parenteral solutions are obtained by conducting 
the total aerobic counts and total yeast and mold counts as specifi ed in the USP 
microbial limits test (61) or an equivalent test [72] . In addition, membrane fi ltration 
of larger than specifi ed volumes may also be used to detect any microbial contamination 
when sample results are expected to contain a negligible number of microbial 
fl ora or in the presence of potential confounding factors, such as antimicrobial 

preservatives [68, 72] . It is important to note that the presence of a high bioburden 
count can present an endotoxin contamination problem, as whole microbial cells 
and spores can be removed by sterilizing grade fi ltration (0.2 . m), while endotoxins 
are not [68] . These issues also underscore the importance of cleaning methods and 
their respective validation as well as assessing relevant product contamination on 
manufacturing equipment. 
1.1.6.3 Scale - Up and Process Changes 
The FDA defi nes process validation as “ establishing documented evidence that 
provides a high degree of assurance that a specifi c process will consistently produce 
a product meeting its predetermined quality attributes ” [73] . While validation studies 
are typically performed at full scale, in most cases scale - down or laboratory - scale 
models were used to initially develop the manufacturing process. Consequently, 
scale - down process precharacterization and characterization studies are considered 
crucial to successful process validation for both API and drug product manufacturing 
schemes [74] . Although they do require qualifi cation work and a signifi cant 
commitment of time and resources, characterization studies provide signifi cant 
insight into the critical process and control parameters for each unit operation as 
well as improved success rates for process validation due to a better, more complete 
understanding of the process [74] . In engineering terms, characterization studies 
identify the critical parameters useful for dimensional analysis that enable successful 
process scale - up. 
While the above explanation attempts to simplify the scale - up process, it is not 
meant to trivialize it. In fact, scale - up is probably the most diffi cult manufacturing 
challenge for traditional small molecules, let alone biopharmaceuticals. Issues such 
as homogeneous mixing, bulk product holding and transfer, and sterile fi ltration 
could all be potentially compounded due to the increased scale and introduced 
stress. However, a QbD approach to rational drug design should enable simplifi ed 
process scale - up and validation. This is only true if experimental design approaches 
have been utilized to identify the design space for the processes involved in the 
production of the molecule. This is also where the greatest benefi t of developing 
empirical phase diagrams early in development could materialize. Essentially, the 
QbD approach identifi es the quality attributes of the product based on scientifi c 
rationale as opposed to attempting to fi t the proverbial square peg into a round 
hole through a trial - and - error approach. This rational design approach goes further 
to identify the limiting factors of each unit operation and provides the means of 
attempting to correlate how each unit operation affects the fi nal product quality 
attributes. 
In order to initiate a successful QbD program, the fi rst step is to identify those 
process parameters that are essential to product quality and develop well - validated 
analytical methodologies to monitor those parameters. In short, the process involves 
identifi cation of the potential design space for production of the molecule and con- 
fi rmation that design space through rational, deliberate experimentation. Ideally, 
process monitoring should be done in real time to minimize production time and if 
possible online; however, this may not always be the case or even necessary depending 
upon the relative duration of the process to the test. Recognizing potential 
quality metrics earlier in the development process could also potentially facilitate 
QUALITY BY DESIGN AND SCALE-UP 27

28 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
greater fl exibility during product development and subsequent process characterization 
[74] . Certainly, manufacturing site - specifi c differences could also potentially 
introduce variability into processes. It is for this reason that site - specifi c personnel 
training, process/technology transfer and validation, and stability assessments are 
required to ensure product quality. 
By defi nition, a process designed under the auspices of QbD should enable a 
degree of process knowledge that allows for controlled process changes without 
affecting the fi nal product or requiring regulatory approval. For immediate - and 
controlled - release solid dosage products, SUPAC guidelines provide direction on 
the studies to conduct to determine the impact of a process change. Although there 
is some regulatory guidance available for biological products (e.g., “ Changes to an 
Approved Application for Specifi ed Biotechnology and Specifi ed Synthetic Biological 
Products ” or “ FDA Guidance Concerning Demonstration of Comparability of 
Human Biological Products, Including Therapeutic Biotechnology - Derived Products 
” ), process changes need to be evaluated on a case - by - case basis. The comparative 
analysis of process changes should also be evaluated with respect to defi ned 
product specifi cations. PAT will be invaluable in determining the potential impact 
of process changes. While stability is often the main metric for small - molecule 
drug product, bioactivity and immunogenicity will need to be added metrics for 
biopharmaceuticals. Therefore, any process change should be approached subjectively 
and care should be taken to validate the relative impact on the safety and 
effi cacy of the product. 
1.1.7 CONCLUDING REMARKS 
Although the goals are the same, developing biotechnology molecules presents 
challenges that are unique compared to the development of conventional small 
molecules. The innate complexity of the molecular and macromolecular structures 
requires three dimensionally viable stability assays and understanding. The complexity 
of possible physiological responses and interactions requires an enhanced 
understanding of the formulation and processing stresses to identify the minor but 
critical changes that result in product unacceptability. A key to addressing these 
challenges is the development of analytical techniques with the sensitivity and reliability 
to detect and monitor such changes and to provide data to another gap - 
closing activity — modeling unit operations. Also the need to develop meaningful 
kinetic models is obvious to everyone involved in the development of both large 
and small molecules. Linking this type of information to the major efforts in the 
discovery arena is a necessary step to bringing the products of the future to 
market. 
The use of biotechnology products is increasing exponentially and many 
opportunities exist to improve their development. The fi rst step may be defi ning 
rational biotechnology - derived drug “ developability ” standards that can be assessed 
during preclinical/early development testing. Such a tiered approach based upon 
the potential risk, the confi dence in methodology, and benefi t has of course been a 
proven strategy for small molecules, and a preliminary version applicable to biotechnology 
drug products is likely possible today given the topics discussed in this 
chapter. 

ACKNOWLEDGMENTS 
The authors would like to thank The School of Pharmacy and Pharmaceutical Sciences, 
the Department of Industrial and Physical Pharmaceutics of Purdue University 
and the National Institutes of General Medical Sciences (R01 - GM65448) for 
their fi nancial support. 
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32 BIOTECHNOLOGY-DERIVED DRUG PRODUCT DEVELOPMENT 
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Industrial Case Studies , Taylor and Francis , Boca Raton, FL . 

33 
1.2 
REGULATORY CONSIDERATIONS IN 
APPROVAL OF FOLLOW - ON PROTEIN 
DRUG PRODUCTS 
Erin Oliver, 1 Stephen M. Carl, 2 Kenneth R. Morris, 2 
Gerald W. Becker, 3 and Gregory T. Knipp 1 
1 Rutgers, The State University of New Jersey, Piscataway, New Jersey 
2 Purdue University, West Lafayette, Indiana 
3 SSCI, West Lafayette, Indiana 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc. 
Contents 
1.2.1 Introduction 
1.2.1.1 Emergence of Biotechnology Industry 
1.2.1.2 Challenges Facing “ Biogenerics ” 
1.2.2 History of Biologics Regulation in United States 
1.2.2.1 Early Biologics Regulation (1800s – 1990s) 
1.2.2.2 Modern Biologics Regulation (1990s – Today) 
1.2.3 Regulatory Classifi cation of Proteins 
1.2.3.1 Defi nitions and Key Terminology 
1.2.3.2 Application of Defi nitions to Proteins: Is It a Drug or a Biologic? 
1.2.3.3 Regulatory Approval Path for Proteins 
1.2.4 Regulation of Generic Drugs 
1.2.4.1 History of Generic Drug Legislation in United States 
1.2.4.2 Approval Process for Generic Drugs 
1.2.4.3 Application of Generic Regulations to Biologics 
1.2.5 Legal Arguments Related to Follow - On Proteins 
1.2.5.1 Constitutionality of 505(b)(2) Process for Drugs 
1.2.5.2 Constitutionality of 505(b)(2) Process for Follow - On Proteins 
1.2.5.3 Applicability of 505(j)(1) or ANDA Process to Biogenerics 
1.2.5.4 Current Rules Relating to Bioequivalence of Generic Drugs 
1.2.5.5 Statutory Authority 
1.2.6 Scientifi c Issues Related to Follow - On Proteins (Data Requirements) 
1.2.6.1 “ Sameness ” as per Orphan Drug Regulations 
1.2.6.2 “ Sameness ” as per Postapproval Change Guidances 

34 REGULATORY CONSIDERATIONS IN APPROVAL 
1.2.7 Proposed Regulatory Paradigm: Case Studies 
1.2.7.1 Case Study 1: Fortical [Calcitonin - Salmon (rDNA Origin)] 
1.2.7.2 Case Study 2: Omnitrope [Somatropin (rDNA Origin)] 
1.2.7.3 Case Study 3: Generic Salmon Calcitonin 
1.2.8 Summary and Conclusions 
References 
1.2.1 INTRODUCTION 
The ongoing need to provide the U.S. population with cost - effective pharmacological 
therapies has led to an emergent public health initiative in this country, namely 
for generic versions of therapeutic proteins. Greater access to generic drugs was 
made possible by the passage of the 1984 Drug Price Competition & Patent Term 
Restoration Act, commonly referred to as Hatch – Waxman. Generics have historically 
afforded considerable savings to the American consumer in need of prescription 
medication. Ten years after the Hatch – Waxman amendments, the Congressional 
Budget Offi ce estimated that purchasers saved a total of $ 8 – $ 10 billion on prescriptions 
at retail pharmacies by substituting generic drugs for their brand - name counterparts 
in 1994 [1] . To put those numbers in the context of today ’ s pharmaceutical 
landscape, a recent report issued by the U.S. Department of Health and Human 
Services estimates that generic drugs constitute 63% of the total prescription medicines 
sold in the United States [2] . This same report suggests that generic drugs cost 
approximately 11% of the total cost of branded pharmaceuticals (on a per - dose 
basis). 
At the same time, the development and use of therapeutic proteins have increased 
dramatically, with more than 850 biotechnology drug products and vaccines currently 
in trials [3] . Further, it is estimated that by the year 2010 nearly one - half of 
all newly approved medicines will be of biological origin [4] . The industrial fi nancial 
incentives for the pursuit of follow - on biologics (heretofore termed biogenerics) are 
substantial with sales of biotechnology medicines in the United States rising 17% 
to approximately $ 30 billion in 2005 and growing at an annual rate of about 20% 
thereafter [3] . 
Not unexpectedly, the U.S. Food and Drug Administration (FDA) is experiencing 
mounting pressure to progress the cause of biogenerics. In a letter dated February 
10, 2006, Senators Henry Waxman and Orrin Hatch (authors of the original “ generic ” 
legislation) urged the FDA to develop and implement clear guidelines for the 
approval of follow - on biological products for certain well - characterized proteins 
like insulin and human growth hormone (HGH) [5] . Additionally, recent litigation 
has compelled the FDA to take action on a pending drug application for a follow - on 
protein (FOP) drug product [Omnitrope, somatropin (recombinant DNA, rDNA 
origin)] [6] . 
A signifi cant barrier to the emergence of “ biogenerics ” is the absence of a clear, 
effi cient abbreviated pathway for approval. This hurdle is linked to signifi cant scientifi 
c and legal issues in the United States in terms of how proteins are classifi ed 
(drug vs. biologic) and subsequently regulated as well as how “ generics ” are tradi

HISTORY OF BIOLOGICS REGULATION IN UNITED STATES 35 
tionally defi ned in terms of equivalence and substitutability. However, an examination 
of the vast array of biologicals on the market today reveals that not all proteins 
are created equal. This range of complexity may provide an opportunity for stepwise 
progress on the regulatory front. This chapter presents the background to this multifaceted 
issue and examines the key regulatory challenges facing biogenerics today. 
An appropriate regulatory paradigm for the approval of FOPs is proposed and 
supported though a discussion of recent case studies. 
1.2.1.1 Emergence of Biotechnology Industry 
The explosion of scientifi c advances over the last quarter century has spawned the 
biotechnology industry and whole new classes of therapeutic agents for the treatment 
and prevention of disease. In October of 1982, the FDA approved the fi rst 
protein - based therapeutic created by DNA technology in the form of Humulin 
(recombinant insulin). Developed by Eli Lilly & Co., with technical assistance from 
Genentech, Humulin is indicated for the treatment of diabetes. At the time, the use 
of recombinant technology was somewhat limited to the production of smaller, 
nonglycosylated proteins such as insulin (51 amino acids) and HGH (191 amino 
acids) using bacterial hosts. The seminal discovery by Columbia ’ s Richard Axel of 
the process of cotransformation enabled complex protein production and glycosylation 
and thus spurred the emergence of the modern biotechnology industry [7] . 
The phenomenal growth observed in the biotechnology sector is notable in terms 
of the extraordinary number and diversity of therapeutic peptides and proteins that 
have been developed within a period of only about 20 years. Examples of therapeutic 
proteins in current use include cytokines, clotting factors, vaccines, and monoclonal 
antibodies, as illustrated in Table 1 [8] . 
As presented in Table 2 , many of these “ early ” biotechnology products have 
reached the end of their period of patent exclusivity [4 – 9] . Thus, it is appropriate to 
now consider the next steps in the “ life cycle ” of these products as potential generic 
drugs. 
1.2.1.2 Challenges Facing “ Biogenerics ” 
The diversity and complexity of biologic molecules that drive their utility as therapeutic 
agents also contribute to the diffi culty in classifying them as pharmacological 
entities, namely, whether they are drugs or biologics. This diffi culty in classifi cation 
is of profound importance since there are fundamental differences in how the FDA 
regulates drugs and biologics. 
To appreciate the current challenges facing the pharmaceutical and biotechnology 
industry, it is informative to review the historical background associated with 
the classifi cation and regulation of biologics in the United States, particularly in the 
context of the nation ’ s evolving drug regulation system. 
1.2.2 HISTORY OF BIOLOGICS REGULATION IN UNITED STATES 
Due to the scientifi c limitations of the early to mid - 1900s, signifi cant differences 
existed between the approaches taken to manufacture and analyze biologics and 

36 REGULATORY CONSIDERATIONS IN APPROVAL 
TABLE 1 Examples of Therapeutic Peptide and Protein Molecules Currently Marketed 
in United States 
Peptides Antibiotics: bacitracin, bleomycin, gramicidine, capreomycin 
Hormones: corticotropin, glucagon, gonadrolein HCl, leuprolide 
acetate, histrelin acetate, oxytocin, secretin, goserelin acetate, 
vassopressin 
Others: polymixin B, eptifi batide, cyclosporine 
Nonglycosylated 
proteins 
Interleukins: andresleukin (IL - 1), denileukin diftitox (fusion, protein - 
IL - 2+ DT), anakinra (IL - 2) 
Interferons: interferon alpha - n1, interferon alpha - n3, interferon alpha - 
2a, peg interferon alfa - 2b, interferon alfacon - 1, Interferon alpha - 2b, 
interferon beta - 1b, interferon gamma - 1b, 
Enzymes/inhibitors: anistreplase, asparaginase, lactase, trypsin, alpha - 
1 proteinase inhibitor, urokinase, deoxyribonuclease, fi brinolysin, 
chymotrypsin, pancreatin, papain, urokinase 
Growth factors/hormones: Filigrastim pegfi lgrastim, somatropin, 
becaplermin, somatrem, menotropins 
Antithrombotic agents: thrombin, fi brinogen, hirudin, hirulog, fi brin 
Others: insulin, gelatin, prolactin, albumin (human), hemoglobin, 
collagen 
Glycosylated 
proteins 
Interferon beta - 1a 
Antithrombotic agents: alteplase, drotrecogin alfa, antithrombin III 
Antianemic: darbopoetin alfa, erythropoietin 
Growth hormones: follitropin alpha, follitropin beta, chorionic 
gonadotropin (Human) 
Immuno globulins (IG): pertusssis IG, rabies IG, tetanus IG, hepatitis 
B IG, varicella zoster IG, rho(D) IG, normal immune globulin, 
lymphocyte anti - thymocyte, IB (equine) 
Coagulation factors: factor VII antihemophilic factor, factor IX 
(human, recombinant) 
Factor VIII (others): etanercept (CSF), sargramostim (TNF) 
Monoclonal 
antiobodies 
avciximab, alemtuzamub, basiliximab, gentuzumab, satumomab, 
infl ixibam, palivizumab 
drugs. This reality led to the creation of separate and distinct regulatory pathways 
for drugs and biologics. As noted earlier, the developments in analytical chemistry 
and improvements in process technologies have, in recent times, blurred the lines 
between drug and biologic drug development. In the current era of pharmaceutical 
development and standards harmonization, one might question the continued need 
for two distinct pathways. Recognizing the shifting paradigm of drug development, 
the history of biologics regulation is discussed below in two parts: early history and 
present day. 
1.2.2.1 Early Biologics Regulation (1800s – 1990s) 
This country ’ s earliest experience with biologics dates back to the infectious scourges 
of the late 1800s and early 1900s when epidemics of typhoid, yellow fever, smallpox, 
diphtheria, and tuberculosis were being battled by new advances in immunology. 
The discovery and development of vaccines and antitoxins led to the creation of a 

HISTORY OF BIOLOGICS REGULATION IN UNITED STATES 37 
TABLE 2 Patent Expiration Dates for U.S. Marketed Biologics 
Brand Name Generic Name Indication Company 
Patent 
Expiry 
Humulin Recombinant insulin Diabetes Eli Lilly Expired 
Nutropin Somatropin Growth disorders Genentech Expired 
Abbokinase Eudurase urokinase Ischaemic events Abbott Expired 
Ceredase Alglucerase Gaucher disease Genzyme Expired 
Cerezyme Imiglucerase Gaucher disease Genzyme Expired 
Streptase Streptokinase Ischaemic events AstraZeneca Expired 
Intron A IFN - . - 2b Hepatitis B and C Biogen/Roche Expired 
Serostim Somatropin AIDS wasting Serono Expired 
Humatrope Somatropin Growth disorders Eli Lilly Expired 
Geref Sermorelin Growth hormone 
defi ciency 
Serono Expired 
(2004) 
Synagis Palivizumab Respiratory 
syncytial virus 
Abbott Expired 
(2004) 
Novolin Human insulin Diabetes Novo Nordisk 2005 
Protropin Somatrem Growth hormone 
defi ciency 
Genentech 2005 
TNKase Tenecteplase 
TNK - tPA 
Acute myocardial 
infarction 
Genentech 2005 
Actimmmune IFN - . - 1b Chronic 
granulomatous 
disease; 
malignant 
osteoporosis 
InterMune 2005, 2006, 
2012 
Activase, 
Alteplase 
tPA Acute myocardial 
infarction 
Genentech 2005, 2010 
Proleukin IL - 2 HIV Chiron 2006, 2012 
Epogen, 
Procrit, 
Eprex 
Erythropoietin Anemia Amgen 2013 
Neupogen Filgrastim (G - CSF) Anemia, 
leukemia, 
neutropenia 
Amgen 2015 
Note: Based on our search of available patent sites for only the reference product. 
IFN - Interferon; tPA - Tissue Plasminogen Activator, IL - interleukin; HIV - Human Immunodefi ciency 
Virus; G-CSF- Granulocyte-Colony Stimulating Factor; TNKase- Tenecteplase. 
whole new “ biopharmaceutical ” industry. As demand increased, the pharmaceutical 
manufacturers responded and in turn supplanted the government ’ s role in the public 
supply of vaccines (per Vaccine Act of 1813) [10] . Unfortunately, the commercialization 
of vaccines by smaller, less experienced, and likely less scrupulous manufacturers 
led to problems. Similar to the history of drug regulation, early advances in 
biologics regulation could be characterized as responsive rather than proactive. 
Change often occurred following tragedy and the result of government ’ s attempt to 
respond. Some of the key milestones of early biologics regulation are summarized 
in Table 3 . The following years saw many administrative changes in terms of the 
specifi c governmental agency responsible for regulating biologics, but with few 
substantive changes to the regulations themselves. 

38 REGULATORY CONSIDERATIONS IN APPROVAL 
TABLE 3 Key Milestones in Early Biologics Regulation 
1901 Ten children died in St. Louis from administration of tetanus - contaminated 
diphtheria antitoxin. In this case, no safety testing had been performed prior to 
use. 
1902 Biologics Control Act (BCA) signed into law: 
• Authorizing the regulation of commercial viruses, serums, toxins, and analogous 
products 
• Requiring the licensure of biologics manufacturers and establishments 
• Providing governmental inspectional authority 
• Making it illegal for the commercial distribution of product not manufactured 
and labeled in accordance with the act 
1906 Pure Food and Drug Act enacted (precursor of modern - day drug regulation). Lack 
of mention of biologics as a class effectively represents fi rst distinction between 
drug and biologic regulation. 
1919 BCA amended: 
• Required reporting of changes in equipment, manufacturing processes, personnel; 
establishment of formal quality control procedures; and submission of samples 
for regulatory inspection and approval for release 
• Recognized potential that slight changes to manufacturing conditions (raw 
materials, process, personnel, etc.) could have signifi cant and adverse effect on 
product quality 
• Required strict control of input (environment and manufacturing conditions) 
rather than end - stage testing of quality attributes due to limitations in analytical 
methodology to detect these effects 
1937 Elixir sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107, 
many of whom are children. 
1938 Food, Drug and Cosmetic Act (FDCA) enacted: 
• Established concept of “ new drugs ” requiring proof of safety prior to marketing 
• Required submission of an investigational new Drug (IND) application prior to 
clinical use of an experimental drug in humans 
• Required approval of a new drug application (NDA) prior to commercial sale of 
drugs 
• Granted federal government power of seizure of misbranded or adulterated 
drugs 
• Defi ned “ drugs ” comprehensively; not excluding potential of “ biologics ” to 
function as drugs 
1941 • Approximately 300 deaths and injuries result from distribution of sulfathiazole 
tablets tainted with the sedative phenobarbital. 
• Insulin Amendment passed to require FDA testing/certifi cation of purity and 
potency. 
1944 Public Health Service (PHS) Act enacted to consolidate and codify previous 
biologics laws: 
• Outlined licensing requirements for biologics — for both product (product 
licensing application, or PLA) and establishment where the product was 
manufactured (establishment licensing application, or ELA) 
• Required submission of samples of each manufactured lot of all biologicals for 
government testing and certifi cation prior to commercial release 
• Required sponsors to own all of manufacturing facilities, effectively eliminating 
multiparty or contract manufacturing 

HISTORY OF BIOLOGICS REGULATION IN UNITED STATES 39 
1.2.2.2 Modern Biologics Regulation (1990s – Today) 
Whereas early biologics regulation was grounded by technical limitations, modern 
biologics regulation is driven by tremendous advances in scientifi c knowledge. 
Development of analytical tools and techniques has dramatically increased the 
ability to characterize proteins and substantiate the structure, composition, and 
function of the therapeutic molecule. These advances enable the detection of small 
differences in molecular weight; elucidation of primary, secondary, and tertiary 
protein structures; detection and quantifi cation of posttranslational modifi cations 
(i.e., patterns of glycosylation); and improved understanding of structure – function 
relationships and potential immunogenic responses. Simultaneously, developments 
in the fi elds of pharmaceutical and biotechnological manufacturing have greatly 
improved process effi ciency and control. This recent technological evolution has had 
a direct impact on biologics regulation as refl ected below in several key events: 
• In 1995, the FDA agreed to eliminate lot testing requirements for certain highly 
characterized products once the company ’ s ability to consistently manufacture 
product of acceptable quality was established. 
• In 1996, the FDA and Congress dismantled the dual - licensing process, requiring 
the submission of a single BLA (biologics license application), making the 
content and format of a biologics application similar to that required for new 
drug applications (NDAs). 
• In 1996, the Center for Biologics Evaluation and Research (CBER) liberalized 
its defi nition of “ legal manufacturer ” and eliminated many of the barriers to 
cooperative, multiparty manufacturing arrangements. 
• In 1997, Congress passed a noteworthy piece of legislation affecting modern 
pharmaceutical regulation in the Food and Drug Modernization Act (FDAMA). 
Among the many goals of the act was to harmonize the drug and biologic 
approval processes. 
In fact, current pharmaceutical/regulatory initiatives appear to extract the best 
practices from biologic and drug approaches which can apply equally to both classes 
of products: 
• The Quality Systems Approach and GMPs for the 21st Century, two initiatives 
being pursued by the FDA for drugs and devices, emphasize the utility of building 
quality into the process, consistent with the strict control of “ input factors ” 
seen in early biologic regulation. 
• Initiatives such as Process Analytical Technologies build on the concept of 
conventional drug product testing using increasingly sophisticated analytical 
techniques to provide continuous process monitoring and fi nished - product 
quality assurance of multiple pharmaceutical dosage forms. 
• The current global initiative to harmonize electronic submission format and 
content requirements effectively creates one standard data package for drugs 
or biologics. Thus, the eNDA (electronic new drug application) or eBLA (electronic 
biologics license application) will eventually be replaced by the eCTD 
(electronic common technical document). 

40 REGULATORY CONSIDERATIONS IN APPROVAL 
1.2.3 REGULATORY CLASSIFICATION OF PROTEINS 
Despite the blurring of lines between drugs and biologics, there remain two different 
mechanisms to bring protein drug products to the U.S. marketplace. The choice of 
approval framework is dependent on the protein ’ s classifi cation as a drug or biologic. 
The history of this regulatory distinction is rooted in the technical differences 
between small - molecule drugs and macromolecular biologics. Traditionally, drugs 
were characterized as having well - defi ned chemistry. Conversely, biologics were 
large, complex macromolecules whose active moiety defi ed characterization and 
quantitation. By necessity, different means of assuring the safety and effi cacy of 
these therapeutic products were required at the time. The modern - day consequence 
is a legal system that distinguishes between proteins as drugs and proteins as biologics. 
The distinction is based on statutory defi nitions as well as historical precedent 
and has implications in terms of the approval pathways for original and follow - on 
products. 
1.2.3.1 Defi nitions and Key Terminology 
Drugs are defi ned by the U.S. Food and Drug Act [FD & C Act, 21 U.S.C. 321(g)(1)] by 
function as any article Federal Food, Drug and Cosmetic Act (a) intended for use 
in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or 
animals and (b) intended to affect the structure or function of the body [11] . 
Biologics as a class may be regulated as drugs but are defi ned within the Public 
Health Service Act [PHSA, 42 U.S.C. 262(a)] by category as “ a virus, therapeutic 
serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic 
product, or analogous product, or arsphenamine (or any other trivalent organic 
arsenic compound), applicable to the prevention, treatment, or cure of diseases or 
injuries of humans ” [12] . 
A cursory examination of these defi nitions reveals that they are not mutually 
exclusive, leading to confusion about how to appropriately and consistently 
apply them. This point is illustrated when one reviews the history of how the FDA 
has categorized and subsequently regulated these drugs and biologics as shown 
below. 
1.2.3.2 Application of Defi nitions to Proteins: Is It a Drug or a Biologic? 
The answer to this fundamental question is not straightforward and has evolved 
over time. Historically, some natural - source - derived proteins such as insulin, hyaluronidase, 
menotropins, and Human Growth Hormone (HGH) have been regulated 
as drugs. While other natural - source - proteins such as blood factors were regulated 
as biologics. When recombinant proteins and monoclonal antibodies began development 
in the 1970s – 1980s, these were regulated as follows: 
1. By the Center for Drug Evaluation and Research (CDER) under the Food, 
Drug and Cosmetic Act (FDCA) as drugs when they were hormones such as 
insulin, HGH, and parathyroid hormone (PTH) derivatives 
2. By the CBER under the PHSA as biologics when they were cytokines or blood 
factors such as factor VIII for hemophilia 

As other recombinant proteins and monoclonal antibodies came under development, 
the CBER held primary responsibility for this review, with the CDER retaining 
responsibility for hormones such as insulin and HGH. However, in 2003 all 
therapeutic proteins were transferred from the CBER to the CDER. This reassignment 
of review responsibility did not impact the legal classifi cation of these protein 
products, such that the Center for Drug Evaluation and Research assumed responsibility 
for the review and approval of biologics approved under Section 351 of the 
PHSA. 
The basic distribution of these therapeutic biologics to the respective FDA center 
is refl ected in Table 4 ; however, many of the current complex biotechnology - derived 
products do not fi t neatly into accepted defi nitions and require case - by - case classi- 
fi cation [13] . 
1.2.3.3 Regulatory Approval Path for Proteins 
The relevance of the preceding discussion becomes important with the understanding 
that therapeutic proteins classifi ed as drugs are governed under a different set 
of laws than those classifi ed as biologics. Drugs are approved via submission of 
NDAs under Section 505 of the FD & C Act, while biologics are supported by BLAs 
under the PHSA. These two approval paths are similar in terms of application 
content, that is, requirement of complete reports of clinical safety and effi cacy data 
to support approval. However, only the drug regulation, that is, Section 505 of the 
FD & C Act, has been amended to outline an abbreviated approval mechanism for 
generic products. 
1.2.4 REGULATION OF GENERIC DRUGS 
1.2.4.1 History of Generic Drug Legislation in United States 
In 1984, Congress responded to America ’ s need for safe, affordable medicines by 
passing a pivotal piece of legislation, The Drug Price Competition and Patent Term 
TABLE 4 FDA Center Regulatory Responsibility for Therapeutic Biological Products 
CDER CBER 
Monoclonal antibodies (in vivo use) 
Proteins intended for therapeutic use: 
Cytokines (e.g., interferons) 
Enzymes (e.g., thrombolytics) 
other novel proteins except those assigned to 
CBER 
Immunomodulators (nonvaccine, nonallergenic) 
Growth factors, cytokines, some hormones and 
monoclonal antibodies intended to mobilize, 
stimulate, decrease, or otherwise alter the 
production of hematopoietic cells in vivo 
Cellular product, including products 
composed of human, bacterial, or 
animal cells 
Vaccines 
Allergenic extracts 
Antitoxins, antivenoms, venoms 
Blood, blood components, plasma - 
derived products (e.g., albumin, 
immunoglobulins, clotting factors, 
fi brin sealants, proteinase inhibitors), 
recombinant and transgenic versions 
of plasma derivatives 
REGULATION OF GENERIC DRUGS 41

42 REGULATORY CONSIDERATIONS IN APPROVAL 
Restoration Act (Hatch – Waxman amendments). The intent of this act was to effectively 
balance the need to encourage pharmaceutical innovation with the desire to 
accelerate the availability of lower cost alternatives to approved drugs. The act also 
sought to eliminate unnecessary or redundant clinical testing to protect patients 
(reduce the number of patients in need receiving placebo in controlled clinical 
trials) and conserve industry and agency resources. To accomplish the goal of faster 
to market, cheaper alternatives, the amendments stipulated the following [14] : 
• For Innovator Companies The act encouraged continued innovation, research, 
and development activities by providing manufacturers with meaningful incentives 
in the form of patent protection/restoration and marketing exclusivity, 
thus allowing them to recoup some of their investments. 
• For Generic Companies The act provided access to certain innovator information 
without the threat of legal action via patent infringement suits (safe harbor 
provisions), allowing generics the opportunity to prepare for market introduction 
prior to the expiration of patent/exclusivity terms. This effectively limited 
the period of innovator exclusivity to the statutory timelines. 
1.2.4.2 Approval Process for Generic Drugs 
The act served as a boon to the generic industry by paving the path to abbreviated 
and accelerated drug approvals. From a legal perspective, the Hatch – Waxman 
amendments modifi ed Section 505 of the FD & C Act to create two new abbreviated 
approval pathways (see Table 5 ) [14] . 
In essence, the abbreviated NDA (ANDA) and 505(b)(2) processes allow generic 
manufacturers the ability to rely on what is already known about the drug and refer 
to the agency ’ s fi nding of safety and effi cacy for the innovator. For an ANDA, the 
generic product must meet certain criteria related to bioequivalence and product 
sameness. However, a 505(b)(2) application often describes a drug with substantial 
differences to the innovator (which would seem more closely related to FOPs). 
1.2.4.3 Application of Generic Regulations to Biologics 
A central question is “ Do biologics fall under the provisions of the Hatch – Waxman 
Act? ” Since the Hatch – Waxman Act specifi cally amended the FD & C Act, biologics 
TABLE 5 Description of NDA Approval Mechanisms 
Traditional path 1. 505(b)(1) — Application that contains full reports of investigations 
of safety and effectiveness to which sponsor has right of reference 
(stand - alone NDA) 
Abbreviated path 2. 505(b)(2) — Application that contains full reports of investigations 
of safety and effectiveness, where the sponsor relies on studies 
conducted by someone else to which the sponsor does not have 
right of reference 
Abbreviated path 3. 505(j)(1) — Abbreviated new drug application (ANDA) containing 
information to show the product is a duplicate of an already 
approved drug product 

approved via a BLA under the PHSA are not covered by this legislation nor does 
the PHSA have similar provisions for biogenerics. However, those few therapeutic 
proteins approved via Section 505 of the FDCA as NDAs are covered by the 
Hatch – Waxman amendments and thus are legally considered appropriate for fi ling 
a 505(b)(2) or 505(j)(1) application. For simple, well - characterized peptides and 
proteins regulated under Section 505 of the FD & C Act, mechanisms are already in 
place to bring FOPs to the market. In fact, several FOPs have already been approved 
by the FDA, including GlucaGen (glucagon recombinant for injection), Hylenex 
(hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), Fortical 
(calcitonin salmon recombinant) Nasal Spray, and Omnitrope [somatropin 
(rDNA origin)] [15] . Further details related to the latter two are presented in the 
discussion of actual case studies. 
1.2.5 LEGAL ARGUMENTS RELATED TO FOLLOW - ON PROTEINS 
The legal arguments regarding the approval of biogenerics relate to several different 
aspects of drug/biologics law. 
1.2.5.1 Constitutionality of 505(b)(2) Process for Drugs 
The agency ’ s authority to grant approval of drugs via the 505(b)(2) process has 
previously been challenged by several companies. The nature of these challenges 
has questioned the FDA ’ s right to use proprietary information of the innovator in 
support of another company ’ s drug approval. Recall that the 505(b)(2) process 
allows a company to use data for which it does not have right of reference (i.e., 
another company ’ s safety and effi cacy data) in support of its own application. The 
FDA ’ s long - standing interpretation of the statute seems fi rm and well founded in 
precedent since over 80 applications for drugs have been approved via the 505(b)(2) 
route since its inception with indications ranging from cancer pain to Attention 
Defi cit Disorder (ADD) [16] . 
1.2.5.2 Constitutionality of 505(b)(2) Process for Follow - On Proteins 
The constitutionality issues related to FOPs are similar to those mentioned above 
for drugs, namely protection of proprietary information and intellectual property 
rights. Some critics opine that issues unique to FOPs create additional legal hurdles. 
For example, the rules pertaining to the disclosure of safety and effectiveness information 
are different for biologics licensed under the PHSA and drugs approved 
under the FDCA. When the rules were originally written (1974), it was thought that 
safety and effectiveness for one biologic would not support the licensure of another. 
So these data were deemed not to be protected trade secrets and could be publicly 
disclosed immediately after issuance of the biologic ’ s license [see 21 CFR 601.51(e), 
1974]. However, since this language applies strictly to the PHSA, it has no bearing 
on discussions related to the 505(b)(2) process. 
In other public challenges, opponents argue that the unique and complex nature 
of biologics and the close relationship between their method of preparation and 
clinical attributes require that the FDA use and disclose the manufacturing methods 
LEGAL ARGUMENTS RELATED TO FOLLOW-ON PROTEINS 43

44 REGULATORY CONSIDERATIONS IN APPROVAL 
and process information contained in an innovator ’ s application. Further, this use 
and disclosure would violate Trade Secret and Constitutional Law (Fifth Amendment 
“ taking clause ” ) [17, 18] . 
The concept of “ the product is the process ” may have been applicable to early 
biologics, but current capabilities allow the chemical, biologic, and functional comparison 
of well - characterized protein drugs. The follow - on manufacturer need not 
necessarily utilize the identical method of manufacture or proprietary technology 
to reproduce a follow - on biologic with similar clinical safety and effi cacy. Additionally, 
it is important to distinguish between the regulatory requirements for approval 
of an actual generic protein (duplicate of innovator; see discussion below) and those 
associated with a 505(b)(2), which requires a showing of similarity between two 
products. Any differences between the two would need to be adequately supported 
by bridging studies and appropriate clinical and/or nonclinical data. 
The FDA has confi rmed this interpretation in its response to petitions fi led 
regarding FOPs (both in general and targeted to specifi c applications). The FDA 
has clearly said, “ the use of the 505(b)(2) pathway does not entail disclosure of trade 
secret or confi dential commercial information, nor does it involve unauthorized 
reliance on such data ” [18] . 
1.2.5.3 Applicability of 505(j)(1) or ANDA Process to Biogenerics 
Biogenerics per se, that is, protein drug products approved via 505(j)(1), would need 
to demonstrate their bioequivalence to the innovator protein. However, due to their 
complexity and heterogeneity, the classical biopharmaceutical principles upon which 
the current ratings of therapeutic equivalence are based do not apply in their current 
language to complex macromolecules. For example, due to the nature and complexity 
of an immunogenic response, one concern would be if traditional bioequivalence 
appropriately addresses the complex safety issues associated with biologics. 
1.2.5.4 Current Rules Relating to Bioequivalence of Generic Drugs 
The list of approved drug products with therapeutic equivalence (Orange Book) 
was originally intended as an information source to states seeking formulary guidance 
[19] . The list provides the FDA ’ s recommendations as to which generic prescription 
drug products are acceptable substitutes for innovator drugs. The term 
innovator is used to describe the reference listed drug, or RLD [21 CFR 314.94(a)(3)], 
upon which an applicant (generic) relies in seeking approval of its ANDA. In layman 
’ s terms the RLD describes the original NDA - approved drug and is often 
referred to as the “ pioneer ” drug. 
Under the Drug Price Competition and Patent Term Restoration Act of 1984, 
manufacturers seeking approval to market a generic drug need to submit data to 
the FDA demonstrating that their proposed drug product is bioequivalent to the 
pioneer (innovator) drug product. A major premise underlying the 1984 law is that 
bioequivalent drug products are therapeutically equivalent, will produce the same 
clinical effect and safety profi le as the innovator product, and are therefore, interchangeable 
[19] . 
So how would FOPs be classifi ed using conventional defi nitions of bioequivalence? 
To answer this question, it is necessary to review current legal defi nitions of 
bioequivalence terms [19] : 

• Two products are bioequivalent in “ the absence of a signifi cant difference in the 
rate and extent to which the active ingredient or active moiety in pharmaceutical 
equivalents or pharmaceutical alternatives becomes available at the site of drug 
action when administered at the same molar dose under similar conditions in an 
appropriately designed study ” [21 CFR 320.1(e)]. An appropriately designed 
comparison could include (1) pharmacokinetic (PK) studies, (2) pharmacodynamic 
(PD) studies, (3) comparative clinical trials, and/or (4) in vitro studies. 
• Pharmaceutical equivalents are those drug products which are formulated to 
contain the same amount of active ingredient in the same dosage form to meet 
the same (compendial or other applicable) standards of quality. 
• Pharmaceutical alternatives are drug products that contain the same therapeutic 
moiety, or its precursor, but not necessarily in the same amount or dosage form. 
Drug products are considered to be therapeutic equivalents only if they are 
pharmaceutical equivalents and if they can be expected to have the same clinical 
effect and safety profi le when administered to patients under the conditions 
specifi ed in the labeling. Although pharmaceutical alternatives may ultimately 
be proven bioequivalent, given their differences they are not automatically 
presumed to be. 
Given these defi nitions, FOPs would likely be considered pharmaceutical alternatives 
if one presumes that pioneer and follow - on proteins are identical at a precursor 
stage, prior to potential post - translational modifi cation. This presumption may also 
be consistent with the similarity standard the agency applies to ascertain orphan 
drug status (see discussion in Section 1.2.6 ). Follow - on proteins cannot be considered 
to be therapeutic equivalents since they are not pharmaceutical equivalents 
and cannot be expected to have the same clinical effect and safety profi le in the 
absence of testing. This assertion is supported by the following: 
• The potential impact of how posttranslational modifi cations, such as glycosylation, 
can directly impact protein conformation and subsequently affect biological 
activity, including the overall safety and effi cacy of the drug product. 
• An underlying premise of bioequivalence assessments is a clearly defi ned pharmacokinetic/
pharmacodynamic relationship; however, the relation between 
blood levels and effect is less clearly established for proteins [20] . 
Consequently, within the current regulatory framework, FOPs are unique products 
that may be “ similar ” but are not the same as innovator proteins, consistent with 
their approval via a 505(b)(2) pathway. This interpretation is supported by the 
FDA ’ s designation of Omnitrope as having a BX rating in the Orange Book. The 
code BX in the Orange Book refers to drug products for which the data are insuf- 
fi cient to determine therapeutic equivalence as compared to a therapeutic rating of 
A indicative of interchangeability. This concept of similarity is also consistent with 
the defi nitions proposed by the European Agency for the Evaluation of Medicinal 
Products (EMEA) for generic versions of proteins [21] : 
Bio - similar products: second and subsequent versions of biologics that are independently 
developed and approved after a pioneer has developed an original version. 
Bio - similar products may or may not be intended to be molecular copies of the innovator 
’ s product; however, they rely on the same mechanism of action and therapeutic 
indication. 
LEGAL ARGUMENTS RELATED TO FOLLOW-ON PROTEINS 45

46 REGULATORY CONSIDERATIONS IN APPROVAL 
1.2.5.5 Statutory Authority 
Unlike the FDCA, which affords therapeutic protein drugs the legal pathway of 
abbreviated drug approval for a FOP, the PHSA currently has no similar provisions. 
Such a pathway for approval or licensure of FOP products under the PHSA would 
require new legislation and recent congressional developments suggest that work is 
underway to create this statutory pathway. 
Legislation proposed on September 29, 2006, by U.S. Representative Henry 
Waxman (D - CA) and Senator Charles Schumer (D - NY) seeks to amend the PHSA 
to authorize the FDA to approve abbreviated applications for biologic products that 
are “ comparable ” to previously approved (brand name) biologic products. Entitled 
The Access to Life - Saving Medicine Act, this bill outlines a process by which the FDA 
could determine, on a product - by - product basis, the studies necessary to demonstrate 
comparability of a FOP product to a brand name product and assure its safety and 
effectiveness. The act allows for an applicant to seek interchangeability with a brand 
name product, recognizing that the extent of data to support such a designation must 
be discussed with the FDA. To encourage the development of interchangeable products, 
the bill would authorize tax incentives and periods of marketing exclusivity. The 
bill would also seek to create an improved process to facilitate early resolution of 
patent disputes which might otherwise delay competition [22] . 
1.2.6 SCIENTIFIC ISSUES RELATED TO FOLLOW - ON PROTEINS 
(DATA REQUIREMENTS) 
The challenge of FOPs demonstrating similar quality, safety, and effi cacy to the 
innovator product relates to the poor predictability of physicochemical characteristics 
and biologic activity. For example, there are several different interferon - . and 
erythropoietin . and . products currently on the market. These variants are characterized 
by differences in sequence, glycosylation pattern, and in vitro measures of 
specifi c activity; however, their clinical safety and effi cacy profi les are considered 
similar [20] . 
In contrast, different formulations of insulin and growth hormone containing the 
same active ingredient exhibit signifi cant differences in bioavailability [20] . Additionally, 
the inability to adequately predict immunogenic responses from in vitro 
data or animal studies remains a concern. 
The answer to the challenge is that generic manufacturers must go through a 
similar process of in - depth characterization, including identifi cation of critical structural 
elements of the product (structure/function) when developing a FOP. Although 
the regulatory standards for demonstrating similarity are currently undefi ned, some 
insight can be gleaned from consideration of FDA expectations in terms of granting 
orphan drug status to similar proteins and assessing postapproval Chemistry, Manufacturing 
and Controls (CMC) changes for innovator proteins. 
1.2.6.1 “ Sameness ” as per Orphan Drugs Regulations 
The Orphan Drug Act of 1983 was implemented in response to the government ’ s 
concern that viable treatments for rare diseases were not being explored due to 
excessive costs of drug development in comparison to the relatively small popula

tion of potential users (and sales). Orphan drugs are (a) those used to treat rare 
diseases, defi ned by the act as affecting < 200,000 persons in the United States, or 
(b) those drugs whose development costs would not be recovered through sales of 
the drug. To encourage development, the government authorized incentives in the 
form of marketing exclusivity (seven years), tax credits, protocol assistance, and 
grants/contracts, with the fi rst being of primary importance to most drug sponsors. 
Since exclusivity is awarded only to the fi rst designated product to obtain approval 
for a given drug/indication, competition is fi erce. No approval would be given to a 
subsequent sponsor ’ s application for the same product/indication unless it was 
shown to be clinically superior (i.e., not the same). Thus, the agency needed to 
develop criteria upon which it would make these determinations. 
In 1992, the FDA ’ s orphan drug regulations fi rst established the conditions under 
which the agency could determine product “ sameness ” of protein drugs and therefore 
take action to block the approval of a second orphan drug product: “ two protein 
drugs would be considered the same if the only differences in structure between 
them were due to post - translational events, or infi delity of translation or transcription, 
or were minor differences in amino acid sequence; other potentially important 
differences, such as different glycosylation patterns or different tertiary structures, 
would not cause the drugs to be considered different unless the differences were 
shown to be clinically superior ” [23] . It should be noted that there may exist exceptions 
to this rule that depend on the interpretation of each individual case. For 
example, Eli Lilly & Co. successfully received orphan drug status in the late 1980s 
for the naturally occurring HGH to compete with the previously marketed Met - 
HGH, which only differed in the N - terminal methionine. 
The support for clinical superiority could be based on evidence of greater effectiveness 
and increased safety or represent a “ major contribution to patient care. ” In 
short, orphan drug regulations utilize clinical data to demonstrate product differences. 
Examples include [23] : 
• 1996: Biogen ’ s Avonex (interferon . ) was considered to be clinically superior to 
Berlex ’ s Betaseron based on improved safety (fewer site injection reactions). 
• 1999: In a law suit involving generic paclitaxel, Baker Norton, challenged the 
FDA ’ s sameness determinations based on active moiety alone, arguing that 
factors such as formulation and labeling should be considered. The challenge 
was unsuccessful. 
• 2002: Serono ’ s Rebif (interferon .1a ) was awarded exclusivity based on the 
clinical demonstration of improved effi cacy (reduced Multiple Sclerosis (MS) 
exacerbations). 
Therefore, it would appear that the orphan drug regulations provide some fl exibility 
to the sponsor (generic) in establishing product sameness but also reaffi rm the 
important role of clinical data in supporting product safety and effi cacy. 
1.2.6.2 “ Sameness ” as per Postapproval Change Guidances 
Guidelines for supporting postapproval changes to the chemistry, manufacturing, 
and controls of approved products (SUPAC guidances) take a somewhat different 
approach to establishing sameness. In essence, the SUPAC guidelines refl ect risk 
SCIENTIFIC ISSUES RELATED TO FOLLOW-ON PROTEINS 47

48 REGULATORY CONSIDERATIONS IN APPROVAL 
management practices in evaluating the potential of certain CMC changes to impact 
the identity, strength, quality, purity, and potency of the product as they may relate 
to overall safety and effi cacy. 
A long - held contention within the biologics industry is that the product is the 
process and, by extension, change is strongly discouraged. Without qualifi cation, this 
rather dated thinking is inconsistent with the fl exibility required in managing change 
throughout the life cycle of a product. Further, this thinking may serve to discourage 
the implementation of advanced technologies designed to improve not only effi - 
ciency but also product quality. Even current biologics regulations recognize 
the need to accommodate change; 21 CFR 601.12 (for biologics) states that for 
changes in the product, production process, quality controls, equipment, facilities, 
and so on, an applicant must assess the effects of the change and demonstrate 
through appropriate validation and/or other clinical and/or nonclinical laboratory 
studies the lack of adverse effect of the change on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or effectiveness of 
the product. 
In fact, many of the challenges that generic manufacturers face in demonstrating 
sameness of FOPs to reference listed drugs are similar to those encountered by 
innovators in managing the dynamic CMC life cycle of a product. One of the tools 
available to assess the potential impact of product differences is a comparability 
protocol. The FDA described its expectations of the data requirements necessary 
to support postapproval CMC changes to protein drug product and biologic products 
in a Guidance to Industry on the use of comparability protocols for such products 
issued in 2003 [24] . Underpinning the successful application of a comparability 
protocol are extensive product development and characterization. 
Initial Product Development Prior to undertaking any comparative analysis, a 
manufacturer must perform two critical steps. First, the manufacturer needs to 
conduct thorough process development and optimization of the therapeutic protein 
product. Second, the sponsor (generic or innovator) needs to prospectively examine 
the impact of changes to all critical processing parameters during the development 
phase and determine the minimum data requirements necessary to assure the 
absence of adverse impact to product quality, safety, or effi cacy. The current state 
of technology provides us with better tools to more fully characterize the protein 
drug substance and drug product at all stages of production. 
Physicochemical Characterization and Process Development Some of the key steps 
to process development and product characterization include: 
• Production of a cell line/clone 
• Identifi cation and characterization of critical raw materials (media, resins, 
formulation excipients) 
• Development of internal standards, in - process controls, product 
specifi cations 
• Conduct of extensive pilot - scale manufacturing development: fermentation and 
downstream processing (separation and purifi cation) 
• Performance of process scale - up and optimization studies 

• Application of a comprehensive array of analytical techniques to fully characterize 
the drug product at each stage of development. Table 6 provides examples 
of methods to probe virtually every property of the protein and develop 
a fi ngerprint of the molecule. 
Other Testing Requirements The need for additional supportive studies beyond 
physicochemical characterization will increase proportionately with the complexity 
of the protein drug. The entire battery of tests may not be required for each FOP 
but may include the following data, bioassay, preclinical (pharmacology/toxicology/ 
pharmacokinetic/pharmacodynamic), clinical safety and effi cacy, and immunogenicity. 
The nature, number, and size of the trials should relate directly to the particular 
drug/indication/patient population. 
Bioassay A biological assay, or “ bioassay, ” is an analytical procedure capable of 
measuring the biologic activity of a substance based on a specifi c functional, biologic 
TABLE 6 Analytical Techniques for Physicochemical Characterization of Proteins 
Parameter Test 
Primary structure Amino acid sequencing, N - terminal Edman 
sequencing, peptide mapping 
Higher order structure CD, NMR, FTIR, Raman 
Mass LC - ESI - MS, MALDI - TOF - MS 
Size SDS - PAGE, DLS, SEC - MALLS 
Hydrophobicity RP - HPLC 
Binding Immunological binding 
Sulfhydryl groups/disulfi de bridges Peptide mapping (under reducing and nonreducing 
conditions) 
Glycan analysis: 
Monosaccharide analysis HPLC, MS 
Sialic acid content HPLC 
Molecular weight MALDI - MS, ESI - MS 
Impurity profi le 
Process - related impurities Immunoassay, HPLC, SDS - PAGE, MS, CD, capillary 
gel electrophoresis, size exclusion chromatography • Cell substrate derived 
• Cell culture derived 
• Downstream derived 
Product - related impurities 
• Truncated forms 
• Other modifi ed forms (i.e., 
deamidated, isomerized) 
• Aggregates 
Evaluation of stability HPLC 
CD, Circular Dichroism; NMR, Nuclear Magnetic Resonance; FTIR, Fourier transform infrared spectroscopy; 
LC - ESI - MS, Liquid chromatography electrospray ionisation mass spectrometry; MALDI - 
TOF - MS, Matrix - assisted laser desorption ionization - time of fl ight - mass spectrometry; SDS - PAGE, 
Sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis; DLS. Dynamic light scattering; SEC - 
MALLS, Size exclusion chromatography - multi - angle laser light scattering; RP - HPLC, Reversed phase - 
high performance liquid chromatography; HPLC, High performance liquid chromatography; MALDI - MS, 
Matrix - assisted laser desorption ionization mass spectrometry; ESI - MS, Electrospray ionisation mass 
spectrometry; MS, Mass spectrometry. 
SCIENTIFIC ISSUES RELATED TO FOLLOW-ON PROTEINS 49

50 REGULATORY CONSIDERATIONS IN APPROVAL 
response of the test system. Bioassays should be predictive of clinical effect and are 
therefore used as a means of quantifying activity (in nonclinical manner) and ensuring 
effi cacy throughout development. They are informative in equivalence studies 
to the extent that a change affects a part of the molecule, which in turn impacts the 
molecule ’ s biologic activity. Bioassays may be based on animal models, in vitro cell 
lines, cell - based biochemical assays (i.e., kinase receptor activity), receptor binding 
assays, or enzyme assays. The selection of an appropriate bioassay is driven in part 
by the ability to demonstrate a correlation to clinical effect. An example of a predictive 
bioassay is the measurement of the antiviral activity of interferon as a function 
of its cytopathic effect on host cells [25] . 
Nonclinical (Pharmtox, PK , PD ) In the context of FOPs, the original sponsor will 
have demonstrated what the molecule per se does to the body; however, since the 
formulation is likely different, nonclinical studies are useful in demonstrating a lack 
of adverse impact due to dosage form, route of administration, excipient changes, 
manufacturing contaminants, and supporting sameness of the active moiety. 
Appropriate toxicology studies would include acute or subchronic testing in at 
least one relevant small animal species. Pharmacokinetic studies are highly useful 
in assessing the impact of changes in the manufacture of natural - source - and 
recombinant - derived proteins. Standard approaches used in bioequivalence studies 
[measurement of the area under the curve (AUC), Cmax, tmax ] can be used to make 
direct comparisons of innovator and follow - on profi les. Pharmacodynamic studies 
are similarly very informative. Direct comparison of innovator and follow - on products 
can be made by evaluating appropriate surrogate markers of effi cacy (i.e., 
platelet aggregation following anticoagulation therapy). 
Clinical ( PK , PD , Safety and Effi cacy) Human clinical studies can range in complexity 
from standard - design PK studies to complicated, long - term effi cacy trials 
evaluating one or more indications in multiple populations. Human PK studies are 
used as the benchmark for establishing bioequivalence of conventional dosage 
forms. For traditional pharmaceuticals for which reliance on systemic exposure may 
not be suitable, PD or clinical safety and effi cacy may be performed to show 
equivalence. 
The appropriate clinical program is infl uenced by many factors, including the 
degree of molecular complexity of the particular protein and the extent of physicochemical 
characterization; the mode of action, indication(s), and use population(s); 
the presence of established structure – activity relationships and validated bioassays; 
and the results of preclinical testing. 
As such, the nature and scope of each clinical support program need to be determined 
on a case - by - case basis in consultation between the sponsor and the regulatory 
agency. 
Immunogenicity The observation of serious adverse events with the use of some 
recombinant and natural source proteins [i.e., pure red cell aplasia (PRCA) detected 
with erythropoietin use] has highlighted immunogenicity as a major issue for consideration 
when assessing within and between manufacturer changes [8] . Although the 
exact immunological mechanism responsible for the increased number of PRCA 
cases is unknown, it appears to be linked to a formulation change associated with 
Eprex, a European epoetin - . product. Replacement of the stabilizer human serum 

albumin with polysorbate 80 and glycine correlated with a surge in PRCA reported 
cases [4] . An immunogenic effect may have no clinical impact or it could have serious 
clinical consequences as seen above. The immune response of the therapeutic protein 
should be fully characterized using both immunoassays which detect antibodies that 
bind to the drug as well as bioassays which detect neutralizing antibodies that might 
block the protein ’ s desired biological effect. Ultimately, this testing needs to be performed 
in humans, as animal testing is not truly predictive of human immune response. 
Antibody detection techniques include enzyme - linked immunosorbent assay radioimmunoassay, 
(ELISA), and surface plasmon resonance [8] . 
Comparability Testing to Demonstrate “Sameness” Following the developmental 
studies described above, comparative studies to directly evaluate pre - and postchange 
materials to one another and assess the impact of any process changes may 
be conducted. In a similar manner, comparative studies between pioneer drug and 
the follow - on can be used to systematically evaluate the impact of any differences 
between reference listed drug and proposed generic protein drug. When compiling 
information into an analytical characterization database, the data should be directly 
compared to the reference product and variation observed in multiple batches 
of test product (generic) should be similar to that of the reference innovator 
product. 
The FDA ’ s expectations in this regard are apparent in their description of the 
CMC data package supporting the comparability of Omnitrope to the innovator 
protein Genotropin. The FDA asserted [18] : 
Each biotechnology manufacturer, whether producing a new molecular entity or a 
follow - on product must independently develop its own cell expression, fermentation, 
isolation and purifi cation systems for the active ingredient in its product. Thus, the 
manufacturing process for each active ingredient is unique to each manufacturer. Nevertheless, 
as Sandoz has demonstrated in its Omnitrope application, for this relatively 
simple recombinant protein, it is possible to determine that the end products of different 
manufacturing processes are highly similar, without having to compare or otherwise 
refer to the [proprietary] processes. 
1.2.7 PROPOSED REGULATORY PARADIGM: CASE STUDIES 
Based on the nature and complexity of therapeutic protein products, an approval 
pathway for follow - ons may require moving away from the traditional generic paradigm 
in place for small molecules and creating a biosimilar paradigm for complex 
molecules. The proposed regulatory paradigm for the approval of FOP products 
could be similar for protein drugs approved under Section 505 of the FDCA or 
licensed as biologics under the PHSA and mirror the current 505(b)(2) process. This 
pathway permits the sponsor and agency to determine exactly what studies are 
necessary to support the proposed differences (see 21 CFR 314.54(a) [ “ a 505(b)(2) 
application need contain only that information needed to support the modifi cation(s) 
of the listed drug ” ]. Application of a 505(b)(2) paradigm removes the need to demonstrate 
bioequivalence per se and potentially reduces innovator intellectual property 
concerns that arise if a generic must “ duplicate ” the innovator. Guidance as to 
how similar a “ biosimilar ” needs to be exists in the form of current regulations 
related to orphan drugs and postapproval manufacturing changes. 
PROPOSED REGULATORY PARADIGM: CASE STUDIES 51

52 REGULATORY CONSIDERATIONS IN APPROVAL 
Several recent drug approvals illustrate how this regulatory framework may be 
applied and are described in the sections to follow. 
1.2.7.1 Case Study 1: Fortical [Calcitonin - Salmon ( r DNA origin)] 
On August 17, 1995, the FDA approved Novartis ’ s NDA for Miacalcin (calcitonin - 
salmon) Nasal Spray (Miacalcin NS) for the treatment of postmenopausal osteoporosis 
in females greater than fi ve years postmenopause with low bone mass relative 
to healthy premenopausal females. The active ingredient in Miacalcin NS is synthetic 
salmon calcitonin. On March 6, 2003, Unigene submitted a new drug application 
under Section 505(b)(2) for Fortical [calcitonin - salmon (rDNA origin)] Nasal 
Spray which relied in part on data submitted in the Miacalcin NS NDA. 
Comparability Program Fortical and Miacalcin NS differed in certain aspects, 
such as the use of recombinant versus synthetic salmon calcitonin and the use of 
different types and amounts of excipients. Given these differences, Unigene was 
required to submit data to establish that the fi ndings of safety and effi cacy for Miacalcin 
were relevant to Fortical (i.e., contain the same active ingredient and have 
comparable bioavailability) and that the formulation differences did not impact 
previous clinical profi le [26, 27] . 
Comparability Results 
Physicochemical Analysis Salmon calcitonin is a 32 - amino - acid, nonglycosylated 
peptide hormone. It is structurally simple, possessing limited secondary structure 
and a single disulfi de bond. The physicochemical characterization studies demonstrated 
that the primary and secondary structure of Fortical ’ s recombinant salmon 
calcitonin (sc) was identical to that of Miacalcin ’ s synthetic sc or naturally occurring 
sc. Further, the tertiary structures of the three were indistinguishable. 
Nonclinical PK / Tox The pharmacokinetic profi le of Fortical by different routes of 
administration was compared to Miacalcin, demonstrating similarity in PK profi les 
between the synthetic and recombinant peptides and toxicity results (28 - day rat 
intranasal toxicity study) were acceptable, particularly in light of clinical safety 
data. 
Clinical PK / PD Calcitonin has a well - established mechanism of action; published 
literature supports that salmon calcitonin, mediated through calcitonin receptors 
located on osteoclasts, inhibits bone resorption, thereby increasing bone mineral 
density. Since serum beta - CTx (C - telopeptides of type 1 collagen, corrected for 
creatinine) is a recognized marker of bone resorption, the effect of administered 
salmon calcitonin on serum beta - CTx is considered to be an adequate surrogate for 
pharmacodynamic comparisons. 
Fortical ’ s PD equivalence was shown in a double - blind, active - controlled, 24 - 
week study in 134 postmenopausal women randomized to Fortical (200 IU per day) 
or Miacalcin (200 IU per day). The primary outcome measure was change in serum 
beta - CTx from baseline. The results fell within prespecifi ed PD equivalence limits 
(. 0.08 to 0.06 ng/mL; equivalence margin of ± 0.2 ng.mL) and indicated Fortical was 
not inferior to Miacalcin. 

Fortical ’ s PK equivalence was assessed by comparing the relative bioavailability 
of Fortical to Miacalcin in a multidose, crossover study of 47 healthy female volunteers. 
Results indicated that Fortical was slightly more bioavailable than Miacalcin, 
but given the demonstration of similar PD activity, this difference were not considered 
to be clinically signifi cant. 
Immunogenicity Archived samples from the 24 - week PD study were used to 
compare the immunogenicity potential of both products. The results indicated there 
was no difference in terms of total immune response and the response of neutralizing 
antibodies between the two drugs. 
Conclusion to Case Study 1 On August 12, 2005, the FDA approved Unigene ’ s 
505(b)(2) application for Fortical for the same indication as Miacalcin NS [26, 27] . 
In the FDA ’ s analysis no statistically and/or clinically signifi cant differences were 
noted in any aspect of the comparability profi le, including clinical performance, and 
Fortical was approved. 
The basis of this comparison was strongly challenged in a citizen petition claiming 
that (1) recombinant salmon calcitonin is not the same as the synthetic version 
which could potentially cause differences in product effi cacy, safety, or both and 
(2) only a long - term clinical study (actual bone fracture data) would provide adequate 
support of sameness [28] . The FDA responded to this citizen petition by 
asserting its decision that the comparability data presented above collectively constituted 
suffi cient demonstration of sameness [27, 29] . 
1.2.7.2 Case Study 2: Omnitrope [Somatropin ( r DNA origin)] 
On August 24, 1995, the FDA approved NDA20 - 280 fi led by the Pharmacia & 
Upjohn Company for Genotropin (somatropin) (rDNA origin) for injection. Since 
that time, Genotropin has been marketed as a safe and effective therapy for growth 
hormone defi ciency (GHD) in children and adults. 
On July 30, 2003, Sandoz submitted a 505(b)(2) application for the approval of 
its recombinant HGH product (recombinant somatropin) indicated for long - term 
treatment of pediatric patients who have growth failure due to an inadequate secretion 
of endogenous growth hormone and for long - term replacement therapy in 
adults with GHD of either childhood or adult onset. This application relied in part 
on data submitted in the Genotropin NDA. 
Comparability Program As with the Fortical case study, Omnitrope and Genotropin 
differed in certain aspects. As such, Sandoz was required to submit substantial 
data to establish that Omnitrope was suffi ciently similar to Genotropin to warrant 
reliance on FDA ’ s fi nding of safety and effectiveness for Genotropin to support the 
approval of Omnitrope [18] . 
Comparability Results 
Physicochemical Analysis In terms of complexity, HGH is fairly simple and well - 
characterized. Human growth hormone is a single - chain, 191 - amino - acid, nonglycosylated 
protein with two intramolecular disulfi de bonds. Sandoz used a variety of 
physicochemical tests and analytical methods to confi rm the primary, secondary, and 
PROPOSED REGULATORY PARADIGM: CASE STUDIES 53

54 REGULATORY CONSIDERATIONS IN APPROVAL 
tertiary structures, molecular weight, and impurity profi le. Characterization studies 
performed to verify somatropin as the active ingredient in Omnitrope included 
reverse - phase liquid chromatography/mass spetrometry (RP - HPLC/MS), DNA 
sequencing, N - terminal and C - terminal sequencing, peptide mapping, circular 
dichroism (CD) analysis, UV spectroscopy, one - dimensional nuclear magnetic 
resonance spectroscopy (1D NMR), two - dimensional (2D) NMR, size exclusion 
chromatography (SEC), isoelectric focusing (IEF), sodium dodecyl sulfate polyacrylamide 
gel electrophoresis (SDS – PAGE), and capillary zone electrophoresis. 
Nonclinical PK / Tox Minimal toxicity data were needed on recombinant HGH 
(rHGH) itself, since the clinical effects of HGH excess are well established and 
understood and are extensively documented in published literature. Sandoz performed 
toxicity studies to appropriately qualify impurities specifi c to Omnitrope, 
that is, a subacute 14 - day rat study and a local (skin) tolerance study in rabbits. 
Further, the bioactivity of Omnitrope was assessed using a validated weight gain 
bioassay using a hypophysectomized (growth - hormone - defi cient) rats. 
Clinical PK / PD HGH has a well - established mechanism of action. Omnitrope was 
demonstrated to be pharmacokinetically and pharmacodynamically “ highly similar ” 
to Genotropin. The dataset comprised a total of three PK/PD studies, including a 
double - blind, randomized, two - way crossover study comparing Omnitrope and 
Genotropin. Additionally, Sandoz conducted three sequential, multicenter phase 3 
pivotal trials in 89 pediatric patients with GHD providing data in some patients for 
up to 30 months. A fourth phase 3 trial ( n = 51, 24 months) was submitted as part 
of its safety update. Collectively, these data in conjunction with the demonstrated 
comparability to the reference listed product provide substantial evidence of Omnitrope 
’ s safety and effectiveness. 
Immunogenicity A signifi cant number of patients who were administered an 
earlier version Omnitrope developed anti – growth hormone antibodies during the 
fi rst and second phase 3 clinical trials. In response, Sandoz implemented changes to 
the drug product to address this immunogenicity and evaluated the impact of these 
changes clinically. Data from the 24 - month clinical study demonstrated that Omnitrope 
has a low and acceptable level of immunogenicity (comparable to other 
rHGH products) as none of the patients developed anti – growth hormone antibodies 
during the duration of the study and only one patient developed anti – host cell 
protein antibodies, which were of no detectable clinical consequence. 
Conclusion to Case Study 2 This case provoked signifi cant challenges from interested 
parties voiced via several citizen petitions [18] . Furthermore, the FDA ’ s delay 
in approval prompted Sandoz to fi le suit to compel the FDA to rule on its application. 
On April 10, 2006, the Washington, D.C., District Court ruled that the FDA 
must meet its statutory obligations and take action on Sandoz ’ s outstanding NDA [6] . 
On May 30, 2006, the FDA approved Omnitrope [somatropin (rDNA origin)] as a 
“ follow - on protein product ” for use in the treatment of pediatric GHD. At the same 
time, the FDA responded to the related citizen petitions and defended its position 
that the data were adequate to demonstrate that Omnitorpe was suffi ciently similar 
to Genotropin to enable reliance on the agency ’ s previous fi ndings of safety and 

effi cacy for Genotropin. These data, in conjunction with the independent evidence 
of safety and effi cacy provided by Sandoz, supported Omnitrope ’ s approval. 
1.2.7.3 Case Study 3: Generic Salmon Calcitonin 
On February 17, 2004, Nastech Pharmaceutical Company announced its fi ling of an 
ANDA for a salmon calcitonin nasal spray drug product for the treatment of postmenopausal 
osteoporosis. As with Fortical, Novartis ’ s Miacalcin was cited as the 
reference listed drug; however, Nastech chose to submit an ANDA via the 505(j)(1) 
route, rather than a 505(b)(2) application. 
The distinction between the two regulatory routes has signifi cant implications for 
FOPs. Whereas 505(b)(2) allows products to be “ suffi ciently similar, ” an ANDA 
requires the applicant establish “ sameness ” of the active ingredients. The scope of 
data necessary to demonstrate that the actives are the same is unclear. Additionally, 
use of the ANDA route is appropriate for circumstances in which “ clinical studies 
are not necessary to show safety and effectiveness. ” If clinical data are required as 
proof of sameness, as in the previous example where clinical data were used to 
demonstrate comparable immunogenicity, then the ANDA route may not represent 
a viable regulatory path. 
On July 10, 2006, Nastech was notifi ed by the FDA that its ANDA for 
intranasal calcitonin salmon was not approvable at present based on concerns 
relating to the potential for immunogenicity that might result from a possible 
interaction between calcitonin salmon and chlorobutanol, the preservative in the 
formulation. 
Nastech has indicated it will continue to work with the agency to understand the 
data requirements and regulatory options, but the fi nal resolution remains presently 
unknown. This case study highlights the fact that demonstration of sameness of 
therapeutic proteins is more complex than for other drugs and that true “ biogenerics 
” may be hard to come by due to the complexity in establishing sameness versus 
similarity. 
1.2.8 SUMMARY AND CONCLUSIONS 
This chapter provides an overview of the complex scientifi c, legal, and policy issues 
facing the development of biogenerics today. Given the rising cost of health care 
and prescription medications in this country and the pivotal and expanding role of 
biologically derived products within the pharmaceutical landscape, these issues 
present a challenge to industry, regulators, and legislators alike. Substantial progress 
has already been made and the regulatory climate continues to evolve in response 
to advancing science and technology. Recent FDA approvals provide insight into 
the technical requirements for approval of well - characterized FOP products. They 
also demonstrate the appropriate use of an abbreviated approval pathway, that is, 
the 505(b)(2) pathway in place for drugs approved under the FDCA. Importantly, 
recent legislative proposals seek to amend the PHSA to eliminate the current legal 
barriers which prohibit abbreviated approval of protein biologics. This legislation 
reaffi rms the need for the FDA to determine on a case - by - case basis the nature and 
extent of supporting data required for a given product. 
SUMMARY AND CONCLUSIONS 55

56 REGULATORY CONSIDERATIONS IN APPROVAL 
REFERENCES 
1. Congressional Budget Offi ce ( 1998 ), How Increased Competition from Generic Drugs 
Has affected Prices and Returns in the Pharmaceutical Industry , Congressional Budge 
Offi ce , Washington, DC . 
2. Crawford , L. M. , Acting Commissioner of the Food and Drug Administration, in a Speech 
to the Generic Pharmaceutical Association on February 26, 2005, available: http://www. 
fda.gov/oc/speeches/2005/GPhA0301.html , accessed Apr. 23, 2005. 
3. Comments of the Generic Pharmaceutical Association (GPhA) (Sept. 29, 2006), available: 
http://www.gphaonline.org/AM/Template.cfm?Section=Media&Template=/CM/ 
HTMLDisplay.cfm&ContentID=2849 , accessed Jan. 23, 2007. 
4. Schellekens , H. ( 2005 ), Follow - on biologics: Challenges of the “ next generation ” , 
Nephrol. Dial. Transplant . 20 ( Suppl. 4 ), iv31 – iv36 . 
5. Congressional letter from Senators O. Hatch and H. Waxman to Andrew von Eschenbach, 
Acting Commissioner of the Food and Drug Administration (Feb. 10, 2006), available: 
http://www.henrywaxman.house.gov/news_letters_2006.htm , accessed Dec. 21, 2006. 
6. Messplay , G. C. , and Heisey , C. ( 2006 ), Follow - on biologics: The evolving regulatory landscape 
, Bioexec Int. , May, 42 – 45 . 
7. Biotechnol. Law Rept. , 2003 , 22(5), 485 – 508 . 
8. Comments from R. Williams, U.S. Pharmacopoeia (USP), to FDA Docket No. 2004N - 
0355, Mar. 15, 2005 . 
9. Herrera , S. ( 2004 ), Biogenerics standoff , Nat. Biotechnol. , 22 ( 11 ), 1343 – 1346 . 
10. Scott , S. R. ( 2004 ) What is a biologic ?, Chapter 1 in Mathieu , M. , Ed., Biologics Development: 
A Regulatory Overview , 3rd ed., Paraxel Intl. , Waltham, MA , pp. 1 – 16 . 
11. Federal Food Drug and Cosmetic Act , available: http://www.fda.gov/opacom/laws/fdcact/ 
fdctoc.htm , accessed Apr. 21, 2005. 
12. Public Health Service Act , available: http://www.fda.gov/opacom/laws/phsvcact/phsvcact. 
htm , accessed Apr. 21, 2005. 
13. U.S. Department of Health and Human Services, Food and Drug Administration Transfer 
of Therapeutic Products to the Center for Drug Evaluation and Research , available: 
http://www.fda.gov/cber/transfer/transfer.htm , accessed Apr. 23, 2005. 
14. U.S. Department of Health and Human Services (DHHS) ( 1999 , Oct.), Food and Drug 
Administration, Center for Drug Evaluation and Research , Guidance for Industry: 
Applications covered by Section 505(b)(2), DHHS, Washington, DC. 
15. U.S. Department of Health and Human Services, Food and Drug Administration, Omnitrope 
(somatropin [rDNA origin]) questions and answers, available: http://www.fda.gov/ 
cder/drug/infopage/somatropin/qa.htm , accessed Dec. 21, 2006. 
16. Letter of J. Woodcock. (CDER, FDA) to Docket Nos. 2001P - 0323/CP1, 2002P - 0447/CP1, 
and 2003P - 0408/CP1 (Oct. 14, 2003 ). 
17. Glidden , S. ( 2001 ), The generic industry going biologic , Biotechnol. Law Rept , 20 ( 2 ), 
172 – 181 . 
18. Letter from S. Galson (CDER, FDA) in response to Docket Nos. 2004P - 023 11CP1 and 
SUP 1,2003P - 0 1 76lCP 1 and EMC 1, 2004P - 0171lCP1 and 2004N - 0355 (May 30, 2006 ). 
19. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research, Offi ce of Pharmaceutical Science, Offi ce of Generic 
Drugs , Electronic orange book: Approved drug products with therapeutic equivalence 
evaluations, available: http://www.fda.gov/cder/ob/default.htm , accessed Apr. 21, 2005. 
20. Schellekens , H. ( 2004 ), How similar do “ biosimilars ” need to be ? Nat. Biotechnol . 22 ( 11 ), 
1357 – 1359 . 

21. Webber , K. ( 2005 ), Relevant terminology. A presentation conducted at the Public Workshop 
on the Development of Follow - On Protein Products, Sept. 14, 2004, available: 
http://www.fda.gov/cder/meeting/followOn/followOnPresentations.htm , accessed Feb. 2, 
2005. 
22. Waxman , H. , Schumer , C. E. , and Clinton , H. R. (2006), Congress of the United States, 
H.R. 6257, Access to Life - Saving Medicine Act, ” available: http://www.waxman.house. 
gov/pdfs/bill_generic_biologics_9.29.06.pdf , accessed Sept. 29, 2006. 
23. Mathieu , M. , and Evans , A. G. ( 2005 ), The FDA ’ s Orphan Drug Development Program , 
in Ed., New Drug Development: A Regulatory Overview , 7th ed., Paraxel Intl. , Waltham, 
MA , pp. 307 – 317 . 
24. U.S. Department of Health and Human Services (DHHS) ( 2003 , Sept.), Food and Drug 
Administration, Center for Drug Evaluation and Research, Guidance for industry: Comparability 
protocols — Protein drug products and biological products — Chemistry, manufacturing 
and controls information , DHHS , Washington, DC . 
25. Beatrice , M. ( 2002 ), Regulatory considerations in the development of protein Pharmaceuticals 
, in Nail , S. , and Akers , M. , Eds., Development and Manufacture of Protein Pharmaceuticals, 
Pharmaceutical Biotechnology , Vol. 14, Kluwer Academic/Plenum ,New York , 
pp. 405 – 457 . 
26. Letter from R. Levy (Unigene) to FDA Docket No. 2004P - 0015 (Apr. 11, 2005 ). 
27. Letter from S. Galson (CDER, FDA) in response to Docket No. 2004P - 0015/CP1 (Aug. 
12, 2005 ). 
28. Letter from N. Buc to FDA Docket No. 2004P - 0115/CP1 (Jan. 9, 2004 ). 
29. FDA Week , 11(34), Aug. 26, 2005. 
REFERENCES 57


59 
1.3 
RADIOPHARMACEUTICAL 
MANUFACTURING 
Brit S. Farstad 1 and Iv a n Pe n uelas 2 
1 Institute for Energy Technology, Isotope Laboratories, Kjeller, Norway 
2 University of Navarra, Pamplona, Spain 
Contents 
1.3.1 Introduction 
1.3.1.1 Radiopharmacy 
1.3.1.2 Characteristics of Radiopharmaceuticals 
1.3.1.3 Ideal Characteristics of Radiopharmaceuticals 
1.3.1.4 Radioactive Decay 
1.3.1.5 Principles of Radiation Protection 
1.3.1.6 Detection Devices for Clinical Nuclear Imaging 
1.3.2 Product Development 
1.3.2.1 Radionuclides 
1.3.2.2 Carrier Molecules/Active Ingredients 
1.3.2.3 Radiolabeling Techniques 
1.3.2.4 Manufacturing Scale - Up 
1.3.2.5 Automation 
1.3.3 Manufacturing Aspects 
1.3.3.1 Design of Manufacturing Sites 
1.3.3.2 Design of Production Processes 
1.3.3.3 Design of Production Equipment 
1.3.3.4 Cleaning and Sanitation of Production Equipment 
1.3.3.5 Environmental Control 
1.3.3.6 Sterilization of Radiopharmaceuticals 
1.3.3.7 Starting Materials 
1.3.3.8 Labeling and Packaging 
1.3.4 Product Manufacturing 
1.3.4.1 Production of Radionuclides 
1.3.4.2 Production of Radiopharmaceuticals 
1.3.5 Quality Considerations 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

60 RADIOPHARMACEUTICAL MANUFACTURING 
1.3.5.1 Documentation 
1.3.5.2 Qualifi cation of Personnel 
1.3.5.3 Quality Control 
1.3.5.4 Validation and Control of Equipment and Procedures 
1.3.5.5 Stability Aspects of Radiopharmaceuticals 
1.3.6 Extemporaneous Preparation of Radiopharmaceuticals 
References 
Further Readings 
1.3.1 INTRODUCTION 
1.3.1.1 Radiopharmacy 
Radiopharmacy is a patient - oriented science that includes the scientifi c knowledge 
and professional judgment required to improve and promote health through assurance 
of the safe and effi cacious use of radiopharmaceuticals. Radiopharmacy encompasses 
studies related to the pharmaceutical, chemical, physical, biochemical, and 
biological aspects of radiopharmaceuticals. 
Radiopharmacy comprises a rational understanding of the design, preparation, 
and quality control of radiopharmaceuticals, the relationship between 
the physicochemical and biological properties of radiopharmaceuticals and 
their clinical applications, as well as radiopharmaceutical chemistry and issues 
related to the management, selection, storage, dispensing, and proper use of 
radiopharmaceuticals. 
1.3.1.2 Characteristics of Radiopharmaceuticals 
A radiopharmaceutical is any medicinal product which, when ready for use, contains 
one or more radionuclides (radioactive isotopes) included for a medicinal purpose. 
This generic defi nition of radiopharmaceutical thus includes both diagnostic and 
therapeutic radiopharmaceuticals. 
A radiopharmaceutical can be as simple as a radioactive element such 
as 133 Xe, a simple salt such as 131 INa, a small labeled molecule such as 
l - ( S - [ 11 C]methyl)methionine, or a protein labeled with a radionuclide such as 
99m Tc - labeled albumin or 90 Y - labeled monoclonal antibodies. 
In clinical nuclear medicine, roughly 95% of radiopharmaceuticals are used with 
diagnostic purposes. Radiopharmaceuticals are administered to the patients only 
once, or a few times at most, in their lifetime. They contain minute amounts of active 
ingredients, with a radionuclide somehow linked to or being the active ingredient 
itself, with the main purpose of obtaining an image or a measure of their biodistribution. 
Radiopharmaceuticals do not usually show any measurable pharmacodynamic 
activity, as they are used in tracer quantities. Hence, there is no dose – response 
relationship in this case and thus differs signifi cantly from conventional drugs. 
Radiation is of course an inherent characteristic of all radiopharmaceuticals. 
Hence, patients always receive an unavoidable radiation dose. In the case of therapeutic 
radiopharmaceuticals, radiation is what produces the therapeutic effect. 

The terms tracer, radiotracer , and radiodiagnostic agent , although long used as 
equivalent to radiopharmaceutical, should be avoided. The preferred and correct 
term is radiopharmaceutical , as the other names can be confusing or do not clearly 
show the nature of these compounds as pharmaceuticals. 
The composition of radiopharmaceuticals is not constant as it varies with time 
as the radionuclide disintegrates. Very often, the half - life of the labeled molecule is 
so short that it must be readily prepared just before its administration to the patient. 
This implies in many cases the use of “ semimanufactured ” , such as radionuclide 
generators, precursors, and cold kits that are also considered a medicinal product 
according to directive 2001/83/EC. 
1.3.1.3 Ideal Characteristics of Radiopharmaceuticals 
Radiopharmaceuticals should have several specifi c characteristics that are a combination 
of the properties of the radionuclide used as the label and of the fi nal radiopharmaceutical 
molecule itself. The radiopharmaceutical should ideally be easily 
produced (both the radionuclide and the unlabeled molecule) and readily available. 
The half - life of the radionuclide should be adequate to the diagnostic or therapeutic 
purpose for which it is designed. It has to be considered that radiopharmaceuticals 
disappear from the organism by a combination of two different processes. The biological 
half - life (showing the disappearance of a radiopharmaceutical from the body 
due to biological processes such as metabolization, excretion, etc.) and the physical 
half - life (due to the radioactive decay of the radionuclide). The combination of both 
parameters gives the effective half - life : 
T 
TT 
T T e 
p b 
p b 
= 
+ 
where T e is the effective half - life, T p the physical half - life, and T b the biological half - 
life. Radiopharmaceuticals should have an effective half - life adequate to the use for 
which they are intended. It should be short (hours) for diagnostic radiopharmaceuticals 
(not longer than the time necessary to complete the study in question) and 
longer for therapeutic radiopharmaceuticals (most often days) as the intended 
effect should have a suffi cient duration. 
The type of decay of the radiopharmaceutical should also be adequate for its 
intended use. Diagnostic radiopharmaceuticals should decay by . emission, electron 
capture, or positron emission, and never emit . or even . particles. On the contrary, 
therapeutic radiopharmaceuticals should decay by . or . emission because the 
intended effect is in fact radiation damage to specifi c cells. 
Regarding the energy emission of diagnostic radiopharmaceuticals, the fi nally 
produced . rays should be powerful enough to be detected from outside of the body 
of the patient. The ideal energy for nuclear medicine equipment is around 150 keV. 
. rays should be monochromatic and photon abundance should be high to decrease 
the imaging time. 
1.3.1.4 Radioactive Decay 
Radionuclides are unstable nuclei that are stabilized upon radioactive decay. More 
than 2000 unstable nuclides have been described so far, most of them radioactive. 
INTRODUCTION 61

62 RADIOPHARMACEUTICAL MANUFACTURING 
The stabilization process can proceed by several different processes, such as spontaneous 
fi ssion, . - particle emission, . - particle emission, positron emission, . - ray 
emission, or electron capture. In all decay processes the mass, energy, and charge of 
radionuclides must be conserved, and many nuclides can decay by a combination 
of any of the above - mentioned processes. 
Fission is the process in which a nucleus breaks down into two fragments (thus 
leading to two different new nuclides) with an emission of two or three neutrons 
and a lot of energy. Spontaneous fi ssion is a rare process that can only occur in heavy 
nuclei. Fission can also be produced by bombardment of certain nuclides with high - 
energy particles (such as neutrons) and is in fact the nuclear process used for the 
production of energy in nuclear energy plants by bombardment of highly enriched 
uranium with neutrons. 
The usual decay process of heavy nuclei is . - particle emission. An . particle is 
a helium ion containing two protons and two neutrons. Alpha particles are heavy 
particles that have a very short range in matter due to their mass, and radiopharmaceuticals 
labeled with . emitters are used only with therapeutic purposes. Their 
clinical use is very limited, and they are mainly used for research purposes or in 
early phase clinical studies. 
Radioactive nuclides that are neutron rich disintegrate by . decay. A . . particle 
is originated by the conversion of a neutron into a proton, along with the emission 
of an antineutrino to conserve energy in the decay process. Beta - emitting radionuclides 
are also used in radiopharmaceuticals for therapeutic purposes. 
Positron decay occurs in proton - rich nuclei. In this case, the positron (or .+ particle) 
is originated by conversion of a proton into a neutron, along with the emission 
of a neutrino to conserve the energy. Positrons are the antiparticle of electrons. In 
a very fast process (10 . 12 s), emitted positrons collide with an electron of a nearby 
atom and both particles disappear in a process called annihilation. The necessary 
conservation of mass and energy accounts for the transformation of the mass of 
both particles into energy, which is characteristically emitted in the form of two 
511 - keV photons almost in opposite directions. Consequently, positron emitters are 
used to label radiopharmaceuticals produced with diagnostic purposes by imaging. 
Proton - rich nuclei can also decay by electron capture. In this process, an electron 
from the innermost electron shell orbitals is captured into the nucleus and transforms 
a proton into a neutron (and a neutrino is emitted for conservation of energy). 
The vacancy created by the lost electron is fi lled by the transition of an electron 
from a higher level orbital, and the energy difference between the intervening orbitals 
is emitted as energy in the form of an X ray. 
For any particular nucleus, several different energy states can be defi ned by 
quantum mechanics. All the excited energy states above the ground state are referred 
to as isomeric states and decay to the ground state by the so - called isomeric transition. 
In . , positron, or electron - capture decay processes, the parent nucleus may 
reach any of these isomeric states of the daughter nucleus. The energy difference 
between the nuclear energy states can be emitted as . rays. A particular situation 
for isomeric transition is that in which the excited state is long lived and is then 
called the metastable state. 
Radioactive Decay Equations, Magnitudes, and Units Radioactive decay is a 
random process, being impossible to tell which particular atom from a group of atoms 
will decay at a specifi c moment. It is then only possible to talk about the average 

number of atoms that disintegrate during a certain period of time, giving the disintegration 
rate ( . dN/dt ) of a particular radionuclide that is proportional to the total 
number of radioactive atoms present at that time. This magnitude is usually called the 
radioactivity (or mainly simply the activity) of a radionuclide and denoted by 
A 
dN 
dt 
N = . = . 
where . is the decay constant and N the number of radioactive atoms. The previous 
differential equation is mathematically solved leading to the exponential equation 
N Ne t 
t = . 
0 
. 
where N t and N are the number of radioactive atoms present at time t = 0 and 
t = t , respectively. 
Radioactivity is expressed in becquerels (Bq), the Internationale System (SI) unit 
for the magnitude A . One Becquerel is defi ned as one disintegration per second 
(dps). Usual activities used in radiopharmacy are in the range of megabecquerels 
or gigabequerels. There is (as usual) a non - SI unit called the curie (Ci). It was 
initially defi ned in a trivial way as the disintegration rate of one gram of radium, 
which was considered to be 3.7 . 10 10 dps. Thus the equivalence between the becquerel 
and the curie is as follows: 
1 27 10 1 37 11 Bq Ci Ci GBq = . = . . 
The decay constant . is a specifi c characteristic of any single radionuclide, but being 
related to probability, it is diffi cult to understand its meaning. Thus, a new magnitude 
is defi ned: the half - life ( t 1/2 ), which is the time required to reduce the initial activity 
of a radionuclide to one - half. In consequence, after one half - life the activity of a 
radionuclide would be A /2, after two half - lives A /4, after three half lives A /8, and 
so on. 
The relationship between the decay constant . and the half - life t 1/2 can be derived 
from the general radioactive decay equation 
t1 2 
2 
/ = ln
. 
An additional (and commonly misunderstood concept) is the mean life . ,which is 
the average life of a certain group of radioactive atoms that is mathematically also 
derived from the decay constant . as 
. 
. 
= = = 1 
2 
1 44 1 2 
1 2 
t 
t / 
/ ln 
. 
1.3.1.5 Principles of Radiation Protection 
Production, transportation, and use of radiopharmaceuticals, as radioactive products, 
is governed by regulatory agencies dealing with radiation protection and 
nuclear safety. 
INTRODUCTION 63

64 RADIOPHARMACEUTICAL MANUFACTURING 
In any case, and albeit the different regulation in different countries, as a general 
principle only licensed personnel working in an authorized facility are authorized 
to handle and use radiopharmaceuticals. Facilities and procedures are subject to 
periodic inspection by offi cial radiation safety offi cers that control production and 
handling of radioactive material, its transportation, proper use, as well as personnel 
dosimetry and radioactive waste disposal. 
The general principles of radiation protection are very simple: 
Justifi cation. All procedures involving radioactive material must be justifi ed. 
Optimization. The radiation exposure to any individual should be as low as reasonable 
achievable. This principle is the widely known ALARA concept, an 
acronym derived from as low as reasonable achievable. 
Limitation. The radiation dose received by the personnel handling radioactive 
material will never exceed the legally established dose limits. It has to be taken 
into account that such limitations do not apply to patients receiving radiopharmaceuticals 
as either diagnostic or therapeutic agents. But nuclear medicine 
physicians, nuclear physicists, and radiopharmacists must ensure that the 
amount of radiopharmaceutical administered to a patient is adapted to his or 
her disease and optimized to obtained the intended result. 
Operational Radiation Protection The fundamentals of operational radiation 
protection (i.e., how to proceed when working with radioactive products) are based 
on three factors: distance, time, and shielding. In any case, it is obvious that the 
radiation hazard is increased with the activity of the radiation source, as can be 
derived from the mathematical equation to calculate the exposure rate X given 
by 
X 
A
d 
= .
2 
where A is the activity of the radiation source, . a constant that is characteristic of 
every radionuclide, and d the distance to the source. 
Distance should be increased as much as possible to decrease exposition and 
exposure time should be reduced to a minimum. Adequate shielding (depending on 
the radionuclide and its emission characteristics) should be used whenever possible 
and handling of high activities should only be carried out by either automated 
systems or proper manipulators. 
1.3.1.6 Detection Devices for Clinical Nuclear Imaging 
Diagnostic radiopharmaceuticals are mostly used for in vivo imaging of the biodistribution 
of the radiopharmaceutical. Depending on whether . or positron emitters 
are used, different devices are employed for clinical imaging. In any case, imaging 
devices are based on detection of the high - energy photons coming from the body 
of the patient upon administration and specifi c uptake of a radiopharmaceutical. 
Advances in nuclear medicine imaging devices now permit in vivo noninvasive 
imaging of such biodistribution and to obtain tomographic (i.e., three - dimensional) 

images that can also give quantitative or semiquantitative information about the 
amount of radiopharmaceutical and even its kinetics. 
1.3.2 PRODUCT DEVELOPMENT 
1.3.2.1 Radionuclides 
When designing a radiopharmaceutical one should have in mind the potential 
hazard the product may have to the patient. The goal must be to have maximum 
amounts of photons with a minimum radiation exposure of the patient. For use in 
therapy, . emitters and . emitters are particularly useful. For diagnostic purposes, 
. emitters are most widely used. In general, those . emitters with a short physical 
half - life and with a . energy between 100 and 300 keV are most widely used in 
medical application, since these can easily be detected by standard . cameras. 
However, positron emission tomography (PET) radiopharmaceuticals involve 
short - lived radionuclides (positron emitters) giving a double set of photons at 
511 keV each. 
1.3.2.2 Carrier Molecules/Active Ingredients 
The function of the carrier molecule is to carry the radioactivity to the target organ 
and to make sure the radioactivity stays there. The uptake of radioactivity should 
be as specifi c as possible in order to minimize irradiation of other organs and parts 
of the body. This is particularly important when using radiopharmaceuticals for 
therapy. But, also, for use in diagnostics, it is desirable that the radiopharmaceutical 
is localized preferentially in the organ under study since the activity from nontarget 
areas can obscure the structural details of the pictures of the target organ. It is 
therefore important to know the specifi c uptake in an organ for a potential chemical 
carrier and also the rate of leaking out of the organ/organ system. Thus, the target - 
to - background activity ratio should be large. There are several approaches to develop 
targeting radiopharmaceuticals. Radioimmunotargeting is one approach frequently 
used for radiopharmaceuticals, where monoclonal antibodies (MAbs) or fractions 
of MAbs are the carrier molecules for the radioactivity. These are binding specifi - 
cally to receptors on cell surfaces in the target organs. 
The target - binding surface of the cell has been well explored with a range of 
tumor - associated and other antigens, identifi ed, and used for pathological tissue 
characterizations. 
The active analog approach in general, whereby a set of compounds is synthesized 
so as to mimic features of a chosen natural compound, has been successful 
[1] . The active analog approach includes the pharmacophore. The concept of the 
pharmacophore is to look at features common to a set of drugs or compounds 
binding to and acting on the same receptors. 
1.3.2.3 Radiolabeling Techniques 
When a labeled compound is to be prepared, the fi rst criterion to consider is whether 
the label can be incorporated into the molecule to be labeled [2] . This may be 
PRODUCT DEVELOPMENT 65

66 RADIOPHARMACEUTICAL MANUFACTURING 
assessed from knowledge of the chemical properties of the two partners. Furthermore, 
one needs to know the amount of each component to be added. This is particularly 
important in tracer level chemistry and in 99m Tc chemistry. 
In a radiolabeled compound, atoms, or groups of atoms of a molecule, are substituted 
by similar or different radioactive atoms or groups of atoms. Saha [2] lists 
six major methods employed in the preparation of labeled compounds for clinical 
use: isotope exchange reactions, introduction of a foreign label, labeling with bifunctional 
chelating agents, biosynthesis, recoil labeling, and excitation labeling. Among 
these, three frequently used methods in radiopharmaceutical synthesis are briefl y 
described below. 
Isotope Exchange Reactions In isotope exchange reactions, isotopes of the same 
elements having different mass numbers replace one or more atoms in a molecule. 
Examples are labelling of iodide - containing material with iodine radioisotopes. 
Since the radiolabeled and parent molecules are identical except for the isotope 
effect, they are expected to have the same biological and chemical properties. 
Introduction of a Foreign Label In this type of labelling, a radionuclide is incorporated 
into a molecule primary by the formation of covalent or coordinated covalent 
bonds. The tagging radionuclide is foreign to the molecule and does not label it 
by exchange of one of its isotopes. Examples are 99m Tc – DTPA (Diethylenetriaminepentacetic 
acid), 51 Cr - labeled red blood cells, and many iodinated proteins and 
enzymes. In many compounds of this category, the chemical bond is formed by chelation. 
In chelation, one atom donates a pair of electrons to the foreign acceptor atom, 
which is usually a transition metal. Most of the 99m Tc - labeled compounds used in 
nuclear medicine are formed by chelation. 
Labeling by Bifunctional Chelating Agents In this approach, a bifunctional chelating 
agent is conjugated to a macromolecule (e.g., protein) on one side and to a metal 
ion by chelation on the other side. Examples of bifunctional chelating agents are 
DTPA, metallothionein, diamide dimercaptide (N 2 S 2 ), and dithiosemi carbazone [2] . 
There are two methods: the preformed radiometal – chelate method and the indirect 
chelator — antibody method. Various antibodies are labelled by the latter, where 
the bifunctional chelating agent is initially conjugated to a macromolecule, which is 
then allowed to react with a metal ion, to form a metal – chelate – macromolecule 
complex. Due to the presence of the chelating agent, the biological properties of 
the labeled protein may be altered and must be assessed before clinical use. 
1.3.2.4 Manufacturing Scale - Up 
As the radiolabeled substances emerge from the laboratory to the clinics, there will 
be a need for scaling up the batch size of the product. This can be done by increasing 
either the total volume of the produced batches or the specifi c activity of the 
product or both. When doing this, the following aspects should be considered: 
The infl uence on the stability of the product itself due to possible radiolysis 
The need for additional operator protection due to handling of increased amounts 
of radioactivity 

Product Stability The stability of a labeled compound is one of the major problems 
in labeling chemistry. It must be stable both in vitro and in vivo. Many labeled 
compounds are decomposed by radiation emitted by the radionuclides in them. This 
kind of decomposition is called radiolysis. Radiation may also decompose the 
solvent, producing free radicals that can break down the chemical bonds of the 
labeled compounds (indirect radiolysis). In general, the risk of radiolysis increases 
with higher specifi c activity of the product. In addition, the more energetic the radiation, 
the greater is the radiolysis. Alpha emitters, leaving most of its energy close by 
the molecules, and thus a high potential risk of radiolysis, give rise to major challenges 
when scaling up is necessary. 
Operator Radiation Protection Even for the largest commercial manufacturer of 
radiopharmaceuticals, the batch volumes are small compared to nonradioactive 
pharmaceuticals. So even a scaled - up production batch can be contained within a 
limited space. When scaling up a radiopharmaceutical production, one always has 
to assure that the radiation outside the contained work unit is acceptable for the 
operator. 
The production of a radiopharmaceutical will normally take place within a contained 
box unit. Depending on the kind of radionuclides used and the amount of 
radioactivity handled in the production process, the box units are shielded by lead 
walls, typically 5 – 15 cm in thickness. When the box is used for production of radiopharmaceuticals 
incorporating . - or . - emitting radionuclides, closed box units 
without any lead coating are suffi cient. Working with these types of radionuclides 
or with smaller amounts of . - emitting radioactivity, as in research scale, suitable 
glove boxes can be used. When working with larger quantities of . - emitting radionuclides, 
the material must be handled by either remote control equipment or 
manipulator tongs incorporated in the wall. 
1.3.2.5 Automation 
Because of the unique operational and safety requirements of radiopharmaceutical 
synthesis, the motivation for the development of automated systems is clear. 
These unique constraints include short synthesis times and control from behind 
bulky shielding structures that make both access to and visibility of radiochemical 
processes and equipment diffi cult. The need for automated systems is particularly 
expressed for PET radiopharmaceutical synthesis, with the short - lived 
radionuclides emitting high - energy . photons at 511 keV. Automated synthesis 
systems require no direct human participation. The short half - lives of the 
PET radionuclides may require repeated synthesis during the day, thus being 
a potential radiation burden for the operator when not using automated 
systems. 
Furthermore, radiopharmaceutical synthesis must be reliable and effi cient and 
result in pharmaceutical - quality products. In addition, the processes must be well 
documented and controlled. Automated systems may support all these challenges 
and requirements. 
One must keep in mind, though, that success in synthesis automation requires 
fi rst and foremost innovative chemistry. PET radiosynthesis draws from a broad 
chemistry knowledgebase rooted in synthetic organic chemistry [3] . 
PRODUCT DEVELOPMENT 67

68 RADIOPHARMACEUTICAL MANUFACTURING 
1.3.3 MANUFACTURING ASPECTS 
1.3.3.1 Design of Manufacturing Sites 
The manufacturing of radiopharmaceuticals is potentially hazardous. Both small - 
and large - scale production must take place on premises designed, constructed, and 
maintained to suit the operations to be carried out. Radiation protection regulations 
stipulate that radionuclides must only be used in specially designed and approved 
“ radioisotope laboratories. ” National regulations with regard to the design and classifi 
cation of radioisotope laboratories must be fulfi lled. Such laboratories are normally 
classifi ed according to the amount of the various radionuclides to be handled 
at any time and the radiotoxicity grading given to each radionuclide. When planning 
the layout of the laboratory, it is recommended to allocate separate working areas 
or contained units for the various procedures to avoid possible cross - contamination 
of radionuclides [4, 5] . Premises must be designed with two important aspects in 
mind: 
The product should not be contaminated by the operator. 
The operator and the environment should be protected from contamination by 
the radioactive product. 
This is the basic principle of good radiopharmaceutical practice (GRPP). 
One of the most important factors in planning a radioisotope laboratory is the 
design of the ventilation system. Laboratories with medium and high grading must 
be designed with the purpose of protecting the personnel from inhaling radioactive 
gases or particles. The system should be designed to provide lower pressure at the 
actual working area compared to the surrounding environment. Furthermore, the 
system should have an appropriate number of air changes per hour and the replacement 
air should be fi ltered. Air extracted from the area where radioactive products 
are handled, though, should not be recirculated. Exhaust air to the environment 
should be monitored for radioactivity, and it may be necessary to install active 
charcoal fi lters to absorb radioactive gases and small particles [4] . 
Aseptic production of radiopharmaceuticals, that is, when the products cannot 
be terminally sterilized, will increase the requirements for the design and construction 
of the premises. Contained workstations and clean - room technology will be 
applied to a much higher degree. The general requirements for the design of such 
premises are the same as for nonradioactive pharmaceuticals, including entry of staff 
and the introduction of materials through air locks. The main difference is found in 
the planning and design of the ventilation system. Laboratories for aseptic work 
normally have a positive pressure relative to the surrounding areas. On the other 
hand, in laboratories for work with radioactivity, it is good practice to have a negative 
pressure to avoid the spread of radioactive material. In order to meet both 
pharmaceutical and radiation protection requirements, it is necessary to balance 
carefully the air pressures in the clean rooms, the air locks, and the surrounding 
areas. From a pharmaceutical point of view a negative pressure in the area designated 
for aseptic work can only be accepted in special cases. There are various ways 
to meet the required balance between these apparently contradictory principles. 
A frequently chosen solution is to use sealed production units or contained work

stations supplied with unidirectional airfl ow (UDAF) and with a lower pressure 
compared to the aseptic laboratory. The laboratory itself may then have positive 
pressure in relation to the surrounding premises. 
Waste management is an important aspect when planning a radiopharmaceutical 
manufacturing site. The key factor is to reduce the amount of radioactive waste to 
a minimum. There should be a system for dividing the waste according to physical 
half - life and radiotoxicity, both for solid and liquid waste. As an example, waste 
containing . emitters is normally kept separately, when possible. National legislation 
will vary considerably and infl uence the requirement that must be set for handling 
of radioactive waste material. 
1.3.3.2 Design of Production Processes 
The design of a radiopharmaceutical production process depends very much upon 
the kind of radiopharmaceutical to be made. Although most radiopharmaceuticals 
are intended for parenteral use, also oral radiopharmaceuticals in different forms 
are widely used. One must emphasize different factors when planning for production 
of parenteral radiopharmaceuticals compared to oral radiopharmaceuticals. 
Still, a common factor is the involvement of radioactive materials, and the radiation 
protection of the personnel must always be an integral part of the design. 
The production of a radiopharmaceutical will normally take place within a contained 
box unit, consisting of either plastic walls or a combination of plastic and 
stainless steel. The latter is more optimal for clean - room work. The box units may 
be shielded by lead, either as large lead panels or as lead brick walls (see Figure 1 ). 
Depending on the kind of radionuclides used and the amount of radioactivity 
handled in the box, the walls are typically 5 – 15 cm in thickness. Shielded production 
units like these are often called “ hotcells. ” 
When the box is used for productions of radiopharmaceuticals incorporating . - 
or . - emitting radionuclides, closed box units without any lead coating may be suffi - 
cient. When handling radionuclides with mixed emitting properties, a possibility is 
to concentrate the shielding to critical parts of the process. This can be done by use 
of local shielding inside the production unit. However, for aseptic production, one 
must keep in mind a potential disturbance of the airfl ow inside the box. 
FIGURE 1 Shielding of box units (hot cells) with lead bricks. ( Photo courtesy of Institute 
for Energy Technology .) 
MANUFACTURING ASPECTS 69

70 RADIOPHARMACEUTICAL MANUFACTURING 
Working with . and . radionuclides and also limited amounts of . - emitting 
radioactivity, the boxes may be mounted with special protection gloves. When 
working with larger quantities of . - emitting radionuclides, the material must be 
handled by either remote control equipment or manipulator tongs incorporated in 
the wall (see Figure 2 ). 
The design of the elements and their assembly on the production unit should be 
such that there are no radiation leaks at the interface. 
When using lead bricks to construct the wall of the production unit, they should 
have a special design. When they are stacked on top of each other, they should 
interlock (see Figure 3 ). This is important to avoid cracks in the wall through which 
radiation can escape. 
Manipulator tongs are fi tted into the wall as part of a large tungsten sphere which 
acts as a ball bearing and thereby allows more fl exibility for the movement of the 
tong inside the box (see Figure 2 ). Lead glass windows, with good shielding properties, 
are fi tted in the lead bricks to allow the operator to overlook the process. 
When large lead panels are used, they should be reinforced with suitable steel 
structures [International Organization for Standardization (ISO) 10648 - 1: 1997]. 
The surfaces of the lead shielding must be smooth and easy to clean. This can be 
achieved by painting the surface of the wall. 
FIGURE 2 Hot cells for manufacturing of larger quantities of . - emitting radionuclides. 
( Photo courtesy of Institute for Energy Technology .) 
FIGURE 3 Lead bricks are interlocked when they are stacked on top of each other. ( Photo 
courtesy of Institute for Energy Technology .) 

In general, the manufacturing of most radiopharmaceuticals consists of the 
following: 
Nuclear synthesis, synthesis of the radionuclide 
Synthesis of the radiolabeled compound 
Pharmaceutical formulation of the radiopharmaceutical 
Nuclear Synthesis Except for radionuclides with ultrashort half - lives, like most 
PET radionuclides, the production of these is normally performed well in advance 
(see Section 1.3.4.1 ). Thus, the radionuclide is considered as a starting material and 
must undergo controls as a starting material. 
Synthesis of Radiolabeled Compound The complexity of a radiopharmaceutical 
may differ greatly, with the radioactive element itself or simple salts as the less 
complex. Very often, though, the radiolabel is part of a larger molecule, and thus a 
radiolabeling procedure is required. This is part of the synthesis of the radiopharmaceuticals, 
which also may involve chemical alteration of a precursor of the active 
ingredient. Both labeling methods and synthesis may involve steps at elevated temperatures 
or even cooling steps. Thus, equipment for heating or cooling must be part 
of the production line. Furthermore, an important part of a synthesis is often the 
purifi cation step, and equipment for this must be available. Typically, this is simple 
chromatographic or ion exchange columns. 
Planning of the process very much depends on the complexity of the process. In 
general, keeping in mind the limited possibilities of direct handling of the materials, 
it is important to keep the processes as simple as possible. For more complex processes, 
automation may be the best solution, if available. 
Pharmaceutical Formulation Even when the radiochemical part of a product is 
simple, the radiopharmaceutical may be a complex solution. A pharmaceutical formulation 
often contains additives in the form of buffers and preservatives: buffers 
to keep the solution at a pH suitable for injection and preservatives to preserve the 
integrity and effi ciency of the radiopharmaceutical. 
Ideally, a solution for injection should be an isotonic solution with a neutral 
(physiological) pH. However, the pH of a radiopharmaceutical is very important for 
its stability, and for labelled compounds, the pH for optimal stability is not always 
equivalent to physiological pH. For iodide solutions, the pH should be alkaline to 
prevent loss of radioiodine. Reducing agents, such as thiosulfate, are often added to 
radioiodide solutions to help this situation. A preservative can act as a stabilizer, an 
antioxidant, or a bactericidal agent. 
Some additives, like benzyl alcohol, are added for a double action. Benzyl alcohol 
0.9% is widely used as a bactericide. In addition, benzyl alcohol reduces radiolysis 
in radiopharmaceuticals and thus acts as a stabilizer. 
1.3.3.3 Design of Production Equipment 
The equipment used for manufacturing operation should be reserved exclusively 
for radiopharmaceuticals [6] . Furthermore, two principles are of utmost importance 
in the design of production equipment [4] : 
MANUFACTURING ASPECTS 71

72 RADIOPHARMACEUTICAL MANUFACTURING 
The equipment must be easy to repair after it has been installed in the production 
unit. 
The equipment must have a simple construction and be easy to assemble, so a 
substitution can be done quickly when total renovation of the equipment is 
necessary. 
Glass is an important material in the construction of production equipment for 
radiopharmaceuticals. This material will become discolored and brittle when affected 
by radiation, and thus repair and/or change of parts of the equipment may be necessary. 
Due to radioactive contamination of the equipment, repair and maintenance 
can often be complicated, and time for decay must be included in the maintenance 
period. To secure the continuous supply of products, it may be necessary to construct 
two production lines in separate production units, where one is kept as a backup 
facility. 
Sometimes it will be necessary to substitute not only parts of a production line 
but also the assembly of equipment as a whole. To facilitate this operation and 
thereby reduce time and radiation exposure, it can be advantageous to build the 
whole production line on a stainless steel support frame fi tted with simple connections 
to electricity, water, and air supplies [4] . The complete withdrawal of a production 
line from a box and the introduction of a new one can then be performed in a 
very short time. 
It is also important to keep in mind, when designing production equipment, that 
all sense of touch is lost when fi ngers are replaced by remote handling tongs. 
The design of the equipment must therefore be as simple as possible. On the 
other hand, when using hot - cell units mounted with handling tongs, it may be favorable 
to use more automated systems in the production line. Systems like these can 
be run and controlled from steering panels outside the box unit. 
Finally, equipment should be constructed so that surfaces that come in contact 
with the product are not reactive, additive, or absorptive so as to alter the quality 
of the radiopharmaceutical. 
1.3.3.4 Cleaning and Sanitation of Production Equipment 
Preparation equipment should be designed so it can be easily and thoroughly 
cleaned. Procedures for cleaning, sanitation, and storage of production equipment 
used in radiopharmaceutical production must be established. Special training is 
necessary for personnel involved in this kind of work with regard to both clean - 
room aspects and radiation protection aspects. 
Before any equipment or materials used during production are removed from 
the production unit, a check for radioactive contamination must be performed. After 
removal, the equipment should be allowed to decay further in a special storage area 
before it is cleaned and made ready for assembly again. 
Glass equipment will normally be sterilized by dry - heat sterilization. Smaller 
equipment, like plastic tubes and rubber stoppers, can be sterilized by autoclaving. 
If available locally, also . irradiation may be a suitable method for sterilization 
of equipment. One must keep in mind, though, that sterilization by irradiation may 
change the composition of plastic and rubber materials. In addition, glass materials 
may be discolored by . irradiation. 

Production equipment that cannot be sterilized must be sanitized and disinfected 
by an appropriate method. This can be done by use of biocides like alcohols (70%), 
hydrogen peroxide, or formaldehyde - based chemicals or a combination of these. 
These can either be used for surface disinfections by wiping or spraying or even 
better by use of gas or dry fog systems for application of the disinfectants. The effect 
of cleaning and sanitation should be monitored. Microbiological media contact 
plates can be used to test critical surfaces, as inside the hot cells or glove boxes. The 
test samples must then be handled and monitored as radioactive contaminated 
units. 
A system must be established for sanitation of all equipment before these are 
transferred into clean areas. 
1.3.3.5 Environmental Control 
Workstations and their environment should be monitored with respect to radioactivity, 
particulate, and microbiological quality. Active air sampling from production 
units for radioactive products (hot cells or glove boxes) is subject to a safety consideration. 
There is always a risk of bringing radioactive contaminated air outside 
the workstation. To avoid the spread of radioactivity during the test, all possible 
exhaust from the test equipment must be sampled and/or controlled. 
A possible approach for testing of particulate and microbiological quality of air 
inside the hot cells or glove boxes is to gain information about airborne particles 
during simulated operations (without radioactivity). 
The use of settle plates is common practice for monitoring of the microbiological 
quality of air inside production units. These must then be placed as close a possible 
to critical parts of the production process in order to show the real microbiological 
burden to the product. 
Warning systems must be installed to indicate failure in the fi ltered air supply to 
the laboratory. Recording instruments should monitor the pressure difference 
between areas where this difference is of importance. 
1.3.3.6 Sterilization of Radiopharmaceuticals 
Sterile radiopharmaceuticals may be divided into those which are manufactured 
aseptically and those which are terminally sterilized. In general, it is advisable to 
use a terminal sterilization whenever this is possible. Terminal sterilization is defi ned 
as a process that subjects the combined product/container/closure system to a sterilization 
process that results in a specifi ed assurance of sterility [7] . Since sterilization 
of solutions normally means autoclaving (steam sterilization), one must assure that 
the radiopharmaceutical product does not decompose when it is heated to temperatures 
above 120 ° C. Many radiolabeled compounds are susceptible to decomposition 
at higher temperatures. Proteins, such as albumin, are good examples of this. Others, 
such as 18 F - fl uodeoxyglucose (FDG), can be autoclaved in some formulation but 
not in others. 
Furthermore, these processes take time, typically 20 – 30 min in total when heating 
up to 121 ° C. For very short - lived product with a half - life of only a few minutes, this 
is not an adequate method. On the other hand, these short - lived products are not 
subject to any storage, and thus the risk of microbiological growth is more limited. 
MANUFACTURING ASPECTS 73

74 RADIOPHARMACEUTICAL MANUFACTURING 
Alternatively, a shorter cycle at a higher temperature might be used, assuming that 
the temperature does not decompose the radiopharmaceutical. 
If terminal sterilization is not possible, aseptic processing must be performed. 
Aseptic processing is a process that combines presterilized materials and presterilized 
equipments in a clean area. 
Heating of radioactive solutions, particularly under elevated pressure (e.g., steam 
sterilization), is also a matter of safety. In order to avoid any contaminated air to 
escape if a container or a seal is broken, autoclaves used for radioactive solutions 
should be placed inside negative - pressure sealed units. Autoclaves used for sterilizing 
high - energy . - emitting radiopharmaceuticals should in addition be supplied with 
proper lead shielding. 
1.3.3.7 Starting Materials 
As for manufacturing of other pharmaceuticals, a system should be established to 
verify the quality of the starting materials used in manufacturing radiopharmaceuticals. 
This system must assure that no material is used for production until it has 
been released by a competent person [qualifi ed person (QP) or others given this 
responsibility]. 
The starting materials as well as the packaging materials should be purchased 
from qualifi ed vendors. It is recommended to use materials described in a pharmacopoeia, 
whenever this is available. Supplier approval should include an evaluation 
that provides adequate assurance that the material consistently meets 
specifi cations. 
Radionuclides involved in manufacturing radiopharmaceuticals must be considered 
as starting materials. For very short - lived radionuclides, where batch analysis 
is not possible, the validation of the production process of the radionuclide is of 
utmost importance. 
1.3.3.8 Labeling and Packaging 
Packaging material should be purchased from qualifi ed vendors. Primary containers 
and closures must be tested to verify that there are no interactions between the 
radiopharmaceutical and packaging material during storage of the product. 
Due to the risk of radiation exposure, it is accepted that most of the labeling of 
the primary (direct) container is done prior to manufacturing. The empty vial can 
be prelabeled with partial information prior to fi ltration and fi lling [6] . This procedure 
should be designed so as to not compromise sterility or prevent visual inspection 
of the fi lled vial. After fi lling of radioactive products, the primary containers 
(vials) must be placed within a shielded container. These containers, which can be 
made of lead or tungsten, vary in size and thickness depending on the amount of 
radioactivity in the vial as well as the radiation properties of the radionuclide. 
Radiopharmaceuticals containing . or . emitters may be placed in thin lead pots, 
typically 2 – 4 mm in wall thickness. On the other hand, for vials containing regular 
doses of high - energy . emitters, such as PET radionuclides, shielding with 3 – 5 cm 
lead/tungsten may be needed. 
Necessary information about the product must be given on the label of the lead 
or tungsten container. Hence, there is no need to study the label on the direct con

PRODUCT MANUFACTURING 75 
tainer. The name of the radiopharmaceutical, including the radionuclide, together 
with the amount of radioactivity in the vial at a stated calibration time is part of the 
necessary information. So is the expiry date of the product. Furthermore, the symbol 
for radioactivity, designed as a black propeller, is obligatory on labels for radioactive 
solutions. 
When the products are intended for distribution and transport, the packaging 
and labeling of the outer packages must be done according to the national regulation 
of the country from which the shipments will depart, transfer, and arrive. The 
outer packaging material must be properly tested in accordance with the type of 
shipment, most frequently type A packages for radiopharmaceuticals. Furthermore, 
the packages must be labeled with radionuclide data, such as type and amount of 
radioactivity, along with the transport index (TI), which indicates the radiation from 
the package at 1 m distance. While the information on the product itself (outside 
the lead pot) is intended for the physicians, the information outside the package is 
intended for the transport personnel. 
1.3.4 PRODUCT MANUFACTURING 
1.3.4.1 Production of Radionuclides 
Radiopharmaceuticals are labeled with artifi cial radionuclides that are obtained by 
bombardment of stable nuclei with subatomic particles or photons. Nuclear reactions 
produced in such a way convert stable in unstable (radioactive nuclei). Several 
kind of devices are used for such purposes, including nuclear reactors, particle accelerators, 
and generators. 
Various types of targets have been designed and used for both reactor and cyclotron 
irradiation. In the design of targets, primary consideration is given to heat 
deposition in the target by irradiation with neutrons in the reactors or charged 
particles in the cyclotrons [2] . As the temperature can rise to 1000 ° C during irradiation 
in both reactors and cyclotrons, the target needs proper cooling to avoid 
burning. Most often, the targets are designed in the form of a foil to maximize the 
heat dissipation. The target element should ideally be monoisotopic or an enriched 
isotope to avoid extraneous nuclear reactions. 
Nuclear Reactors Nuclear reactors are highly complex systems in which two kinds 
of nuclear reactions are useful for the production of clinically useful radionuclides: 
Neutrons produced by the fi ssion of heavy nuclides (such as 235 U or 239 Pu) are used 
in a neutron capture (n, . ) reaction to produce an isotope of the same element 
that is bombarded by the neutrons. Such reactions can be produced almost in all 
elements with different probability. Examples of useful nuclear reactions are 
130 Te(n, . ) 131 Te (which produces 131 I after emission of . particles with a half - life of 
25 min), 50 Cr(n, . ) 51 Cr, 58 Fe(n, . ) 59 Fe, and 98 Mo(n, . ) 99 Mo. The second possibility for 
the use of nuclear reactors is to use fi ssion reactions (n,f) in which a heavy nuclide 
is broken down into two fragments. Many clinically relevant radionuclides can be 
produced from thermal fi ssion of 235 U, such as 131 I, 117 Pd, 133 Xe, and 137 Cs. The isotopes 
produced by this kind of fi ssion reaction must be separated and purifi ed by appropriate 
chemical procedures, but since the chemical behavior of many different heavy 

76 RADIOPHARMACEUTICAL MANUFACTURING 
elements is similar, contamination can often become a problem in the isolation of 
the radionuclide of interest. 
As an example, and due to the particular interest of 99 Mo in radiopharmacy (as 
it is the parent nuclide of 99m Tc in the 99 Mo – 99 mTc generator), the complex process 
used to produce and purify 99 Mo is described below. 
Molybdenum - 99 is produced by fi ssion of 236 U as follows: 
235 1 236 99 135 1 2 U n U Mo Sn n + > > + + 
After irradiation of the uranium target, it is dissolved in nitric acid and the fi nal 
solution adsorbed on an alumina column that is washed with nitric acid to remove 
uranium (and other fi ssion products). Molybdenum is fi nally eluted with ammonium 
hydroxide and further purifi ed by absorption on an anion exchange column from 
which ammonium molibdate is eluted with dilute hydrochloric acid after washing 
the resin with concentrated HCl. The 99 Mo is obtained in no - carrier - added conditions, 
and the most common contaminants can be 131 I and 103 Ru. 
Particle Accelerators: Cyclotrons Both linear and circular particle accelerators 
(cyclotrons) can be used, but the latter have many advantages and are mainly used 
for the production of clinically relevant radionuclides. 
A cyclotron is basically a cylinder - shaped high - vacuum chamber in which by 
means of a magnetic fi eld and a radio - frequency system used to generate an alternating 
electric fi eld, elemental particles can be accelerated to very high energies and 
used as projectiles. The bombardment of stable elements loaded in a properly 
designed target (either solid or fi lled with a liquid or a gas) induces different types 
of nuclear reactions that fi nally lead to the production of radioactive elements. 
Most cyclotrons accelerate negative particles (such as 2 H, 1 H, or even heavier 
particles such as helium cations) that are stripped off the electrons in the stripping 
foils that are used also to focus the beam on the target. As the energy of the incident 
particle is increased, a much greater variety of nuclides can be produced. 
When the nuclides produced have atomic numbers different from those of the 
target elements, such preparations have no stable isotope of the intended element 
and can be considered to be produced in no - carrier - added conditions. 
The target material should ideally be monoisotopic to avoid the production of 
extraneous radionuclides. However, in many cases this is not possible and only isotopically 
enriched targets can be used, thus leading to the production of different 
radionuclides. In this case appropriate methods must be used to separate the different 
elements produced in the target. 
An interesting concept that must always be taken into account in cyclotron - 
produced radionuclides is the saturation activity characteristic of each target and 
each nuclear reaction. The saturation activity is the activity of the radionuclide in 
which the secular equilibrium is obtained between the activity produced in the 
target and the disintegration of the radioisotope. The activity produced at a target 
can be calculated by the equation 
A A e t T = .. 
S 
/ A ( )( ) (ln ) 1 2 . 
where A is the activity obtained for a radionuclide with a half - life of T after irradiation 
of the target during a time of t at a current of . A microamperes. From the 

PRODUCT MANUFACTURING 77 
practical point of view, almost 97% of the saturation activity value is reached after 
irradiation of the target for fi ve half - lives of the radionuclide. Longer irradiation 
times do not produce signifi cant increases in the activity obtained. Methods to 
obtain several cyclotron - produced radionuclides are described below. 
Iodine - 123 can be produced either directly or indirectly in a cyclotron. Direct 
reactions usually lead to 123 I contaminated with other iodine radioisotopes, such as 
124 I or 125 I, due to side nuclear reactions. Using nuclear reactions such as 123 Te(p,n) 123 I, 
122 Te(d,n) 123 I, or 124 (p,2n) 123 I produces 123 I that is obtained after dissolving the target 
in hydrochloric acid by distillation into dilute NaOH. 
In the indirect methods the radionuclide produced after bombardment of the 
target is not 123 I, but a radionuclide that decays to 123 I with a short half - life. The most 
widely used nuclear reactions produce 133 Xe (which decays to 123 I with a half - life of 
2.1 h) by bombardment with high - energy 3 He or 4 He particles or 123 Cs (which decays 
to 123 Xe with a half - life of 5.9 min, and then 123 Xe decays to 123 I) after irradiation of 
124 Xe with high - energy protons. Complex processing and purifi cation processes must 
be used to obtain 123 I in any of these cases, and adequate design and composition 
of the target are critical to facilitate the process. 
Thallium - 201 is obtained using an indirect reaction such as 203 Tl(p,3n) 201 Pb in 
which 201 Pb decays to 201 Tl with a half - life of 9.4 h. Thallium - 201 can in this way be 
obtained pure and free from other contaminants after several purifi cation steps and 
letting the target product decay for 35 h. 
Indium - 111 is produced by a direct nuclear reaction by irradiation of an 111 Cd 
target with 15 - MeV protons. After irradiation the target is dissolved in HCl and 
purifi ed in an anion exchange column. 
Positron emission tomography has become a widely used diagnostic technique in 
nuclear medicine. Ultrashort half - live radionuclides are used in these cases, and such 
radionuclides are mostly obtained in small cyclotrons with high yields and short 
irradiation times. The overall process will be described further in this chapter when 
PET radiopharmaceuticals are described. 
Generators A generator is constructed on the principle of the decay – growth relationship 
between a parent radionuclide with longer half - life that produces by disintegration 
a daughter radionuclide with shorter half - life. The parent and the 
daughter radionuclide must have suffi ciently different chemical properties in order 
to be separated. The daughter radionuclide is then used either directly or to label 
different molecules to produce radiopharmaceutical molecules. 
A typical radionuclide generator consists of a column fi lled with adsorbent material 
in which the parent radionuclide is fi xed. The daughter radionuclide is eluted 
from the column once it has grown as a result of the decay of the parent radionuclide. 
The elution process consists of passing through the column a solvent that 
specifi cally dissolves the daughter radionuclide leaving the parent radionuclide 
adsorbed to the column matrix. 
The main advantage of the generators is that they can serve as top - of - the - bench 
sources of short - lived radionuclides in places located far from the site of a cyclotron 
or nuclear reactor facilities. 
A generator should ideally be simple to build, the parent radionuclide should 
have a relatively long half - life, and the daughter radionuclide should be obtained 
by a simple elution process with high yield and chemical and radiochemical purity. 
The generator must be properly shielded to allow its transport and manipulation. 

78 RADIOPHARMACEUTICAL MANUFACTURING 
Several different generators are used in radiopharmaceutical procedures, but the 
99 Mo/ 99m Tc is with great difference the most important generator of all of them and 
will be described in detail later on in this chapter. 
1.3.4.2 Production of Radiopharmaceuticals 
More than 90% of the radiopharmaceuticals used in nuclear medicine are for diagnostic 
use. PET radiopharmaceuticals, with their ultrashort half - lives, have become 
a signifi cant part of this group of products. Hence PET investigation has been the 
fastest growing imaging modality worldwide the last few years [8] . 
Also for conventional radiopharmaceuticals used in diagnostic, it is favorable to 
use products with short half - lives. Radionuclide generator systems are widely used 
for supply of short - lived radionuclides/radiopharmaceuticals. Several generator 
systems are available and routinely in use within nuclear medicine. Some of these 
are listed in Table 1 . 
Because of the short half - life, the coupling of the radionuclide to the carrier 
molecule must be done immediately before the administration. Hence, there is a 
need to have a constant supply of carrier molecules that can be labeled effi ciently 
on site. For this purpose, several preparation kits have been developed. 
Ready - for - use diagnostic radiopharmaceuticals which are intended for transport 
over some distance typically include radionuclides with half - lives from 13 h and up. 
Among these, products involving the radionuclide 131 I are used for both diagnostic 
and therapeutic indications. This is based upon the mixed emitting properties of 
the radionuclide, giving both . and . emission. The availability, price, and half - life 
(8 days) of this radionuclide, together with the physical properties, have probably 
made it the most commonly used radionuclide in radiotherapy. Although 131 I also is 
frequently used for diagnostic purposes, the radiation characteristics of this radionuclide 
are not really ideal for use in conventional scintigraphy (SPECT) due to 
the high . energies. In addition, the . emission from this radionuclide gives the 
patients an unnecessary radiation burden. Hence, other radionuclides are preferred 
for use in diagnostic nuclear medicine. 
The radioiodine 123 I, on the other hand, is very useful in nuclear medicine because 
it has good radiation characteristics for scintigraphy, such as decay by electron 
capture, a half - life of 13 h, and . emmision of 159 keV. However, the much shorter 
half - life, together with the more complex radionuclide production, makes this radionuclide 
less available and more expensive compared to 131 I. 
There are several 131 I and 123 I radiopharmaceuticals on the market, for both oral 
and parenteral administration. Ready - for - use radiopharmaceuticals that contain 
TABLE 1 Several Radionuclide Generator Systems Useful in Nuclear Medicine 
Parent Nuclide t1/2 Daughter Nuclide t1/2 
68 Ge 280 days > 68 Ga 68 min 
81 Rb 4.7 h > 81m Kr 13 s 
99 Mo 66 h > 99m Tc 6 h 
113 Sn 117 days > 113m In 100 min 
188 W 69.4 days > 188 Re 17 h 

PRODUCT MANUFACTURING 79 
these radionuclides will normally be manufactured by radiopharmaceutical 
companies and distributed to the marked according to a marketing authorization 
(MA). 
Although therapeutic application represents less than 10% of the nuclear medicine 
investigations, therapeutic radiopharmaceuticals are a very important group 
of radiopharmaceuticals. Hence, a brief description is outlined for production of 
therapeutic radiopharmaceuticals following some other selected groups of 
radiopharmaceuticals. 
99 M o / 99m T c Generators The essential part of the most commonly available generator 
system is a simple chromatography column to which the mother radionuclide is 
absorbed on a suitable support material. The daughter radionuclide is a decay 
product of the mother nuclide. Since it is the daughter nuclide that is used to label 
the carrier molecules, it must be possible to separate this from the parent nuclide 
by a chemical separation. 
In a 99 Mo/ 99m Tc generator, the 99 Mo (molybdenum) is fi xed as molybdate to aluminum 
oxide in the column. The daughter nuclide, 99m Tc (technetium), is eluted from 
the column as pertechnetate when using saline solution. Molybdenum - 99 has a half - 
life of 66 h, while 99m Tc has a half - life of 6 h. This is an ideal combination of half - lives, 
giving a system where the daily supply of 99m Tc can easily be calculated from the 
known amount of 99 Mo on the column. The half - life of 99m Tc, along with the radiation 
characteristics of the nuclide, makes it excellent for use in nuclear medicine 
imaging. After reconstitution of kits and formation of various radiopharmaceuticals, 
this radionuclide is used in a major part of all nuclear medicine procedures. 
Although the principle for the generators is similar, the design of 99 Mo/ 99m Tc 
generators from different manufacturers can differ a lot. A drawing of a 99 Mo/ 99m Tc 
generator is shown in Figure 4 . In general, the generator consists of a column with 
adsorbent material where the radionuclide 99 Mo is applied. The column is combined 
with a needle system necessary for the elution process. A sterile fi lter is fi tted on 
the air inlet side of the needles to keep an aseptic system during elution. The saline 
solution for elution may be supplied as a bulk solution suffi cient for several elutions 
FIGURE 4 Typical radionuclide generator system ( ISOTEC, GE Healthcare, AS ). 
1. Saline solution, volume: 5,10, or 15mL 
2. Evacuated vial 
3. Lead shield for eluate 
4. Air filter (0.22 .m) 
5. Special designed stainless steel needles 
6. Glass column with Al2O3 
7. Plastic container 
8. Lead shield (min. 45-mm lead) 
9. Laboratory shield (min. 50-mm lead)

80 RADIOPHARMACEUTICAL MANUFACTURING 
or dispensed volumes suffi cient for a single elution. For both, vacuum is normally 
used to run the elution of the column using sterile evacuated vials. 
Finally, due to the relatively high radiation from 99 Mo, the system must be properly 
shielded by either lead or a combination of lead and tungsten. 
Whether the column is designed to contain liquid after and between elutions, 
determine if this is a wet - column generator or a dry - column generator. When 
liquid is retained at the column (wet generator), radiolysis of water on the column 
may occur as a result . irradiation from 99 Mo. This may change the chemistry on 
the column and thus reduce the yield when eluting the generator. Most commonly, 
when manufacturing wet - column generators, oxidizing agents are added either to 
the saline or to the column itself to avoid reduction of pertechnetate on the 
column. 
A radionuclide generator must be sterile and pyrogen free. Most commonly, the 
generator is sterilized by autoclaving the entire column after the molybdate has 
been bound to the aluminum oxide. Other critical procedures during the production 
and the assembly of the generator must be performed under aseptic conditions. 
Elution of the generator must also be carried out under aseptic conditions while 
using only sterile accessories. 
Other Generators Of the generators listed in Table 1 , two systems are of particular 
interest in nuclear medicine today along with the 99 Mo/ 99m Tc generator, namely the 
68 Ge/ 68 Ga generator and the 81 Rb/ 81m Kr generator. 
68 G e / 68 G a Generator Germanium - 68 has a half - life of 271 days, and 68 Ga (gallium) 
a half - life of 68 min. Gallium - 68 is a PET emitter, and this generator system is a 
valuable source of a short - lived radionuclide in a radiopharmacy or nuclear medicine 
department. However, the system is not as easy or effi cient as the 99 Mo/ 99m Tc 
generator. On the other hand, the longer half - life of the mother nuclide allows use 
of the system for several months. 
This generator can be made up of aluminum loaded on a plastic or glass column. 
Carrier - free 68 Ge in concentrated HCl is neutralized in ethylenediaminetetraacetic 
acid (EDTA) solution and adsorbed to the column. Then 68 Ga is eluted from the 
column with 0.005 M EDTA solution. Alternatively, 68 Ge is adsorbed on a stannous 
dioxide column and 68 Ga is eluted with 1 N HCl [2] . 
81 R b / 81m K r Generator Rubidium - 81 has a half - life of 4.6 h and decays to 81m Kr 
(krypton) by electron capture. Krypton - 81m has a half - life of 13 s and decays by 
isomeric transition emitting . rays of 190 keV. Being an inert gas 81m Kr is used for 
lung ventilation study. 
The parent 81 Rb is adsorbed on an ion exchange resin, and the daughter 81m Kr is 
eluted with air. Because of the very short half - life of 13 s, the studies can be repeated 
every few minutes, and no radiation safety precaution for trapping 81m Kr is needed 
[2] . 
Radiopharmaceutical Kits Radiopharmaceutical kits are nonradioactive ( “ cold ” ) 
products containing the sterile ingredients needed to prepare the fi nal radiopharmaceutical. 
Immediately before administration to the patient, the radionuclide is 
added. From the point of licensing, these semimanufactured products are defi ned 
as radiopharmaceuticals, as they have no other application in medicine [2] . 

PRODUCT MANUFACTURING 81 
Most of these preparation kits have been developed for labeling of various substances 
with 99m Tc. Labeling is normally a single - or two - step procedure consisting 
of adding a solution of 99m Tc - pertechnetate to the preparation kit. The preparation 
kit contains the ingredient necessary for labeling, such as the substance or ligand to 
be labeled, a reducing agent, buffers for pH adjustments, and various stabilizers. The 
reducing agent, very often a stannous salt, is added to bring the radionuclide into a 
valence state with high reactivity. 
Most preparation kits are lyophilized, and the reason for this is to extend the 
shelf life of the products. Some preparation kits can in fact be stored for more than 
one year. Since these products are not radioactive, conventional clean rooms and 
clean - room technology can be applied for production of preparation kits. Most of 
these products have to be produced aseptically, as they cannot be sterilized with 
other methods. During lyophilization of the preparation kits used for 99m Tc labeling, 
it is very important to remove all the oxygen from the kit vial. This is to ensure the 
right valence of the tin salt. Normally, the vials are fi lled with an inert gas, such as 
nitrogen, before the vials are closed completely. It is important, though, that the gas 
is dried. Some manufacturer chose to not completely replace the removed oxygen, 
giving a slightly negative pressure inside the kit vial. This may be favorable for the 
kit - labeling procedure. 
Therapeutic Radiopharmaceuticals Radiopharmaceuticals used for therapy 
(radiotherapy) are designed such that, after administration, they act locally at a 
target by either damaging or killing cells by irradiation. One of the attractions of 
radionuclide therapy is the existence of radiation with quite different dimensions 
of effectiveness, ranging from subcellular (Auger electrons) to hundreds of cell 
diameters ( . particles). In between, . emitters have a tissue range equivalent to 
only a few cell diameters [9] . Alpha emitters have a very high linear energy transfer 
(LET), being very potent at short distances. 
Table 2 lists a selection of radionuclides and radiopharmaceuticals used in 
radiotheraphy. 
TABLE 2 Selected Radionuclides and Radiopharmaceuticals Used for Radiotherapy in 
Routine Use or as Part of Clinical Investigations 
Radionuclide Mode of decay t1/2 Radiopharmaceuticals 
131 I . . / . 8.04 days 131 I - NaI, 131 I - MIBG, 131 I - mAbs 
90 Y . . 2.7 days 90 Y - colloid, 90 Y - DOTATOC, 90 Y - mAbs 
186 Re . . / . 3.8 days 186 Re - sulfi de, 186 Re - HEDP 
188 Re . . / . 17 h 188 Re - HEDP 
177 Lu . . / . 6.6 days 177 Lu - DOTA - Tyr3 - octreotide 
153 Sm . . / . 1.9 days 153 Sm - EDTMP 
89 Sr . . 50.6 days 89 Sr - chloride 
223 Ra . / . 11.4 days 223 Ra - chloride 
211 At . 7.2 h 211 At - mAbs 
213 Bi . 46 min 213 Bi - mAbs 
166 Ho . . / . 26.8 days 166 Ho - colloid 
169 Er . . 9.4 days 169 Er - citrate colloid 
165 Dy . . / . 2.3 h 165 Dy - ferric hydroxide macroaggregate 
32 P .. 14.3 days 32 P - ortho - phosphate 

82 RADIOPHARMACEUTICAL MANUFACTURING 
Pure . and . emitters are easy to shield, and thus production involving these can 
be performed in sealed production units with no lead protection. One must keep in 
mind, though, the potential hazard when inhaling some of these materials. Moreover, 
many radionuclides used for radiotherapy have an additional . component. 
Hence, local lead shielding may be necessary. If the . component is larger or represents 
very high energy emission, a total lead shielded unit may be necessary. The 
latter will be the case when manufacturing 131 I radiopharmaceuticals for therapy, 
since 131 I is a radionuclide consisting of a high - energy . photon together with the . 
component. 
Radiopharmaceuticals for therapeutic use must have a high target - to - background 
ratio. Targeted radiotherapy involves the use of molecular carrier such as a 
receptor - avid compound or an antibody to deliver a radionuclide to cell 
populations. 
A challenge when performing radiolabeling of carrier molecules for targeted 
radiotherapy is the potential risk of radiolysis due to the radiation characteristics 
of the radionuclides involved. When increasing the specifi c activity, as part of the 
scaling up, the risk of radiolytic decomposition of the labeled compound also 
increases. This is particularly pronounced when using . emitters. The addition of 
stabilizers in the form of scavengers can reduce this risk. Benzyl alcohol is an 
example of a compound that acts as a scavenger by catching up with free radicals 
in the solution. 
Another approach is to use kit formulations also for this kind of product. Therapeutic 
radiopharmaceuticals have been developed where the carrier molecule is 
formulated in a lyophilized kit and supplied together with the radionuclide. An 
example of this is the MAb ibritumomab tiuxetan formulated for labeling with the 
. - emitting radionuclide 90 Y. Yttrium - 90 ibritumomab tiuxetan (Zevalin) is used in 
the treatment of non - Hodgkin ’ s lymphoma (NHL). 
The labeling is performed in a centralized radiopharmacy, hospital radiopharmacy, 
or nuclear medicine department immediately before use. 
Radioactive Sanitary Products Radioactive sanitary products could be considered 
as radiopharmaceuticals according to the defi nition given in directive 2001/83/ 
EC, although there are signifi cant differences between radioactive sanitary products 
and classical radiopharmaceuticals. The former can in fact be considered as 
encapsulated radioactive sources, although with the use of microencapsulated sanitary 
products (such as micrometer - sized glass or polymer beads loaded with a 
radionuclide), the difference between both types is becoming more diffi cult to 
establish. 
In any case, radioactive sanitary products are delivered locally (and not systemically 
or orally) for the local treatment of a disease. The idea is to give a high dose 
of radiation to a specifi c part of the body by the implantation of the corresponding 
sanitary product in the desired zone. The sanitary product must not be metabolized, 
destroyed, or removed from the place it has been located during a suffi ciently long 
time as to give the desired high radiation dose. 
The most commonly used radioactive sanitary products are millimeter - sized 
seeds or needles loaded with 103 P, 192 Ir, 90 Sr, or 125 I. Currently micrometer - sized or 
even nanometer - sized beads loaded with 90 Y are being used for the treatment of 
specifi c diseases. 

PRODUCT MANUFACTURING 83 
PET Radiopharmaceuticals PET radiopharmaceuticals are labeled with short - 
lived positron - emitting radionuclides. Such radionuclides can either be produced in 
a cyclotron or obtained from an appropriate radionuclide generator. 
General Considerations The synthesis of PET radiopharmaceuticals has several 
peculiarities substantially different from the procedures followed to prepare conventional 
. - emitting radiopharmaceuticals. A very important issue that must be 
considered is the specifi c activity. For all radiopharmaceuticals it is usually very high 
and can be calculated from the formula 
A 
k 
AT e 
/ 
= 
1 2 
where A e is the specifi c activity, A the mass number of the radionuclide, and T 1/2 its 
half - life. It is then clear that the achievable specifi c activity is higher for radionuclides 
with shorter half - lives, as is the case for the most relevant PET radionuclides 
( 18 F and 11 C). As an example, 18 F produced in no - carrier - added conditions can be 
obtained with specifi c activities of almost 10 10 Ci/mmol, resulting in PET radiopharmaceuticals 
with extremely high specifi c activities. 
For PET radiopharmaceuticals we must always consider that synthesis processes 
must be extremely fast. Consequently, synthesis schemes with as few steps as possible 
must be used, and each of the steps must proceed with high effi ciency. The 
incorporation of the radionuclide to the molecule should ideally be done in the fi nal 
steps of the synthesis. In this way two objectives can be achieved: reduce the overall 
synthesis time (thus increasing the yield) and reduce the number of side reactions 
and secondary undesired products obtained during the synthesis. 
The synthesis of PET radiopharmaceuticals is always carried out at very small 
scale (only a few dozen micrograms of the radiopharmaceutical are obtained) and 
each batch can sometimes only be used for a single patient or a few patients at most. 
Consequently, there is always a big excess of the precursor in the reaction medium, 
and proper purifi cation systems must be used to get rid of all the possible contaminants. 
Such systems must also be very effi cient and fast, and the most usual is to 
apply either semipreparative high - performance liquid chromatography (HPLC) or 
solid - phase extraction - based procedures. 
The position of the radionuclide in the molecule of interest is also critical as it 
will affect the biological behavior of the radiopharmaceutical. Chemical reactions 
must be designed to be stereospecifi c in many cases, as the production of a mixture 
of different stereoisomers complicates the purifi cation of the fi nal radiopharmaceutical. 
Synthesis procedures must also be easy to automate, as very elevated activities 
are used for the synthesis of PET radiopharmaceuticals (several curies usually) and 
appropriate radiation protection systems must be used. 
PET Generators Table 3 summarizes the characteristics of some PET generators. 
So far, the most widely used system has been the 82 Sr/ 82 Rb generator, although due 
to the specifi c physical and chemical characteristics of the daughter radionuclide 
and the half - life of the parent radionuclide, the 68 Ge/ 68 Ga generator is probably one 
of the most interesting systems. Recent advances in gallium chemistry have permitted 
the development of 68 Ga radiopharmaceuticals of clinical interest making 

84 RADIOPHARMACEUTICAL MANUFACTURING 
available PET studies at stand - alone PET centers without a cyclotron with other 
compounds different from the classical 18 FDG. 
PET Cyclotrons Cyclotrons used to produce positron emitters of clinical interest 
(see Tables 4 and 5 ), mainly 18 F and 11 C, do not need to be very big. In fact, small 
devices installed in hospital or academic institutions have long been used for such 
purposes (see Figure 5 ). These devices are easy to operate and maintain, and even 
with single - particle low - energy cyclotrons, it is possible to produce multicurie 
amounts of 18 F and 11 C. 
Some Positron Emitters of Clinical Interest Fluorine - 18 is undoubtedly the most 
widely used positron - emitting radionuclide. This is mainly due to the wide use of 
18 FDG, the PET radiopharmaceutical that has permitted PET to become an everyday 
clinical tool. With the exception of 18 FDG and probably 18 FDOPA, the use of 
other 18 F - labeled radiopharmaceuticals is very limited. However, the chemical and 
physical characteristics of 18 F are excellent: 
TABLE 4 Physical Characteristics of Some Positron 
Emitters of Clinical Use 
Isotope T1/2 (min) % E. + (keV) 
11 C 20.4 99.7 960 
13 N 9.9 99.8 1198 
15 O 2.0 99.9 1732 
18 F 109.6 96.7 634 
TABLE 5 Nuclear Reactions for Production of Most 
Widely Used Positron Emitters 
11 C 13 N 15 O 18 F 
14N(p,a)11C 16O(p,a)13 N 14 N(d,n) 15 O 18 O(p,n) 18 F 
10 B(d,n) 11 C 13 C(p,n) 13 N 15 N(p,n) 15 O 20 Ne(d, . ) 18 F 
11 B(d,2n) 11 C 12 C(d,n) 13 N 16 O( . ,pn) 18 F 
11 B(p,n) 11 C 19 F(p,pn) 18 F 
12 C(p,pn) 11 C 
Note: Most common reactions used in small cyclotrons are bolded. 
Different energies of the incident particle are needed for the different 
nuclear reactions 
TABLE 3 Selected of PET Generators 
Generator Parent T1/2 Daughter T1/2 
Fe/Mn 52 Fe 8.27 h 52m Mn 21.1 min 
Zn/Cu 62 Zn 9.13 h 62 Cu 9.73 min 
Ge/Ga 68 Ge 270.8 days 68 Ga 68.3 min 
Sr/Rb 82 Sr 25.6 days 82 Rb 76.4 s 

PRODUCT MANUFACTURING 85 
It can easily be produced in very high quantities (up to 7 – 9 Ci per batch) even 
in small cyclotrons with just a few hours irradiation time. 
The mean positron emission energy of 18 F is just 0.64 MeV (the lowest of all 
positron emitters with clinical use) and this has several important consequences: 
The dose of radiation received by the patient will be lower and the 
distance between disintegration of the radionuclide and the annihilation site 
(after collision of the positron with an electron) is reduced, thus making PET 
images with higher resolution possible. 
The half - life of 18 F (109 min) is suffi ciently long to carry out complex synthesis 
procedures, apply long PET imaging protocols, and carry out metabolite analysis. 
Furthermore, it is possible to produce the radiopharmaceutical in a laboratory 
and transport it to a distant site only equipped with an imaging device. 
These kinds of “ satellite PET centers ” have boomed all around the world and 
permitted the fast expansion of PET as an everyday clinical tool in certain 
pathologies (mainly in oncological diseases). 
Fluorine is not common in biological molecules, but many drugs contain this 
atom. Fluorine and hydrogen have quite similar radii, and changing a hydrogen to 
a fl uorine atom in a molecule does not usually generate substantial steric differences 
between both molecules. Nonetheless, the electronegativity of fl uorine is usually 
FIGURE 5 Small (less than 2 m in diameter) dual - beam negative ion cyclotron capable of 
easily producing multicurie amounts of 18 F and 11 C. ( Photo courtesy of PET - CUN Center, 
University of Navarra .)

86 RADIOPHARMACEUTICAL MANUFACTURING 
going to change substantially the physicochemical properties of the molecule (reactivity, 
hydrogen bonding, interactions with cognate receptors, metabolization, etc.). 
It is not possible to assume that the biological behavior of a molecule and its fl uorinated 
analog is going to be similar. On the contrary, it is advisable to fi nd substantial 
differences in lipophilicity, biodistribution, protein binding, affi nity for receptors, 
and so on. However, such modifi cations are in many cases very useful to permit the 
use of a 18 F - fl uorinated analog as a PET radiopharmaceutical. In fact, that is the 
case for the most widely use one: FDG. This compound, which accounts for probably 
more than 90% of the PET studies performed in the world every day, is a glucose 
analog that is taken up by the cells by GLUT transporters and metabolized just as 
glucose at the very fi rst steps of glicolysis. But as a consequence of the change of 
the C 2 OH group in natural glucose by a 18 F atom in FDG, the latter cannot be 
isomerized (once phosphorilated) and suffers metabolic trapping being specifi cally 
accumulated in tumoral cells. 
Carbon - 11 has a very short half - life (just 20.4 min) but the chance to substitute 
a carbon atom in any biological molecule by a positron - emitting 11 C is a very interesting 
possibility. This has led to a substantial development of 11 C - labeled tracers. 
The short half - life conditions everything and only PET centers equipped with a 
cyclotron can have a clinical program with 11 C tracers. The production of the radiopharmaceutical 
must in these cases be performed just before the imaging study and 
is usually not started until the patient is already on the PET scanner. 
The 12 C – 11 C substitution will produce chemically identical molecules and give the 
chance to study many biological processes by this noninvasive methodology and can 
also be used in new - drug research and development (R & D). 
Synthesis of PET Radiopharmaceuticals Albeit the requirements for the synthesis 
of PET radiopharmaceuticals previously described, the synthesis process could conceptually 
be reduced to a very simple scheme, as shown in Figure 6 . 
The concept is really simple, but there are considerable diffi culties in each of the 
steps. In many cases it is diffi cult to synthesize a properly designed cold precursor 
that will permit a simple direct reaction with few secondary products. No modifi ca- 
FIGURE 6 General reaction scheme for synthesis of PET radiopharmaceuticals. The precursor 
molecule (A) is designed with the adequate protecting groups (  ) and a reactive 
leaving group ( . ). A reactive form of the radionuclide (  ) is covalently joined to the precursor 
at the reaction site, while the leaving group is eliminated. An intermediate radioactive 
product (B) is obtained that is hence deprotected (2) to produce the fi nal radiopharmaceutical 
(C). A fast and effi cient purifi cation process of C is needed to get read of unreacted cold 
precursor, radionuclide, and intermediate products. 

PRODUCT MANUFACTURING 87 
tions in the confi guration of the chiral centers should be produced during the overall 
process and a simple purifi cation system able to purify the fi nal product in a very 
short time should be found. Additionally, all the reactions should be very fast (just 
several minutes at most) and be easy to automate to be performed in a computer - 
controlled device placed in a shielded hot cell. 
Production Process and Quality Control The production process includes the 
following: 
• Production of the radionuclide in the cyclotron and sending it to the PET 
radiopharmaceutical laboratory 
• Reaction of the radionuclide with an appropriate cold precursor, either in solution 
or in solid phase 
• Purifi cation of the radiopharmaceutical, usually by semipreparative radio 
HPLC or solid - phase extraction 
• Formulation of the fi nal product as an injectable solution (frequently including 
phase change in a rotary evaporator) and the adjustment of tonicity and pH 
• Sterile fi ltration or autoclaving 
The quality control of the fi nal product must be carried out before release of the 
batch (except for the sterility and the endotoxin tests for extremely short - lived 
radionuclides). Consequently, all procedures must not only be very fast but also very 
accurate, and in all cases it is very important to have a properly established quality 
assurance system that might permit parametric release of the produced batches. The 
quality control assays that must be carried out in the radiopharmaceutical includ 
the following: 
• Radionuclidic purity 
• Radionuclidic identity 
• Chemical purity 
• Radiochemical purity 
• Specifi c activity 
• Residual solvents 
• Visual inspection 
• Tonicity 
• pH 
• Sterility 
• Endotoxin 
A PET radiopharmaceutical laboratory must include the cyclotron bunker (where 
positron - emitting radionuclides are produced), the production laboratory, the 
quality control laboratory, and several different ancillary areas. 
In the production laboratory all synthesis and purifi cation processes are carried 
out in remote - operated fully automated computer - controlled systems (synthesis 
modules, see Figure 7 ) located in heavily shielded hot cells (see Figure 8 ). Dispensing 
of individual doses is in many cases also carried out by automated systems. 

88 RADIOPHARMACEUTICAL MANUFACTURING 
1.3.5 QUALITY CONSIDERATIONS 
1.3.5.1 Documentation 
Good documentation constitutes an essential part of the quality assurance system. 
As claimed in the European Community (EC) Guide to Good Manufacturing Practice 
(GMP), Chapter 4: “ Clearly written documentation prevents errors from spoken 
communications and permits tracing of batch history. ” In general, the requirements 
for documentation related to manufacturing of pharmaceuticals, as set in the GMP 
FIGURE 7 Automated synthesis module for PET radiopharmaceutical synthesis located in 
a shielded hot cell. ( Photo courtesy of PET - CUN Center, University of Navarra .) 
FIGURE 8 Production laboratory for PET radiopharmaceuticals. The 10 - cm lead shielded 
hot cells contain computer - controlled automated synthesis modules. ( Photo courtesy of PET - 
CUN Center, University of Navarra .)

regulations, are also valid for manufacturing of radiopharmaceuticals. A recent draft 
proposal of EC GMP Annex 3, “ Manufacture of Radiopharmaceuticals, ” outlines 
the following regarding this issue: 
All documents related to the manufacture of radiopharmaceuticals should 
be prepared, reviewed, approved, and distributed according to written 
procedures. 
Specifi cations should be established and documented for raw materials, labeling 
and packaging materials, critical intermediates, the fi nished radiopharmaceutical, 
and any other critical material. 
Acceptance criteria should be established for the radiopharmaceutical, including 
criteria for release and shelf life specifi cations. 
Records of major equipment use, cleaning, sanitization or sterilization, and maintenance 
should show the product, batch number, date and time, and signatures 
of the persons involved. 
Records should be retained for at least three years unless another time frame is 
specifi ed in national requirements. 
It is of utmost importance to have a system for implementing such documents. 
Any new master document or a new version of such a document must be followed 
by a training process for relevant operators. This training must be recorded as 
well. 
The recording of production data will make it necessary to bring batch documentation 
into the radioisotope laboratory. Hence, it is important to have routines that 
minimize the risk for radioactive contamination of the documents and to ensure 
that any contaminated documents will not leave the controlled area. Today, the use 
of computers instead of paper documents in the laboratory leaves most of the 
paperwork outside the controlled area. 
1.3.5.2 Qualifi cation of Personnel 
As a general principle in GMP, there should be suffi cient qualifi ed personnel to 
carry out all the tasks that are the responsibility of the manufacturer. Furthermore, 
individual responsibilities should be clearly understood by the individuals and 
recorded. 
For personnel working with radiopharmaceuticals, training and qualifi cation 
should cover general principles of GMP and radiation protection. This includes also 
personnel in charge of cleaning premises and equipment used for this type of production. 
All manufacturing operations should be carried out under the responsibility 
of a QP with additional competence in radiation protection. 
1.3.5.3 Quality Control 
All quality control procedures that are applied to nonradioactive pharmaceuticals 
are in principle applicable to radiopharmaceuticals. In addition, tests for radionuclidic 
and radiochemical purity must be carried out. Furthermore, since radiopharmaceuticals 
are short - lived products, methods used for quality control should 
QUALITY CONSIDERATIONS 89

90 RADIOPHARMACEUTICAL MANUFACTURING 
be fast and effective. Still, some radiopharmaceuticals with very short half - lives may 
have to be distributed and used after assessment of batch documentation even 
though all quality control tests have not been completed. It is acceptable, though, 
for these products to be released in a two - stage process, before and after full analytical 
testing. In this case there should be a written procedure detailing all production 
and quality control data that should be considered before the batch is dispatched. 
A procedure should also describe the measures to be taken by the QP if unsatisfactory 
test results are obtained after dispatch (GMP, Annex 3). 
The quality control tests fall in two categories: biological tests and physiochemical 
tests. The biological tests establish the sterility and apyrogenicity, while the 
physiochemical tests include radionuclidic, chemical, and radiochemical purity tests 
along with determination of pH, osmotic pressure, and physical state of the sample 
(for colloids). 
For lyophilized preparation kits containing reducing agents, such as 99m Tc kits, a 
test for moisture content can be necessary. Residual water in the freeze - dried pellet 
may lead to oxidation of the reducing agent. 
Radionuclidic Purity Radionuclidic purity is defi ned as the fraction of the total 
radioactivity in the form of the desired radionuclide present in a radiopharmaceutical. 
Radionuclide impurities may arise from impurities in the target material or from 
fi ssion of heavy elements in the reactor [2] . In radionuclide generator systems, the 
appearance of the parent nuclide in the daughter nuclide product is a radionuclidic 
impurity. In a 99 Mo/ 99m Tc generator, 99 Mo may be found in the 99m Tc eluate due to 
breakthrough of 99 Mo on the aluminum column. The presence of these extraneous 
radionuclides increases the radiation dose to the patient and may also obscure the 
scintigraphic image. 
Radionuclidic purity is determined by measuring the characteristic radiations 
emitted by individual radionuclides. Gamma emitters are distinguished from another 
by identifi cation of their . energies on the spectra obtained from a NaI crystal or a 
Ge (germanium) detector. This method is called . spectroscopy. 
Pure . emitters are not as easy to check as the . emitters. However, they may be 
checked for purity with a . spectrometer or a liquid scintillation counter. 
Radiochemical Purity The radiochemical purity (RCP) of a radiopharmaceutical 
is the fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical. 
Radiochemical impurities arise from decomposition due to the 
action of solvent, change in temperature or pH, light, presence of oxidizing or reducing 
agents, and radiolysis [2] . Examples of radiochemical purity are free 99m Tc - 
pertechenetate and hydrolyzed 99m Tc in labeled 99m Tc radiopharmaceuticals. The 
presence of radiochemical impurities in a radiopharmaceutical results in poor - 
quality images due to the high background from the surrounding tissues and blood. 
It also gives the patient unnecessary radiation doses. 
A number of analytical methods are used to detect and determine the radiochemical 
impurities in a given radiopharmaceutical. Most commonly used are 
methods like paper (PC), thin - layer (TLC), and gel chromatography, paper and gel 
electrophoresis, HPLC, and precipitation. A common principle for the different 
methods is that they can chemically separate the different radiolabeled components 
in the radiopharmaceutical. It may sometimes be necessary to perform more than 

one test method, for instance, TLC and HPLC, to get a complete picture of the different 
radiochemical impurities. Alternatively, one can use one chromatographic 
method consisting of a constant stationary phase but varying the mobile phase 
(solvent). An example is the radiochemical purity test of 99m Tc - methylenediphosphate 
(MDP), a radiolabeled phosphate used in bone scintigraphy. When using two 
TLC systems, one with sodium acetate as a solvent and one with methyl ethyl ketone 
(MEK) as a solvent, the different 99m Tc compunds in the product can be determined. 
A small aliquot of the radiopharmaceutical preparation is spotted on an instant 
thin - layer chromatography (ITLC) strip. The strip is dipped into the chromatography 
fl ask while keeping the spot above the solvent. During the chromatography 
process, the different components of the sample distribute differently in the ITLC 
strip, depending on the solubility and polarity of the components. In systems like 
this, each component is characterized by an R f value, defi ned as the ratio of the distance 
traveled by the component to the distance the solvent front has advanced 
from the original point of application of the test material. The distribution of the 
radioactive components on the strips can be monitored by use of an appropriate 
device for measuring radioactivity and printed in a chromatogram. Figure 9 shows 
typical chromatograms for 99m Tc - MDP in the TLC systems described above. 
Chemical Purity The chemical purity of a radiopharmaceutical is the fraction of 
the material in the desired chemical form. Chemical impurities may arise from the 
breakdown of the material either before or after labeling. Chemical impurities may 
also arise from the manufacturing process, such as aluminum in a 99m Tc eluate, 
coming from the aluminum column on the generator. Residuals of solvent from the 
radiopharmaceutical synthesis are also considered as chemical impurities. If the 
chemical impurity is present before labeling, the result may be undesirable labeled 
molecules. Furthermore, chemical impurities may cause a toxic effect. High - 
performance liquid chromatography and gas chromatography (GC) are important 
methods for determination of chemical impurities in a radiopharmaceutical. 
FIGURE 9 Typical chromatograms for 99m Tc - MDP. The left strip and chromatogram are 
obtained with ITLC - SG in sodium acetate. The right strip and chromatogram are obtained 
in methyl ethyl ketone (MEK). When combining these, any free pertechnetate ( 99m TcO 4 . ) 
and/or hydrolyzed 99m Tc can be detected. Thus the fraction representing 99m Tc - MDP (RCP) 
can be calculated. 
L1 L2 
TC-MDP + Hydr. Tc 
TC-MDP + Tc04– 
==> RCP =100% 
3954 
2966 
1978 
991
3
0.0
O F F 
51.5 103.0 154.5 206.0 
26054 1 1 
19540 
13027 
6514
0
0.0
O 
51.5 103.0 154.5 206.0 
Counts 
Counts 
Distance (mm) Distance (mm) 
QUALITY CONSIDERATIONS 91

92 RADIOPHARMACEUTICAL MANUFACTURING 
Sterility and Pyrogen Testing Sterility indicates the absence of any viable bacteria 
or microorganisms in a radiopharmaceutical preparation. Hence, sterility testing is 
performed to prove that radiopharmaceuticals are essentially free of viable microorganism. 
The test for microbial contamination of these products is best carried out 
with fi lter methods. It is a great advantage to incubate only the fi lters instead of the 
radioactive solutions. 
The test is performed according to the Ph.Eur/USP monograph on Sterility tests 
[13, 14] , but with an important modifi cation. Small batch sizes, typical for radiopharmaceuticals, 
make it necessary to use smaller test volumes than required in the 
monographs. Also the risk for radiation exposure supports this modifi cation. 
All radiopharmaceuticals for human administration are required to be pyrogen 
free. Also the tests for apyrogenicity must be modifi ed when applied for these products. 
The classical rabbit test for pyrogens was never a convenient test for parenteral 
radiopharmaceuticals. Practical problems due to radioactive rabbits and the need 
for larger test volumes made this a diffi cult task. Today, the Limulus amebocyte test 
(LAL) is the method of choice and has been accepted by the Ph. monographs for 
many years. This test is normally done within an hour, compared to several days for 
the rabbit test. 
However, even the LAL test may be too time consuming for the very short lived 
PET radiopharmaceuticals. Hence, less time consuming methods are in progress and 
will probably improve this situation. Meanwhile, it is accepted that the test for apyrogenicity, 
like the sterility test is for most radiopharmaceuticals, is fi nished after 
release of the most short lived radiopharmaceuticals. 
Bubble Point Testing of Filters Parenteral radiopharmaceuticals that are not terminally 
sterilized must undergo a sterile fi ltration process as part of the aseptic 
production procedure. Although the supplier certifi es the fi lters used, they must be 
checked for integrity after use to assure that there has been no leakage during the 
fi ltration. The integrity of the fi lter may be demonstrated by bubble point testing . In 
this test, the fi lter is placed and monitored under controlled pressure. When the test 
is done on wet fi lters, the pressure needed to push gas through the fi lter is defi ned 
as the bubble point. A fi lter with given pore width has a corresponding bubble point 
value. Most frequently, sterile fi ltration is performed by 0.22 - . m fi lters; hence the 
bubble point is about 3 – 4 bars. However, the fi lter supplier should specify the bubble 
point valid for a specifi c fi lter. 
Since this is an in - process test, special caution must be given to radiation protection. 
The test equipment should be placed within a closed and shielded unit and a 
system should be in place to collect any radioactive spill from the test. 
When the fi lter integrity test fails, the sterile fi ltration process must be rejected. 
Visual Inspection of Finished Product As part of the quality control, all parenterals 
will be subject to an inspection for the possible content of particles. Visual 
inspection of radiopharmaceuticals is more complicated than for other pharmaceuticals, 
as radiation protection guidelines strongly discourage any direct eye contact 
with radioactive sources. Normally, the visual inspection of a radiopharmaceutical 
is performed by placing the vial on a rotating station connected to a camera. The 
station is properly shielded, and the operators can study the solution on a distant 
screen. 

1.3.5.4 Validation and Control of Equipment and Procedures 
Preventive maintenance, calibration, and qualifi cation programs should be operated 
to ensure that all facilities and equipment used in the manufacture of radiopharmaceuticals 
are suitable and qualifi ed (GMP, Annex 3). Special emphasis should be put 
on critical equipment for handling of radiopharmaceuticals, such as dose calibrators 
that are used to check the accuracy of the dispensing of patient doses. Particular 
programs are outlined for checking the dose calibrator, including constancy, accuracy, 
linearity, and geometry. The general principles of validation outlined in the 
GMP regulations are valid for radiopharmaceuticals as well as for other pharmaceuticals. 
All validation activities should be planned and clearly defi ned and documented 
in a validation master plan (VMP). Special emphasis should be given on 
the validation of aseptic processes in the production of radiopharmaceuticals. 
Studies, including media fi ll tests, must be performed and recorded to demonstrate 
maintenance of sterility throughout the production process. This is particularly 
important since most radiopharmaceuticals are dispatched and used before the 
sterility test is fi nished. 
1.3.5.5 Stability Aspects of Radiopharmaceuticals 
As discussed already, radiopharmaceuticals are exposed to stability problems, particularly 
when radiolabeled compounds are involved. Decomposition of labeled 
compounds by radiolysis depends on the specifi c activity of the radioactive material, 
the energy of the emitted radiation, and the half - life of the radionuclide. Particles, 
such as . and . radiation, are more damaging than . rays, due to their short range 
and local absorption in matter. The stability of a compound is time dependent on 
exposure to light, change in temperature, and radiolysis. The longer a compound is 
exposed to these conditions, the more it will tend to break down. 
Stabilizers such as ascorbic acid and benzyl alcohol may be added to inhibit or 
delay the decompostion. Many preparations are stored in the dark under refrigeration 
to slow down the degradation of the material [2] . The expiry date of a radiopharmaceutical 
is based upon data from stability studies designed to demonstrate 
the described effects on the product after storage. 
Hence, for most stability studies on radiolabeled compounds, the radiochemical 
purity and pH are the most important physiochemical parameters to study. Moreover, 
for parenteral radiopharmaceuticals, a stability study also has to demonstrate 
the maintenance of sterility and apyrogenicity after storage. 
1.3.6 EXTEMPORANEOUS PREPARATION OF 
RADIOPHARMACEUTICALS 
An extemporaneous preparation is defi ned as a product which is dispensed immediately 
after preparation and not kept in stock [10] . Hence, many radiopharmaceuticals 
could fall into this category due to their limited shelf life. 
The use of extemporaneous preparation should be limited to situations where 
there is no product with marketing authorization (MA) available. This could be 
prepared based upon a prescription for a named patient (magistral preparation) or 
a production based upon a formula and prepared on a regular basis. The latter is a 
EXTEMPORANEOUS PREPARATION OF RADIOPHARMACEUTICALS 93

94 RADIOPHARMACEUTICAL MANUFACTURING 
common situation for many radiopharmaceuticals. For radiopharmaceuticals with 
short half - lives or rare indications, no sizable commercial market exists. Consequently, 
no pharmaceutical company will be prepared to obtain a MA for a product 
that will not yield a profi t due to these limitations. Still, there is a need from a 
medical point of view to have such products available. For radiopharmaceuticals 
incorporating radionuclides with a physical half - life of only a few minutes, only 
local production is feasible. They are therefore prepared in hospital pharmacies or 
laboratories and supplied for individual or small numbers of patients on a daily 
basis. 
The extemporaneous preparation of radiopharmaceuticals is regulated on a 
national level, and hence this regulation may differ from country to country. The 
Pharmaceutical Inspection Convention (PIC/S) has drafted a guide to good practices 
for preparations of medicinal products in pharmacies [10] , valid for medicinal 
products that do not have a MA, prepared extemporaneously or for stock. For 
medicinal products prepared to a larger extent or for use in clinical trials, industrial 
GMPs are applicable. Although the suggested guide outlines a general principle 
according to GMP, different requirements are particularly evident when it comes to 
documentation and quality control testing. There is also a discussion about the 
grades of background environment needed for production, with a differentiation 
between products with shelf lives less than or longer than 24 h [10] . While aseptic 
manufacturing according to industrial GMP has to be performed in grade A with a 
grade B background, this proposed guide opens for a relaxation to this. For an 
aseptic preparation of a product with a shelf life of less than 24 h, using a biohazard 
safety cabinet (BSC), the background environment may be grade D. Even for products 
with a shelf life longer than 24 h, an extensively documented procedure may 
allow grade C in background, as long as grade B clothing is worn. In general, the 
referred draft guide is based much upon a risk related approach and is graduated, 
depending on the size and type of prepared medicinal products. 
As to documentation for extemporaneous prepared products, the proposed guide 
set as a minimum requirement to specify the name, strength, and expiry date of the 
product. If a product is prepared for a single patient (magistral production), it is 
assumed that no end product testing will be required. For radiopharmaceuticals, 
though, the activity in each dose must be measured before administration. Chemical 
and microbiological quality control is not required for products that have a shelf 
life of 24 h or less, provided that frequent process validation is performed. In addition, 
chemical and microbiological information must be available to justify the shelf 
life for the product. 
For products that are prepared extemporaneously at a regular basis or even for 
a limited stock, a product specifi c documentation (product fi le) is needed. This will 
include specifi cations, instructions, and records but also a pharmaceutical assessment 
of safety data, toxicity, biopharmaceutical aspects, stability, and product design. 
The product fi le should also include a product review as soon as a product is used 
repeatedly or over longer periods. 
Furthermore, the drafted guide suggests that the level of end - product testing 
for those products will depend on the associated risk connected to the scale of 
operation, shelf life of the product, frequency of preparation, as well as type of 
product (parenterals, orals) and type of facility where the product has been 
prepared. 

Independent of which regulation applies at a national level to extemporaneous 
or magistral preparation of radiopharmaceuticals, the patients should be entitled to 
expect that these products are prepared accurately, are suitable for use, and will 
meet the expected standards for quality assurance. Pharmacists involved in this kind 
of production must ensure that they and any other staff involved are competent to 
undertake the tasks to be performed and that the requisite facilities and equipment 
are available [11] . As for other radiopharmaceutical production, systems must be in 
place to ensure the operator safety due to handling of radioactive materials. All 
involved staff must have suffi cient training in radiation safety issues, in addition to 
training in GMP. 
REFERENCES 
1. Britton , K. ( 1996 ), Radiopharmaceuticals for the future , Curr. Dir. Radiopharma. Res. 
Dev . (Ed. by Stephen Mather ), viii. Developments in Nuclear medicine, Vol XXX. London, 
UK. 
2. Saha , G. B. ( 1998 ), Fundamentals of Nuclear Pharmacy , 4th ed., Springer , Heidelberg, 
Germany . 
3. Alexoff , D. L. Automation for the synthesis and application of PET radiopharmaceuticals, 
BNL - 68614 Offi cinal File Copy. 
4. Bremer , P. O. ( 1995 ), Aseptic production of radiopharmaceuticals , in Aseptic Pharmaceutical 
Manufacturing , Vol. II, Application for the 1990s , Interpharm , Michael J. Groves and 
Ram Murty , pp. 153 – 180 . 
5. Nordic Council on Medicines . ( 1989 ), Radiopharmacy: Preparation and Control of Radiopharmaceuticals 
in Hospitals , NLN Publications No. 26 , Uppsala, Sweden . 
6. European Commision ( 2003 ), EU Guide to Good Manufacturing Practice , Annex 1 and 
3, Brussels, Belgium, October 8. 
7. Dabbah , R. ( 1995 ), Controlled environments in the pharmaceutical and medical products 
industry: A global review from regulatory, compendial, and industrial perspectives , in 
Aseptic Pharmaceutical Manufacturing, Vol. II, Application for the 1990s , Interpharm , 
Michael J. Groves and Ram Murty , pp. 11 – 40 . 
8. Lee , M. C. , PET and PET/CT are the fastest growing imaging modalities worldwide, paper 
presented at the 5th International Conference on Isotopes (5ICI), Brussels, Belgium, Apr. 
25 – 29 , 2005 . 
9. Zalutsky , M. R. , Pozzi , O. , and Vaidyanatha , G. , Targeted radiotherapy with alpha particle 
emitting radionuclides, paper presented at the International Symposium on Trends in 
Radiopharmaceuticals (ISTR -2005), Vienna, Austria, Nov. 14–18, 2005. 
10. Pharmaceutical Inspection Convention (2006, Aug.), PIC/S guide to good practices 
for preparation of medicinal products in pharmacies, PE 010 - 1 (Draft 2), Geneva , 
Switzerland . 
11. Standards for good professional practice ( 2000 ), Pharm. J . 265 ( 7109 ), 233 . 
12. Kowalsky , R. J. , and Falen , S. W. ( 2004 ), Radiopharmaceuticals in Nuclear Pharmacy and 
Nuclear Medicine , American Pharmacists Association , Forrester Center, WV . 
FURTHER READINGS 
European Commision . ( 2006 ), EU Guide to Good Manufacturing Practice , Annex 3; draft 
proposal, Brussels, Belgium, Apr. 12. 
FURTHER READINGS 95

96 RADIOPHARMACEUTICAL MANUFACTURING 
Rootwelt , K. ( 2005 ), Nukle . rmedisin , 2nd ed. Gyldendal Norsk Forlag AS , Oslo, Norway . 
Schwochau , K. ( 2000 ), Technetium: Chemistry and Radiopharmaceutical Applications , VCH 
Verlagsgesellschaft Mbh , Weinheim, Germany . 
Welch , M. J. , and Redvanly , C. S. , Eds. ( 2002 ), Handbook of Radiopharmaceuticals , Wiley , 
Hoboken, NJ . 

ASEPTIC PROCESSING 
SECTION 2


99 
2.1 
STERILE PRODUCT 
MANUFACTURING 
James Agalloco 1 and James Akers 2 
1 Agalloco & Associates, Belle Mead, New Jersey 
2 Akers Kennedy & Associates, Kansas City, Missouri 
Contents 
2.1.1 Introduction 
2.1.2 Process Selection and Control 
2.1.2.1 Formulation and Compounding 
2.1.2.2 Primary Packaging 
2.1.2.3 Process Objectives 
2.1.3 Facility Design 
2.1.3.1 Warehousing 
2.1.3.2 Preparation Area 
2.1.3.3 Compounding Area 
2.1.3.4 Aseptic Compound Area (If Present) 
2.1.3.5 Aseptic Filling Rooms and Aseptic Processing Area 
2.1.3.6 Capping and Crimping Sealing Areas 
2.1.3.7 Sterilizer Unload (Cooldown) Rooms 
2.1.3.8 Corridors 
2.1.3.9 Aseptic Storage Rooms 
2.1.3.10 Lyophilizer Loading and Unloading Rooms 
2.1.3.11 Air Locks and Pass - Throughs 
2.1.3.12 Gowning Rooms 
2.1.3.13 Terminal Sterilization Area 
2.1.3.14 Inspection, Labeling, and Packaging 
2.1.4 Aseptic Processing Facility Alternatives 
2.1.4.1 Expandability 
2.1.5 Utility Requirements 
2.1.5.1 Water for Injection 
2.1.5.2 Clean (Pure) Steam 
2.1.5.3 Process Gases 
2.1.5.4 Other Utilities 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

100 STERILE PRODUCT MANUFACTURING 
2.1.6 Sterilization and Depyrogenation 
2.1.6.1 Steam Sterilization 
2.1.6.2 Dry - Heat Sterilization and Depyrogenation 
2.1.6.3 Gas and Vapor Sterilization 
2.1.6.4 Radiation Sterilization 
2.1.6.5 Sterilization by Filtration 
2.1.7 Facility and System: Qualifi cation and Validation 
2.1.8 Environmental Control and Monitoring 
2.1.8.1 Sanitization and Disinfection 
2.1.8.2 Monitoring 
2.1.9 Production Activities 
2.1.9.1 Material and Component Entry 
2.1.9.2 Cleaning and Preparation 
2.1.9.3 Compounding 
2.1.9.4 Filling 
2.1.9.5 Stoppering and Crimping 
2.1.9.6 Lyophilization 
2.1.10 Personnel 
2.1.11 Aseptic Processing Control and Evaluation 
2.1.11.1 In - Process Testing 
2.1.11.2 End - Product Testing 
2.1.11.3 Process Simulations 
2.1.12 Terminal Sterilization 
2.1.13 Conclusion 
Appendix 
References 
Additional Readings 
2.1.1 INTRODUCTION 
The manufacture of sterile products is universally acknowledged to be the most 
diffi cult of all pharmaceutical production activities to execute. When these products 
are manufactured using aseptic processing, poorly controlled processes can expose 
the patient to an unacceptable level of contamination. In rare instances contaminated 
products can lead to microbial infection resulting from products intended to 
hasten the patient ’ s recovery. The production of sterile products requires fastidious 
design, operation, and maintenance of facilities and equipment. It also requires 
attention to detail in process development and validation to ensure success. This 
chapter will review the salient elements of sterile manufacturing necessary to 
provide acceptable levels of risk regarding sterility assurance. 
Commensurate with the criticality associated with sterile products, the global 
regulatory community has established a substantial number of the basic requirements 
that fi rms are expected to adhere to in the manufacture of sterile products. 
The most extensive of these are those defi ned by the Food and Drug Administration 

(FDA) in its 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing 
and the European Agency for the Evaluation of Medicinal Products (EMEA) 
Annex 1 on Sterile Medicinal Products [1, 2] . Substantial additional information is 
available from the International Organization for Standardization (ISO), the Parenteral 
Drug Association (PDA), and the International Society for Pharmaceutical 
Engineering (ISPE) (see Appendix ) [3] . The organizations have provided a level of 
practical, experience - based detail not found in the regulatory documents, thereby 
better defi ning practices that are both compliant with regulatory expectations and 
based upon rational, evidence - based science and engineering. 
Consideration of patient risk associated with pharmaceutical production emerged 
largely from regulatory impetus, by which the regulatory community stated its 
intended goal to structure its inspectional process using patient safety as a major 
focus in determining where to allocate their inspectional and review resources. 
Emanating from the International Conference on Harmonization (ICH) efforts to 
produce a harmonized approach to pharmaceutical regulation, risk - based compliance 
has been adopted in Europe, Japan, and the United States [4, 5] . Sterile products, 
especially those made by aseptic processing, have been properly identifi ed as 
a high priority by the global regulatory community. Several risk analysis approaches 
have been developed that can help the practitioner review practices with the goal 
of minimizing risk to the patient [6 – 8] . 
2.1.2 PROCESS SELECTION AND DESIGN 
The production of sterile products is profoundly impacted both by formulation and 
the selection of primary packaging components. Design parameters for a facility and 
selection of appropriate manufacturing technologies for the product require that 
the formulation process and packaging components be chosen and evaluated in 
advance. 
2.1.2.1 Formulation and Compounding 
The vast majority of parenteral formulations are solutions requiring a variety of 
tankage, piping, and ancillary equipment for liquid mixing (or powder blending), 
fi ltration, transfer, and related activities. Suspensions, ointments, and other similar 
products, including the preparation of the solutions for lyophilized products, can be 
manufactured in the same or very similar equipment. The scale of manufacturing 
can vary substantially, with the largest batches being well in excess of 5000 L (typically 
for large - volume parenteral production), down to less than 50 mL for radiopharmaceuticals 
or biologicals customized for a particular patient. 
The majority of this equipment is composed of 300 series austenitic stainless steel, 
with tantalum or glass - lined vessels employed for preparation of formulations sensitive 
to iron and other metal ions. The vessels can be equipped with external jackets 
for heating and/or cooling and various types of agitators, depending upon the mixing 
requirements of the individual formulation. In many facilities, a variety of tank sizes 
are available for use. Larger facilities may have the high - capacity tanks permanently 
installed and permanently connected to process utilities. Smaller vessels are generally 
mobile and positioned in individual processing booths or rooms as needed. 
PROCESS SELECTION AND DESIGN 101

102 STERILE PRODUCT MANUFACTURING 
After sterilizing fi ltration (or sterilization by heat or other means), comparably sized 
vessels are sometimes utilized to contain the product prior to and during the fi lling 
process. These holding vessels are often steam sterilized along with the connecting 
piping prior to use. There are a number of fi rms that fi ll directly from the compounding 
vessel using in - line fi ltration eliminating the intermediate vessel. When this 
approach is used, a small moist - heat - sterilized surge tank or reservoir tank may be 
required, particularly with modern time – pressure fi lling systems. This practice may 
reduce initial facility and equipment cost but places additional constraints 
on operational fl exibility. The use of disposable equipment for compounding and 
holding of sterile formulations is coming into greater use. This eliminates the cleaning 
of vessels prior to reuse, but confi rmation of material compatibility is required. 
Disposable equipment is often used with products manufactured in small to moderate 
volumes, and while reducing initial equipment expenses disposable equipment 
also results in contaminated waste, which cannot be recycled or reused and must be 
treated appropriately. 
Aseptic compounding as required for suspensions and other formulations in 
which open - vessel processes are required mandate an ISO 5 environment providing 
ideally > 400 air changes/hour in which these steps can be performed with minimal 
opportunity for adventitious contamination. This could be accomplished using a 
protective curtain and a unidirectional fl ow hood (UFH) or other more evolved 
designs such as a restricted access barrier (RABs) system or an isolator (technologies 
that provide a higher level of employee separation from the area in which 
materials are handled can get by with lower air exchange rates). All activities requiring 
opening of processing lines such as sampling or fi lter integrity testing should be 
performed using similar protective measures. The preparation of sterile suspensions 
requires a facility/equipment design capable of safe addition of sterile solids to a 
liquid vehicle and is conventionally performed using a specifi cally designed processing 
area to minimize contamination potential. Comparable and greater complexity 
is generally required for creams, ointments, emulsions, and the increasingly common 
liposome formulations. 
Some sterile powder formulations (these are predominantly, but not exclusively, 
antibiotics) may require sampling, mixing, milling, and subdivision activities similar 
to those found in oral powder manufacturing. The facilities and equipment utilized 
for these products is substantially different from that used for liquids, and the production 
area bears little resemblance to that utilized for liquids. These materials are 
received sterile and must be processed through sterilized equipment specifi cally 
intended for powder handling in a fully aseptic environment with ISO 5 protection 
over all open container activities. 
2.1.2.2 Primary Packaging 
The primary package for parenteral formulations provides protection to the sterile 
materials throughout the shelf life. The components of the primary package are 
every bit as important to contamination control and hence safety of the fi nished 
product as the formulation itself, and their preparation must be given a comparable 
level of consideration. The most commonly used container is glass; vials are still the 
most common, although increasingly prefi lled syringes are chosen. Glass ampoules 
are still seen. However, although convenient from a manufacturing perspective, the 

diffi culty involved in opening ampoules while at the same time avoiding problems 
with glass particulate or microbial contamination has reduced their popularity. The 
use of plastic containers (as vials, ampoules, or syringes) is increasingly common 
given their reduced weight and resistance to breakage. Blow - fi ll seal (BFS) and 
form - fi ll seal (FFS) are utilized for the fi lling of numerous ophthalmic and other 
noninjectable formulations in predominantly low - density polyethylene (LDPE) 
containers. With the exception of ampoules and BFS/FFS, an elastomeric closure 
system is also necessary to seal the containers. Some delivery systems (i.e., prefi lled 
syringes, multichamber vials, and others may require more than one elastomeric 
component to operate properly. In the case of vials, an aluminum crimp is applied 
to secure the closure to the vial. Prefi lled syringes may require the preparation and 
assembly of additional components such as needles, needle guards, stoppers, diaphragms, 
or plungers, depending on the specifi cs of the design. Lyophilization is 
required to ensure the stability of some formulations and requires the use of closures 
that allow venting of the container during the freeze - drying process. Full 
seating of the closure is accomplished within the lyophilizer using moving shelves 
to seat the closure. 
Glass is ordinarily washed prior to sterilization/depyrogenation to reduce contamination 
with foreign material prior to fi lling. In aseptic fi ll processes, the glass is 
then depyrogenated using dry heat. This can be accomplished using either a continuous 
tunnel (common for larger volumes and high - speed lines) or a dry heat oven 
(predominantly for small batches). The depyrogenation process serves to sterilize 
the glass at the same time, and thus the glass components must be protected postprocessing. 
This is generally accomplished by short - term storage in an ISO 5 environment 
often accompanied by covering within a lidded tray. There are suppliers 
that offer depyrogenated glass vials and partially assembled syringes in sealed packages 
for fi lling at a customer ’ s site. In this instance, the supplier assumes responsibility 
for the preparation, depyrogenation, and aseptic packaging. Glass ampoules are 
available presealed and depyrogenated; the end user has merely to open, fi ll, and 
reseal the syringe under appropriate conditions. 
Plastic components (whether container or closure) can be sterilized using steam, 
ethylene oxide, hydrogen peroxide, or ionizing radiation. The . irradiation is accomplished 
off - site by a subcontractor with appropriate expertise as these methods are 
considered the province of specialists because of the extreme health hazards directly 
related to the sterilization method. Electron beam sterilization may also be done 
by a contractor, although compact lower energy electron beam systems have been 
introduced that allow sterilization in - house. Steam sterilization is ordinarily performed 
in house, though many common components are becoming available presterilized 
by the supplier. Preparation steps prior to sterilization vary with the 
component and the methods used to produce the component. Rubber components 
are washed to reduce particles, while this is less common with plastic materials. 
Syringes vary substantially in design details and can be aseptically assembled 
from individual components. However, increasingly, these are supplied as presterilized 
partial assemblies in sealed containers. 
The BFS and FFS are unique systems in that the fi nal container is formed as a 
sterile container just prior to the aseptic fi lling step. The BFS requires careful control 
over the endotoxin content of the LDPE (and other polymeric materials) beads 
used to create the containers as well as the melting conditions utilized to form them. 
PROCESS SELECTION AND DESIGN 103

104 STERILE PRODUCT MANUFACTURING 
The FFS utilizes in - line sterilization/drying of the fi lm prior to shaping of the 
containers. 
2.1.2.3 Process Objectives 
The production of parenteral products requires near absolute control over microorganisms. 
Endotoxin contamination is a serious health concern, particularly among 
neonates and infants and also requires a high level of control and validation. Additionally, 
the control of foreign matter, including particles and fi bers of various types, 
is also vitally important to end - user safety. Assuring appropriate control over these 
potential contaminants requires careful attention to several factors: facility design, 
equipment selection, sterilization procedures, cleaning regimens, management of 
personnel, and the process details associated with compounding, fi lling, and sealing 
of product containers. Each of these will be discussed in detail. 
2.1.3 FACILITY DESIGN 
To provide control of microbial, pyrogen, and particles controls over the production 
environment are essential. The facility concerns encompass the entire building, but 
the most relevant components are those in which production materials are exposed 
to the environment. 
2.1.3.1 Warehousing 
Environmental protection of materials commences upon receipt where samples for 
release are taken from the bulk containers. Protection of the bulk materials is 
accomplished by the use of ISO 7 classifi ed environments for sampling. All samples 
should be taken aseptically, which mandates unidirectional airfl ow and full operator 
gowning. This practice is mandated by current good manufacturing practice (CGMP) 
and assures that sampling does not introduce contaminants to the materials that 
will be used in the production. Where central weighing/subdivision of active ingredients 
and excipients are performed, similar protection is provided for identical 
reasons. The expectation is that these measures reduce the potential for contamination 
ingress into materials that have yet to receive any processing at the site. Materials 
and components that are supplied sterile are received in this area, but samples 
are often packaged separately by the supplier to eliminate the need for potentially 
invasive sampling of the bulk containers. Where so - called delivery samples are used, 
it is critical that these samples are known to be fully representative of the production 
process. Additionally, where sterility or bioburden control of sampled materials 
is critical, thought must be given to the methods used to reseal the containers to 
ensure that moisture levels, bioburden levels, or in the case of sterile products sterility 
assurance are not compromised. 
2.1.3.2 Preparation Area 
The materials utilized for production of sterile processes move toward the fi lling 
area through a series of progressively cleaner environments. Typically, the fi rst step 

is transfer into an ISO 8 [Class 100,000, European Union (EU) Grade D] environment 
in which the presterilization preparation steps are performed. Wooden pallets 
and corrugated materials should always be excluded from this zone (and any classifi 
ed environment), and transfers of materials are performed in air locks designed 
to reduce the potential for particle ingress and to a lesser extent microbial ingress. 
Preparation areas provide protection to materials and components for a variety of 
activities: component washing (glass, rubber, and other package components), cleaning 
of equipment (product contact fi ll parts, process tools, etc.), and preassembly/ 
wrapping for sterilization. In some facilities, this area is also utilized to support 
compounding operations in which case process utensils, small containers, and even 
portable equipment will be cleaned and prepared for sterilization. 
Careful attention must be given to material fl ow patterns for clean and dirty 
equipment to prevent cross contamination. In larger facilities, the equipment wash 
room may be a separate room proximate to the preparations area with defi ned fl ows 
for materials and personnel. Ideally, materials should move through the facility in 
a unidirectional fashion, with no cross over of any kind. 
The preparations area typically includes storage areas where clean and wrapped 
change parts, components, and vessels can be held until required for use in the fi ll 
or compounding areas. (Just - in - time practices are desirable for all parenteral operations 
to avoid extensive and extended storage of materials in the higher classifi ed 
fi ll or compounding areas.) The preparations area is ordinarily located between the 
warehouse and the fi lling/compounding areas and connected to each of those by 
material/equipment air locks. 
Preparation areas are supplied with high - effi ciency particulate air (HEPA) fi lters 
(remote - mounted HEPAs are commonplace). The common design requirement is 
more than 20 air changes per hour, turbulent airfl ow (see below), and temperature 
and relative humidity controlled for personnel comfort. As in any clean room area 
designed for total particulate control, the air returns should be low mounted. 
Wall and ceiling surfaces should be smooth, easily cleaned, and tolerant of 
localized high humidity. Floors should be typically monolithic with integral drains 
to prevent standing water. Common utilities are water for injection, deionized 
water, compressed air, and clean/plant steam. Clean - in - place (CIP) and sterilize - 
in - place (SIP) connections may be present if the prep area supports compounding 
as well. 
Ordinarily, present within the preparation area are localized areas of ISO 5 unidirectional 
airfl ow (Class 100) utilized to protect washed components prior to sterilization 
and/or depyrogenation. These areas are not aseptic and should not be 
subjected to the more rigorous microbial expectations of aseptic processing. They 
are designed to reduce/eliminate the potential for particle contamination of 
unwrapped washed materials. Operators accessing these protective zones wear 
gloves at all times when handling materials. 
Operators in the preparations area are typically garbed in low particle uniforms 
(or suits) with shoe, hair, and beard covers. The use of latex or other gloves is 
required when contacting washed components. Sterilized gowns and three - stage 
gowning facilities are not required to enter or work in this ISO 8 environment. 
Gowns are generally donned within a single - stage airlock, which is maintained at a 
pressure slightly negative to the ISO 8 working environment. Separate personnel 
entry/exit are not typically necessary for this lower classifi ed environment. 
FACILITY DESIGN 105

106 STERILE PRODUCT MANUFACTURING 
Equipment within the preparations area varies with the practices of the fi rm and 
can include manual or ultrasonic wash/rinse sinks; single or double door automated 
parts washers; batch or continuous glass washers; stopper washers for closure components; 
CIP/SIP stations; equipment wrap areas (as described above); and staging 
areas for incoming (prewash) components, dirty equipment, and cleaned components/
equipment. An adjacent classifi ed storage area(s) may be present in larger 
facilities to accommodate the full variety of change parts and equipment that is not 
in immediate use. Where the preparations area also supports compounding, it may 
include additional equipment such as pH meters, fi lter integrity apparatus, and the 
like in support of those operations. ( Note: Where compounding requires aseptic 
conditions for rigorous control of bioburden, as is the case for unpreserved biologics 
and other contamination - sensitive products, it is best to provide separate entry for 
compounding. The moisture level and hence contamination potential in a typical 
preparation area is unsuitable for entry into an aseptic compounding area). 
Depending on the scale of the operation, the preparations area may include the 
loading areas for both sterilizers and ovens. In high - throughput operations where 
the use of tunnels for glass depyrogenation is more prevalent, glass washers and 
tunnels for each fi lling line may be in separate ISO 8 rooms accessed from the 
preparations area. 
2.1.3.3 Compounding Area 
The manufacture of parenteral solutions is ordinarily performed in ISO 7 (Class 
10,000, EU Grade C) controlled environments in which localized ISO 5 unidirectional 
fl ow hoods are utilized to provide greater environmental control during 
material addition. These areas are designed to minimize the microbial, pyrogen, and 
particle contributions to the formulation prior to sterilization. Depending upon the 
scale of manufacture, this can range from small containers (up to 200 L) (disposable 
containers are coming into use for these applications), to portable tanks (up to 
600 L) to large fi xed vessel (10,000 L or more have been used) in which the ingredients 
are formulated using mixing, heating, cooling, or other unit operations. Smaller 
vessels are placed or rolled onto scales, while fi xed vessels are ordinarily mounted 
on weigh cells. The vessels may be equipped for temperature and pressure measurement 
instruments, as mandated by process requirements. Compounding areas often 
include equipment for measuring mass and volume of liquid and solid materials 
including, for example, graduated cylinders, and scales of various ranges, transfer 
and metering pumps, homogenizers, prefi lters, and a variety of other liquid/powder 
handling equipment. Liquid handling may be accomplished by single - use fl exible 
hose, assemblies of sanitary fi ttings, or some combination thereof. A range of smaller 
vessels to be used for the addition of formulation subcomponents or excipients to 
the primary compounding tank may be required as well. Because parenteral formulations 
can include aqueous and nonaqueous vehicles, suspensions, emulsions, and 
other liquids, the capabilities of the compounding area may vary. Agitators can be 
propeller, turbine, high shear, or anchor designs depending upon the requirements 
of the products being manufactured, and it is not uncommon to fi nd examples of 
each in larger facilities. It is preferable to perform as much of the process as possible 
while the formulated liquid is nonsterile to ease sterilization requirements, although 
precautions to prevent microbial and endotoxin contamination are important risk 
abatement features. 

FACILITY DESIGN 107 
The formulation area is customarily a combination of open fl oor space, adjacent 
to three - sided booths and individual processing rooms in which the ingredients are 
handled and individual batches are produced. Walls and ceiling materials are selected 
to be impervious to liquids and chemical spills and are easy to clean. Floors in these 
areas are monolithic and should be sloped (at 1 – 3 : 100) to drains with appropriate 
design elements and control procedures to eliminate backfl ow potential (regulatory 
bans on drains in classifi ed areas are focused on protecting aseptic environments 
and are inappropriate for nonsterile compounding areas). Pit scales should be 
avoided in new installations; fl oor - mounted scales intended for cleaning underneath 
the base are preferable. 
Compounding areas are supplied with HEPA fi lters (ceiling - mounted terminal 
HEPAs are more common, though central supply is possible in areas of low contamination 
risk). The common design requirement is more than 50 – 60 air changes 
per hour, turbulent airfl ow (see below), with temperature and relative humidity for 
personnel comfort. Air returns may be at or near fl oor level, with localized extraction 
provided as necessary to minimize dusting of powder materials. Where substantial 
heat is generated from processing or sterilization, a ceiling or high wall return 
may be more appropriate. Wall and ceiling surfaces are smooth, easy to clean, and 
tolerant of localized high humidity. Floors are typically monolithic with integral 
drains to prevent standing water. Common utilities are water for injection, deionized 
water, nitrogen, compressed air, clean/plant steam, and heating and cooling media 
for the fi xed and portable tanks. Water for injection use points are often equipped 
with sanitizable heat exchangers for operator safety. 
Cleaning of the fi xed vessels and portable tanks is accomplished using either 
manual sequenced cleaning procedures or more commonly with a CIP system. 
Cleaning of other items can be accomplished in a wash area accessed from the 
compounding area or in a common wash room incorporating both fi lling and compounding 
equipment. Sterilization of the nonsterile processing equipment and vessel 
is often provided for as an option, even where it is not routinely required to control 
product bioburden. Where production volumes or physical location dictate, the 
compounding area may have a separate preparations area from that utilized to 
support fi lling operations. 
Personnel working in the compounding area typically wear a coverall (which may 
be sterilized for contamination control as required), with head/beard covers, as well 
as dust masks and sterile gloves. Additional personnel protective equipment may 
be necessary for some of the materials being processed. A fresh gown should be 
donned upon each entry into the compounding area. Separate gowning/degowning 
rooms should be provided to minimize cross - contamination potential for personnel 
working with different materials. As nonsterile compounding areas are often ISO 
6 – 7 environments but are not aseptic, the more rigorous contamination controlling 
designs required of aseptic gowning areas (see below) are somewhat reduced. 
2.1.3.4 Aseptic Compounding Area (If Present) 
Where products are fi lled using in - line fi ltration direct to the fi lling machine, an 
aseptic compounding area may not be present. In those instances the fi nal sterilizing 
fi lter will be located in the fi ll room. 
Products that are held/processed in sterilized vessels prior to fi lling require an 
aseptic compounding area. This is typically an ISO 7 in environment with localized 

108 STERILE PRODUCT MANUFACTURING 
ISO 5 unidirectional fl ow present where open - product containers or aseptic operations 
are conducted. Some products may require larger ISO 5 suites with full HEPA 
coverage rather than the more common ISO 5 clean booth design. Fixed vessels in 
this area are cleaned and sterilized in situ, while portable vessels are typically relocated 
to the wash area for cleaning. Sterilization of portable vessels may be accomplished 
at an SIP station in the aseptic core, compounding, or preparations areas. 
When accomplished outside the aseptic processing area, resterilization of the connecting 
lines may be appropriate. Filters for sterilization of solutions from compounding 
to holding vessels are typically located in this environment as well, with 
sterilization by either SIP or sterilization in an autoclave. The use of integrated, 
programmable logic controlled ( PLC) fi lter skids with automatic CIP/SIP and fi lter 
integrity testing is frequently seen for contamination sensitive products. 
Depending upon the formulations being produced, additional sterilized processing 
equipment may be present in this area for use in the process. This can include 
in - line homogenizers, static mixers, and colloid mills. Where sterile powders are 
produced, the aseptic compounding processes can include blending, milling, and 
subdivision equipment. 
Aseptic compounding areas typically require a means to introduce sterile equipment, 
tubing, and other items, so access to a sterilizer is desirable. The aseptic compounding 
area may be contiguous to the aseptic fi lling suites. If it is not, separate 
gowning areas must be provided for personnel as well as separate air locks/pass - 
throughs (see below). 
Personnel working in aseptic compounding wear full aseptic garb: sterile gown, 
hood, face mask, goggles, foot covers, and gloves. Adaptations may be necessary 
for potent/toxic compounds to assure operators are properly protected from 
hazardous materials. Gowning areas are ordinarily shared with aseptic fi lling, 
but where they are not shared a comparable design, albeit on a smaller scale, 
is appropriate. 
The facility design features match that of the aseptic fi lling room/aseptic processing 
areas described in greater detail below. Utility services would mimic those utilized 
in the nonsterile compounding area that is usually adjacent (next to or above) 
to the aseptic compounding area. Temperature and humidity should be controlled 
to similar levels as those required for aseptic fi lling. Since CIP/SIP systems tend to 
generate heat and humidity, suffi cient capacity must be available to control temperatures 
to approximately 18 – 20 ° C and < 50% relative humidity (RH). 
2.1.3.5 Aseptic Filling Rooms and Aseptic Processing Area * 
The fi lling of aseptic formulations (and many terminally sterilized products as well, 
by reason of their lesser number) is performed in an ISO 5 (Class 100) environment, 
which is accessed from an ISO 6/7 background environment in which personnel are 
present. Some measure of physical separation is provided between the ISO 5 and 
ISO 6/7 environments as a means of environmental protection as well as a reminder 
to personnel to restrict their exposure to ISO 5. 
* This section describes the conventional manned clean room; a later section in this chapter will address 
alternative aseptic processing environmental control designs with somewhat different features and 
control measures. 

FACILITY DESIGN 109 
In large operations an aseptic fi lling room is generally one of a multiple suite of 
aseptic rooms which allow simultaneous production of multiple products. The fi lling 
rooms are independent of each other; however, sharing the supporting rooms is 
common. Sterilizer unload rooms, corridors, air locks, storage rooms, lyophilizer 
loading rooms, and gowning rooms (each will be briefl y described as well) may all 
be present, and their arrangement must suit production volumes. Where shared 
common areas are required, the design should feature unidirectional materials fl ow 
to prevent cross - contamination and to minimize the potential for mix - ups. In the 
smallest facilities, only the gowning area might be separate from the fi ll room, and 
all of the supportive activities could be inclusive in a single room (however, unloading 
activities should not occur during fi lling operations). All of these aseptic processing 
areas (APAs) are built to the same design standards: smooth, impervious ceilings, 
walls and fl oors, fl ush - mounted windows, clean room door designs, coved corners, 
fi nishes capable of withstanding the aggressive chemicals utilized for cleaning and 
sanitization. Air returns throughout the APA are located at or near fl oor level. 
Unidirectional airfl ow is provided over all exposed sterile materials, that is, fi ll zone, 
sterilizer/oven/tunnel unload areas, and anywhere else sterile materials are exposed 
to the environment. Air changes in these ISO 5 environments can approach 600 per 
hour, though lesser values have proven successful. Air changes in the background 
environment vary from 60 to 120 per hour. 
The glass container fi ll rooms fi lling machines are connected to depyrogenating 
tunnels and exit ports leading to capping stations. Batch handling of glass is discouraged 
unless isolator systems are employed. In some operations, the in - feed and discharge 
of containers/components may utilize trays, tubs, or bag systems for material 
feed/discharge. Wherever possible, automation of component feeding should 
be considered to reduce contamination risk. Supportive equipment present might 
include carts, weigh stations, stoppering, crimping, sealing, and other fi ll system 
related machinery depending upon requirements. 
The product contact surfaces in this environment are typically removed for cleaning; 
however, in some installations, the sterilization, transfer, and reinstallation of 
the component feed hoppers present such diffi culty that these systems are decontaminated 
in situ with a sporicidal agent, rather than removed after each use. These 
units should still be removed for cleaning and sterilization on a validated periodic 
basis to prevent the buildup of residues that might impact their in - situ decontamination 
or create particle control problems. All other product contact surfaces should 
be sterilized prior to each use. Nonsterilized items should not be allowed to enter 
the ISO 5 portion of the fi ll zone, and sanitization is essential for all nonproduct 
surfaces in the fi ll zone, as well as the surrounding background environment. 
Discharge of sealed containers can be accomplished via a exit port or “ mouse 
hole ” that allows for the passage of the containers from the APA to the surrounding 
environment. Proper design of the mouse hole system ensures protection of the 
classifi ed fi ll area from contamination fl owing against the fl ow of the containers. In 
many instances the discharge is into a nonclassifi ed inspection area that may lead 
directly to the secondary labeling/packaging area. 
Personnel working in aseptic compounding wear full aseptic garb: sterile gown, 
hood, face mask, goggles, foot covers, and gloves. Adaptations may be necessary for 
potent/toxic compounds to assure operators are properly protected from hazardous 
materials. 

110 STERILE PRODUCT MANUFACTURING 
2.1.3.6 Capping and Crimp Sealing Areas 
The application of aluminum seals over rubber stoppers is essential to secure them 
properly. In many older facilities this was accomplished outside the aseptic processing 
area in an unclassifi ed environment. Current practice requires that air supplied 
to this activity meet ISO 5 under static conditions. The protection of crimping has 
resulted in a variety of designs to meet the requirement: Sterile crimps can be 
applied with the aseptic core on the fi lling line; sterile crimps can be applied in a 
separate crimping room accessible from the fi lling room. If the crimpling operation 
is located within the APA, it should be in a separate room maintained at a negative 
pressure differential relative to the fi lling environment. Crimping may alternatively 
be performed in a classifi ed room accessed from a controlled but unclassifi ed environment. 
In this case it is imperative to verify that the environmental controls satisfy 
regulatory expectations for all relevant markets. 
2.1.3.7 Sterilizer Unload (Cooldown) Rooms 
Sterilizers/ovens are unloaded and items staged prior to transfer to the individual 
fi ll rooms. ISO 5 air is provided over the discharge area of ovens (and autoclaves if 
items are sterilized unwrapped) to provide protection until the items are ready for 
transfer. The heat loads in this room may be such that special high - temperature 
sprinkler heads may be necessary to avoid unintentional discharge when unloading 
hot materials. This room may not be separate from the corridor used to connect the 
fi ll rooms. It is ordinarily adjacent to any aseptic storage area. 
2.1.3.8 Corridors 
Corridors serve to interconnect the various rooms that comprise the APA. Fill 
rooms, air locks, and gowning rooms are accessed from the corridor. They can also 
be utilized for modest storage as well. 
2.1.3.9 Aseptic Storage Rooms 
In general, extensive use of in - process storage areas should be avoided. It is best to 
operate the aseptic facility in a just - in - time mode in which components and 
equipment are sterilized shortly before they are required for use in the fi lling or 
compounding areas. Some limited storage is necessary for nonproduct contact 
materials such as sanitizing agents, environmental supplies and equipment, and 
other items. 
2.1.3.10 Lyophilizer Loading and Unloading Rooms 
The loading of lyophilizers is accomplished under ISO 5 environmental conditions 
within the aseptic processing area. Several possible locations are possible: within 
the aseptic fi ll room itself, in a separate room adjacent to the fi ll room, or in a separate 
room remote from the fi ll room. There are pros and cons with each of these 
selections which should be carefully considered in the facility design. There is a 

universal expectation that fi lled containers of product should be maintained under 
ISO 5 conditions during transfer and lyophilizer loading. Many modern facilities 
incorporate automatic lyophilizer loading and unloading. Automation of loading, 
unloading, and in the case of vials transfer to the crimping station greatly reduces 
contamination risk and is highly recommended. 
If manual transfer is unavoidable, location of the lyophilizer relatively close to 
the fi lling line enables protected transfer to be accomplished rather easily. Remote 
locations may require transfer of product in carts capable of providing ISO 5 quality 
air. These carts will generally require battery power in order to run the necessary 
air blowers and control systems. Alternatively, product trays could be placed in air - 
tight carriers; this activity and the sealing of the carriers would have to be accomplished 
under ISO 5 conditions. Locating the lyophilizer in the fi ll room may restrict 
the ability to unload the dryer while the fi lling line is in use, particularly if the 
lyophilizer is loaded and unloaded manually, which would increase the clean room 
personnel load and potentially increase contamination risk. 
The use of trays during lyophilization is less common, nevertheless, ring trays 
with removable bottoms are sometimes used to transfer vials to/from the lyophilizer. 
Where trays are used, they must be cleaned and sterilized prior to each batch. Large 
lyophilization facilities will sometimes use an automated loading/unloading system 
in which all shelves or a shelf at a time are processed. Regardless of the practice, 
ISO 5 conditions are required for all areas of the facility in which partially stoppered 
containers are transferred or handled. As previously mentioned, it may be possible 
in some operations to transfer containers in a manner that they are not exposed to 
the environment during transfer. 
Upon completion of the drying process, the containers will ordinarily have their 
stoppers fully seated on the container within the freeze dryer. The stoppered containers 
are then passed through a sealing station in which aluminum crimps are 
applied. This may be accomplished on the fi ll line, or using a separate crimping 
machine. Precautions will need to be taken to ensure that only fully stoppered vials 
are transferred to the crimping station. This can be accomplished by automatic 
inspection systems of various designs. It is increasingly common for product transfer 
to crimping and crimping itself to be done under unidirectional airfl ow. It should 
be noted that a crimpling station will generally not meet ISO 5 particulate air quality 
requirements when the crimper is operating since the generation of relatively high 
levels of particulate is an inherent feature of this process. 
2.1.3.11 Air Locks and Pass - Throughs 
Air locks serve as transition points between one environment and another. Ordinarily, 
they are designed to separate environments of different classifi cation: that is, 
ISO 6 from ISO 7. When this is the case, they are designed to achieve the higher of 
the two air quality levels in operation. If they are utilized for decontamination purposes 
for materials/equipment that cannot be sterilized, but must be introduced into 
the higher air quality environment, they may be fi tted with ultraviolet (UV) lights, 
spray systems, vapor phase hydrogen peroxide generators, or other devices that may 
be effectively utilized for decontamination of materials. Regardless of the design or 
the decontamination method employed, the process should be validated to ensure 
FACILITY DESIGN 111

112 STERILE PRODUCT MANUFACTURING 
consistent effi cacy. The doors at each end can be automatically interlocked or 
managed by standard operating procedure. In some instances a demarcation line is 
used to delineate the extent to which individuals from one side should access the 
air lock. It is good practice to carefully control and to minimize the time that any 
operator spends accessing an air lock, therefore transfer of materials should be 
carefully planned to minimize frequent and spontaneous access. Additionally, the 
capacity of the air lock should be carefully considered relative to the actual production 
requirements. Air locks that lack suffi cient capacity and that cannot provide 
suffi cient air exchange will be less suited to the control of contamination into more 
critical areas of the aseptic processing environment. 
A smaller scale system with comparable capabilities is the pass - through. This 
differs from the air lock primarily in dimension, as items are typically placed into the 
pass - through by personnel, whereas the air lock is customary for pallet, portable 
tanks, and larger items that are either rolled or mechanically lifted into position. 
The operation of the pass - through can be either manual or automatic with similar 
capabilities to that of the air lock described above. In general pass - throughs should 
be supplied with HEPA fi lters and should be designed to meet the air quality level of 
the higher air quality classifi cation room served. Pass - throughs should also be interlocked 
and provide adequate facilities for decontamination of materials being 
transferred. 
Air locks and pass - throughs are bidirectional and can be used for movement in 
either direction. When used as an exit route, the decontamination procedure can be 
omitted. Where production volumes warrant separate entry and exit, air locks may 
be necessary to maintain both adequate capacity and separation between clean and 
used items. In an emergency, airlocks can serve as emergency exits for personnel, in 
which case the interlocks can be overridden. 
2.1.3.12 Gowning Rooms 
The gowning area used for personnel entry/exit presents some unique problems. 
Gowning facilities must be designed to the standards of the aseptic processing area, 
yet personnel upon entry are certainly not gowned. Because ungowned staff will 
release higher concentrations of contaminants into the environment, gown rooms 
must be designed with suffi cient air exchange so that this contamination is effectively 
and promptly removed. In general, the contamination load within a gowning 
environment will require air exchange rates at the high end of recommended levels 
for a given ISO 14644 air quality classifi cation. Gowning areas are separated into 
well - defi ned zones where personnel can progress through the various stages of the 
gowning process. 
The most common approach in industry is a three - stage gowning area design in 
which three linked rooms with increasing air quality levels are utilized to effi ciently 
and safely affect clothing change. Staff should enter the fi rst state of the gowning 
room wearing plant uniforms. No articles of outerwear worn outside the facility 
should be worn to the gowning area. Therefore, a pregowning room equipped with 
lockers is required so that operators can change into dedicated plant clothing prior 
to moving to the gowning area. Generally, the pregowning locker area is not classi- 
fi ed, although entry is controlled and temperature and humidity are maintained at 
20 – 24 ° C and 50% ± 10%. The pregown area should have extensive hand - washing 

facilities equipped with antibacterial soap, warm water, and brushes for cleaning 
fi nger nails. Soap and water dispensing should be automatic and hands should be 
air rather than towel dried. The pregown area should have typical clean room wall 
and fl oor fi nishes along for frequent and rigorous cleaning and sanitization. The 
pregown area is bidirectional as it is used as both an entry and exit point. Separate 
pregown areas are required for female and male personnel. A typical complement 
of garments for exit of the pregown area includes surgical scrubs or other nonparticulate 
shedding plant uniform. Ideally, the uniform should have a high neck and 
sleeves which extend to the lower wrist. Hair covers and beard covers are donned 
in the pregown area. 
Upon entry into the fi rst - stage gowning room, which is generally designed to an 
ISO 7 air quality level, the operators often don a second hair cover, sterilized gloves, 
and a sterilized surgical mask. In the second and third stages of the gowning area 
room classifi cation is typically ISO 6 or ISO 6 followed by ISO 5 at the exit point. 
Different fi rms have different gowning sequences. However, in every case the fl ow 
of personnel and arrangement of gowning materials should be such that personnel 
fl ow is in one direction. In the last of the three gowning stages, secondary protective 
equipment can be donned, including sleeve covers and a second set of gloves. Some 
fi rms will use tape to secure the gloves to the sleeves to prevent separation. A dry 
glove decontamination point utilizing disinfectant foam is generally provided prior 
to exiting the gowning area; this should be a hands - free operation. In some facilities 
air showers, which provide a high - intensity blast of HEPA air for a predetermined 
length of time, are employed after gowning is completed. Side - by - side gowning of 
personnel should be avoided to preclude adventitious contamination. Similarly, 
personnel exiting the aseptic area should use a separate degowning area. These 
design practices are appropriate in all but the very smallest facilities where only a 
single aseptic operator is present. 
2.1.3.13 Terminal Sterilization Area 
The terminal sterilization of fi nished product containers may be performed in the 
same sterilizers utilized to supply the aseptic processing operations. The differing 
process needs of terminal sterilization will sometimes dictate the use of sterilizers 
specifi cally designed for terminal sterilization incorporating air - over pressure 
systems, internal fans, and spray cooling. Where this is the case, the terminal sterilizer 
is located proximate to the crimping/sealing areas. A double - door sterilizer 
design is preferred with staging areas for fi lled containers to be sterilized and a 
separate area for containers that have completed the process. Classifi cation of these 
areas is not required as the containers are closed throughout the sterilization process. 
The fl ooring materials in this area should be monolithic to allow for easy cleanup 
in the event of container breakage. 
2.1.3.14 Inspection, Labeling, and Packaging 
These activities are performed on fi nished product containers in unclassifi ed environments. 
The primary design requirements are straightforward: separation of products 
to prevent mix - up, adequate lighting for the processes, and control over labeling 
materials. 
FACILITY DESIGN 113

114 STERILE PRODUCT MANUFACTURING 
2.1.4 ASEPTIC PROCESSING FACILITY ALTERNATIVES 
The successful production of parenteral drugs by aseptic processing requires an 
environment in which microorganisms and particles are very well controlled. The 
means to accomplish this has undergone substantial change over the last 50 years 
(see Figure 1 ) with continuing refi nement. The earliest aseptic processing systems 
used glove boxes with minimal (if any) airfl ow and manual disinfection in which 
manual processes were performed. The availability of HEPA fi lters in the late 1950s 
led to human - scale clean rooms in which processing equipment could be installed. 
Aseptic processing changed radically once entire clean rooms became feasible. 
As it had always been recognized that personnel were the dominant source of 
contamination, the majority of designs utilized some measure of physical separation 
between the operator and the critical zone (sterile fi eld) in which the aseptic 
processing activities were performed. Separative devices (a term that is now 
embodied in ISO 14644 - 7 Separative Enclosures) of different design and varying 
capability have been successfully employed including fl exible curtains and fi xed 
plastic shields with or without integrated gloves/sleeves [9] . In the most evolved 
designs operation of the equipment is interlocked with the surrounding enclosure, 
such that equipment stops running when the doors are opened. These latter designs 
represented the pinnacle of clean room - based aseptic processing into the early 
1990s. 
Isolators represent a return to operator separation principles utilized during the 
glove box era, albeit with substantial improvements in the form of rapid transfer 
ports for material transfer, air - handling systems utilizing modern HEPA fi lters, and 
reliable decontamination systems. The salient element of all isolator designs is the 
completeness of separation between the internal and external environments. This 
single feature affords vastly superior performance relative to manned clean rooms 
in excluding personnel - derived contamination and has comparable advantages for 
the containment of potent compounds. While initial adoption of the technology was 
slowed by the novelty that isolators presented to users, much of the initial reluctance 
has been overcome [10, 11] . Isolators for aseptic processing vary in complexity, size, 
and amount of processing equipment. They can be utilized for processing ranging 
Aseptic Processing Family Tree 
Gloveboxes 
Conventional 
Cleanroom 
Barrier 
Systems 
RABs 
Closed 
Isolators 
Open 
Isolators 
BFS/FFS 
FIGURE 1 Aseptic processing family tree. 

from manual compounding of small batches to high - speed fi lling of fi nal product 
containers. Depending upon the process requirements, isolators can be utilized for 
containment of potent compounds (under negative pressure while still nonsterile) 
during the compounding, aseptic operation (under positive pressure) for preparation 
and transfer of components and aseptic containment (also under positive pressure) 
for aseptic fi lling of the potent drug solution. 
Firms that were intimidated by or unconvinced of the superiority of isolators 
developed the restricted - access barrier (RAB) system as a potentially less complex 
and less costly alternative [12] . The real - world utility of RABs systems is unknown; 
there are still relatively few installations; thus, the experience base is still emerging. 
Also unconfi rmed at this point are the actual validation and ongoing process control 
requirements which make direct comparison of project time lines and overall costs 
with isolators somewhat speculative. 
There are specialized technologies such as BFS and FFS that are appropriate for 
aseptic processing, but these are restricted to fi lling processes only. A number of 
other new technologies are being developed for use in aseptic processing, including 
vial isolators and closed vial fi lling [13 – 15] . All of these have the objective of reducing 
contamination through reduction in human involvement or increased protection 
of the container. Further advances in processing including gloveless isolator designs, 
robotics, and others are already under active development to further improve the 
safety of parenteral products. 
2.1.4.1 Expandability 
Large facilities often include design elements that facilitate later expansion of the 
facility to add additional capacity. The most common of these is extension of an 
aseptic corridor to additional fi lling suites; reservation of space for additional sterilizers; 
and allocating space for additional or oversizing initial utility systems. Obviously, 
these types of changes require careful design and must be properly managed 
during execution to avoid impact on existing operations. 
Isolation technology changes this dynamic signifi cantly by eliminating most of 
the disruption on current activities, as fabrication of the isolator occurs off - site, and 
installation can be minimally disruptive compared to what is required with a clean - 
room design. Isolators are generally installed in ISO 8 space; therefore, it is possible 
to build a rather large ISO 8 facility in which equipment can be moved, replaced, 
or reconfi gured quite easily compared to conventional human - scale zoned aseptic 
processing areas. 
2.1.5 UTILITY REQUIREMENTS 
Any utility in direct product contact is subject to formal qualifi cation through con- 
fi rmation of the quality of the delivered material at each use point. Water - for - 
injection (WFI) systems are considered the most critical of all, and the qualifi cation 
period for WFI is the longest and may be as long as 3 months. The remaining product 
contact utilities can be qualifi ed more rapidly. Nonproduct utilities requirements 
can be satisfi ed by commissioning. 
UTILITY REQUIREMENTS 115

116 STERILE PRODUCT MANUFACTURING 
2.1.5.1 Water for Injection 
The most important utility in sterile manufacturing is WFI. Not only is it a major 
component in many formulations, it is also utilized as a fi nal rinse of process equipment, 
product contact parts, utensils, and components. In some facilities it may be 
the only grade of water available and is used for initial cleaning of items as well. 
The WFI may be produced by either distillation (multiple effect or vapor compression) 
or reverse osmosis (generally in conjunction with deionization) and is ordinarily 
stored and recirculated at an elevated temperature greater than 70 ° C to prevent 
microbial growth [16, 17] . Where cold water is required, it may be supplied by use 
point heat exchangers or using a separate cold loop (usually without a storage 
capability). Point - of - use cool water drops and reduced temperature circulation 
loops are generally sterilized or high - temperature sanitized at defi ned and validated 
intervals. The design details of the WFI system varies with the incoming water 
quality, local utility costs, and operational demands. Very small operations may not 
have a WFI system and will utilize larger (5 L or larger) packages of WFI for formulation 
and cleaning. 
Other grades of water may be present in parenteral facilities for use as initial 
rinses and detergent cleaning. The water utilized for these purposes is generally of 
relatively low bioburden and is often deionized, softened, ultra - fi ltered, or in some 
instances prepared by distillation or reverse osmosis, resulting in chemical purity 
similar to, if not identical to, WFI. Systems for the preparation of this water are 
subject to qualifi cation, validation, and routine analysis to assure consistent quality. 
2.1.5.2 Clean (Pure) Steam 
Sterilizers and SIP systems in the facility are supplied with steam which upon condensation 
meets WFI quality requirements (testing steam condensate for microbial 
content is not fruitful). The steam can be produced directly from the water of suffi - 
cient purity to meet the input requirements of the steam generator. Steam generators 
are phase transition technologies that operate like a still, so it is no more 
necessary to provide these devices with WFI feed water than it would be to double 
distill WFI. (Production from WFI is certainly possible, but that is both expensive 
and an unnecessary precaution.) Modest quantities of steam can be produced from 
the fi rst effect of a multiple effect WFI still, however, with a resultant loss of WFI 
output [18] . 
2.1.5.3 Process Gases 
Air or nitrogen used in product contact is often supplied in stainless steel piping 
and ordinarily equipped with point - of - use fi lters; quite often an additional fi lter is 
placed within the distribution loop or at the entry point into a room resulting in a 
form of redundant fi ltration. Compressed air is typically provided by oil - free compressors 
to minimize potential contaminants and is often treated with a drier to 
obviate the possibility of condensation within the lines which could be a source of 
contamination. Nitrogen is supplied as a bulk cryogenic liquid. Argon and carbon 
dioxide have also been utilized as inerting gases, while propane or natural gas may 
be needed for sealing of ampoules. 

2.1.5.4 Other Utilities 
The operation of a parenteral facility often entails other utilities for the operation 
of the equipment. These include plant steam, jacket cooling water, and instrument 
air. 
2.1.6 STERILIZATION AND DEPYROGENATION 
The preparation of the drug formulation, components, and equipment entails the 
use of various sterilization/depyrogenation treatments to control bioburden, avoid 
excessive pyrogens, and to sterilize. The selection of the specifi c process must always 
fully consider the impact of the treatment on the items being sterilized/depyrogenated. 
Sterilization and heat depyrogenation processes must balance the effect of 
the treatment on the microorganism with the effect of that same treatment on the 
materials being processed. The choice of one method over another is often based 
upon achieving the desired sterilization/depyrogenation effect with minimal impact 
on the items critical quality attributes. 
2.1.6.1 Steam Sterilization 
The method of choice in nearly every instance is moist heat due to its lethality, 
simplicity, speed, and general ease of process development and validation. For the 
majority of items, this is accomplished in a double - door steam sterilizer, which is 
conventionally located between the preparations and aseptic processing (fi lling or 
compounding) areas. Steam sterilizers are routinely utilized for items such as elastomeric 
closures, process and vent fi lters, product contact parts, heat stabile environmental 
monitoring equipment, tools and utensils, hoses, sample containers, and 
other items unaffected by contact with saturated steam at commonly used sterilizing 
temperature and pressure [19] . Similar items utilized in the nonsterile compounding 
area would be processed in a similar manner. Regardless of their fi nal 
destination or usage, items for steam sterilization should be protected from poststerilization 
contamination by materials that are permeable to steam, air, or condensate 
but impenetrable by microorganisms. The wrapping materials would be 
maintained on the sterilized items until just prior to use. There are numerous 
publications that provide additional details on steam sterilization procedures 
[19 – 21] . 
Sealed containers of aqueous solutions, suspensions, and other liquids can be 
processed through steam sterilizers as well. These liquids might be used in formulation 
or cleaning procedures, and sterilization in this manner may be more effi cient 
and more reliable than sterilizing fi ltration. Larger volumes of aqueous liquids are 
often sterilized in bulk using a jacketed and agitated pressure vessel (the vessel is 
usually rated for full vacuum as well). 
Steam SIP is a widely used practice for the sterilization of equipment prior to 
the introduction of process materials and is the method of choice for holding tanks, 
process transfer lines, lyophilizers, and other large items. Conceptually, it has many 
similarities to sterilization in autoclaves but differs markedly due to the often 
custom designs of process equipment requiring SIP. Systems must be designed with 
careful consideration given to air removal and condensate draining, process sequenc- 
STERILIZATION AND DEPYROGENATION 117

118 STERILE PRODUCT MANUFACTURING 
ing, and poststerilization integrity to assure success [22] . Terminal sterilization of 
fi nished product containers is addressed later in this chapter. 
2.1.6.2 Dry - Heat Sterilization and Depyrogenation 
The use of dry heat for depyrogenation (and sterilization) is almost universal for 
glass containers. Temperatures of 250 ° C or higher are utilized to render the glass 
endotoxin free. The depyrogenation is necessary because the washing of glass to 
reduce particles can introduce unacceptable levels of gram - negative microorganisms 
whose presence could result in pyrogen formation. The depyrogenation process 
can assist in component surface treatment (siliconization is required for some formulations) 
and will also render the glass sterile as well (depyrogenation temperature 
conditions far exceed those needed for sterilization [23] ). 
Sterilization by dry heat is only infrequently used, preference being given to the 
use of steam (due to its higher speed) or dry - heat depyrogenation (affording an 
added measure of safety using the same equipment). Where it is employed temperatures 
in the range of 170 – 180 ° C are employed, and a batch oven is customarily 
used. 
Dry - heat processes are conducted in either batch ovens or continuous tunnels, 
which are also installed between preparations and aseptic processing areas. Ovens 
have lower capacity and are typically found in smaller facilities. They offer the ability 
to handle items other than fi nal product containers and thus can replace autoclaves 
in facilities where fi lling parts, feed hoppers, tools, and other items that must be 
extremely dry. Ovens should be equipped with internal HEPA fi lters, recirculating 
fans, heating/cooling coils, and a sophisticated control system [24] . Items prepared 
for dry - heat treatment in ovens are inverted or covered to protect them after exiting 
from the oven as there are no sealed protective systems suitable for the higher 
temperatures necessary for dry - heat depyrogenation or sterilization. Oven discharge 
is typically into a cool - down area (usually the same as that used for the sterilizer), 
though in small facilities it might discharge directly into the fi ll room. Unless ovens 
are used in conjunction with isolators, they require direct operator intervention to 
transfer containers to the fi lling line and to charge the line with depyrogenated glass. 
This constitutes a risky intervention which should be avoided. For this reason, batch 
glass processing is rare in all but the lowest throughput facilities. 
Dry - heat tunnels are typically utilized where the production volumes are higher 
and allow for continuous supply of depyrogenated glass to the aseptic fi ll room. 
Tunnels are operated at high temperatures ( > 300 ° C) to increase processing speed 
and include a cooling zone that facilities discharge at or near room temperature. 
Typically, heating of the glass to 300 ° C or more for 3 or more minutes will result in 
much greater than the three - log endotoxin reduction required in current industry 
standards. The air inside the tunnel is HEPA fi ltered, and newer designs allow for 
dry - heat sterilization of the cooling zone as an added protective measure. Tunnels 
must be positioned with some care as they ordinarily will terminate into a fi ll room. 
A pressure differential between the cooling zone of the tunnel and the fi ll room is 
critical for proper operation of the tunnel. The pressure differential must conform 
to the requirements stipulated by the tunnel manufacturer. It is not necessary to 
have a > 12.5 PA (particulate air) differential between the in - feed side of the heating 
zone of the tunnel and the exit side of the cooling zone. It has been suggested by 

some that, since the in - feed side of the tunnel is typically in ISO 7 or 8 space, a 
greater differential is required; however, this is not true since the cooling zone is 
ISO 5, and the heating zone is certain to be sterile and is also ISO 5 in terms of 
particulate air quality. Their in - feed is often direct from a glass washer, which may 
be remote from the main preparations area utilized for washing, wrapping, and 
sterilizer loading. 
2.1.6.3 Gas and Vapor Sterilization 
The sterilization of materials using noncondensing gases (ethylene oxide, chlorine 
dioxide, or ozone) or condensing vapors such as hydrogen peroxide is a supplementary 
process intended for items that cannot be exposed to heat. The utilization of gas/ 
vapor designs is coming into increased use as a supportive technology for isolation 
technology for presterilized items such as syringes and stoppers that must be introduced 
into the isolators aseptic zone. Air locks using these agents can be utilized in 
similar fashion for the supply of materials to manned clean rooms. Control over agent 
concentration or injection mass, relative humidity, and temperature may be required 
for these systems. There are different types of vapor processes available, and users 
should generally follow the cycle development strategy suggested by the manufacturer 
of the equipment they have chosen. Specifi c temperature and humidity ranges 
may be required for some vapor processes to assure appropriate effi cacy [25, 26] . 
2.1.6.4 Radiation Sterilization 
The use of radiation within a parenteral facility would have been considered unthinkable 
prior to the start of the twenty - fi rst century. While . irradiation is typically a 
contracted service provided off - site, electron beam sterilization advances can make 
the installation of an in - house (and generally an in - line) system a real possibility. 
An in - line system would be utilized similarly to the gas/vapor systems described 
above for treatment of external surfaces for entry into either a clean room or 
isolator - based aseptic processing facility. The use of this same technology for terminal 
sterilization is also possible [1] . Association for the Advancement of Medical 
Instrumentation (AAMI)/ISO 11137 provides widely accepted guidance on the 
development and validation of radiation sterilization processes. 
2.1.6.5 Sterilization by Filtration 
Filters are utilized to sterilize liquids and gases by passage through membranes that 
retain microorganisms by a combination of sieve retention, impaction, and attractive 
mechanisms [27] . In contrast with the other forms of sterilization that are destructive 
of the microorganisms, fi lters rely on separation of the undesirable items (microorganisms 
as well as nonviable particles) from the fl uid. Because fi ltration requires 
passage of the fl uid from the “ dirty ” (upstream) side of fi lter to the clean (downstream) 
side of the fi lter, the downstream piping and equipment must be both 
“ clean ” and sterile prior to the start of the fi ltration process. This will ordinarily 
require the use of SIP procedures or sterilization followed by aseptic assembly. 
Sterilizing fi ltration of parenterals is a complex and often inadequately considered 
subject, and numerous controls are required on the fi lter, fl uid, and sterilizing/ 
STERILIZATION AND DEPYROGENATION 119

120 STERILE PRODUCT MANUFACTURING 
operating practices employed. PDA Technical Reports 26 and 40 can be instructive 
in understanding the relevant concerns [28, 29] . 
2.1.7 FACILITY AND SYSTEM: QUALIFICATION AND VALIDATION 
Facilities for the manufacture of sterile products require the qualifi cation/validation 
of the systems/equipment and procedures utilized for that production. Each system 
described above and others with a direct/indirect impact on the quality of the products 
being produced should be placed into operation using a defi ned set of practices. 
The general approach is described below, and best practices include the development 
of traceable documentation from project onset. The preferred approach begins 
during a project ’ s conceptual design phase where provisions for meeting the CGMP 
expectations and user requirement specifi cations establishing the technical basis for 
the processes are fi rst defi ned. This is commonly followed by the validation master 
planning exercise in which the user requirement specifi cations are used as a basis 
for the development of acceptance criteria for process control studies. This effort 
should be accompanied by an analysis of risk that considers product attributes, 
target patient population, as well as technical and compliance requirements. Detailed 
design follows in which the specifi cs of the various systems are refi ned. Construction 
of the facility and fabrication of the process equipment follows and a variety of 
controls are necessary during these activities to satisfy user requirements for compliance 
of the various elements of the facility. Typically, factory acceptance testing 
(FAT) will be done on all key process equipment, usually at the manufacturer ’ s 
plant site; much of the information gathered during FAT can be referenced in the 
qualifi cation activities to follow. Physical completion is followed by a well - defi ned 
step termed commissioning in which construction and fabrication errors and omissions 
are addressed. Site acceptance testing of installed process equipment may be 
done in parallel with facility commissioning. Formal qualifi cation of the facility 
ensues in which the installed systems and equipment are evaluated for their conformance 
to the design expectations. The very last steps in this process are variously 
termed performance qualifi cation. Detailed discussion of these subjects is not possible 
within the constraints of this chapter, however the qualifi cation/validation of 
equipment, systems, and processes has been extensively addressed in the literature 
[30] . 
2.1.8 ENVIRONMENTAL CONTROL AND MONITORING 
Confi rmation of appropriate conditions for aseptic processing and its supportive 
activities is required by regulation. In the highest air quality environment utilized 
for aseptic processing, ISO 5, there is a general expectation that the air and surfaces 
be largely free of microbial contamination and the number of particles be within 
defi ned limits (less than 3500 particles greater than 0.5 . m/m 3 ). Proving the complete 
absence of something is an impossible requirement, so the usual expectation is that 
99+% of all samples taken from this most critical environment be free of detectable 
microorganisms. The minimum monitoring expectations for these environments as 
defi ned by the regulators are consistently attainable in nearly all instances, 

especially those with lesser expectations. This is accomplished by proper design, 
periodic facility disinfection, and measures to control the ingress of microorganisms 
and particles for materials entering each environment from adjacent less clean areas 
[31] . 
2.1.8.1 Sanitization and Disinfection 
Disinfection is customarily performed by gowned personnel during nonoperating 
periods using such agents as phenolics, quaternary ammonium compounds, aldehydes, 
and other nonsporicidal agents. The frequency of treatment varies with the 
ability of the facility to maintain the desired conditions between disinfection. Sporicidal 
agents such as dilute hydrogen peroxide or bleach are reserved for those 
occasional periods when control over the spore population warrants and is often 
employed after lengthy maintenance shutdowns or at the end of construction. Isolation 
technology replaces the manual disinfection with reproducible decontamination 
with a sporicidal agent and thus assures a superior level of environmental 
control as compared to manned environments. The manual treatments fall short of 
this level of control due to the uncertainties of the manual procedure and recontamination 
of the environment as a consequence of the very personnel and activities 
utilized to disinfect it. To mitigate these weaknesses, automatic sporicidal disinfection 
of manned clean spaces has been developed by multiple vendors. Disinfection 
of the less critical environments is accomplished in the same manner albeit on a less 
frequent interval befi tting their higher allowable levels of microorganisms. 
2.1.8.2 Monitoring 
Aseptic environments are subject to a variety of monitoring systems including air, 
surface, and personnel monitoring for viable microorganisms and for nonviable 
particles. Environmental monitoring programs are often developed during the qualifi 
cation of a new facility using a multiphase approach. Methods for the monitoring 
and expectations for performance have been extensively discussed in the literature 
and will only be addressed briefl y in the context of this chapter [1, 2, 31, 32] . In 
general, the frequency and intensity of monitoring and concern for cleanliness 
increases as the product progresses from preparation steps (typically in ISO 7/8 
environments) to more important activities (nonsterile compounding in ISO 6) and 
ultimately into the aseptic core (aseptic compounding and fi lling in ISO 5). Sampling 
site and time selection should be a balance between the need to collect meaningful 
data and avoidance of sampling interventions that could adversely (and inadvertently) 
impact product quality. Microbiological sampling must always be done by 
well - trained staff utilizing careful aseptic technique. This will both minimize risk to 
the product and also improve the reliability of the data by reducing the likelihood 
of false - positive results. 
Air Sampling The relative cleanliness of air in the most critical environment is 
assessed using passive sampling systems such as settle plates or estimated volumetrically 
using active air samplers. Active air samplers should be designed to be isokinetic 
in operation to avoid disruptions to unidirectional airfl ow. Considerable 
variability has been reported among the several sampling methods employed for 
ENVIRONMENTAL CONTROL AND MONITORING 121

122 STERILE PRODUCT MANUFACTURING 
active air sampling, and there are also reports that active air sampling may have 
advantages in terms of sensitivity. Passive sampling using settle plates can be a useful 
adjunct in critical areas with limited access and where an active sampler might 
interfere with airfl ow or entail a worrisome intervention risk. It must be recognized 
that attempts to support the “ sterility ” of the cleanest aseptic environments (those 
in ISO 5) by aggressive sampling may have exactly the opposite effect. Sampling 
too frequently will increase process contamination risk by causing critical interventions 
that are best avoided within these very clean environments. As personnel are 
the greatest single source of microbial contamination and conduct the sampling, 
sampling intensity should be carefully considered. There is no value to taking air 
samples beyond those required to assess the relative cleanliness level within the 
environment. 
Surface Sampling Surfaces in the classifi ed environments are monitored using a 
variety of methods but most commonly with contact plates (on smooth surfaces) or 
swabs (for irregular surfaces). Surface sampling in aseptic environments (ISO 5/6) 
is typically performed after the completion of the process to avoid the potential for 
adventitious contamination of the production materials as a consequence of sampling 
activities during the process. Fortunately, studies indicate that contamination 
does not build up during typical processing operations in modern clean rooms. 
Sampling with these materials may leave a trace of media or water on the sampled 
surface, and cleaning of the surface immediately after sampling is commonplace. 
Sampling of product contact surfaces (i.e., fi ll needles, feeder bowls, etc.) should only 
be performed after completion of the process, and the results of this testing should 
not be considered as an additional sterility test on the products. As in any form of 
manual environmental sampling, the risk of contamination by samplers during the 
processing of a sample makes the data less than completely reliable. Sampling of 
surfaces such as walls and fl oors should not be overdone because with good attention 
to aseptic technique they should be of little concern relative to actual process 
risk. Sampling on these surfaces is probably most useful in assessing ongoing changes 
in microfl ora and to confi rm the adequacy of the disinfection program. 
Personnel Sampling The monitoring of personnel gown surfaces is an adaptation 
of surface sampling in which samples are taken from surfaces on the operator. In 
ISO 5 environments, this ordinarily entails the gloved hands and perhaps forearms. 
As with any other sampling of a critical surface (the gloved hand is often in closest 
proximity to sterile product contact surfaces and sterilized components), the sampling 
should be performed at the conclusion of the aseptic activity. Sampling during 
the midst of the process risks contamination of the product and should be avoided. 
Sampling of other aseptic gown surfaces is ordinarily restricted to gowning certifi cation 
or postmedia fi ll testing, where more aggressive sampling can sometimes be 
informative. Whenever a gowned individual is sampled, the sample should be taken 
in the background environment (not ISO 5), and the individual should immediately 
exit and regown before continuing any further activity in the aseptic core area. 
Sampling of personnel in less critical environments can be useful; however, meeting 
regulatory expectations in these areas is ordinarily straightforward. Recommended 
contamination levels often distinguish among the different room classifi cation levels 
found within clean rooms. While this may seem reasonable, it is not completely 

logical since operators often move frequently between these different levels of classifi 
cation during the conduct of their work. 
Total Particulate Monitoring Confi rming the ability of the facility ’ s heating, ventilation, 
and air - conditioning (HVAC) system to maintain the appropriate conditions 
throughout (to the extent practical) the classifi ed environments is most easily 
accomplished using electronic total particle counters that can provide near immediate 
feedback on conditions during production operations. Total particle samples can 
be taken automatically, using permanently installed probes oriented into the unidirectional 
airfl ow. As such, they can be positioned proximate to critical activities to 
reaffi rm the continued quality of the air in the vicinity of the sterile materials and 
surfaces. Manual total particulate air sampling can be a dangerous intervention and 
therefore if required should be timed so as to minimize risk to product. Attempts 
to correlate total particle counts with microbial counts have proven diffi cult. Correlations 
are only meaningful when the source of foreign material is personnel since 
people are the only source of airborne contamination within an aseptic processing 
area. When personnel are the only source of particulate, the ratio between viable 
and nonviable particles have been consistently found to be > 1000 : 1, which means 
that in ISO 5 environments even relatively large total particulate count excursions 
would typically contribute microbial contamination that fell far below the limit of 
detection. Process equipment can and often does contribute airborne particulate 
matter but not detectable levels of microbial contamination. Also, microbial sampling 
is highly variable with respect to sensitivity, accuracy, precision, and limit of 
detection making correlations, particularly in rooms of highest air quality. So, it 
might seem logical to think that particle excursions are indicative of coincident 
microbial excursions especially in the cleaner environments (ISO 5) where the 
aseptic process takes place. 
It is common practice for fi rms to interrupt their aseptic processes when atypical 
total particulate excursions are observed so that the scientists and engineers can 
determine the source of the foreign material. Monitoring frequency and expectations 
in the less critical environments is always reduced relative to the critical aseptic 
environments. 
Where fi rms have introduced unidirectional air systems in preparations and 
compounding areas for particle control, there is often the temptation to expect these 
areas to meet the same microbial limits that these locations might attain in the 
aseptic core. This temptation should be resisted to avoid unnecessary sampling and 
deviations associated with expecting these environs to meet the conditions of aseptic 
areas where sanitization frequency, background environment, and most importantly 
personnel gowning are far superior to that found in the less clean locales [33] . 
Housekeeping An important component of environmental control are the housekeeping 
activities utilized to clean the facility external to the controlled environments. 
Aseptic operations utilize a series of protective environments to protect the 
sterile fi eld. Controls on the surrounding unclassifi ed areas are an important part 
of the overall control scheme for sterile manufacturing. These unclassifi ed areas 
support sterile operations in a variety of ways, and it is important to conduct activities 
therein that assist in the environmental control. Routine housekeeping, periodic 
sanitization, and even occasional environmental monitoring may be appropriate to 
ENVIRONMENTAL CONTROL AND MONITORING 123

124 STERILE PRODUCT MANUFACTURING 
assure that microbial and particle loads on items, equipment, and personnel entering 
the classifi ed environments is appropriately controlled. 
2.1.9 PRODUCTION ACTIVITIES 
The preparation of sterile materials requires execution of a number of supportive 
processes that together constitute the manufacturing process. They are intended to 
control bioburden, reduce particle levels, remove contaminants, sterilize, and/or 
depyrogenate. Nearly all of these activities occur within the controlled environments 
and are subject to qualifi cation/validation. 
2.1.9.1 Material and Component Entry 
Prior to the start of any production activity, materials and components must be 
transferred from a warehouse environment into a classifi ed environment. For most 
items this will necessitate removal from boxes or cartons, transfer to a nonwooden 
pallet, and passage through an air lock which serves as the transfer system between 
the controlled and uncontrolled environments. Often components are contained 
within plastic bags within a box or carton, and in some cases there are multiple bag 
layers to facilitate disinfection and passage through air locks into different zones of 
operation within the aseptic area. The fi rm may utilize an external disinfection 
of the materials in conjunction with this transfer. The concern is for minimization 
of particles and bioburden on these as yet unprocessed items in order to protect the 
controlled environment. 
Raw materials may be weighed in a weigh area in which they are transferred to 
plastic bags and/or noncorrugate containers prior to the transfer. The weighing area 
provides ISO 7 or better conditions, and may be a dedicated portion of the warehouse 
proper; in a central weighing/dispensing area; or in a location contiguous to 
the compounding area. Sterile ingredients are never opened anywhere other than 
an aseptic environment and must be handled aseptically at all times including sampling 
and processing of samples. 
2.1.9.2 Cleaning and Preparation 
Once the container component items have been introduced into the preparations 
area, they must be readied for sterilization/depyrogenation. For many items this 
consists of washing/rinsing processes designed to remove particles and reduce bioburden 
and endotoxin levels. The application of silicone suspensions for glass or 
closure materials is sometimes employed to provide lubrication allowing smoother 
feeding of components or dispensing (elimination of product accumulation on vial). 
Following the cleaning, items for sterilization are dried, wrapped, and staged/stored 
for steam sterilization. Washed containers are either placed in trays or boxes for 
depyrogenation in ovens or are directly loaded into dry - heat tunnels. It is common 
practice to protect all washed items with ISO 5 air from the completion of washing, 
through either wrapping or placement into a sterilizer or oven for passage into the 
aseptic area. The intention is to avoid foreign matter that could result in contamination 
of product. 

It is increasingly common for components to be supplied by the vendor in a 
ready - to - sterilize condition (washed and pretreated as necessary). Some items are 
available in a ready - to - use confi guration with the supplier providing sterile and 
pyrogen - free components. The use of supplier - prepared items eliminates the need 
for preparation activities at the fi ll site and requires modifi cation of material in - feed 
practices relative to on - site prepared items. 
The process equipment (portable tanks, valves, fi ll needles, etc.) and consumable 
materials (fi lters, hoses, gaskets, etc.) are prepared using a variety of methods. Portable 
tanks are subjected to CIP (and perhaps SIP as well) in the preparation area. 
Smaller items are disassembled (if necessary) and cleaned either manually or in a 
cabinet washer. After cleaning they are wrapped and staged/stored prior to sterilization. 
Tubing should not be reused; its preparation typically consists of fl ushing with 
WFI followed by cutting to the required length. It is best to preassemble fi ll sets 
with tubing, fi lters, and fi ll needles/pumps and then wrap them in preparation for 
sterilization. This process obviates poststerilization assembly steps and therefore 
mitigates contamination risk. These steps may be performed in ISO 5 environments 
to reduce total particulate contamination on the items. 
There are items that must be transferred into the aseptic processing area that 
cannot be treated within a sterilizer/oven. These include portable tanks, electronic 
equipment, and containers of sterile materials (ready - to - use items, sterile powders, 
environmental monitoring media, etc.). Air locks, pass - throughs, and similar designs 
are employed in which the exterior surfaces of the items are disinfected. The disinfection 
process may be completed by personnel outside and/or inside the aseptic 
area depending upon the specifi cs of the design. 
At the completion of the cleaning process, the items should be free of contaminating 
residues including traces of prior products, free of endotoxin, and well - controlled 
in terms of total particulate and microbial levels. This level of control would be 
appropriate regardless of whether the items, equipment, or components are to be 
sterilized or not. Sterilization, other than by relatively high temperature dry heat, has 
only a modest impact on endotoxin levels; cleaning provides the only means to 
control endotoxin for materials and equipment that is sterilized by other means. 
2.1.9.3 Compounding 
Fixed equipment in the compounding area (nonaseptic or aseptic) is cleaned in 
place. This eliminates traces of prior products, particles, and pyrogens. Sterilization 
in place is required for the aseptic fi xed equipment and is sometimes employed for 
the nonaseptic equipment as well as a bioburden control measure. Fixed transfer 
lines must be cleaned and sterilized as well, and this is accomplished independently 
or in conjunction with the vessels. The reuse of hoses and tubing is discouraged as 
cleaning and extractables cannot be confi rmed beyond a single use. 
The preparation of the product is performed within a classifi ed environment with 
careful attention to the batch record, especially for time limits and appropriate 
protection of materials during handling to guard against all forms of contamination. 
This is proper for nonsterile compounding to minimize contamination prior to fi ltration/
sterilization and is required for aseptic compounding activities. Barrier designs 
and other means of physically separating the worker from the product are recommended 
as a minimum even in nonaseptic compounding. As compounding may 
PRODUCTION ACTIVITIES 125

126 STERILE PRODUCT MANUFACTURING 
expose the worker to a variety of potent/toxic materials, the use of personnel protective 
equipment may be required. In extreme cases, the use of containment system 
may be required to protect the compounding operator. 
Where the compounding is nonaseptic, careful control over the environment, 
materials, and equipment is still appropriate to reduce viable/nonviable levels and 
to reduce the potential for endotoxin. Time limits should be imposed on manufacturing 
operations for additional control over microorganisms and thus microbial 
toxins. 
Once the materials have been sterilized, interventions near either the formulation 
or product contact surfaces/parts should be minimized. Direct handling of these 
materials should only be done with sterilized tools or implements; nonsterile objects, 
such as operator gloves, should never directly contact a sterilized surface. Sampling, 
fi lter integrity testing, process connection, and other activities should all be designed 
to eliminate the need for personnel exposure to sterile items. 
Aseptic compounding is often a required activity for sterile products that cannot 
be fi lter sterilized. The preparation of the sterile solids for use in these formulations 
is outside the scope of this chapter, but it is often acknowledged as the most diffi cult 
of all pharmaceutical processes to properly execute. Handling these materials at the 
fi ll site is performed using ISO 5 environments, and the use of closed systems is 
preferred [34] . 
2.1.9.4 Filling 
Aseptic fi lling is performed in ISO 5 environments, and a variety of approaches are 
utilized with the technology choice largely dependent upon the facility design, batch 
size, and package design. Older plants utilize manned clean rooms in which 
aseptically gowned personnel operate the fi lling equipment: performing the setup, 
supplying components, making any required adjustments, and conducting the environmental 
monitoring. As human operators are directly or indirectly responsible 
for essentially all microbial contamination, aseptic fi lling operations are increasingly 
designed to minimize the potential for operator contamination to enter the critical 
environment. Barriers of various sophistication and effectiveness are employed to 
increase the protection afforded to sterile materials. The most evolved of the clean - 
room designs are RAB systems in which personnel interventions are restricted to 
defi ned locations. Many newer facilities utilize isolation technology in which the 
fi lling environment is fully enclosed and personnel contamination is completely 
avoided. 
Filling designs for syringes and ampoules differ only with respect to the details 
of component handling and closure design. However, it is wise not to underestimate 
the infl uence of both component quality and component handling reliability on 
contamination control in aseptic processing. Components that minimize the need 
for intervention and equipment that is rather tolerant of component variability will 
result in better contamination control performance. Aside from these distinctions, 
the range of fi lling technologies previously described is also possible. 
The fi lling of plastic containers is accomplished using two very different 
approaches. Pre - formed containers can be sterilized in bulk, introduced into the 
aseptic suite via air locks, oriented (unscrambled), and fi lled. Blow-fi ll - seal prepares 
sterile bottles (most often LDPE) on line just prior to fi lling and sealing. 

Filling of suspensions, emulsions, and other liquids may require slightly different 
fi lling designs to assure uniformity of dose in each container. Ointments and creams 
are sometimes fi lled at elevated temperatures to improve their fl ow properties 
through the delivery and fi lling equipment. These are ordinarily fi lled into presterilized 
plastic tubes that have largely replaced aluminum tubes for these formulations. 
Powders are typically fi lled in vials using equipment specifi cally engineered for that 
purpose. 
An inerting gas (typically nitrogen, but other gases can be utilized) may be added 
to the headspace of the container to protect formulations that are oxygen sensitive. 
If the product is particularly sensitive to oxygen, purging may be done in the empty 
container prior to fi lling and again immediately after fi lling. Products may also be 
fi lled in an isolator under a nitrogen atmosphere if required. Products that require 
inert gas purging will also generally require inert gas for pressurization of tanks to 
provide motive force to drive the product through the fi lter(s) and into the fi lling 
reservoir. 
2.1.9.5 Stoppering and Crimping 
If the product is not freeze dried, the primary closure or “ stopper ” is applied shortly 
after completion of the fi lling process to better assure the sterility of the contents. 
When the product is to be lyophilized, the stopper may be partially inserted after 
fi lling and be fully seated after completion of the lyophilization cycle. Alternatively, 
the container could be left open and a stopper applied after completion of the 
drying. 
Crimping is the act of securing the closure to the vial. It must be performed with 
suffi cient uniform downward force to assure the container is properly secured. Too 
little downward force results in inadequately secured closures, while excessive force 
can result in container breakage. The force contributed by the crimp roller may be 
controllable as well. 
Applying the closure to syringes, ampoules, and other containers usually differs 
in methodology from the approaches used for vials, but the objective is identical to 
secure the container ’ s contents fully assuring the product ’ s critical quality attributes 
(especially sterility) are maintained throughout its shelf life. 
2.1.9.6 Lyophilization 
Lyophilization (or freeze - drying) is a process utilized to convert a water - soluble 
material fi lled into a container to a solid state by removal of the liquid while frozen. 
The process requires the use of deep vacuums and careful control of temperatures. 
By conducting the process under reduced pressure, the water in the container converts 
from ice directly to vapor as heat is applied and is removed from the container 
by the vacuum. The dissolved solids in the formulation cannot undergo this phase 
change and remain in the container. At the completion of the cycle, the container 
will be returned to near atmospheric pressure; stoppers are applied or fully seated 
and crimped as described above. Lyophilization is particularly common with biological 
materials whose stability in aqueous solution may be relatively poor. The time 
period in solution and the temperature of the solution are kept at a specifi ed low 
temperature to prevent product degradation [35] . 
PRODUCTION ACTIVITIES 127

128 STERILE PRODUCT MANUFACTURING 
As partially stoppered but unsealed containers must be transferred to the 
lyophilizer from the fi ll line, various designs have been utilized to protect the containers 
during this transit. Among the common alternatives utilized are the 
following: 
• Placement of the lyophilization in the wall of the fi ll room to allow for direct 
loading 
• Battery - operated unidirectional airfl ow carts to a remote lyophilizer 
• ISO 5 – protected conveyors with single shelf loading 
• Transfer utilizing isolator technology 
The use of trays for supporting the containers during the transfer, loading, lyophilization, 
and unloading steps was at one time common. The major problem with the 
use of trays for this purpose was the heat/handling - related distortion of the tray 
bottom that impacted the uniformity of the heating process in the freeze dryer. This 
was overcome by the use of trays with bottoms that were removed after loading 
and reinserted after completion of the drying. The current preference is for the 
placement of the containers directly on the shelf eliminating the trays entirely. This 
is accomplished by single height loading/unloading of the individual shelves with 
various pusher designs. 
The use of thermocouples to monitor product temperature inside selected 
vials with the lyophilizer is still the prevalent practice. The utility of this data is 
questionable and the current trend is to eliminate this “ requirement ” as soon as 
possible to better assure sterility of the unsealed vials by eliminating placement of 
the thermocouples. 
The lyophilizer chamber and condenser should be cleaned with a CIP system 
after each batch to prevent cross - contamination and, after cleaning, both should be 
sterilized. If a slot door loading system is utilized, periodic opening of a full door in 
the lyophilizer may be required to remove stoppers and glass that may have 
fallen. 
2.1.10 PERSONNEL 
Aseptic processing in the pharmaceutical industry is almost entirely dependent 
upon the profi ciency of the personnel assigned to this most critical of all activities. 
The operators must be able to consistently aseptically transfer sterile equipment 
and materials in a manner that avoids contamination of those materials [1] . This is 
no mean feat given the contamination continuously released by personnel and the 
prevailing need for personnel for execution of the process activities. 
Personnel profi ciency in aseptic operations must be fi rmly established before 
they are allowed to conduct critical aseptic process steps. Operators must master a 
number of relevant skills in order to be declared competent. The usual progression 
is from classroom training (CGMP, microbiology, sterilization, etc.) to relevant 
practical exercises (aseptic media transfers, aseptic gowning rehearsals) and ultimately 
to the core aseptic skills required (aseptic gowning certifi cation, aseptic 

assembly/technique) using a growth medium. Through this approach the operator 
gradually acquires the necessary skills to be a fully qualifi ed member of the production 
staff. Training/qualifi cation of personnel is an ongoing requirement and must 
be repeated periodically to assure the skills are maintained. Continuing evaluation 
of operator qualifi cation is accomplished using written examinations, practical challenges, 
documented observation, and participation in process simulation trials. 
There is general acknowledgment of the risk associated with heavy reliance on 
personnel for aseptic processing. This has fostered much of the innovative designs 
for aseptic fi lling such as RABS and isolators where personnel are largely removed 
from the critical environment. The future will undoubtedly witness aseptic technologies 
where human interaction with sterile materials has been eliminated. 
2.1.11 ASEPTIC PROCESSING CONTROL AND EVALUATION 
The preparation of any pharmaceutical product requires controls over the production 
operations to assure the end result is a product that meets the required quality 
attributes. The methods utilized for this control are supported by formalized validation 
studies in which proof of consistency is demonstrated by appropriately designed 
experiments. The defi nition of appropriate operating parameters is the primary 
objective of the development activities and is further confi rmed during scale - up to 
commercial operations. The validation supports that the routine controls applied to 
the process are appropriate to assure product quality [36] . This is typically accomplished 
in formalized validation activities in which expanded sampling/testing of the 
product materials is performed to substantiate their uniformity and suitability for 
use [30] . 
2.1.11.1 In - Process Testing 
The sampling and testing of in - process materials during the course of the manufacturing 
process can confi rm that essential conditions have been provided. This is 
appropriate in preparation, compounding, and fi lling activities. Sampling in preparation 
processes can confi rm the absence of particles, proper siliconization levels, and 
cleanliness of equipment to assure that production items and equipment are suitable 
for use. Samples for microbiological quality, must, as previously mentioned, always 
be done by fully gowned staff under ISO 5 conditions using excellent aseptic techniques. 
During compounding, in - process testing can confi rm proper pH, dissolution 
of materials, bioburden, and potency prior to fi lling. Filling operations can be monitored 
for fi ll volume (weight), headspace oxygen, and particles. These activities can 
all be automated to reduce interventions. These are typical examples of in - process 
controls utilized to assure acceptability of the process while it is underway. In the 
event of an abnormal result, corrective measures could be applied before further 
processing. The validation effort supports that these control measures are suffi cient 
to assure product quality, when met during production operations. The sample 
intervals, sizes, and locations for in - process testing are chosen to enhance the validation. 
The tolerance limits are usually tightened relative to the release requirements 
to further assure that no out - of - tolerance materials are produced. 
ASEPTIC PROCESSING CONTROL AND EVALUATION 129

130 STERILE PRODUCT MANUFACTURING 
2.1.11.2 End - Product Testing 
Upon completion of the process, samples are taken to establish that the batch meets 
the fi nal product specifi cations defi ned for release. Predefi ned sampling plans are 
utilized to obtain representative samples of the entire batch, the prior validation 
effort having assured through an expanded sampling effort that the process provides 
a uniform product. End - product sampling often suffers from the inability to link an 
anomalous result with a specifi c portion/segment of the batch. If the validation is 
insuffi ciently rigorous, an out - of - specifi cation result will ordinarily result in rejection 
of the batch and little opportunity to take effective corrective action. 
The FDA has been supportive of the use of process analytical technologies 
(PATs) as an improvement on end - product testing [37] . These are intended to act 
as on - line indicators of critical product attributes enabling immediate corrective 
action and preventing the production of off - specifi cation materials. This approach 
is common in the continuous process industries where feedforward controls are 
often employed. Their application to the more batch - oriented pharmaceutical/biotechnology 
industry is an acknowledgment that this approach can assure product 
quality more fully than a sampling - based approach. The PAT applications are still 
relatively few in number, but their utility in lieu of traditional quality methods is 
certainly promising. 
The preceding relates solely to product quality attributes, based upon chemical 
or physical requirements. Assurance of sterility, the most critical of all the quality 
components for an aseptically fi lled sterile product relies on the following: 
• The validation of the various sterilization processes for preparation of materials, 
equipment, and formulations 
• The design of the aseptic manufacturing process and facility 
• The establishment and maintenance of a proper processing environment 
• Most importantly, the profi ciency of the operating personnel directly involved 
with the aseptic process 
There is no direct means to evaluate the cumulative capability of these measures. 
We infer success in aseptic processing through the evaluation of indirect measures 
of performance: air pressure differentials, total particle counts, viable monitoring 
results, and end - product sterility testing. The enormous challenge of aseptic processing 
is that none of the in - process or end - product testing results can prove that the 
attribute of sterility is attained with a high degree of certainty. Therefore, we rely 
on validation and the demonstration of a validated state of control to infer the 
adequacy of our contamination control efforts. 
2.1.11.3 Process Simulations 
An indirect means of assessing a facility ’ s aseptic processing performance is the 
process simulation (or media fi ll) test [38] . This test substitutes a growth medium 
for the product in the process from the point of sterilization through to closure of 
the product container. The expectation is that successful handling of the growth 
media through the operating steps provides assurance that product formulations 
handled in a similar fashion would also be successful [39] . Process simulations 

culminate in the incubation of the media - fi lled containers with success defi ned as a 
limited number of contaminated units in a larger number of fi lled units. The result 
is a contamination rate for the media fi ll, and not a direct indication of the level of 
sterility assurance afforded to aseptically processed materials using the same procedures. 
At the present time, the level of sterility provided to aseptically processed 
materials cannot be measured. The FDA and EMEA have harmonized their expectations 
relative to process simulation performance, but they have also asserted that 
the goal in every process simulation is zero contamination [1, 2] . This formalized 
expectation and recognition that patient safety should always be preeminent have 
resulted in substantial improvements in aseptic processing technology over the last 
20 years. 
2.1.12 TERMINAL STERILIZATION 
Terminal sterilization is a process by which product is sterilized in its fi nal container. 
Terminal sterilization is the method of choice for products that are suffi ciently 
stabile when subjected to a compatible lethal treatment. Because the process utilized 
is expected to be lethal to the microorganisms present, is highly reproducible, 
and generally readily validated, there is a clear preference for its use [1, 40, 41] . 
The predominant method for terminal sterilization is moist heat, and a substantial 
percentage of sterile products are processed in this manner. (Estimates range 
from 5 to 15% of all sterile products are terminally sterilized.) The sterilization often 
requires the attainment of a balance between sterility assurance and degradation of 
the material ’ s essential properties [42] . The overkill sterilization method is preferred 
for heat - resistant materials, and may be usable for terminal sterilization where the 
formulation can tolerate substantial heat input. The bioburden/biological indicator 
approach uses less heat input but requires increased control over the titer and 
resistance of the bioburden organisms present. 
The large - volume parenteral (LVP) industry sometimes uses dedicated nonaseptic 
fi lling systems for its containers prior to subjecting them to terminal treatments. 
These LVP systems may approach the aseptic designs described earlier, but they are 
not supported by the same levels of environmental monitoring nor process simulation. 
Application of terminal sterilization at small volume parenteral producers may 
be done after the product is aseptically fi lled, although this practice is usual only 
where the fi rm produces predominantly aseptically fi lled products and would not 
have a fi lling system dedicated to terminally sterilized formulations. Product 
that will be subject to terminal sterilization may be fi lled under clean conditions 
with reduced environmental monitoring and control. However, control of total 
particulate levels requires unidirectional airfl ow for critical fi lling or assembly 
processes. 
Terminal sterilization is most commonly accomplished by moist heat. Terminal 
sterilization by other means is certainly possible, and a very limited number of parenteral 
drugs are treated with dry heat or radiation after fi lling. There is growing 
interest in the use of radiation, including low - energy E - beam, as a terminal treatment 
suggesting more products will be processed in this manner. 
Although there are numerous advantages to terminal sterilization, there can be 
very good reasons for aseptically fi lling products that are stabile enough to be com- 
TERMINAL STERILIZATION 131

132 STERILE PRODUCT MANUFACTURING 
patible with a sterilization process. For example, multichamber containers that 
cannot withstand terminal sterilization may provide a very important safety benefi t 
to the patient by reducing aseptic admixture or reconstitution in the clinic. These 
aseptic activities when conducted in clinics are generally not able to be done within 
anything like the controls required in industrial aseptic processing. It is often benefi - 
cial to discuss processing technology choices with regulatory authorities early in the 
development of a new product. 
2.1.13 CONCLUSION 
The manufacture of parenteral drugs by aseptic processing has long been considered 
a diffi cult technical challenge. These products require careful control and stringent 
attention to detail to assure their safety. Aseptic processing done with discipline and 
taking advantage of the numerous technical developments that have occurred over 
the years results in sterile products that can be administered with complete confi - 
dence. The wider adaptation of advanced aseptic processing will result in further 
evolutionary improvements in aseptic processing. The industry is at the beginning 
of an era in which human - scale aseptic processing will be completely replaced by 
separative technologies and process automation. Additionally, improved in - process 
controls are likely to be implemented making validation easier and easing the compliance 
burden. 
APPENDIX 
Parenteral Drug Association, Bethesda, Maryland 
TM 1: Validation of Steam Sterilization Cycles, 1978 
TR 3: Validation of Dry Heat Processes used for Sterilization & Depyrogenation, 
1981 
TR 7: Depyrogenation, 1985 
TR 11: Sterilization of Parenterals by Gamma Irradiation, 1988 
TR 13: Fundamentals of an Environmental Monitoring Program, 2001 
TR 22: Process Simulation Testing for Aseptically Filled Products, 1996 
TR 26: Sterilizing Filtration of Liquids, 1998 
TR 28: Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals, 
2006 
TR 34: Design & Validation of Isolator Systems for the Manufacture & Testing 
of Health Care Products, 2001 
TR 36: Current Practices in the validation of Aseptic Processing, 2002 
TR 40: Sterilizing Filtration of Gases, 2005 
International Society For Pharmaceutical Engineering, Tampa, Florida 
Baseline Guide, Vol. 3: Sterile Manufacturing Facilities, 1999 
Baseline Guide, Vol. 4: Water and Steam Systems, 2001 
Baseline Guide, Vol. 5: Commissioning and Qualifi cation, 2001 

REFERENCES 
1. U.S. Food and Drug Administration (FDA) ( 2004 ), Guideline on sterile drug products 
produced by aseptic processing, FDA, Washington, DC. 
2. European Union (EU) (2006), Annex 1—Sterile medicinal products—draft revision. 
3. International Organization for Standardization (ISO) , international standard 14644 1 - 3. 
4. U.S. Food and Drug Administration (FDA) ( 2004 ), Pharmaceutical CGMPs for the 
twenty - fi rst century —A risk-based approach, FDA, Washington, DC. 
5. International Conference on Organization (ICH) ( 2005 ), Draft consensus guideline 
quality risk management Q9, draft. 
6. Whyte , W. , and Eaton , T. ( 2004 ), Microbiological contamination models for use in risk 
assessment during pharmaceutical production , Eur J Parenteral Pharm Sci , 9 ( 1 ). 
7. Whyte , W. , and Eaton , T. ( 2004 ), Microbial risk assessment in pharmaceutical cleanrooms , 
Eur J Parenteral Pharm Sci , 9 ( 1 ). 
8. Agalloco , J. , and Akers , J. ( 2006 ), Simplifi ed risk analysis for aseptic processing: The 
Akers - Agalloco method , Pharm Technol , 30 ( 7 ), 60 – 76 . 
9. International Organization for Standardization (ISO) ( 2004 ), Cleanrooms and associated 
controlled environments — Part 7: Separative devices (clean air hoods, gloveboxes, isolators 
and mini - environments), ISO 14644 - 7 . 
10. Agalloco , J. ( 2006 ), Thinking inside the box: The application of isolation technology for 
aseptic processing , Pharm Technol ., p. S8 – 11 . 
11. Lysford , J. , and Porter , M. ( 2003 ), Barrier isolators history and trends , Pharm Eng , 23 ( 2 ), 
58 – 64 . 
12. ISPE ( 2005 ), Restricted access barrier systems (RABS) for aseptic processing, ISPE defi - 
nition, Aug. 16. 
13. Wikol , M. ( 2004 ), GoreTM vial isolator, ISPE presentation, Feb. 12. 
14. Py , D. ( 2004 ), Development challenges for intact sterile fi lling, PDA presentation, 
Mar. 9. 
15. Thilly , J. ( 2004 ), CVFL technology from lab scale to industry, PDA presentation, Mar. 8. 
16. ISPE (2001), Water and Steam Systems Baseline® guide. 
17. ISPE ( 1999 ), Sterile Manufacturing Facilities Baseline ® guide. 
18. ISPE (2001), Water and Steam Systems Baseline® guide. 
19. PDA ( 2006 ), Technical Monograph 1, Industrial moist heat sterilization in autoclaves, 
draft 17. 
20. Perkins , J. ( 1969 ), Principles and Methods of Sterilization in Health Sciences , Charles 
Thomas , Springfi eld, IL . 
21. Phillips , G. B. , and Morrissey , R. F. ( 1993 ), Sterilization Technology: A Practical Guide for 
Manufacturers and Users of Health Care Products , Van Nostrand Reinhold , New York . 
22. Agalloco , J. ( 1998 ), Sterilization in place technology and validation , in Agalloco , J. , and 
Carleton , F. J. , Eds., Validation of Pharmaceutical Processes: Sterile Products , Marcel 
Dekker , New York . 
23. PDA ( 1981 ), Technical Report 3, Validation of dry heat processes used for sterilization 
and depyrogenation. 
24. Case , L. , and Heffernan , G. ( 1998 ), Dry heat sterilization and depyrogenation: Validation 
and monitoring , in Agalloco , J. , and Carleton , F. J. , Eds., Validation of Pharmaceutical 
Processes: Sterile Products , Marcel Dekker , New York . 
25. Burgess , D. , and Reich , R. ( 1993 ), Industrial ethylene oxide sterilization , in Phillips , G. B. , 
and Morrissey , R. F. Eds., Sterilization Technology: A Practical Guide for Manufacturers 
and Users of Health Care Products , Van Nostrand Reinhold , New York . 
REFERENCES 133

134 STERILE PRODUCT MANUFACTURING 
26. Sintim - Damao , K. ( 1993 ), Other gaseous sterilization methods , in Phillips , G. B. , and Morrissey 
, R. F. Eds., Sterilization Technology: A Practical Guide for Manufacturers and Users 
of Health Care Products , Van Nostrand Reinhold , New Youk . 
27. Meltzer , T. , Agalloco , J. , et al. ( 2001 ), Filter integrity testing in liquid applications ; Revisited, 
Part 1, Pharm Technol , 25 ( 10 ), and Part 2, Pharm Technol , 25 ( 11 ). 
28. PDA (1998), Technical Report 26, Sterilizing fi ltration of liquids. 
29. PDA (2005), Technical Report 40, Sterilizing fi ltration of gases. 
30. Agalloco , J. , and Carleton , F. J. , Eds. ( 1998 ), Validation of Pharmaceutical Processes: Sterile 
Products , Marcel Dekker , New York . 
31. PDA (2001), Technical Report 13, Fundamentals of an environmental control program. 
32. USP . 1116 . ( 2005 ), Microbiological control and monitoring environments used for the 
manufacture of healthcare products , Pharm Forum , 31 ( 2 ), Mar. – Apr. 
33. Agalloco , J. ( 1996 ), Qualifi cation and validation of environmental control systems , PDA 
J Pharm Sci Technol , 50 ( 5 ), 280 – 289 . 
34. PDA ( 2006 ), Technical Report 28, Process simulation testing for sterile bulk pharmaceutical 
chemicals. 
35. Trappler , E. ( 1998 ), Validation of lyophilization , in Agalloco , J. , and Carleton , F. J. , Eds., 
Validation of Pharmaceutical Processes: Sterile Products , Marcel Dekker , New York . 
36. Chapman , K. G. ( 1984 ), The PAR approach to process validation , Pharm Technol , 8 ( 12 ), 
22 – 36 . 
37. Food and Drug Administration (FDA) ( 2004 ), PAT guidance for industry — A framework 
for innovative pharmaceutical development, manufacturing, and quality assurance, FDA, 
Washington, DC. 
38. PDA ( 1998 ), Technical Report 22, Process simulation testing for aseptically fi lled 
products. 
39. Agalloco , J. , and Akers , J. ( 2006 ), Aseptic processing for dosage form manufacture: Organization 
& validation , in Carleton , F. J. , and Agalloco , J. P. , Eds., Validation of Pharmaceutical 
Processes: Sterile Products , Marcel Dekker , New York . 
40. Food and Drug Administration (FDA) ( 1991 ), Use of aseptic processing and terminal 
sterilization in the preparation of sterile pharmaceuticals, FR 56, 354 – 358 . 
41. PIC/S41. ( 1999 ), Decision trees for the selection of sterilisation methods 
(CPMP/QWP/054/98). 
42. PDA ( 2006 ), Technical Monograph 1, Industrial moist heat sterilization in autoclaves, 
draft 17. 
ADDITIONAL READINGS 
Akers , J. ( 2001 ), An overview of facilities for the control of microbial agents , in Block , S. S. , 
Ed., Disinfection, Sterilization and Preservation , 5th ed, Lippincott, Williams and Wilkins , 
Philadelphia , pp. 1123 – 1138 . 
Akers , J. , and Agalloco , J. ( 1997 ), Sterility and sterility assurance , J Pharm Sci Technol 51 , 
72 – 77 . 
Cole , J. C. ( 1990 ), Pharmaceutical Production Facilities — Design and Application , Ellis 
Norwood , Chicester . 
Institute of Environmental Science and Technology (IEST) ( 1995 ), Compendium of standards, 
practices, and similar documents relating to contamination control, CC009/ 
IESCC009.2, IEST, Mt. Prospect, IL. 

Ljungvist , B. , and Reinmueller , B. ( 1995 ), Ventilation and Airborne Contamination in Clean 
Rooms , Pharmacia A/B , Stockholm . 
Reinmuller , B. ( 2000 ), Microbiological risk assessment of airborne contaminants in clean 
zones, Bulletin No. 52, Royal Institute of Technology/Building Services and Engineering, 
Stockholm. 
United States Pharmacopoeia/National Formulary ( 2006 ), 29, Chapter 1116, Microbial evaluation 
of clean rooms, Rockville, Maryland, pp. 2969 – 2976 . 
ADDITIONAL READINGS 135


FACILITY 
SECTION 3


139 
3.1 
FROM PILOT PLANT TO 
MANUFACTURING: EFFECT OF 
SCALE - UP ON OPERATION OF 
JACKETED REACTORS 
B. Wayne Bequette 
Rensselaer Polytechnic Institute, Troy, New York 
Contents 
3.1.1 Motivation 
3.1.2 Background 
3.1.2.1 Pharmaceutical Process Development 
3.1.2.2 Batch Reactors 
3.1.2.3 Reaction Calorimetry 
3.1.3 Laboratory Vessels and Reaction Calorimeters 
3.1.3.1 Material and Energy Balances 
3.1.3.2 Estimating Fluid Properties and Heat Transfer Coeffi cients from Calorimeter 
Data 
3.1.3.3 Estimating Heat Flows 
3.1.3.4 Relating Heat Flows and Conversion 
3.1.3.5 Semibatch Reactions 
3.1.3.6 Rapid Scale - Up Relationships 
3.1.3.7 Strategy under a Cooling System Failure 
3.1.4 Heat Transfer in Process Vessels 
3.1.4.1 Heat Transfer Relationships 
3.1.4.2 Effect of Reactor Type, Jacket Heat Transfer Fluid, and Reactor Fluid 
Viscosity 
3.1.4.3 Pilot - and Production - Scale Experiments 
3.1.5 Dynamic Simulation Studies 
3.1.6 Summary 
References 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

140 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
3.1.1 MOTIVATION 
There are many phases of process development between the discovery of an active 
pharmaceutical ingredient and the design, construction, and operation of a manufacturing 
process to produce a drug. A sequence of reactions and separations that 
is successful at the bench scale may lead to a process that is unsafe, is diffi cult to 
operate, or produces unsatisfactory product at the manufacturing scale. A manufacturing 
process typically has a large sequence of steps, involving several different unit 
operations (heat exchangers, reactors, separators, etc.), and a complete review of the 
design and scale - up of these unit operations would constitute a chemical engineering 
curriculum; thus, the focus of this chapter is the scale - up of jacketed batch 
chemical reactors from the laboratory to the pilot plant and manufacturing. These 
reaction vessels often serve many functions, including mixing, heating, cooling, 
distillation, and crystallization. 
Temperature control for laboratory reactors is typically easy because of high heat 
transfer area – reactor volume ratios, which do not require large driving forces (temperature 
differences) for heat transfer from the reactor to the jacket. Pilot - and 
full - scale reactors, however, often have a limited heat transfer capability. A process 
development engineer will usually have a choice of reactors when moving from the 
laboratory to the pilot plant. Kinetic and heat of reaction parameters obtained from 
the laboratory reactor, in conjunction with information on the heat transfer characteristics 
of each pilot plant vessel, can be used to select the proper pilot plant 
reactor. 
Similarly, when moving from the pilot plant to manufacturing, a process engineer 
will either choose an existing vessel or specify the design criteria for a new reactor. 
A necessary condition for operation with a specifi ed reactor temperature profi le is 
that the required jacket temperature is feasible. We have therefore chosen to focus 
on heat transfer – related issues in scale - up. Clearly there are other scale - up issues, 
such as mixing sensitive reactions. See Paul [1] for several examples of mixing scale - 
up in the pharmaceutical industry. 
In this chapter we discuss important issues as we move from laboratory to pilot 
plant and manufacturing. A review of batch process operation and pharmaceutical 
research is covered in Section 3.1.2 , followed by laboratory vessels and reaction 
calorimetry in Section 3.1.3 . In Section 3.1.4 heat transfer in process vessels is presented, 
including the effect of reactor type and heat transfer fl uid on the vessel heat 
transfer capability. In Section 3.1.5 dynamic behavior based on simulation studies 
is discussed. 
3.1.2 BACKGROUND 
3.1.2.1 Pharmaceutical Process Development 
Anderson [2] presents a wide range of topics on pharmaceutical process development, 
including a number of different problems related to process scale - up, such as 
solvent and reagent selection, purifi cation, and limitations to various operations. He 
notes that most reactors used for scale - up operations are selected for fl exibility in 
running many different processes, especially for pilot plants and multiproduct manufacturing 
plants. 

BACKGROUND 141 
Pisano [3] discusses the management of process development projects in the 
pharmaceutical industry. Case studies are used to illustrate the effect of resource 
allocation decisions at different stages of a project. While there has been a focus on 
product development in the pharmaceutical industry, clearly process development 
plays an important role in getting a product to market and lowering the long - term 
product manufacturing costs. 
3.1.2.2 Batch Reactors 
Batch processes present challenging control problems due to the time - varying 
nature of operation. Chylla and Haase [4] present a detailed example of a batch 
reactor problem in the polymer products industry. This reactor has an overall heat 
transfer coeffi cient that decreases from batch to batch due to fouling of the heat 
transfer surface inside the reactor. Bonvin [5] discusses a number of important 
topics in batch processing, including safety, product quality, and scale - up. He notes 
that the frequent repetition of batch runs enables the results from previous runs to 
be used to optimize the operation of subsequent ones. 
LeLann et al. [6] discuss tendency modeling (using approximate stoichiometric 
and kinetic models for a reaction) and the use of model predictive control (linear 
and nonlinear) in batch reactor operation. Studies of a hybrid heating – cooling 
system on a 16 - L pilot plant are presented. 
Various aspects of the effect of process scale - up on the safety of batch reactors 
have been discussed by Gygax [7] , who presents methods to assess thermal runaway. 
Shukla and Pushpavanam [8] present parametric sensitivy and safety results for 
three exothermic systems modeled using pseudohomogenous rate expressions from 
the literature. Caygill et al. [9] identify the common factors that cause a reduction 
in performance on scale - up. They present results of a survey of pharmaceutical and 
fi ne chemicals companies indicating that problems with mixing and heat transfer 
are commonly experienced with large - scale reactors. 
3.1.2.3 Reaction Calorimetry 
The microanalytical methods of differential thermal analysis, differential scanning 
calorimetry, accelerating rate calorimetry, and thermomechanical analysis provide 
important information about chemical kinetics and thermodynamics but do not 
provide information about large - scale effects. Although a number of techniques are 
available for kinetics and heat - of - reaction analysis, a major advantage to heat fl ow 
calorimetry is that it better simulates the effects of real process conditions, such as 
degree of mixing or heat transfer coeffi cients. 
Regenass [10] reviews a number of uses for heat fl ow calorimetry, particularly 
process development. The hydrolysis of acetic anhydride and the isomerization of 
trimethyl phosphite are used to illustrate how the technique can be used for process 
development. Kaarlsen and Villadsen [11, 12] provide reviews of isothermal reaction 
calorimeters that have a sample volume of at least 0.1 L and are used to measure 
the rate of evolution of heat at a constant reaction temperature. Bourne et al. [13] 
show that the plant - scale heat transfer coeffi cient can be estimated rapidly and 
accurately from a few runs in a heat fl ow calorimeter. 
Landau et al. [14] use a heat fl ow calorimeter to investigate feasible pilot plant 
operating conditions for the production of a pharmaceutical intermediate. They 

142 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
determine kinetic and heat fl ow parameters using the calorimeter and further estimate 
heat transfer parameters for a pilot - scale reactor. Simulation studies are used 
to fi nd the required jacket temperature for desired batch reactor temperature pro- 
fi les. Semibatch operation is shown to be safer than normal batch operation. Landau 
[15] provides a detailed review of reaction calorimetry, including mathematical 
expressions for energy balances, and a number of application examples. 
3.1.3 LABORATORY VESSELS AND REACTION CALORIMETERS 
As reviewed in Section 3.1.2.3 , reaction calorimeters can be used to better understand 
and characterize scale - related process phenomena, such as mixing and heat 
transfer. A heat fl ow calorimeter, the Mettler RC1e, is shown in Figure 1 . A 
schematic of a similar calorimeter system is shown in Figure 2 [16] . A heat fl ow 
calorimeter can be used to estimate: 
• Physical parameters (heat capacity) 
• Reaction rate constants 
• Heat transfer coeffi cients (overall, U or, or fi lm, h i ) 
3.1.3.1 Material and Energy Balances 
The overall energy balance for a process with no reaction has the form 
Energy accumulation energy in heat transfer from jacket 
energy i 
= 
+ n by calibration probe energy lost by ambient heat transfer . 
FIGURE 1 Mettler RC1e heat fl ow calorimeter system ( www.mt.com ). 

FIGURE 2 Schematic of HEL SIMULAR reaction calorimeter. From ref. 16 . 
Additional heater 
F3 F2 F1 
Stirrer 
Tamb 
Qadd 
n 
Condenser 
Tw,in 
TR pHR pR 
Tj,out 
Tj,in 
Tw,out and mw 
Inert gas 
venting 
Circulation 
thermostat, 
heater, chiller 
Liquid 
surface 
Oil jacket 
Outlet valve Scale Scale Scale 
which is shown mathematically as 
( ) ( ) ( ) mc 
dT 
dt 
UAT T q k T T p r j = . . + . . cal loss amb (1) 
where ( mc p ) r 
is the reactor thermal capacitance, T is the reactor temperature, T j is 
the jacket temperature, U is the overall heat transfer coeffi cient, A is the area for 
heat transfer, q cal is the heat fl ow from the calibration probe, and the fi nal term 
accounts for heat loss from the reactor system. The thermal capacitance is composed 
of the fl uid in the vessel as well as the inert components in contact with the fl uid, 
including the vessel wall, agitator (stirrer), and sensors (e.g., thermocouple), as 
shown in the equation 
( ) mc V c m c p r p v pv = + . (2) 
where V is the volume of liquid, . is the liquid density, c p is the liquid heat capacity, 
m v is the mass of the vessel wall and other inerts, and c pv is the average heat capacity 
of the vessel wall and inerts. The inert contributions and heat transfer to the ambient 
can be found from extensive calibration studies. For small - scale reactors, such as 
reaction calorimeters, the thermal mass of the inerts can be signifi cant. The thermal 
capacitance ratio, sometimes called the Lewis number, is given as 
. 
. . 
= =+ 
( ) mc 
V c 
m c 
V c 
p r 
p 
v pv
p 
1 (3) 
which can be on the order of 1.5 – 2 for a small - scale reactors and adiabatic calorimeters 
but is often 1.05 – 1.10 for small pilot plant reactors and less than 1.02 for 
manufacturing - scale reactors. 
LABORATORY VESSELS AND REACTION CALORIMETERS 143

144 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
3.1.3.2 Estimating Fluid Properties and Heat Transfer Coeffi cients from 
Calorimeter Data 
In a heat fl ow calorimeter, a feedback controller is used to maintain a constant 
desired reactor temperature by adjusting the jacket temperature. From (1), with a 
constant calibration probe heat fl ow, at steady state ( dT / dt = 0), the overall heat 
transfer coeffi cient can be found from 
UA 
q k T T 
T Tj 
= 
. . 
. 
cal loss amb ( ) 
(4) 
Also, the fl uid heat capacity can be found by ramping up the reactor temperature 
and using 
( ) 
( ) ( ) 
mc 
UAT T q k T T 
dT dt p r 
j =
. . + . . cal loss amb 
/ 
(5) 
and solving for c p from (2), assuming that the reactor inert component contributions 
are known from previous studies. An example calibration study is shown in Figure 
3 , where a constant heat fl ow is applied from 35 to 42 min, enabling the heat transfer 
coeffi cient to be estimated from the temperature difference using Equation (4) . 
Then, the heat capacity is estimated from the temperature ramp applied between 5 
and 20 min. It should be noted that the heat transfer coeffi cient and heat capacity 
of the fl uid may vary with concentration and temperature. Typically, calibration 
experiments are performed before and after the reaction; then the heat transfer 
coeffi cient and heat capacity are assumed to vary linearly with conversion or batch 
time. For polymerization reactions in particular, the viscosity can increase tremendously 
with conversion, causing a substantial decrease in the heat transfer coeffi - 
FIGURE 3 Example reaction calorimetry study without reaction. The overall heat transfer 
coeffi cient area can be found during the steady - state temperature difference and known calibration 
probe heat fl ow, between 35 and 42 min. The heat capacity can then be found from 
the temperature ramp between 5 and 20 min. 
RC1 Calibration profiles 
Determine UA 
Determine cp 
Time, min Temperature, °C 
28 
26 
24 
22 
20 
20 30 40 50 60 
18
0 10 
reactor 
jacket

cient. Reaction experiments can be run at several temperatures to fi nd the functional 
relationship with temperature. 
Since the heat transfer area as a function of liquid volume is known, the overall 
heat transfer coeffi cient U can be calculated from (4). The overall heat transfer 
coeffi cient is calculated as 
1 1 
U h 
x
k i 
g
g 
= + (6) 
where the jacket side resistance is negligible. The glass vessel heat transfer resistance 
( x g / k g , thickness/thermal conductivity) can be used to fi nd the reactor fl uid heat 
transfer coeffi cient ( h i ). 
3.1.3.3 Estimating Heat Flows 
The reaction heat fl ow can be found by rearranging (1), with the calibration heat 
probe replaced by the reaction heat fl ow, to fi nd 
q mc 
dT 
dt 
UA T T k T T r p r j = + . + . ( ) ( ) ( ) loss amb (7) 
The total heat released during the reaction can be found by integrating (7), 
Q qdt r 
tf 
tot = .0 (8) 
or, represented as a scaled (per - unit mass) total heat release, 
Q 
Q
V 
Q
m tot 
tot tot = = 
. 
(9) 
The molar heat of reaction can be found from 
.H 
Q 
n rxn 
tot 
rxn 
= 
. 
(10) 
where n rxn is the molar amount reacted. 
As a “ fi rst - pass ” calculation, if it is assumed that the dominant heat transfer 
resistance is on the reactor side, then the overall heat transfer coeffi cient ( U ) from 
(4) can be used for scale - up. 
3.1.3.4 Relating Heat Flows and Conversion 
The reaction heat fl ows are directly related to the conversion of reactants [14] . 
Consider a fi rst - order reaction of a limiting reactant, with the rate expression 
dC 
dt 
kC = . (11) 
LABORATORY VESSELS AND REACTION CALORIMETERS 145

146 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
where C is the molar concentration of the reactant. The heat fl ow is 
q 
dC 
dt 
H V kC H V r =( ) = . . . rxn rxn (12) 
with an initial heat fl ow of 
q kC H V r0 0 = . . rxn (13) 
dividing (12) by (13), we fi nd the relationship between concentration and heat 
fl ow: 
C 
C 
q 
q 
r 
r 0 0 
= (14) 
For an isothermal reaction, the solution to (11) is 
C 
C 
e kt 
0 
= . (15) 
so, the heat fl ow for an isothermal reaction is 
q 
q 
e r 
r 
kt 
0 
= . (16) 
Thus, the reaction rate constant k can be estimated from the reaction heat fl ow 
without making any concentration measurements. Assuming an Arrhenius rate 
expression 
k Ae E RT = . 
0 
/ (17) 
the rate constant at several temperatures can be used to estimate the frequency 
factor ( A 0 ) and activation energy ( E ). (See ref. 14 for an example application.) 
3.1.3.5 Semibatch Reactions 
For extremely exothermic reactions it is necessary to slowly add the feed over time, 
that is, operate in a semibatch fashion. The heat fl ow for a semibatch reaction can 
be found from 
q UAT T mc 
dT 
dt 
m c T T r j p r f pf f = . + + . ( ) ( ) ( )  (18) 
where  mf is the mass fl ow rate of the feed stream. If the reactor temperature is 
maintained constant, this reduces to 
q UAT T mc T T r j f pf f = . + . ( ) ( )  (19) 

For reactions with essentially instantaneous kinetics, the reaction rate is limited by 
the feed addition rate. For other reactions, particularly if the reactor is operated at 
too low of a temperature, a reactant concentration can “ build up, ” eventually reaching 
an unsafe level that could lead to a rapid temperature rise and explosion. It is 
important for these reactions to monitor the heat fl ow to confi rm that the reactant 
concentration is not increasing to unacceptable levels. 
3.1.3.6 Rapid Scale - Up Relationships 
Lacking knowledge of the larger scale reactor, it is tempting to simply assume that 
only the area for heat transfer varies upon scale - up. A natural parameter is the 
cooling time , 1 defi ned as 
. 
. . 
co= = 
( ) mc 
UA 
V c 
UA 
p r p (20) 
The heat transfer area varies with the square of the vessel diameter, and the volume 
varies with the cube of the vessel diameter. Thus the area – volume ratio ( A / V ) varies 
with volume as 
A
V V 
~ 
1
1/3 
(21) 
The inverse cooling time relationship for scale - up from volume V 1 to V 2 is 
UA 
V c 
UA 
V c 
V
V p p . . . . 
.
. . 
.
. . 
= .
. . 
.
. . 
( ) 2 1 
1
2 
1/3 
(22) 
The required reactor - jacket temperature difference on scale - up, with a constant 
Lewis number, is 
[ ] [ ] T T T T 
V
V j j . = . ( ) 2 1 
2
1 
1/3 
(23) 
so the temperature difference can increase dramatically when a process is scaled up 
several orders of magnitude. Reactor - jacket temperature difference constraints can 
be particularly important for glass - lined vessels, where the limit is often 75 ° C. 
3.1.3.7 Safety under a Cooling System Failure 
In the event of a cooling system failure it can be assumed that the reactor operates 
adiabatically. The adiabatic temperature rise can be found from 
1 The notion of cooling time can be understood by writing (1) and assuming no calibration energy or heat 
loss. Then (1) becomes . co ( dT / dt ) = . ( T . T j ). If a constant temperature difference T . T j is applied, it 
will take . co time units for the reactor temperature to change by the temperature difference. 
LABORATORY VESSELS AND REACTION CALORIMETERS 147

148 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
.T 
Q
mcp r 
ad 
tot =
( ) 
(24) 
and the fi nal temperature is 
T T T final initial ad = +. (25) 
As long as the fi nal temperature is less than some critical “ onset ” temperature where 
a secondary decomposition reaction occurs, then the process can safely handle a 
cooling system failure. If a batch reactor temperature cannot be assured to remain 
less than the onset temperature after a cooling system failure, then a semibatch 
operation should be used. As noted in Section 3.1.3.5 , it is necessary to assure that 
reactant concentration is not increasing above an onset concentration where a 
similar decomposition could occur with a cooling system failure. 
3.1.4 HEAT TRANSFER IN PROCESS VESSELS 
Based on initial heat fl ow calorimetry studies, a process development engineer must 
choose the appropriate reactor vessels for pilot plant studies. A pilot plant typically 
has vessels that range from 80 to 5000 L, some constructed of alloy and others that 
are glass lined. In addition some vessels may have half - pipe coils for heat transfer, 
while others have jackets with agitation nozzles. A process drawing for a typical 
glass - lined vessel is shown in Figure 4 . In Sections 3.1.4.1 and 3.1.4.2 we review 
fundamental heat transfer relationships in order to predict overall heat transfer 
coeffi cients. In Section 3.1.4.3 we review experimental techniques to estimate heat 
transfer coeffi cients in process vessels. 
3.1.4.1 Heat Transfer Relationships 
Reactor - Side Coeffi cient The reactor - side heat transfer coeffi cient is calculated 
as 
h a
k
D i 
i
i 
i i = Re Pr . . 0 67 0 33 (26) 
where a is the agitation constant (0.33), k i is the fl uid thermal conductivity, Re i is 
the Reynolds number, and Pr i is the Prandtl number, 
Rei 
ag i 
i 
D N 
= 
2 . 
. 
(27) 
Pri 
i pi 
i 
c 
k 
= 
. 
(28) 

FIGURE 4 Typical 300 - or 500 - gal jacketed vessel ( www.pfaudler.com ). 
SRW 3525 drive 
Lubricated dry 
mechanical seal 
Drive nozzle 
face 
E
10. 
5. 
6. 
3. 18. 
12. 
3. Legs (four) 
45. Leg circle 
54. O.D. 
48. I.D. 
13. 
(3. Nozs.) (4. Nozs.) 
A 
B 
C 
D 
F 
Optional side 
supports 
Fin Battle w/RTD 
Temperature Sansor 
23. Span 
Cryo-Lock CBT 
2. Cplgs. (Two) 
1/2. Cplg. 
1/2. Cplg. 
(4) 3/4. dia. holes 
equally spaced on 
a 10. BC 
14 1/4. (6. Noz.) 
4 1/4. 
3. Noz. 
1 1/2. Cplgs. 
13 1/4. 
1 1/2. agit. 
nozs. 
(Offset) 
and N is the agitator rotation rate. It should be noted that the fi lm heat transfer 
coeffi cient varies inversely with the viscosity, that is, 
hi 
i 
~ . 
1
0 33 . 
(29) 
Reactions where the viscosity increases substantially with conversion, such as some 
polymerization reactions, can be particularly diffi cult to control upon scale - up. 
Jacket - Side Coeffi cient Here the calculations are shown for a jacket equipped 
with agitation nozzles that greatly increase the jacket fl uid velocity. The jacket “ swirl 
velocity ” v j is calculated (iteratively) from the nonlinear algebraic relationship 
[17] 
m v v 
fL 
D 
v 
A n n j 
e 
j 
f ( ) . =( ).. . 
.. . 
4 
2
2 
. (30) 
HEAT TRANSFER IN PROCESS VESSELS 149

150 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
where  mn the is the nozzle mass fl ow rate, v n is the nozzle velocity, the friction factor 
is 
f = 
. 2 0 023 
0 2 
. 
Re . 
(31) 
the jacket - side fi lm coeffi cient is 
h 
k
D j 
j
e 
j j = 0 027 0 8 0 33 . Re Pr . . (32) 
and the Reynolds and Prandtl numbers are 
Rej 
e j j 
j 
D v 
= 
. 
. 
(33) 
Prj 
j pj 
j 
c 
k 
= 
. 
(34) 
Overall Coeffi cient The overall heat transfer coeffi cient is found from the sum of 
the resistances, 
1 1 1 
U h h 
x
k 
x
k 
ff ff 
i j 
m
m 
g
g 
i j = + + + + + (35) 
which includes reactor fi lm, jacket fi lm, vessel metal, vessel glass, and fouling factors 
for both the reactor and jacket sides. 
3.1.4.2 Effect of Reactor Type, Jacket Heat Transfer Fluid, and Reactor 
Fluid Viscosity 
Here we present examples of how the reactor type and heat transfer fl uid affect the 
heat transfer coeffi cient. When the reactor fl uid has a low viscosity, the dominant 
heat transfer resistance tends to be on the jacket side. When the reactor fl uid has a 
high viscosity, however, the dominant resistance is typically on the reactor side. 
Parameter values for the studies are presented in Figures 5 – 7 and are given in the 
literature [18] . 
The overall heat transfer coeffi cient is much higher for an alloy reactor/half - pipe 
jacket than for a glass - lined carbon steel reactor/agitation nozzle jacket, as shown 
in Figure 5 , where Syltherm is the heat transfer fl uid. Syltherm has a signifi cantly 
lower heat transfer coeffi cient than an ethylene glycol mixture, as shown in Figure 
6 , but is capable of operating over a wider range of temperatures. The reactor fl uid 
viscosity has a tremendous effect on the overall heat transfer coeffi cient, as shown 
in Figure 7 . This can be particularly important in polymerization reactions where 
viscosity increases with conversion. 

FIGURE 5 Overall heat transfer coeffi cient for 500 - gal reactors. Comparison of alloy half 
pipe with glass - lined carbon steel (GLCS). Syltherm is the heat transfer fl uid. ( From ref. 18 , 
with permission .) 
–50 0 50 100 150 200 250 
20 
30 
40 
50 
60 
70 
80 
Jacket temperature °C 
Overall U, English units 
Half pipe 
Jacket w/nozzles 
FIGURE 6 Overall heat transfer coeffi cient for 500 - gal GLCS reactor. Comparison of Syltherm 
with Glycol. ( From ref. 18 , with permission .) 
–50 0 50 100 150 200 250 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
Jacket temperature °C 
Overall U, English units 
Syltherm 
Glycol 
3.1.4.3 Pilot - and Production - Scale Experiments 
The relationships shown in Section 3.1.3 are also pertinent to large - scale reactors. 
By using different solvents and volumes of solvent, pilot and production reactor 
heat transfer characteristics can be determined from a series of experiments. A 
primary limitation, compared to reaction calorimeter characterization, is that a calibration 
probe is rarely available. Thus, heat - up and cool - down studies, performed 
HEAT TRANSFER IN PROCESS VESSELS 151

152 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
FIGURE 7 Overall heat transfer coeffi cient for 500 - gal GLCS reactor with glycol heat 
transfer fl uid. Comparison of effect of reactor - side viscosity. 
–20 0 20 40 60 80 100 120 
10 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
Jacket temperature °C 
Overall U, English units 
500 gal. GLCS. 1 cp vs. 3000 cp 
1 cP 
3000 cP 
by varying the jacket temperature and observing the changes in the reactor temperature 
(for solvents with known heat capacity), are used to characterize the 
reactor. The inverse cooling time, 
UA 
mc 
dT dt 
T T p r j ( ) 
= 
.
/ 
(36) 
can be estimated from the temperature data collected from a heat - up/cool - down 
study. A characteristic example for a pilot - scale reactor is shown in Figure 8 . The 
FIGURE 8 Temperature profi les (jacket inlet, jacket outlet, and reactor) for a pilot plant 
reactor. ( From ref. 19 .) 
Time, min 
0 20 40 60 80 100 120 140 160 180 
100 
80 
60 
40 
20
0 
temperature, °C

FIGURE 9 Cooling time estimates based on data presented in Figure 8 . ( From ref. 19 .) 
0 10 
28 
27 
26 
25 
24 
23 
22 
21 
20 
19 
20 30 
Jacket temperature, °C 
mCp/UA, min 
40 50 60 70 80 90 
cool-down 
heat-up 
resulting cooling time estimates are shown in Figure 9 . Notice that the overall heat 
transfer coeffi cient is clearly a function of the jacket temperature. The reduced heat 
transfer at the lower jacket temperatures is due to the strong relationship between 
viscosity and temperature for the 40% glycol solution used in the jacket. The discontinuity 
in the cooling time estimate at around 45 ° C may be due to two factors. 
One factor is the assumption of no heat loss from the vessel, which would tend to 
lower the UA estimates during the heat - up phase. Another factor is the assumption 
that the metal and glass inerts in the reactor are at the temperature of the reactor; 
in practice it might be a better assumption that the reactor wall in particular is at a 
temperature that is intermediate between the jacket and reactor temperatures. 
The fl uid and inert thermal masses can be independently estimated by conducting 
experiments with a number of different solvent amounts. From the cooling time 
expression 
( ) mc 
UA 
m c 
UA 
V c 
UA 
p r v pv p = + 
. 
(37) 
writing this as a function of the reactor fl uid volume, 
( ) mc 
UA 
m c 
UA 
c 
UA 
V p r v pv p = + . 
. 
(38) 
and conducting experiments at a number of different fl uid volumes or, equivalently, 
masses ( V . ), 
( ) mc 
UA 
m c 
UA 
c 
UA 
V p r v pv p = + .. (39) 
the linear regression can be used to fi nd the slope and intercept and thus estimate 
the UA and m v c pv terms [19] . This approach is shown in Figure 10 for a jacket tem- 
HEAT TRANSFER IN PROCESS VESSELS 153

154 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
FIGURE 10 Linear regression to estimate thermal mass and UA . ( From ref. 19 .) 
200 250 300 350 
Mass of water, kg 
30 
28 
26 
24 
22 
20 
18 
mCp/UA, min 
perature of 60 ° C (based on a total of eight experiments at fi ve different reactor 
fl uid volumes). 
3.1.5 DYNAMIC SIMULATION STUDIES 
Older pilot plant and manufacturing processes often used steam for heating and 
water for cooling, with a switch - and - purge strategy between the two modes. Recent 
process designs have two heat transfer fl uid systems (hot and cold heat transfer 
fl uids) that are used for most of the heating and cooling needs. In addition, some 
vessels may have nitrogen coolers for cryogenic operation. 
A simplifi ed schematic for a jacket heat transfer service is shown in Figure 11 
[18] . Here, two separate heat transfer fl uid headers are used, and the control valve 
is on the outlet stream to reduce the temperature shocks that might occur if a single 
FIGURE 11 Characteristic pilot plant vessel control strategy. Slave (secondary) controller 
based on jacket outlet temperature is shown. The control valve is on the outlet stream to 
minimize temperature gradients (when switching from hot to cold fl uids) that would be 
imposed if the valve was on the inlet. ( From ref. 18 , with permission .) 
TC1 
TC2 
From hot HT 
fluid system 
From cold HT 
fluid system 
To cold HT 
fluid system 
To hot HT 
fluid system

control valve was on the inlet stream. Depending on the range of temperatures, 
either ethylene glycol or a proprietary fl uid such as Syltherm is used. Depending 
on whether heating or cooling is needed, either the hot or cold process control 
valve is open. Similarly, on – off valves return fl uid to the appropriate distribution 
system. 
Although the heat transfer fl uid can be used over a wide range of temperatures, 
the fi lm heat transfer coeffi cient is a strong function of temperature due to viscosity 
effects. The “ cooling time ” of a large reactor operating at a low temperature can be 
substantially longer than that of a small reactor operating at a high temperature 
due to this strong temperature effect. Simulation studies can be used to: 
• Understand the effect of heat transfer fl uid 
• Understand possible performance limitations due to scale and operating 
conditions 
• Test the effect of specifi ed temperature gradient constraints 
• Assist with controller design and selection of tuning parameters for system 
start - up 
Various levels of models can be used to describe the behavior of pilot - scale jacketed 
batch reactors. For online reaction calorimetry and for rapid scale - up, a simple 
model characterizing the heat transfer from the reactor to the jacket can be used. 
Another level of modeling detail includes both the jacket and reactor dynamics. 
Finally, the complete set of equations simultaneously describing the integrated 
reactor/jacket and recirculating system dynamics can be used for feedback control 
system design and simulation. The complete model can more accurately assess the 
operability and safety of the pilot - scale system and can be used for more accurate 
process scale - up. 
In the simulation studies that follow, it is assumed that the reactor and jacket are 
well mixed, resulting in differential equations for the material and energy balances 
[18] . The reactor shell (including a glass lining, if used) and reactor internals (agitator 
and baffl es) are at the same temperature as the reactor, so their “ thermal mass ” 
is included in the reactor energy balance. Similarly, the jacket shell is at the jacket 
temperature, with an associated thermal mass. The heat transfer area A is proportional 
to the reactor liquid level (between volumes associated with the minimum 
and maximum heat transfer area); also, the reactor shell thermal mass varies linearly 
with the liquid level. Heat transfer coeffi cients are calculated using the relationships 
presented in Section 3.1.4 ; see Garvin [20] or Dream [21] for detailed examples. 
Parameters, viscosity in particular, are a function of temperature. 
We focus on the effect of reactor size and material of construction on the expected 
dynamic behavior of the reactors. Details on the model development and simulation 
environment are presented elsewhere [18] . Figure 12 illustrates that a vessel can 
have signifi cantly different dynamic behavior depending on whether it is being 
heated or cooled (for illustrative purposes, the freezing point of water is neglected 
in this simulation). The increase in reactor temperature results in a much faster 
response than a decrease for two reasons: (i) the jacket heat transfer fl uid has a 
much higher viscosity (resulting in a lower overall heat transfer coeffi cient) at low 
temperatures and (ii) the fl uid fl ow rate/jacket temperature gain is proportional to 
DYNAMIC SIMULATION STUDIES 155

156 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
FIGURE 12 Comparison of responses for ± 30 ° C reactor temperature setpoint changes at 
t = 10 min; 500 - gal GLCS fi lled with water (1925 kg). 
0 20 40 60 80 100 120 140 160 180 200 
–40 
–20
0 
20 
40 
60 
80 
100 
Time, min 
Temperature, °C 
FIGURE 13 Comparison of temperature responses for 30 ° C batch setpoint change; 500 - gal 
GLCS, water (1925 L) vs. organic (1700 L). 
0 20 40 60 80 100 120 140 160 180 200 
20 
30 
40 
50 
60 
70 
80 
90 
100 
Time, min 
Temperature, °C 
Water 
Organic 
the difference between the jacket temperature and make - up fl uid temperature, 
which becomes small at low jacket temperatures. Notice that the initial response for 
the temperature increase is constrained by the ramp limit of 5 ° C/min on the jacket 
temperature. The temperature response of an organic solvent is much faster than 
water because of the heat capacity difference, as shown in Figure 13 . The previous 
plots were for simple heating/cooling applications (ref. 18 presents further studies 
for cryogenic and semibatch systems). 

3.1.6 SUMMARY 
In this chapter we have presented an overview of scale - up considerations involved 
as one moves from bench - scale reaction calorimetry to larger scale pilot plant and 
production reactors. Our focus has been on heat transfer and single - phase processes, 
addressing primarily the problem that the heat transfer area per unit reactor volume 
decreases with scale. Clearly, there are many challenging problems associated with 
multiphase vessels, with evaporation/distillation and crystallization as obvious 
examples, but these topics are beyond the scope of this chapter. 
REFERENCES 
1. Paul , E. L. ( 1988 ), Design of reaction systems for specialty organic chemicals , Chem. Eng. 
Sci. , 43 ( 8 ), 1773 – 1782 . 
2. Anderson , N. G. ( 2000 ), Practical Process Research and Development , Academic , New 
York . 
3. Pisano , G. P. ( 1997 ), The Development Factory , Harvard Business School , Boston . 
4. Chylla , R. W. , and Hasse , D. R. ( 1993 ), Temperature control of semi - batch polymerization 
reactors , Comp. Chem. Eng. , 17 ( 3 ), 257 – 264 . 
5. Bonvin , D. ( 1998 ), Optimal operation of batch reactors — A personal view , J. Proc. Cont. , 
8 ( 5 – 6 ), 355 – 368 . 
6. LeLann , M. V. , Cabassud , M. , and Casamatta , G. ( 1999 ), Modeling, optimization and 
control of batch chemical reactors in fi ne chemical production , Annu. Rev. Control , 23 , 
25 – 34 . 
7. Gygax , R. W. ( 1990 , Feb.), Scale - up principles for assessing thermal runaway risks , Chem. 
Eng. Prog. , 86 ( 2 ), 53 – 60 . 
8. Shukla , P. K. , and Pushpavanam , S. ( 1994 ), Parametric sensitivity, runaway, and safety in 
batch reactors: Experiments and models , Ind. Eng. Chem. Res. , 33 ( 12 ), 3202 – 3208 . 
9. Caygill , G. , Zanfi r , M. , and Gavrildis , A. ( 2006 ), Scalable reactor design for pharmaceuticals 
and fi ne chemicals production. 1: Potential scale - up obstacles , Org. Proc. Res. Dev. , 
10 ( 3 ), 539 – 552 . 
10. Regenass , W. ( 1985 ), Calorimetric monitoring of industrial chemical processes , Thermochim. 
Acta , 95 , 351 – 369 . 
11. Kaarlsen, L. G. , and Villadsen, J. (1987), Isothermal reaction calorimeters—I. A literature 
review , Chem. Eng. Sci. , 42 ( 5 ), 1153 – 1164 . 
12. Kaarlsen , L. G. , and Villadsen , J. ( 1987 ), Isothermal reaction calorimeters — II. Data treatment 
, Chem. Eng. Sci. , 42 ( 5 ), 1165 – 1173 . 
13. Bourne , J. R. , Buerli , M. , and Regenass , W. ( 1981 ), Heat transfer and power measurements 
in stirred tanks using heat fl ow calorimetry , Chem. Eng. Sci. , 36 , 347 – 354 . 
14. Landau , R. N. , Blackmond , D. G. , and Tung , H. - H. ( 1994 ), Calorimetric investigation of an 
exothermic reaction: Kinetic and heat fl ow modeling , Ind. Eng. Chem. Res. , 33 , 814 – 820 . 
15. Landau, R. N. (1996), Expanding the role of reaction calorimetry , Thermochim. Acta , 289 , 
101 – 126 . 
16. Obenndip , D. A. , and Sharratt , P. N. ( 2006 ), Towards an information - rich process development. 
Part I: Interfacing experimentation with qualitatitive/semiquantitative modeling , 
Org. Proc. Res. Dev. , 10 ( 3 ), 430 – 440 . 
REFERENCES 157

158 EFFECT OF SCALE-UP ON OPERATION OF JACKETED REACTORS 
17. Bolliger , D. H. ( 1982 ), Assessing heat transfer in process - vessel jackets , Chem. Eng. , Sept. 
20 , 95 – 100 . 
18. Bequette , B. W. , Holihan , S. , and Bacher , S. ( 2004 ), Automation and control issues in the 
design of a pharmaceutical pilot plant , Control Eng. Practice , 12 , 901 – 908 . 
19. Zima , A. , Spencer , G. , and Bequette , B. W. ( 1996 ), Model development for batch reactor 
calorimetry and control, Preprint, presented at the AIChE Annual Meeting, Chicago, IL, 
Nov. 1996. 
20. Garvin , J. ( 1999 ), Understand the thermal design of jacketed vessels , Chem. Eng. Prog. , 
95 ( 6 ), 61 – 68 . 
21. Dream , R. F. ( 1999 ), Heat transfer in agitated jacketed vessels , Chem. Eng. , Jan., 90 – 96 . 

159 
3.2 
PACKAGING AND LABELING 
Maria In e s Rocha Miritello Santoro and Anil Kumar Singh 
University of S a o Paulo, S a o Paulo, Brazil 
Contents 
3.2.1 Introduction 
3.2.2 Packaging Materials 
3.2.2.1 General Considerations 
3.2.2.2 Glass as packaging material 
3.2.2.3 Plastic as Packaging Material 
3.2.2.4 Metal as Packaging Material 
3.2.2.5 Applications: Some Examples 
3.2.3 Quality Control of Packaging Material 
3.2.3.1 General Considerations 
3.2.3.2 Packaging Components 
3.2.3.3 Inhalation Drug Products 
3.2.3.4 Drug Products for Injection and Ophthalmic Drug Products 
3.2.3.5 Liquid - Based Oral Products, Topical Drug Products, and Topical Delivery 
Systems 
3.2.3.6 Solid Oral Dosage Forms and Powders for Reconstitution 
3.2.4 Importance of Proper Packaging and Labeling 
3.2.5 Regulatory Aspects 
3.2.5.1 General Considerations 
3.2.5.2 Food, Drug and Cosmetic Act 
3.2.5.3 New Drugs 
3.2.5.4 Labeling Requisites 
3.2.5.5 Prescription Drugs 
3.2.5.6 Drug Information Leafl et 
3.2.5.7 Other Regulatory Federal Laws 
3.2.5.8 Fair Packaging and Labeling Act 
3.2.5.9 United States Pharmacopeia Center for the Advancement of Patient 
Safety 
3.2.5.10 National Agency of Sanitary Vigilance (ANVISA, Brazil) 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

160 PACKAGING AND LABELING 
3.2.5.11 International Committee on Harmonization (ICH) 
3.2.5.12 European Union Regulatory Bodies 
References 
3.2.1 INTRODUCTION 
The packaging of a pharmaceutical product fulfi ls a variety of roles, such as product 
presentation, identifi cation, convenience, and protection until administration or use. 
Selection of packaging requires a basic knowledge of packaging materials, the environmental 
conditions to which the product will be exposed, and the characteristics 
of the formulation. Several types of packaging are used to contain and protect the 
pharmaceutical preparations, such as the primary packaging around the product and 
secondary packaging such as a carton and subsequent transit cases [1] . 
The principal objective of the modern pharmaceutical industry is to manufacture 
pharmaceutical preparations presenting high quality, identity, purity, effectiveness, 
and innocuity in order to guarantee the satisfaction and safety of patients. The 
development of a new drug must involve the synthesis of a molecule, determination 
of its pharmacological activity, industrial - scale production, and its commercialization 
to guarantee quality of the fi nal product. 
Packaging system development, including primary and secondary packaging 
components, is of critical importance. The material should be selected based on the 
characteristics of pharmaceutical product and dosage form. After the production 
phase, packaging must be planned according to regulatory requirements and its 
quality should be controlled according to the specifi cations. 
Commercially, the packaging material is used as a barrier to protect the pharmaceutical 
preparations against external factors that can degrade them and consequently 
decrease their effectiveness and increase toxic effects. 
Once the type of packaging material is decided based on such factors as size, 
shape, capacity, and physicochemical properties, all these data, including quality 
control tests, should be included in the specifi cation of the products in order to 
assure the therapeutic effectiveness during its shelf life. 
Several types of materials are in use in the preparation of containers and closure 
systems: glass, plastics, metals, and combinations of these materials. However, care 
should be taken in the selection of appropriate material. These materials should not 
present any physical or chemical reactivity that could modify drug activity, quality, 
purity, or physical characteristics of the drug and pharmaceutical preparations. Any 
minor modifi cation in the pharmacopeial specifi cation is acceptable if it does not 
present a threat to patient ’ s health. 
The aim of this chapter is to discuss the importance of the packaging and labeling 
of pharmaceutical preparations. The role of packaging and labeling in the pharmaceutical 
industry has grown substantially over the past decade. The total packaging 
operation is part of any drug development program. Pharmaceutical products generally 
require a standard of packaging which is superior to that of most other products 
in order to support and comply with their main requirements, such as effi cacy, integrity, 
purity, safety, and stability. 

PACKAGING MATERIALS 161 
For these reasons packaging technology should be based on the understanding 
of pharmaceutical products, characteristics of formulations, and dosage forms, 
including the physical and chemical properties of the drug substance. 
In the past, packaging concerns often arose only during the later steps of product 
development. Today, packaging is integrated with the development step and is 
among the earliest considerations of new pharmaceutical preparations being studied. 
Labels of products can vary from the simple to the extremely complex. But, even 
at the most basic level, product identifi cation should meet regulatory requirements. 
More complex are the labels that make use of bar code technologies. New components 
such as microchips, biosensors, and deoxyribonucleic acid (DNA) arrays are 
making possible the development of new technologies leading to fi nished products 
individually packed that require specialized packaging materials and design expertise. 
The challenge now is to maintain low packaging cost, that is, always integrated 
into the cost of the product itself. 
Packaging in the post – World War II period benefi ted immensely from the commercialization 
of plastics, which were little known or used in prior years. Since then, 
the packaging industry has openly adopted plastics as a powerful new tool in the 
development of new packaging forms and functions. 
Quality control of a packaging component starts at the design stage. All aspects 
of package development that may give rise to quality problems must be identifi ed 
and minimized by good design. Identifying and correcting mistakes in packaging 
will avoid product recall and rejection of pharmaceutical preparations [2, 3] . 
3.2.2 PACKAGING MATERIALS 
3.2.2.1 General Considerations 
Packaging refers to all the operations, including fi lling and labeling, through which 
a bulk product should pass to become a fi nished product. Usually, sterile fi lling is 
not considered part of the packing process, although the bulk product is contained 
in a primary container. 
A packaging component means any single part of a container closure system. 
Typical components are containers (e.g., ampules, vials, bottles), container liners 
(e.g., tube liners), closures (e.g., screw caps, stoppers), closure liners, stopper overseals, 
container inner seals, administration ports [e.g., on large - volume parenterals 
(LVPs)], overwraps, administration accessories, and container labels [4] . 
A primary packaging component is one that is or may be in direct contact with 
the dosage form. A secondary packaging component is one that is not and will not 
be in direct contact with the dosage form [4] . 
A container closure system refers to 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. A packaging system is equivalent 
to a container closure system [4] . 
The role of packaging material on the overall perceived and actual stability of 
the dosage form is well established. Packaging plays an important role in quality 
maintenance, and the resistance of packaging materials to moisture and light can 

162 PACKAGING AND LABELING 
signifi cantly affect the stability of drugs and their dosage forms. It is crucial that 
stability testing of dosage forms in their fi nal packaging be performed. The primary 
role of packaging, other than its esthetic one, is to protect the dosage forms from 
moisture and oxygen present in the atmosphere, light, and other types of exposure, 
especially if these factors affect the overall quality of the product on long - term 
storage [5] . 
The compliance packaging such as for fi xed - dose combination pills and unit 
dosage form packaging is a therapy - related intervention and is designed to facilitate 
medication regimens and so potentially improve adherence. Compliance packaging 
can be defi ned as a prepackaged unit that provides one treatment cycle of the 
medication, to both the pharmacist and the patient, in a ready - to - use package. This 
innovation type of packaging is usually based on blister packaging that contain unit 
therapeutic dose for one time use. The separate dosage units and separate days are 
usually indicated on the dosage cards to help remind the patient when and how 
much of the medication to take, for example, blister packed oral dosage forms with 
drug information leafl ets and contraceptive pills [6, 7] . 
The selection of packaging material for any pharmaceutical product is as important 
as proper pharmaceutical dosage form. To guarantee the safe and adequate 
delivery of drug product to the patient and improve patient compliance, the manufacturer 
should consider the following factors: 
1. Compatibility and safety concerns raised by the route of administration of the 
drug product and the nature of the dosage form (e.g., solid or liquid based) 
2. Kinds of protection the container closure system should provide to the dosage 
form (e.g., photosensitive, hygroscopic, easily oxidized drug products) 
3. Potential effect of any treatment or handling that may be unique to the drug 
product in the packaging system 
4. Patient compliance to the treatment and ease of drug administration 
5. Safety, effi cacy, and quality of drug product throughout its shelf - life 
The acquisition, handling, and quality control of primary and secondary packaging 
materials and of printed materials should be accomplished in the same way as 
that for the raw materials. The printed materials should be stocked in a reserved 
place so the possibility of unauthorized access is avoided. The labels and other 
rejected printed materials should be stored and transported with proper identifi cation 
before being destroyed. There should be a destruction record of the printed 
materials. Each batch of printed material and packaging material should receive a 
specifi c reference number for identifi cation. 
The identifi cation affi xed on the containers, on the equipment, in the facilities, 
and on the product containers should be clear, without ambiguity, and in a format 
approved by the company and contain the necessary data. Besides the text, differentiated 
colors indicating its condition could be used (e.g., in quarantine, approved, 
rejected, and cleaned). 
The packing materials should attend to the specifi cations, giving emphasis to the 
compatibility of the same with the pharmaceutical product that it contains. The 
material should be examined with relation to visible physical and critical defects as 
well as the required specifi cations. 

PACKAGING MATERIALS 163 
3.2.2.2 Glass as Packaging Material 
A packaging system found acceptable for one drug product may not be appropriate 
for another. Each application should contain enough information to show that each 
proposed container closure system and its components are suitable for the intended 
use. 
Nonsterile Products 
Solids Some topical drug products such as powders may be considered for marketing 
in glass bottles with appropriate dispenser. These topical drug products may be 
sterile and could be subject to microbial limits. 
The most common glass - packed solid oral dosage forms are oral powders and 
granules for reconstitution. A typical solid oral dosage form container closure system 
is a glass bottle (although plastic bottles are also used) with a screw - on or snap - off 
closure. A typical closure consists of a metal cap, often with a liner and frequently 
with an inner seal. 
The dry powders that are reconstituted in their marketed container need not be 
sterile; however, the possibility of an interaction between the packaging components 
and the reconstituting fl uid can’t be discarded. Although the contact time will be 
relatively short when compared to the component/dosage form contact time for 
liquid - based oral dosage forms, it should still be taken into consideration when the 
compatibility and safety of the container closure system are being evaluated. 
Powders for oral administration that are reconstituted in their market container, 
however, have an additional possibility of interaction between the packaging components 
and the reconstituting fl uid. Although the contact time will be relatively 
short when compared to the component/dosage form contact time for liquid - based 
oral dosage forms, it should still be taken into consideration when the compatibility 
and safety of the container closure system are being evaluated. 
Nonsolids For nonsterile products the preservative provides some protection, but 
continual microbial challenge will diminish the effi cacy of the preservative, and 
spoilage or disease transmission may occur [8] . 
Antimicrobial preservatives such as phenylmercuric acetate are known to partition 
into rubbers during storage, thus reducing the formulation concentration below 
effective antimicrobial levels [9] . A complication of modern packaging is the need 
for the application of security seals to protect against deliberate adulteration and 
maintain consumer confi dence. 
Sterile Products The sterile dosage forms share the common attributes that they 
are generally solutions, emulsions, or suspensions and are all required to be sterile. 
Injectable dosage forms represent one of the highest risk drug products (Table 1 ). 
Any contaminants present (as a result of contact with a packaging component or 
due to the packaging system ’ s failure to provide adequate protection) can be rapidly 
and completely introduced into the patient ’ s general circulation. Injectable drug 
products may be liquids in the form of solutions, emulsions, or suspensions or dry 
solids that are to be combined with an appropriate vehicle to yield a solution or 
suspension. 

164 PACKAGING AND LABELING 
Although ophthalmic drug products can be considered topical products, they 
have been grouped here with injectables because they are required to be sterile and 
the descriptive, suitability, and quality control information is typically the same as 
that for an injectable drug product. 
The potential effects of packaging component/dosage form interactions are 
numerous. Hemolytic effects may result from a decrease in tonicity and pyrogenic 
effects may result from the presence of impurities. The potency of the drug product 
or concentration of the antimicrobial preservatives may decrease due to adsorption 
or absorption. 
A cosolvent system essential to the solubilization of a poorly soluble drug can 
also serve as a potent extractant of plastic additives. 
A disposable syringe may be made of plastic, glass, rubber, and metal components, 
and such multicomponent construction provides a potential for interaction 
that is greater than when a container consists of a single material. 
Injectable drug products require protection from microbial contamination (loss 
of sterility or added bioburden) and may also need to be protected from light or 
exposure to gases (e.g., oxygen). 
Performance of a syringe is usually addressed by establishing the force to initiate 
and maintain plunger movement down the barrel and the capability of the syringe 
to deliver the labeled amount of the drug product. 
Solids For solids that must be dissolved or dispersed in an appropriate diluent 
before being injected, the diluent may be in the same container closure system (e. 
g., a two - part vial) or be part of the same market package (e.g., a kit containing a 
vial of diluent). 
Sterile powders or powders for injection may need to be protected from exposure 
to water vapor. For elastomeric components, data showing that a component meets 
the requirements of U.S. Pharmacopeia (USP) elastomeric closures for injections 
will typically be considered suffi cient evidence of safety. 
Nonsolids The package must prevent the entry of organisms; for example, packaging 
of sterile products must be absolutely microorganism proof — hence the continued 
use of glass ampules. Liquid injections are classifi ed as small - volume parenterals 
(SVPs), if they have a solution volume of 100 mL or less, or as LVPs, if the solution 
volume exceeds 100 mL [10] . Liquid - based injectables may need to be protected 
from solvent loss. 
An SVP may be packaged in a vial or an ampule. An LVP may be packaged in 
a vial, a glass bottle or, in some cases, as a disposable syringe. Packaging material 
for vials, and ampules are usually composed of type I or II glass. Stoppers and septa 
in cartridges, and vials are typically composed of elastomeric materials. 
Pharmaceuticals may interact with packaging and containers, resulting in the loss 
of drug substances by adsorption onto and absorption into container components 
and the incorporation of container components into pharmaceuticals. Diazepam in 
intravenous fl uid containers and administration sets exhibited a loss during storage 
due to adsorption onto glass [11, 12] . 
Glass surfaces are also known to adsorb drug substances. Chloroquine solutions 
in glass containers decreased in concentration owing to adsorption of the drug onto 
the glass [13] . 

PACKAGING MATERIALS 165 
Rubber closures are also known to absorb materials, including drugs. Absorption 
of preservatives such as chlorocresol into the rubber closures of injectable formulations 
has been studied extensively [13] . 
The water permeability of rubber closures used in injection vials is considered 
an important parameter in assessing the closures, but quantitative prediction of 
water permeability through rubber closures is diffi cult because the diffusion coeffi - 
cient of water is dependent on relative humidity [14] . 
Liquid - based oral drug products are usually dispensed in glass bottles (sometimes 
in plastic), often with a screw cap with a liner, and possibly with a tamper - resistant 
seal or an overcap that is welded onto the bottle. The same cap liners and inner 
seals are sometimes used with solid oral dosage forms. A laminated material can be 
used to overwrap glass bottles for extra safety. 
The USP - grade glass packaging components are chemically resistant and can be 
considered suffi cient evidence of safety and compatibility. In some cases (e.g., for 
some chelating agents), a glass packaging component may need to meet additional 
criteria to ensure the absence of signifi cant interactions between the packaging 
component and the dosage form. 
Several ophthalmic preparations are commercialized in glass containers. Although 
the risk factors associated with ophthalmic preparations are generally considered 
to be lower than for injectables, any potential for causing harm to the eyes demands 
caution. 
A large - volume intraocular solution (for irrigation) may be packaged in a polyolefi 
n (polyethylene and/or polypropylene) container. 
The liquid - based oral dosage forms may be marketed in multiple - unit bottles. 
The dosage form may be used as is or admixed fi rst with a compatible diluent or 
dispersant. Liquid - based oral drug products in glass container must meet the requirements 
for USP containers. Glass containers are accepted as suffi cient evidence of 
safety and compatibility. Performance is typically not a factor for liquid - based oral 
drug products but should be considered while treating pressurized liquid - based oral 
drug products (e.g., elixir spray). 
Topical dosage forms such as unpressurized sprays, lotions, ointments, solutions, 
and suspensions may be considered for marketing in glass bottles with appropriate 
dispenser. Some topical drug products, especially ophthalmic, are sterile or may be 
subject to microbial limits. In these cases, packaging material and handling should 
be done as those for injectables. 
3.2.2.3 Plastic as Packaging Material 
For plastic components, data from USP biological reactivity tests will typically be 
considered suffi cient evidence of safety. Whenever possible, extraction studies 
should be performed using the drug product. If the extraction properties of the drug 
product vehicle may reasonably be expected to differ from that of water (e.g., due 
to high or low pH or to a solubilizing excipient), then drug product should be used 
as the extracting medium. If the drug substance signifi cantly affects extraction characteristics, 
it may be necessary to perform the extractions using the drug product 
vehicle. If the total extract signifi cantly exceeds the amount obtained from water 
extraction, then an extraction profi le should be obtained. It may be advisable 
to obtain a quantitative extraction profi le of an elastomeric or plastic packaging 

166 PACKAGING AND LABELING 
component and to compare this periodically to the profi le from a new batch of the 
packaging component. Extractables should be identifi ed whenever possible. 
Nonsterile Products 
Solids The most common solid oral dosage forms are capsules and tablets. A 
typical solid oral dosage forms container closure system is a plastic, usually high - 
density polyethylene (HDPE), bottle with a screw - on or snap - off closure and a 
fl exible packaging system such as a pouch or a blister package. A typical closure 
consists of a cap, often with a liner, frequently with an inner seal. If used, fi llers, 
desiccants, and other absorbent materials are considered primary packaging 
components. 
A change in the selection of packing materials combined with a change in storage 
conditions or conditions during administration of the drug products may provoke 
stability problems. 
Many studies have been conducted on predicting the role of packaging in moisture 
adsorption by dosage forms. Adsorption of moisture by tablets contained in 
polypropylene fi lms was successfully modeled from storage temperature and the 
difference in water vapor pressure between the inside and outside of the packaging 
[15] . 
Chemical and physical degradation of packaged dosage forms caused by moisture 
adsorption has been predicted from the moisture permeability of the packaging. For 
example, strength changes of lactose – corn starch tablets in strip packaging [16] and 
discoloration of sugar - coated tablets of ascorbic acid [17, 18] were predicted using 
the moisture permeability coeffi cient of the packaging. 
Typical fl exible forms of packaging containing solid oral dosage forms are the 
blister package and the pouch. A blister package usually consists of a lidding material 
and a forming fi lm. The lidding material is usually a laminate which includes a 
barrier layer (e.g., aluminum foil) with a print primer on one side and a sealing agent 
(e.g., a heat - sealing lacquer) on the other side. 
The sealing agent contacts the dosage form and the forming fi lm. The forming 
fi lm may be a single fi lm, a coated fi lm, or a laminate. A pouch typically consists of 
fi lm or laminate which is sealed at the edges by heat or adhesive. 
Solid oral dosage forms generally need to be protected from the potential adverse 
effects of the following: 
1. Water vapor (e.g., moisture may affect the decomposition rate of the active 
drug substance or the dissolution rate of the dosage form) 
2. Incident light (e.g., in case of photosensitive products) 
3. Reactive gases (e.g., oxygen could provoke oxidative reactions) 
Carefully selected packaging material may help protect drug products. For 
example, a blister or pouch and use of secondary packing may be used to protect 
pack photosensitive material, especially when a dark polymeric fi lm with a covering 
lid made of aluminum is used for blister packing. Blister packaging using multilayer 
HDPE material and selection of an adequate sealing technique may help prevent 
moisture in the blister system. However, plastics and glass for packaging of solid 
oral dosage forms and for powders for reconstitution should meet the requirements 

PACKAGING MATERIALS 167 
of the USP container test. Incorporating oxygen adsorbents such as iron powder 
into packaging units can reduce the effect of oxygen. Protection from light can be 
achieved using primary packaging (packaging that is in direct contact with the 
dosage forms) and secondary packaging made of light - resistant materials. May be 
involved in the photolytic degradation kinetics. The velocity of the photochemical 
reaction may be affected not only by the light source, intensity, and wavelength of 
the light but also by the size, shape, composition, and color of the container. 
Great effort should be taken to stabilize a formulation in such a way that the 
shelf life becomes independent of the storage conditions. The photostability of drugs 
and excipients should be evaluated at the formulation development stage in order 
to assess the effects of packaging on the stability of the fi nal product. Molsidomine 
tablet preparations in inadequate primary containers (blister) without secondary 
containers when exposed to irradiation may produce morpholine. These results 
illustrate the importance of packaging for the stability of molsidomine [19] . 
Three standard tests for water vapor permeation have been established by the 
USP for use with solid oral dosage forms. 
1. Polyethylene containers (USP . 661 . ) [10] 
2. Single - unit containers and unit - dose containers for capsules and tablets (USP 
. 671 . ) 
3. Multiple - unit containers for capsules and tablets (USP . 671 . ) [10] 
The cotton and rayon used as fi llers in solid oral dosage form containers may not 
meet pharmacopeial standards, but through appropriate tests and acceptance criteria 
for identifi cation and moisture content, their adequacy should be shown. For 
example, rayon has been found to be a potential source of dissolution problems for 
gelatin capsules and gelatin - coated tablets. 
Desiccants are often used to eliminate moisture in packaging when the moisture 
resistance of the packaging is not suffi cient to prevent exposure. The utility of desiccants 
has been assessed based on a sorption – desorption moisture transfer model 
[20] . 
Desiccants or other absorbent materials are primary packaging component. The 
components should differ in shape and/or size from the tablets or capsules with 
which they are packaged. Their composition should be provided and their inertness 
should be proved through appropriate tests, and acceptance criteria should be 
established. 
A topical powder product may be marketed in a sifter - top container made of 
fl exible plastic tubes or as part of a sterile dressing (e.g., antibacterial product). The 
topical formulations in a collapsible tube can be constructed from low - density polyethylene 
(LDPE), with or without a laminated material. Normally, there is no 
product contact with the cap during storage. Thus usually there is no cap liner, 
especially in collapsible polypropylene screw caps. Normally separate applicator 
devices are made from LDPE. Product contact is possible if the applicator is part 
of the closure, and therefore an applicator ’ s compatibility with the drug product 
should be established, as appropriate (e.g., vaginal applicators). 
Nonsolids Typical liquid - based oral dosage forms are elixirs, emulsions, extracts, 
fl uid extracts, solutions, gels, syrups, spirits, tinctures, aromatic waters, and suspen

168 PACKAGING AND LABELING 
sions. These products are usually nonsterile but typically need to be protected from 
solvent loss, microbial contamination, and sometimes exposure to light or reactive 
gases (e.g., oxygen). 
The presence of a liquid phase implies a signifi cant potential for the transfer of 
materials from a packaging component into the dosage form. 
The higher viscosity of semisolid dosage forms and transdermal systems may 
cause the rate of migration of leachable substances into these dosage forms to be 
slower than for aqueous solutions. Due to extended contact, the amount of leachables 
in these drug products may depend more on a leachable material ’ s affi nity for 
the liquid/semisolid phase than on the rate of migration. 
In addition to absorption onto and absorption into containers, transfer of 
container components into pharmaceuticals may affect the perceived stability/ 
quality of drug dosage forms. Adsorption of volatile components from rubber 
closures onto freeze - dried parenterals during both dosage form processing and 
storage brought about haze formation upon reconstitution [21 – 23] . Leaching 
of dioctyl phthalate, a plasticizer used especially in polyvingl chloride (PVC) 
plastics, into intravenous solutions containing surfactants was observed [24, 25] . 
Plastics contain additives to enhance polymer performance. PVC may contain 
phthalate diester plasticizer, which can leach into infusion fl uids from packaging 
[26] . 
The liquid - based oral dosage forms may be marketed in multiple - unit bottles or 
in unit - dose or single - use pouches or cups. The dosage form may be used as is or 
admixed fi rst with a compatible diluent or dispersant. A liquid - based oral drug 
pouch may be a single - layer plastic or a laminated material. The pouches may use 
an overwrap, which is usually a laminated material. 
For LDPE components, data from USP container tests are typically considered 
suffi cient evidence of compatibility. The USP general chapters do not specifi cally 
address safety for polyethylene (HDPE or LDPE), polypropylene (PP), or laminate 
components. 
In such cases, an appropriate reference to the indirect food additive regulations 
[27] is typically considered suffi cient. This reference is considered valid for liquid - 
based oral dosage forms which the patient will take only for a relatively short 
time. 
For liquid - based oral drug products which the patient will continue to take for 
an extended period, that is, months or years, and is expected to extract greater 
amounts of substances from plastic packaging components than from water (presence 
of cosolvents), additional extractable information may be needed to address 
safety issues. 
Topical dosage forms such as creams, emulsions, gels, lotions, ointments, pastes, 
and powders may be marketed in plastic materials. Topical dosage formulations are 
for local (not systemic) effect and are generally applied to the skin or oral mucosal 
surfaces. Some vaginal and rectal creams and nasal, otic, and ophthalmic solutions 
may be considered for topical drug products. 
A rigid bottle, a collapsible tube, or a fl exible pouch made of plastic material may 
be used for liquid - based topical product. These preparations are marketed in a 
single - or multiple - unit container. For example, dissolved drug (or any substance, 
e.g., benzocaine) may diffuse in the suppository base and can, for instance, partition 
into polyethylene linings of the suppository wrap. 

PACKAGING MATERIALS 169 
Topical delivery systems are self - contained, discrete dosage forms that are 
designed to deliver drug for an extended period via intact skin or body surface, for 
example, transdermal, ocular, and intrauterine. 
These systems may be constructed of a plastic or polymeric material loaded with 
active ingredients or a coated metal. Each of these systems is generally marketed 
in a single - unit soft blister pack or a preformed tray with a preformed cover or 
overwrap. The compatibility and safety for topical delivery systems are addressed 
in the same manner as for topical drug products. Performance and quality control 
should be addressed for the rate - controlling membrane. 
Sterile Products 
Nonsolids An SVP may be packaged in a disposable cartridge, a disposable syringe, 
or a fl exible bag made of polymeric plastic. Flexible bags are typically constructed 
with multilayered plastic (Table 2 ). 
An LVP may be packaged in a vial, a fl exible bag, or, in some cases, a disposable 
syringe. Packaging material for cartridges, syringes, vials, and ampules are usually 
composed of polypropylene (Table 2 ). 
Stoppers and septa in cartridges and syringes are typically composed of elastomeric 
materials. An overwrap may be used with fl exible bags to retard solvent loss 
and to protect the fl exible packaging system from rough handling. 
Diazepam in intravenous fl uid containers and administration sets exhibited 
a loss during storage due to adsorption onto and absorption into plastics 
[11, 12] . 
Absorption of clomethiazole edisylate and thiopental sodium into PVC infusion 
bags was observed [28] . 
The pH dependence of adsorption/absorption of acidic drug substances such as 
warfarin and thiopental and basic drug substances such as chlorpromazine and diltiazem 
indicates that only the un - ionized form of the drug substance is adsorbed 
onto or absorbed into PVC infusion bags [29] . 
The absorption was correlated to the octanol – water partition coeffi cients of the 
drugs, suggesting that prediction of absorption from partition data is possible [30, 
31] . Polymers such as Nylon - 6 (polycaprolactam) are known to adsorb drug substances 
such as benzocaine [32] . 
The ophthalmic drug products are usually solutions marketed in a LDPE bottle 
with a dropper built into the neck. A few solution products use a glass container 
due to stability concerns regarding plastic packaging components. 
3.2.2.4 Metal as Packaging Material 
Metal tubes constructed of a single material are the packaging material of choice 
for topical dosage forms and may be tested readily for stability with a product. Tubes 
with a coating, however, present additional problems. The inertness of coating material 
must be established through adequate tests and guarantee that it completely 
covers underlying material. The coating material must be resistant to creaking, 
leaking, leaching, and solvent erosion. For example, frequently used aluminum tubes 
have demonstrated reactivity with fatty alcohol emulsions, mercurial compounds, 
and preparations with pH below 6.5 and above 8.0. Nonreactive, epoxy linings have 
been found to make aluminum tubes resistant to attack [6] . 

170 PACKAGING AND LABELING 
TABLE 2 Parenteral Drug Administration Devices 
Sterile Device Plastic Material 
Containers for blood products Polyvinyl chloride 
Disposable syringes Polycarbonate, polyethylene, polypropylene 
Irrigating solution containers Polyethylene, polypropylene, polyvinyl chloride 
Intravenous infusion fl uid containers Polyethylene, polypropylene, polyvinyl chloride 
Administration sets Nylon (spike), polyvinyl chloride (tubing), 
polymethylmethacrylate (needle adapter), 
polypropylene (clamp) 
Catheter Tefl on, polypropylene, thermoplastic elastomers 
Source : From ref. 6 . 
Some examples of plastic additives and parenteral drug administration devices used 
as packaging materials for sterile products can be seen in Tables 1 and 2 . 
Ophthalmic ointments are marketed in a metal tube with an ophthalmic tip. 
Ophthalmic ointments that are reactive toward metal may be packaged in a tube 
lined with an epoxy or vinyl plastic coating. 
Metal containers, pressurized or not, may also be used for topical drug products. 
Topical dosage forms include aerosols, emulsions, gels, powders, and solutions 
and may be marketed in metallic fl asks, pressurized or not. Topical dosage formulations 
are for local (not systemic) effect and are generally applied to the skin or 
oral mucosal surfaces. Some vaginal and rectal creams and nasal and otic spray 
drug products may be considered for marketing in metallic containers for topical 
use. 
A number of topical products marketed as a pressurized aerosol may be dispensed 
in a metallic bottle with a screw cap. Topical dosage forms in aluminum tubes 
usually include a liner. A tube liner is frequently a lacquer or shellac whose composition 
should be stated. A metallic pressurized packaging system for a liquid - 
TABLE 1 Plastic Additives 
Type Purpose Examples 
Lubricants Improve processability Stearic acid paraffi n waxes, polyethylene 
(PE) waxes 
Stabilizers Retard degradation Epoxy compounds, organotins, mixed 
metals 
Plasticizers Enhance fl exibility, 
resiliency, melt fl ow 
Phthalates 
Antioxidants Prevent oxidative 
degradation 
Hindered phenolics (BHT), aromatic 
amines, thioesters, phosphites 
Antistatic agents Minimize surface static 
charge 
Quaternary ammonium compounds 
Slip agents Minimize coeffi cient of 
friction, especially 
polyolefi ns 
Dyes, pigments Color additives 
Source : From ref. 6 . 

PACKAGING MATERIALS 171 
based topical product may deter solvent loss and may provide protection from light 
when appropriate. 
The droplet size of topical aerosol sprays does not need to be carefully controlled, 
and the dose usually is not metered as in inhalers. The spray may be used to apply 
the drug to the skin (topical aerosol) or mouth (lingual aerosol) and the functionality 
of the sprayer should be addressed. The drug product has no contact with the 
cap and short - term contact with the nozzle. A topical aerosol may be sterile or may 
conform to acceptance criteria for microbial limits. However, the physical stability 
of aerosols can lead to changes in total drug delivered per dose and total number 
of doses that may be obtained from the container. 
3.2.2.5 Applications: Some Examples 
Many research papers in the scientifi c literature present studies showing the importance 
of the effect of packaging materials on the stability of pharmaceutical and 
cosmetic preparations: 
1. Santoro and co - workers [33] presented results of the stability of oral rehydration 
salts (ORSs) in different types of packaging materials. The objective of the 
research was to give guidance on the adequate choice of packaging material presenting 
the indispensable characteristics in order to protect ORS preparation. This 
pharmaceutical preparation is essential to children living in developing countries 
with tropical climate and its distribution is one of the programs of the World Health 
Organization (WHO) [34] . 
It has been proved in several research papers that water is the most important 
factor in the component ’ s degradation of ORSs. To proceed with the study, the 
pharmaceutical formulation was prepared by a pharmaceutical manufacture. The 
batch was packed in six types of packaging material. After storage of samples for 
36 weeks maintained at ambient temperature, at ambient temperature and 76% 
relative humidity, and at 40 ° C with 80% relative humidity, analyses of water determination 
were made at different intervals of time. Water determination was performed 
by loss on drying at 50 ° C and Karl Fisher methods. 
The studied ORS preparation contained anhydrous glucose (20 g), sodium chloride 
(3.5 g), trisodium dehydrate citrate (2.9 g), and potassium chloride (1.5 g) 
According to the results, the packaging material that better protected the ORS 
preparation is the one constituted of polyester (18 g), aluminum (35%), and polyethylene 
(50 g). 
2. The effect of packaging materials on the stability of sunscreen emulsions was 
also studied by Santoro and co - workers [35, 36] . The purpose of the research was 
to study the stability of an emulsion containing UVA, UVB, and infrared sunscreens 
after storage in different types of packaging materials (glass and plastic fl asks, plastic 
and metallic tubes). The samples, emulsions containing benzophenone - 3 (B - 3), octyl 
methoxycinnamate (OM), and Phycocorail , were stored at 10, 25, 35, and 45 ° C and 
representative samples were analyzed after 2, 7, 30, 60, and 90 days. Stability studies 
were conducted by analyzing samples at predetermined intervals by high - 
performance liquid chromatography (HPLC) along with periodic rheological 
measurements. 
The proposed HPLC method enabled the separation and quantitative determination 
of B - 3 and OM present in sunscreens. The method was successfully applied in 

172 PACKAGING AND LABELING 
the stability studies of the emulsions. The method is simple, precise, and accurate; 
there was no interference from formulation components. The sample emulsions 
stored at different temperatures presented similar rheological behavior, at least 
during the period of the study (three months). Most of the samples showed a pseudoplastic 
non - Newtonian thixotropic profi le. There were no signifi cant changes in 
the physical and chemical stability of emulsions stored in different packaging material. 
The studied glass and plastic packaging materials were found adequate for 
storing referred solar protector emulsions. 
3. Sarbach and co-workers [48] , studied the effect of plastics packaging materials 
on parenteral pharmaceutical products. Compatibility studies of these containers 
with different contents are required for drug registration. The authors demonstrated 
the migration phenomena which occurred between a trilaminated fi lm and a parenteral 
solution of metronidazole at 0.5%. The main migration products found in 
the solution were e - caprolactam and a phthalic derivative. The authors also separated 
several unidentifi ed compounds probably coming from the polyurethane 
adhesive. 
4. Molsidomine is sensitive to light and shows a fast decomposition in solutions 
and in tablets. Thoma and co - workers [37] showed the importance of light - resistant 
packaging material for photolabile pharmaceuticals. They irradiated molsidomine 
preparations over a period of 72 h in a light cabinet according to storage at daylight 
for about 4 – 6 weeks. Losses of 23 – 90% in tablets and 43 – 60% in solutions were 
found. The photodegradation could be overcome by selection of suitable packaging 
materials, colorants or vanillin. The degradation product morpholine after dansylation 
was determined by HPLC and showed contents of 0.10 – 0.67 mg in tablets and 
0.10 – 0.38 mg/mL in solution after irradiation. 
These examples, among many others described in the scientifi c literature, illustrate 
the importance of proper selection of packaging material for the stability and 
effectiveness of pharmaceutical dosage forms. 
3.2.3 QUALITY CONTROL OF PACKAGING MATERIAL 
3.2.3.1 General Considerations 
Several regulatory agencies as well as private agencies [Food and Drug Administration 
(FDA), British Pharmacopoeia, WHO, USP] [4, 10, 34, 38] have issued guidelines 
on the safety evaluation of materials and container closure systems. However, 
the ultimate proof of the safety and suitability of a container closure system and 
the packaging process is established by full shelf life stability studies. An important 
step in such evaluations is characterization of the packaging materials and the 
chemicals that can migrate or extract from container closure system components to 
the drug product. This extractable material belongs to diverse chemical classes that 
can migrate from polymeric materials, such as antioxidants, contaminants, lubricants, 
monomers, plasticizers, and preservatives. Such basic information is critical to understanding 
the biological safety and suitability of a container. 
Establishing the safety of container closure systems is of key importance to the 
medical and pharmaceutical industries (Table 3 ). It is no less important than the 
contents themselves. The FDA ’ s document “ Guidance on Container Closure Systems 
for Packaging Human Drugs and Biologics ” makes this point clear [4] . 

The FDA ’ s guidance document requires the evaluation of four attributes to 
establish suitability: protection, compatibility, safety, and performance/drug delivery. 
The document also provides a structured approach to ranking packaging concerns 
according to the route of drug administration and likelihood of packaging component 
– dosage form interaction. A container closure system acceptable for one drug 
product cannot be assumed to be appropriate for another. Each product should have 
suffi cient information to establish that a container and its components are right for 
their intended use [4] . 
To establish suitability, all four attributes must be evaluated and be shown to 
pose no concern to the drug product or to product performance. Suitability refers 
to the tests used for the initial qualifi cation of the container closure system with 
regard to its intended use. The guidance defi nes what tests must be done to evaluate 
each of the attributes of suitability. 
While the tests and methods described in Table 4 allow one to provide data that 
the container closure system is suitable for its intended use, an application must also 
describe the quality control (QC) measures that will be used to ensure consistency 
in the packaging components. The principal considerations for the QC measures are 
the physical characteristics and the chemical composition. By choosing two or three 
of the tests done in the initial suitability study, a QC program can be established 
that will ensure the consistency of the container closure system (Table 4 ). 
Protection A container closure system should provide the dosage form with adequate 
protection from factors (e.g., temperature, light) that can cause a degradation 
in the quality of that dosage form over its shelf life. Common causes of such degradation 
are exposure to light, loss of solvent, exposure to reactive gases (e.g., oxygen), 
absorption of water vapor, and microbial contamination. 
A container intended to provide protection from light or offered as a light - resistant 
container must meet the requirements of the USP . 661 . light transmission test. 
The procedure requires the use of a spectrophotometer, with the required sensitivity 
TABLE 3 Examples of Packaging Concerns for Common Classes of Drug Products 
Degree of Concern 
Associated with 
Route of 
Administration 
Likelihood of Packaging Component – Dosage Form Interaction 
High Medium Low 
Highest Inhalation aerosols and 
solutions; injection; 
injectable suspensions 
Sterile powders 
and powders 
for injections 
and inhalation 
powders 
High Ophthalmic solutions and 
suspensions; transdermal 
ointments and patches; 
nasal aerosols and sprays 
Low Topical solutions and 
suspensions; topical and 
lingual aerosols; oral 
solutions and suspensions 
Topical powders; 
oral powders 
Oral tablets and 
oral (hard and 
soft; gelatin) 
capsules 
QUALITY CONTROL OF PACKAGING MATERIAL 173

174 PACKAGING AND LABELING 
and accuracy, adapted for measuring the amount of light transmitted by the plastic 
material used for the container. 
The ability of a container closure system to protect against moisture can be 
ascertained by performing the USP . 661 . water vapor permeation test. The USP 
sets limits on the amount of moisture that can penetrate based upon the size and 
composition of the plastic components [HDPE, LDPE, or polyethylene terephthalate 
(PET)]. 
Evaluating the integrity of the container can be done in several ways. Two of the 
most common tests are dye penetration and microbial ingress. Container closure 
systems stored in a dye solution and exposed to pressure and vacuum cycles are 
examined for dye leakage into the container. The microbial ingress is similar in 
fashion but determines the microbial contamination of the contents when soaked 
in a media contaminated with bacteria. Other quantitative tests that can be run are 
vacuum/pressure decay, helium mass spectrometry, and gas detection. 
Compatibility Packaging components that are compatible with a dosage form will 
not interact suffi ciently to cause unacceptable changes in the quality of either the 
dosage form or the packaging component. A leachability study designed to evaluate 
the amount and/or nature of any chemical migrating from the plastic material to 
the drug product should be considered. The study should evaluate substances that 
migrate into the drug product vehicle for the length of shelf life. The drug product 
should be evaluated at regular intervals, such as at one, three, or six months or one 
or two years, until the length of the shelf - life claim has been met. 
Analytical techniques such as liquid chromatography/mass spectrometry (LC/ 
MS) to evaluate nonvolatile organics, gas chromatography/mass spectrometry (GC/ 
MS) to evaluate semivolatile organics, and inductively coupled plasma (ICP) spectroscopy 
to detect and quantitate inorganic elements should be a part of this 
study. 
Unknown impurities and degradation products can be identifi ed using liquid or 
gas chromatography along with MS. Information or substances identifi ed from 
extractable chemical evaluation can be used to help prepare standards specifi c for 
the plastic container being studied during leachability studies. Development and 
validation of the selective analytical method should be thoroughly studied before 
its application in the detection of leachable chemicals in active drug substance and 
drug product. 
Organoleptic and chemical changes such as precipitates, discoloration, strange 
odor, and pH modifi cation are signs of degradation of drug product. Changes in the 
physical characteristics of the container, such as brittleness, should be evaluated 
using thermal analysis and hardness testing. An infrared spectroscopic scan can fi ngerprint 
the materials and also provide proof of identity. Spectrophotometry and 
LC with ultraviolet detection can be used for the analysis of drug product stored at 
different stress conditions. These tests can be used for the quality control of drug 
product as well as for conducting stability studies on different products stored in 
the same container material. 
Safety Packaging components should be constructed of materials that will not 
leach harmful or undesirable amounts of substances to which a patient will be 
exposed when being treated with the drug product. This consideration is especially 

important for those packaging components which may be in direct contact with the 
dosage form, but it is also applicable to any component from which substances may 
migrate into the dosage form (e.g., an ink or adhesive). Determining the safety of 
a packaging component is not a simple process, and a standardized approach has 
not been established. However, an extraction study should be one of the fi rst 
considerations. 
A good knowledge regarding possible extractable material could help analysts 
develop specifi c and selective methods to identify extractables from container 
closure components under various control extraction study conditions. 
Precise information on the synthesis of the polymer and descriptions of the 
monomers used in the polymerization, the solvents used in the synthesis, and the 
special additives that have been added during material production as well as knowledge 
of degradation products that may be released into the drug product are also 
important. 
Some potential extractable chemicals from packaging materials are water soluble, 
while others are soluble only in nonpolar environments. The USP includes physicochemical 
tests for plastics based on water extracts, while water, alcohol, and hexane 
extracts are required for polyethylene containers under controlled temperature and 
time parameters (70 ° C for 24 h for water and alcohol and 50 ° C for 24 h for hexane). 
The USP physicochemical tests for extractables should be a part of all suitability 
programs, regardless of the criticality of the drug dosage form. USP elastomeric 
closures for injections should also be a part of the extractables study to establish 
safety. These USP tests, which have evolved over many years, are relevant, sensitive, 
rapid, and inexpensive. They help establish material safety. 
TABLE 4 Properties of Suitability Concerns and Interactions 
Attributes Concerns and Interactions Proposed Methods 
Protection Exposure to light, moisture, 
microbial ingress, and 
oxidation from presence 
of oxygen 
USP . 661 . light transmission and water 
vapor permeation, container integrity 
(microbial ingress, dye penetration, 
helium leak) 
Compatibility Leachable induced 
degradation, absorption 
or adsorption of drug, 
precipitation, change in 
pH, discoloration, 
brittleness of packaging 
materials 
Leachability study (migration of chemicals 
into drug product) using LC/MS, GC/MS, 
ICP/AA, pH, appearance of drug and 
container, thermal analysis (DSC, TGA), 
and infrared (IR) 
Safety No leached harmful or 
undesirable amounts of 
substances to expose 
patients treated with drug 
Extraction study (USP physicochemical 
tests – plastics), USP elastomeric closures 
for injections, toxicological evaluation, 
USP biological reactivity and complies 
with CFR, additives and purity 
Performance Container closure system 
functionality, drug 
delivery 
Functionality (improved patient compliance 
or use), delivery (transfer dose in right 
amount or rate) 
Abbreviations : DSC, differential scanning calorimetry; ICP, Inductively coupled plasma spectrometer; 
AA, Atomic absorption. 
Source : From ref. 39 . 
QUALITY CONTROL OF PACKAGING MATERIAL 175

176 PACKAGING AND LABELING 
The safety of material can be guaranteed by using appropriate analytical methods 
and instrumentation to identify and quantitate extracted chemicals. Liquid and gas 
chromatography and MS are powerful analytical tools that can separate and quantitate 
volatile and nonvolatile chemicals along with useful structural information. 
The mass spectrum or fragmentation pattern acquired for each molecule makes 
these excellent and effective tools for identifying unknown impurities or degradation 
products. 
Toxicological evaluation of identifi ed and unidentifi ed impurities from a container 
can help improve the safety index of drug products. The toxicological evaluation 
should take into consideration container closure system properties, drug 
product formulation, dosage form, route of administration, and dose regimen. A 
close correlation between chemical and toxicological information can provide better 
control on safety and compatibility of containers and closures. 
Performance The fourth attribute of the suitability of the container closure system, 
performance and drug delivery, refers to its ability to function in the manner for 
which it was designed. There are two major considerations when evaluating performance. 
The fi rst consideration is functionality that may improve patient compliance, 
[e.g., a two - chamber vial or intravenous (IV) bag], or improve ease of use (e.g., a 
cap that contains a counter, a prefi lled syringe). The second consideration is drug 
delivery, which is the ability of the packaging system to deliver the right amount or 
rate (e.g., a prefi lled syringe, a transdermal patch, a metered tube, a dropper or spray 
bottle, a dry - powder inhaler, and a metered - dose inhaler). 
3.2.3.2 Packaging Components 
Quality control refers to the tests typically used and accepted to establish that, after 
the application is approved, the components and the container closure system continue 
to possess the characteristics established in the suitability studies. 
To ensure consistency, protection, compatibility, safety, and performance of the 
packaging components, it is necessary to defi ne QC measures that will be used to 
ensure consistency in the packaging components. These controls are intended to 
limit unintended postapproval variations in the manufacturing procedures or materials 
of construction for a packaging component and to prevent adverse effects on 
the quality of a dosage form. 
The USP tests and studies for establishing suitability and QC of container closure 
system and for associated component materials are summarized in Table 5 . 
Hydrolysis and oxidation are the two main routes of degradation for the majority 
of drugs. To gain more information, the drug could be subjected to a range of temperature 
and relative humidity conditions. In addition, photostability studies could 
be conducted by exposure to artifi cial or natural light conditions. Elevated temperature, 
humidity, and light stress the drug and induce rapid degradation. Harmonized 
guidelines are available for new drug substances and products and may provide 
useful information to characterize degradation processes and selection of appropriate 
packaging material. 
The primary packaging must physically protect the product from the mechanical 
stresses of warehousing, handling, and distribution. Mechanical stress may take a 

TABLE 5 U.S. Pharmacopeia General Tests and Assays 
Chapter Topic 
. 1 . Injections 
. 51 . Antimicrobial preservatives — effectiveness 
. 61 . Microbial limit tests 
. 71 . Sterility tests 
. 87 . Biological reactivity tests, in vitro 
. 88 . Biological reactivity tests, in vivo 
. 161 . Transfusion and infusion assemblies 
. 381 . Elastomeric closures for injections, biological test procedures, physicochemical 
test procedures 
. 601 . Aerosols 
. 661 . Containers: light transmission; chemical resistance — glass containers; biological 
tests — plastics and other polymers; physicochemical tests — plastics; 
containers for ophthalmics — plastics; polyethylene containers; polyethylene 
terephthalate bottles and polyethylene; terephthalate G bottles; single - unit 
containers and unit - dose containers for nonsterile; solid and liquid dosage 
forms; customized patient medication packages 
. 671 . Containers — permeation: multiple - unit containers for capsules and tablets; 
single - unit containers and unit - dose containers for capsules and tablets 
. 691 . Cotton (or the monograph for purifi ed rayon USP) 
. 771 . Ophthalmic ointments 
. 1041 . Biologics 
. 1151 . Pharmaceutical dosage forms 
Source : From ref. 10 . 
variety of forms, from impact through vibration in transit and compression forces 
on stacking. 
The demands for mechanical protection will vary with product type: Glass 
ampules will require greater protection than plastic eye drop bottles, for example. 
Other protection is required from environmental factors such as moisture, temperature 
changes, light, gases, and biological agents such as microorganisms and, importantly, 
humans. 
The global market for medicinal products requires that the products are stable 
over a wide range of temperatures ranging from subzero in the polar region, 15 ° C 
in temperate zones, up to 32 ° C in the tropics. Along with this temperature variation, 
relative humidity can vary from below 50% to up to 90%, a feature that the packaging 
should be able to resist if necessary. The majority of packaging materials (including 
plastics) are to some degree permeable to moisture and the type of closure 
employed, such as screw fi ttings, may also permit ingress of moisture. The susceptibility 
of the product to moisture and its hygroscopicity will have to be considered 
and may require packaging with a desiccant or the use of specialized strip packs 
using low - permeability materials such as foil. 
Temperature fl uctuations can lead to condensation of moisture on the product 
and, with liquids, formation of a condensate layer on top of the product. This latter 
problem is well known and can lead to microbiological spoilage as the condensate 
is preservative free. 
QUALITY CONTROL OF PACKAGING MATERIAL 177

178 PACKAGING AND LABELING 
If the product is sensitive to photolysis, then opaque materials may be required. 
Most secondary packaging materials (e.g., cartons) do not transmit light, but in 
some cases specialized primary packaging designed to limit light transmission is 
employed. 
The package must also prevent the entry of organisms; for example, packaging 
of sterile products must be microorganism proof — hence the continued use of glass 
ampules. For nonsterile products the preservative provides some protection, but 
continual microbial challenge will diminish the effi cacy of the preservative, and 
spoilage or disease transmission may occur. 
The packaging material must not interact with the product either to adsorb substances 
from the product or to leach chemicals into the product. Plastics contain 
additives to enhance polymer performance. PVC may contain phthalate diester 
plasticizer, which can leach into infusion fl uids from packaging. Antimicrobial preservatives 
such as phenylmercuric acetate are known to partition into rubbers and 
plastics during storage, thus reducing the formulation concentration below effective 
antimicrobial levels. 
A complication of modern packaging is the need for the application of security 
seals to protect against deliberate adulteration and maintain consumer confi dence. 
The active products used must also be stability tested in the proposed packaging 
material. 
The FDA guidance for industry suggests considering consistency in physical and 
chemical composition. Using a few simple tests, the quality of components and ultimately 
the container closure system can be monitored. 
Physical Characteristics The physical characteristics of interest include dimensional 
criteria (e.g., shape, neck fi nish, wall thickness, design tolerances), physical 
parameters critical to the consistent manufacture of a packaging component (e.g., 
unit weight), and performance characteristics (e.g., metering valve delivery volume 
or the ease of movement of syringe plungers). Unintended variations in dimensional 
parameters, if undetected, may affect package permeability, drug delivery performance, 
or the adequacy of the seal between the container and the closure. Variation 
in any physical parameter is considered important if it can affect the quality of a 
dosage form. 
Physical considerations such as water vapor transmission to evaluate seal integrity, 
thermal analysis such as DSC to monitor melting point and glass transitions of 
plastics, and IR scanning to prove identity should be part of an ongoing quality 
control monitoring program. 
Chemical Composition The chemical composition of the materials of construction 
may affect the safety of a packaging component. New materials may result in new 
substances being extracted into the dosage form or a change in the amount of known 
extractables. The chemical composition may also affect the compatibility, functional 
characteristics, or protective properties of packaging components by changing rheological 
or other physical properties (e.g., elasticity, resistance to solvents, or gas 
permeability). 
The chemical composition should also be evaluated by performing the simple but 
informative USP physicochemical tests using water, drug product vehicle, and 
alcohol extractions of plastic components. Specifi cations should be set for nonvola

tile residue (total extractables) during the initial suitability tests and then used to 
monitor the level of polar and nonpolar extractables as part of a quality control 
plan. 
A change in the composition of packaging raw material or a change in formulation 
is considered a change in the specifi cations. Due care must be taken to guarantee 
the safety, compatibility, and performance of a new dosage form in a new 
packaging system. 
The use of stability studies for monitoring the consistency of a container closure 
system in terms of compatibility with the dosage form and the degree of protection 
provided to the dosage form is essential. Except for inhalation drug products, for 
which batch - to - batch monitoring of the extraction profi le for the polymeric and 
elastomeric components is routine, no general policy concerning the monitoring of 
a packaging system and components with regard to safety is available. 
Secondary packaging components are not intended to make contact with the 
dosage form. Examples are cartons, which are generally constructed of paper or 
plastic, and overwraps, fabricated from a single layer of plastic or from a laminate 
made of metal foil, plastic, and/or paper. In special cases, secondary packaging components 
provide some additional measure of protection to the drug product. In such 
cases it could be considered a potential source of contamination and the safety of 
the raw materials should be taken into consideration. 
3.2.3.3 Inhalation Drug Products 
Inhalation drug products include inhalation aerosols (metered - dose inhalers); inhalation 
solutions, suspensions, and sprays (administered via nebulizers); inhalation 
powders (dry - powder inhalers); and nasal sprays. The carboxymethylcellulose 
(CMC) and preclinical considerations for inhalation drug products are unique in 
that these drug products are intended for respiratory tract compromised patients. 
This is refl ected in the level of concern given to the nature of the packaging components 
that may come in contact with the dosage form or the patient (Table 4 ). 
In October 1998, the FDA issued guidance for industry regarding container 
closure systems such as metered - dose inhaler (MDI) and dry - powder Inhaler (DPI) 
drug products. 
3.2.3.4 Drug Products for Injection and Ophthalmic Drug Products 
Injectable dosage forms are sterile and represent one of the highest risk drug products. 
Injectable drug products may be liquids in the form of solutions, emulsions, 
and suspensions or dry solids that are to be combined with an appropriate vehicle 
to yield a solution or suspension. 
Cartridges, syringes, vials, and ampules are usually composed of type I or II glass 
or polypropylene frequently used to deliver SVP and LVPs. Flexible bags are typically 
constructed with multilayered plastic. Stoppers and septa in cartridges, syringes, 
and vials are typically composed of elastomeric materials. An overwrap may be used 
with fl exible bags to retard solvent loss and to protect the fl exible packaging system 
from rough handling. 
Injectable drug products require protection from microbial contamination (loss 
of sterility or added bioburden) and may also need to be protected from light or 
QUALITY CONTROL OF PACKAGING MATERIAL 179

180 PACKAGING AND LABELING 
exposure to gases (e.g., oxygen). Liquid - based injectables may need to be protected 
from solvent loss, while sterile powders or powders for injection may need to be 
protected from exposure to water vapor. 
For elastomeric components, data showing that a component meets the requirements 
of USP elastomeric closures for injections should typically be performed to 
assure safety. For plastic components, USP biological reactivity tests are recommended 
to assure evidence of safety. Whenever possible, the extraction studies 
described in USP should be performed using the drug product. Extractables should 
be identifi ed whenever possible. For a glass packaging component, data from USP 
“ Containers: Chemical resistance — Glass containers ” will typically be considered 
suffi cient evidence of safety and compatibility. In some cases (e.g., for some chelating 
agents), a glass packaging component may need to meet additional criteria to 
ensure the absence of signifi cant interactions between the packaging component 
and the dosage form. 
The performance of a syringe is usually addressed by establishing the force to 
initiate and maintain plunger movement down the barrel and the capability of the 
syringe to deliver the labeled amount of the drug product. 
Ophthalmic drug products are usually solutions marketed in a LDPE bottle with 
a dropper built into the neck or ointments marketed in a metal tube lined with an 
epoxy or vinyl plastic coating with an ophthalmic tip. 
Since ophthalmic drug products are applied to the eye, compatibility and safety 
concerns should also address the container closure system ’ s potential to form substances 
which irritate the eye or introduce particulate matter into the product (USP 
. 771 . , ophthalmic ointments). 
3.2.3.5 Liquid - Based Oral Products, Topical Drug Products, and 
Topical Delivery Systems 
The presence of a liquid phase implies a signifi cant potential for the transfer of 
materials from a packaging component into the dosage form. 
Liquid - Based Oral Drug Products Typical liquid - based oral dosage forms are 
elixirs, emulsions, extracts, fl uid extracts, solutions, gels, syrups, spirits, tinctures, 
aromatic waters, and suspensions. These products are usually nonsterile but may be 
monitored for changes in bioburden or for the presence of specifi c microbes. 
A liquid - based oral drug product typically needs to be protected from solvent 
loss, microbial contamination, and sometimes exposure to light or reactive gases 
(e.g., oxygen). For glass components, data showing that a component meets the 
requirements of USP “ Containers: Glass containers ” are accepted as suffi cient evidence 
of safety and compatibility. For LDPE components, data from USP container 
tests are typically considered suffi cient evidence of compatibility. 
The USP general chapters do not specifi cally address safety for polyethylene 
(HDPE or LDPE), PP, or laminate components. A patient ’ s exposure to substances 
extracted from a plastic packaging component (e.g., HDPE, LDPE, PP, laminated 
components) into a liquid - based oral dosage form is expected to be comparable to 
a patient ’ s exposure to the same substances through the use of the same material 
when used to package food [27] . 

Topical Drug Products Topical dosage forms include aerosols, creams, emulsions, 
gels, lotions, ointments, pastes, powders, solutions, and suspensions. These dosage 
forms are generally intended for local (not systemic) effect and are generally applied 
to the skin or oral mucosal surfaces. Topical products also include some nasal and 
otic preparations as well as some ophthalmic drug products. Some topical drug 
products are sterile and should be subject to microbial limits. 
A rigid bottle or jar is usually made of glass or polypropylene with a screw cap. 
The same cap liners and inner seals are sometimes used as with solid oral dosage 
forms. A collapsible tube is usually constructed from metal or is metal lined from 
LDPE or from a laminated material. 
Topical Delivery Systems Topical delivery systems are self - contained, discrete 
dosage forms that are designed to deliver drug via intact skin or body surface, 
namely transdermal, ocular, and intrauterine. 
Each of these systems is generally marketed in a single - unit soft blister pack or 
a preformed tray with a preformed cover or overwrap. Compatibility and safety for 
topical delivery systems are addressed in the same manner as for topical drug products. 
Performance and quality control should be addressed for the rate - controlling 
membrane. Appropriate microbial limits should be established and justifi ed for each 
delivery system. 
3.2.3.6 Solid Oral Dosage Forms and Powders for Reconstitution 
The most common solid oral dosage forms are capsules and tablets. A typical container 
closure system is a plastic (usually HDPE) or a glass bottle with a screw - on 
or snap - off closure and a fl exible packaging system, such as a pouch or a blister 
package. If used, fi llers, desiccants, and other absorbent materials are considered 
primary packaging components. 
Solid oral dosage forms generally need to be protected from the potential adverse 
effects of water vapor, light, and reactive gases. For example, the presence of moisture 
may affect the decomposition rate of the active drug substance or the dissolution 
rate of a dosage form. The potential adverse effects of water vapor can be 
determined with leak testing on a fl exible package system (pouch or blister package). 
Three standard tests for water vapor permeation have been established by the USP, 
namely polyethylene containers (USP . 661 . ), single - unit containers and unit - dose 
containers for capsules and tablets (USP . 671 . ), and multiple - unit containers for 
capsules and tablets (USP . 671 . ). 
3.2.4 IMPORTANCE OF PROPER PACKAGING AND LABELING 
The Poison Prevention Packaging Act ( www.cpsc.gov/businfo/pppa.html) requires 
special packaging of most human oral prescription drugs, oral controlled drugs, 
certain normal prescription drugs, certain dietary supplements, and many over - the - 
counter (OTC) drug preparations in order to protect the public from personal injury 
or illness from misuse of these preparations. 
IMPORTANCE OF PROPER PACKAGING AND LABELING 181

182 PACKAGING AND LABELING 
In many countries there are very strict regulations for packaging of many drug 
substances. Nevertheless, special packaging is not required for drugs dispensed 
within a hospital setting for inpatient administration. Manufacturers and packagers 
of bulk - packaged prescription drugs do not have to use special packaging if the drug 
will be repackaged by the pharmacist. 
Various types of child - resistant packages are covered in ASTM International 
standard D - 3475. Medication errors linked to poor labeling and packaging can be 
controlled through the use of error potential analysis. The recognition that a drug 
name, label, or package may constitute a hazard to safety typically occurs after the 
drug has been approved for use and is being marketed. Calls for change almost 
always result from accumulating reports of serious injuries associated with the use 
of a drug. 
Numerous reports of medication errors are being reported, some of which have 
resulted in patient injury or death. In a number of these reports, a medication was 
mistakenly administered either because the drug container (bag, ampule, prefi lled 
syringe and bottle) was similar in appearance to the intended medication ’ s container 
or because the packages had similar labeling. Obviously, the severity of such errors 
depends largely on the medication administered. 
The problem of medical errors associated with the naming, labeling, and packaging 
of pharmaceuticals is being very much discussed. Sound - alike and look - alike 
drug names and packages can lead pharmacists and nurses to unintended interchanges 
of drugs that can result in patient injury or death. Simplicity, standardization, 
differentiation, lack of duplication, and unambiguous communication are 
human factors that are relevant to the medication use process. These factors have 
often been ignored in drug naming, labeling, and packaging. 
The process for naming a marketable drug is always lengthy and complex and 
involves submission of a new entity and patent application, generic naming, brand 
naming, FDA — or other corresponding organization all over the world — review, and 
fi nal approval. Drug companies seek the fastest possible approval and may believe 
that the incremental benefi t of human factor evaluation is small. Very often, the 
drug companies are resistant to changing, for example, brand names. Although a 
variety of private - sector organizations in many countries have called for reforms in 
drug naming, labeling, and packaging standards, the problem remains. 
Drug names, labels, and packages are not selected and designed in accordance with 
human factor principles. FDA standards or other corresponding organizations in 
other countries do not require application of these principles, the drug industry has 
struggled with change, and private - sector initiatives have had only limited success. 
A number of factors can contribute to the mistaking of one medication for 
another. Failure to read the package label is one cause. Another if a medication is 
stored in the wrong location or if clinicians select the medication based solely on 
the appearance of its package. Also, confusion can occur between medications with 
names that look alike or sound alike or between premixed medications packaged 
in similar - looking containers. Another potential source for confusion with premixed 
medications is the presence of different concentrations of the same medication in 
a particular location (e.g., a package with 100 mg/mL concentration of a drug could 
be mistaken for one with 10 mg/mL concentration). 
Daily, physicians, nurses, and pharmacists base medical decisions on the information 
provided by a drug product ’ s labeling and packaging. Unfortunately, poor 

labeling and packaging have been linked all too often to medication errors. To help 
practitioners avoid errors, drug manufacturers should present information in a clear 
manner that can be grasped quickly and easily. 
To determine what presentation is most clear, manufacturers should invite and 
consider the input of physicians, nurses, and pharmacists, because they work with 
these products every day and are more likely than label and package designers to 
discover potential problems. Such input provides the basis for failure and effect 
analysis (FMEA), also known as error potential analysis or error prevention analysis. 
FMEA is a systematic process that can predict how and where systems might 
fail. Using FMEA, health care practitioners examine a product ’ s packaging or labeling 
in order to identify the ways in which it might fail. A number of steps to reduce 
confusion and improve the readability of a drug product ’ s label have already been 
determined through the use of FMEA. 
The fi rst step is to reduce label clutter. Only essential information, such as the 
brand and generic names, strength or concentration, and warnings, should appear 
prominently on the front label. Numerous deaths have been prevented through the 
addition of a warning to concentrated vials of injectable potassium chloride, for 
example. Another step includes the use of typeface to enhance distinctive portions 
of look - alike drug names on look - alike packaging. 
Medication errors are also associated with poor product packaging design. Unfortunately, 
medication errors linked to poor labeling and packaging are sometimes 
used in the health care environment to justify the damage. Participation of an expertise 
from health care practitioners, during labeling and packaging design phase, 
might have prevented several errors. 
Whether for established drugs or new entities going through the approval process, 
the principles of safe practice in naming, labeling, and packaging are the same and 
must be very well controlled. Safety experts may differ about specifi c details, but 
there is little disagreement about the fundamental principles that should be incorporated 
into the drug approval process. 
Based on reports of errors associated with packaging and labeling, many recommendations 
have been proposed. Some of them are: 
1. Avoid storing medications with similar packaging in the same location or in 
close proximity. 
2. Follow the American Society of Health System Pharmacists (ASHP) guidelines 
or other legislation of a specifi c country for preventing hospital medication 
errors [40, 41] . The ASHP ’ s recommendations include the following: 
Fully document all medication prescription and deliveries and instruct staff 
that discrepancy or misunderstanding about prescription or patient 
information should be verifi ed with the prescribing physician. Staff 
members should be told that all caregivers (regardless of level) have the 
duty to question the prescribing physician (regardless of the physician ’ s 
relative position in the hospital hierarchy) if they have concerns about 
a drug, dose, or patient. 
Periodically train staffs in practices that will help avoid medication errors. 
Ensure that the medication storage and distribution to hospital locations 
outside the pharmacy are supervised by hospital pharmacy staff only. 
IMPORTANCE OF PROPER PACKAGING AND LABELING 183

184 PACKAGING AND LABELING 
Nonpharmacists should not be allowed to enter the pharmacy if it is 
closed. 
3. Perform failure mode and effects analysis. This is a technique used to identify 
all medication errors that could occur, determine how they occur, and estimate 
what their consequences would be. Steps then should be taken to prevent 
errors from occurring, when possible, and to minimize the effects of any errors 
that do occur. 
4. Report any information relating to medication errors to the Medication Errors 
Reporting Program operated by USP convention [10] and the Institute for 
Safe Medication Practice (ISMP) or other corresponding institutions in the 
different countries. The program shares information on medication errors with 
health care professionals to prevent similar errors from recurring. 
5. Hospitals should report incidents in which a device caused or helped cause a 
medication error. 
6. Urge suppliers to provide clear and unique labels and packages for their 
various individual medications. 
Some other considerations relating to standards for drug names, labeling standards, 
and packaging standards are as follows: 
1. Standard for Drug Names. The most critical issue in drug name selection is that 
one name should not be easily confused with another. This applies to both generic and 
brand names. A name must neither sound like that of another drug nor look like 
another drug name when it is written out by hand. From the industry ’ s standpoint, the 
challenge is to fi nd a name that is easy to recollect and appropriate for the connotation 
desired, do not lead astray (safe), and not already a trade name. 
Nowadays, increasing sophisticated and effective methods are available for determining 
the likelihood of confusion by sound or sight. 
2. Labeling Standards. To minimize the possibility of error, labels should be easy 
to read and avoid nonessential material. The name of the drug, and not the name 
of the manufacturer, should be the most prominent feature and should be in at least 
12 - point type. The use of color is very controversial; some believe that all colors 
should be prohibited to force personnel to read the labels. 
In the 1990s, a Washington State legislator proposed that every drug product 
entering the state must have a color - coded label. There was concern on the part of 
many that the state legislature would turn this idea into law. The prospect of having 
to color - code all the drugs entering a single state galvanized a response by industry, 
regulators, practitioners, and safe experts who agreed to revise pharmaceutical 
labeling. A Committee to Reduce Medication Errors was formed to study the 
problem. The effort eventually satisfi ed the color coders and the proposed legislation 
was dropped. 
The committee made several recommendations for standardizing and simplifying 
labels: 
1. Eliminate unnecessary words from the label, such as “ sterile, ” “ nonpyrogenic, ” 
and “ may be habit forming. ” 
2. Allow some abbreviations such as “ HCl ” and “ Inj. ” 
3. Make label information consistent. 

4. Require that vials containing medication that must be diluted bear the words 
“ Concentrated, must be diluted ” in a box on the label, that the vial have a 
black fl ip - top with those words on it, and that the ampules carry a black 
band. 
3. Packaging Standards. While there is no evidence that trademark colors and 
logos on boxes pose a problem, the use of color on bottle tops and labels creates 
many diffi culties. There are dozens of drugs whose names are quite different but 
whose packages look alike. This creates the potential for error when people “ see ” 
what they expect to see on the label. 
Standards need to be set for color on both caps and labels. Some believe that 
prohibiting all color would be safest — in effect, taking away a cue that could divert 
someone from reading the label. 
3.2.5 REGULATORY ASPECTS 
3.2.5.1 General Considerations 
Once the fi nished dosage form is made, the product should be packed into the 
primary container and labeled. Additional packaging and labeling are also included. 
Because of the many products and labeling materials, personnel in this area must 
be alert to prevent mix - ups. Controls and in - process checks should be carried out 
throughout the packaging/labeling operation to ensure proper labeling. 
Some examples of good manufacturing practices (GMP) requirements specifi c 
to packaging and labeling in different countries are as follows: 
In the United States the requirements should be written procedures designed to 
assure that correct labels, labeling, and packaging materials are used for drug 
products; such written procedures should be followed. These procedures 
should incorporate features such as prevention of mix - ups and cross - 
contamination by physical or spatial separation from operations on other drug 
products. 
In Canada, packaging operations are performed according to comprehensive and 
detailed written operating procedures or specifi cations, which include identi- 
fi cation of equipment and packaging lines used to package the drug, adequate 
separation, and, if necessary, the dedication of packaging lines packaging different 
drugs and disposal procedures for unused printed packaging materials. 
Packaging orders are individually numbered. 
In the European Union, the requirements should be formally authorized in the 
“ packaging instructions ” for each product containing pack size and type. They 
are normally included in process controls with instructions for sampling and 
acceptance limits [42] . 
3.2.5.2 Food, Drug and Cosmetic Act 
About 100 years after its foundation, the Congress of the United States recognized 
that subjects related to safety and public health could not exclusively be state 
dependent and measures should be taken to protect the population in vital areas. 
Therefore, the federal government became interested in regulating products for 
consumption. 
REGULATORY ASPECTS 185

186 PACKAGING AND LABELING 
In 1906, the Congress approved the Wiley Law to avoid the production, sale, or 
transport of food, medications, and alcoholic beverages that were inadequate or 
falsifi ed, poisonous, or harmful. It was the fi rst food and medication regulation 
adopted in interstate commerce. The Congress was given power to regulate commerce 
between foreign nations and several U.S. states. 
In 1912 a civil code law was enacted prohibiting any false affi rmation of curing 
or therapeutic effect on medication labels. The current law was enacted on June 27, 
1938, and regulates food, medications, medical devices, and diagnostic and cosmetic 
products. The law of 1938 stopped regulating the trade of alcoholic beverages. This 
law stated, among other recommendations, the following: 
1. The label of each medication had to give the name of each active component 
and the quantity of some specifi c substances, active or not. 
2. Cosmetics had to be inoffensive and be properly labeled and packaged. 
The 1938 law states that the label of a medication should contain adequate information 
regarding its use. However, in practice, it became evident that some pharmaceuticals 
and medications had to be administered by or under the orientation of 
a medical practitioner, due to the inability of a layman to diagnose a disease, choose 
an effective treatment, and recognize the cure or the symptoms. Several products 
were thus classifi ed, but “ the prescription concept of a medication ” was introduced 
only after Alteration in the Law of Durham - Humphrey ’ s in 1951. Since then, a label 
had to carry the warring “ Caution, the Federal Law prohibits dispensation without 
medical prescription. ” The use of these medications had to be restricted to prescription 
by a practitioner and the packing or printed material inside had to contain 
adequate information so that the practitioner could prescribe them safely. 
Alterations in 1962 of the 1938 Law constituted an attempt to establish rigid 
controls on the research, production, divulging, promotion, sale, and use of medications 
as well as to assure its quality, effi ciency, and effectiveness [43] . 
3.2.5.3 New Drugs 
Before starting clinical trials in humans, an authorization should be obtained from 
the FDA. This is known as a clinical trial authorization request for a new medication 
(AEM), on which it is necessary to establish the following: 
1. The name that best describes the medication, including the chemical name 
and the structure of any new molecule 
2. A complete list of medication components. 
3. A quantitative composition of the medication. 
4. The name and address of the vendor and an acquired description of the new 
drug 
5. The methods, facilities, and controls used for the production, processing, and 
packing of a new medication 
6. All available results available from preclinical and clinical trials 
7. Copies of medication labels and the informative material that will be supplied 
to the researchers 

8. A description of the scientifi c training and the appropriate experience considered 
by the proponent to qualify a researcher as an adequate expert to 
investigate the medication 
9. The names and “ curricula vitae ” of all researchers 
10. An investigation layout planned for test accomplishment in humans 
Solicitations for release of new medications are generally very extensive, 
sometimes thousands of pages. The information has to be enough to justify the 
affi rmations contained in the label of the proposed medication with respect to 
effectiveness, dosage, and safety. The exact composition of the content on the 
medication label is usually decided by consensus between the proponent and the 
FDA. 
The requisites for solicitation of new medications, whether by prescription or not, 
are identical. The instructions contained in the medication labels for use without 
prescription should demonstrate that the medication can be used safely without 
medical supervision. 
Once the medications are perfected, the publicity related to them has to be routinely 
presented to the FDA. 
The rules of 1985 also changed the requisites regarding addendums that are 
necessary when alterations are proposed in the medication or in its labeling, for 
example. 
In regulations promulgated by the FDA on February 12, 1972, a clinic should be 
called upon regarding the effectiveness of a medication. After that the information 
may be included in the label or in the drug informative leafl et with eligible sentence 
and defi ned by dark lines that contour it [43] . 
Other dispositions contained in the alterations to the 1962 law are as follows: 
1. Immediate registration with the FDA before starting the production, repacking, 
or relabeling of medications and later annual registration, with inspections 
to be made at least once every two years. 
2. Supportive inspections in the factory, particularly where prescription medications 
are produced. 
3. The procedures used by the manufacturers should be in conformity with the 
good manufacturing practices, which permits the government to better inspect 
of all the operations. 
4. The common name should be presented on the label. 
5. The publicity of a prescription medication should present a brief summary 
mentioning the secondary effects, the contraindications, and the medication 
effectiveness. 
6. All antibiotics are subject for certifi cation procedures. 
3.2.5.4 Labeling Requisites 
According to a 1962 law, the main requisites for labeling are as described below. 
The labeling of over - the - counter medications is regulated by the Food, Drug and 
Cosmetic Act, which states: 
REGULATORY ASPECTS 187

188 PACKAGING AND LABELING 
A medication should be considered falsifi ed unless the label contains: 1. Indications of 
adequate use and 2. Adequate warnings regarding the pathological indications in those 
it should not be used or not for children use, when its use can be dangerous for health, 
of dosages, methods or interval of administration, or unsafe application, of mode and 
in necessary form for patients ’ protection. 
“ Indications of use ” were defi ned in the regulations as information with which even 
a layman can use the medication safely and for the purpose to which it is 
designated. 
The label of an over - the - counter medication must refer to the active substances, 
but it is not necessary to indicate its relative quantity, except where the ingredient 
leads to habituation. In this case the warning “ Can lead to habituation ” should 
appear on the label. 
A drug can be considered falsifi ed if it does not provide, besides indications of 
adequate use, warnings against its use in some pathological conditions (or for children) 
in which the medication can constitute a health risk. Regulations have suggested 
warnings that can be used for most well - known dangerous substances. 
3.2.5.5 Prescription Drugs 
Specifi c requisites for labeling of ethical medications or of prescription medications 
are also found in the Food, Drug and Cosmetic Act. These need not to contain 
“ adequate indications of use ” ; however, they must contain indications for the 
practitioner, inside or outside the package in which the medication is going to be 
dispensed, with adequate information for its use. This information may in - 
clude indications, effects, dosages, route of administration, methods, frequency 
and duration of administration, important dangers, contraindications, secondary 
effects, and cautions “ according to which the practitioners can prescribe the medication 
assuredly and for the desirable effects, including those for which it is 
proclaimed. ” 
Regarding all medications, the act requires that the label present a precise affi rmation 
on the weight of the content, measure or counting, as well as the name and 
manufacturer ’ s address, packer or distributor. 
The label of a prescription medication destined for oral administration has to 
contain the quantity or proportion of each active substance. 
If the medication is for parenteral administration, the quantity or proportion of 
all the excipients have also to be mentioned on the label, except for those that are 
added to adjust pH or make it isotonic, in which case only the name and its effect 
are needed. However, if the vehicle for injection is water, this does not need to be 
mentioned. 
If the medication is not to be administered by any of the routes mentioned above, 
for example, a pomade or a suppository, all excipients must to be mentioned, except 
for perfuming agents. Perfumes can be designated as such without the need to 
mention the specifi c components. 
Coloring agents can be assigned without being specifi ed individually, unless this 
is required in a separate section for regulation of coloring agents, and inoffensive 
substances added exclusively for individual identifi cation of each product need not 
be mentioned. 

The only warning that is necessary, “ Attention: the Law prohibits the dispensing 
without prescription, ” should be on the label of a prescription medication or in its 
secondary packing if the label is too little to contain it. 
3.2.5.6 Drug Information Leafl et 
The inclusion of a drug information leafl et is not compulsory whatever the medication. 
However, all medications, whether prescription or of over the counter, have to 
contain a label with adequate indications for use. If the medication label does not have 
enough space to contain all the information, the drug information leafl et has to be 
included with necessary information. The drug information leafl et and labels containing 
indication information must include the date when the text was last revised. 
To satisfy the act, the drug information leafl et usually included in the prescription 
medication packaging should contain “ adequate information on usage, including 
indications, effects, dosages, methods, route, frequency and duration of administration. 
Any important dangers, contraindications, secondary effects and cautions, 
based on which the practitioner can prescribe the medication safely and for desirable 
effects, including those for which a clam is made. ” To present the information 
in a uniform manner, the FDA issued labeling policies describing its format and the 
order and headings for the drug information leafl et description, action, indication, 
contraindications, alerts, cautions, adverse reactions, dosage and administration, 
overdose (when applicable), and as it is supplied. 
The drug information leafl et can contain the following optional information: 
Animal pharmacology and toxicology 
Clinical studies 
References 
Other specifi c cautions on medication have to appear in a visible manner at the 
beginning of the drug information leafl et so that practitioners, pharmacists, and 
patients can easily see them. 
According to GMP, an inspector should be cautious with several aspects of drug 
production, including the following: 
1. Product containers and other components have to be tested and be considered 
adequate for their intended use only if they are not reactive, departure byproducts, 
or even have absorption capacity; so that they do not affect the safety, 
identity, potency, quality, or purity of the medication or its components. 
2. Packing and labeling operations should be adequately controlled to (1) guarantee 
that only those medications that own quality standards and attain established 
specifi cations in their production and control be distributed, (2) avoid 
mix - ups during the fi lling operations, packing, and labeling, (3) assure that the 
labels and labeling used are correct for the medication, and (4) identify the 
fi nished product with a batch or a control number that allows determination 
of the batch production and control history. 
Application of the federal law on food, drug, and cosmetics is the FDA ’ s responsibility, 
which is a subdivision of the Department of Health and Human Services. 
REGULATORY ASPECTS 189

190 PACKAGING AND LABELING 
The institution is managed by a Commissaries and is subdivided into several departments: 
Food safety and applied nutrition (CFSAN), Drug evaluation and research 
(CDER), Biologics evaluation and research (CBER), Devices and radiological 
health (CDRH), Veterinary medicine (CVM), Toxicological research (NCTR), 
Regulatory affairs (ORA) and the offi ce of the commissioner (OC) [4, 44] . 
3.2.5.7 Other Regulatory Federal Laws 
There are other federal laws with which a pharmacist should be familiar. Perhaps 
the most important are laws on packing and labeling, operations that are regulated 
by the FDA and the Federal Communications Commission (FCC). The law on 
packing and labeling is targeted mostly to protecting the consumer. In the case of 
liquid the ingredients should be on the visible part of the package. The law presents 
specifi c requisites concerning the location and size of the type. Violation of this law 
can lead to apprehension by the FDA or a withdrawal order from the FCC. 
Many times a pharmacist involved in developing a product is called upon in the 
publicity of the medication. For this, he or she must understand the politics of the 
regulatory agency involved. The FCC, according to the Federal Law of Commerce, 
has jurisdiction over the announcement and promotion of all consumables, including 
medications and cosmetics. 
This law extends to all publicity and has to do with practices of fraudulent publicity 
and with promotion that is understood to be false and fraudulent. In general, the 
FCC controls the publicity of nonprescription drugs and cosmetics with respect to 
false or fraudulent affi rmations, and the FDA is responsible for labeling of medications 
and for all publicity related to prescription medications. The principal objective 
of this is to avoid unnecessary duplication of procedures while enforcing the law. 
The agencies work closely together and the FCC relies strongly on the FDA due to 
its scientifi c knowledge. Any government has the right to approve laws for its citizens 
’ protection. This right constitutes the base on which laws regulate the drug 
substance, the drug product, and its production, distribution, and sale. It is common 
that these laws exist at a district level, state level, and national level and deal with 
falsifi cation and adulteration, fraudulent publicity, and maintenance of appropriated 
sanitary conditions. 
Most U.S. states specify the purity requisites, labeling, and applicable packaging 
of a medication that are generally defi ned in identical language in federal law. 
Almost all states, prohibit the commercialization of a new medication until an 
authorization request for commercialization of a new medication has been submitted 
to the FDA and has been approved. Medication labeling requisites in each 
state are established, just as the local laws are defi ned, taking into consideration 
arguments and information, such as name and place of activity (production), content 
quantity, drug name, name of ingredients, quantity or proportion of some ingredients, 
usage indications, warning regarding dependence, caution against deterioration 
(degradation), warning about situations in which the use can be dangerous, and 
special requisites for labeling of offi cial drugs [43] . 
3.2.5.8 Fair Packaging and Labeling Act [44] 
The FDA through Fair Packaging and Labeling Act regulates the labels on many 
consumer products, including health products. Title 15: Commerce and Trade 
Chapter 39: Fair Packaging and Labeling Program [44] 

Section 1451. Congressional Delegation of Policy Informed consumers are essential 
to the fair and effi cient functioning of a free market economy. Packages and 
their labels should enable consumers to obtain accurate information as to the quantity 
of the contents and should facilitate value comparisons. Therefore, it is hereby 
declared to be the policy of the Congress to assist consumers and manufacturers in 
reaching these goals in the marketing of consumer goods [44] . 
Section 1452. Unfair and Deceptive Packaging and Labeling: Scope of 
Prohibition 
(a) Nonconforming Labels It shall be unlawful for any person engaged in the 
packaging or labeling of any consumer commodity (as defi ned in this chapter) for 
distribution in commerce, or for any person (other than a common carrier for hire, 
a contract carrier for hire, or a freight forwarder for hire) engaged in the distribution 
in commerce of any packaged or labeled consumer commodity, to distribute or 
to cause to be distributed in commerce any such commodity if such commodity is 
contained in a package, or if there is affi xed to that commodity a label, which does 
not conform to the provisions of this chapter and of regulations promulgated under 
the authority of this chapter. 
(b) Exemptions The prohibition contained in subsection (a) of this section shall 
not apply to persons engaged in business as wholesale or retail distributors of consumer 
commodities except to the extent that such persons (1) are engaged in the 
packaging or labeling of such commodities, or (2) prescribe or specify by any means 
the manner in which such commodities are packaged or labeled. 
Section 1453. Requirements of Labeling; Placement, Form, and Contents of 
Statement of Quantity; Supplemental Statement of Quantity 
(a) Contents of Label No person subject to the prohibition contained in section 
1452 of this title shall distribute or cause to be distributed in commerce any packaged 
consumer commodity unless in conformity with regulations which shall be 
established by the promulgating authority pursuant to section 1455 of this title 
which shall provide that: 
• (1) The commodity shall bear a label specifying the identity of the commodity 
and the name and place of business of the manufacturer, packer, or 
distributor; 
• (2) The net quantity of contents (in terms of weight or mass, measure, or 
numerical count) shall be separately and accurately stated in a uniform location 
upon the principal display panel of that label, using the most appropriate units 
of both the customary inch/pound system of measure, as provided in paragraph 
(3) of this subsection, and, except as provided in paragraph (3)(A)(ii) or paragraph 
(6) of this subsection, the SI metric system; 
• (3) The separate label statement of net quantity of contents appearing upon or 
affi xed to any package: 
• (A) 
• (i) if on a package labeled in terms of weight, shall be expressed in pounds, 
with any remainder in terms of ounces or common or decimal fractions of 
REGULATORY ASPECTS 191

192 PACKAGING AND LABELING 
the pound; or in the case of liquid measure, in the largest whole unit (quart, 
quarts and pint, or pints, as appropriate) with any remainder in terms of 
fl uid ounces or common or decimal fractions of the pint or quart; 
• (ii) if on a random package, may be expressed in terms of pounds and 
decimal fractions of the pound carried out to not more than three decimal 
places and is not required to, but may, include a statement in terms of the 
SI metric system carried out to not more than three decimal places; 
• (iii) if on a package labeled in terms of linear measure, shall be expressed 
in terms of the largest whole unit (yards, yards and feet, or feet, as appropriate) 
with any remainder in terms of inches or common or decimal fractions 
of the foot or yard; 
• (iv) if on a package labeled in terms of measure of area, shall be expressed 
in terms of the largest whole square unit (square yards, square yards and 
square feet, or square feet, as appropriate) with any remainder in terms of 
square inches or common or decimal fractions of the square foot or square 
yard; 
• (B) shall appear in conspicuous and easily legible type in distinct contrast (by 
topography, layout, color, embossing, or molding) with other matter on the 
package; 
• (C) shall contain letters or numerals in a type size which shall be 
• (i) established in relationship to the area of the principal display panel of 
the package, and 
• (ii) uniform for all packages of substantially the same size; and 
• (D) shall be so placed that the lines of printed matter included in that statement 
are generally parallel to the base on which the package rests as it is 
designed to be displayed; and 
• (4) The label of any package of a consumer commodity which bears a representation 
as to the number of servings of such commodity contained in such 
package shall bear a statement of the net quantity (in terms of weight or mass, 
measure, or numerical count) of each such serving. 
• (5) For purposes of paragraph (3)(A)(ii) of this subsection the term “ random 
package ” means a package which is one of a lot, shipment, or delivery of packages 
of the same consumer commodity with varying weights or masses, that is, 
packages with no fi xed weight or mass pattern. 
• (6) The requirement of paragraph (2) that the statement of net quantity of 
contents include a statement in terms of the SI metric system shall not apply 
to foods that are packaged at the retail store level. 
(b) Supplemental Statements No person subject to the prohibition contained in 
section 1452 of this title shall distribute or cause to be distributed in commerce any 
packaged consumer commodity if any qualifying words or phrases appear in conjunction 
with the separate statement of the net quantity of contents required by 
subsection (a) of this section, but nothing in this subsection or in paragraph (2) of 
subsection (a) of this section shall prohibit supplemental statements, at other places 
on the package, describing in nondeceptive terms the net quantity of contents: Provided 
, That such supplemental statements of net quantity of contents shall not 

include any term qualifying a unit of weight or mass, measure, or count that tends 
to exaggerate the amount of the commodity contained in the package. 
Section 1454. Rules and Regulations 
(a) Promulgating Authority The authority to promulgate regulations under this 
chapter is vested in (A) the Secretary of Health and Human Services (referred to 
hereinafter as the “ Secretary ” ) with respect to any consumer commodity which is 
a food, drug, device, or cosmetic, as each such term is defi ned by section 321 of title 
21; and (B) the Federal Trade Commission (referred to hereinafter as the “ Commission 
” ) with respect to any other consumer commodity. 
(b) Exemption of Commodities from Regulations If the promulgating authority 
specifi ed in this section fi nds that, because of the nature, form, or quantity of a particular 
consumer commodity, or for other good and suffi cient reasons, full compliance 
with all the requirements otherwise applicable under section 1453 of this title 
is impracticable or is not necessary for the adequate protection of consumers, the 
Secretary or the Commission (whichever the case may be) shall promulgate regulations 
exempting such commodity from those requirements to the extent and under 
such conditions as the promulgating authority determines to be consistent with 
section 1451 of this title: 
(c) Scope of Additional Regulations Whenever the promulgating authority determines 
that regulations containing prohibitions or requirements other than those 
prescribed by section 1453 of this title are necessary to prevent the deception of 
consumers or to facilitate value comparisons as to any consumer commodity, such 
authority shall promulgate with respect to that commodity regulations effective 
to: 
• (1) establish and defi ne standards for characterization of the size of a package 
enclosing any consumer commodity, which may be used to supplement the label 
statement of net quantity of contents of packages containing such commodity, 
but this paragraph shall not be construed as authorizing any limitation on the 
size, shape, weight or mass, dimensions, or number of packages which may be 
used to enclose any commodity; 
• (2) regulate the placement upon any package containing any commodity, or 
upon any label affi xed to such commodity, of any printed matter stating or 
representing by implication that such commodity is offered for retail sale at a 
price lower than the ordinary and customary retail sale price or that a retail 
sale price advantage is accorded to purchasers thereof by reason of the size of 
that package or the quantity of its contents; 
• (3) require that the label on each package of a consumer commodity (other 
than one which is a food within the meaning of section 321(f) of title 21) bear 
(A) the common or usual name of such consumer commodity, if any, and 
(B) in case such consumer commodity consists of two or more ingredients, the 
common or usual name of each such ingredient listed in order of decreasing 
predominance, but nothing in this paragraph shall be deemed to require that 
any trade secret be divulged; or 
REGULATORY ASPECTS 193

194 PACKAGING AND LABELING 
• (4) prevent the nonfunctional - slack - fi ll of packages containing consumer commodities. 
For purposes of paragraph (4) of this subsection, a package shall be 
deemed to be nonfunctionally slack - fi lled if it is fi lled to substantially less than 
its capacity for reasons other than (A) protection of the contents of such 
package or (B) the requirements of machines used for enclosing the contents 
in such package. 
(d) Development by Manufacturers, Packers, and Distributors of Voluntary Product 
Standards Whenever the Secretary of Commerce determines that there is undue 
proliferation of the weights or masses, measures, or quantities in which any consumer 
commodity or reasonably comparable consumer commodities are being distributed 
in packages for sale at retail and such undue proliferation impairs the 
reasonable ability of consumers to make value comparisons with respect to such 
consumer commodity or commodities, he shall request manufacturers, packers, and 
distributors of the commodity or commodities to participate in the development of 
a voluntary product standard for such commodity or commodities under the procedures 
for the development of voluntary products standards established by the 
Secretary pursuant to section 272 of this title. Such procedures shall provide adequate 
manufacturer, packer, distributor, and consumer representation. 
(e) Report and Recommendations to Congress upon Industry Failure to Develop or 
Abide by Voluntary Product Standards If (1) after one year after the date on which 
the Secretary of Commerce fi rst makes the request of manufacturers, packers, and 
distributors to participate in the development of a voluntary product standard as 
provided in subsection (d) of this section, he determines that such a standard will 
not be published pursuant to the provisions of such subsection (d), or (2) if such a 
standard is published and the Secretary of Commerce determines that it has not 
been observed, he shall promptly report such determination to the Congress with 
a statement of the efforts that have been made under the voluntary standards 
program and his recommendation as to whether Congress should enact legislation 
providing regulatory authority to deal with the situation in question. 
Section 1455. Procedures for Promulgation of Regulations 
(a) Hearings by Secretary of Health and Human Services Regulations promulgated 
by the Secretary under section 1453 or 1454 of this title shall be promulgated, 
and shall be subject to judicial review, pursuant to the provisions of subsections (e), 
(f), and (g) of section 371 of title 21. Hearings authorized or required for the promulgation 
of any such regulations by the Secretary shall be conducted by the Secretary 
or by such offi cer or employees of the Department of Health and Human 
Services as he may designate for that purpose. 
(b) Judicial Review; Hearings by Federal Trade Commission Regulations promulgated 
by the Commission under section 1453 or 1454 of this title shall be promulgated, 
and shall be subject to judicial review, by proceedings taken in conformity 
with the provisions of subsections (e), (f), and (g) of section 371 of title 21 in the 
same manner, and with the same effect, as if such proceedings were taken by the 
Secretary pursuant to subsection (a) of this section. Hearings authorized or required 

for the promulgation of any such regulations by the Commission shall be conducted 
by the Commission or by such offi cer or employee of the Commission as the Commission 
may designate for that purpose. 
(c) Cooperation with Other Departments and Agencies In carrying into effect the 
provisions of this chapter, the Secretary and the Commission are authorized to 
cooperate with any department or agency of the United States, with any State, Commonwealth, 
or possession of the United States, and with any department, agency, or 
political subdivision of any such State, Commonwealth, or possession. 
(d) Returnable or Reusable Glass Containers for Beverages No regulation adopted 
under this chapter shall preclude the continued use of returnable or reusable glass 
containers for beverages in inventory or with the trade as of the effective date of 
this Act, nor shall any regulation under this chapter preclude the orderly disposal 
of packages in inventory or with the trade as of the effective date of such 
regulation. 
3.2.5.9 United States Pharmacopeia Center for the Advancement of Patient 
Safety [45] 
For nearly 33 years, the USP has been reporting programs for health care professionals 
to share experiences and observations about the quality and safe use of 
medications. This year, the USP Center for the Advancement of Patient Safety 
publishes its sixth annual report to the nation on medication errors reported to 
MEDMARX (Table 6 ). It was observed that drug product packaging/labeling is one 
of the main courses of medication errors in hospitals. 
3.2.5.10 National Agency of Sanitary Vigilance ( ANVISA , Brazil) 
ANVISA is a federal organization linked to Brazil ’ s Health Ministry, which has the 
incumbency of looking after medication quality and other health products aimed at 
patients ’ safety. Several documents regarding GMP and quality control are easily 
accessed. The agency is also responsible for establishing enforcing the rules and can 
take corrective measures and punish the offenders [46] . 
Product stability and compatibility with the conditioning material are distinct, 
separate, and complementary concepts which should be applied to the pharmaceutical 
product before being made available for health care. 
TABLE 6 Selected Causes of Error Related to Equipment, Product Packaging/Labeling, 
and Communication in ICUs 
Cause of Error N (Nonharmful + Harmful) Percent Harmful 
Label (the facility ’ s) design 1,236 6,9 
Similar packaging/labeling 
Packaging/container design 
Label (manufacturer ’ s) design 
Brand/generic names look - alike 
Source : MEDMARX Data Report: A Chartbook of 2000 – 2004 Findings from Intensive Care Units 
(ICUs) and Radiological Services. 
REGULATORY ASPECTS 195

196 PACKAGING AND LABELING 
In the compatibility test between formulation and the conditioning material, 
several options of conditioning materials are evaluated to determine the most adequate 
for the product. 
The environmental conditions and periodicity analyses can be the same as those 
mentioned for the stability studies for the formulation. In this phase, the possible 
interactions between the product and the conditioning material which is in direct 
contact with the medication are verifi ed. Phenomena such as absorption, migration, 
corrosion, and others that compromise integrity can be observed. Considering that 
these types of tests are generally destructive, it is necessary to defi ne the number of 
samples to be tested. 
In ANVISA ’ s documents, different types of tests are established that should be 
carried out with different types of available materials and employed for conditioning 
medications and cosmetics (cellulose packagings, metallic, plastic, pressurized, 
etc.) [46] . 
3.2.5.11 International Committee on Harmonization ( ICH ) 
In the document “ Good Manufacturing Practice Guide for Active Pharmaceutical 
Ingredients (APIs) ” of the ICH Harmonized Tripartite Guideline, the following 
instructions are given for packaging and identifi cation labeling of APIs and intermediates 
[47] . 
General 
• There should be written procedures describing the receipt, identifi cation, quarantine, 
sampling, examination and/or testing and release, and handling of packaging 
and labeling materials. 
• Packaging and labeling materials should conform to established specifi cations. 
Those that do not comply with such specifi cations should be rejected to prevent 
their use in operations for which they are unsuitable. 
• Records should be maintained for each shipment of labels and packaging 
materials showing receipt, examination, or testing, and whether accepted or 
reject. 
Packaging Materials 
• Containers should provide adequate protection against deterioration or contamination 
of the intermediate or API that may occur during transportation 
and recommended storage. 
• Containers should be clean and, where indicated by the nature of the intermediate 
or API, sanitized to ensure that they are suitable for their intended use. 
These containers should not be reactive, addictive, or absorptive so that the 
quality of the intermediate or API complies with the specifi cations. 
• If containers are reused, they should be cleaned in accordance with documented 
procedures and all previous labels should be removed or defaced. 

Label Issuance and Control 
• Access to the label storage areas should be limited to authorized personnel. 
• Procedures should be used to reconcile the quantities of labels issued, used, 
and returned and to evaluate discrepancies found between the number of containers 
labeled and the number of labels issued. Such discrepancies should be 
investigated and the investigation should be approved by the quality unit(s). 
• All excess labels bearing batch numbers or other batch - related printing should 
be destroyed. Returned labels should be maintained and stored in a manner 
that prevents mix - ups and provides proper identifi cation. 
• Obsolete and outdated labels should be destroyed. 
• Printing devices used to print labels for packaging operations should be controlled 
to ensure that all imprinting conforms to the print specifi ed in the batch 
production record. 
• Printed labels issued for a batch should be carefully examined for proper identity 
and conformity to specifi cations in the master production record. The 
results of this examination should be documented. 
• A printed label representative of those used should be included in the batch 
production record. 
Packaging and Labeling Operations 
• There should be documented procedures designed to ensure that correct packaging 
materials and labels are used. 
• Labeling operations should be designed to prevent mix - ups. There should be 
physical or spatial separation from operations involving other intermediates or 
APIs. 
• Labels used on containers of intermediates or APIs should indicate the name 
or identifying code, the batch number of the product, and storage conditions, 
when such information is critical to assure the quality of intermediate API. 
• If the intermediate or API is intended to be transferred outside the control of 
the manufacturer ’ s material management system, the name and address of the 
manufacturer, quantity of contents and special transport conditions, and any 
special legal requirements should also be included on the label. For intermediates 
or APIs with an expiry date, the expiry date should be indicated on the 
label and certifi cate of analysis. For intermediates or APIs with a retest date, 
the retest date should be indicated on the label and/or certifi cate of analysis. 
• Packaging and labeling facilities should be inspected immediately before use 
to ensure that all materials not needed for the next packaging operation have 
been removed. This examination should be documented in the batch production 
records, the facility log, or other documentation system. 
• Packaged and labeled intermediates or APIs should be examined to ensure that 
containers and packages in the batch have the correct label. This examination 
should be part of the packaging operation. Results of these examinations should 
be recorded in the batch production or control records. 
REGULATORY ASPECTS 197

198 PACKAGING AND LABELING 
• Intermediate or API containers that are transported outside of the manufacturer 
’ s control should be sealed in a manner such that, if the seal is breached 
or missing, the recipient will be alerted to the possibility that the contents may 
have been altered. 
3.2.5.12 European Union Regulatory Bodies 
European regulatory requirements say little to date about container closure integrity 
of parenteral or sterile pharmaceutical products. Regulations provide for 
package integrity verifi cation of parenteral vials to be supported by the performance 
of sterility tests as part of the stability program. More specifi c information is 
described in the European Union (EU) 1998 “ Rules Governing Medical Products 
in the European Union, Pharmaceutical Legislation. ” These GMP regulations 
require that the sealing or closure process be validated. Packages sealed by fusion 
(e.g., ampules) should be 100% integrity tested. Other packages should be sampled 
and checked appropriately. Packages sealed under vacuum should be checked for 
the presence of vacuum. While not as detailed as the FDA guidances, it is evident 
that the EU rules also require the verifi cation of parenteral product package seal 
integrity. It is important to note that the EU rules specifi cally require 100% product 
testing for fusion - sealed packages, sampling and testing of all other packages, and 
vacuum verifi cation for packages sealed under partial pressure [42] . 
The vacuum/pressure decay test is performed by placing the package in a tightly 
closed test chamber, a pressure or vacuum is applied inside the chamber, and then 
the rate of pressure/vacuum change in the chamber over time is monitored. The rate 
or extent of change is compared to that previously exhibited by a control, nonleaking 
package. Signifi cantly greater change for a test package is indicative of a leak. 
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9. Aspinall , J. A. , Duffy , T. D. , Saunders , M. B. , and Taylor , C. G. ( 1980 ), The effect of low 
density polyethylene containers on some hospital - manufactured eye drop formulations. 
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fl uid containers and administration sets , Am. J. Hosp. Pharm. , 37 , 496 – 500 . 
12. Mizutani , T. , Wagi , K. , and Terai , Y. ( 1981 ), Estimation of diazepam adsorbed on glass 
surfaces and silicone - coated surfaces as models of surfaces of containers , Chem. Pharm. 
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rubber closures of injection vials , Int. J. Pharm. , 79 , 301 – 308 . 
15. Matsuura , I. , and Kawamata , M. ( 1978 ), Studies on the prediction of shelf life. III. Moisture 
sorption of pharmaceutical preparation under the shelf condition , Yakugaku Zusshi , 
98 , 986 – 996 . 
16. Nakabayashi , K. , Tuchida , T. , and Mima , H. ( 1980 ), Stability of packaged solid dosage 
forms. I. Shelf - life prediction of packaged tablets liable to moisture damage , Chem. 
Pharm. Bull. , 28 , 1090 – 1098 . 
17. Nakabayashi , K. , Shimamoto , T. , and Mima , H. ( 1980 ), Stability of packaged solid dosage 
forms. II. Shelf - life prediction for packaged sugar - coated tablets liable to moisture and 
heat damage , Chem. Pharm. Bull. , 28 , 1099 – 1106 . 
18. Nakabayashi , K. , Shimamoto , T. , and Mima , H. ( 1980 ), Stability of packaged solid dosage 
forms. III. Kinetic studies by differential analysis on the deterioration of sugar - coated 
tablets under the infl uence of moisture and heat , Chem. Pharm. Bull. , 28 , 1107 – 1111 . 
19. Tonnesen , H. H. ( 1996 ), Photostability of Drugs and Drug Formulations , CRC Press , 
London . 
20. Kontny , M. J. , Koppenol , S. , and Graham , E. T. ( 1992 ), Use of the sorption – desorption 
moisture transfer model to assess the utility of a desiccant in a solid product , Int. J. Pharm. , 
84 , 261 – 271 . 
21. Pikal , M. J. , and Lang , J. E. ( 1978 ), Rubber closures as a source of haze in freeze dried 
parenterals: Test methodology for closure evaluation , J. Parenteral drug Assoc. , 32 , 
162 – 173 . 
22. Jaehnke , R. W. O. , Kreuter , J. , and Ross , G. ( 1990 ), Interaction of rubber closures with 
powders for parenteral administration , J. Parenteral sci. Tech. , 44 , 282 – 288 . 
23. Jaehnke , R. W. O. , Kreuter , J. , and Ross , G. ( 1991 ), Content/container interactions: The 
phenomenon of haze formation on reconstitution of solids for parenteral use , Int. J. 
Pharm. , 77 , 4755 . 
24. Moorhatch , P. , and Chiou , W. L. ( 1974 ), Interactions between drugs and plastic intravenous 
fl uid bags. II: Leaching of chemicals from bags containing various solvent media , 
Am. J. Hosp. Pharm. , 31 , 149 – 152 . 
25. Venkataramanan , R. , Burckart , G. J. , Ptachcinski , R. J. , Blaha , R. , Logue , L. W. , Bahnson , 
A. C. , and Brady , G. J. E. ( 1986 ), Leaching of diethylhexyl phthalate from polyvinyl 
chloride bags into intravenous cyclosporine solution , Am. J. Hosp. Pharm. , 43 , 2800 – 
2802 . 
26. Boruchoff , S. A. ( 1987 ), Hypotension and cardiac arrest in rats after infusion of mono 
(2ethylhexyl) phthalate (MEHP), a contaminant of stored blood , N. Engl. J. Med. , 316 , 
1218 – 1219 . 
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200 PACKAGING AND LABELING 
27. U.S. Food and Drug Administration , Code of Federal Regulations (CFR) — Title 21, Food 
and drugs, Chapters 174 – 186, available: http://www.access.gpo.gov/nara/cfr/index.html , 
accessed Mar. 11, 2005. 
28. Kowaluk , E. A. , Roberts , M. S. , Blackburn , H. D. , and Polack , A. E. ( 1981 ), Interactions 
between drugs and polyvinyl chloride infusion bags , Am. J. Hosp. Pharm. , 38 , 1308 – 1314 . 
29. Illum , L. , and Bundgaard , H. ( 1982 ), Sorption of drugs by plastic infusion bags , Int. J. 
Pharm. , 10 , 339 – 351 . 
30. Illum , L. , Bundgaard , H. , and Davis , S. S. ( 1983 ), A constant partition model for examining 
the sorption of drugs by plastic infusion bags , Int. J. Pharm. , 17 , 183 – 192 . 
31. Atkinson , H. C. , and Duffull , S. B. ( 1990 ), Prediction of drug loss from PVC infusion bags , 
J. Pharm. Pharmacol. , 43 , 374 – 376 . 
32. Richardson , N. E. , and Meakin , B. J. ( 1974 ), The sorption of benzocaine from aqueous 
solution by nylon 6 powder , J. Pharm. Phamacol. , 26 , 166 – 174 . 
33. Santoro , M. I. R. M. , Kedor - Hackmann , E. R. M. , and Moudatsos , K. M. ( 1993 ), Estabilidade 
de sais de reidrata c a o oral em diferentes tipos de embalagem . Bol. Sanit. Panam. , 
115 , 310 – 315 . 
34. World Health Organization (WHO) ( 2003 ), The International Pharmacopoeia, Tests and 
General Requirements for Dosage Forms: Quality Specifi cations for Pharmaceutical Substances 
and Tablets , 3rd ed., Vol. 5, WHO , Geneva. 
35. Santoro , M. I. R. M. , Oliveira , D. A. G. C. , Kedor - Hackmann , E. R. M. , and Singh , A. K. 
( 2004 ), Quantifying benzophenone - 3 and octyl methoxycinnamate in sunscreen emulsions 
, Cosm. & Toil. , 119 , 77 – 82 . 
36. Santoro , M. I. R. M. , Oliveira , D. A. G. C. , Kedor - Hackmann , E. R. , and Singh , A. K. ( 2005 ), 
The effect of packaging materials on the stability of sunscreen emulsions , Int. J. Pharm. , 
13 , 197 – 203 . 
37. Thoma , K. , and Kerker , R. ( 1992 ), Photoinstability of drugs. 6. Investigations on the photosansibility 
of molsidomine , Pharm. Ind. , 54 , 630 – 638 . 
38. British Pharmacopoeia ( 2002 ), Her Majesty ’ s Stationary Offi ce, London, pp A144, 135 – 
136, 196, 671 – 673, 778 – 780, 976 – 978, 1145 – 1146. 
39. Albert , D. E. ( 2004 ), Evaluating pharmaceutical container closure systems , Pharm. & 
Med. Packaging News , 3 , 76 – 78 . 
40. ASHP Council on Professional Affairs ( 1993 ), ASHP Guidelines on preventing medication 
errors in hospital , Am. J. Hosp. Pharm. , 50 , 305 – 314 . 
41. ASHP Council on Professional Affairs ( 2001 ), ASHP guidelines on preventing medication 
errors in hospital , Am. J. Hosp. Pharm. , 58 , 3033 – 3041 . 
42. European Pharmacopoeia ( 2001 ), 4th ed., Council of Europe, Strasbourg. 
43. Lachman , L. , Lieberman , H. A. , and Kanig , J. L. ( 2001 ), Teoria e pr a tica na ind u stria 
farmac e utica , Funda c a o Calouste Gulbenkian , Lisboa . 
44. U.S. Food and Drug Administration, Fair Packaging and Labeling Act . Title 15 — 
Commerce and Trade, Chapter 39 — Fair Packaging and Labeling Program, available: 
http://www.fda.gov/opacom/laws/fplact.htm accessed Mar. 11, 2005. 
45. Santell , J. P. , Hicks , R. W. , and Cousins , D. D. ( 2005 ), MEDMARX Data Report: A Chartbook 
of 2000 – 2004 Findings from Intensive Care Units and Radiological Services , USP 
Center for Advancement of Patient Safety , Rockville, MD . 
46. Ag e ncia Nacional de Vigil a ncia Sanit a ria (ANVISA) ( 2004 ), Guia de Estabilidade de 
Produtos Cosm e ticos , ANVISA , Bras i lia . 
47. International Organization on Harmonisation (2000), ICH harmonized tripartite guideline: 
Good manufacturing practice guide for active pharmaceutical ingredients, available: 
http://www.ICH.org , accessed June 23, 2005. 
48. Sarbach , C. , Yagoubi , N. , Sauzieres , J. , Renaux , C. , Ferrier , D. , and Postaire , E. ( 1996 ), 
Migration of impurities from a multi-layer plastics container into a parenteral infusion 
solution , Int. J. Pharm. , 140 , 169 – 174 . 

201 
3.3 
CLEAN - FACILITY DESIGN, 
CONSTRUCTION, AND 
MAINTENANCE ISSUES 
Raymond K. Schneider 
Clemson University, Clemson, South Carolina 
Contents 
3.3.1 Introduction 
3.3.2 Planning for Project Success 
3.3.2.1 Needs Assessment 
3.3.2.2 Front - End Planning 
3.3.2.3 Preliminary Design 
3.3.2.4 Procurement 
3.3.2.5 Construction 
3.3.2.6 Start - Up and Validation 
3.3.2.7 Summary 
3.3.3 Design Options 
3.3.3.1 Clean - Facility Scope 
3.3.3.2 Design Parameters 
3.3.3.3 Architectural Design Issues 
3.3.3.4 Materials of Construction 
3.3.3.5 HVAC System 
3.3.3.6 Clean - Room Testing 
3.3.3.7 Utilities 
3.3.4 Construction Phase: Clean Build Protocol 
3.3.4.1 General 
3.3.4.2 Level I Clean Construction 
3.3.4.3 Level II Clean Construction 
3.3.5 Maintenance 
Appendix A: Guidelines for Construction Personnel and Work Tools in a Clean 
Room 
Appendix B: Cleaning the Clean Room 
Bibliography 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

202 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
3.3.1 INTRODUCTION 
While there are discrete steps in the design and construction of a pharmaceutical 
manufacturing plant project, those projects deemed successful incorporate certain 
practices that promote fl ow of the construction process toward completion on time 
and within budget. Proper front - end planning is not completed until it results in 
appropriate values for design parameters, “ buy - in ” at all levels of management, and 
clear direction for the design phase. Engineering the clean room in accordance with 
recognized industry practice would produce construction documents that facilitate 
clear procurement and construction planning as well as a focused, effi cient, construction 
effort. A full return on the energy expended through the construction phase 
cannot be realized without a well - executed start - up and validation process that 
provides baseline data for effective ongoing operation and maintenance. 
The steps in the clean - room construction project include: 
Needs assessment 
Front - end planning 
Preliminary design 
Construction document development 
Procurement 
Construction 
Start - up and validation 
One of the truisms of the construction industry is that the greatest impact on the 
cost of a facility can be made at the earliest stages of the process. The construction 
process can be likened to a snowball rolling down a snow - covered hill. It grows and 
gains momentum, seemingly taking on a life of its own, until it can only be brought 
under control with a major effort. So too with manufacturing plant projects. Careful 
work during the fi rst three stages will ensure that the project begins on a well - 
directed course and moves to a successful conclusion. 
Sometimes the special nature of pharmaceutical manufacturing plant projects 
clouds the fact that building such a plant is in fact a construction project. The facility 
engineering team of a small to medium company may be tempted to turn away from 
such projects due to the projects ’ perceived uniqueness and leave the key decision 
making to others. In fact, it is the construction experience of that team that is most 
required to keep the project costs under control. The way to accomplish this is for 
the team to be involved in the process from its earliest stages. 
Let us review the steps in such a project and identify what should occur at each 
step and the potential for trouble. 
3.3.2 PLANNING FOR PROJECT SUCCESS 
3.3.2.1 Needs Assessment 
It is during this early stage that a requirement for a clean manufacturing facility is 
perceived. The need for the facility may be precipitated by a new product, an 

improved product, an improved manufacturing methodology, new or more stringent 
regulation requirements, or perhaps a change in marketing strategy. 
At this point a study should be undertaken to determine the benefi ts to be realized 
by the new facility as well as the costs to be incurred. Costs arise from not only 
construction but also ongoing operation and maintenance. These costs are affected 
by the plant location and the availability of a trained or trainable workforce. Does 
the day - to - day operation of the facility generally require that special attire be worn? 
Are special procedures, possibly more time consuming than those presently used, 
required? It is important that this study is complete and accurate in order to prevent 
any unrealistic expectations on the part of management and plant operations and 
to permit advanced planning for revised procedures once the facility is in use. 
The study should describe the goals of the project, its impact on present operations, 
budget restraints, tentative schedule, and path forward. It will serve as the 
basis for front - end planning and will provide the standard against which the success 
of the program is measured. 
3.3.2.2 Front - End Planning 
While the needs assessment study may be conducted by a limited number of people, 
the front - end planning process should be open to all. Plant facilities people will be 
bearing the brunt of the responsibility for bringing the facility online, on schedule, 
and within budget. Process people are responsible for ensuring that the facility will 
adequately house the process equipment and that the facility incorporates suffi cient 
space, utilities, process fl ow considerations, and provision for fl ow of people and 
material to support the goals of the building program. Human resources people 
have to staff the facility, either out of the present employee pool or from the general 
local labor market. They must know the requirements of potential employees as 
well as the conditions under which they will be working. 
Procurement people will be purchasing furnishings and process equipment for 
the plant as well as overseeing the contracts let to the design and construction professionals. 
Operations people should have input regarding design parameters such 
as temperature, humidity, lighting, vibration, cleanliness class, and energy needs. 
Materials handling people should participate in order to understand the requirements 
for storing and transporting raw materials as well as retrieving, storing, and 
shipping fi nished goods from the plant. 
An integral part of the front - end planning team should be the design professionals 
charged with developing the plant design based on client input in such a way as 
to satisfy as many requirements developed in needs assessment as possible. This 
team may be assembled internally but frequently is drawn from specialty builders, 
architectural and engineering (A & E) fi rms, and design/build fi rms active in the 
pharmaceutical industry. The team of design professionals should have pharmaceutical 
experience on facilities comparable in size and complexity to that being planned 
as well as extensive experience in construction projects of all types. The design team 
may offer design only, design/build, procurement, construction management, or 
combinations of these services. This design team should be considered a resource 
during the front - end planning phase. It is the wise client who takes advantage of 
the experience of the design team, permitting them a large role as facilitators of the 
planning sessions. 
PLANNING FOR PROJECT SUCCESS 203

204 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
An appropriate design team will demonstrate expertise in contamination control 
philosophies, space planning, code compliance, and mechanical and electrical design 
and will be familiar with materials of construction currently being used in pharmaceutical 
projects. It is frequently helpful to include a member of the construction 
team in the front - end planning effort to advise on constructibility of the facility 
being planned. Unrealistic construction schedules will be avoided and fi eld rework 
will be minimized if appropriate attention is paid to the construction phase early in 
the planning process. 
3.3.2.3 Preliminary Design 
Front - end planning typically utilizes the expertise of client process people to convey 
the requirements of the pharmaceutical facility to the design team. With this information 
in hand the design team begins the facility design incorporating process 
needs, code requirements, safety issues, material and personnel fl ow, work - in - process 
storage, utility needs, and so on, into a fi rst - cut approach. 
Client representatives have an opportunity to review the effort and begin fi ne 
tuning the design to incorporate late - breaking process changes. The preliminary 
design is a target that helps both the design team and the client solidify design goals. 
Change is inexpensive, and therefore encouraged, at this stage and buy - in by all 
concerned is a major objective of this phase of the design effort. 
A budget based on the agreed - upon preliminary design should be developed to 
make sure that the overall project is on course. This will minimize surprises further 
along in the design/build process. Ideally the design will be “ cast in stone ” at the 
end of the preliminary phase. This permits the production work on the design documents 
to proceed unhindered. The more unknowns left at the end of the preliminary 
phase, the more diffi cult it will be to complete design documents in a timely 
fashion. 
Construction Document Development The construction documents should convey 
the intent of the design team and client to the construction team. A good set of 
construction documents should result in a tight spread of construction bids as there 
should be little room for varying interpretation on the part of the potential construction 
contractors. The drawings should have suffi cient notes to convey the design 
intent without creating a cluttered appearance. The written specifi cations should be 
as brief as possible consistent with clarity. 
Complicated documents create the impression that a project may be more 
involved, and therefore more costly, than it should be. Cautious contractors may 
unnecessarily infl ate their bid to cover perceived contingencies. Specifi cations that 
are too wordy may be diffi cult to follow and similarly result in higher prices as 
bidders make sure all bases are covered. No one likes surprises. 
The development of construction documents should be a straightforward process 
with little involvement by the client except to monitor the process and ensure that 
the original design intent is followed. While changes will always occur during this 
phase ( “ cast in stone ” is a euphemism for “ let ’ s keep the changes under control ” ), 
they are certainly less costly at this point than during the construction phase. It is 
desirable to minimize such changes. A continuous sequence of changes suggests that 
the preliminary design phase was not entered into seriously. It demonstrates a lack 

of preparedness on the part of the client and a lack of ability to communicate and 
draw out the client ’ s needs on the part of the design team. A sense of clarity of 
purpose slips away with ongoing change and the possibility for errors in construction 
documents, which eventually surface as costly construction changes, increases. 
3.3.2.4 Procurement 
A detailed scope of work describing the materials and services required is a vital 
part of the procurement process. There is no purpose to keeping the project bidders 
in the dark regarding what is required of them. The role of the procurement function 
is to obtain maximum value, that is, the best quality and schedule at the lowest 
price. The clearer the scope of work and construction documents, the better will be 
the chance of this happening. A low price is not a good value if the schedule slips 
by several months as a result. A marginal plant that does not maintain design conditions 
or meet production goals is a poor value even if it was delivered within 
schedule. 
The procurement process should qualify potential bidders by ensuring that similar 
pharmaceutical projects have been delivered on time, within budget, and on schedule. 
References should be checked. It is expected that references offered by a 
potential bidder would have good things to say about that bidder, but this is not a 
certainty and pointed questioning about personnel, schedule, quality, change orders, 
follow - up, and so on, can help develop a warm feeling or an uncertain feeling about 
potential bidders. If bids are in fact quite close, it is the quality of references that 
might suggest a particular bidder be given preference. 
There are a number of ways in which the project can be procured. Use of in - house 
engineering and construction expertise may work in special situations or on smaller 
projects. Typically problems arise when facilities departments, stretched to their 
limit with ongoing plant requirements, must lower the priority of the new facility to 
meet other commitments. Schedules may stretch out unacceptably. 
A number of specialty contractors have proven over the years to be adept at 
installing small turnkey facilities of limited complexity in a timely and economical 
fashion. If extensive engineering is required, if local code compliance becomes an 
issue, if complex process requirements must be met, or if the client requirements 
exceed the experience of the supplier there could be cause for concern. 
Design/build is a popular approach in that it suggests a single source of responsibility 
for all phases of the project. Frequently fi rms billing themselves as “ design/ 
build ” are strong in either design or build, but not both. The strong design fi rm can 
put the essentials on paper but the fi nal price and schedule may suffer. The strong 
construction fi rm may lack the expertise to create an appropriate manufacturing 
environment, particularly where clean - room expertise is required. The project may 
be outstanding in all respects except performance. A good review of references is 
essential before selecting a design/build fi rm. 
Construction management has been increasingly used on larger projects. A good 
construction management fi rm will work closely with the client - selected design 
company to review constructability and adequacy of construction documents. It will 
assist to qualify bidders, maintain schedule, track costs, administer and oversee, and 
generally ensure that a team incorporating the strongest skills is assembled to complete 
the project. Pharmaceutical experience is essential. 
PLANNING FOR PROJECT SUCCESS 205

206 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
3.3.2.5 Construction 
The construction process should proceed smoothly if the remarks presented above 
are followed. Cost can increase during this phase if changes must be implemented. 
While change is inevitable, a construction change procedure negotiated during the 
bidding phase and in place during construction will keep such change from getting 
out of control. 
The requirement for “ building clean ” has arisen in recent years as more stringent 
clean rooms have become more popular. Imposing a clean construction protocol on 
contractors can lengthen the schedule and increase cost. The protocol should be 
developed during the construction document phase and be an integral part of the 
bid documents. Once the decision is made to work clean, protocols developed 
should be followed by everyone on the jobsite associated with the clean areas. A 
poorly conceived and enforced protocol will be a costly and futile exercise. The 
tendency to build clean on every new or retrofi t project should be carefully evaluated 
and a practical protocol should be developed consistent with the needs of the 
project. 
Client end users should be encouraged to observe construction as it progresses. 
They will be more intelligent about how their facility was built and therefore more 
attuned to maintaining the facility once it is completed and in operation. While 
suggestions should be welcomed as construction progresses, it is important that a 
chain of command be enforced. Any questions or suggestions or concerns should 
not be expressed to workers on the site but rather through project management 
channels. In this way good ideas can be implemented and bad ideas shelved without 
impacting the construction effort in a negative manner. Note the one exception to 
this practice is in regard to safety. Everyone on the site has safety responsibility. 
Any unsafe acts should be questioned and supervisors consulted immediately. 
3.3.2.6 Start - Up and Validation 
Subcontractors on the jobsite should be responsible for start - up as well as installation 
of equipment. Equipment manufacturers typically have personnel available to 
ensure appropriate start - up procedures are followed. If several trades are involved 
in the installation of a particular piece of equipment, then one trade should be 
assigned, by contract, as having coordinating responsibility for that piece of equipment. 
This will minimize “ fi nger pointing ” when equipment does not start or operate 
properly. This can be a sensitive issue and a construction manager can set the tone 
for cooperation in this area. 
An independent contractor responsible to the construction manager or owner 
should do testing and balancing (TAB) of mechanical systems. All start - up should 
be complete and initial valve or damper settings made (and recorded) by the subcontractor 
before testing and balancing begins. The TAB contractor should not have 
to repair equipment or troubleshoot inoperative equipment but rather only adjust 
and verify performance of equipment. 
A separate contractor should certify clean - room areas. This might be the TAB 
contractor if that fi rm is suitably qualifi ed. There should be no question of equipment 
being operative at this stage of the project since start - up and testing and 
balancing are complete. Certifi cation is the verifi cation of facility compliance 

DESIGN OPTIONS 207 
with clean - room specifi cations. If the facility design is well conceived and the construction 
team has installed a quality project, any certifi cation test failure will most 
likely be corrected through fairly minor adjustments. Failure of the clean room to 
pass certifi cation tests might require redesign but more frequently requires some 
equipment adjustment or perhaps a fi lter repair and then a retest. It is important 
that a clear understanding of responsibility be communicated before problems are 
encountered. Failure to plan for potential problems could result in extending the 
schedule and incurring unforeseen costs at a crucial point in the project. 
3.3.2.7 Summary 
Recognizing the step - by - step process involved in even the smallest pharmaceutical 
project can help focus attention in a manner that will result in a successful project. 
The formal schedule of a well - conceived project will include needs assessment, 
front - end planning, and preliminary design. It is important that project progress is 
measured against such a schedule and not just by the visual impact caused by bricks 
and mortar being installed. 
3.3.3 DESIGN OPTIONS 
3.3.3.1 Clean - Facility Scope 
The purpose of this section is to identify design and construction options for those 
parts of a pharmaceutical facility intended to house process equipment. These suggestions 
are intended to assure that the facilities, when used as designed, will meet 
the requirements of current good manufacturing practices (cGMPs). Air cleanliness 
within the facility may range from International Organization for Standardization 
(ISO) 5 (Class 100) through ISO 8 (Class 100,000). In addition, areas may be considered 
clean or labeled as “ controlled environment ” without having a cleanliness 
class assigned to the space. Note that throughout this chapter cleanliness class will 
be described using the designation presented in the new ISO 14644 (e.g., ISO 5, ISO 
8) and parenthetically as presented in the currently obsolete (but widely understood 
and quoted) U.S. Federal Standard 209 (e.g., Class 100, Class 100,000). 
A cleanliness classifi cation in accordance with the latest revision of ISO 14644 is 
generally inadequate by itself to describe a facility used for pharmaceutical processes. 
The presence of viable particles (living organisms) within the particle count 
achieved by applying methods described in the standard may affect the product 
within the facility. A measure of both viable and nonviable particles is required to 
provide suffi cient information upon which to base a decision regarding the suitability 
of the clean room for its intended purpose. 
The options presented herein are intended to provide facilities that will effectively 
restrict both viable and nonviable particles from entering the clean areas, 
minimize contamination introduced by the facility itself, and continuously remove 
contaminants generated during normal operations. 
Measurement of total particle count in the clean room is described in ISO 14644. 
This count may be composed of viable, nonviable, or nonviable host particles with 
a viable traveler. There is no generally accepted relationship between total particle 

208 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
count and viable particle count. While maintaining appropriate particle counts is 
important in clean - room design and operation, a protocol designed to identify viable 
particles should be inherent in the certifi cation/validation testing of a pharmaceutical 
clean room. 
No facility design can compensate for excessive contamination generated within 
it. In addition to effective facility design, the user must also institute a routine maintenance 
program as well as maintain personnel and operational disciplines that limit 
particles both entering and being generated within the facility. 
While this section identifi es options for contamination control in facility design, 
any such options must be implemented in accordance with all appropriate government 
and regulatory building and safety codes. The design guideline is nonspecifi c 
as regards biological or chemical materials that may be used within the facility but 
generally addresses bulk pharmaceutical chemical plants (BPCs), secondary manufacturing 
chemical plants, bulk biopharmaceutical plants, and plants used for fi ll and 
fi nish operations. Good practice as well as any regulations governing biological and 
pharmaceutical processes conducted within the facility must be adhered to as 
required and could modify some of the suggestions contained herein. 
3.3.3.2 Design Parameters 
The design of the facility is based upon specifi cation of certain design parameters. 
These in turn are used to calculate building system equipment capacities and aid in 
the selection of the appropriate types of equipment that are required. Design 
parameters that may be critical are discussed below. 
Cleanliness Classifi cation The classifi cation of the clean areas is determined by 
the using organization consistent with the level of nonviable and viable particulate 
contamination acceptable to the process conducted within the facility. This may be 
governed by regulatory agencies, client organizations, or company protocols. Target 
goals are set for nonviable particle count in accordance with the ISO. Viable particle 
target goals should be stated in colony - forming units (CFU) per square centimeter. 
In accordance with ISO 14644, particle goals will typically be identifi ed for “ at rest ” 
and “ operational ” modes. 
In the absence of other guidance governing the cleanliness classifi cation and 
acceptable levels of microbial contamination of the clean room, the values presented 
in Table 1 may be used. The room grades presented are from most critical 
(A) to least critical (E). The defi nition of criticality is left to the clean - room user 
organization. 
Other Design Parameters Facility design parameters that support the process 
within the clean room should be established by the user organization. Parameters 
such as temperature, humidity, lighting requirements, sound level, and/or vibration 
may be process driven or comfort driven and therefore are selected to accommodate 
specifi c process or comfort requirements as determined by the end user. 
Local Control Under some circumstances, cleanliness requirements can be 
achieved through the use of localized controls such as clean tents, glove boxes, 
minienvironments, or isolators. These provide unidirectional fi ltered airfl ow within 

DESIGN OPTIONS 209 
a limited area. They may be located within a facility that provides the necessary 
temperature and humidity conditions or they may be provided with integral environmental 
control equipment designed to maintain necessary conditions. 
Air Change Rate The airfl ow pattern and air change rate in a clean room largely 
determines the class of cleanliness that can be maintained during a given operation. 
Non - unidirectional fl ow clean rooms rely on air dilution as well as a general ceiling - 
to - fl oor airfl ow pattern to continuously remove contaminants generated within the 
room. Unidirectional fl ow is more effective in continuously sweeping particles from 
the air due to the piston effect created by the uniform air velocity. The desired air 
change rate is determined based on the cleanliness class of the room and the density 
of operations expected in the room. An air change rate of 10 – 25 per hour is common 
for a large, low - density ISO 8 (Class 100,000) clean room. ISO 7 (Class 10,000) clean 
rooms typically require 40 – 60 air changes per hour. In unidirectional fl ow clean 
rooms, the air change rate is generally not used as the measure of airfl ow but rather 
the average clean - room air velocity is the specifi ed criterion. The average velocity 
in a typical ISO 5 (Class 100) clean room will be 70 – 90 ft/min. A tolerance of plus 
or minus 20% of design airfl ow is usually acceptable in the clean room. The foregoing 
values have been found to be appropriate in many facilities. Generally air change 
rate or air velocity is not a part of regulations. It is left to the user to demonstrate 
that the selected design parameter is appropriate for the products being manufactured. 
An exception to this may be in the case of fi lling operations where a unidirectional 
fl ow velocity of 90 ± 20 ft/min may be required. 
Pressurization A pressure differential should be maintained between adjacent 
areas, with the cleaner area having the higher pressure. This will minimize infi ltration 
of external contamination through leaks and during the opening and closing of 
personnel doors. A minimum overpressure between clean areas of 5 Pa [0.02 in. of 
TABLE 1 An Example of Cleanliness Classifi cation Goals 
Room 
Grade 
Cleanliness 
Class a 
Particle Counts e Microbial Contamination 
At Rest Operational 
Air 
Sample 
Settle 
Plates 
Contact 
Plates 
Glove 
Print 
(cfu/m 3 ) (cfu/4 h) b (cfu/plate) c (cfu/glove) d 
A f M3.5 (100) 3,500 3,500 < 1 < 1 < 1 < 1 
B g M3.5 (100) 3,500 35,000 10 5 5 5 
C M5.5 (10000) 350,000 3,500,000 100 50 25 — 
D M6.5 (100000) 3,500,000 N/A 200 100 50 — 
E Uncontrolled N/A N/A N/A N/A N/A N/A 
a In accordance with U.S. Federal Standard 209E. 
b 90 - mm - diameter settling plate. These are average values and individual plates may have < 4 h of exposure. 
c 55 - mm contact plates. 
d Five - fi ngered glove. 
e Maximum particle counts per cubic meter > 0.5 . m. 
f Unidirectional airfl ow at 90 ft/min. 
g Non - unidirectional airfl ow. 

210 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
water column (in. WC)] is recommended. The pressure between a clean area and 
an adjacent unclean area should be 12 – 14 Pa (0.05 in. WC). Where several clean 
rooms of varying levels of cleanliness are joined as one complex, a positive - pressure 
hierarchy of cleanliness levels should be maintained, including air locks and gowning 
rooms. Note that for certain processes and products it may be desirable to have a 
negative pressure relative to the surrounding ambient in one or more rooms when 
containment is a major concern. A “ room within a room ” may have to be designed 
to achieve this negative pressure yet still meet the needs of clean operation. 
Temperature Control Where occupant comfort is the main concern, a temperature 
of 68 – 70 ° F ± 2 ° F will usually provide a comfortable environment for people wearing 
a typical lab coat. Where a full “ bunny suit ” or protective attire is to be worn, room 
temperature as low as 66 ° F may be required. If the temperature is to be controlled 
in response to process concerns, the value and tolerance should be specifi ed early 
in the design phase to ensure that system selection is appropriate and that budgeting 
is accurate. Note that a tight tolerance (e.g., ± 1 ° F or less) will typically be more 
costly to maintain than a less stringent tolerance. 
Humidity Control The humidity requirement for comfort is in the range of 30 – 
60% relative humidity (RH). If process concerns suggest another value, it should 
be specifi ed as soon as possible in the design process. Biopharmaceutical materials 
sensitive to humidity variations or excessively high or low values may require stringent 
controls. 
3.3.3.3 Architectural Design Issues 
Facility Layout The facility layout should support the process contained within 
the clean room. While a rectangular shape is easiest to accommodate, other shapes 
may be incorporated into the facility as long as appropriate attention is paid to 
airfl ow patterns. The facility should be able to accommodate movement of equipment, 
material, and personnel into and out of the clean room. The layout of the 
clean suite should facilitate maintaining cleanliness class, pressure differentials, and 
temperature/humidity conditions by isolating critical spaces and by excluding nonclean 
operations. See Figure 1 . The potential for cross - contamination is addressed 
as both an architectural and a mechanical issue. Generally, in a facility where multiple 
products are to be processed, each product has a dedicated space, isolated 
physically from adjacent spaces, and each has its own air conditioning system, independent 
of adjacent systems. 
Air Locks or Anteroom This is a room between the clean room and an unrated 
or less clean area surrounding the clean room or between two rooms of differing 
cleanliness class. The purpose of the room is to maintain pressurization differentials 
between spaces of different cleanliness class while still permitting movement 
between the spaces. An air lock can serve as a gowning area. Certain air locks may 
be designated as an equipment or material air lock and provide a space to remove 
packaging material and/or to clean equipment or materials before they are introduced 
into the clean room. Interlocks are recommended for air lock door sets to 
prevent opening of both doors simultaneously. The air lock is intended to separate 
the clean from the unclean areas. 

DESIGN OPTIONS 211 
Prior to equipment or raw materials being introduced into the clean room, they 
should be prepared. This may mean removing an outer package wrap or perhaps 
surface cleaning of the object. Material handling equipment used within the clean 
room should be dedicated to the clean room. Physical barriers may be integrated 
into the material air lock design to prevent material handling equipment from 
leaving the clean room or outside equipment from passing into the clean room. 
Windows Windows are recommended in interior clean - room walls to facilitate 
supervision and for safety, unless prohibited by the facility protocol for visual security 
reasons. Windows in exterior building walls adjacent to a clean space are problematic. 
Windows can be a source of leakage and can result in contaminants entering 
the space. Windows should be placed to permit viewing of operations in order to 
minimize the need for non - clean - room personnel to enter the clean room. Windows 
should be impact - resistant glass or acrylic, fully glazed, installed in a manner that 
eliminates or minimizes a ledge within the clean space. Double glazing is frequently 
used to provide a fl ush surface on both sides of the wall containing the window. 
Windows may be included if there is a public relations requirement for visitors to 
view the operations. Speaking diaphragms or fl ush, wall - mounted, intercom systems 
are recommended near all windows to facilitate communication with occupants of 
the clean room. 
Pass - Through A pass - through air lock should be provided for the transfer of 
product or materials from uncontrolled areas into the clean room or between areas 
of different cleanliness class (Figure 2 ). The pass - through may include a speaking 
diaphragm, intercom, or telephone for communication when items are transferred 
and interlocks to prevent both doors from being opened at the same time. A cart - 
size pass - through installed at fl oor level can be used to simplify the movement 
of carts between clean areas. Stainless steel is typically the material of choice 
(Figure 3 ). 
FIGURE 1 Sample clean - room lay - out. 
Bench 
Emergency exit 
Main clean room 
Material 
air lock 
Window wall 
(Eg. 4' wide x 3' high x no. of windows) 
Gowning 
room 
Personal 
Locker 
Area 
Air lock 
Clean-room 
entrance 
Clean-room 
exit 
Pass-thru 
window 
Clean 
Garment 
Storage 
Soiled 
Garment 
Disposal 
Pass-thru 
window

212 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
Gowning Room Gowning rooms should be designed to support the garment protocol 
established for the facility. A typical gowning room may have a wall - or fl oor - 
mounted coat rack for clean garment storage (Figure 4 ); a bench specifi cally designed 
for clean - room use (Figure 5 ); a full - length mirror installed near the door for 
gowning self - inspection; storage for new packaged garments; and bins for disposal 
of soiled garments. 
Personal lockers and coat racks for the storage of notebooks, coats, and personal 
items should be located outside the gowning room or in an anteroom separate from 
FIGURE 2 Stainless steel pass - through with interlock designed to permit safe passage of 
small items between spaces of differing cleanliness. ( Courtesy of Terra Universal. ) 
FIGURE 3 Cart pass - through enabling larger amounts and sizes of items to be transported. 
Note that the cart shown is not to be taken from the clean room. Typically a physical barrier 
is incorporated into the cart pass - through design. ( Courtesy of Terra Universal. )

DESIGN OPTIONS 213 
the clean gowning area. Restroom facilities may also be located outside the gowning 
room or in an anteroom adjacent to the clean gowning area. A common gowning 
room design has two areas divided by a bench. The “ unclean ” area is used to remove 
and store outer garments. Stepping over the bench as the clean - room footwear is 
being put on ensures that the “ clean ” side of the gowning room will remain that 
way. Final donning of the clean - room garb is then accomplished. 
FIGURE 4 Furnishings in the gowning room are typically of a nonshedding material such 
as the stainless steel designs shown. The gown rack will generally have a ceiling - mounted 
HEPA fi lter above it to continually bathe the garments in clean air. ( Courtesy of Terra 
Universal. ) 
FIGURE 5 The stainless steel clean benches have has a perforated seat to permit airfl ow 
from ceiling to fl oor essentially unobstructed. ( Courtesy of Terra Universal. )

214 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
Male and female gowning rooms may be required depending on the make - up of 
the work force and the type of garments being used. 
Siting A clean room that serves as an element of a larger process line should be 
integrated into the line to permit movement of personnel and materials in and out 
of the room. A free - standing clean room may be located in any convenient site; 
however, certain conditions adjacent to the facility may degrade its performance. 
Vibration sources inside or near a clean room will encourage particle release within 
the room and under severe conditions may cause leaks in fi lters and ductwork. 
Heavy equipment, including the heating, ventilation, and air conditioning (HVAC) 
system components, pumps, house and vacuum system, ought to be vibration isolated. 
Location of a clean room directly adjacent to heavy equipment or loading 
docks that see heavy truck traffi c and other sources of vibration, shock, and noise 
may be problematic. The outdoor air intake for the clean - room makeup air must be 
carefully located to prevent overloading of fi lters or entrance of contaminating gases 
that the fi lter will not remove. Clean - room air intakes should not be located near 
loading docks, traffi c lanes, or other areas where vehicles may drive through or idle. 
These intakes should not be located near the exhaust locations of other processing 
facilities. Use of gas - phase fi ltration may be required if the quality of make - up air 
is not acceptable. 
3.3.3.4 Materials of Construction 
Walls Generally wall material selection should be based on the operations and 
material handling equipment to be used within the space. The walls should be 
strong enough to withstand repeated impact of carts or other equipment without 
deterioration. The materials should also be selected with the sanitizing protocol 
in mind. Chemicals, high - pressure wash, and steam can cause reduced wall life if 
proper materials are not selected. Seamless walls, to the extent possible, are 
desirable. 
Basic steel stud construction with gypsum board paneling can be used in biopharmaceutical 
clean rooms when appropriately coated with a nonshedding fi nish. 
Modular wall systems utilizing coated steel or aluminum panel construction are 
growing in popularity due to the ability to easily retrofi t a lab or production space 
at a later date with minimal disruption and construction debris. Stainless steel may 
be appropriate but costly. Modular systems have been developed that address the 
concerns of the biopharmaceutical clean - room user relative to surface fi nish integrity 
and smooth surfaces. The joint between adjacent modular panels is commonly 
treated with a gunnable sealant to provide a smooth, cleanable joint that will not 
hold contaminants. 
Concrete masonry unit (CMU) construction is widely used (Figure 6 ). It can 
prevent buildup of contaminants when fi nished with an epoxy or other smooth, 
chemical - resistant coating. Where retrofi t is not a regular practice, the strength of 
concrete block and its long life recommend it. 
Rounded, easy - to - clean corners and smooth transitions between architectural 
features such as windows and walls (Figure 7 ) should be featured in all wall system 
designs, whether modular or “ stick built. ” 

DESIGN OPTIONS 215 
Wall Finishes Inexpensive latex wall paints will deteriorate over time and are unacceptable 
in clean rooms. Acceptable wall fi nishes include epoxy paint, polyurethane, 
or baked enamel of a semigloss or gloss type. These may be applied in the factory to 
metal wall system panels. Field application of epoxy to gypsum board or CMU should 
be done to ensure a smooth, nonporous, monolithic surface that will not provide a 
breeding site for organisms. Exposed outside corners in high traffi c areas as well as 
on lower wall surfaces may have stainless steel facings or guards to prevent impact 
FIGURE 6 A CMU wall treated with block fi ller and epoxy fi nish to provide a smooth, 
cleanable wall surface. ( Courtesy of Niagara Walls. ) 
FIGURE 7 A window detail that provides a smooth, easy - to - clean surface on both wall 
faces. ( Courtesy of Portafab. ) 

216 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
damage to the wall. This is particularly true when gypsum board construction is used. 
Corner and wall guards should extend from the fl oor to at least the 4 - ft height. Traditionally 
the clean room has been white throughout as an indication of the clean nature 
of the facility and to identify it as a special work space. Other colors may be used in 
the clean room to provide an interesting environment as long as the materials of construction 
do not contribute particles to the air stream and will withstand the sanitizing 
agents and procedures used in the facility (Figure 8 ). 
Doors Entry should be through air locks to maintain clean - room pressure differentials. 
Emergency exit doors should incorporate a panic - bar mechanism (or a 
similar emergency opening device) with alarms for exit only. Emergency exit doors 
must be secured in a manner that prevents entry from the outside yet permits exiting 
from within. All doors should include essentially air - tight seals. Neoprene seals are 
generally acceptable. Brush - type door seals are not recommended. Foam rubber 
door seals are not recommended as these have been found to quickly deteriorate 
and shed particles. All personnel doors and swinging equipment doors should 
include self - closing mechanisms. Manual and automatic sliding doors may be useful 
when space is an issue or to facilitate movement between spaces of similar cleanliness 
class for personnel whose hands are otherwise engaged. As the mechanism of 
such doors can generate particles, a design specifi cally intended for clean - room 
application should be selected. 
Ceilings The ceiling fi nish should be similar to that used on the walls. The requirements 
for sanitizing typically address the ceiling as well as the walls and ceiling 
material and fi nish selection should refl ect this. Suspended ceilings using an inverted - 
T grid and lay - in panels may have a place in that part of the clean - room suite not 
subjected to the rigors of frequent sanitizing and where the possibility of trapped 
FIGURE 8 A modular wall system has been installed in a manner that provides a smooth 
surface for cleaning. The fi t of the components and the method of sealing are important when 
a modular wall is selected. ( Courtesy of Portafab. ) 

DESIGN OPTIONS 217 
spaces to support organism growth is not considered an issue (Figure 9 ). When suspended 
panel ceilings are used, the panels must be securely clipped or sealed in 
place to prevent movement due to air pressure changes. 
Modular wall systems designed for biopharmaceutical applications frequently 
have a “ walk - on ” ceiling designed using materials and fi nish similar to the wall. A 
rounded, easy - to - clean intersection between ceiling and walls should be a feature 
of the clean - room ceiling design, whether modular or stick built. Monolithic (seamless) 
ceilings can be installed using inverted - T grid supports and gypsum panels 
(Figure 10 ). This design permits incorporation of fi ltration and lighting into what is 
essentially a monolithic ceiling. 
FIGURE 9 A suspended ceiling utilizing lay - in panels and lay - in lighting troffers. A variety 
of cleanable materials can be used for the panels. The lay - in lights should be of 
a design that will provide appropriate service based on the cleaning protocol to be used. 
( Courtesy of CleanTek. ) 
FIGURE 10 An area of HEPA fi lters is installed above a process machining. Tear drop 
lighting is used to permit maximum fi lter coverage. A monolithic ceiling construction of 
gypsum panels suspended from a framework. The panels are fi nished with an epoxy coating 
compatible with cleaning/sterilization procedures. ( Courtesy of CleanTek. ) 

218 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
Floors Commonly used fl oor fi nishes for biopharmaceutical clean rooms include 
sheet vinyl installed using heat - welded or chemically fused seams to provide a seamless 
surface. Troweled epoxy and epoxy paint (Figure 11 ) have also found wide use. 
Compatibility of the fl oor material with solvents, chemicals, and cleaning agents to 
be used in the room must be considered. A minimum 4 - in. cove at the junction of 
fl oor and walls is recommended to facilitate cleaning. Some modular wall systems 
have a recess or offset that permits sheet vinyl to be installed in a manner that 
creates a seamless junction between fl oor and wall. When a stick - built approach is 
used, care should be taken to design cleanable intersections of walls and fl oors 
(Figure 12 ). 
3.3.3.5 HVAC System 
Air Side The clean - room HVAC system must be designed to maintain the required 
particulate cleanliness, temperature, humidity, and positive pressure at the expected 
outside environmental extremes and during the expected worst - case use operations. 
Rapid recovery from upset conditions such as door openings and contaminant - 
generating events is also a consideration. The high cost of conditioning outside air 
suggests that as much air as possible be recirculated. Recirculated air should be 
high - effi ciency particulate air (HEPA) fi ltered in those spaces requiring a cleanliness 
classifi cation in accordance with ISO 14644. Air that may be hazardous to 
health, even after HEPA fi ltration, should be exhausted after appropriate treatment. 
The required quantity of make - up air is calculated based on process exhaust plus 
air leakage from the clean room. A rate of two air changes per hour for clean room 
pressurization may be used in the absence of a more detailed calculation of air 
FIGURE 11 The process area is subjected to substantial chemical action due to the sterilizing 
protocol. It has a troweled epoxy, easy - to - clean fi nish. ( Courtesy of Dex - O - Tex. ) 

DESIGN OPTIONS 219 
leakage. Make - up air should be drawn from the outdoors, conditioned, and fi ltered 
as necessary before being introduced into the clean - room recirculation air stream. 
Care should be taken to ensure that make - up air intakes are not drawing in contaminated 
air. 
The potential for cross - contamination is an issue that should be addressed. A 
fl exible manufacturing facility is one in which a variety of products can be manufactured 
simultaneously. If the facility has a single air - handling system, the likelihood 
of materials from one space intruding into an adjacent space is high. For this 
reason each fi lling or compounding operation, or operation where noncompatible 
product can be expected to be picked up by the air stream, should be served by its 
own air - handling system (Figure 13 ). Isolated systems will minimize the possibility 
of cross - contamination. This can be a costly option and should not be undertaken 
FIGURE 12 The wall system used in the facility incorporates a monolithic sheet vinyl fl ooring 
junction between fl oor and wall face. Note the coving run up the wall around the edges 
to provide a smooth surface for cleaning. ( Courtesy of Portafab. ) 
FIGURE 13 The air handler has several stages of fi ltration combined with heating, cooling, 
humidifi cation, and dehumidifi cation capability. ( Courtesy of Air Enterprises. ) 

220 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
lightly. The current use of the plant and the anticipated future use should be assessed 
before a blanket decision that may lead to costly duplicated systems is made. 
Filtration The fi ltration system for a biopharmaceutical clean room typically consists 
of several stages of fi lters. Prefi lters are selected, sized, and installed to maximize 
the life of the fi nal HEPA fi lters. With proper selection of prefi lters, the fi nal 
HEPA fi lters should not require replacement within the life of the fi lter media and 
seal materials, a period of several years (perhaps as long as 10 – 15 years). Make - up 
air is commonly fi ltered by a low - effi ciency [30% as set by the American Society of 
Heating, Refrigerating, and Air Conditioning Engineers (ASHRAE)] prefi lter followed 
by an intermediate - (60% ASHRAE) or high - effi ciency (95% ASHRAE) 
fi nal fi lter (Figure 14 ). A screen should be included at the make - up air inlet to keep 
out pests and large debris. The make - up air is then directed to the recirculating air 
handler which also may have a low - effi ciency prefi lter, although prefi ltration of 
recirculated clean - room air is often omitted because of its high cleanliness level 
even after having passed through the clean room. The air is then directed through 
HEPA fi lters into the clean room. HEPA fi lters must be a minimum of 99.97% effi - 
cient on 0.3 - . m particles in accordance with military standard Mil - F - 51068 or the 
Institute of Environmental Science and Technology IEST - RP - CC001. Note that the 
fi ltration system for an unrated “ controlled area ” is the same, except that the HEPA 
fi lter stage may be omitted. Refer to Figure 15 . 
Filter Location HEPA fi lters may be installed in a facility either within an air 
handler or at the inlet to a plenum above the clean room or in the clean room ceiling. 
High - velocity HEPA fi lters, that is, fi lters with a face velocity up to 500 ft/min, are 
frequently installed in air handlers serving Class 100,000 clean rooms and are also 
used in make - up air handlers. Where hazardous materials may be trapped by the 
fi lters a “ bag - in – bag - out ” fi lter arrangement, such as that depicted in Figure 16 , may 
FIGURE 14 Non - unidirectional clean - room with lay - in HEPA fi lter modules. 
Make-up air unit 
Outside 
air 
95% Prefilter 
Cooling coil 
Reheat coil 
Humidifier 
Fan 
Prefilter 
Cooling coil 
Fan 
Air handler 
30% Prefilter 
Clean room 
HEPA filter modules 
Preheat coil 
Air handler 
Prefilter 
Cooling coil 
Fan

DESIGN OPTIONS 221 
be employed. Figure 17 shows a schematic arrangement with HEPA fi lters installed 
in the air handler. During the design phase care should be taken to provide access 
to both the upstream and downstream face of these fi lters to permit periodic challenging 
and leak testing. 
To provide HEPA fi ltered air over a limited area within a larger controlled space, 
a ceiling - mounted pressure plenum may be used. This plenum has an air distribution 
means at its lower face that permits air to be introduced in a unidirectional manner 
over the critical process area. Refer to Figure 18 . 
HEPA fi lters are installed at the upper face of the pressure plenum and the 
plenum is pressurized with fi ltered air. The ceiling - mounted HEPA fi lters have a 
face velocity up to 100 – 120 ft/min. This is somewhat higher than the HEPA fi lters 
serving the rest of the clean room. The fi lters are commonly supplied with air by a 
FIGURE 15 Several panel - type fi lters commonly used as prefi lters in air handlers. Second 
from left is a high - dust - loading fi lter available in ASHRAE effi ciency as high as 95% frequently 
used in make - up air handlers. If HEPA fi ltration of the make - up air is required, the 
high - velocity duct - mounted HEPA fi lter third from the left is appropriate. It can tolerate face 
velocities up to 500 fpm, compared to the standard HEPA, which is usually designed for face 
velocity on the order of 90 – 100 fpm. A standard HEPA designed for bio - pharma facility 
ceiling installation is shown at right. ( Courtesy of of CamFil. ) 
FIGURE 16 The “ bag - in – bag - out ” fi lter unit contains a HEPA fi lter and permits personnel 
to change the fi lter without coming into contact with possibly hazardous materials that may 
have been fi ltered from the air. ( Courtesy of Flanders Filters Inc. ) 

222 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
duct distribution network consisting of rectangular or round trunk ducts and fl exible 
or rigid round branch ducts. Full coverage, typical for ISO 5 (Class 100) clean rooms, 
or partial coverage, for higher class (less stringent) clean rooms, can be accomplished 
using 2 . 4 - ft lay - in HEPA fi lter modules installed in the ceiling. 
3.3.3.6 Clean - Room Testing 
ISO 14644 describes methodology and instrumentation for particle counting in the 
clean room. The tests described there are the basis for assigning a cleanliness rating 
FIGURE 17 Non - unidirectional clean - room with air handler mounted HEPA fi lters. 
Make-up air unit 
Outside 
air 
95% Prefilter 
Cooling coil 
Reheat coil 
Humidifier 
Fan 
Prefilter 
Cooling coil 
Fan 
Air handler 
30% Prefilter 
Clean room 
Preheat coil 
Air handler 
Prefilter 
Cooling coil 
Fan 
Ceiling diffuser 
HEPA filter 
HEPA filter 
FIGURE 18 Non - unidirectional clean - room with critical area unidirectional fl ow 
plenum. 
Make-up air unit 
Outside 
air 
95% prefilter 
Cooling coil 
Reheat coil 
Humidifier 
Fan 
Prefilter
Cooling coil 
Fan 
Air handler 
30% Prefilter Preheat coil 
Air handler 
Prefilter 
Cooling coil 
Fan 
Unidirectional airflow over 
critical process machine/surface 
Standard velocity 
HEPA filters 
Pressure plenum 
Air distributor 
Clean room 
High-velocity HEPA filters

to the facility. IEST - RP - CC006 similarly provides a procedure for particle counting 
but goes beyond that to a full series of tests that can be conducted to determine the 
effectiveness of the clean - room design and operability. The determination of which 
tests should be run is up to the clean - room end user. As a minimum, particle counting, 
room pressurization, and fi lter leakage tests should be run. Other tests dealing 
with airfl ow patterns, temperature, humidity, lighting, and sound levels are available. 
The array of tests selected is determined by the owner based on the effect the 
various design parameters will have on the product. The data obtained in acceptance 
tests become baseline data against which future testing is compared to determine 
if clean - room performance is changing over time. Ongoing periodic monitoring of 
the facility will ensure that clean - room performance degradation is identifi ed as it 
occurs. Pass – fail criteria are not part of the ISO standards but are to be developed 
on a case - by - case basis by the end user of the facility. These standards become part 
of the operational protocol of the facility. 
The clean - room testing described here is part of the commissioning or validation 
process wherein all equipment in the facility is run, tested, and observed to ensure 
it is working as designed. 
3.3.3.7 Utilities 
Biopharmaceutical clean - rooms typically house process equipment requiring utilities 
such as pure water, electricity, vacuum, and clean compressed air. The source of 
these utilities is usually outside the clean room. During the design phase a utility 
matrix is developed, in conjunction with end users and equipment manufacturers, 
identifying all equipment and the utilities required. This is the basis for determining 
the capacity of the utility systems as well as the point - of - use location of specifi c 
utilities. 
When bringing the utilities to the point of use, care should be taken to ensure 
that the clean room is not compromised. A clean construction protocol should be 
implemented and wall, ceiling, and fl oor penetrations, if needed, should be fl ashed 
and sealed in such a manner as to prevent contaminants from entering the clean 
room. Such entry points should also be smoothly sealed to ensure that there are no 
crevices to harbor organisms. Drains should be avoided in the clean room wherever 
possible. When this is not possible, the drains should be covered when not in use 
with a means specifi cally designed for biopharmaceutical clean - room application. 
Such means are tight, smooth, cleanable, and corrosion resistant. 
In small facilities an individual pipeline may be run from outside the facility to 
the point of use. In large facilities a utility chase (Figure 19 ) that enables major 
utility lines to be brought to the vicinity of process tools may be provided. Final 
hook - up between the chase and point of use then becomes a relatively simple, 
minimally intrusive procedure. The utility chase concept is also benefi cial in facilities 
that undergo frequent retrofi t or upgrade. 
3.3.4 CONSTRUCTION PHASE: CLEAN BUILD PROTOCOL 
Ongoing experience has demonstrated that an aggressive clean construction protocol 
program is generally not required for biopharmaceutical facilities that do not 
CONSTRUCTION PHASE: CLEAN BUILD PROTOCOL 223

224 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
carry a cleanliness rating. Where cleanliness classifi cations less stringent than Class 
10,000 are used, standard construction techniques followed by careful cleanup and 
wipe - down within the clean space have proven quite acceptable. Cleanliness levels 
of Class 1000 or Class 10,000 are achievable shortly after startup and maintainable 
thereafter. For cleanliness levels of Class 100 a somewhat more restrictive protocol 
is required. Once a facility is up and running, any intrusion into clean areas for retrofi 
t work should be done in conjunction with some level of clean build protocol 
in place, dependent on the rating of the facility and the degree of disruption 
encountered during the retrofi t project. 
The levels of clean construction described herein can provide a practical means 
of meeting operational cleanliness goals in a cost - effective fashion. Each project, 
whether new construction or retrofi t of an existing process, should have as part of 
it an evaluation of the required elements of the build clean protocol to be employed. 
The information provided below is broad and can act as a template for the protocol 
put in place for a specifi c project. 
A key to successful clean construction is the appointment of an individual as a 
clean - room monitor who is well versed in the clean - room construction protocol. 
That person is charged with maintaining a clean environment and monitoring the 
activities of all personnel within the clean area during the construction phase and 
is concerned with maintaining budget and schedule goals. The clean - room monitor 
should have the confi dence to make “ real - world ” decisions supporting the “ spirit ” 
of the protocol as well as the “ letter. ” 
FIGURE 19 The utility chase is located between two clean rooms. Major utility lines are 
installed within the chase and hook - up lines for local pieces of process equipment are connected 
through the clean - room walls. A major benefi t of this arrangement is that installers 
need not be fully garbed in clean - room attire to access the utility lines. ( Courtesy of 
CleanTek. )

3.3.4.1 General 
All clean - facility construction, while employing standard construction techniques, 
should be accomplished in a manner that does not create excessive particulate 
contamination. A temporary lay - down area within the building adjacent to the clean 
area should be set aside for storage of clean construction components. All tools used 
for clean construction should be in an “ as - new ” condition and be cleaned and 
inspected prior to use. The pass – fail criteria for tool and material inspection is “ no 
visible dirt. ” 
Cleanup within the clean area at the end of each shift should consist of broom 
cleaning and vacuum cleaning the fl oor with a clean vacuum, that is, a vacuum with 
a HEPA fi lter (99.97% effi cient on 0.3 - . m particles). 
Clean - facility construction materials should be left in an outer shipping wrap 
until moved to the temporary lay - down area, where they should then be unwrapped 
and wiped down before being moved into the clean space. 
Adherence to these guidelines will make fi nal clean - up faster and acceptable 
start - up and certifi cation/validation more certain. While a goal of clean construction 
is rapid start - up and certifi cation/validation, a long - range goal is the maintenance 
of the facility cleanliness without intrusion, over an extended period of time, of 
contaminants deposited during construction due to a poor protocol or improper 
implementation of the protocol. 
Appendix A and Appendix B offer a template for working in a clean environment 
as well as clean - room cleaning procedures. Procedures should be modifi ed 
with caution to suit a particular project. 
3.3.4.2 Level I Clean Construction 
Level I clean construction is used for all areas with a cleanliness rating of Class 1000 
(ISO 6) or higher (less stringent), including those spaces within which clean processes 
are conducted in minienvironments/isolators and those unrated areas identi- 
fi ed as being “ controlled environments. ” 
Standard construction techniques are used until the clean - room envelope is 
completed, HEPA fi lters with protective fi lm in place are installed and air handlers 
are ready to start. The clean envelope consists of clean - room walls, ceiling, and fl oor. 
Prior to starting the air handlers, a thorough clean - up of the space within the clean 
envelope is accomplished as described in Appendix B, 2A – 2J. Following clean - up 
and start - up of the clean - space air - handling system, particle counts should quickly 
drop to well within operational requirements. 
Once the clean room is operational, as described above, additional construction 
related to process equipment installation and facility modifi cation within the clean 
room can be done in compliance with the Guidelines in Appendix A. 
3.3.4.3 Level II Clean Construction 
This is used for construction of those areas rated at Class 100 (ISO 5) employing a 
100% HEPA fi lter ceiling. Generally standard construction techniques should be 
used. The clean - room envelope includes walls, ceiling, fl oor, return ductwork, supply 
fans, and supply ductwork. 
CONSTRUCTION PHASE: CLEAN BUILD PROTOCOL 225

226 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
All ductwork sections should be cleaned and sealed with plastic wrap at the time 
of fabrication until just prior to installation or start - up to prevent contaminants from 
accumulating inside air - handling passageways. The sections of ductwork should be 
unsealed only as required for installation. Open ends of ducts and fans should 
remain sealed until connecting duct is about to be installed. A fi nal isopropyl alcohol 
(IPA) wipe - down of all interior duct sections and fan surfaces should be done 
immediately prior to installation. 
When general construction of the clean room is completed, steps 2A – 2J of 
Appendix B describing coarse cleaning can be implemented. Following coarse 
cleaning the protective fi lm can be removed from the HEPA fi lters and the air - 
handling system started. 
Successful completion of the cleaning process described above will indicate that 
installation of process equipment may begin. Note that procedures described in 
Appendix A should be followed. After installation of all process equipment or when 
the clean room is to be prepared for certifi cation, steps 2K – 2O of Appendix B for 
fi nal wipe - down can be followed. 
A black - and - white felt rub - down test is performed to demonstrate adequate 
cleanliness of the interior clean - envelope surfaces. This test consists of both black - 
and - white felt being wiped over any surface for 1 m linear distance with a fi rm hand 
pressure. No residue should be visible on the cloth. Each cloth should be 60 cm 
square black or white static - free natural fi ber felt folded with cut edges inside to a 
25 - cm square. The cut edges should be sealed with an approved latex sealant. 
3.3.5 MAINTENANCE 
To maximize the life and effectiveness of the facility, it must be maintainable. The 
facility should be designed to permit ongoing day - to - day preventive maintenance 
of the mechanical systems and, should a failure occur, permit needed repairs to be 
made in an expeditious manner. Perhaps of equal importance is the janitorial maintenance 
required to keep the facility suitable for pharmaceutical manufacturing. 
Proper janitorial maintenance begins with the design of the facility and evolves into 
an operational protocol, personnel training, and effective implementation. 
In the design phase it is important to provide suffi cient access to mechanical and 
process equipment to enable preventive maintenance procedures to be carried out 
with minimum effort. Typically manufacturer ’ s installation instructions offer guidelines 
as to how much space should be left open around equipment to permit removal 
of critical components. One driver of construction cost is fl oor space. Making a space 
as small as possible to house an operation presumably will result in fi rst - cost savings. 
If the space does not provide suffi cient access for lubrication, fi lter changes, belt 
adjustments, and the like, there is a strong possibility that this preventive maintenance 
will be ignored. A predictable result is shortened equipment life and the disappearance 
of any fi rst - cost savings that may have been realized. If there is a major 
equipment failure that requires replacement of an inaccessible component, the cost 
associated with knocking down a wall to gain equipment access will very likely 
negate fi rst - cost savings. 
Storage of maintenance items should be identifi ed early in the design process. 
Spare - parts storage, janitorial supply storage, janitors ’ sink closets, repair work shops, 

and storage space for consumable maintenance items (e.g. air fi lters) will require fl oor 
space in the facility design. Frequently tools are dedicated to the clean facility or are 
required specifi cally for unique process equipment and must also have a storage area. 
Accommodation of these items is an important part of the planning process. 
A requirement of a clean facility is that the cleaning materials should be specifi - 
cally intended for use in a “ clean ” operation, should be kept in good ( “ like new ” ) 
repair, and should not be used in other, nonclean, areas of the facility. Using general 
cleaning materials manned by the “ house ” janitorial staff will invariable introduce 
more contamination into the clean portions of the facility than it removes. 
A central housekeeping vacuum is very useful in keeping contamination under 
control. While “ wet - and - dry ” versions of the central vacuum are available, the 
manner in which each is to be used should be carefully reviewed to ensure that it 
is in keeping with the sanitary requirements of the facility. A common housekeeping 
procedure addresses spills with local clean - up and uses a dry - type central vacuum 
for dry particulate contaminants. 
APPENDIX A: GUIDELINES FOR CONSTRUCTION PERSONNEL AND 
WORK TOOLS IN A CLEAN ROOM 
1.0 General requirements 
A. Makeup will not be allowed inside the clean room. 
B. Smoking will not be allowed in or around the clean room. 
C. Tobacco chewing will not be allowed in the clean room. 
D. Paper or paper by - products will not be allowed in the clean room except 
clean - room approved paper and pens. 
E. Prints or papers will be allowed only if totally laminated in plastic and 
cleaned with isopropyl alcohol prior to entry. 
F. Lead pencils will not be allowed in the clean room. Ball point pens only. 
G. Clean - room garments, to include shoe covers, coveralls, and head cover, 
will be worn within the clean room. 
H. Clean - room garments will not be unfastened or unzipped while inside the 
clean room. 
I. No writing will be allowed on the clean - room garments. 
J. Food and drink will not be allowed in the clean room. 
K. Combing of hair will not be allowed in the clean room or gowning area. 
L. Stepping on chairs, work benches, test equipment or process equipment is 
not allowed. 
M. Damaged garments (rips, worn booties, torn gloves) will be replaced immediately. 
Do not wait for a convenient time. DO IT NOW! 
N. Tool pouches are not allowed in a clean room. 
O. All work areas and adjacent areas will be vacuumed after completion of 
work and prior to leaving the clean room. 
P. ALWAYS wash hands before entering the clean room to remove residues 
from food, smoke, and/or other sources. 
2.0 Personnel 
A. All personnel working inside a clean room will be required to follow all 
dress codes associated with the particular clean space. 
APPENDIX A 227

228 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
B. Street clothes or company uniforms will be allowed as standard undergarments 
provided they are well maintained and clean. No such garments will 
be allowed that are soiled with grease, dirt, or any detectable stains. 
C. Any garments producing excessive fi bers (such as fuzzy sweaters) will not 
be allowed as an undergarment. 
D. Standard safety shoes (or other specifi ed footware) will be required. Shoe 
covers must be worn. 
E. Bare feet, socks, and stockings are not allowed inside booties. 
F. Coats, lunches, and private items will not be allowed inside the clean 
room. 
3.0 Gowning procedure 
A. Each individual is responsible for knowing and using the correct method 
of gowning prior to entering the clean room. (See Figure 20 .) 
1. Clean shoes prior to entering the gowning room. 
2. The order of dress should be as follows: 
a. Shoe covers 
b. Hairnet/beard cover (required after fi nal cleaning) 
c. Hood 
d. Coveralls 
e. Face cover (required after fi nal cleaning) 
f. Gloves (required after fi nal cleaning) 
B. Ensure that hoods are tucked inside neck opening of coveralls and pants 
legs are tucked and snapped inside booties. Garments are to be snapped 
FIGURE 20 Clean - room garments are intended to keep contaminants from entering the 
clean room. In a critical environment the “ bunny suit ” shown may be required. In a less critical 
environment a lab coat may suffi ce. The clean - room construction protocol should identify 
the type of garment that will be required at various stages of construction and for process 
equipment installation. ( Courtesy of Terra Universal. )

closed at the neck, wrist and ankle opening and sleeves tucked inside 
gloves. 
C. All head hair must be covered at all times. 
D. Do not allow garments to touch the fl oor while dressing or undressing. 
E. Avoid leaning on walls, lockers, or other personnel at all times. DO NOT 
place feet on benches. 
F. The order of undress should be as follows: 
1. Gloves 
2. Coveralls 
3. Face cover and hood 
4. Shoe covers 
G. If you will be reentering the clean room, unsoiled garments may be hung 
for reuse; gloves are not to be reused. 
4.0 Work tools, parts, and equipment 
A. All tools and equipment used in a clean room should be in like - new 
condition. 
B. All parts will be removed from their shipping container prior to cleaning 
and introduction into the clean room. NO PAPER PRODUCTS will be 
allowed inside the clean room. 
C. All tools, parts, and equipment will be properly cleaned prior to entering 
the clean room. Minimum cleaning should be a total wipe - down with isopropyl 
alcohol, using certifi ed clean - room wipes, to assure that the last wipe 
does not leave visible residue on the wipe. Parts should be blown off 
outside the clean room using fi ltered nitrogen when available. 
D. All parts and equipment should be sent through the equipment wipe - down 
area (material air lock) and not carried through the gowning area. 
5.0 Working in a Clean Room 
A. A major concern when working in a clean room is the generation of particles 
of the size that cannot be seen and spreading these particles throughout 
the clean room. Every possible precaution must be taken to contain 
these contaminants and protect the clean - room environment. Everything 
that is done as a standard operation must be analyzed to determine if it 
will adversely affect the cleanroom. If you have any concerns, ask the clean - 
room monitor before you damage the environment and incur unnecessary 
clean - up cost. 
B. All procedures must be reviewed with the clean - room monitor to ensure 
compliance with clean - room operation practices. All procedures that can 
generate particles should be done outside the clean - room whenever possible. 
In the listing below all prohibited procedures are subject to review 
by the clean - room monitor. The intent is to get the job done; however, some 
preplanning with the clean - room monitor can result in a positive result and 
a clean facility. 
1. Drilling: 
a. All power drills will be wrapped to encapsulate any contamination 
generated during operation. 
b. Drills may be operated in sealed enclosures equipped with an exhaust 
vacuum. 
APPENDIX A 229

230 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
c. Surface to be drilled will be tented or vacuumed to prevent the 
spread of contamination. 
2. Grinding: NO GRINDING will be allowed in the clean room. 
3. Welding: NO WELDING will be allowed inside the clean room. 
4. Soldering: May be allowed after total review. 
5. Painting: NO PAINTING will be allowed after the start - up of the clean 
room. 
6. Sanding/fi ling: Will be allowed only within a properly tented space. 
7. Cutting: Will be allowed with clean - room approved vacuums removing 
particles created. 
APPENDIX B: CLEANING THE CLEANROOM 
1.0 Final cleaning: During this cleaning phase, the clean - room proper should be 
prepared for certifi cation to the appropriate cleanliness level. Extreme care 
must be exercised by all those involved in this procedure to minimize the 
potential for contamination. 
2.0 Procedure 
A. Secure the entrance to the clean space “ envelope, ” the gowning area, and 
the entrance from the gowning room to the clean room with locks or 
limited access via card keys. Post a restriction notice: YOU ARE ENTERING 
A CONTROLLED, PARTICULATE - FREE ENVIRONMENT, 
CONTACT ____________ FOR PERMISSION TO ENTER. 
B. Perform two coarse cleanings of the clean room. Each cleaning should 
include the following: 
1. Wipe - down of the HEPA fi lter grid, all lights, walls, fl oors, windows, and 
all exposed interior surfaces. This will include any outlet boxes or fl oor/ 
wall recesses. 
2. Wipe - down should be by clean potable water and mild nonphosphate 
detergent using clean, lint - free cloths approved by the clean - room 
monitor. 
3. A second wash - down should commence using clean potable water in 
the same manner. 
4. Floors should be scrubbed and polished using a fl oor - polishing machine. 
No wax is to be used. 
C. Partitions and fl oors should be washed to maintain a dust - free condition. 
D. Access into the clean room should be restricted to discourage infi ltration 
of outside particulates. 
E. Tacky mats 3 ft by 6 ft should be installed inside the entrance of the gowning 
area as well as at the entrance to the clean room. 
F. Foot covers should be worn by all personnel entering the clean room after 
the second coarse cleaning is complete. 
G. Caulking crew should be assigned and commence work after the second 
coarse cleaning is completed. They should complete all caulking as required 
by specifi cation. 
H. Simultaneously with the caulking procedure, air handlers and associated 
ducts and plenums should be checked for cleanliness. 

I. The HEPA fi lter protective fi lm should be removed. Air - handling equipment 
should be activated and the clean space pressurized to maintain a 
positive static pressure. 
J. From this point forward, clean - room garments and head covers should be 
worn by all personnel entering the clean space. 
K. Commence with the fi rst of two fi nal wipe - downs. Nonshedding clean - 
room wipes (saturated with isopropyl alcohol) or tacky wipes should be 
used. All exposed surfaces should be wiped. 
L. A particle counter should be installed in the clean space and samples taken 
at several control points over the next 48 hours. A steady decrease in the 
particle count over time should be achieved. 
M. If particle counts stabilize at a level above that desired, a search for fi lter 
leakage will be required. 
N. If the search for fi lter leakage fails to fi nd a leak, the entire area should be 
recleaned as described for the fi nal wipe - down. 
O. Once the air standards are achieved, fi nal air balance can begin followed 
by clean - room certifi cation testing. 
BIBLIOGRAPHY 
U . S . Food and Drug Administration, Washington, DC 
21 CFR Part 210, Current good manufacturing practice in manufacturing, processing, packing, 
or holding of drugs. 
21 CFR Part 211, Current good manufacturing practice for fi nished pharmaceuticals. 
Institute of Environmental Sciences and Technology, Rolling Meadows, IL 
IEST - RP - CC001.4: HEPA and ULPA Filters , Nov. 7, 2005 . 
IEST - RP - CC002.2: Unidirectional Flow Clean - Air Devices , Jan. 19, 1999 . 
IEST - RP - CC003.3: Garments Systems Considerations for Cleanrooms and Other Controlled 
Environments , Aug. 11, 2003 . 
IEST - RP - CC004.3: Evaluating Wiping Materials Used in Cleanrooms and Other Controlled 
Environments , Aug. 23, 2004 . 
IEST - RP - CC005.3: Gloves and Finger Cots Used in Cleanrooms and Other Controlled 
Environments , May 1, 2003 . 
IEST - RP - CC006.3: Testing Cleanrooms , Aug. 30, 2004 . 
IEST - RP - CC008 - 84: Gas - Phase Adsorber Cells , Nov. 1, 1984 . 
IEST - RP - CC012.1: Considerations in Cleanroom Design , Mar. 1, 1998 . 
IEST - RP - CC013 - 86 - T: Equipment Calibration or Validation Procedures , Nov. 1, 1986 . 
IEST - RP - CC016.2: The Rate of Deposition of Nonvolatile Residue in Cleanrooms , Nov. 15, 
2002 . 
IEST - RP - CC018.3: Cleanroom Housekeeping: Operating and Monitoring Procedures , Jan. 1, 
2002 . 
IEST - RP - CC019.1: Qualifi cations for Organizations Engaged in the Testing and Certifi cation 
of Cleanrooms and Clean - Air Devices , Jan. 23, 2006 . 
IEST - RP - CC023.2: Microorganisms in Cleanrooms , Jan. 31, 2006 . 
BIBLIOGRAPHY 231

232 CLEAN-FACILITY DESIGN, CONSTRUCTION, AND MAINTENANCE ISSUES 
IEST - RP - CC026.2: Cleanroom Operations , July 21, 2004 . 
IEST - RP - CC027.1: Personnel Practices and Procedures in Cleanrooms and Controlled Environments 
, Apr. 1, 1999 . 
IEST - RP - CC028.1: Minienvironments , Sept. 1, 2002 . 
IEST - RP - CC034.2: Hepa and ULPA Filter Leak Tests , June 23, 2005 . 
IEST - STD - CC1246D: Product Cleanliness Levels and Contamination Control Program , 
Jan. 1, 2002 . 
International Organization for Standardization ( ISO ) Standards 
ISO 14644 - 1: Classifi cation of air cleanliness. 
ISO 14644 - 2: Specifi cations for testing and monitoring to prove continued compliance. 
ISO 14644-3: Test methods. 
ISO 14644 - 4: Design, construction and start - up. 
ISO 14644 - 5: Operations. 
ISO 14644-6: Terms and defi nitions. 
ISO 14644 - 7: Separative devices (clean air hoods, gloveboxes, isolators, and 
minienvironments). 
ISO 14644 - 8: Classifi cation of airborne molecular contamination. 
ISO 14698 - 1: Bicontamination control — General principles. 
ISO 14698 - 2: Biocontamination control — Evaluation and interpretation of biocontamination 
data. 
ISO 14698 - 3: Biocontamination control — Methodology for measuring the effi ciency of processes 
of cleaning and/or disinfection of inert surfaces bearing biocontaminated wet soiling 
or biofi lms. 

NORMAL DOSAGE FORMS 
SECTION 4


235 
4.1 
SOLID DOSAGE FORMS 
Barbara R. Conway 
Aston University, Birmingham, United Kingdom 
Contents 
4.1.1 Biopharmaceutics Classifi cation System 
4.1.2 Systematic Formulation Development 
4.1.3 Standard and Compressed Tablets 
4.1.4 Excipients in Solid Does Formulations 
4.1.4.1 Diluents 
4.1.4.2 Binders 
4.1.4.3 Lubricants 
4.1.4.4 Glidants and antiadherents 
4.1.4.5 Disintegrants 
4.1.4.6 Superdisintegrants 
4.1.4.7 Added Functionality Excipients 
4.1.4.8 Colorants 
4.1.4.9 Interactions and Safety of Excipients 
4.1.5 Coated Tablets 
4.1.5.1 Sugar - Coated Tablets 
4.1.5.2 Compression Coating and Layered Tablets 
4.1.5.3 Film - Coated Tablets 
4.1.5.4 Tablet Wrapping or Enrobing 
4.1.6 Hard and soft gelatin capsules 
4.1.6.1 Hard - Shell Gelatin Capsules 
4.1.6.2 Manufacture of Hard Gelatin Shells 
4.1.6.3 Hard Gelatin Capsule Filling 
4.1.6.4 Soft Gelatin Capsules 
4.1.6.5 Manufacture of Soft Gelatin Capsules 
4.1.6.6 Dissolution Testing of Capsules 
4.1.7 Effervescent Tablets 
4.1.7.1 Manufacture of Effervescent Tablets 
4.1.8 Lozenges 
4.1.8.1 Chewable Lozenges 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

236 SOLID DOSAGE FORMS 
4.1.9 Chewable Tablets 
4.1.9.1 Testing of Chewable Tablets 
4.1.10 Chewing Gums 
4.1.10.1 Composition of Chewing Gum 
4.1.10.2 Manufacture of Chewing Gum 
4.1.10.3 Drug Release from Chewing Gums 
4.1.10.4 Applications for Chewing Gums 
4.1.11 Orally Disintegrating Tablets 
4.1.11.1 Dissolution Testing of ODTs 
4.1.12 Solid Dosage Forms for Nonoral Routes 
References 
Drug substances are most frequently administered as solid dosage formulations, 
mainly by the oral route. The drug substance ’ s physicochemical characteristics, as 
well the excipients added to the formulations, all contribute to ensuring the desired 
therapeutic activity. Tablets and capsules are the most frequently used solid dosage 
forms, have been in existence since the nineteenth century, and are unit dosage 
forms, comprising a mixture of ingredients presented in a single rigid entity, usually 
containing an accurate dose of a drug. There are other types of solid dosage forms 
designed to fulfi ll specifi c delivery requirements, but they are generally intended for 
oral administration and for systemic delivery. The major solid oral dosage form is 
the tablet, and these can range from relatively simple, single, immediate - release 
dosage forms to complex modifi ed - release systems. Tablets offer advantages for 
both patients and manufacturers (Table 1 ). Most tablets are intended to be swallowed 
whole and to rapidly disintegrate and release drug in the gastrointestinal 
tract. Tablets are classifi ed by their route of administration or their function, form, 
or manufacturing process. For example, some tablets are designed to be placed in 
the oral cavity and to dissolve there or to be chewed before swallowing, and 
there are many kinds of formulation designed for sustained or controlled release 
(Table 2 ). 
Solid dose formulations, including tablets, must have the desired release properties 
coupled with manufacturability and aesthetics and must involve rational formulation 
design. The dose of the drug and its solubility are important considerations 
TABLE 1 Advantages of Tablets as a Dosage Form 
Easy to handle 
Variety of manufacturing methods 
Can be mass produced at low cost 
Consistent quality and dosing precision 
Can be self - administered 
Enhanced mechanical, chemical, and microbiological stability compared to liquid dosage 
forms 
Tamperproof 
Lend themselves to adaptation for other profi les, e.g., coating for sustained release 

in the design of the formulation as are the type of dosage form and its method of 
preparation. 
4.1.1 BIOPHARMACEUTICS CLASSIFICATION SYSTEM 
Dissolution of the drug must occur before or on reaching the absorption site before 
absorption can occur, and generally water - soluble drugs do not exhibit formulation 
diffi culties. For poorly water - soluble drugs, the absorption rate may be dictated by 
the dissolution rate, and, if dissolution is slow, bioavailability may be compromised. 
The solubility of a drug should, therefore, be considered along with its dose when 
designing formulations, and unsuitable biopharmaceutical properties is the major 
reason for the failure of new drugs. 
In 1995, the Biopharmaceutics Classifi cation System (BCS) was devised to classify 
drugs based on their aqueous solubility and intestinal permeability [1] . According 
to the BCS, drug substances are classifi ed as follows [2] : 
Class I: high permeability, high solubility 
Class II: high permeability, low solubility 
Class III: low permeability, high solubility 
Class IV: low permeability, low solubility 
TABLE 2 Types of Solid Dosage Form 
Formulation type Description 
Immediate - release tablet/capsule Intended to release the drug immediately after 
administration 
Delayed - release tablet/capsule Drug is not released until a physical event has 
occurred, e.g., change in pH 
Sustained - release tablet/capsule Drug is released slowly over extended time 
Soluble tablets Tablet is dissolved in water prior to administration 
Dispersible tablet Tablet is added to water to form a suspension prior to 
administration 
Effervescent tablet Tablet is added to water, releasing carbon dioxide to 
form a effervescent solution 
Chewable tablet Tablet is chewed and swallowed 
Chewable gum Formulation is chewed and removed from the mouth 
after a directed time 
Buccal and sublingual tablets Tablet is placed in the oral cavity for local or systemic 
action 
Orally disintegrating tablet Tablet dissolves or disintegrates in the mouth without 
the need for water 
Lozenge Slowly dissolving tablet designed to be sucked 
Pastille Tablet comprising gelatin and glycerine designed to 
dissolve slowly in the mouth 
Hard gelatin capsule Two - piece capsule shell that can be fi lled with powder, 
granulate, semisolid or liquid 
Soft gelatin capsule (softgel) One - piece capsule containing a liquid or semisolid fi ll 
BIOPHARMACEUTICS CLASSIFICATION SYSTEM 237

238 SOLID DOSAGE FORMS 
A dose solubility volume can be defi ned for all drugs (i.e., the volume required 
to dissolve the dose). A drug substance is considered highly soluble when the highest 
dose strength is soluble in . 250 mL water over a pH range of 1 – 7.5. A drug substance 
is considered highly permeable when the extent of absorption in humans is determined 
to be . 90% of an administered dose, based on mass balance or in comparison 
to an intravenous reference dose. A drug product is considered to be rapidly dissolving 
when . 85% of the labeled amount of drug substance dissolves within 30 min 
using U.S. Pharmacopeia (USP) apparatus I or II in a volume of . 900 mL buffer 
solutions. 
It was recognized that dissolution rate has a negligible impact on bioavailability 
of highly soluble and highly permeable (BCS class I) drugs when dissolution of their 
formulation is suffi ciently rapid. As a result, various regulatory agencies including 
the U.S. Food and Drug Administration (FDA) now allow bioequivalence of formulations 
of BCS class I drugs to be demonstrated by in vitro dissolution (often 
called a biowaiver) [3] . Therefore, one of the goals of the BCS is to recommend a 
class of immediate - release (IR) solid oral dosage forms for which bioequivalence 
may be assessed based on in vitro dissolution tests. 
4.1.2 SYSTEMATIC FORMULATION DEVELOPMENT 
Systematic development approaches are needed to gather a full and detailed understanding 
of marketable formulations in order to satisfy the requirements of regulatory 
bodies and to provide a research database. Effi cient experimental design using 
in - house or commercial software packages can ensure quality while avoiding expensive 
mistakes and lost time. Information from various categories such as the properties 
of the drug substance and excipients, interactions between materials, unit 
operations, and equipment are required [4] . Design of experiments (DOE) and 
statistical analysis have been applied widely to formulation development. Using 
DOE facilitates evaluation of all formulation factors in a systematic and timely 
manner to optimize the formulation and manufacturing process. Abbreviated excipient 
evaluation techniques such as Plackett – Burman design can be applied to minimize 
the number of experiments and identify critical components or processes. 
Optimization processes can then be applied. When the formulation and manufacturing 
processes of a pharmaceutical product are optimized by a systematic approach, 
the scale - up and processes validation can be very effi cient because of the robustness 
of the formulation and manufacturing process. 
Innovations in statistical tools such as multivariate analysis, artifi cial intelligence, 
and response surface methodology have enabled rational development of formulations, 
and such methods allow formulators to identify critical variables without 
having to test each combination. 
4.1.3 STANDARD AND COMPRESSED TABLETS 
The simplest tablet formulations are uncoated products that are made by direct 
compression or compression following wet or dry granulation. They are a versatile 
drug delivery system and can be intended for local action in the gastrointestinal 

(GI) tract or for systemic effects. General design criteria for tablets are accuracy 
and uniformity of drug content, stability of the drug candidate and the formulation, 
optimal dissolution and availability for absorption (whether immediate or extended 
release), and patient acceptability in terms of organoleptic properties and appearance. 
Flocculant, low - density drugs can be diffi cult to compress and formulate into 
tablets. This is a particular issue with drugs of low potency. Also some poorly water - 
soluble, poorly permeable drugs or highly metabolized drugs cannot be given this 
way. Additionally, local irritant effects can be harmful to the mucosa of the GI 
tract. 
Tablets are a popular dosage form due to their simplicity and economy of manufacture, 
relative stability, and convenience in packaging, shipping, and storage. For 
the patient, uniformity of dose, blandness of taste, and ease of administration ensure 
their popularity. Thus, the purpose of the formulation and the identifi cation of suitable 
excipients are of primary importance in the development of a successful formulation. 
A well - designed formulation should contain, within limits, the stated 
quantity of active ingredient, and it should be capable of releasing that amount of 
drug at the intended rate and site. Tablets need to be strong enough to withstand 
the rigors of manufacture, transport, and handling, and they need to be of acceptable 
size, taste, and appearance. A typical manufacturing process for a tablet product 
includes weighing, milling, granulation and drying, blending and lubrication, compression, 
and coating. Each processing step involves several process parameters. For 
a given formulation, all processing steps should be thoroughly evaluated so that a 
robust manufacturing process can be defi ned, and DOE can be applied effectively 
to optimize this process. 
Direct compression is a simple process being more economical and less stressful 
to ingredients in terms of heat and moisture, However, there are limitations governed 
by the physical properties of the ingredients, and raw materials must be carefully 
controlled. It is diffi cult to form directly compressed tablets containing 
high - dose and poorly compactible drugs. Granulation can be employed to improve 
the compaction characteristics of the powder. Granulation can also improve fl ow 
properties and reduce the tendency for segregation of the mix due to a more even 
particle size and bulk density. Granules can be produced by either wet or dry 
methods based on the stability of the drug and excipients. 
Although the basic mechanical process of producing tablets by compression has 
not changed, there has been much work on improving tableting technology [5] . 
Understanding of the physical and mechanical properties of powders and the compaction 
process has improved and will continue to improve product design while 
increases in the speed and uniformity of action of tableting presses improve the 
process. 
4.1.4 EXCIPIENTS IN SOLID DOSE FORMULATIONS 
In addition to the active ingredients, solid oral dosage forms will also contain a range 
of substances called excipients. The role of excipients is essential in ensuring that 
the manufacturing process is successful and that the quality of the resultant formulation 
can be guaranteed. The appropriate selection of excipients and their relative 
concentrations in the formulation is critical in development of a successful product. 
EXCIPIENTS IN SOLID DOSE FORMULATIONS 239

240 SOLID DOSAGE FORMS 
Although they are often categorized as inert, preformulation studies can determine 
the infl uence of excipients on stability, bioavailability, and processability. Excipients 
are categorized into groups according to their main function, although some may 
be multifunctional, and examples of common excipients used in the manufacture of 
tablets and capsule are detailed in Table 3 . 
4.1.4.1 Diluents 
An inert substance is frequently added to increase the bulk of a tablet for processing 
and handling. The lower weight limit for formulation of a tablet is usually 50 mg. 
Ideally, diluents should be chemically inert, nonhygroscopic, and hydrophilic. Having 
an acceptable taste is important for oral formulations, and cost is always a signifi cant 
factor in excipient selection. 
Lactose is a common diluent in both tablets and capsules, and it fulfi ls most of 
these criteria but is unsuitable for those who are lactose intolerant. Various lactose 
grades are commercially available which have different physical properties such as 
particle size distribution and fl ow characteristics. This permits the selection of the 
most suitable material for a particular application. Usually, fi ne grades of lactose 
are used for preparation of tablets by wet granulation or when milling during processing 
is carried out, since the fi ne size permits better mixing with other formulation 
ingredients and facilitates more effective action of the binder [6] . 
Diluents for direct compression formulations are often subject to prior processing 
to improve fl owability and compression, for example, amorphous lactose, but 
this can contribute to reduced stability especially under high - humidity conditions 
when reversion to the crystalline form is more likely [6] . 
Microcrystalline cellulose (Avicel) is purifi ed partially depolymerized cellulose, 
prepared by treating . - cellulose with mineral acids. In addition to being used as a 
fi ller, it is also used as dry binder and disintegrant in tablet formulations. Depending 
on the preparation conditions, it can be produced with a variety of technical speci- 
fi cations depending on particle size and crystallinity. It is often used as an excipient 
in direct compression formulations but can also be incorporated as a diluent for 
tablets prepared by wet granulation, as a fi ller for capsules and for the production 
of spheres. 
TABLE 3 Excipients Used in Solid Dose Formulations 
Excipient Category Examples 
Fillers/diluents Lactose, sucrose, glucose, microcrystalline cellulose 
Binders Polyvinyl pyrrolidone, starch, gelatin, cellulose derivatives 
Lubricants Magnesium stearate, stearic acid, polyethylene glycol, sodium 
chloride 
Glidants Fine silica, talc, magnesium stearate 
Antiadherents Talc, cornstarch, sodium dodecylsulfate 
Disintegrants and 
superdisintegrants 
Starch, sodium starch glycollate, cross - linked polyvinyl pyrrolidone 
Colorants Iron oxide, natural pigments 
Flavor modifi ers Mannitol, aspartame 

Diluents, although commonly presumed inert, do have the ability to infl uence the 
stability or bioavailability of the dosage form. For example, dibasic calcium phosphate 
(both anhydrous and dihydrate forms) is the most common inorganic salt 
used as a fi ller – binder for direct compression. It is particularly useful in vitamin 
products as a source of both calcium and phosphorous. Milled material is typically 
used in wet - granulated or roller - compacted formulations. The coarse - grade material 
is typically used in direct compression formulations. It is insoluble in water, but its 
surface is alkaline and it is therefore incompatible with drugs sensitive to alkaline 
pH. Additionally, it may interfere with the absorption of tetracyclines [7] . 
4.1.4.2 Binders 
Binders (or adhesives) are added to formulations to promote cohesiveness within 
powders, thereby ensuring that the tablet remains intact after compression as well 
as improving the fl ow by forming granules. A binder should impart adequate cohesion 
without retarding disintegration or dissolution. Binders can be added either as 
a solution or as a dry powder. Binders added as dry powders are mixed with other 
powders prior to agglomeration, dissolving in water or solvent added during granulation, 
or added prior to compaction. Solution binders can be sprayed, poured, or 
mixed with the powder blend for agglomeration and are generally more effective, 
but further dry binder can be added prior to tableting. Starch, gelatin, and sugars 
are used along with gums, such as acacia and sodium alginate, and are used at concentrations 
between 2 and 10% w/w. Celluloses and polyvinyl pyrrolidone (PVP) 
are also utilized, often as dry binders. 
4.1.4.3 Lubricants 
Lubricants can reduce friction between the tablet and the die wall during compression 
and ejection by interposing an intermediate fi lm of low shear strength at the 
interface between the tablet and the die wall. The best lubricants are those with low 
shear strength but strong cohesive tendencies perpendicular to the line of shear [8] . 
The hydrophobic stearic acid and stearic acid salts, primarily magnesium stearate, 
are the most widely used and are included at concentrations less than 1% w/w in 
order to minimize any deleterious effects on disintegration or dissolution. They 
should be added after the disintegrant to avoid coating it and preferably at the fi nal 
stage prior to compression to ensure mixing time is kept to a minimum. Hydrophilic 
lubricants such as polyethylene glycols (PEGs) and lauryl sulfates can be used to 
redress the issues with dissolution but may not be as effi cient as their hydrophobic 
counterparts. 
4.1.4.4 Glidants and Antiadherents 
Like lubricants, glidants are fi ne powders and may be required for tablet compression 
at high production speeds to improve the fl ow properties of the material 
into the die or during initial compression stages. They are added in the dry state 
immediately prior to compression and, by virtue of their low adhesive potential, 
reduce the friction between particles. Colloidal silica is popular, as are starches 
and talc. 
EXCIPIENTS IN SOLID DOSE FORMULATIONS 241

242 SOLID DOSAGE FORMS 
Antiadherents can also be added to a formulation that is especially prone to 
sticking to the die surface (or picking). Water - insoluble lubricants such as magnesium 
stearate can be used as antiadherents, as can talc and starch. 
4.1.4.5 Disintegrants 
Disintegrants are added to a formulation to overcome the cohesive strength imparted 
during compression, thus facilitating break up of the formulation in the body and 
increasing the surface area for dissolution. They can be either intragranular, extragranular, 
or both, and there is still a lack of understanding concerning their precise 
mechanism of action. On contact, disintegrants can draw water into the tablet, swelling 
and forcing the tablet apart. Starch, a traditional and still widely used disintegrant, 
will swell when wet, although it has been reported that its disintegrant action 
could be due to capillary action [6] . Levels can be increased beyond the normal 5% 
w/w to 15 – 20% w/w if a rapid disintegration is required. Surfactants can also act as 
disintegrants promoting wetting of the formulation, and sodium lauryl sulfate can 
be combined with starch to increase effectiveness. 
Tablet disruption following production of carbon dioxide is another mechanism 
used to enhance disintegration. This uses a mixture of sodium bicarbonate and a 
weak acid such as citric acid or tartaric acid and is exploited for effervescent 
formulations. 
4.1.4.6 Superdisintegrants 
Compared to the more traditional starch, newer disintegrants are effective at much 
lower levels and comprise three groups: modifi ed starches, modifi ed cellulose, and 
cross - linked povidone. Their likely mechanism of action is a combination of proposed 
theories including water wicking, swelling, deformation recovery, repulsion, 
and heat of wetting [9] . Superdisintegrants are so called because of the relatively 
low levels required (2 – 4% w/w). Sodium starch glycollate (Primojel, Explotab) is 
made by cross - linking potato starch and can swell up to 12 - fold in less than 30 s. 
Crospovidone is completely insoluble in water, although it rapidly disperses and 
swells in water, but does not gel even after prolonged exposure. It rapidly exhibits 
high capillary activity and pronounced hydration capacity with little tendency to 
form gels and has a greater surface area – volume ratio compared to other disintegrants. 
Micronized versions are available to improve uniformity of mix. Croscarmellose 
sodium, a cross - linked polymer of carboxymethyl cellulose sodium is also 
insoluble in water, although it rapidly swells to 4 – 8 times its original volume on 
contact with water [6] . 
4.1.4.7 Added Functionality Excipients 
Adverse physiochemical and mechanical properties of new chemical entities prove 
challenging for formulation development. There is an increasing demand for faster 
and more effi cient production processes. Also, biotechnological developments and 
various emerging protein - based therapies are broadening the defi nition for excipient 
products. Although the description of excipients from inactive ingredients is shifting 
toward functionally active materials and will continue to grow in this area, the intro

duction of improved versions of long - existing excipients is probably the more successful 
development. New single - component and coprocessed products have been 
introduced, for example, fi ller – binders. In addition, there have been advances in the 
understanding of how such substances act and hence how they can be optimally 
designed. Excipients for use in direct compression product forms or physically or 
chemically modifi ed excipients used in relatively new drug delivery systems, such as 
patches or inhalation systems, are examples of these developments. 
4.1.4.8 Colorants 
Colorants are frequently used in uncoated tablets, coated tablets, and hard and soft 
gelatin capsules. They can mask color changes in the formulation and are used to 
provide uniqueness and identity to a commercial product. Concerns over the safety 
of coloring agents in formulations generally arise from adverse effects in food substances. 
Colorants are therefore subject to regulations not associated with other 
pharmaceutical excipients. Legislation specifi es which colorants may be used in 
medicinal products and also provides for purity specifi cations. The number of permitted 
colors has decreased in recent years, and a list of approved colorants allowed 
by regulatory bodies can vary from country to country. 
Colorants can be divided into water - soluble dyes and water - insoluble pigments. 
Some of the insoluble colors or pigments can also provide opacity to tablet coatings 
or gelatin shells, which can promote stability of light - sensitive active materials. Pigments 
such as the iron oxides, titanium dioxide, and some of the aluminum lakes 
are especially useful for this purpose. 
Water - soluble dyes are usually incorporated within the granulation process to 
ensure even distribution throughout the formulation, but there can be an uneven 
distribution due to migration of the dye during drying processes. Therefore, water - 
soluble dyes can also be adsorbed into a carrier such as starch or lactose and dry 
blended prior to the fi nal mix. Water - insoluble pigments are more popular in direct 
compression and are dry blended with the other ingredients. 
Lakes are largely water - insoluble forms of common synthetic water - soluble dyes 
and are prepared by adsorbing the sodium or potassium salt of a dye onto a very 
fi ne substrate of hydrated alumina, followed by treatment with a further soluble 
aluminum salt. The lake is then purifi ed and dried. Lakes are frequently used in 
coloring tablet coatings since they are more stable and have greater opacity than a 
water - soluble dye [6] . 
4.1.4.9 Interactions and Safety of Excipients 
Because there is such a wide selection available, rational choice of the necessary 
excipients and their concentration is required. Consideration must also be given to 
cost, reliability, availability, and international acceptability. Although generally considered 
inert, formulation incompatibility of excipients is also necessary. Lactose, 
for example, can react with primary and secondary amines via its aldehyde group 
by Maillaird condensation reaction [6] , and calcium carbonate is incompatible with 
acids due to acid – base chemical reaction and with tetracyclines due to complexation. 
Additionally, excipients can contribute to the instability of the active substance 
through moisture distribution. 
EXCIPIENTS IN SOLID DOSE FORMULATIONS 243

244 SOLID DOSAGE FORMS 
Despite the importance of drug – excipient compatibility testing, there is no generally 
accepted method available for this purpose. After identifi cation of any major 
known incompatibilities, a compatibility screen needs to be proposed. Issues such 
as sample preparation, storage conditions, and methods of analysis should be 
addressed and factorial design applied to reduce the number if tests required. 
Drug – excipient compatibility studies can be performed with minimal amounts of 
materials. Usually, small amounts of each material are weighed into a glass vial, in 
a ratio representative of the expected ratio in the formulation. The vials can be 
sealed as is or with additional water, either in an air environment or oxygen - free 
(nitrogen head space) environment, and stored in the presence or absence of ambient 
light, at various temperatures. Factorial or partial factorial design experiments can 
be set up to determine important binary and multiple component interaction factors. 
This information helps determine which excipients should be avoided and whether 
oxidation or light instability in the formulation is a consideration. Controls consisting 
of the active pharmaceutical ingredient (API) alone in the various conditions 
also should be run to determine whether the API is susceptible alone or must have 
the mediating excipient or water additives for instability. 
4.1.5 COATED TABLETS 
Tablets are often coated to protect the drug from the external environment, to mask 
bitter tastes, add mechanical strength, or to enhance ease of swallowing. A coating 
can also be used for aesthetic or commercial purposes, improving product appearance 
and identity. 
4.1.5.1 Sugar - Coated Tablets 
Sugar coating can be benefi cial in masking taste, odors, and colors. It is useful in 
protecting against oxidation, and sugar coating was once very common due to its 
aesthetic results and cheapness of materials. Use has declined in recent years due 
to the complexity of the process and skills required, but advances in technology 
have led to a resurgence in popularity. Typical excipients used are sucrose (although 
this can be substituted with low - calorie alternatives), fi llers, fl avors, fi lm formers, 
colorants, and surfactants. It is usually carried out in tumbling coating pans and 
comprises several stages. 
The fi rst sealing stage uses shellac or cellulose acetate phthalate, for example, to 
prevent moisture from reaching the tablet core. This has to be kept to a minimum 
to prevent impairment of drug release. The subcoating is an adhesive coat of gum 
(such as acacia or gelatin) and sucrose used to round off the edges, and the tablets 
can be dusted with substances such as kaolin or calcium carbonate to harden the 
coating. A smoothing coat is built up in layers using 70% v/v sucrose syrup and often 
opacifi ers such as titanium dioxide, and the tablets are dried between each application. 
A colorant is added to the fi nal few layers and followed with a fi nal polishing 
step which can make further embossing diffi cult. The coating is relatively brittle, 
prone to chipping or cracking, and there is a substantial increase in weight, up to 
50%, and size of the product. 

HARD AND SOFT GELATIN CAPSULES 245 
4.1.5.2 Compression Coating and Layered Tablets 
A coating can be applied by compression using specially designed tablet presses. 
The same process can be used to produce layered tablets which can comprise two 
or even three layers if complete separation of the ingredients is required. This 
process is used when physical separation of ingredients is desired due to incompatibility 
or to produce a repeat - action product. The formulation can also be designed 
to provide an immediate and a slow - release component. Release rates can be 
controlled by modifi cation of the geometry, the composition of the core, and the 
inclusion of a membrane layer. 
The technique involves using a preliminary compression step to produce a relatively 
soft tablet core which is then placed in a large die containing coating material. 
Further coating material is added and the content compressed. A similar light compression 
is used for the production of layers and a fi nal main compression step used 
to bind the layers together. 
4.1.5.3 Film - Coated Tablets 
Film coating, although most often applied to tablets, can also be used to coat other 
formulations including capsules. Film coating imparts the same general characteristics 
as sugar coating but weight gain is signifi cantly less (typically up to 5%), it is 
easier to automate, and it has capacity to include organic solvents if required. The 
main methods involved are modifi ed conventional coating pans, side - vented pans, 
and fl uid - bed coating. Celluloses are often used as fi lm - forming polymers, as detailed 
in Table 4 , and usually require addition of a compatible plasticizer as glass transition 
temperatures are higher than the temperatures used in the process. Polyethylene 
glycol, propylene glycol, and glycerol are commonly used, and colorants and opaci- 
fi ers can also be added to the coating solution. Specialist coatings such as Opadry 
fx and Opaglos 2 can be used to give a high gloss fi nish to improve brand identity 
and consumer recognition. 
4.1.5.4 Tablet Wrapping or Enrobing 1 
Recent innovations in tablet coating include the use of gelatin and non - animal - 
derived coatings for tablets that require formulation of a pre - formed fi lm that is 
then used to encapsulate the product (e.g., Banner ’ s Sofl et Gelcaps or Bioprogress ’ 
Nrobe technology). The coated formulations are tamper evident and can be designed 
with different colors for branding purposes. They are reported to be preferred by 
patients due to their ease of swallowing and superior taste - and odor - masking properties. 
An alternative is the Press - fi t Geltabs system, which uses a high - gloss gelatin 
capsule shell to encapsulate a denser caplet formulation. 
4.1.6 HARD AND SOFT GELATIN CAPSULES 
Capsules are solid oral dosage forms in which the drug is enclosed within a hard or 
soft shell. The shell is normally made from gelatin and results in a simple, easy - to - 
swallow formulation with no requirement for a further coating step. They can be 
1 See http://www.banpharm.com/technologiesSofl etGelcap.cfm and http://www.fmcmagenta.com/NRobe/ 
tabid/145/Default.aspx . 

246 SOLID DOSAGE FORMS 
TABLE 4 Polymers Commonly Used in Film Coating of Tablets 
Polymer Soluble in Description 
Methylcellulose (MC) Cold water, GI fl uids, 
and organic solvents 
Low - viscosity grades best for aqueous 
fi lms 
Ethylcellulose (EC) Organic solvents and 
GI fl uids (insoluble 
in water) 
Used in combination with water - 
soluble agents for immediate 
release 
Hydroxyethyl cellulose 
(HEC) 
Water and GI fl uids Similar to MC with clear solutions 
Hydroxypropyl 
cellulose (HPC) 
Cold water, GI fl uids, 
and polar solvents 
Results in a tacky coat and used in 
combination to promote adhesion 
Hydroxypropylmethyl 
cellulose (HPMC) 
Cold water, GI fl uids, 
and alcohols 
Excellent fi lm former, low - viscosity 
grades best 
Sodium carboxymethyl 
cellulose 
Water and polar 
solvents 
Cannot be used if presence of 
moisture is a problem 
Methylhydroxyethyl 
cellulose (MHEC) 
Water and GI fl uids Similar to HPMC but less soluble in 
organic solvents 
Povidone (PVP) Water, GI fl uids, 
alcohol, and 
isoproplyl alcohol 
(IPA) 
Can lead to tackiness during drying, 
often brittle and hygroscopic 
PEGs Water, GI fl uids, some 
organic solvents 
High molecular weights best for fi lm 
forming and low molecular weights 
used as plasticizer; can be waxy 
Enteric coatings such as 
poly(methacrylates) 
or cellulose acetate 
phthalate 
Soluble at elevated 
pHs 
Used for delayed - release formulations 
Source : Adapted from refs. 5 and 10 . 
either hard or soft depending on the nature of the capsule shell, with soft capsules 
possessing a fl exible, plasticized gelatin fi lm. Hard gelatin capsules are usually rigid 
two - piece capsules that are manufactured in one procedure and packed in another 
totally separate operation, whereas the formulation of soft gelatin capsules is more 
complex but all steps are integrated. 
There is a growing interest in using non - animal - derived products for formulation 
of the capsule shells to address cultural, religious, and dietary requirements. HPMC 
(e.g., V - caps, Quali - VC, Vegicaps) and pullulan shells (NPCaps) and starch are 
alternatives. 
4.1.6.1 Hard - Shell Gelatin Capsules 
Although the challenges of powder blending, homogeneity, and lubcricity exist for 
capsules as for tablets, they are generally perceived to be a more fl exible formulation 
as there is no requirement for the powders to form a robust compact. This 
means that they may also be more suitable for delivery of granular and beadlike 
formulations, fragile formulations that could be crushed by the normal compaction 
step. They are commonly employed in clinical trials due to the relative ease of blinding 
and are useful for taste masking. 

HARD AND SOFT GELATIN CAPSULES 247 
Capsules are usually more expensive dosage forms than an equivalent tablet 
formulation due to the increased cost of the shells and the slower production rates. 
Even with modern fi lling equipment, the fi lling speeds of capsule machines are much 
slower than tablet presses. However, increased costs can be offset by avoiding a 
granulation step. Capsules, although smoother and easy to swallow, also tend to be 
larger than corresponding tablet formulations, potentially leading to retention in 
the esophagus. Humidity needs to be considered during manufacture and storage, 
with moisture leading to stickiness and desiccation causing brittleness. Cross - linking 
of gelatin in the formulation can also lead to dissolution and bioavailability 
concerns. 
Capsule excipients are similar to those required for formulation of tablets and 
include diluents, binders, disintegrants, surfactants, glidants, lubricants, and dyes or 
colorants. The development of a capsule formulation follows the same principles as 
tablet development, and consideration should be given to the same BCS issues. The 
powder for encapsulation can comprise simple blends of excipients or granules 
prepared by dry granulation or wet granulation. There is a reduced requirement for 
compressibility, and often the fl ow properties are not as critical as in an equivalent 
tablet formulation. The degree of compressibility required is the major difference, 
and capsules can therefore be employed when the active ingredient does not possess 
suitable compression characteristics. 
4.1.6.2 Manufacture of Hard Gelatin Shells 
Gelatin is a generic term for a mixture of purifi ed protein fractions obtained either 
by partial acid hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B 
gelatin) of animal collagen. Type A normally originates from porcine skin while B 
is usually derived from animal bones, and they have different isoelectric points 
(7.0 – 9.0 and 4.8 – 5.0, respectively) [6] . The protein fractions consist almost entirely 
of amino acids joined together by amide linkages to form linear polymers, varying 
in molecular weight from 15,000 to 250,000. Gelatin can comprise a mixture of both 
types in order to optimize desired characteristics, with bone gelatin imparting fi rmness 
while porcine skin gelatin provides plasticity. Gelatin Bloom strength is measured 
in a Bloom gelometer, which determines the weight in grams required to 
depress a standard plunger in a 6.67% w/w gel under standard conditions. Bloom 
strength and viscosity are the major properties of interest for formulation of capsules, 
and Bloom strength of 215 – 280 is used in capsule manufacture. 
Gelatin is commonly used in foods and has global regulatory acceptability, is a 
good fi lm former, is water soluble, and generally dissolves rapidly within the body 
without imparting any lag effect on dissolution. Gelatin capsules are strong and 
robust enough to withstand the mechanical stresses involved in the automated fi lling 
and packaging procedures. 
In addition to gelatin, the shells may contain colorants, opacifi ers, and preservatives 
(often parabens esters). There are eight standard capsule sizes, and the largest 
capsule size considered suitable for oral use is size 0 (Table 5 ). 
To manufacture the shells, pairs of molds, for the body and the cap, are dipped 
into an aqueous gelatin solution (25 – 30% w/w), which is maintained at about 50 ° C 
in a jacketed heating pan. As the pins are withdrawn, they are rotated to distribute 
the gelatin evenly and blasted with cool air to set the fi lm. Drying is carried out by 

248 SOLID DOSAGE FORMS 
passing dry air over the shell as heating temperatures are limited due to the low 
melting point of gelatin. The two parts are removed from the pins, trimmed, and 
joined using a prelock mechanism. The external diameter of the body is usually 
wider at the open end than the internal diameter of the cap to ensure a tight fi t. 
They can be made self - locking by forming indentations or grooves on the inside of 
both parts so that when they are engaged, a positive interlock is formed (e.g., 
Posilok, Conicap, Loxit). 
Alternatively, they may be hermetically sealed using a band of gelatin around 
the seam between the body and the cap (Qualicaps). This can be applied without 
the application of heat and provide a tamper - evident seal. LEMS (liquid encapsulation 
microspray sealing) used in Licaps is a more elegant seal in which sealing fl uid 
(water and ethanol) is sprayed onto the joint between the cap and body of the 
capsule. This lowers the melting point of gelatin in the wetted area. Gentle heat is 
then applied which fuses the cap to the body of the Licaps capsule. The moisture 
content of manufactured shells is 15 – 18% w/w and levels below 13% will result in 
problems with the capsule fi lling machinery. Therefore, capsules are stored and fi lled 
in areas where relative humidity is controlled to between 30 and 50%. 
4.1.6.3 Hard - Gelatin Capsule Filling 
The fi lling material must be compatible with the gelatin shell and, therefore, deliquescent 
or hygroscopic materials cannot be used. Conversely, due the moisture 
content in the capsule shells, they cannot be used for moisture - sensitive drugs. All 
ingredients need to be free of even trace amounts of formaldehyde to minimize 
cross - linking of gelatin. 
Powders and granules are the most common fi lling materials for hard - shell gelatin 
capsules, although pellets, tablets, pastes, oily liquids, and nonaqueous solutions and 
suspensions have been used. Filling machines are differentiated by the way they 
measure the dose of material and range in capacity from bench - top to high - output, 
industrial, fully automated machines. Those that rely on the volume of the shell are 
known as capsule dependent, whereas capsule - independent forms measure the 
quantity to be fi lled in a separate operation. The simplest dependent method of 
fi lling is leveling where powder is transferred directly from a hopper to the capsule 
TABLE 5 Capsule Size and Corresponding Volume or 
Weight of Fill 
Size Volume (mL) Fill weight a (g) 
000 1.37 1.096 
00 0.95 0.760 
0 0.68 0.544 
1 0.50 0.400 
2 0.37 0.296 
3 0.30 0.240 
4 0.21 0.168 
5 0.13 0.104 
Source : Adapted from http://capsugel.onlinemore.info/download/ 
BAS192 - 2002.pdf . 
a Assumes a powder density of 0.8 g/cm 3 . 

HARD AND SOFT GELATIN CAPSULES 249 
body, aided by a revolving auger or vibration. Additional powder can be added to 
fi ll the space arising, and the fi ll weight depends on the bulk density of the powder 
and the degree of tamping applied. 
Most automated machinery is of the independent type and compresses a controlled 
amount of powder using a low compression force (typically 50 – 200 N ) to 
form a plug. Most are piston - tamp fi llers and are dosator or dosing disk machines. 
The powder is passed over a dosing plate containing cavities slightly smaller than 
the capsule diameter, and powder that falls into the holes is tamped by a pin to form 
a plug. This can be repeated until the cavity is full and the plugs (or slugs) are ejected 
into the capsule shells. The minimum force required to form a plug should be used 
to reduce slowing of subsequent dissolution. 
In the dosator method, the plug is formed within a tube with a movable piston 
that controls the dosing volume and applies the force to form the plug. The dose is 
controlled by the dimensions of the dosator, the position of the dosator in the 
powder bed, and the height of the powder bed. Fundamental powder properties to 
ensure even fi lling are good powder fl ow, lubricity, and compressibility. The auger 
or screw method, now largely surpassed, uses a revolving archimedian screw to feed 
powder into the capsule shell. 
A liquid fi ll can be useful when manufacturing small batches if limited quantities 
of API are available. Liquid fi lls also offer improved content uniformity for potent, 
low - dose compounds and can reduce dust - related problems arising with toxic compounds. 
Two types of liquid can be fi lled into hard gelatin capsules: nonaqueous 
solutions and suspensions or formulations that become liquid on application of heat 
or shear stress. These require hoppers with heating or stirring systems. For those 
formulations that are liquid at room temperature, the capsule shells need to be 
sealed after fi lling to prevent leakage of the contents and sticking of the shells. It is 
essential to ensure the liquid is compatible with the shell (Table 6 ). 
4.1.6.4 Soft - Gelatin Capsules 
Soft gelatin capsules are hermetically sealed one - piece capsules containing a liquid 
or a semisolid fi ll. Like liquid - fi lled hard capsules, although the drug is presented in 
a liquid formulation, it is enclosed within a solid, thus combining the attributes 
TABLE 6 Liquid Excipients Compatible with Hard 
Gelatin Capsules 
Peanut oil Paraffi n oil 
Hydrogenated peanut oil Cetyl alchohol 
Castor oil Cetostearyl alcohol 
Hydrogenated castor oil Stearyl alcohol 
Fractionated coconut oil Stearic acid 
Corn oil Beeswax 
Olive oil Silica dioxide 
Hydrogenated vegetable oil Polyethylene glycols 
Silicone oil Macrogol glycerides 
Soya oil Poloxamers 
Source : Adapted from http://www.capsugel.com/products/licaps_ 
oil_chart.php . 

250 SOLID DOSAGE FORMS 
of both. Soft gelatin capsules (softgels) offer a number of advantages including 
improved bioavailability, as the drug is presented in a solubilized form, and enhanced 
drug stability. Consumer preference regarding ease of swallowing, convenience, and 
taste can improve compliance, and they offer opportunities for product differentiation 
via color, shape, and size and product line extension. The softgels can be enteric 
coated for delayed release. They are popular for pharmaceuticals, cosmetics, and 
nutritional products, but highly water - soluble drugs and aldehydes are not suitable 
for encapsulation in softgels. Formulations are tamper evident and can be used for 
highly potent or toxic drugs. However, they do require specialist manufacture and 
incur high production costs. 
4.1.6.5 Manufacture of Soft Gelatin Capsules 
The shell is primarily composed of gelatin, plasticizer, and water (30 – 40% wet gel), 
and the fi ll can be a solution or suspension, liquid, or semisolid. The size of a softgel 
represents its nominal capacity in minims, for example, a 30 oval softgel can accommodate 
30 minims (or 1.848 cm 3 ). Glycerol is the major plasticizer used, although 
sorbitol and propylene glycol can also be used. Other excipients are dyes, pigments, 
preservatives, and fl avors. Up to 5% sugar can be added to give a chewable quality. 
Most softgels are manufactured by the process developed by Scherer [11] . The 
glycerol – gelatin solution is heated and pumped onto two chilled drums to form two 
separate ribbons (usually 0.02 – 0.04 in. thick) which form each half of the softgel. 
The ribbons are lubricated and fed into the fi lling machine, forcing the gelatin to 
adopt the contours of the die. The fi ll is manufactured in a separate process and 
pumped in, and the softgels are sealed by the application of heat and pressure. Once 
cut from the ribbon, they are tumble - dried and conditioned at 20% relative 
humidity. 
Fill solvents are selected based on a balance between adequate solubility of the 
drug and physical stability. Water - miscible solvents such as low - molecular - weight 
PEGs, polysorbates, and small amounts of propylene glycol, ethanol, and glycerin 
can be used. Water - immiscible solvents include vegetable and aromatic oils, aliphatic, 
aromatic, and chlorinated hydrocarbons, ethers, esters, and some alcohols. 
Emulsions, liquids with extremes of pH ( < 2.5 and > 7.5), and volatile components 
can cause problems with stability, and drugs that do not have adequate stability in 
the solvents can be formulated as suspensions. In these instances, the particle size 
needs to be carefully controlled and surfactants can be added to promote wetting. 
Vegicaps soft capsules from Cardinal Health are an alternative to traditional 
softgels, containing carageenan and hydroxyproyl starch. As with traditional soft 
gelatin capsules, the most important packaging and storage criterion is for adequate 
protection against extremes of relative humidity. The extent of protection required 
also depends on the fi ll formulation and on the anticipated storage conditions. 
4.1.6.6 Dissolution Testing of Capsules 
In general, capsule dosage forms tend to fl oat during dissolution testing with the 
paddle method. In such cases, it is recommended that a few turns of a wire helix 
around the capsule be used [12] . Inclusion of enzymes in the dissolution media must 
be considered on case - by - case basis. A Gelatin Capsule Working Group (including 

participants from the FDA, industry, and the USP) was formed to assess the noncompliance 
of certain gelatin capsule products with the required dissolution speci- 
fi cations and the potential implications on bioavailability [13] . The working group 
recommended the addition of a second tier to the standard USP and new drug and 
abbreviated new drug applications (NDA/ANDA) dissolution tests: the incorporation 
of enzyme (pepsin with simulated gastric fl uid and pancreatin with simulated 
intestinal fl uid) into the dissolution medium. If the drug product fails the fi rst tier 
but passes the second tier, the product ’ s performance is acceptable. The two - tier 
dissolution test is appropriate for all gelatin capsule and gelatin - coated tablets and 
the phenomenon may have little signifi cance in vivo. 
4.1.7 EFFERVESCENT TABLETS 
Effervescence is the reaction in water of acids and bases to produce carbon dioxide, 
and effervescent tablets are dissolved or dispersed in water before administration. 
Advantages of effervescent formulations over conventional formulations are that 
the drug is usually already in solution prior to ingestion and can therefore have a 
faster onset of action. Although the solution may become diluted in the GI tract, 
any precipitation should be as fi ne particles that can be readily redissolved. Variability 
in absorption can also be reduced. Formulations can be made more palatable 
and there can be improved tolerance after ingestion. Thus, the types of drugs suited 
to this formulation method are those that are diffi cult to digest or are irritant to 
mucosa. Analgesics such as paracetamol and aspirin and vitamins are common 
effervescent formulations. The inclusion of buffering agents can aid stability of pH - 
sensitive drugs. There is also the opportunity to extend market share and to deliver 
large doses of medication. 
Effervescents comprise a soluble organic acid and an alkali metal carbonate salt. 
Citric acid is most commonly used for its fl avor - enhancing properties. Malic acid 
imparts a smoother after taste and fumaric, ascorbic, adipic, and tartaric acids are 
less commonly used [14] . Sodium bicarbonate is the most common alkali, but potassium 
bicarbonate can be used if sodium levels are a potential issue with the formulation. 
Both sodium and potassium carbonate can also be employed. Other excipients 
include water - soluble binders such as dextrose or lactose, and binder levels are kept 
to a minimum to avoid retardation of disintegration. All ingredients must be anhydrous 
to prevent the components within the formulation reacting with each other 
during storage. 
Lubricants such as magnesium stearate are not used as their aqueous insolubility 
leads to cloudy solutions and extended disintegration times. Spray - dried leucine and 
PEG are water - soluble alternatives [15, 16] . Both artifi cial and natural sweeteners 
are used and an additional water - soluble fl avoring agent may also be required. If a 
surfactant is added to enhance wetting and dissolution, the addition of an antifoaming 
agent may also be considered [17] . 
4.1.7.1 Manufacture of Effervescent Tablets 
Essentially, effervescent formulations are produced in the same way as conventional 
tablets, although due to the hygroscopicity and potential onset of the effervescence 
EFFERVESCENT TABLETS 251

252 SOLID DOSAGE FORMS 
reaction in the presence of water, environmental control of relative humidity and 
water levels is of major importance during manufacture. A maximum of 25% relative 
humidity (RH) at 25 ° C is required. Closed material - handling systems can be 
used or open systems with minimum moisture content in the ventilating air. 
A dry method of granulation is preferred as no liquid is involved but may not 
always be possible. Wet granulation can be carried out under carefully controlled 
conditions using two separate granulators for the alkaline and acid components. 
Water can be added at 0.1 – 1.0% w/w, and it initiates a preeffervescent reaction. The 
cycle is stopped by drying, usually by transfer into a preheated fl uidized - bed dryer. 
Fluid - bed spray granulation is a process wherein granulation and drying are simultaneous 
and can be useful for effervescent formulations. Water (or a binder solution) is 
sprayed onto the mixture, which is suspended in a stream of hot, dry air. Organic solvents 
can also be employed for granulation avoiding the need for water and are useful 
for heat - labile formulations, although complex handling equipment is required. 
Effervescent formulations must contain less than 0.3% w/w water and are often 
quite large. Sticking due to insuffi cient lubrication can be overcome by adaptation 
of punches for external lubrication or using fl at - faced punches with disks of poly 
(tetrafl uoroethylene) (PTFE). Poor lubrication can also be the cause of poor fl ow 
characteristics, and this can be addressed by using a constant level powder feed 
system. The tablets should be stored in tightly closed containers or moisture - proof 
packs. In tube arrangements, dry air is added prior to sealing and desiccants to 
reduce enclosed moisture levels once the pack has been opened. Foil packaging 
should be heavy gauge to minimize risk of holes, and the surrounding pocket should 
be large enough to hold the tablets but minimize inclusion of air. 
In - process quality control is of major importance for these formulations as are 
stability testing and stress testing of packaging. Tablet disintegration and dissolution 
are of prime importance, and disintegration should be carried out using representative 
conditions. Hardness and friability are also important as these large tablets tend 
to chip easily. Common areas for problems are that the packaging permits entry of 
water, the seal is compromised or that the excipients can react with each other. 
4.1.8 LOZENGES 
Lozenges are tablets that dissolve or disintegrate slowly in the mouth to release 
drug into the saliva. They are easy to administer to pediatric and geriatric patients 
and are useful for extending drug form retention within the oral cavity. They usually 
contain one or more ingredient in a sweetened fl avored base. Drug delivery can be 
either for local administration in the mouth, such as anaesthetics, antiseptics, and 
antimicrobials or for systemic effects if the drug is well absorbed through the buccal 
lining or is swallowed. More traditional drugs used in this dosage form include 
phenol, sodium phenolate, benzocaine, and cetylpyridinium chloride. Decongestants 
and antitussives are in many over - the - counter (OTC) lozenge formulations, and 
there are also lozenges that contain nicotine (as bitartrate salt or as nicotine polacrilex 
resin), fl urbiprofen (Strefen), or mucin for treatment of dry mouth (A.S Saliva 
Orthana). 
Lozenges can be made by molding or by compression at high pressures, often 
following wet granulation, resulting in a mechanically strong tablet that can dissolve 

in the mouth. Compressed lozenges (or troches) differ from conventional tablets in 
that they are nonporous and do not contain disintegrant. As the formulation is 
designed to release drug slowly in the mouth, it must have a pleasant taste, smoothness, 
and mouth feel. The choice of binder, fi ller, color, and fl avor is therefore most 
important. The binder is particularly important in ensuring retardation of dissolution 
and pleasant mouth feel. Suitable binders include gelatin, guar gum, and acacia 
gum. Sugars such as sucrose, dextrose, and mannitol are preferred to lactose, and 
xylitol is often included in sugar - free formulations. In order to ensure adequate 
sweetness and taste masking, artifi cial sweeteners including aspartame, saccharin, 
and sucralose are also included subject to regulatory guidelines. 
Other variations include hard - candy - type and soft or chewable lozenges. Most 
hard - candy - type lozenges contain sugar, corn syrup, acidulant, colorant, and fl avors. 
They are made by heating sugars and other ingredients together and then pouring 
the mixture into a mold. Corn syrup combined with sucrose and dextrose can form 
an amorphous glass suitable for such formulations [18] . Colorants can be added to 
enhance product appearance or to mask products of degradation. Stability and 
compatibility with the drug must be established along with the other excipients. 
Flavors tend to be complex entities, and stability or compatibility can pose major 
formulation challenges. Acidulants such as citric and tartaric acids are often added 
to enhance fl avors, thus lowering pH of the formulation as low as 2.5 – 3.0. Addition 
of bases such as calcium carbonate, sodium bicarbonate, and magnesium trisilicate 
is common to increase pH and enhance drug stability. For example, in vivo and in 
vitro studies confi rmed that the pH of the dissolved lozenge solution was the single 
most infl uential, readily adjustable formulation parameter infl uencing the activity 
of cetylpyridinium chloride activity in candy - based lozenges [19] . The dosage form 
needs a low moisture content (0.5 – 1.5% w/w), so water is evaporated off by boiling 
the sugar mixture during the compounding process, thus limiting the process to 
nonlabile drugs, and the manufacture requires specialized candy processing facilities. 
Packaging also needs to protect the formulated product from moisture and 
ranges from individual bunch wrapping to foil wraps. 
4.1.8.1 Chewable Lozenges 
Chewable lozenges are popular with the pediatric population since they are “ gummy - 
type ” lozenges. Most formulations are based on a modifi ed suppository formula consisting 
of glycerin, gelatin, and water. These lozenges are often highly fruit - 
fl avored and may have a slightly acidic taste to cover the acrid taste associated with 
glycerin. Soft lozenges typically comprise ingredients such as PEG 1000 or 1450, or a 
sugar – acacia base. Silica gel can be added to prevent sedimentation, and again this 
dosage form requires fl avors and sweeteners to aid compliance. Soft lozenges tend to 
dissolve faster than gelatin bases and can be used if taste masking is not effective. 
4.1.9 CHEWABLE TABLETS 
Chewable tablets are designed to be mechanically disintegrated in the mouth. 
Potential advantages of chewable tablets are mainly concerning patient convenience 
and acceptance, although enhanced bioavailability is also claimed. This can be due 
CHEWABLE TABLETS 253

254 SOLID DOSAGE FORMS 
to a rapid onset of action as disintegrate is more rapid and complete compared to 
standard formulations that must disintegrate in the GI tract. The dosage form is an 
appealing alternative for pediatric and geriatric consumers. Chewable tablets also 
offer convenience for consumers, avoiding the necessity of coadministration with 
water, and creation of palatable formulations can increase compliance. Antacids and 
pediatric vitamins are often formulated as chewable tablets, but other formulations 
include antihistamines (Zyrtec), antimotility agents (Imodium Plus) and antiepileptic 
agents (Epanutin Infatabs), antibiotics (Augmentin Chewable), asthma treatments 
(Singulair), and analgesics (Motrin). 
Constraints with these systems are that many pharmaceutical actives have an 
unpleasant bitter taste that can actually reduce compliance among patients. Iron 
salts, for example, can impart a rusty taste, and some antihistamines such as promethazine 
HCl can have a bitter aftertaste. As such, active formulations require 
very effective taste - masking strategies to provide acceptable patient tolerance and 
to ensure patient adherence to their pharmaceutical regimen. 
Formulation factors governing design are similar to standard formulations (e.g., 
compactability, fl ow, etc.), but disintegrants are not included. Organoleptic properties 
are a major concern, especially in the design of products for children, and usage 
has been limited as formulators have encountered diffi culties in achieving satisfactory 
sensory characteristics. 
Certain diluents are benefi cial in the formulation of chewable tablets by compression 
such as mannitol, lactose, sucrose, and sorbitol. They can aid disintegration upon 
chewing and can help with acceptable taste and mouth feel. Mannitol, for example, 
can impart a cooling or soothing sensation. Specialist excipients with improved 
sensory components such as mouth feel and lack of grittiness have been developed 
for formulation of chewable tablets. For example, Avicel CE - 15 [a combination of 
microcrystalline cellulose (MCC) and guar gum] can reduce grittiness, leading to a 
creamier mouth feel and improved overall compatibility. 
Citric acid, grape, raspberry, lemon, and cherry fl avors are often used in chewable 
tablets and lozenges (Table 7 ). Flavoring agents are commonly volatile oils, and they 
can be dissolved in alcohol and then sprayed onto another excipient or granules. 
They are usually added immediately prior to compression to avoid loss due to their 
volatile nature. Dry fl avors have advantages in terms of stability and ease of handling 
and are formed by emulsifi cation of the fl avor into an aqueous solution of a 
carrier followed by drying, encapsulating the fl avor within the carrier. This is useful 
if the agent is prone to oxidation. Common carrier substances are acacia gum, starch, 
and maltodextrin. Sweeteners such as aspartame can also be added. Low - calorie 
and non - sugar - based excipients may present a marketing advantage. 
Issues of taste masking for chewable formulations may be addressed by coating 
in wet granulation. The granulating/coating agent should form a fl exible rather than 
TABLE 7 Flavor Groups for Taste Types 
Sweet Vanilla, grape, maple, honey 
Sour Citrus, raspberry, anise 
Salty Mixed fruit, mixed citrus, butterscotch, maple 
Bitter Licorice, coffee, mint, cherry, grapefruit 
Metallic Grape, lemon, lime 
Source : From ref. 18 . 

brittle fi lm, have no unpleasant taste of its own, not interfere with dissolution, and 
be insoluble in saliva. Microencapsulation for taste masking can be achieved by 
phase separation or coacervation and may also impart stability. The same taste - 
masking technologies may be used to encapsulate drugs for formulation into 
chewable, softchew, and fast dissolving dosage forms. Coating materials include 
carboxymethylcellulose, polyvinyl alcohol (PVA), and ethylcellulose. Xylitol is the 
sweetest sugar alcohol, and it has a high negative heat of solution, making it a good 
candidate as an excipient for chewable tablets. There are many types of compressible 
sugars today, and most of them are composed of sucrose granulated with small 
amounts of modifi ed dextrins in order to make the sucrose more compressible [20] . 
Modifi cations to sugar - based excipients such as spray - dried crystalline maltose and 
directly compressible sucrose (95% sucrose and 5% sorbitol) to facilitate direct 
compression are also aiding development in this area [21] . 
4.1.9.1 Testing of Chewable Tablets 
Dissolution testing for chewable tablets should be the same as that used for regular 
tablets [22] . This is because patients could swallow the dosage form without adequate 
chewing, in which case the drug would still need to be released to ensure 
the desired pharmacological action. However, as outlined, chewable tablets will 
typically have different excipients than standard formulations, including agents to 
either mask or add fl avor, and may undergo a different manufacturing process. 
Where applicable, test conditions would preferably be the same as used for nonchewable 
tablets of the same active pharmaceutical ingredient, but because of the 
nondisintegrating nature of the dosage form, it may be necessary to alter test 
conditions (e.g., increase the agitation rate) and specifi cations (e.g., increase the 
test duration). The reciprocating cylinder (USP apparatus 3) with the addition of 
glass beads may also provide more intensive agitation for in vitro dissolution 
testing of chewable tablets. As another option, mechanical breaking of chewable 
tablets prior to exposing the specimen to dissolution testing could be considered. 
Chewable tablets should also be evaluated for in vivo bioavailability and/or 
bioequivalence. 
Additional concerns in the testing of chewable tablets are organoleptic, chemical, 
and physical stability. As it is a critical factor in the design of such formulations, 
taste masking should be incorporated into excipient testing during preformulation 
studies. Technologies like the “ electronic tongue ” can be used to match desirable 
taste characteristics [23, 24] . 
4.1.10 CHEWING GUMS 
4.1.10.1 Composition of Chewing Gum 
Medicated chewing gums are gums made with a tasteless masticatory gum base that 
consists of natural or synthetic elastomers [25] . They include excipients such as 
fi llers, softeners, and sweetening and fl avoring agents. Natural gum bases include 
chicle and smoked natural rubber and are permitted in formulations by the FDA, 
but modern gum bases are mostly synthetic in origin and approved bases include 
CHEWING GUMS 255

256 SOLID DOSAGE FORMS 
styrene – butadiene rubber, polyethylene, and polyvinylacetate. Gum base usually 
forms about 40% of the gum, but can comprise up to 65%, and is a complex mixture, 
insoluble in saliva, comprising mainly of elastomer, plasticizers, waxes, lipids, and 
emulsifi ers (see Table 8 ). It will also contain an adjuvant such as talc to modify the 
texture of the gum and low quantities of additional excipients including colorants 
and antioxidants such as butylated hydroxyanisole. Elastomers control the gummy 
texture while the plasticizers and texture agents regulate the cohesiveness of the 
product. The lipid and waxes melt in the mouth to provide a cooling, lubricating 
feeling while the juicy feel of the gum texture is from the emulsifi ers. The choice 
and formulation of gum base will affect the release of active ingredient, and the 
texture, stability, and method of manufacture of the product. 
The remaining ingredients in the chewing gum itself include drug, sweeteners, 
softeners, and fl avoring and coloring agents. A typical chewing gum formulation is 
shown in Table 9 . The sugar is for sweetening the product while the corn syrup keeps 
the gum fresh and fl exible. Softeners or fi llers are included to help blend the ingredients 
and retain moisture. Sugar - free gum has sorbitol, mannitol, aspartame, or 
saccharin instead of sugar. Optimized chewing gum formulations will require tailoring 
for each individual product. For example, nicotine - containing gums are formulated 
with the nicotine within an ion exchange resin and pH - modifying carbonates 
and/or bicarbonates to increase the percentage of the drug in its free base form 
in saliva. 
TABLE 8 Typical Formulation of Gum Base 
Ingredient Weight (%) Example 
Elastomer 10 Styrene – butadiene rubber 
Plasticizer 30 Rosin esters 
Texture agent/fi ller 35 Calcium carbonate 
Wax 15 Paraffi n wax 
Lipid 7 Soya oil 
Emulsifi er 3 Lecithin 
Miscellaneous 1 Colorant, antioxidant 
Source : From ref. 26 . 
TABLE 9 Example Chewing Gum Formulations 
Ingredient (%) Sugar Gum Sugar - Free Gum 
Gum base 19.4 25.0 
Corn syrup 19.8 — 
Sorbitol, 70% — 15.0 
Sugar 59.7 — 
Glycerin 0.5 6.5 
Sorbitol — 52.3 
Flavor 0.6 1.2 
Source : From ref. 26 . 

4.1.10.2 Manufacture of Chewing Gum 
The majority of chewing gum delivery systems today are manufactured using conventional 
gum processes. The gum base is softened or melted and placed in a kettle 
mixer where sweeteners, syrups, active ingredients, and other excipients are added 
at a defi ned time. The gum is then sent to a series of rollers that form it into a thin, 
wide ribbon. During this process, a light coating of an antisticking agent can be 
added (e.g., magnesium stearate, calcium carbonate, or fi nely powdered sugar or 
sugar substitute). Finally, the gum is cut to the desired size and cooled at a carefully 
controlled temperature and humidity. 
As the heating process involved in conventional methods may limit the applicability 
of the process for formulation of thermally labile drugs, directly compressible, 
free - fl owing powdered gums such as Pharmagum (SPI Pharma) and MedGumBase 
(Gumbase Co) have been proposed to simplify the process. These formulations 
can be compacted into a gum tablet using a conventional tablet press and have 
the potential to simplify the manufacture, facilitating inclusion of a wider range 
of drugs. 
4.1.10.3 Drug Release from Chewing Gums 
Until recently, the release of substances from chewing gums during mastication was 
studied using a panel of tasters and chew - out studies. During the mastication process, 
the medication contained within the gum product should be released into the saliva 
and is either absorbed through the buccal mucosa or swallowed and absorbed via 
the GI tract. The need for, and value of, in vitro drug release testing is well established 
for a range of dosage forms, however, standard dissolution apparatus is not 
suitable for monitoring release of drug from chewing gums as mastication is essential 
in order to provide a renewable surface for drug release after chew action. A 
number of devices to mimic the chewing action have been reported [26 – 28] . In 2000, 
the European Pharmacopoeia produced a monograph describing a suitable apparatus 
for studying the in vitro release of drug substances from chewing gums [25] . 
The chewing machine consists of a temperature - controlled chewing chamber in 
which the gum piece is chewed by two electronically controlled horizontal pistons 
driven by compressed air. The two pistons transmit twisting and pressing forces to 
the gum while a third vertical piston operates alternately to the two horizontal 
pistons to ensure that the gum stays in the right place (see Figure 1 ). The temperature 
of the chamber can be maintained at 37 ° C ± 0.5 ° C and the chew rate varied. 
Other adjustable settings include the volume of the medium, distance between the 
jaws and the twisting movement. The European Pharmacopoeia recommends using 
20 mL of unspecifi ed buffer in a chewing chamber of 40 mL and a chew rate of 60 
strokes per minute. This apparatus has been used to study release of nicotine from 
commercial gums and directly compressible gums [26] . 
Factors affecting the release of medicament from chewing gum can be divided 
into three groups: the physicochemical properties of the drug, the gum properties, 
and chew - related factors, including rate and frequency. Drugs can be incorporated 
into gums as solids or liquids. For most pharmaceuticals, aqueous solubility of the 
drug will be a major factor affecting the release rate. In order for drugs to be 
CHEWING GUMS 257

258 SOLID DOSAGE FORMS 
released, the gum would need to become hydrated; the drugs can then dissolve and 
diffuse through the gum base under the action of chewing. 
For treatment of local conditions, a release period less than 1 h may be desirable, 
but a faster release may be required if a rapid onset of action is required for a systemically 
absorbed formulation. There are a number of strategies that can be undertaken 
in order to achieve the desired release rate. Decreasing the amount of the 
gum base will enhance the release of lipophilic drugs and addition of excipients 
designed to promote release can also be considered. Release can be sustained using, 
for example, ion exchange resins as described for nicotine - containing gums. Changes 
in gum texture as a consequence of changes in excipient levels provide a further 
challenge to controlling the release of drugs. A quantitative measure of gum texture 
during the process is possible using texture analysis techniques [26] . 
4.1.10.4 Applications for Chewing Gums 
The promotion of sugar - free gums to counteract dental caries by stimulation of 
saliva secretion has led to a more widespread use and acceptance of gums. Medicated 
gums for delivery of dental products to the oral cavity are marketed in a 
number of countries, for example, fl uoride - containing gums as an alternative to 
mouthwashes and tablets or chlorhexidine gum for treatment of gingivitis. The 
potential use of medicated chewing gums in the treatment of oral infections has also 
been reported. Gums have been prepared containing antifungal agents such as 
nystatin [29] and miconazole [30] or antibiotics, such as penicillin and metronidazole 
for the treatment of oral gingivitis [31] . 
Chewing gum is also useful as a delivery system for agents intended for systemic 
delivery. Drug that is released from the gum within the oral cavity can act locally, 
be absorbed via the buccal mucosa, or swallowed with the saliva. The buccal mucosa 
is well vascularized, and if a drug is absorbed by this route, then fi rst - pass metabolism 
could be avoided. Associated increases in bioavailability can permit the use of 
lower dosages. Like orally disintegrating tablets, chewing gum is a convenient dosage 
form; it can be administered without water and to those who have diffi culty swallowing. 
Although medicated gums are generally intended to be chewed for 10 – 
30 min and can therefore be designed for sustained release, a fast onset of action 
can result either from buccal absorption or as a consequence of the active being 
FIGURE 1 Schematic of chewing chamber of in vitro chewing apparatus [26] . 
Chewing pistons 
Base of chewing chamber 
Piston 
Chewing chamber 

already dissolved in the saliva prior to swallowing. Guidance can be given regarding 
chewing conditions (e.g., time, frequency), but factors such as the force of chewing 
and salivary fl ow will impact on drug release and the fraction of drug absorbed via 
the oral mucosa. Released drug can be swallowed with the saliva, therefore leading 
to multiple absorption sites, which can result in variable pharmacokinetics. 
Along with nicotine replacement patches, nicotine chewing gum for smoking 
cessation therapy has met with major sales success. The principal active ingredient 
of currently marketed nicotine chewing gums is nicotine polacrilex USP. The nicotine 
is loaded at approximately 18% w/w on an ion exchange resin (Amberlite 
IRP64). Recent product variations have been launched with improved fl avors such 
as mint and fruit, rather than the original peppery fl avoring, designed to reduce the 
unpleasant taste and burning sensation arising from nicotine itself and fl avored 
coated gums that are sweeter and easier to chew. 
Other applications for chewing gum formulations include delivery of antacids 
such as calcium carbonate, antiemetics for travel sickness, and vitamins and minerals. 
However, the potential for a buccal delivery, a fast onset of action, and the opportunity 
for product line extension makes it an attractive alternative delivery form for 
other applications. 
4.1.11 ORALLY DISINTEGRATING TABLETS 
The demand for fast - dissolving/disintegrating tablets or fast - melting tablets that can 
dissolve or disintegrate in the mouth has been growing particularly for those with 
diffi culty swallowing tablets such as the elderly and children. They are referred to 
using a range of terminologies: fast dissolving, orodispersible, and fast melting and 
the FDA has adopted the term orally disintegrating tablets (ODTs). Patients with 
persistent nausea or those who have little or no access to water could also benefi t 
from ODTs. Other advantages include product differentiation and market expansion, 
and applications exist in the veterinary market for oral administration to 
animals. 
Orally disintegrating tablets disintegrate and/or dissolve rapidly in the saliva 
without the need for water, within seconds to minutes. Some tablets are designed 
to dissolve rapidly in saliva, within a few seconds, and are true fast - dissolving tablets. 
Others contain agents to enhance the rate of tablet disintegration in the oral cavity 
and are more appropriately termed fast - disintegrating tablets, as they may take up 
to a minute to completely disintegrate. Increased bioavailability using such formulations 
is sometimes possible if there is suffi cient absorption via the oral cavity prior 
to swallowing [32] . However, if the amount of swallowed drug varies, there is the 
potential for inconsistent bioavailability. Patented orally disintegrating tablet technologies 
include OraSolv, DuraSolv, Zydis, FlashTab, WOWTAB, and others. They 
are generally prepared using freeze drying, compaction, or molding. Examples of 
marketed products, excipients, and technologies used are given in Table 10 . 
Platform technologies based on freeze drying include Zydis (Cardinal Health) 
and Quicksolv (Janssen Pharmaceutica). Zydis was the fi rst ODT to be successfully 
launched, and it is ideal for poorly soluble drugs. It can incorporate doses up to 
400 mg, but high loadings can extend disintegration time. The porous matrix consists 
of a network of water - soluble carriers and active ingredient. The maximum dose for 
ORALLY DISINTEGRATING TABLETS 259

260 SOLID DOSAGE FORMS 
TABLE 10 Examples of Marketed ODT Products and Technologies 
Name (Company) Examples Ingredients a Technology 
Zydis 
(Cardinal Health) 
Claritin 
Reditab 
Micronized loratadine (10 mg) , citric 
acid, gelatin, mannitol, mint fl avor 
Freeze 
drying 
Zydis 
(Cardinal Health) 
Zofran 
ODT 
Ondansetron (4 or 8 mg) , aspartame, 
gelatin, mannitol, methylparaben 
sodium, propylparaben sodium, 
strawberry fl avor 
Freeze 
drying 
Zydis 
(Cardinal Health) 
Zyprexa 
Zydis 
Olanzapine (5, 10, 15, or 20 mg) , gelatin, 
mannitol, aspartame, methylparaben 
sodium, propylparaben sodium 
Freeze 
drying 
Oralsolv 
(CIMA Labs Inc.) 
Remeron 
Soltab 
Mirtazepine (15, 30, or 45 mg) , 
aspartame, citric acid, crospovidone, 
hydroxypropyl methylcellulose, 
magnesium stearate, mannitol, 
microcrystalline cellulose, 
polymethacrylate, povidone, sodium 
bicarbonate, starch, sucrose, orange 
fl avor 
Compression 
Durasolv 
(CIMA Labs Inc.) 
Zomig ZMT Zolmitriptan (2.5 mg) , mannitol, 
microcrystalline cellulose, 
crospovidone, aspartame, sodium 
bicarbonate, citric acid, anhydrous, 
colloidal silicon dioxide, magnesium 
stearate, orange fl avor 
Compression 
WOWTAB 
(Yamanouchi 
Pharma 
Technologies, 
Inc.) 
Benadryl 
Allergy & 
Sinus 
Fastmelt 
Diphenhydramine citrate (19 mg), 
pseudoephedrine HCl (30 mg), 
aspartame, citric acid, D & C red no. 7 
calcium lake, ethylcellulose, fl avor, 
lactitol, magnesium stearate, 
mannitol, and stearic acid 
Compression 
molded 
tablet 
Flashtab 
(Prographarm/ 
Ethypharm) 
Excedrin 
Quicktabs 
Acetaminophen (500 mg), caffeine 
(65 mg) , aminoalkyl methacrylate 
copolymers, citric acid, colloidal 
silicon dioxide, crospovidone, 
distilled acetylated monoglycerides, 
ethylcellulose, fl avors, magnesium 
stearate, mannitol, methacrylester 
copolymer, polyvinyl acetate, 
povidone, propylene glycol, propyl 
gallate, silica gel, sodium lauryl 
sulfate, sucralose, talc 
Compression 
a Active ingredients appear in italics. 
water - soluble drugs is 60 mg, and particle sizes of drug and excipients should be 
below 50 . m. 
Excipients used in the formulation usually include a mixture of a water - soluble 
polymer and a crystalline sugar. Mannitol and natural polysaccharides such as gelatin 
and alginates are used. Microencapsulation and complexation with ion exchange 
resins can be combined with additional fl avors and sweeteners for taste masking of 
bitter drugs. The fairly complex nature of manufacture and scale - up contributes to 

a relatively high manufacturing cost. Manufacture comprises three stages. The production 
sequence begins with the bulk preparation of an aqueous drug solution or 
suspension and subsequent precise dosing into preformed blisters. It is the blister 
that actually forms the tablet shape and is, therefore, an integral component of the 
total product package. The second phase of manufacturing entails passing the fi lled 
blisters through a cryogenic freezing process to control the ultimate size of the ice 
crystals. This aids in ensuring porosity and the product is freeze dried. The fi nal phase 
of production involves sealing the open blisters via a heat - seal process to ensure 
stability and protect the fragile tablet during removal by the patient. 
The manufacture of Flashdose (Fuisz Technologies/Biovail) is patented as 
Shearform process and utilizes a unique spinning mechanism to produce a fl osslike 
or shear - form crystalline structure, much like cotton candy. The matrix comprises 
saccharides or polysaccharides which are subjected to simultaneous melting and 
centrifugal force and then partially recrystallized [33] . High temperatures are 
involved so the technology is only suitable for thermostable agents. Drug can then 
be incorporated, either as coated or uncoated microspheres, into the sugar and the 
formulation is compressed into a tablet. Manufacture of the microspheres is patented 
as Ceform and will help with taste masking. The fi nal product has a very high 
surface area for dissolution and it disperses and dissolves quickly once placed onto 
the tongue. Like freeze - drying processes, the manufacture is expensive and resultant 
formulations are friable and moisture sensitive, therefore requiring specialized 
packaging. 
Most commercial ODTs have been developed using mannitol as the bulk excipient 
of choice because of its extremely low hygroscopicity, excellent compatibility, 
good compressibility, better sweetness, and relatively slower dissolution kinetics. 
Although lactose also has a relatively low aqueous solubility compared with other 
excipients that have acceptable palatabilities, the dispersibility of a bulk excipient 
is more important than its aqueous solubility for a successful ODT formulation. 
Many of the initially marketed ODTs were prepared by the wet granulation of 
mannitol followed by direct compression. However, added functionality mannitols 
are now available to simplify the process of ODT manufacturing by direct 
compression. 
Direct compression is, as for normal tablets, the most straightforward process for 
manufacturing ODTs. Conventional equipment can be used and high doses can be 
incorporated. The excipients play a major role in the successful formulation and 
superdisintegrants, hydrophilic polymers, and effervescent compounds are included. 
Patented technologies include Orasolv and Durasolv (Cima Labs) and Ziplets 
(Eurand). The OraSolv technology is best described as a fast disintegrating, slightly 
effervescing tablet; the tablet matrix dissolves in less than one minute, leaving 
coated drug powder. Both the coating and the effervescence contribute to taste 
masking in OraSolv. The tablet is prepared by direct compression but at a low pressure, 
yielding a weaker and more brittle tablet in comparison with conventional 
tablets. For that reason, Cima developed a special handling and packaging system 
for OraSolv called Packsolv. Acidic compounds such as citric or fumaric acid are 
included in the formulation together with a carbonate or bicarbonate. An advantage 
that goes along with the low degree of compaction of OraSolv is that the particle 
coating used for taste masking is not compromised by fracture during processing. 
DuraSolv is Cima ’ s second - generation fast - dissolving/disintegrating tablet formulation 
and is also produced using direct compression but using higher compaction 
ORALLY DISINTEGRATING TABLETS 261

262 SOLID DOSAGE FORMS 
pressures during tableting, resulting in a stronger product. It is thus produced in a 
faster and more cost - effective manner and may not require specialized packaging. 
Large amounts of fi nely milled conventional fi llers are used (mannitol, lactose) 
while the effervescing agents are reduced. It is best suited to potent drugs, requiring 
only low doses, and the taste - masking coating can be disturbed following 
compaction. DuraSolv is currently available in two products: NuLev and Zomig 
ZMT. 
Compression following wet or dry granulation is also employed in the manufacture 
of ODTs. Patented formulations include WOWTAB and Flashtab. WOWTAB 
relies on a combination of low moldable sahharides (mannitol, glucose, sucrose) 
with a highly moldable saccharide (malitol, sorbitol, maltose) using conventional 
granulation and tableting techniques to form a tablet of suitable mechanical properties 
with desired disintegration. It is manufactured by compression of molded granules, 
can accommodate a high level of drug loading (up to 50% in some cases), and 
can be packed using conventional methodology. 
Flashtab (Ethypharm) is the technology behind Exedrin QuickTabs and uses 
swellable agents and disintegrants along with sugars and polyalcohols to achieve a 
fast dispersible formulation. The manufacture involves either wet or dry granulation 
of the excipients, blending with the active followed by direct compression. 
4.1.11.1 Dissolution Testing of ODT s 
Taste masking (drug coating) is very often an essential feature of ODTs and thus 
can also be the rate - determining mechanism for dissolution/release. If taste masking 
is not an issue, then the development of dissolution methods is comparable to the 
approach taken for conventional tablets and pharmacopeial conditions should be 
used [34] . Due to the nature of the product, the dissolution of orally disintegrating 
tablets is very fast when using USP monograph conditions, and slower paddle speeds 
can be used to obtain a profi le. Other media such as 0.1 N HCl can also be used. 
USP 2 paddle apparatus is the most suitable and common choice for orally disintegrating 
tablets, with a paddle speed of 50 rpm commonly used [34] . Faster agitation 
rates may be necessary in the case of sample mounding. The method can be applied 
to the ODTs (fi nished product) as well as to the bulk intermediate (in the case of 
coated drug powder/granulate). A potential diffi culty for in vitro dissolution testing 
may arise from fl oating particles [35] . Similarly, diffi culties can arise using USP I 
due to trapping of disintegrated fragments. 
A single - point specifi cation is considered appropriate for ODTs with fast dissolution 
properties. For ODTs that dissolve very quickly, a disintegration test may be 
used in lieu of a dissolution test if it is shown to be a good discriminating method. 
If taste masking (using a polymer coating) is a key aspect of the dosage form, a 
multipoint profi le in a neutral pH medium with early points of analysis (e.g., . 5 min) 
may be recommended [34] . 
4.1.12 SOLID DOSAGE FORMS FOR NONORAL ROUTES 
Although the majority of tablets and capsules are intended for oral delivery, there 
are a number of other delivery routes suitable for drug delivery by these formula

tions. Some buccal formulations have been discussed above, and tablets can also be 
administered via the rectal and vaginal routes for local and systemic treatment. 
Many types of product have been designed for vaginal administration with 
creams, gels, and pessaries being most popular, although powders and tablets have 
also been used. Despite the effectiveness of systemic vaginal absorption, the majority 
of products administered by this route are for the treatment of localized infections, 
especially Candida albicans , (e.g., Canestan vaginal tablets). Estradiol tablets 
(Vagifem) were also designed for delivery via vaginal route to address patient preference 
issues with vaginal creams. The formulations are administered with an applicator 
and are designed to dissolve or erode slowly in the vaginal secretions [36] . 
Bioadhesion as a means of retaining the formulation at the site of delivery is widely 
accepted to retain formulations in the buccal cavity [37] and has also been reported 
for the vaginal route [38] . An increased residence time may improve drug absorption 
by these routes. 
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, 4th ed. , Pharmaceutical Press , London . 
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Characterization and function , in Swarbrick , J. , and Boylan , J. V. , Eds., Encyclopedia of 
Pharmaceutical Technology , Vol. 3, 2nd ed. , Marcel Dekker , New York . 
10. Gibson , M. ( 2001 ), Pharmaceutical preformulation and formulation; a practical guide 
from candidate drug selection to commercial dosage form, IHS Health Group, 
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11. Stanley , J. P. ( 1986 ), Soft gelatin capsules , in Lachman , L. , Lieberman , H. A. , and 
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264 SOLID DOSAGE FORMS 
12. The United States Pharmacopeia , 26th revision, United States Pharmacopeial Convention, 
Rockville, MD, 2003 . 
13. Gelatin Capsule Working Group, Collaborative development of two - tier dissolution 
testing for gelatin capsules and gelatin - coated tablets using enzyme - containing media, 
Pharmacop. Forum , 24(5), Sept./Oct. 1998 . 
14. Lee , R. E. , Effervescent tablets. Key facts about a unique effective dosage form, Tablets 
Capsules , available: http://www.amerilabtech.com/EffervescentTablets&KeyFacts.pdf , 
accessed Aug. 6, 2004 . 
15. Rotthauser , B. , Kraus , G. , and Schmidt , P. C. ( 1998 ), Optimization of an effervescent tablet 
formulations containing spray - dried l - leucine and polyethylene glycol 6000 as lubricants 
using a central composite design , Eur. J. Pharm. Biopharm. , 46 , 85 – 94 . 
16. Stahl , H. ( 2003 ), Effervescent dosage manufacturing , Pharm. Technol. Eur. , 4 , 25 – 28 . 
17. Lindberg , N. - O. , and Hansson , H. ( 2002 ), Effervescent pharmaceuticals , in Swarbrick , J. , 
and Boylan , J. V. , Eds., Encyclopedia of Pharmaceutical Technology , Vol. 2, 2nd ed. , Marcel 
Dekker , New York . 
18. Mendes , R. W. , and Bhargava , H. ( 2002 ), Lozenges , in Swarbrick J. , and Boylan , J. V. , 
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York . 
19. Richards , R. M. E. , Xing , J. Z. , and Weir , L. F. C. ( 1996 ), The effect of formulation on the 
antimicrobial activity of cetylpyridinium chloride in candy based lozenges , Pharm. Res. , 
13 , 583 – 587 . 
20. Bolhuis , G. , and Armstrong , A. N. ( 2006 ), Excipients for direct compaction — An update , 
Pharm. Dev. Technol. , 11 , 111 – 124 . 
21. Bowe , K. E. ( 1998 ), Recent advances in sugar - based excipients , Pharm. Sci. Technol. 
Today , 1 ( 4 ), 166 – 173 . 
22. FDA guidance for industry: Bioavailability and bioequivalence studies for orally 
administered drug products — General considerations, Oct. 2000 . 
23. Murray , O. J. , Dang , W. , and Bergstrom , D. ( 2004 ), Using an electronic tongue to optimize 
taste - masking in a lyophilized orally disintegrating tablet formulation , Pharm. Technol. 
Outsourcing Res. , 42 – 52 . 
24. Zheng , J. Y. , and Keeney , M. P. ( 2004 ), Taste masking analysis in pharmaceutical formulation 
development using an electronic tongue , Int. J. Pharm. , 310 , 118 – 124 . 
25. European Pharmacopoeia , 4th ed., European Directorate for the Quality of Medicines, 
Strasbourg, 2001 . 
26. Morjaria , Y. , Irwin , W. J. , Barnett , P. X. , Chan , R. S. , and Conway , B. R. ( 2004 ), In vitro 
release of nicotine from chewing gum formulations , Dissolution Technol. , 11 , 12 – 15 . 
27. Rider , J. N. , Brunson , E. L. , Chambliss , W. G. , Cleary , R. W. , Hikal , A. H. , Rider , P. H. , 
Walker , L. A. , Wyandt , C. M. , and Jones , A. B. ( 1992 ), Development and evaluation of a 
novel dissolution apparatus for medicated chewing gum products , Pharm. Res. , 9 , 
255 – 260 . 
28. Kvist , C. , Andersson , S. - B. , Fors , S. , Wennergren , B. , and Berglund , J. ( 1999 ), Apparatus 
for studying in vitro release from medicated chewing gums , Int. J. Pharm. , 89 , 57 – 65 . 
29. Andersen , T. , Gram - Hansen , M. , Pedersen , M. , and Rassing , M. R. ( 1990 ), Chewing gum 
as a drug delivery system for nystatin. Infl uence of solubilising agents on the release of 
water - soluble drugs , Drug Dev. Ind. Pharm. , 16 , 1985 – 1994 . 
30. Pedersen , M. , and Rassing , M. R. ( 1991 ), Miconazole chewing gum as a drug delivery 
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31. Emslie , R. D. ( 1967 ), Treatment of acute ulcerative gingivitis. A clinical trial using chewing 
gums containing metronidazole or penicillin , Br. Dent. J. , 122 , 307 – 308 . 

32. Habib , W. , Khankari , R. , and Hontz , J. ( 2002 ), Fast - dissolve drug delivery system , Crit. 
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REFERENCES 265


267 
4.2 
SEMISOLID DOSAGES: OINTMENTS, 
CREAMS, AND GELS 
Ravichandran Mahalingam , Xiaoling Li , and Bhaskara R. Jasti 
University of the Pacifi c, Stockton, California 
Contents 
4.2.1 Introduction 
4.2.2 Ointments and Creams 
4.2.2.1 Defi nition 
4.2.2.2 Bases 
4.2.2.3 Preparation and Packaging 
4.2.2.4 Evaluation 
4.2.2.5 Typical Pharmacopeial/Commercial Examples 
4.2.3 Gels 
4.2.3.1 Defi nition 
4.2.3.2 Characteristics 
4.2.3.3 Classifi cation 
4.2.3.4 Stimuli - Responsive Hydrogels 
4.2.3.5 Gelling Agents 
4.2.3.6 Preparation and Packaging 
4.2.3.7 Evaluation 
4.2.3.8 Typical Pharmacopeial and Commercial Examples 
4.2.4 Regulatory Requirements for Semisolids 
References 
4.2.1 INTRODUCTION 
Semisolid dosage forms are traditionally used for treating topical ailments. The vast 
majority of them are meant for skin applications. They are also used for treating 
ophthalmic, nasal, buccal, rectal, and vaginal ailments. Various categories of drugs 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

268 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
such as antibacterials, antifungals, antivirals, antipruritics, local anesthetics, anti - 
infl ammatories, analgesics, keratolytics, astringents, and mydriatic agents are incorporated 
into these products. Drugs incorporated into semisolids either show their 
activity on the surface layers of tissues or penetrate into internal layers to reach the 
site of action. For example, an antiseptic ointment should be able to penetrate the 
skin layers and reach the deep - seated infections in order to prevent the growth of 
microbes and heal the wound. 
Systemic entry of drugs from these products is limited due to various physicochemical 
properties of dosage forms and biological factors. The barrier nature of 
most surface biological layers such as skin, cornea and conjunctiva of the eye, and 
mucosa of nose, mouth, rectum, and vagina greatly limits their entry into the systemic 
circulation. Systemic delivery of drugs from topical dosages is however feasible by 
suitable formulation modifi cations. Semisolid dosage forms are also used in nontherapeutic 
conditions for providing protective and lubricating functions. They 
protect the skin against external environments such as air, moisture, and sun rays and 
hence their components do not necessarily penetrate the skin layers. Cold creams 
and vanishing creams are classic examples of such semisolid preparations. 
The formulation, evaluation, and regulatory feature of the three most commonly 
used semisolid dosage forms, ointments, creams, and gels, are described in this 
chapter. 
4.2.2 OINTMENTS AND CREAMS 
4.2.2.1 Defi nition 
Ointments are semisolid preparations intended for topical application. They are 
used to provide protective and emollient effects on the skin or carry medicaments 
for treating certain topical ailments. They are also used to deliver drugs into eye, 
nose, vagina, and rectum. Ointments intended for ophthalmic purposes are required 
to be sterile. When applied to the eyes, they reside in the conjunctival sac for prolonged 
periods compared to solutions and suspensions and improve the fraction of 
drug absorbed across ocular tissues. Ophthalmic ointments are preferred for nighttime 
applications as they spread over the entire corneal and conjunctival surface 
and cause blurred vision. 
Creams are basically ointments which are made less greasy by incorporation of 
water. Presence of water in creams makes them act as emulsions and therefore are 
sometimes referred as semisolid emulsions. Hydrophilic creams contain large 
amounts of water in their external phase (e.g., vanishing cream) and hydrophobic 
creams contain water in the internal phase (e.g., cold cream). An emulsifying agent 
is used to disperse the aqueous phase in the oily phase or vice versa. As with ointments, 
creams are formulated to provide protective, emollient actions or deliver 
drugs to surface or interior layers of skin, rectum, and vagina. Creams are softer 
than ointments and are preferred because of their easy removal from containers 
and good spreadability over the absorption site. 
4.2.2.2 Bases 
Bases are classifi ed based on their composition and physical characteristics. The U.S. 
Pharmacopeia (USP) classifi es ointment bases as hydrocarbon bases (oleaginous 

OINTMENTS AND CREAMS 269 
bases), absorption bases, water - removable bases, and water - soluble bases (water - 
miscible bases) [1] . 
Hydrocarbon bases are made of oleaginous materials. They provide emollient 
and protective properties and remain in the skin for prolonged periods. It is diffi cult 
to incorporate aqueous phases into hydrocarbon bases. However, powders can be 
incorporated into these bases with the aid of liquid petrolatum. Removal of hydrocarbon 
bases from the skin is diffi cult due to their oily nature. Petrolatum USP, white 
petrolatum USP, yellow ointment USP, and white ointment USP are examples of 
hydrocarbon bases. 
Absorption bases contain small amounts of water. They provide relatively less 
emollient properties than hydrocarbon bases. Similar to hydrocarbon bases, absorption 
bases are also diffi cult to remove from the skin due to their hydrophobic nature. 
Hydrophilic petrolatum USP and lanolin USP are examples of absorption bases. 
Water - removable bases are basically oil - in - water emulsions. Unlike hydrocarbon 
and absorption bases, a large proportion of aqueous phase can be incorporated into 
water - removable bases with the aid of suitable emulsifying agents. It is easy to 
remove these bases from the skin due to their hydrophilic nature. Hydrophilic ointment 
USP is an example of a water - removable ointment base. 
Water - soluble bases do not contain any oily or oleaginous phase. Solids can be 
easily incorporated into these bases. They may be completely removed from the 
skin due to their water solubility. Polyethylene glycol (PEG) ointment National 
Formulary (NF) is an example of a water - soluble base. 
Selection of an appropriate base for an ointment or cream formulation depends 
on the type of activity desired (e.g., topical or percutaneous absorption), compatibility 
with other components, physicochemical and microbial stability of the product, 
ease of manufacture, pourability and spreadability of the formulation, duration of 
contact, chances of hypersensitivity reactions, and ease of washing from the site of 
application. In addition, bases that are used in ophthalmic preparations should be 
nonirritating and should soften at body temperatures. White petrolatum and liquid 
petrolatum are generally used in ophthalmic preparations. Table 1 summarizes 
TABLE 1 Some Compendial Bases Used in Ointments and Creams 
Name Synonyms 
Offi cial 
Compendia Specifi cations 
Carnauba wax Caranda wax, 
Brazil wax 
BP, JP, 
PhEur, 
USPNF 
Melting range 80 – 88 ° C a ; iodine value 
5 – 14b ; acid value 2 – 7; saponifi cation 
value 78 – 95; total ash . 0.25% 
Cetyl alcohol Cetanol, Avol, 
Lipocol C 
BP, JP, 
PhEur, 
USPNF 
Melting range 47 – 53 ° C b ; residue on 
ignition . 0.05% b ; iodine value . 5.0; 
acid value . 2.0; saponifi cation value 
. 2.0 a 
Cetyl ester wax Crodamol SS, 
Ritachol SS, 
Starfol wax 
USPNF Melting range 43 – 47 ° C; acid value 
. 5.0; saponifi cation value 109 – 120; 
iodine value . 1.0 
Emulsifying 
wax 
Collone HV, 
Crodex A, 
Lipowax PA 
BP Saponifi cation value . 2.0; iodine value 
. 3.0 c

270 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
Name Synonyms 
Offi cial 
Compendia Specifi cations 
Hydrous lanolin Hydrous wool 
fat, Lipolan 
BP, JP, 
PhEur 
Melting range 38 – 44 ° C; acid value 
. 0.8; saponifi cation value 67 – 79; 
nonvolatile matter 72.5 – 77.5%; 
iodine value 18 – 36b 
Lanolin Wool fat, 
purifi ed wool 
fat, Corona 
BP, JP, 
PhEur, 
USPNF 
Melting range 38 – 44 ° C; loss on drying 
. 0.25%; residue on ignition . 0.1%; 
iodine value 18 – 36; acid value . 1.0 b 
Lanolin 
alcohols 
Argowax, 
Ritawax, wool 
wax alcohol 
BP, PhEur, 
USPNF 
Melting range . 56 ° C; loss on drying 
. 0.50%; residue on ignition . 0.15%; 
acid value . 2.0; saponifi cation value 
. 12 
Microcrystalline 
wax 
Petroleum 
ceresin 
USPNF Melting range 54 – 102 ° C; residue on 
ignition . 0.10% 
Paraffi n Paraffi n wax, 
hard wax, 
hard paraffi n 
BP, JP, 
PhEur, 
USPNF 
Melting range 47 – 65 ° C 
Petrolatum Yellow soft 
paraffi n, 
yellow 
petroleum 
jelly 
BP, JP, 
PhEur, 
USPNF 
Melting range 38 – 60 ° C; residue on 
ignition . 0.1% 
Poloxamer Polyethylene – 
propylene 
glycol, Lutrol, 
Pluronic 
BP, PhEur, 
USPNF 
Melting point . 50 ° C 
Polyethylene 
glycol (PEG) 
Macrogol, 
Carbowax, 
PEG, Lutrol 
BP, JP, 
PhEur, 
USPNF 
Melting range of PEG 1000, 37 – 40 ° C; 
melting range of PEG 8000, 60 – 
63 ° C; residue on ignition . 0.1% 
Stearic acid Emersol, 
Hystrene 
BP, JP, 
PhEur, 
USPNF 
Melting range . 54 ° C; iodine value . 4.0 
Stearyl alcohol Lipocol S, 
Cachalot, Rita 
SA 
BP, JP, 
PhEur, 
USPNF 
Melting range 55 – 60 ° C; residue on 
ignition 0.05% b ; iodine value . 2.0; 
acid value . 2.0; saponifi cation value 
. 2.0 a 
White wax Bleached wax BP, JP, 
PhEur, 
USPNF 
Melting range 62 – 65 ° C; acid value 17 – 
24; saponifi cation value 87 – 104a 
Yellow wax Refi ned wax BP, JP, 
PhEur, 
USPNF 
Acid value 17 – 22 a ; saponifi cation value 
87 – 102a 
Note : BP, British Pharmacopoeia; JP, Japanese Pharmacopoeia; PhEur, European Pharmacopoeia; 
USPNF, U.S. Pharmacopeia/National Formulary. All are USPNF specifi cations, except as indicated 
below. 
a European Pharmacopoeia. 
b Japanese Pharmacopoeia. 
c British Pharmacopoeia. 
TABLE 1 Continued

OINTMENTS AND CREAMS 271 
compendial status, synonym, and specifi cations of some of the bases used in ointments 
and creams. 
The following sections describe the source, physicochemical properties, formulation 
considerations, stability, incompatibility, storage, and hypersensitivity reactions 
of some of these bases. 
Lanolin Lanolin is a refi ned, decolorized, and deodorized material obtained from 
sheep wool. It is available as a pale yellow, waxy material with a characteristic odor. 
It is extensively used in the preparation of hydrophobic ointments and water - in - oil 
creams. As lanolin is prone to oxidation, antioxidants such as butylated hydroxytoluene 
are generally included. Although lanolin is insoluble in water, it is miscible 
with water up to 1 : 2 ratio. This property favors in preparing physically stable creams. 
Addition of soft paraffi n or vegetable oil improves the emollient property of lanolin 
preparations. Exposure of lanolin to higher temperature usually leads to discoloration 
and rancidlike odor, and hence prolonged heating is avoided during the 
preparation and preservation of lanolin - containing preparations. Gamma sterilization 
or fi ltration sterilization is usually employed for sterilizing ophthalmic ointments 
containing lanolin. Lanolin and some of its derivatives are reported to cause 
hypersensitivity reactions and therefore are avoided in patients with known hypersensitivity. 
One of the reasons for hypersensitivity reactions is free fatty alcohols. 
Modifi ed lanolins containing reduced levels of free fatty alcohols are commercially 
available [2, 3] . 
Hydrous Lanolin Incorporation of about 25 – 30% of water into lanolin gives 
hydrous lanolin. Gradual addition of water into molten lanolin with constant stirring 
helps in water incorporation. It is available as a pale yellow, oily material with a 
characteristic odor. The water uptake capacity of hydrous lanolin is higher than 
lanolin, and it is used for preparing topical hydrophobic ointments or water - in - oil 
creams with larger aqueous phase. Exposure of these preparations to higher temperatures 
results in separations of oily and aqueous layers. Addition of antioxidants 
and preservation in well - fi lled, airtight, light - resistant containers in a cool and dry 
place improve the stability of lanolin products. Well - preserved preparations can be 
stored up to two years. Hydrous lanolin that contains free fatty alcohols is avoided 
in hypersensitive patients [2, 3] . 
Lanolin Alcohols Lanolin alcohol is prepared from lanolin by the saponifi cation 
process and is used as a hydrophobic vehicle in pharmaceutical ointments and 
creams. It is composed of steroidal and triterpene alcohols and is available as a 
brittle solid material pale yellow in color with a faint characteristic odor. The brittle 
powder becomes plastic under warm conditions. It is practically insoluble in water 
and soluble in boiling ethanol. Lanolin alcohol possesses emollient properties, which 
makes it suitable for preparing dry - skin ointments, eye ointments, and water - in - oil 
creams. Creams containing lanolin alcohols do not show surface darkening and 
do not produce objectionable odor compared to lanolin - containing preparations. 
Inclusion of about 0.1% antioxidant, however, minimizes the oxidation on storage. 
Preparations containing lanolin alcohols can be stored up to two years if preserved 
in well - fi lled, well - closed, light - resistant containers in a cool and dry place. As with 

272 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
other lanolin bases, hypersensitivity reactions may occur in some individuals while 
using preparations containing lanolin alcohols [2, 3] . 
Petrolatum Petrolatum is also known as yellow soft paraffi n. It is an inert material 
obtained from petroleum, which contains branched and unbranched hydrocarbons. 
It is available as soft oily material and appears pale yellow to yellow in color. Various 
grades of petrolatum are commercially available with varying physical properties. 
All these grades are generally insoluble in water and possess emollient properties. 
Concentrations up to 30% are used in creams. Petrolatum shows phase transitions 
on heating to about 35 ° C. As it possesses a higher coeffi cient of thermal expansion, 
prolonged heating is avoided during processing. The presence of minor impurities 
can oxidize petrolatum and discolor the product. Antioxidants are therefore added 
to prevent such physical changes in preparations during storage. Butylated hydroxyanisole, 
butylated hydroxytoluene, or . - tocopherol is generally incorporated as an 
antioxidant in petrolatum products. In addition, use of well - closed, airtight, light - 
resistant containers and storage in a cool and dry place improve stability of preparations. 
Minor quantities of polycyclic aromatic hydrocarbon impurities in petrolatum 
sometimes cause hypersensitivity reactions. Substituting yellow soft paraffi n with 
white soft paraffi n reduces such reactions [4] . 
Petrolatum and Lanolin Alcohols Various quantities of lanolin alcohols are mixed 
with petrolatum to form these mixtures. Wool ointment British Pharmacopoeia (BP) 
2001 contains 6% lanolin alcohols and 10% petrolatum. These proportions can be 
varied to alter physical properties such as consistency and melting range. They are 
available as soft solids pale ivory in color and possess a characteristic odor. These 
mixtures are insoluble in water, and concentrations ranging 5 – 50% are used for 
preparing hydrophobic ointments. They are also used for preparing water - in - oil 
emollient creams. Preparations containing petrolatum and lanolin alcohols need to 
be preserved in airtight, well - closed, light - resistant containers in a cool and dry place 
to avoid oxidation of impurities and discoloration. Antioxidants improve the stability 
of these products. Although these mixtures are safe for topical applications, 
hypersensitivity reactions may occur in some individuals due to the presence of 
lanolin alcohol [5] . 
Paraffi n Paraffi n is obtained by distillation of crude petroleum followed by puri- 
fi cation processes. The purifi ed fraction contains saturated hydrocarbons. Paraffi n is 
available as a white color solid and does not possess any specifi c odor or taste. Different 
purity grades are available. Use of highly purifi ed grades can avoid batch - to - 
batch variations in formulations, especially the hardness, melting behavior, and 
malleability. Paraffi n is insoluble in water and is generally used to prepare hydrophobic 
topical ointments and water - in - oil creams. Repeated heating and congealing 
are avoided during formulation as they change the physical properties of paraffi n. 
These preparations need to be preserved in well - closed container at room temperature. 
Synthetic paraffi ns, which melt between 96 and 105 ° C, are sometimes used to 
increase the melting point and stiffness of formulations [6] . 
Polyethylene Glycol Also known as macrogol, PEG is synthesized by condensation 
of ethylene oxide and water under suitable reaction conditions. Based on the 

OINTMENTS AND CREAMS 273 
number of oxyethylene groups present, their molecular weights vary from few hundreds 
to several thousands. Usually the number that follows PEG represents their 
average molecular weight. They are available as liquids or solids based on molecular 
weight. PEGs 600 or less are liquids, whereas PEGs above 1000 are solids. PEG 
liquids are usually clear or pale yellow in color. Their viscosity increases with 
increase in molecular weight. Solid PEGs are usually white in color and available 
as pastes, waxy fl akes, or free - fl owing solids based on their molecular weight. Table 
2 shows the physicochemical properties of some PEGs. 
PEGs are hydrophilic materials and are extensively used in the preparation of 
hydrophilic ointments and creams. They are nonirritants and are easily washed 
from skin surfaces. Products with varying consistency are prepared by mixing different 
grades of PEGs. Excessive heating is avoided while melting PEGs. This will 
prevent oxidation and discoloration of products. In addition, use of purifi ed grades 
that are free from peroxide impurities, inclusion of suitable antioxidants, and 
heating under nitrogen atmosphere can minimize the oxidation. PEGs are prone 
to etherifi cation or esterfi cation reactions due to the presence of two terminal 
hydroxyl groups. They are incompatible with some antibiotics, antimicrobial preservatives, 
iron, tannic acid, and salicylic acid and also interact with plastic containers 
made of polyvinyl chloride and polyethylene. PEG - containing products are 
usually packed in aluminum, glass, or stainless steel containers to avoid such interactions. 
Although low - molecular - weight PEGs are hygroscopic, they do not promote 
microbial growth. PEG - containing products are generally stored in well - closed 
containers in a cool, dry place. These products can cause stinging sensation on 
mucus and some hypersensitivity reactions, especially when applied onto open 
wounds [7, 8] . 
Stearic Acid Stearic acid is obtained by hydrolysis of fat or hydrogenation of 
vegetable oils. Compendial stearic acid contains a mixture of stearic acid and palmitic 
acids. It is available as powder or crystalline solid which is white to yellowish 
white in color and possesses a characteristic odor. Although stearic acid is insoluble 
TABLE 2 Properties of Different Grades of PEG 
Property 
By Grade 
200 400 600 1000 2000 3000 4000 8000 
Physical 
state 
Liquid Liquid Liquid Solid Solid Solid Solid Solid 
Average 
molecular 
weight 
190 – 210 380 – 420 570 – 613 950 – 1050 1800 – 2200 2700 – 3300 3000 – 4800 7000 – 9000 
Melting 
( ° C) 
— — — 37 – 40 45 – 50 48 – 54 50 – 58 60 – 63 
Density 
(g/cm3 ) 
1.11 – 1.14 1.11 – 1.14 1.11 – 1.14 1.15 – 1.21 1.15 – 1.21 1.15 – 1.21 1.15 – 1.21 1.15 – 1.21 
Kinematic 
viscositya 
(cS) 
3.9 – 4.8 6.8 – 8.0 9.9 – 11.3 16.0 – 19.0 38 – 49 67 – 93 110 – 158 470 – 900 
a At 98.9 ° C. 

274 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
in water, partially neutralized grades form a cream base when combined with about 
10 times its weight of aqueous solvents. The appearance and consistency of these 
grades are based on the proportion of alkali or triethanolamine used for neutralization. 
Concentrations up to 20% are used for formulating creams and ointments. 
Different grades of stearic acids are commercially available with varying stearic acid 
content, melting temperature, and other physical properties. A suitable antioxidant 
is included in formulations containing stearic acid. As stearic acid interacts with 
metals, it is avoided in preparations which contain salts, especially divalent metals 
such as calcium and zinc. It also reacts with metal hydroxides and some drugs. Compatibility 
evaluation between stearic acid and other formulation components is 
therefore essential when formulating newer products with stearic acid [9] . 
Carnauba Wax Carnauba wax contains a mixture of esters of acids and hydroxyacids 
isolated from Brazilian carnauba palm. It also contains various resins, hydrocarbons, 
acids, polyhydric alcohols, and water. It is available as lumps, powder, or 
fl akes which are brown to pale yellow in color and possesses a characteristic odor. 
Carnauba wax is practically insoluble in water and melts at 80 – 88 ° C. Being a hard 
material, it improves the stiffness of topical preparations [6] . 
Cetyl Alcohol Cetyl alcohol is obtained by hydrogenolysis or esterfi cation of fatty 
acids and contains not less than 90% cetyl alcohol along with other aliphatic alcohols. 
It is available as fl akes or granules white in color and possesses a characteristic 
odor. Different grades are commercially available with varying proportions of cetyl 
alcohol, stearyl alcohol, and related alcohols. Although insoluble in water, cetyl 
alcohol has good water - absorptive and emulsifying properties. This property makes 
it suitable for preparing emollient ointments and creams. Its viscosity - enhancing 
properties reduce coalescence of dispersed phase and improves the physical stability 
of creams. Concentrations ranging from 2 to 10% are used in topical preparations 
to impart emollient, emulsifying, water - absorptive, and stiffening properties. Mixtures 
of petrolatum and cetyl alcohol are sometimes used for preparing creams. Such 
mixtures minimize the quantity of additional emulsifying agents in preparations. 
Although cetyl alcohol forms stable preparations, it is incompatible with strong 
oxidizing materials and some drugs. Compatibility studies are therefore conducted 
when including cetyl alcohol into formulations. Highly purifi ed grades are free from 
hypersensitivity reactions [3, 10] . 
Emulsifying Wax Emulsifying wax, also known as anionic emulsifying wax, is a 
mixture of cetostearyl alcohol, sodium lauryl sulfate, and purifi ed water. Emulsifying 
wax BP contains about 90% cetostearyl alcohol, 10% sodium lauryl sulfate, and 4% 
purifi ed water. Emulsifying wax USP contains nonionic surfactants. It is available 
as fl akes or solids which are white to pale yellow in color and possesses a characteristic 
odor. Although emulsifying wax is insoluble in water, its emulsifying properties 
help in preparing hydrophilic oil - in - water emulsions. Ointment bases are 
prepared by mixing up to 50% emulsifying wax with liquid or soft paraffi ns. At 
concentrations up to 10%, it forms creams. Although emulsifying wax is compatible 
with many acids and alkalis, it is incompatible with many cationic materials and 
polyvalent metal salts. Stainless steel vessels are preferred for mixing operations. 

OINTMENTS AND CREAMS 275 
Preparations containing emulsifying wax are preserved in well - closed container in 
a cool, dry place [11] . 
Cetyl Esters Wax Cetyl esters wax is obtained by esterifi cation of some fatty alcohols 
and fatty acids. It is available as crystalline fl akes which are white to off - white 
in color and possesses a characteristic aromatic odor. It is insoluble in water and 
has emollient and stiffening properties. About 10% of cetyl ester wax is used for 
preparing hydrophobic creams and about 20% is used for preparing topical ointments. 
Various grades of cetyl esters wax are available commercially and vary in 
their fatty alcohol and fatty acids content and melting range. As this wax is incompatible 
with strong acids and bases, it should be avoided in certain formulations. 
Cetyl ester wax – containing products are stored in well - closed containers in a cool, 
dry place [6] . 
Hydrogenated Castor Oil It is used as stiffening agent in hydrophobic ointments 
and creams due to its higher melting point. Hydrogenated castor oil contains triglyceride 
of hydroxystearic acid and is available as white color fl akes or powder. It 
is insoluble in water and melts at 85 – 88 ° C. Different grades with varying compositions 
and physical properties are commercially available. Products can be prepared 
at higher temperatures, as hydrogenated castor oil is stable up to 150 ° C. It is compatible 
with other waxes obtained from vegetable and animal sources. Preparations 
containing hydrogenated castor oil need to be preserved in well - closed containers 
in a cool and dry place [12] . 
Microcrystalline Wax Microcrystalline wax is obtained from petroleum by solvent 
fractionation and dewaxing procedures. It contains many straight - chain and 
branched - chain alkanes, with carbon chain lengths ranging from 41 to 57. It is available 
as fi ne fl akes or crystals which are white or yellow in color. Microcrystalline 
wax is insoluble in water and possesses a wide melting range (54 – 102 ° C). High - 
melting and stiffening properties of microcrystalline wax make it suitable for preparing 
ointments and cream with higher consistency. Acids, alkalis, oxygen, and light 
do not affect its stability [6] . 
Stearyl Alcohol Reduction of ethyl stearate in the presence of lithium aluminum 
hydride yields stearyl alcohol, which contains not less than 90% of 1 - octadecanol. 
It is available as fl akes or granules which are white in color and possesses a characteristic 
odor. It is insoluble in water and melts at 55 – 60 ° C. Stearyl alcohol has stiffening, 
viscosity - enhancing, and emollient properties and hence is used in the 
preparation of hydrophobic ointments and creams. Its weak emulsifying properties 
help in improving the water - holding capacity of ointments. Hypersensitivity reactions 
are sometimes observed due to the presence of some minor impurities. Stearyl 
alcohol preparations are compatible with acids and alkalis and are preserved in 
well - closed containers in a cool and dry place [6] . 
White Wax White wax is a bleached form of yellow wax which is usually obtained 
from the honeycomb of bees and hence is known as bleached wax or white bees wax . 
It contains about 70% esters of straight - chain monohydric alcohols, 15% free acids, 

276 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty acids. It is 
available as granules or sheets which are white in color and possesses a characteristic 
odor. White wax is insoluble in water and melts between 61 and 65 ° C. It has stiffening 
and viscosity - enhancing properties and therefore is used in hydrophobic ointments 
and oil - in - water creams. Although it is thermally stable, heating to above 
150 ° C results in reduction of its acid value. White wax is incompatible with oxidizing 
agents. The presence of small quantities of impurities results in hypersensitivity 
reactions in rare occasions. Preparations are stored in well - closed, light - resistant 
containers in a cool, dry place [13] . 
Yellow Wax Yellow wax, also known as yellow beeswax, is obtained from honey 
combs. It contains about 70% esters of straight - chain monohydric alcohols, 15% 
free acids, 12% carbohydrates, and 1% free wax alcohols and stearic esters of fatty 
acids. It is available as noncrystalline pieces which are yellow in color and possesses 
a characteristic odor. It is practically insoluble in water and melts at 61 – 65 ° C. It is 
used in the preparation of hydrophobic ointments and water - in - oil creams because 
of its viscosity - enhancing properties. Concentrations up to 20% are used for producing 
ointments and creams. It is incompatible with oxidizing agents. Esterifi cation 
occurs while heating to 150 ° C and hence should be avoided during preparation. 
Hypersensitivity reactions sometimes occur on topical application of yellow wax – 
containing ointments and creams due to the presence of some minor impurities. 
These products are preserved in well - closed, light - resistant containers [13] . 
Combinations of bases are sometimes used to acquire better stability. Gelling 
agents such as carbomers and PEG are also included in some ointment and cream 
preparations. Table 3 shows examples of cream bases used in some commercial 
cream preparations. 
4.2.2.3 Preparation and Packaging 
In addition to the base and drug, ointments and creams may also contain other 
components such as stabilizers, preservatives, and levigating agents. Usually levigation 
and fusion methods are employed for incorporating these components into the 
base. Levigation involves simple mixing of base and other components over an ointment 
slab using a stainless steel ointment spatula. A fusion process is employed only 
when the components are stable at fusion temperatures. Ointments and creams 
containing white wax, yellow wax, paraffi n, stearyl alcohol, and high - molecular - 
weight PEGs are generally prepared by the fusion process. Selection of levigation 
or the fusion method depends on the type base, the quantity of other components, 
and their solubility and stability characteristics. 
Oleaginous ointments are prepared by both levigation and fusion processes. 
Small quantities of powders are incorporated into hydrocarbon bases with the aid 
of a levigating agent such as liquid petrolatum, which helps in wetting of powders. 
The powder component is mixed with the levigating agent by trituration and is then 
incorporated into the base by spatulation. All solid components are milled to fi ner 
size and screened before incorporating into the base to avoid gritty sensation of the 
fi nal product. Roller mills are used for producing large quantities of ointments in 
pharmaceutical industries. Uniform mixing can be obtained by the geometric dilution 
procedure, which usually involves stepwise dilution of solids into the ointment 

OINTMENTS AND CREAMS 277 
TABLE 3 Cream Bases Present in Some Commercial Creams 
Commercial Name Drug Cream Base (s) Used 
Dritho - Calp, 
Psoriatec 
Anthralin, 0.5%, 1.0% White petrolatum, cetostearyl alcohol 
Temovate E Clobetasol propionate, 
0.05% 
Propylene glycol, glyceryl monostearate, 
cetostearyl alcohol, glyceryl stearate, 
PEG 100 stearate, white wax 
Eurax Crotamiton, 10% Petrolatum, propylene glycol, cetyl 
alcohol, carbomer - 934 
Topicort Desoximetasone, 
0.25% 
White petrolatum USP, isopropyl 
myristate NF, lanolin alcohols NF, 
mineral oil USP, cetostearyl alcohol NF 
Apexicon, Maxifl or, 
Psorcon 
Difl orasone diacetate, 
0.05% 
Hydrophilic vanishing cream base of 
propylene glycol, stearyl alcohol, cetyl 
alcohol 
Lidex Cream, Vanos Fluocinonide, 0.05%, 
0.10% 
Polyethylene glycol 8000, propylene 
glycol, stearyl alcohol 
Carac Fluorouracil, 0.5%, 
1.0%, 5.0% 
Carbomer - 940, PEG 400, propylene 
glycol, stearic acid 
Halog Halcinonide, 0.1% Polyethylene and mineral oil gel base 
with PEG 400, PEG 6000, PEG 300, 
PEG 1450 
Cortaid, Anusol-Hc, 
Proctosol HC 
Hydrocortisone, 2.5% 
water washable 
Petrolatum, stearyl alcohol, propylene 
glycol, carbomer - 934 
Monistat - Derm Miconazole nitrate, 
2% 
Water - miscible base consisting of pegoxol 
7 stearate, peglicol 5 oleate, mineral oil, 
butylated hydroxyanisole 
base. The fusion method is followed when the drugs and other solids are soluble in 
the ointment bases. The base is liquefi ed, and the soluble components are dissolved 
in the molten base. The mixture is then allowed to congeal by cooling. Fusion is 
performed using steam - jacketed vessels or a porcelain dish. The congealed mixture 
is then spatulated or triturated to obtain a smooth texture. Care is taken to avoid 
thermal degradation of the base or other components during the fusion process. 
Absorption - type ointments and creams are prepared by incorporating large 
quantities of water into hydrocarbon bases with the aid of a hydrophobic emulsifying 
agent. Water - insoluble drugs are added by mechanical addition or fusion methods. 
As with oleaginous ointments, levigating agents are also included to improve wetting 
of solids. Water - soluble or water - miscible agents such as alcohol, glycerin, or propylene 
glycol are used if the drug needs to be incorporated into the internal aqueous 
phase. If the drug needs to be incorporated into the external oily phase, mineral oils 
are used as the levigating agent. Incorporation of water - soluble components is 
achieved by slowly adding the aqueous drug solution to the hydrophobic base using 
pill tile and spatula. If the proportion of aqueous phase is larger, inclusion of additional 
quantities of emulsifi er and application of heat may be needed to achieve 
uniform dispersion. Care must be taken to avoid excessive heating as it can result 
in evaporation aqueous phase and precipitation of water - soluble components and 
formation of stiff and waxy product. 

278 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
Water - removable ointments and creams are basically hydrophilic - type emulsions. 
They are prepared by fusion followed by mechanical addition approach. Hydrocarbon 
components are melted together and added to the aqueous phase that 
contains water - soluble components with constant stirring until the mixture congeals. 
A hydrophilic emulsifying agent is included in the aqueous phase in order to obtain 
stable oil - in - water dispersion. Sodium lauryl sulfate is used in the preparation of 
hydrophilic ointment USP. 
Water - soluble ointments and creams do not contain any oily phase. Both water - 
soluble and water - insoluble components are incorporated into water - soluble bases 
by both levigation and fusion methods. If the drug and other components are water 
soluble, they are dissolved in a small quantity of water and incorporated into the 
base by simple mixing over an ointment slab. If the components are insoluble in 
water, aqueous levigating agents such as glycerin, propylene glycol, or a liquid PEG 
are used. The hydrophobic components are mixed with the levigating agent and then 
incorporated into the base. Heat aids incorporation of a large quantity of hydrophobic 
components. 
A wide range of machines are available for the large - scale production of ointments 
and creams. Each of these machines is designed to perform certain unit 
operations, such as milling, separation, mixing, emulsifi cation, and deaeration. 
Milling is performed to reduce the size of actives and other additives. Various fl uid 
energy mills, impact mills, cutter mills, compression mills, screening mills, and tumbling 
mills are used for this purpose. Alpine, Bepex, Fluid Air, and Sturtevant are 
some of the manufacturers of these mills. Separators are employed for separating 
materials of different size, shape, and densities. Either centrifugal separators or 
vibratory shakers are used for separation. Mixing of the actives and other formulation 
components with the ointment or cream base is performed using various types 
of low - shear mixers, high - shear mixers, roller mills, and static mixers. Mixers with 
heating provisions are also used to aid in the melting of bases and mixing of components. 
Chemineer, Fryma, Gate, IKA, Koruma (Romaco), Moorhouse - Cowles, 
Ross, and Stokes Merrill are some of the manufacturers of semisolids mixers. 
Creams are produced with the help of low - shear and high - shear emulsifi ers. 
These emulsifi ers are used to disperse the hydrophilic components in the hydrophobic 
dispersion phase (e.g., water - in - oil creams) or oleaginous materials in aqueous 
dispersion medium (oil - in - water creams). Bematek, Fryma, Koruma (Romaco), 
Lightnin, Moorhouse, and Ross supply various types of emulsifi ers. Entrapment of 
air into the fi nal product due to mixing processes is a common issue in the large - 
scale manufacturing of semisolid dosage forms. Various offl ine and in - line deaeration 
procedures are adopted to minimize this issue. Effective deaeration is generally 
achieved by using vacuum vessel deaerators. Some of the recent large - scale machines 
are designed to perform heating, high - shear mixing, scrapping, and deaeration processes 
in a single vessel. Figure 1 shows the design feature of a semisolid production 
machine manufactured by Ross. 
Various low - and high - shear shifters are used to transfer materials from the production 
vessel to the packaging machines. In the packaging area, various types of 
holders (e.g., pneumatic, gravity, and auger holders), fi llers (e.g., piston, peristaltic 
pump, gear pump, orifi ce, and auger fi llers), and sealers (e.g., heat, torque, microwave, 
indication, and mechanical crimping sealers) are used to complete the unit 

OINTMENTS AND CREAMS 279 
operations. These equipments are supplied by various manufacturers, namely Bosch, 
Bonafacci, Erweka, Fryma - Maschinenbau, IWKA, Kalish, and Norden. 
Sterility of ointments, especially those intended for ophthalmic use, is achieved 
by aseptic handling and processing. Improper processing, handling, packing, or use 
of ophthalmic ointments lead to microbial contaminations and eventually result in 
ocular infections. In general, the empty containers are separately sterilized and fi lled 
under aseptic condition. Final product sterilization by moist heat sterilization or 
gaseous sterilization is ineffective because of product viscosity. Dry - heat sterilization 
is associated with stability issues. Strict aseptic procedures are therefore practiced 
when processing ophthalmic preparations. Antimicrobial preservatives such as 
benzalkonium chloride, phenyl mercuric acetate, chlorobutanol, or a combination 
of methyl paraben and propyl paraben are included in ophthalmic ointments to 
retain microbial stability. 
Packaging An ideal container should protect the product from the external atmosphere 
such as heat, humidity, and particulates, be nonreactive with the product 
components, and be easy to use, light in weight, and economic [14] . As tubes made 
of aluminum and plastic meet most of these qualities, they are extensively used for 
packaging semisolids. Aluminum tubes with special internal epoxy coatings are 
commercially available for improving the compatibility and stability of products. 
Various modifi ed plastic materials are used for making ointment tubes. Tubes made 
FIGURE 1 Semisolid production machine with heat jacketed vessel, high - shear mixer, 
scrapper, vacuum attachments, and control station. (Courtesy of Ross, Inc.) 

280 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
of low - density polyethylene (LDPE) are generally soft and fl exible and offer good 
moisture protection. Tubes made of high - density polyethylene (HDPE) are relatively 
harder but offer high moisture protection. Polypropylene containers offer 
high heat resistance. Plastic containers made of polyethylene terephthalate (PET) 
are transparent and provide superior chemical compatibility. Ointments meant for 
ophthalmic, nasal, rectal, and vaginal applications are supplied with special application 
tips for the ease of product administration. 
A recent method known as blow fi ll sealing (BFS) performs fabrication of 
container, fi lling of product, and sealing operations in a single stage and hence is 
gaining greater attention. The products can be sterile fi lled, which makes BFS a 
cost - effective alternative for aseptic fi lling. All plastic materials are suitable for 
BFS processing. In most cases, monolayered LDPE materials are used for making 
small - size containers. If the product is not compatible with the LDPE or sensitive 
to oxygen, barrier layers are added to the container wall by coextrusion methods. 
As the container is formed inside the BFS machine, upstream handling problems 
are avoided. The BFS machine can hand the container off to any secondary packaging 
operation that needs to be performed. Typically a secondary overwrap is added 
to the containers prior to cartooning. An additional advantage of BFS containers is 
the integrated design of the applicator into the product container. Figure 2 shows 
some of the custom - designed BFS containers for topical products. 
4.2.2.4 Evaluation 
Ointments and creams are evaluated for various pharmacopeial and nonpharmacopeial 
tests to ascertain their physicochemical, microbial, in vitro, and in vivo 
characteristics. These tests help in retaining their quality and minimizing the batch - 
to - batch variations. The USP recommends storage and labeling, microbial screening, 
minimum fi ll, and assays for most ointments and creams. Tables 4 and 5 summarize 
the compendial requirements for some pharmacopeial ointments and creams. 
FIGURE 2 Custom - designed LDPE containers made by BFS process for packaging topical 
products. (Courtesy of Rommelag USA, Inc.) 

OINTMENTS AND CREAMS 281 
TABLE 4 USP Specifi cations for Some Offi cial Ointments 
Drug Quality Control Tests Packaging and Storage Requirements 
Acyclovir Staphylococcus aureus, 
Pseudomonas aeruginosa , 
minimum fi ll, limit of 
guanine, and assay 
Tight containers; store between 15 and 
25 ° C in a dry place 
Alclometasone 
dipropionate 
S. aureus, P. aeruginosa , 
minimum fi ll, and assay 
Collapsible tubes or tight containers, 
store at controlled room temperature 
Amphotericin B Minimum fi ll, water, and 
assay 
Collapsible tubes or other well - closed 
containers 
Anthralin Assay Tight containers; in a cool place; protect 
from light 
Bacitracin Minimum fi ll, water, and 
assay 
Well - closed containers containing not 
more than 60 g; controlled temperature 
Benzocaine S. aureus, P. aeruginosa , 
minimum fi ll, and assay 
Tight containers; protect from light; avoid 
prolonged exposure to temperatures 
exceeding 30 ° C 
Betamethasone 
valerate 
S. aureus, P. aeruginosa , 
minimum fi ll, and assay 
Collapsible tubes or tight containers; 
avoid exposure to excessive heat. 
Clioquinol Assay Collapsible tubes or tight, light - resistant 
containers 
Clobetasol 
propionate 
S. aureus, P. aeruginosa, 
Escherichia coli, 
Salmonella species, total 
aerobic microbial count, 
minimum fi ll, and assay 
Collapsible tubes or in tight containers; 
store at controlled room temperature; 
do not refrigerate 
Erythromycin Minimum fi ll, water, and 
assay 
Collapsible tubes or in tight containers at 
controlled room temperature 
Fluocinolone 
acetonide 
S. aureus, P. aeruginosa , and 
assay 
Tight containers 
Gentamycin 
sulfate 
Minimum fi ll, water, and 
assay 
Collapsible tubes or in tight containers; 
avoid exposure to excessive heat 
Hydrocortisone 
valerate 
S. aureus, P. aeruginosa , 
total microbial count, 
minimum fi ll, and assay 
Tight container; store at room 
temperature 
Ichthammol Assay Collapsible tubes or in tight containers; 
avoid prolonged exposure to 
temperatures exceeding 30 ° C 
Lidocaine S. aureus, P. aeruginosa , 
minimum fi ll, and assay 
Tight containers 
Mometasone 
furoate 
S. aureus, P. aeruginosa, E. 
coli, Salmonella species, 
minimum fi ll, and assay 
Well - closed containers 
Nitrofurazone Completeness of solution 
and assay 
Tight, light - resistant containers; avoid 
exposure to direct sunlight, strong 
fl uorescent lighting, and excessive heat 
Nitroglycerine Minimum fi ll, homogeneity, 
and assay 
Tight containers 
Nystatin Minimum fi ll, water, and 
assay 
Well - closed containers at controlled 
room temperature 
Tetracycline 
hydrochloride 
Minimum fi ll, water, and 
assay 
Well - closed containers at controlled 
room temperature 
Zinc oxide Minimum fi ll, calcium, 
magnesium, other foreign 
substances, and assay 
Tight containers; avoid prolonged 
exposure to temperatures exceeding 
30 ° C 

282 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
TABLE 5 USP Specifi cations for Some Offi cial Creams 
Cream Quality Control Tests Packaging and Storage Requirements 
Alclometasone 
dipropionate 
Microbial limits, minimum 
fi ll, and assay 
Collapsible tubes or tight containers; store 
at controlled room temperature 
Amphotericin B Minimum fi ll and assay Collapsible tubes or other well - closed 
containers 
Benzocaine Microbial limits, minimum 
fi ll, and assay 
Tight containers, protected from light, 
and avoid prolonged exposure to 
temperatures exceeding 30 ° C 
Betamethasone 
dipropionate 
Minimum fi ll and assay Collapsible tubes or tight containers; store 
at 25 ° C; excursions permitted between 
15 and 30; protect from freezing 
Ciclopirox 
olamine 
Minimum fi ll, pH, content 
of benzyl alcohol, and 
assay 
Collapsible tubes at controlled room 
temperature 
Clobetasol 
propionate 
Microbial limits, minimum 
fi ll, pH, and assay 
Collapsible tubes or tight containers; store 
at controlled room temperature; do not 
refrigerate 
Clotrimazole Assay Collapsible tubes or tight containers at a 
temperature between 2 and 30 ° C 
Desoximetasone Minimum fi ll, pH, and 
assay 
Collapsible tubes at controlled room 
temperature 
Dibucaine Microbial limits, minimum 
fi ll, and assay 
Collapsible tubes or in tight, light - resistant 
containers 
Dienestrol Minimum fi ll and assay Collapsible tubes or in tight containers 
Difl orasone 
diacetate 
Microbial limits, minimum 
fi ll, and assay 
Collapsible tubes, preferably at controlled 
room temperature 
Fluocinolone 
acetonide 
Microbial limits, minimum 
fi ll, and assay 
Collapsible tubes or in tight containers 
Fluorouracil Microbial limits, minimum 
fi ll, and assay 
Tight containers and stored at controlled 
room temperature 
Gentamycin 
sulfate 
Minimum fi ll and assay Collapsible tubes or in other tight 
containers; avoid exposure to excessive 
heat 
Hydrocortisone 
butyrate 
Microbial limits, minimum 
fi ll, pH, and assay 
Well - closed containers 
Hydroquinone Minimum fi ll and assay Well - closed, light - resistant containers 
Lindane pH and assay Tight containers 
Meclocycline 
sulfosalicylate 
Minimum fi ll and assay Tight containers, protected from light 
Miconazole 
nitrate 
Minimum fi ll and assay Collapsible tubes or tight containers; store 
at controlled room temperature 
Monobenzone Assay Tight containers; avoid exposure to 
temperatures higher than 30 ° C 
Nystatin Minimum fi ll and assay Collapsible tubes or in other tight 
containers; avoid exposure to excessive 
heat 
Prednisolone Minimum fi ll and assay Collapsible tubes or in tight containers 
Tetracaine 
hydrochloride 
Microbial limits, minimum 
fi ll, pH between 3.2 and 
3.8, and assay 
Collapsible, lined metal tubes 
Triamcinolone 
acetonide 
Microbial limits, minimum 
fi ll, and assay 
Tight containers 

OINTMENTS AND CREAMS 283 
Packaging and Storage The USP recommends packaging and storage requirements 
for each offi cial ointment and cream. Generally collapsible tubes, tight containers, 
or other well - closed containers are recommended for packing. They are 
stored in either a cool place or at controlled room temperatures. In some cases, 
special storage conditions are recommended: for example, protect from light, avoid 
exposure to excessive heat, avoid exposure to direct sunlight, avoid strong fl uorescent 
lighting, do not refrigerate, and avoid prolonged exposure to temperatures 
exceeding 30 ° C. 
Minimum Fill This test is performed to compare the weight or volume of product 
fi lled into each container with their labeled weight or volume. It helps in assessing 
the content uniformity of product. A minimum - fi ll test is applied only to those 
containers that contain not more than 150 g or mL of preparation. It is performed 
in two steps. Initially, labels from the product containers are removed. After washing 
and drying the surface, their weights are recorded ( W1 ). In the second step, the entire 
product from each container is removed. After cleaning and drying, the weight of 
empty containers is recorded ( W2 ). The difference between total weight ( W1 ) and 
empty - container weight ( W2 ) gives the weight of product. The USP recommends 
that the average net content of 10 containers should not be less than the labeled 
amount. If the product weight is less than 60 g or mL, the net content of any single 
container should not be less than 90% of the labeled amount. If the product weight 
is between 60 and 150 g or mL, the net content of any single container should not 
be less than 95% of the labeled amount. If these limits are not met, the test is 
repeated with an additional 20 containers. All semisolid topical preparations should 
meet these specifi cations [15] . 
Water Content The presence of minor quantities of water may alter the microbial, 
physical, and chemical stability of ointments and creams. Titrimetric methods 
(method I) are usually performed for determining the water content in these preparations. 
These methods are based on the quantitative reaction between water and 
anhydrous solution of sulfur and iodine in the presence of a buffer that can react 
with hydrogen ions. Special titration setups and reagents (Karl Fischer, KF) are used 
in these determinations. In the direct method (method Ia), about 35 mL of methanol 
is titrated with suffi cient quantity of KF reagent to the electrometric or visual endpoint 
(color change from canary yellow to amber). This blank titration helps to 
consume any moisture that may be present in the reaction medium. A known quantity 
of test material (ointment or cream) is added to the reaction medium, mixed, 
and again titrated with KF reagent to the reaction endpoint. The water content is 
determined by considering the volume of KF reagent consumed and its water 
equivalence factor. In the residual titration method (method Ib), a known excess 
quantity of KF reagent is added to the titration vessel, which is then back titrated 
with standardized water to the electrometric or visual endpoint. In the coulometric 
titration method (method Ic), the sample is dissolved in anhydrous methanol and 
injected into the reaction vessel that contains the anolyte, and the coulometric reaction 
is performed until the reaction endpoint. In some cases, methanol is replaced 
with other solvents. The maximum allowable limit of water in ointment preparations 
varies between 0.5 and 1.0%. The limit of water in bacitracin, chlortetracycline 
hydrochloride, and nystatin ointments is not more than 0.5%, whereas amphotericin 

284 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
B, erythromycin, gentamycin sulfate, neomycin sulfate, and tetracycline hydrochloride 
ointments may contain up to 1% moisture [15] . 
Metal Particles This test is required only for ophthalmic ointments. The presence 
of metal particles will irritate the corneal or conjunctival surfaces of the eye. It is 
performed using 10 ointment tubes. The content from each tube is completely 
removed onto a clean 60 - mm - diameter petridish which possesses a fl at bottom. The 
lid is closed and the product is heated at 85 ° C for 2 h. Once the product is melted 
and distributed uniformly, it is cooled to room temperature. The lid is removed after 
solidifi cation. The bottom surface is then viewed through an optical microscope at 
30. magnifi cation. The viewing surface is illuminated using an external light source 
positioned at 45 ° on the top. The entire bottom surface of the ointment is examined, 
and the number of particles 50 . m or above are counted using a calibrated eyepiece 
micrometer. The USP recommends that the number of such particles in 10 tubes 
should not exceed 50, with not more than 8 particles in any individual tube. If these 
limits are not met, the test is repeated with an additional 20 tubes. In this case, the 
total number of particles in 30 tubes should not exceed 150, and not more than 3 
tubes are allowed to contain more than 8 particles [15] . 
Leakage Test This test is mandatory for ophthalmic ointments, which evaluates 
the intactness of the ointment tube and its seal. Ten sealed containers are selected, 
and their exterior surfaces are cleaned. They are horizontally placed over absorbent 
blotting paper and maintained at 60 ± 3 ° C for 8 h. The test passes if leakage is not 
observed from any tube. If leakage is observed, the test is repeated with an additional 
20 tubes. The test passes if not more than 1 tube shows leakage out of 30 
tubes [15] . 
Sterility Tests Ophthalmic semisolids should be free from anaerobic and aerobic 
bacteria and fungi. Sterility tests are therefore performed by the membrane fi ltration 
technique or direct - inoculation techniques. In the membrane fi ltration method, 
a solution of test product (1%) is prepared in isopropyl myristate and allowed to 
penetrate through cellulose nitrate fi lter with pore size less than 0.45 . m. If necessary, 
gradual suction or pressure is applied to aid fi ltration. The membrane is then 
washed three times with 100 - mL quantities of sterile diluting and rinsing fl uid and 
transferred aseptically into fl uid thioglycolate (FTG) and soybean – casein digest 
(SBCD) medium. The membrane is fi nally incubated for 14 days. Growth on FTG 
medium indicates the presence of anaerobic and aerobic bacteria, and SBCD 
medium indicates fungi and aerobic bacteria. Absence of any growth in both these 
media establishes the sterility of the product. In the direct - inoculation technique, 1 
part of the product is diluted with 10 parts of sterile diluting and rinsing fl uid with 
the help of an emulsifying agent and incubated in FTG and SBCD media for 14 
days. In both techniques, the number of test articles is based on the batch size of 
the product. If the batch size is less than 200 the containers, either 5% of the containers 
or 2 containers (whichever is greater) are used. If the batch size is more than 
200, 10 containers are used for sterility testing [15] . 
Microbial Screening Semisolid preparations are required to be free from any 
microbial contamination. Hence, most of the topical ointments are screened for the 

OINTMENTS AND CREAMS 285 
presence of Staphylococcus aureus and Pseudomonas aeruginosa . In some cases, 
screening for Escherichia coli, Salmonella species, and total aerobic microbial counts 
is recommended by the USP. For instance, clobetasol propionate ointment USP and 
mometasone furoate ointment USP are screened for all these organisms. In addition, 
preparations meant for rectal, vaginal, and urethral applications are tested for yeasts 
and molds [15] . 
Test for S. aureus and P. aeruginosa The test sample is mixed with about 100 mL 
of fl uid soybean – casein digest (FSBCD) medium and incubated. If microbial growth 
is observed, it is inoculated in agar medium by the streaking technique. Vogel – 
Johnson agar (VJA) medium is used for S. aureus screening, and cetrimide agar 
(CA) medium is used for screening P. aeruginosa . The petridishes are then closed, 
inverted, and incubated under appropriate conditions. The appearance of black 
colonies surrounded by a yellow zone over VJA medium and greenish colonies in 
CA medium indicates the presence of S. aureus and P. aeruginosa , respectively. 
Various other agar media are also available for screening these organisms. A coagulase 
test is then performed for confi rming the presence of S. aureus and oxidase and 
pigment tests for confi rming P. aeruginosa . 
Test for Salmonella Species and E. coli The test sample is mixed with about 100 mL 
of fl uid lactose (FL) medium and incubated. If microbial growth is observed, the 
contents are mixed and 1 mL is transferred to vessels containing 10 mL of fl uid 
selinite cystine (FSC) medium and fl uid tetrathionate (FT) medium and incubated 
for 12 – 24 h under appropriate conditions. To identify the presence of Salmonella , 
samples from the above two media are streaked over brilliant green agar (BGA) 
medium, xylose lysine desoxycholate agar (XLDA) medium, and bismuth sulfi te 
agar (BSA) medium and incubated. The appearance of small, transparent or pink - 
to - white opaque colonies over BGA medium, red colonies with or without black 
centers over XLDA medium, and black or green colonies over BSA medium indicates 
the presence of Salmonella . It is further confi rmed in triple sugar iron agar 
medium. The presence of E. coli is screened by streaking the samples from FL 
medium over MacConkey agar medium. The appearance of brick red colonies indicates 
the presence of E. coli . It is further confi rmed using Levine eosin methylene 
blue agar medium. 
total aerobic microbial counts The plate method or multiple - tube method is 
performed to estimate the total count. About 10 g or 10 mL of the test sample is 
dissolved or suspended in suffi cient volume of phosphate buffer (pH 7.2), fl uid 
soybean casein digest (FSBCD) medium, or fl uid casein digest – soy lecithin – 
polysorbate 20 medium to make the fi nal volume 100 mL. In the plate method, about 
1 mL of this diluted sample is mixed with molten soybean – casein digest agar 
(SBCDA) medium and solidifi ed at room temperature. The plates are inverted and 
incubated for two to three days. The number of colonies that are on the surface of 
nutrient media are counted. The multiple tube method is performed using sterile 
fl uid SBCD medium. The number of colonies formed should not exceed the limits 
specifi ed in an individual monograph. For example, clobetasol propionate ointment 
USP and hydrocortisone valerate ointment USP contains less than 100 colony - 
forming units (CFU) per gram of sample. 

286 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
Test for Yeasts and Molds The plate method is used for testing molds and yeast in 
semisolids. The procedure is similar to that of the total count test. Instead of SBCDA 
medium, Sabouraud dextrose agar (SDA) medium or potato dextrose agar (PDA) 
medium is used. Samples are incubated for fi ve to seven days at 20 – 25 ° C to identify 
the presence of yeasts and molds. 
Assay The quantity of drug present in a unit weight or volume of ointment or 
cream is determined by various methods. Spectrophotometric, titrimetric, chromatographic, 
and in some cases microbial assays are performed. Selection of a particular 
method is based on the nature of drug, its concentration in the product, interference 
between the drug and other formulation components, and offi cial requirements. 
Although spectrophotometric methods are accurate and easy to perform, the complexity 
of ointment matrix sometimes reduced the specifi city of analysis compare 
to liquid chromatographic methods. The USP prescribes high - performance liquid 
chromatographic (HPLC) assays for many offi cial ointments due to its specifi city, 
accuracy, and precision. For example, amcinonide, anthralin, betamethasone dipropionate, 
clobetasol propionate, dibucaine, nitroglycerine, hydrocortisone, and triamcinolone 
acetonide are assayed by HPLC methods. These methods involve extraction 
of drug from the formulation matrix using suitable solvents followed by chromatographic 
separation using suitable reversed - phase columns followed by ultraviolet 
(UV) detection. Clioquinol preparation is assayed by gas chromatography. The USP 
also recommends potentiometric titrations (benzocaine, lidocaine, and ichthammol) 
and complexometric titrations (zinc oxide) for some semisolid preparations. 
Microbial assays are recommended for certain preparations containing antibiotics 
such as amphotericin B, bacitracin, chlortetracycline hydrochloride, gentamycin 
sulfate, neomycin sulfate, and nystatin. These tests evaluate the potency of an antibiotic 
by means of its inhibitory effects on specifi c microorganism. Two types of 
microbial assays are performed to determine the antibiotic potency. They are known 
as cylindrical plate or plate assays and turbidimetric or tube assays. The plate 
method measures the extent of growth inhibition of a particular microorganism in 
solidifi ed agar medium in the presence of the test antibiotic (commonly known as 
zone of inhibition ). The tube method measures the turbidity of a liquid medium that 
contains a particular organism in the presence and absence of the test antibiotic. 
These methods involve extracting drug from the formulation matrix, diluting the 
drug to a known concentration, and measuring the zone of inhibition or turbidity. 
In Vitro Drug Release Studies These studies are conducted to ascertain release 
of drug from the formulation matrix. Open - chamber diffusion cells such as Franz 
cells are used for performing in vitro studies. These cells consist of a donor side and 
a receiver side separated by a synthetic membrane such as cellulose acetate/nitrate 
mixed ester, polysulfone, or polytetrafl uoroethylene. The membranes are usually 
pretreated with the receiver fl uid to avoid any lag phase in drug release. The receiver 
side is fi lled with a known volume of release medium and is heated to 32 ± 0.5 ° C 
by circulating warm water through an outer jacket. Aqueous buffers are used for 
water - soluble drugs. Phosphate buffer solution of pH 5.4 is considered most appropriate 
for dermatological products as it mimics the pH of skin. Hydroalcoholic or 
other suitable medium may also be used for sparingly water soluble drugs. A known 
quantity of the test product is applied uniformly over the membrane on the donor 

OINTMENTS AND CREAMS 287 
side and samples are withdrawn from the receiver side at different time intervals. 
After each sampling, an equal volume of fresh medium is replaced to the receiver 
side. The sampling time points are different for different formulations; however, at 
least fi ve samples are withdrawn during the study period for determining the release 
rate. A typical sample time sequence for a 6 - h study is 0.5, 1.0, 2.0, 4.0, and 6.0 h. 
The receiver samples are analyzed by a suitable analytical method to quantify the 
amount of drug released from the formulation at different time intervals. The slope 
of the straight line which is obtained from a plot of cumulative amount drug release 
across 1 - cm 2 membrane versus the square root of time represents the release rate. 
Experiments are conducted in hexaplicate to obtain statistically signifi cant results 
[16] . 
In Vivo Bioequivalence Studies In vivo studies are conducted to establish the 
biological availability or activity of the drug from a topically applied semisolid formulation. 
Dermatopharmacokinetic studies, pharmacodynamic studies, or comparative 
clinical trials are generally conducted to assess the bioequivalence of topical 
products [16, 17] . 
Dermatopharmacokinetic (DPK) studies are applicable for topical semisolid 
products that contain antifungals, antivirals, corticosteroids, and antibiotics and 
vaginally applied products. They are not applicable for ophthalmic, otic, and other 
products that damage stratum corneum. DPK studies involve measurement of drug 
concentrations in stratum corneum, drug uptake, apparent steady state, and elimination 
after application of the test product onto skin. These studies are conducted in 
healthy human subjects adopting crossover design. The test and the reference products 
are applied onto eight to nine sites in the forearm. The surface area of each 
site is based on the strength of drug, extent of drug diffusion, exposure time, and 
sensitivity of the analytical technique. The application site is washed and allowed to 
normalize for at least 2 h prior to drug application. A known amount of product is 
applied onto these selected sites. At appropriate time intervals, the excess of drug 
from each area is removed using cotton swabs or soft tissue papers. Care is taken 
to avoid stratum corneum damage during sample collection. Stripping of stratum 
corneum is performed using adhesive tape - strips (e.g., D - Squame, Transpore). In the 
elimination phase, the excess drug is removed at the steady - state time point, and 
the stratum corneum is harvested at succeeding times over 24 h. The drug content 
from strips from each time point are extracted using suitable solvents and quantifi ed 
by a validated analytical method. A stratum corneum drug levels – time curve is 
developed, and pharmacokinetic parameters such as maximum concentration at 
steady state ( Cmax - ss ), time to reach Cmax - ss ( Tmax - ss ), and areas under the curve for the 
test and standard (AUC test and AUC reference ) are computed. DPK studies are performed 
in either one or two occasions. If performed in one occasion, both arms of 
a single subject are used to compare the test and reference products. If performed 
in two occasions, a wash - out period of at least 28 days is allowed to rejuvenate the 
harvested stratum corneum. 
Pharmacodynamic (PD) studies are also performed to estimate the bioavailability 
and bioequivalence of drugs from topically applied semisolids. In this case, 
known therapeutic responses from drug products such as skin blanching due to 
vasoconstrictor effects caused by corticosteroids and transepidermal water loss 
caused by retinoids are measured and compared between the test and reference 

288 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
products. Comparative clinical studies are rarely conducted due to the diffi culties 
involved in performing the study, variability in study results, and their poor 
sensitivity. 
4.2.2.5 Typical Pharmacopeial/Commercial Examples 
The vast majority of topical ointments and creams are meant for dermatological 
applications. They are used to treat various skin conditions such as eczema, dermatitis, 
allergies, infl ammatory and pruritic manifestations, minor skin wounds, pain, 
insect bites, psoriasis, herpes and other infections of the skin (e.g., impetigo), acne, 
and precancerous and cancerous skin growths. Similarly, ophthalmic conditions such 
as infections, infl ammation, allergy, and dry - eye symptoms are treated with semisolid 
preparations. Products are also available for certain eye examinations. Vaginal preparations 
are available for treating genital herpes, yeast infections, and vaginosis 
caused by bacteria and to reduce menopausal symptoms (e.g., vaginal dryness), and 
rectal preparations are available for treating minor pain, itching, swelling, and discomfort 
caused by hemorrhoids and other problems of the anal area. Tables 6 and 
7 show some of the commercially available compendial ointment and cream preparations 
used for treating various topical ailments. 
4.2.3 GELS 
4.2.3.1 Defi nition 
Gels are semisolid preparations that contain small inorganic particles or large 
organic molecules interpenetrated by a liquid. Gels made of inorganic materials are 
usually two - phase systems where small discrete particles are dispersed throughout 
the dispersion medium. When the particle size of the dispersed phase is larger, they 
are referred to as magmas. Gels made of organic molecules are single - phase systems, 
where no apparent physical boundary is seen between the dispersed phase and the 
dispersion medium. In most cases, the dispersion medium is aqueous. Hydroalcoholic 
or oleaginous dispersion media are also used in some cases. Unlike dispersed 
systems like suspensions and emulsions, movement of the dispersed phase is 
restricted in gels because of the solvated organic macromolecules or interconnecting 
three - dimensional networks of particles. 
Gels are attractive delivery systems as they are simple to manufacture and 
suitable for administering drugs through skin, oral, buccal, ophthalmic, nasal, 
otic, and vaginal routes. They also provide intimate contact between the drug and 
the site of action or absorption. With the advancement in polymer science, gel - based 
systems that respond to specifi c biological or external stimuli like pH, temperature, 
ionic strength, enzymes, antigens, light, magnetic fi eld, ultrasound, and electric 
current are being designed and evaluated as smart delivery systems for various 
applications. 
4.2.3.2 Characteristics 
Gels may appear transparent or turbid based on the type of gelling agent used. They 
exhibit different physical properties, namely, imbibition, swelling, syneresis, and 

TABLE 6 Examples of Compendial/Commercial Ointments 
Drug a Category Indication 
Commercial 
Names 
Strength(s) 
Available 
(%) 
Acyclovir Antiviral Genital herpes, 
herpes infections 
of the skin, and 
oral herpes 
Zovirax 5 
Atropine 
sulfate (oph) 
Mydriatic Relax muscles in the 
eye, treat 
infl ammation of 
certain parts of 
the eye (uveal 
tract), and used 
for certain eye 
exams 
Atropisol, 
Isopto 
Atropine 
0.5, 1 
Bacitracin First - aid antibiotic Treat or prevent skin 
infections 
Baciguent 
Oint, 
Bacitracin 
Top 
500 units/g 
Bacitracin 
(oph) 
Antibiotic Treat or prevent eye 
infections 
Ak - Tracin, 
Bacticin 
500 units/g 
Benzocaine Antipruritic and 
local anesthetic 
Itching, minor skin 
wound pain, and 
insect bites 
Americaine 20 
Ciprofl oxacin 
(oph) 
Antibiotic Eye infections Ciloxan 0.3 
Clobetasol 
propionate 
Anti - infl ammatory 
agent 
Relieve 
infl ammatory 
and pruritic 
manifestations of 
corticosteroid - 
responsive 
dermatoses 
Temovate 
Ointment 
0.05 
Erythromycin Antibiotic Treatment of acne Akne - Mycin 2.0 
Erythromycin 
(oph) 
Antibiotic Infections of eye or 
ear 
Erythromycin 
Ophthalmic 
0.5 
Gentamicin 
sulfate (oph) 
Antibacterial Infections of eye or 
ear 
Gentamicin 
Sulfate 
0.3 
Hydrocortisone Anti - infl ammatory 
agent 
Minor pain, itching, 
swelling, and 
discomfort caused 
by hemorrhoids 
and other 
problems of 
anal area 
Cortaid, 
Anusol - HC, 
Proctosol 
HC 
2.5 
Mupirocin Antibiotic Treat certain skin 
infections (e.g., 
impetigo) 
Bactroban 2.0 
Sodium 
chloride 
(oph) 
Miscellaneous Treat fl uid 
accumulation in 
cornea of eye 
causing swelling 
Muro - 128, 
Sochlor 
2.0 
a oph: ophthalmic ointment. 
GELS 289

290 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
TABLE 7 Examples of Compendial/Commercial Creams 
Drug a Category Indication 
Commercial 
Products 
Strength(s) 
Available 
(%) 
Alclometasone 
dipropionate 
Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Aclovate 0.05 
Amcinonide Anti - 
infl ammatory 
Lymphomas of the skin, 
atopic dermatitis, 
contact dermatitis, 
and skin rash 
Cyclocort 0.1 
Amphotericin B Antifungal 
antibiotic 
Treat skin infection due 
to a Candida yeast 
and diaper rash 
Fungizone 3.0 
Anthralin Keratolytic Long - term psoriasis Dritho - Calp, 
Psoriatec 
0.5, 1.0 
Betamethasone 
dipropionate 
Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Diprolene 
AF 
0.05 
Butoconazole 
nitrate (vag) 
Antifungal Vaginal yeast infections Gynazole - 1 2.0 
Clindamycin 
phosphate 
(vag) 
Antibiotic Vaginosis caused by 
bacteria 
Clindesse 2.0 
Clobetasol 
propionate 
Anti - 
infl ammatory 
Infl ammatory 
and pruritic 
manifestations of 
corticosteroid - 
responsive 
dermatoses 
Temovate E 
Cream 
0.05 
Clotrimazole Antifungal Ringworm of groin 
area, athlete ’ s foot, 
ringworm of the body, 
fungal infection of 
the skin with yellow 
patches, skin infection 
due to a candida 
yeast, and diaper rash 
Lotrimin 1.0 
Crotamiton Scabicidal and 
antipruritic 
Scabies infection and 
itching 
Eurax 10.0 
Desoximetasone Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Topicort 0.25 
Dienestrol Estrogen Reduce menopause 
symptoms such as 
vaginal dryness 
Ortho - 
Dienestrol 
0.01 
Difl orasone 
diacetate 
Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Apexicon, 
Maxifl or 
0.05 
Fluocinonide Anti - 
infl ammatory 
and 
antipruritic 
Psoriasis, eczema, 
dermatitis, allergies, 
and rash 
Lidex, Vanos 0.05, 0.10 
Fluorouracil Anticancer Precancerous and 
cancerous skin 
growths 
Fluoroplex, 
Carac, 
Efudex 
0.5, 1.0, 5.0 

thixotropy. Imbibition refers to the uptake of water or other liquids by gels without 
any considerable increase in its volume. Swelling refers to the increase in the volume 
of gel by uptake of water or other liquids. This property of most gels is infl uenced 
by temperature, pH, presence of electrolytes, and other formulation ingredients. 
Syneresis refers to the contraction or shrinkage of gels as a result of squeezing out 
of dispersion medium from the gel matrix. It is due to the excessive stretching of 
macromolecules and expansion of elastic forces during swelling. At equilibrium, the 
system still maintains its physical stability because the osmotic forces of swelling 
balance the expanded elastic forces of macromolecules. On cooling, the osmotic 
pressure of the system decreases and therefore the expanded elastic forces return 
to normal. This results in shrinkage of the stretched molecules and squeezing of 
dispersion medium from the gel matrix. Addition of osmotic agents such as sucrose, 
glucose, and other electrolytes helps in retaining higher osmotic pressure even at 
lower temperatures and avoids syneresis of gels. Thixotropy refers to the non - 
Newtonian fl ow nature of gels, which is characterized by a reversible gel - to - sol 
formation with no change in volume or temperature [18] . 
4.2.3.3 Classifi cation 
Gels are classifi ed as hydrogels and organogels based on the physical state of the 
gelling agent in the dispersion. Hydrogels are prepared with water - soluble materials 
or water - dispersible colloids. Organogels are prepared using water - insoluble oleaginous 
materials. 
Hydrogels Natural and synthetic gums such as tragacanth, sodium alginate, and 
pectin, inorganic materials such as alumina, bentonite, silica, and veegum, and 
organic materials such as cellulose polymers form hydrogels in water. They may 
either be dispersed as fi ne colloidal particles in aqueous phase or completely dissolve 
in water to gain gel structure. Gums and inorganic gelling agents form gel 
structure due to their viscosity - increasing nature. Organic gelling agents which are 
generally high - molecular - weight cellulose polymer derivatives produce gel structure 
Drug a Category Indication 
Commercial 
Products 
Strength(s) 
Available 
(%) 
Halcinonide Anti - 
infl ammatory 
and 
antipruritic 
Eczema, dermatitis, 
allergies, and rash 
Halog 0.1 
Mometasone 
furoate 
Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Elocon 0.1 
Naftifi ne 
hydrochloride 
Antifungal Jock itch, athlete ’ s feet, 
or ringworm 
Naftin 1 
Nystatin Antifungal Fungal skin infections Mycostatin 100,000 
units/g 
a vag, vaginal cream. 
TABLE 7 Continued 
GELS 291

292 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
because of their swelling and chain entanglement properties. The swollen molecular 
chains are held together by secondary valence forces, which help in retaining their 
gel structure. The physical strength of the gel structure is based on the quantity of 
gelling agent, nature and molecular weight of gelling agent, product pH, and gelling 
temperature. Generally high - molecular - weight polymers at higher concentrations 
produce thick gels. The gel - forming temperature ( gel point ) varies with different 
polymers. Generally natural gums form gel at lower temperatures. Gelatin, a natural 
protein polymer, forms gel at about 30 ° C. If the temperature is increased, gel consistency 
is not obtained even at higher concentrations of gelatin. On the other hand, 
polymers such as methylcellulose gain gel structure only when the temperature is 
above 50 ° C due to its decreased solubility and precipitation. Knowledge of the gel 
point for each gelling agent is therefore essential for preparing physically stable 
hydrogels. 
Organogels Organogels are also known as oleaginous gels. They are prepared 
using water - insoluble lipids such as glycerol esters of fatty acids, which swell in water 
and form different types of lyotropic liquid crystals. Widely used glycerol esters of 
fatty acids include glycerol monooleate, glycerol monopalmito stearete, and glycerol 
monolinoleate. They generally exist as waxes at room temperature and form cubic 
liquid crystals in water and increase the viscosity of dispersion. Waxes such as carnauba 
wax, esparto wax, wool wax, and spermaceti are used in cosmetic organogel 
preparations. A large quantity of water is entrapped between the three - dimensional 
lipid bilayers. The equilibrium water content in organogels is about 35%. The structural 
properties of the lipid, quantity of water in the system, solubility of drug 
incorporated, and external temperature infl uence the nature of the liquid crystalline 
phase. The bipolar nature of organogels allows incorporation of both hydrophilic 
and lipophilic drugs. Release rates can be controlled by altering the hydrophilic and 
hydrophobic components. Biodegradability of these waxes by the lipase enzyme in 
the body makes organogels suitable for parenteral administration. 
The water present in the gel framework can be completely removed with some 
gelling agents. Gelatin sheets, acacia tears, and tragacanth ribbons are generally 
prepared by removal of water from their respective gel matrix. These dehydrated 
gel frameworks are called as xerogels. 
4.2.3.4 Stimuli - Responsive Hydrogels 
The three - dimensional networks of hydrophilic polymers absorb a large quantity of 
water and form soft structures which resemble biological tissues. Swelling properties 
of these hydrogels can be altered by various physicochemical parameters. Physical 
factors such as temperature, pH, and ionic strength of the swelling medium 
and chemical factors such as the structure of polymer (linear/branched) and chemical 
modifi cations (cross - linking) can be altered to tailor their swelling rate. This 
feature makes them very attractive for drug delivery and biomedical applications 
[19 – 23] . 
pH-Responsive Hydrogels Some polymers show pH - dependent swelling and 
gelling characteristics in aqueous media. A polymer that exhibits such phase transition 
properties is very useful from the point of drug delivery. Methacrylic acids 

(e.g., carbomers) that contain many carboxylic acid groups exist as solution at lower 
pH conditions. When the pH is increased, they undergo a sol - to - gel transition. This 
is because of the increase in the degree of ionization of acidic carboxylic groups at 
higher pH conditions, which in turn results in electrostatic repulsions between 
chains and, increased hydrophilicity and swelling. Conversely, polymers that contain 
amine - pendant groups swell at lower pH environment due to ionization and repulsion 
between polymer chains. The ionic strength of surrounding fl uids signifi cantly 
infl uences the equilibrium swelling of these pH - responsive polymers. Higher ionic 
strength favors gel – counter ionic interactions and reduces the osmotic swelling 
forces. 
Thermoresponsive Hydrogels A dispersion which exists as solution at room temperature 
and transforms into gel on instillation into a body cavity can improve the 
administration mode and help in modulating the drug release. Many polymers with 
thermoresponsive gelling properties are currently being synthesized and evaluated. 
A triblock copolymer that consists of polyethylene glycol – polylactic acid, glycolic 
acid – polyethylene glycerol (PEG – PLGA – PEG) is solution at room temperature 
and gels at body temperature. Poloxamers, which are made of triblock poly(ethylene 
oxide) – poly(propylene oxide) – poly(ethylene oxide), exhibit gelatin properties at 
body temperatures. Similarly, xyloglucan and xanthan gum aqueous dispersions are 
solutions at room temperature and become gel at body temperature. These are 
considered convenient alternatives for rectal suppository formulations which usually 
cause mucosal irritations due to their physical state. The physicochemical properties 
of these chemically modifi ed thermoresponsive hydrogels are altered by changing 
the ratio of hydrophilic and hydrophobic segments, block length, and polydispersity. 
ReGel by MacroMed contains a triblock copolymer PLGA – PEG – PLGA, undergoes 
sol - to - gel transition on intratumoral injection, and releases paclitaxel for six 
weeks. 
Ionic-Responsive Hydrogels Administration of sodium alginate aqueous drops 
into the eye results in alginate gelation due to its interaction with calcium ions in 
the tear fl uid. Alginate with high guluronic acid and deacetylated gellan gum 
(Gelrite) show sol - to - gel conversions in the eye due to their interaction with cations 
in the tear fl uid. Timolol maleate sterile ophthalmic gel - forming solution (Timoptic - 
XE) that contains Gelrite gellan gum is commercially available. 
4.2.3.5 Gelling Agents 
A large number of gelling agents are commercially available for the preparation of 
pharmaceutical gels. In general, these materials are high - molecular - weight compounds 
obtained from either natural sources or synthetic pathways. They are water 
dispersible, possess swelling properties, and improve the viscosity of dispersions. An 
ideal gelling agent should not interact with other formulation components and 
should be free from microbial attack. Changes in the temperature and pH during 
preparation and preservation should not alter its rheological properties. In addition, 
it should be economic, readily available, form colorless gels, provide cooling sensation 
on the site of application, and possess a pleasant odor. Based on these factors, 
gelling agents are selected for different formulations. Table 8 summarizes the 
GELS 293

294 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
TABLE 8 Some Compendial Gelling Agents Used in Gels 
Name 
Molecular 
Weight 
Gelling 
Strength 
(%) Synonyms 
Offi cial 
Compendia 
Bentonite 359.16 10 – 20 Magnabrite, 
mineral soap, 
Polargel, Veegum 
HS 
BP, JP, PhEur, 
USPNF 
Carbomer 7 . 10 5 – 4 . 10 9 0.5 – 2.0 Acritamer, 
Carbopol, 
polyacrylic acid 
BP, PhEur, 
USPNF 
Carboxymethyl 
cellulose sodium 
90,000–700,000 3.0–6.0 Akucell, Aquasorb, 
Sodium CMC, 
Tylose CB 
BP, JP, PhEur, 
USPNF 
Carrageenan . 1,000,000 0.3 – 2.0 Gelcarin, Genu, 
Hygum Marine 
colloids 
USPNF 
Colloidal silicon 
dioxide 
60.08 2.0 – 10.0 Aerosil, colloidal 
silica, fumed 
silica 
BP, PhEur, 
USPNF 
Gelatin 15,000 – 25,0000 10.0 – 20.0 Cryogel, Solugel BP, JP, PhEur, 
USPNF 
Glyceryl behenate 1059.8 1.0 – 15.0 Docosanoic acid, 
glycerol behenate 
BP, PhEur, 
USPNF 
Guar gum . 220,000 1.0 – 5.0 Galactosal, Guar 
fl our, Jaguar gum, 
Meyproguar 
BP, PhEur, 
USPNF 
Hydroxypropyl 
cellulose 
50,000–1,250,000 2.0 – 5.0 Hyprolose, klucel, 
Methocel 
BP, JP, PhEur, 
USPNF 
Hydroxypropylmethyl 
cellulose 
10,000–1,500,000 1.0 – 10.0 Hypromellose BP, JP, PhEur, 
USPNF 
Magnesium aluminum 
silicate 
— 5.0 – 15.0 Veegum, 
aluminosilicic 
acid, Carrisorb, 
Magnabite 
BP, PhEur, 
USPNF 
Methylcellulose 10,000 – 220,000 1.0 – 5.0 Benecel, Methocel, 
Metolose 
BP, JP, PhEur, 
USPNF 
Poloxamer 2090 – 17,400 15.0 – 20.0 Lutrol, Monolan, 
Pluronic, 
Supronic 
BP, phEur, 
USPNF 
Polyvinyl alcohol . 20,000 – 200,000 2.5 – 10.0 Airvol, Elvanol, 
PVA, vinyl 
alcohol 
USP 
Povidone 2500–3,000,000 2.0 – 20.0 Kollidon, Plasdone, 
Polyvidone, PVP 
BP, JP, PhEur, 
USPNF 
Sodium alginate 20,000 – 240,000 10.0 – 20.0 Algin, alginic acid, 
sodium salt, 
Protanal 
BP, PhEur, 
USPNF 
Tragacanth 840,000 1.0 – 8.0 Gum Benjamin, 
Gum dragon, 
Trag, Tragant 
BP, JP, PhEur, 
USPNF 
Note : BP, British Pharmacopoeia; JP, Japanese Pharmacopoeia; PhEur, European Pharmacopoeia; USPNF, U.S. 
Pharmacopeia/National Formulary 

molecular weight, gelling strength, synonyms, and compendial status of some of 
these agents. 
The following sections briefl y describe the source, physicochemical properties, 
formulation, and preservation of some pharmacopeial gelling agents. 
Alginic Acid Alginic acid is tasteless and odorless and occurs as a yellowish white 
fi brous powder. The main source for this naturally occurring hydrophilic colloidal 
polysaccharide is different species of brown sea weed, known as Phaeophyceae. It 
consists of a mixture of d - mannuronic acid and l - glucuronic acids. It is used in gels 
due to its thickening and swelling properties. Alginic acid is insoluble in water; 
however, it absorbs 200 – 300 times its own weight of water and swells. The viscosity 
of alginic acid gels can be altered by changing the molecular weight and concentration. 
Addition of calcium salts increases the viscosity of alginic acid gels. Its viscosity 
decreases at higher temperature. Depolymerization due to microbial attack also 
results in viscosity reduction. Inclusion of an antimicrobial preservative avoids 
depolymerization and viscosity reduction during storage [6] . 
Bentonite Bentonite is a naturally occurring colloidal hydrated aluminum silicate 
and contains traces of calcium, magnesium, and iron. It is odorless, available as fi ne 
crystalline powder, and is cream to grayish in color. The particles are negatively 
charged. Its high water uptake and swelling and thickening properties make it suitable 
for preparing gels. It swells to about 12 - fold when it comes in contact with 
water. The viscosity of bentonite dispersion increases with increase in concentration. 
The gel - forming properties increase with addition of alkaline materials such as 
magnesium oxide and decrease with addition of alcohol or electrolytes. Use of hot 
water and stirring improve wetting and dispersion of bentonite particles in the 
preparation of the gel. Mixing with magnesium oxide or zinc oxide prior to addition 
helps in dispersion of bentonite in water. Prior trituration of bentonite with glycerin 
also helps in easy dispersibility in water. These dispersions are generally left for 
about 24 h to complete the swelling process. At lower concentration (10%) bentonite 
suspension exhibits the properties of shear thinning systems and at high concentrations 
(about 50 – 60%) it forms gel with fi nite yield strength [24] . 
Carbomer Carbomers are one of the widely used gelling agents in topical preparations 
due to their extensive swelling properties. They are obtained by cross - 
linking acrylic acid with allyl sucrose or allyl pentaerythritol. Various grades with 
varying degree of cross - linking and molecular weight are commercially available. 
Carbomers are generally available as hygroscopic powders, are white in color, and 
possess a characteristic odor. Presence of about 60% carboxylic acid in its composition 
makes them acidic. Carbomer 934P, 971P, 974P, and so on, are used for preparing 
clear gels. Aqueous dispersions of carbomers are usually low viscous, and on 
neutralization they form high - viscous gels. Basic materials such as sodium hydroxide, 
potassium hydroxide, sodium bicarbonate, and borax are being used for neutralizing 
carbomer dispersions. About 0.4 g of sodium hydroxide is used to neutralize 
1 g of carbomer dispersion. The viscosity of gels depends on the molecular weight 
of carbomer and its degree of cross - linking. Inclusion of antioxidants, protection 
from light, and preservation at room temperature help in retaining their viscosity 
for prolonged periods. Microbial stability of carbopol gels can be improved by 
GELS 295

296 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
adding antimicrobial preservatives. These gels are prone to discoloration in the 
presence of large amounts of electrolytes, strong acids, and cationic polymers. Glass, 
plastic, and resin - lined containers which possess good corrosion - resistant properties 
are used for packing carbomer gels [6] . 
Carboxymethylcellulose Calcium (Calcium CMC) A calcium salt of polycarboxymethyl 
ether of cellulose, calcium CMC is obtained by carboxymethylation of 
cellulose and conversion into calcium salt. Different molecular grades are prepared 
by changing the degree of carboxymethylation. It is available as a fi ne powder, white 
to yellowish white in color, and hygroscopic in nature. Calcium CMC has swelling 
and viscosity - enhancing properties in water. It can swell twice its volume in water 
[25] . 
Carboxymethylcellulose Sodium (Sodium CMC) A sodium salt of polycarboxymethyl 
ether of cellulose, sodium CMC is obtained by treating alkaline cellulose 
with sodium monochloroacetate. It is available as white - colored granular powder. 
Various viscosity grades of sodium CMC commercially available basically differ in 
their degree of substitution. The degree of substitution represents the average 
number of hydroxyl groups that are substituted per anhydroglucose unit. It is readily 
dispersible in water and forms clear gels. The aqueous solubility of CMC sodium is 
governed by the degree of substitution. Higher concentrations generally yield 
thicker gels. Although the viscosity of gels is stable over a wide range of pH (4 – 10), 
a fall in pH below 2 or a rise to above 10 results in physical instability and viscosity 
reduction. Higher viscosity is obtained at neutral pH conditions. Exposure of gels 
to higher temperature also results in viscosity reduction. Preservation at optimum 
temperature and inclusion of an antimicrobial preservative improve the physical 
and microbial stability of CMC sodium gels [25] . 
Carrageenan Extraction of some red seaweed belonging to the Rhodophyceae 
class with water or aqueous alkali yields carrageenan. It is a hydrocolloid and mainly 
contains sodium, potassium, calcium, magnesium, and ammonium sulfate esters of 
galactose and copolymers of 3, 6 - anhydrogalactose. They differ in their ester sulfate 
and anhydrogalactose content. It is available as a coarse to fi ne powder which is 
yellow to brown in color. It is odorless and tasteless. Carrageenan is soluble in hot 
water and forms gels at 0.3 – 2.0%. . - Carrageenan and . - carrageenan show good 
gelling properties [26] . 
Colloidal Silicon Dioxide Colloidal silicon dioxide is a fumed silica obtained by 
vapor hydrolysis of chlorosilanes. It is available as nongritty amorphous powder 
which is bluish white in color. It is tasteless and odorless and possesses low tapped 
density. Although insoluble in water, it readily forms a colloidal dispersion due to 
its fi ne particle size, higher surface area, and water - adsorbing properties. The bulk 
density and particle size of colloidal silicon dioxide can be altered by changing the 
method of manufacture. Transparent gels can be formed by mixing with other materials 
that possess similar refractive index. Under acidic and neutral pH conditions, 
it shows viscosity - increasing properties. This property is lost at higher pH conditions 
because of its dissolution. Viscosity of gels is not generally affected by temperature 
[27] . 

Ethylcellulose Ethylcellulose is a synthetic polymer made of . - anhydroglucose 
units connected by acetyl linkages. It is obtained by ethylating alkaline cellulose 
solution with chloroethane. Ethylcellulose is available as a free - fl owing powder 
which is tasteless and white in color. Although it is insoluble in water, it is incorporated 
into topical preparations due to its viscosity - enhancing properties. Ethanol or 
a mixture of ethanol and toluene (2 : 8) is used as a solvent. A decrease in the ratio 
of alcohol increases the viscosity. The viscosity of the dispersion is increased by 
increasing the concentration of ethylcellulose or by using a high - molecular - weight 
material. As ethylcellulose is prone to photo - oxidation at higher temperature, and 
gels are prepared and preserved at room temperature and dispensed in airtight 
containers [28] . 
Gelatin Gelatin is a protein obtained by acid or alkali hydrolysis of animal tissues 
that contain large amounts of collagen. Based on the method of manufacture, it is 
named type A or type B gelatin. Type A is obtained by partial acid hydrolysis and 
type B is obtained by partial alkaline hydrolysis. They differ in their pH, density, 
and isoelectric point. Gelatin is available as yellow - colored powder or granules. It 
swells in water and improves the viscosity of dispersions. Different molecular weights 
and particle size grades are commercially available. Gels can be prepared by dissolving 
gelatin in hot water and cooling to 35 ° C. Temperature greatly infl uences the 
viscosity and stability of gelatin dispersions. It transforms to a gel at temperatures 
above 40 ° C and undergoes depolymerization above 50 ° C. The viscosity of gelatin 
gel is also affected by microbes [29] . 
Guar Gum Guar gum is a high - molecular - weight polysaccharide obtained from 
the endosperms of guar plant. It mainly contains d - galactan and d - mannan. It is 
available as powder which is odorless and white to yellowish white in color. It readily 
disperses in water and forms viscous gels. The viscosity of gel is infl uenced by the 
particle size of material, pH of the dispersion, rate of agitation, swelling time, and 
temperature. Viscosity reduces on long - time heating. Maximum viscosity can be 
achieved within 2 – 4 h. Gels are stable at pH between 7 and 9 and show liquifi cation 
below pH 7. Addition of antimicrobial preservatives improves the microbial stability 
of guar gum gels. Rheological properties of these gels can be modifi ed by incorporating 
other plant hydrocolloids such as tragacanth and xanthan gum [30] . 
Hydroxyethyl Cellulose ( HEC) HEC is a partially substituted poly(hydroxyethyl) 
ether of cellulose. It is obtained by treating alkali cellulose with ethylene oxide. HEC 
is available as a powder and appears light tan to white in color. Different viscosity 
grades of HEC are commercially available which differ in their molecular weights. 
Clear gels are prepared by dissolving HEC in hot or cold water. Dispersions can be 
prepared quickly by altering the stirring rate of dispersion, temperature, and pH. 
Slow stirring at room temperature during the initial stages favors wetting. Increasing 
the temperature at this stage increases the rate of dispersion. Although HEC dispersions 
are stable over a wide pH range, maintaining basic pH improves the dispersion. 
The preservation temperature, formulation pH, and microbial attack infl uence the 
rheological properties of HEC dispersions. Viscosity reduces at higher temperature, 
but reverts to the original value on returning to room temperature. Lower 
and higher pH of the vehicle usually results in hydrolysis or oxidation of HEC, 
GELS 297

298 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
respectively. Some of the enzymes secreted by microbes decrease the viscosity of 
HEC dispersions. The presence of higher levels of electrolytes may also destabilize 
HEC dispersions. Inclusion of a suitable antimicrobial preservative is essential to 
retain the viscosity of HEC gels [31] . 
Hydroxyethylmethyl Cellulose ( HEMC) HEMC is a partially o - methylated and 
o - (2 - hydroxyethylated) cellulose. It is available as powder or granules which are 
white, grayish white, or yellowish white in color. Various viscosity grades of HEMC 
are commercially available, and form viscous colloidal dispersions or gels in cold 
water which has a pH in the range of 5.5 – 8 [6] . 
Hydroxypropyl Cellulose ( HPC) HPC is a partially substituted poly(hydroxypropyl) 
ether of cellulose. It is obtained by treating alkali cellulose with propylene oxide at 
higher temperatures. It is available as tasteless and odorless powder which is yellowish 
or white in color. Different viscosity grades are commercially available. 
Gradual addition of HPC powder into vigorously stirred water yields clear viscous 
dispersions or gels below 38 ° C. Increase in temperature destabilizes the dispersion 
and leads to precipitation. The viscosity of dispersions can be increased by increasing 
the concentration of HPC or by using high - molecular - weight grades. Inclusion 
of a cosolvent such as dichloromethane or methane produces viscous dispersion or 
gels with modifi ed texture. The viscosity of HPC dispersions can be increased by 
mixing with an anionic polymer. High concentrations of electrolytes destabilize 
HPC dispersions. HPC dispersions are neutral in pH (6 – 8). They undergo acid 
hydrolysis at lower pH and oxidation at higher pH. Both processes decrease the 
dispersion viscosity. In addition, certain enzymes produced by microbes degrade 
HPC and reduce its viscosity. Addition of an antimicrobial preservative is therefore 
recommended for HPC gels. Preservation of these gels from light can further 
improve its physical stability [25] . 
Hydroxypropylmethyl Cellulose ( HPMC) HPMC is a partly o - methylated and 
o - (2 - hydroxypropylated) cellulose obtained by treating alkali cellulose with chloromethane 
and propylene oxide. It is available as odorless and tasteless granular or 
fi brous powder which is creamy white or white in color. HPMC is soluble in cold 
water. Aqueous dispersions are prepared by dispersing material in about 25% hot 
water (80 ° C) under vigorous stirring. On complete hydration of HPMC, a suffi cient 
quantity of cold water is added and mixed. The gel point of HPMC dispersions varies 
from 50 to 90 ° C. Gels are stable over a wide pH range (3 – 11). The viscosity HPMC 
dispersions depends on the concentration of material used, its molecular weight, 
vehicle composition, presence of preservatives, and so on. Viscous gels can be prepared 
using high concentrations of high - molecular - weight grades. Inclusion of 
organic solvents such as ethanol or dichloromethane improves the viscosity. Addition 
of an antimicrobial preservative (e.g., benzalkonium chloride) minimizes microbial 
spoilage of HPMC gels [25] . 
Glyceryl Behenate Glyceryl behenate is a mixture of glycerides of fatty acids 
which is obtained by esterifi cation of glycerin with behenic acid. It may also contain 
arachidic acid, stearic acid, erucic acid, lignoceric acid, and palmitic acid. It is available 
as a waxy mass or powder, possesses a faint odor, and is white in color. It is 

practically insoluble in water and soluble in dichloromethane and chloroform. It is 
used as a viscosity - increasing agent in silicon gels [6] . 
Glyceryl Monooleate ( GMO) GMO is a mixture of glycerides of fatty acids 
obtained by esterifi cation of glycerol with oleic acid. It may also contain linoleic 
acid, palmitic acid, stearic acid, linolenic acid, arachidic acid, and eicosenoic acid. It 
is available as a partially solidifi ed or oily liquid. GMO is insoluble in water. Self - 
emulsifying grades that contain an anionic surfactant disperse easily and swell in 
water. The nonemulsifying grades are used as emollients in topical preparations and 
self - emulsifying grades are used as emulsifi ers in aqueous emulsions [6] . 
Magnesium Aluminum Silicate ( MAS) MAS is also known as veegum. It is a 
polymeric complex of magnesium, aluminum, silicon, oxygen, and water and is 
obtained from silicate ores. Based on the ratio of aluminum and magnesium and 
viscosity, it is classifi ed as types IA, IB, IC, and IIA. It is available as fi ne powder 
that is odorless, tasteless, and off - white to creamy white in color. Although MAS is 
insoluble in water, it swells to a large extent and produces viscous colloidal dispersions. 
Use of higher concentration, addition of electrolytes, and heating of dispersion 
usually improve the viscosity [32] . 
Methylcellulose ( MC) MC is a long - chain cellulose polymer with methoxyl substitutions 
at positions 2, 3, and 6 of the anhydroglucose ring. It is synthesized by 
methylating alkali cellulose with methyl chloride. The degree of substitution of 
methoxy groups infl uences the molecular weight, viscosity, and solubility characteristics 
of MC. It is available as powder or granules and is odorless, tasteless, and white 
to yellowish white in color. MC is insoluble in hot water but slowly swells and forms 
viscous colloidal dispersions in cold water. Gels can be prepared by initially mixing 
the methylcellulose with half the volume of hot water ( . 70 ° C) followed by addition 
of the remaining volume of cold water. Viscosity of these dispersions can be increased 
by using high - concentration or high - molecular - weight grades of methylcellulose. 
Higher processing or preservation temperatures reduce the viscosity of formulations, 
which regain their original state on cooling to room temperature. MC aqueous 
dispersions show pH values of 5 – 8. Reduction in pH to less than 3 leads to acid - 
catalyzed hydrolysis of glucose – glucose linkages and results in low viscosity. Antimicrobial 
preservatives are generally included to enhance the microbial stability of 
dispersions. Salting out is observed when high concentrations of electrolytes are 
added to methylcellulose dispersions. The viscosity of methylcellulose dispersions is 
also infl uenced by the presence of formulation excipients and drugs [25] . 
Poloxamer Poloxamers are copolymers of ethylene oxide and propylene oxide. 
Different molecular weight grades that are different in physical form, solubility, and 
melting point are available. Poloxamer 124 is a colorless liquid, whereas poloxamers 
188, 237, 338, and 407 are solids at room temperature. All poloxamer grades are 
freely soluble in water and form gels at higher concentrations. The pH of aqueous 
liquids ranges between 5 and 7.5 [33] . 
Polyethylene Oxide Polyethylene oxide is a nonionic homopolymer of ethylene 
oxide synthesized by polymerization of ethylene oxide. It is available as a free - 
GELS 299

300 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
fl owing powder white to off - white in color with a slight ammonia odor. Various 
molecular weight grades of polyethylene oxide are commercially available. They 
swell in water and form viscous dispersions or gels based on the concentration and 
grade used. Inclusion of alcohol improves the rheological stability of polyethylene 
oxide dispersions [6] . 
Polyvinyl Alcohol ( PVA ) PVA is a synthetic polymer prepared by hydrolysis of 
polyvinyl acetate. It is available as a granular powder which is odorless and white 
in color. Mixing with water at room temperature, heating for about 5 min at 90 ° C, 
followed by cooling with constant mixing yield aqueous dispersions or gels. Higher 
viscosities can be obtained by using high - viscosity grades. Addition of borax improves 
the gelling properties of PVA, whereas inorganic salts destabilize these dispersions. 
The pH of PVA dispersions ranges between 5 and 8. Physical and chemical decompositions 
occur at lower and higher pH conditions. Incorporation of an antimicrobial 
preservative and storage at room temperature improve its stability [6] . 
Povidone Povidone is a synthetic polymer consisting of 1 - vinyl - 2 - pyrrolidinone 
units. It is available as a fi ne powder and appears white to creamy - white in color. 
Various molecular weight grades of povidone are available which differ in their 
degree of polymerization. Povidone is soluble in water and forms viscous solutions 
and gels based on the concentration and viscosity grade used. Decomposition occurs 
when dispersions are heated to about 150 ° C. The pH of aqueous dispersions ranges 
from 3 to 7. The microbial stability of povidone aqueous dispersions can be increased 
by adding preservatives [6] . 
Propylene Carbonate ( PC) PC is prepared by reacting propylene chlorohydrin 
with sodium bicarbonate. It is available as a clear liquid with a faint odor. Mixtures 
of PC and propylene glycol are good solvents for corticosteroids in topical preparations. 
It is incompatible with strong acids, bases, and amines. The pH of 10% aqueous 
dispersion is 6.0 – 7.5 [34] . 
Propylene Glycol Alginate ( PGA) PGA is a propylene glycol ester of alginic acid 
obtained by treating alginic acid with propylene oxide. It is available as granular or 
fi brous powder which is odorless, tasteless, and white to yellowish - white in color. 
PGA is soluble in water and forms viscous colloidal dispersions. The viscosity of 
these dispersions is based on the concentration of PGA, temperature, and pH. Its 
aqueous solubility decreases at higher temperatures. The aqueous dispersions are 
acidic in nature and more stable at pH 3 – 6. Higher pH leads to saponifi cation. As 
these dispersions are prone to microbial spoilage, antimicrobial preservatives are 
generally included [6] . 
Sodium Alginate Sodium alginate is obtained by extraction of alginic acid from 
brown seaweed followed by neutralization with sodium bicarbonate. Alginic acid is 
composed of d - mannuronic acid and l - guluronic acid. It is available as a powder 
which is tasteless, odorless, and white to yellowish - brown in color. Sodium alginate 
forms viscous gels in water. Dispersing agents such as glycerol, propylene glycol, 
sucrose, and alcohol are added to improve dispersion. The presence of low concentration 
of electrolytes improves the viscosity, whereas at high concentrations salting 

out takes place. The viscosity of gel is based on the concentration of sodium alginate, 
temperature, pH, and other additives. Various viscosity grades of sodium alginate 
are commercially available. Aqueous dispersions are stable at pH 4 – 10. Precipitation 
or decrease in viscosity is observed when the pH is below or above these values. 
Autoclaving or heating above 70 ° C results in depolymerization and decrease in 
viscosity. Inclusion of preservative is essential to maintain the microbial stability of 
sodium alginate topical gels [35] . 
Tragacanth Tragacanth is a polysaccharide polymer obtained from some Astragalus 
species. It is composed of two polysaccharides: bassorin (water insoluble) and 
tragacanthin (water soluble). It is available as odorless powder white to yellowish 
in color and possesses mucilaginous taste. Tragacanth swells about 10 times its 
weight in water and forms viscous solutions or gels. Tragacanth is usually added with 
vigorous stirring to avoid lump formation. Wetting agents such as glycerin, propylene 
glycol, and 95% ethanol are used in initial stages to improve wetting and dispersion 
of tragacanth in water. The viscosity of tragacanth dispersions is infl uenced by 
the processing temperature and formulation pH. High temperature usually increases 
the viscosity of gels. Tragacanth dispersions show higher viscosity at pH 8 and starts 
decreasing at higher pH. These gels usually contain preservatives such as benzoic 
acid or a combination of methyl and propyl parabens for effective preservation from 
microbial attack. The viscosity of tragacanth dispersions reduces in the presence of 
strong mineral and organic acids and sodium chloride [6] . 
4.2.3.6 Preparation and Packaging 
Gels are relatively easier to prepare compare to ointments and creams. In addition 
to the gelling agent, medicated gels contain drug, antimicrobial preservatives, stabilizers, 
dispersing agents, and permeation enhancers. Some of the factors discussed 
below are essential to obtain a uniform gel preparation. 
Order of Mixing The order of mixing of these ingredients with the gelling agent 
is based on their infl uence on the gelling process. If they are likely to infl uence the 
rate and extent of swelling of the gelling agent, they are mixed after the formation 
of gel. In the absence of such interference, the drug and other additives are mixed 
prior to the swelling process. In this case, the effects of mixing temperature, swelling 
duration, and other processing conditions on the physicochemical stability of the 
drug and additives are also considered. Ideally the drug and other additives are 
dissolved in the swelling solvent, and the swelling agent is added to this solution 
and allowed to swell. 
Gelling Medium Purifi ed water is the most widely used dispersion medium in the 
preparation of gels. Under certain circumstances, gels may also contain cosolvents 
or dispersing agents. A mixture of ethanol and toluene improves the dispersion of 
ethylcellulose, dichloromethane and methanol increase the viscosity of hydroxypropyl 
cellulose dispersions, alcohol improves the rheological stability of polyethylene 
oxide gels, and inclusion of glycerin, propylene glycol, sucrose, and alcohol improves 
the dispersion of sodium alginate dispersions. Borax is included in polyvinyl alcohol 
gels and magnesium oxide, zinc oxide, and glycerin are included in bentonite gel as 
GELS 301

302 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
dispersing agents. Care should be taken to avoid the evaporation or degradation of 
these cosolvents and dispersing agents during the preparation of gels. 
Processing Conditions and Duration of Swelling The processing temperature, pH 
of the dispersion, and duration of swelling are critical parameters in the preparation 
of gels. These conditions vary with each gelling agent. For instance, hot water is 
preferred for gelatin and polyvinyl alcohol, and cold water is preferred for methylcellulose 
dispersions. Carbomers, guar gum, hydroxypropyl cellulose, poloxamer, 
and tragacanth form gels at weakly acidic or near - neutral pH conditions (pH 5 – 8). 
Gelling agents such as carboxymethyl cellulose sodium, hydroxypropylmethyl cellulose, 
and sodium alginate form gels over a wide pH range (4 – 10). Hydroxyethyl 
cellulose forms gel at alkaline pH condition. A swelling duration of about 24 – 48 h 
generally helps in obtaining homogeneous gels. Natural gums need about 24 h and 
cellulose polymers require about 48 h for complete hydration. 
Removal of Entrapped Air Entrapment of air bubbles in the gel matrix is a 
common issue, especially when the swelling process involves a mixing procedure or 
the drug and other additives are added after the swelling process. Positioning the 
propeller at the bottom of the mixing container minimizes this issue to a larger 
extent. Further removal of air bubbles can be achieved by long - term standing, low - 
temperature storage, sonication, or inclusion of silicon antifoaming agents. In large - 
scale production, vacuum vessel deaerators are used to remove the entrapped air. 
Packaging Being viscous and non - Newtonian systems, gels need high attention 
during packing into containers. Usually they are packed into squeeze tubes or jars 
made of plastic materials. Aluminum containers are also used when the product pH 
is slightly acidic. Pump dispensers and prefi lled syringes are sometimes used for 
packing gels. As most of the gels contain an aqueous phase, preservation in airtight 
containers helps in protecting them from microbial attack. Usually they are preserved 
at room temperature and protected from direct sunlight and moisture. 
In large - scale production, different mills, separators, mixers, deaerators, shifters, 
and packaging machines are used. Most of this equipment is similar to those discussed 
under ointments and creams. Figure 3 shows a “ one - bowl ” vacuum processing 
machine manufactured by FrymaKoruma - Rheinfelden (Romaco) for the 
preparation gels. Batch sizes ranging from 15 to 160 L are processed using this 
machine. It uses an extremely effi cient high - shear rotor/stator system for homogenizing 
and a counterrotating mixing system for macromixing. The raw materials are 
drawn into the multichamber system of the homogenizer by vacuum and then mixed 
and pumped into the homogenizing zone. The product which enters the vessel is 
mixed, sheared, and recirculated. All the entrapped air is removed during the recirculation. 
The machine also has an insulated jacket for controlling the processing 
temperature. 
4.2.3.7 Evaluation 
Various pharmacopeial and nonpharmacopeial tests are carried out to evaluate the 
physicochemical, microbial, in vitro, and in vivo characteristics of gels. These tests 
are meant for assessing the quality of gel formulations and minimizing the batch -

to - batch variations. Some of the tests recommended by the USP for gels include 
minimum fi ll, pH, viscosity, microbial screening, and assay. In some cases sterility 
and alcohol content are also specifi ed. The USP also recommends storage for each 
compendial gel formulation. Table 9 shows the quality control tests and storage 
requirements that are specifi ed for some pharmacopeial gels. The procedures for 
minimum fi ll, microbial screening, sterility, assay, in vitro drug release, and in vivo 
bioequivalence are similar to those of ointments and creams. The procedures for 
additional tests such as homogeneity, surface morphology, pH, alcohol content, 
rheological properties, bioadhesion, stability, and ex vivo penetration are described 
below. 
Homogeneity and Surface Morphology The homogeneity of gel formulations is 
usually assessed by visual inspection and the surface morphology by using scanning 
electron microscopy. Generally, the swollen gel is allowed to freeze in liquid nitrogen 
and then lyophilized by freeze drying. It is assumed that the morphologies of 
the swollen samples are retained during this process. The lyophilized hydrogel is 
gold sputter coated and viewed under an electron microscope. 
pH Many gelling agents show pH - dependent gelling behavior. They show highest 
viscosity at their gel point. Determination of pH is therefore important to maintain 
consistent quality. As conventional pH measurements are diffi cult and often give 
erratic results, special pH electrodes are used for viscous gels. Flat - surface digital 
FIGURE 3 Vacuum processing machine used for preparation of gels. (Courtesy of 
FrymaKoruma - Rheinfelden, Switzerland.) 
GELS 303

304 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
TABLE 9 USP Specifi cations for Some Offi cial Gels 
Drug Quality Control Tests Packaging and Storage Requirements 
Aminobenzoic 
acid 
Minimum fi ll, pH (4.0 – 6.0), 
alcohol content, and assay 
Tight, light - resistant containers 
Benzocaine Microbial limits, minimum fi ll, 
and assay 
Well - closed containers 
Benzoyl peroxide pH (2.8 – 6.6), and assay Tight containers 
Betamethasone 
benzoate 
Microbial limits, minimum fi ll, 
and assay 
Tight containers; store at 25 ° C, 
excursions permitted between 15 
and 30 ° C; protect from freezing 
Clindamycin 
phosphate 
Minimum fi ll, pH (4.5 and 
6.5), and assay 
Tight containers 
Desoximetasone Minimum fi ll, alcohol content, 
and assay 
Collapsible tubes at controlled room 
temperature 
Dexamethasone Minimum fi ll and assay Collapsible tubes; keep tightly closed; 
avoid exposure to temperatures 
exceeding 30 ° C 
Dyclonine 
hydrochloride 
pH (2.0 and 4.0), and assay Collapsible, opaque plastic tubes or in 
tight, light - resistant glass containers 
Erythromycin Minimum fi ll and assay Tight containers 
Fluocinonide Minimum fi ll and assay Collapsible tubes or tight containers 
Hydrocortisone Minimum fi ll and assay Tight containers 
Lidocaine 
hydrochloride 
Sterility, minimum fi ll, pH 
(7.0 – 7.4), and assay 
Tight containers 
Metronidazole Minimum fi ll, pH (4.0 and 
6.5), and assay 
Laminated collapsible tubes at 
controlled room temperature 
Naftifi ne 
hydrochloride 
Microbial limits, minimum fi ll, 
pH (5.5 – 7.5), content of 
alcohol, and assay 
Tight containers 
Salicylic acid Alcohol content and assay Collapsible tubes or tight containers, 
preferably at controlled room 
temperature 
Sodium sulfi de pH (11.5 – 13.5) and assay Tight containers at controlled room 
temperature or in a cool place 
Stannous fl uoride Viscosity, pH (2.8 – 4.0), 
stannous ion content, total 
tin content, and assay 
Well - closed containers 
Tolnaftate Minimum fi ll and assay Tight containers 
pH electrodes from Crison, combination electrodes that contain a built - in temperature 
probe, a bridge electrolyte chamber and movable sleeve junction from 
Mettler, and combination pH puncture electrodes with spear - shaped tip from 
Mettler are some commercially available pH measurement systems for semisolid 
formulations. 
Alcohol Content Alcohol levels in some gel preparations are determined by gas 
chromatographic (GC) methods. Desoxymetasone gel USP and naftifi ne hydrochloride 
gel USP contain 18 – 24% and 40 – 45% (w/w) of ethyl alcohol, respectively. In a 
desoxymetasone gel, the sample is dissolved in methanol and injected into a gas 

chramatograph for quantitative analysis. Isopropyl alcohol is used as an internal 
standard. In naftifi ne hydrochloride gel, n - propyl alcohol is used as an internal 
standard and water is used as the diluting solvent [15] . 
Rheological Studies Viscosity measurement is often the quickest, most accurate, 
reliable method to charactreize gels. It gives an idea about the ease with which gels 
can be processed, handled, or used. Some of the commonly used tests for characterizing 
rheology of gels are yield stress, critical strain, and creep. Yield stress refers to 
the stress that must be exceeded to induce fl ow. This helps in characterizing the fl ow 
nature of non - Newtonian systems. Critical strain or gel strength refers to the minimum 
energy needed to disrupt the gel structure. When samples are subjected to increasing 
stress, viscosity is maintained as long as the gel structure is maintained. When the 
gel ’ s intermolecular forces are overcome by the oscillation stress, the sample breaks 
down and the viscosity falls. The higher the critical strain, the better the physical 
integrity of gel systems. Creep or recovery helps in assessing the strength of bonds 
in a gel structure. This is assessed by determining relaxation times, zero - shear viscosity, 
and viscoelastic properties. 
Based on the nature of the test material, different techniques are employed to 
measure the rheological parametrs of gels. Very sophisticated automatic equipment 
is commercially available for measurements. Cup - and - bob viscometers and cone - 
and - plate viscometers are widely used for viscous liquids and gels. They measure 
the frictional force that is created when gels start fl owing. These viscometers are 
usually calibrated with certifi ed viscosity standards before each measurement. 
General - purpose silicone fl uids which are less sensitive to temperature change are 
used as standards. The viscosity of gels is affected by the experimental temperature 
and shear rate and the gels exhibit liquid - or solidlike properties. Hence the viscosity 
of these non - Newtonian systems are recorded at several shear rates under controlled 
temperatures. The USP specifi es the operating conditions for each gel formulation. 
Commercially available viscometers include Brookfi eld rotational 
viscometers, Haake rheometers, Schott viscoeasy rotational viscometers, Malvern 
viscometers, and Ferranti - Shirley cone - and - plate viscometers. 
Bioadhesion This test is performed to assess the force of adhesion of a gel with 
biological membranes. The bioadhesive property is preferred for ophthalmic, nasal 
buccal, and gastroretentive gel formulations. Drugs applied as solutions, viscous 
solutions, and suspensions drain out from these biological locations within a short 
time and only a limited fraction of drug elicits the pharmacological activity. Products 
with higher bioadhesion thus help in increasing the contact time between drugs and 
absorbing surface and improve their availability. The bioadhesive properties of 
gels are measured using various custom - designed equipment. All the equipment, 
however, measures the force required to detach the gel from a biological surface 
under controlled experimental conditions (e.g., temperature, wetting level, contact 
time, contact force, surface area of tissue). A typical bioadhesion measurement 
system consists of a moving platform and a static platform. A tissue from a particular 
biological region is fi xed onto these platforms and a known quantity of the test 
product is uniformly applied to the tissue surface of the lower static platform. The 
upper moving platform is allowed to contact with the product surface with a known 
contact force. After allowing for a short contact time, the moving platform is 
GELS 305

306 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
separated from the product with a constant rate. The force required to detach the 
mucosal surface from the product is recorded. The analog signals generated by 
precision load cells are then converted to digital signals through data acquisition 
systems and processed using specifi c software programs. 
Stability Studies Being dispersed systems containing water in their matrix, gels 
are prone to physical, chemical, and microbial stability issues. Syneresis is a commonly 
observed physical stability problem with gels. It involves squeezing out dispersion 
medium due to elastic contraction of polymeric gelling agents. This results 
in shrinkage of gels. Syneresis can be determined by heating the gels to a higher 
temperature followed by rapid cooling using an ice water bath at room temperature. 
The sample is preserved at 4 ° C for about a week, and water loss from the gel matrix 
is measured. Water loss is measured by weighing the mass of the gel matrix after 
centrifugation. Absence of syneresis indicates higher physical stability of gels. The 
chemical stability of drugs in the gel matrix is determined using stability - indicating 
analytical methods. Studies are conducted at accelerated temperature, moisture, and 
light conditions to determine the possible degradation of drug in the gel. 
Ex Vivo Penetration Ex vivo studies are carried out to examine the permeation 
of drug from gels through the skin or any other biological membrane. As with in 
vitro release studies, ex vivo penetration is conducted using vertical diffusion cells 
or modifi ed cells with fl ow - through design. In this case, the receiver side is fi lled 
with phosphate buffer solution of pH 7.4 to simulate the biological pH of human 
blood. Skin samples from different animal sources such as rats, rabbits, pigs, and 
human cadavers are used for screening dermatological products. The stratum 
corneum layer of the skin is separated from the dermis before mounting onto the 
diffusion cells. The epidermis is separated by immersing the skin sample in normal 
saline or purifi ed water which is maintained at 60 ° C for 2 min followed by immersion 
into cold water for 30 s. Careful peeling helps in the separation of the epidermis 
layer from the dermis. This layer is mounted between the donor and receiver sides 
and studies are conducted after application of test gel over the surface of the stratum 
corneum in the donor side. Samples are withdrawn at different time intervals and 
analyzed for drug permeation by suitable analytical techniques. 
4.2.3.8 Typical Pharmacopeial and Commercial Examples 
Gels are becoming popular dosage forms for delivering various categories of drugs 
for treating dermatological, oral, ophthalmic, vaginal, and other conditions. Many 
dermatological gels are used for treating mild to moderate acne, eczema, dermatitis, 
allergies, rash, and psoriasis and for removal of common warts. Oral gels are available 
for relieving painful mouth sores, treating tooth decay, preventing tooth plaque, 
and relieving infl ammation of the gums, and vaginal gels are available for treating 
certain type of vaginal infections (e.g., bacterial vaginosis). Some special types of 
gels are available for preventing or controlling pain during certain medical procedures, 
numbing and treating urinary tract infl ammation (urethritis), and numbing 
mucous membranes. Table 10 shows some of the commercially available compendial 
gels. 

TABLE 10 Examples of Compendial/Commercial Gels 
Drug a Category Indication 
Commercial 
Products 
Strength 
(%) 
Benzocaine Local 
anesthetic 
In mouth to relieve pain 
or irritation caused by 
many conditions 
Oratect Gel, 
Num Zit 
Gel 
7.5, 10 
Benzoyl 
peroxide 
Keratolytic Mild to moderate acne Persa - Gel, 5 
Benzagel 
10 
5.0, 10 
Betamethasone Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash 
Diprolene 0.05 
Clindamycin 
phosphate 
(vag) 
Antibiotic Certain types of vaginal 
infection (e.g., bacterial 
vaginosis) 
Cleocin T 1.0 
Desoximetasone Anti - 
infl ammatory 
Eczema, dermatitis, 
allergies, and rash. 
Topicort 0.05 
Dyclonine 
hydrochloride 
Antipruritic 
and local 
anesthetic 
Relieve painful mouth 
sores 
Dyclone 0.5, 1.0 
Erythromycin Antibiotic Acne and skin infection 
due to bacteria 
Erygel 2.0 
Fluocinonide Anti - 
infl ammatory 
Psoriasis, eczema, 
dermatitis, allergies, 
and rash 
Lidex 0.05 
Lidocaine 
hydrochloride 
Local 
anesthetic 
Prevent and control pain 
during certain medical 
procedures, numb and 
treat urinary tract 
infl ammation 
(urethritis), and numb 
mucous membranes 
Xylocaine, 
Anestacon 
2.0 
Metronidazole 
(vag) 
Antifungal Certain types of bacterial 
infections in the vagina 
Metrogel 0.75, 1.0 
Naftifi ne 
hydrochloride 
Antifungal Fungal infections of skin 
such as jock itch, 
athlete ’ s feet, or 
ringworm 
Naftin 1.0 
Salicylic acid Keratolytic Removal of common 
warts 
Sal - Plant 
Gel 
17.0 
Stannous 
fl uoride 
Fluoride Treat tooth decay, prevent 
tooth plaque and 
infl ammation of gums 
Flo - Gel, 
Gel - Kam 
0.4 
Tolnaftate Antifungal Skin infections such as 
athlete ’ s foot, jock itch, 
and ringworm 
Tolnaftate 1.0 
a vag: vaginal gel. 
GELS 307

308 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
TABLE 11 Description on SUPAC Guidelines for Nonsterile Semisolid Dosage Forms 
Type of Change Level Description 
Change in 
components 
and 
composition 
1 Partial deletion or deletion of color, fragrance, or fl avor; up to 
5% excipient change in approved amount; change in supplier 
for structure forming or technical - grade excipient 
2 Excipient changes from 5 to 10%; change in supplier for 
structure forming excipient, which is not covered under level 
1; change in technical grade of structure forming excipient; 
change in particle size of drug if drug is in suspension 
3 Qualitative and quantitative changes in excipient not covered 
under levels 1 and 2; any change in crystallinity of drug if 
drug is in suspension 
4.2.4 REGULATORY REQUIREMENTS FOR SEMISOLIDS 
Regulatory agencies such as the Center for Drug Evaluation and Research (CDER) 
have at the Food and Drug Administration (FDA) have set forth guidelines for 
various pharmaceutical activities to ensure the identity, strength, quality, safety, and 
effi cacy of semisolid drug products. A manufacturer of semisolid formulations needs 
to fulfi ll these requirements at the time of fi ling for investigational new drug (IND), 
abbreviated new drug application (ANDA), or abbreviated antibiotic drug application 
(AADA). Standard chemistry, manufacturing, and control (CMC) tests are 
necessitated for all dermatological drug products. Additional information on polymorphic 
form, particle size distribution, and other characteristics is needed for 
submitting an NDA. When an ANDA for a semisolid product is fi led, the manufacturer 
should meet the standards of compendial requirements if available and match 
the important in vitro and in vivo characteristics of the reference listed drug (RLD). 
If such information is not available, appropriate in vitro release methods are submitted 
to ensure batch - to - batch consistency. Even at later stages, if changes are 
made for an approved semisolid product with respect to its components, composition, 
equipment, process, batch size, and manufacturing site, the formulator should 
submit necessary details to the regulatory agency. 
A typical guideline that defi nes the types and levels of scale - up and postapproval 
changes (SUPAC) is outlined in Table 11 . Based on the type and level of change, 
the manufacturer needs to submit application and compendial product release 
requirements, executed batch records, accelerated and long - term stability data, identifi 
cation and assay for new preservative, preservative effectiveness test at lowest 
specifi ed level, validation methods to support absence of interference of preservative 
with other tests, in vitro release test, and in vivo bioequivalence data to the 
FDA. When changes are made with respect to the quality and quantity of excipients 
or crystallinity of drug, especially if the drug is in suspension, in vivo bioequivalence 
studies are recommended. As routine pharmacokinetic studies do not produce 
measurable quantities of drug in blood, plasma, urine, and other extracutaneous 
biological fl uids, dermatopharmacokinetic (DPK) studies and pharmacodynamic or 
comparative clinical trials are recommended to establish bioequivalence of topical 
products. Table 12 shows specifi c requirements for various SUPAC levels. If bioavailability 
or bioequivalence data of a highest strength product are already available, 

TABLE 12 SUPAC Requirements for Nonsterile Semisolid Dosage Forms 
Parameter 
Change 
Level 
Requirements a 
A B C D E F G H I J K 
Change in 
components 
and 
composition 
1 • • 
2 • • • • 
3 • • • • • 
Change in 
preservative 
components 
and 
composition 
1 • • 
2 • • 
3 • • • • • 
Change in 
manufacturing 
equipment 
1 • • 
2 • • • • 
Change in 
manufacturing 
process 
1 • 
2 • • • • 
Change in batch 
size 
1 • • • 
2 • • • 
REGULATORY REQUIREMENTS FOR SEMISOLIDS 309 
Type of Change Level Description 
Change in 
preservative 
components 
and 
composition 
1 Less than 10% quantitative change in preservative 
2 10 – 20% quantitative change in preservative 
3 Deletion or more than 20% quantitative change in 
preservative; inclusion of a different preservative 
Change in 
manufacturing 
equipment 
1 Change to automated or mechanical equipment for transfer of 
ingredients; use of alternative equipment of same design and 
operating principles 
2 Use of alternative equipment of different design and operating 
principles; change in type of mixing equipment 
Change in 
manufacturing 
process 
1 Changes in process within approved application ranges; 
addition of formulation additives 
2 Changes in process outside approved application ranges; 
process of combining phases 
Change in batch 
size 
1 Batch size changes upto 10 times of pivotal clinical trial or 
biobatch 
2 Batch size changes above 10 times of pivotal clinical trial or 
biobatch 
Change in 
manufacturing 
site 
1 Changes within existing facility 
2 Changes within same campus or facilities in adjacent city 
blocks 
3 Change to different campus; change to a contract manufacturer 
TABLE 11 Continued

310 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
in vitro release data are used to evaluate the in vivo bioequivalence of a lower 
strength product [16] . 
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Parameter 
Change 
Level 
Requirements a 
A B C D E F G H I J K 
Change in 
manufacturing 
site 
1 • 
2 • • • • 
3 • • • • • 
a Only those highlighted with black circles: 
A: Application/compendial product release requirement. 
B: Executed batch records. 
C: long - term stability data for fi rst production batch. 
D: 3 - month accelerated stability data for 1 batch and long - term data for fi rst production batch. 
E: 3 - month accelerated stability data for 1 batch and long - term data for fi rst 3 production batches if signifi 
cant information is available or 3 - month accelerated stability data for 3 batches and long - term data 
for fi rst 3 production batches if signifi cant information is not available. 
F: 3 - month accelerated stability data for 1 batch and long - term data for fi rst production batch if signifi - 
cant information is available or 3 - month accelerated stability data for 3 batches and long - term data for 
fi rst 3 production batches if signifi cant information is not available. 
G: In vitro release test. 
H: In vivo bioequivalence. 
I: Preservative effectiveness test at lowest specifi ed preservative level. 
J: Identifi cation and assay for new preservative; validation methods to support absence of interference 
with other tests. 
K: Location of new site. 
TABLE 12 Continued

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10. Mapstone , G. E. ( 1974 ), Crystalization of cetyl alcohol from cosmetic emulsions , Cosmet. 
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32 – 36 . 
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REFERENCES 311

312 SEMISOLID DOSAGES: OINTMENTS, CREAMS, AND GELS 
30. Goldstein , A. M. , Alter , E. N. , and Seaman , J. K. ( 1973 ), Guar gum , in Whistler , R. L. , Ed., 
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40 , 52 – 59 . 

313 
4.3 
LIQUID DOSAGE FORMS 
Maria V. Rubio - Bonilla 1 , Roberto Londono 1 , and Arcesio Rubio 2 
1 Washington State University, Pullman, Washington 
2 Caracas, Venezuela 
Contents 
4.3.1 Introduction 
4.3.2 Generalities 
4.3.2.1 Dosage Form 
4.3.2.2 Liquid Dosage Form 
4.3.2.3 Dispersed Systems 
4.3.2.4 Solutions 
4.3.2.5 Manufacturing of Nonparenteral Liquid Dosage Forms 
4.3.2.6 Optimizing Drug Development Strategies 
4.3.2.7 Unit Operation or Batch 
4.3.2.8 Batch Management 
4.3.2.9 Steps of Liquids Manufacturing Process 
4.3.2.10 Protocols 
4.3.3 Approaches 
4.3.4 Critical Aspects of Liquids Manufacturing Process 
4.3.4.1 Physical Plant 
4.3.4.2 Equipment 
4.3.4.3 Particle Size of Raw Materials 
4.3.4.4 Compounding: Effects of Heat and Process Time 
4.3.4.5 Uniformity of Oral Suspensions 
4.3.4.6 Uniformity of Emulsions 
4.3.4.7 Microbiological Quality 
4.3.4.8 Filling and Packing 
4.3.4.9 Stability 
4.3.4.10 Process Validation 
4.3.5 Liquid Dosage Forms 
References 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

314 LIQUID DOSAGE FORMS 
4.3.1 INTRODUCTION 
Liquid dosage forms are designed to provide the maximum therapeutic response in 
a target population with diffi culty swallowing tablets and capsules and/or to produce 
rapid therapeutic effects. The major ingredient in most liquid dosage forms is water. 
While it is the safest and most palatable solvent option, water quality is signifi cant 
for the stability of pharmaceutical dosage forms. Furthermore, the Food and 
Drug Administration (FDA) “ Guide to Inspections of Dosage Form Drug Manufacturer 
’ s — CGMPRs ” considers microbial contamination due to inappropriate 
design and control of purifi ed water systems as the most common problem of liquid 
dosage forms. Solutions and dispersions studied in this chapter are chemically, 
microbiologically, and/or physically unstable systems that require a high level of 
organizational management of manufacturing processes in order to maintain a state 
of apparent stability, at least until the expiration date [1] . 
The pharmaceutical industry manufactures dosage forms in large - scale formulations. 
The decision to scale up is based on the economics of the production process 
related to costs of materials, personnel, equipment, and control [2] . To reduce costs 
of wastes and to obtain high - quality and effi cacious drug products, the strategic plan 
to be applied during the process has to be developed carefully. In fact, the variables 
that affect product quality are identifi ed and understood in the process instead of 
tested into the fi nal product [3] . 
Commercial liquid dosage forms reach large - scale production after being preformulated 
at the laboratory level followed by formulation at the small scale and then 
at the pilot plant scale. Due to the complexity of the manufacturing process, scale - up 
from pilot to commercial production is not a simple extrapolation. The approaches 
to the four levels of production are different. Most of the formulation ingredients 
are analyzed, studied, and selected at the laboratory scale. While small - scale production 
is more focused on the liquid preparation procedure with higher amounts of 
ingredients, the main issues at the pilot plant scale are the design of infrastructure 
and reduction of costs. Commercial production introduces problems that are not a 
major issue on a small scale, for instance, materials handling and storage, pulverizing, 
mixing, dissipation of the generated heat during production, time control, personnel 
administration, and bottle - fi lling capabilities. Furthermore, purifi ed water is essential 
for the manufacturing of these products as well as on - site packing capabilities 
[2] . 
The organization and advance of the pharmaceutical industry should be focused 
on three main points of project development based on quality by design (QbD): 
product objective (design of experiment, DoE), production resources (process analytical 
technology, PAT), and product acceptability (quality system) [3] . Manufacturers 
of liquid dosage forms must ensure safety, effi cacy, stability, elegance, and 
acceptability of the fi nal drug product while achieving development and clinical 
milestones [1] . Achieving the desirable clinical attributes of the product effi cacy 
means ensuring potency stability by confi rming the functionability of the manufacturing 
process and quality system. The stability and safety of the product are 
goals to be reached through chemical and microbiological stability by establishing 
and updating manufacturing and quality control protocols of product development. 
Time control and aesthetic considerations refl ect the physical stability through 
product elegance and acceptability. Flavoring, sweetening, coloring, and texturing 

are both challenges and opportunities. They are challenges because “ no single 
correct method exists to solve signifi cant problems of elegance ” ; they are opportunities 
because “ they enable a pharmacist to prepare a product more easily 
accepted by the patient ” [4] . Although the most important characteristic of a 
dosage form is effi cacy, there are other characteristics that remain important subjects 
for the manufacturing of liquid dosage forms such as safety as well as chemical, 
physical, and microbiological stabilities. From a pharmaceutical point of view, 
stability problems are the main causes of safety complaints. Despite its signifi cance, 
some companies decide to outsource stability services [5] . To solve or minimize 
stability problems in drug products, it is necessary to analyze and enhance the 
development of critical control points in each operation of the full manufacturing 
process as well as expected variances and tolerance limits. 
Except some aqueous acids, water in aqueous solutions is an excellent media for 
microbiological growth, such as molds, yeast, and bacteria. Typical microorganisms 
affecting drug microbiological stability are Pseudomonas, Escherichia coli Salmonella 
, and Staphylococcus [1] . Defi cient methods or an insuffi cient preservative 
system may be the principal causes of microbiological contamination in the pharmaceutical 
industry of liquid manufacturing [6] . 
Chemical instability reactions appear with or without microbiological contribution 
through reactions such as hydrolysis, oxidation, isomerization, and epimerization. 
Interactions between ingredients and ingredients with container closure 
materials are established as the principal causes of these reactions [1] , for instance, 
the hydrolysis of cefotaxime sodium, the oxidation of vitamin C, the isomerization 
of epinephrine, and the epimerization of tetracycline [7] . 
In most cases, physical instabilities are consequences of previous chemical instabilities. 
Physical instabilities can arise principally from changes in uniformity of 
suspensions or emulsions, diffi culties related to dissolution of ingredients, and 
volume changes [6] . For instance, some cases where physical stability has been 
affected are cloudiness, fl occulence, fi lm formation, separation of phases, precipitation, 
crystal formation, droplets of fog forming on the inside of container, and swelling 
of the container [8] . 
Although commercial oral solution and emulsion dosage forms rarely present 
bioequivalence issues, some bioequivalence problems have been reported for oral 
suspensions such as phenytoin [9] . The possibility of microbiological contamination 
and physicochemical instabilities during the manufacturing process also needs 
to be carefully considered. To approach the stability problems of liquid dosage 
forms, in this chapter, the main critical aspects during the manufacturing process 
are based on FDA inspection. From physical plant systems to batching management 
and packing, the potential sources of microbiological, chemical, and physical instabilities 
will be analyzed using defi nitions, case - by - case explanations, and practical 
examples. 
Final product stability, which determines the therapeutic activity and uniformity 
among other characteristics of the fi nal product, refl ects the dynamic of the production 
process. Conceptualization of stability issues is important to determine the 
changes to enhance the design space as well as protocols of manufacturing and 
quality control [3] . An information technology (IT) solution like Enterprice Resource 
Planning (ERP) may support the pharmaceutical industry ’ s current challenges of 
organization [10] . 
INTRODUCTION 315

316 LIQUID DOSAGE FORMS 
4.3.2 GENERALITIES 
4.3.2.1 Dosage Form 
According to the FDA: “ A dosage form is the physical form in which a drug is produced 
and dispensed. In determining dosage form, FDA examines such factors as 
(1) Elegance: physical appearance of the drug product, (2) Stability: physical form 
of the drug product prior to dispensing to the patient, (3) Acceptability: the way the 
product is administered, (4) Effi cacy: frequency of dosing, and (5) Safety: how pharmacists 
and other health professionals might recognize and handle the product ” 
[11] . The term dosage form is different from “ dose, ” which is defi ned as a specifi c 
amount of a therapeutic agent that can be taken at one time or at intervals. 
4.3.2.2 Liquid Dosage Form 
The physical form of a drug product that is pourable displays Newtonian or pseudoplastic 
fl ow behavior and conforms to its container at room temperature. In contrast, 
a semisolid is not pourable and does not fl ow at low shear stress or conform 
to its container at room temperature [12] . According to its physical characteristics, 
liquid dosage forms may be dispersed systems or solutions. 
4.3.2.3 Dispersed Systems 
Dispersed systems are dosage forms composed of two or more phases, where one 
phase is distributed in another [2] . If a dispersed system is formed by liquid phases, 
then it is known as an “ emulsion. ” In contrast, the dispersed system is named a 
“ suspension ” when the liquid dosage form is accomplished by the distribution of a 
solid phase suspended in a liquid matrix. The solid phase of a suspension is usually 
the drug substance, which is insoluble or very poorly soluble in the matrix [12] . 
4.3.2.4 Solutions 
A solution refers two or more substances mixed homogeneously [2] . Although solubility 
refers to the concentration of a solute in a saturated solution at a specifi c 
temperature, in pharmacy, solution liquid dosage forms are unsatured to avoid 
crystallization of the drug by seeding of particles or changes of pH or temperature 
[13] . The precipitation of drug crystals is one of the most important physical instabilities 
of solutions that may affect its performance [14] . Water is the most used 
solvent in solutions manufacturing; however, there are also some commercial nonaqueous 
solutions in the pharmaceutical market [1] . 
4.3.2.5 Manufacturing of Nonparenteral Liquid Dosage Forms 
The manufacturing of liquid dosage forms with market - oriented planning includes 
the following stages with respect to special good manufacturing practice (GMP) 
requirements: planning of material requirements, liquid preparation, fi lling and 
packing, sales of drug products, vendor handling, and customer service [15] . From 
the viewpoint of product stability, each stage of the process includes critical batches 

that are more decisive than others. Also, each decisive batch contains one or several 
unit operations that are more critical than others. The FDA inspection focuses on 
those critical unit operations to ensure the safety and stability of the liquid dosage 
forms [6] . 
4.3.2.6 Optimizing Drug Development Strategies 
According to Sokoll [16] : The phases of drug development include discovery, preclinical 
development, clinical development, fi ling for licensure, approval/licensure and post - 
approval. Discovery typically includes basic research, drug identifi cation and early - 
stage process and analytical method development. . . . Emerging companies that review 
their pipeline objectively and strike a balance between properly resourcing and developing 
their lead candidates in the clinic while nurturing their next generation of drug 
candidates will have the best chance for success and sustainability. 
4.3.2.7 Unit Operation or Batch 
A “ batch ” job or operation is defi ned as a unit of work. Raw materials, semifi nished 
drug products (bulk), and fi nished drug products are handled in batches. Each different 
type of material used during the process, such as product packing, should be 
managed by batches. This applies also to process aids and operation facilities [15] . 
4.3.2.8 Batch Management 
The batch management of production simplifi es the process and makes it easier to 
control the status of transformation between raw and fi nal products [2] . Some of 
the data used to follow the material performance around and out of the product 
manufacturing process are batch - where - used - list, initial status, batch determinations, 
master data, and expiration date check [15] . 
The functionality of the overall process to manufacture liquid dosage forms 
depends on the successful linkage of one unit operation to another. To use mathematical 
formulations to scale up the manufacturing process, it is necessary to divide 
the process into stages, batches, and unit operations. Each single unit operation is 
scalable, but the composite manufacturing process is not. Production problems 
result from attempts to follow a process scale - up instead of a unit operation scale - 
up. By using mathematical formulations, it is possible to understand the level of 
similarity between two scale sizes. In addition, nonlinear similarities between two 
scale sizes might require the use of conversion factors to achieve an extrapolation 
point for the scale [2] . 
4.3.2.9 Steps of Liquids Manufacturing Process 
Establishing short - term goals makes it easier to measure effi ciency as well as evaluate 
the diffi culties [2] . Based on these concepts, the problems of manufacturing 
liquid dosage forms can be approached as problems in one or more batches of the 
following process steps [6, 15] : 
Planning of Material Requirements Research and development of protocols and 
selection of materials; acquisition and analysis of raw materials; physical plant 
GENERALITIES 317

318 LIQUID DOSAGE FORMS 
design, building, and installation; equipment selection and acquisition; personnel 
selection and initial training; and monitoring information system. 
Liquid Preparation Research and development of protocols concerning liquid 
compounding; scale - up of the bulk product compounding; physical plant control 
and maintenance; equipment maintenance and renovation; continuous 
training of personnel and personnel compensation plan; and supervision of 
system reports. 
Filling and Packing Research and development of protocols concerning fi lling 
and packing; scale - up of the fi nished drug product fi lling and packing; physical 
plant control and maintenance; equipment maintenance and renovation; continuous 
training of personnel and personnel compensation plan; and supervision 
of system reports. 
Sales of Drug Products Research and development of protocols concerning 
product storage; distribution process; continuous training of personnel and 
personnel compensation plan; and supervision of system reports. 
Vendor Handling Research and development protocols concerning precautions 
to maintain product stability; control of vendor stock; and sales system 
reports. 
Customer Service Research and development of protocols concerning home 
storage and handling to maintain product stability; relations with health insurance 
companies and health care professionals; educational materials for patient 
counseling; and customer service system reports. 
4.3.2.10 Protocols 
Protocols are patterns developed by repeating procedures and fi xing the identifi ed 
problems each time that the procedure is followed. Therefore, protocols are dynamic 
entities that originally can be developed at a laboratory level but must be adjusted 
in every new step of the scal - up process. When the manufacturing process moves 
up in scale, the number of people affected by the protocol increases geometrically. 
Initially, the information can be obtained from library references, personal tests, 
interpersonal training, and previous laboratory protocols. However, when the production 
is scaled up, the information required to fi ne tune the process comes from 
monitoring the process itself [2] . 
4.3.3 APPROACHES 
Quality by Design is a systemic approach that applies the scientifi c method to the 
process. QbD theory contains components of management, statistics, psychology, 
and sociology. The FDA ’ s new century has identifi ed the QbD approach as its “ key 
component ” based on process quality control before industry end results [3, 17] . 
The cooperation between industry members and regulators is increased when the 
industry explains clearly what it is doing and the agency can understand the formulation 
and production process. In these cases, regulatory relief appears when industry 
explores its issues and receives active guidance and programs from the FDA. 
The agency takes the role of facilitator, or even partner of the industry, in order to 
improve the strength of the process and formulation [3, 17] . 

To apply QbD as a systemic approach, the company starts by understanding, 
step by step, the space design, the design of the dosage form, the manufacturing 
process, and the critical process parameters to be controlled in order to reach the 
new building block which is the expectation of variances within those critical 
process parameters that can be accepted. This approach allows the establishment 
of priorities and fl exible boundaries in the process [3] . Infl exible specifi cations 
allow uncontrolled small variances that can follow the butterfl y effect of the theory 
of chaos by producing unpredictable large variations in the long - term behavior of 
the product shelf - life [18, 19] . In contrast, fl exibility, with knowledge of potential 
variances, reduces changes in the approved spaces and manufacturing protocols 
[3, 17] . 
According to the FDA [6] , critical parameters during the manufacturing process 
of nonparenteral liquid dosage forms may appear in the design of physical plant 
systems, equipment, protocols of usage and maintenance, raw materials, compounding, 
microbiological quality control, uniformity of suspensions and emulsions, and 
fi lling and packing [6] . 
Process isolation and installation of an appropriate air fi ltration system in the 
physical plant may reduce product exposition to chemical and microbiological 
contaminations. In addition, the use of a suitable dust removal system as well as 
a heating, ventilation, and air conditioning system (HVACS) may help to repress 
product chemical instabilities [6] . 
The equipment of sanitary design, including transfer lines, as well as appropriate 
cleaning and sanitization protocols may reduce chemical and microbiological contaminations 
in the fi nal product. Chemical instabilities may be reduced by weighting 
the right amount of liquids instead of using a volumetric measurement, avoiding the 
common use of connections between processes, and using appropriate batching 
equipment [6] . 
Particle sizes of raw materials are critical to control dissolution in solutions as 
well as uniformity in suspensions and emulsions. Temperature control during compounding 
is important since heat helps to support mixing and/or fi lling operations, 
but, in contrast, high - energy mixers may produce adverse levels of heat that affect 
product stability. Too much heat may cause chemical and physical instabilities such 
as change of particle size or crystallization of drugs in suspensions, dissolution and 
potency loss of drugs in suspensions, oxidation of components, and activation of 
microbiological growth after degradation of compounds as well as precipitation of 
dissolved compounds in solution [20] . In addition, uniformity of suspensions depends 
on viscosity and segregation factors while solubility, particle size, and crystalline 
form determine uniformity of emulsions. Application of pharmaceutical GMP for 
product processes and storage assures microbiological quality. A defi cient deionizer 
water - monitoring program and product preservative system facilitate microbial contamination. 
Filling uniformity is indispensable for potency uniformity of unit - dose 
products and depends on the mixing operation. Calibration of provided measuring 
devices and the use of clean containers will allow administering the right amount 
of the expected components in the liquid dosage form [6] . 
Principal product specifi cations are microbial limits and testing methods, particle 
size, viscosity, pH, and dissolution of components. Process validation requires control 
of critical parameters observed during compounding and scale - up. Product stability 
examination is based on chemical degradation of the active components and interac- 
APPROACHES 319

320 LIQUID DOSAGE FORMS 
tions with closure systems, physical consequences of moisture loss, and microbial 
contamination control [6] . 
4.3.4 CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 
4.3.4.1 Physical Plant 
Heating, Ventilation, and Air Conditioning System The manufacturer has to 
warrant adequate heating, ventilation, and air conditioning in places where labile 
drugs are processed [6] . 
The effect of long processing times at suboptimal temperatures should be considered 
at the production scale in terms of the consequences on the physical or chemical 
stability of individual ingredients and product. A pilot plant or production scale 
differs from laboratory scale in that their volume - to - surface - area ratio is relatively 
large. Thus, for prolonged suboptimal temperatures, jacketed vessels or immersion 
heaters or cooling units with rapid circulation times are absolutely necessary [2] . 
For heat - labile drugs, uncontrolled temperature increments can activate auto - 
oxidation chains when the drug product ingredients react with oxygen and generate 
free radicals but without drastic external interference. Vitamins, essential oils, and 
almost all fats and oils can be oxidized. A good example of a heat - labile drug solution 
is clindamycin, which has to be stored at room temperature and away from 
excess heat and moisture [19] . Auto - oxidation chains are fi nished when free radicals 
react with each other or with antioxidant molecules (quenching). The tocopherols, 
some esters of gallic acid, as well as BHA and BHT (butylated hydroxyanisole and 
butylated hydroxytoluene) are common antioxidants used in the pharmaceutical 
industry [1] . 
Isolation of Processes To minimize cross - contamination and microbiological contamination, 
the manufacturer may develop special procedures for the isolation of 
processes. The level of facilities isolation depends on the types of products to be 
manufactured. For instance, steroids and sulfas require more isolation than over - 
the - counter (OTC) oral products [6] . To minimize exposure of personnel to drug 
aerosols and loss of product, a sealed pressure vessel must be used to compound 
aerosol suspensions and emulsions [21] . An example of cross - contamination with 
steroids was the controversial case of a topical drug manufactured for the treatment 
of skin diseases. High - performance liquid chromatography/ultraviolet and mass 
spectrometry (HPLC/UV, HPLC/MS) techniques were used by the FDA for the 
detection of clobetasol propionate, a class 1 superpotent steroid, as an undeclared 
steroid in zinc pyrithione formulations. The product was forbidden and a warning 
was widely published [22] . 
Dust Removal System The effi ciency of the dust removal system depends on the 
amount and characteristics of dust generated during the addition of drug substance 
and powdered excipients to manufacturing vessels [6] . Pharmaceutical industries 
usually generate some type of dust or fume during processing. Important factors for 
selecting dust collectors are maintenance, surrogate test, economics, and containment. 
In addition, reentrainment of the fi ne particles, vertical or horizontal position, 
effi ciency, pressure resistant, service life time, as well as sealing capacity to work 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 321 
through the bag are signifi cant factors concerning fi lter selection of dust removal 
systems. Some examples of dust collection applications in the manufacture of liquid 
dosage forms are handling and pulverization of raw materials, spray dryers, and 
general room ventilation [23] . 
Air Filtration System The effi ciency of the air fi ltration system has to be demonstrated 
by surface or air - sampling data where the air is recirculated [6] . To monitor 
the levels of contamination in the air, there are commercial automatic samplers for 
microbiological contamination or gas presence. Air trace environmental samplers 
for pharmaceutical industries are based on the slit - to - agar impaction technique for 
the presence of viable microorganisms. Automatic samplers for compressed gas 
analyze the presence of a specifi ed gas in 1 m 3 by absorbing air at a fi xed fl ow rate 
for a sampling period of 1 h or a different adjusted time. These solutions to the 
sampling needs of the pharmaceutical industry are robust, require low maintenance, 
and are easy to use. This allows for validation of sampling data at the moment of 
application fi lling to support the process control. Sampling time and selection of 
microbiological growth media or analysis technique are important components to 
consider when developing a sampling plan [24] . 
4.3.4.2 Equipment 
Sanitary Design Pumps, valves, fl owmeters, and other equipment should be easily 
sanitized. Some examples of identifi ed sources of contamination are ball valves, 
packing in pumps, and pockets in fl owmeters [6] . 
The sanitary design and performance of equipment make it accessible for inspection, 
cleaning, and maintenance. It has to be cleanable at a microbiological level and 
its performance during normal operations should contribute to sanitary conditions. 
The materials used in the design have to assure hygienic compatibility with other 
equipment, the product, the environment, other systems such as electrical, hydraulics, 
steam, air, and water, as well as the method and products used for cleaning and 
sanitation. The equipment should be self - draining to assure product or liquid collection. 
Small niches, for example, pits, cracks, corrosion, recesses, open seams, gaps, 
lap seams, protruding ledges, inside threads, bolt rivets, and dead ends, as well as 
inaccessible cavities of equipment such as entrap and curlers must be eliminated 
whenever possible; otherwise they have to be permanently sealed. Enclosures, for 
example, push buttons, valve handles, switches, and touch screens, should be prepared 
for a hygienic design of maintenance. Standards have been developed by the 
American Meat Institute [25] . 
Standard Operating Procedures for Cleaning Production Equipments Current 
GMPs are defi ned as the basic principles, procedures, and resources required to guarantee 
an environment appropriate for manufacturing products of adequate quality 
[26] . To minimize cross - contamination and microbiological contamination, it is GMP 
for a manufacturer to create and pursue written standard operating procedures 
(SOPs) to clean and sanitize production equipment in a way that avoids contamination 
of in - progress and upcoming batches. When the drug is known as a potent generator 
of allergic reactions, such as steroids, antibiotics, or sulfas, cross - contamination 
becomes an issue of safety [20] . In addition, validation and data analysis procedures, 

322 LIQUID DOSAGE FORMS 
FIGURE 1 Mixing and fi lling lines for pharmaceutical dosage forms. Positive indoor pressure 
of 5 psi over outdoor pressure assures constant airfl ow from inside to outside in order 
to reduce entrance of contaminating agents. 
UV Rays 
Collector Tank 
Continuous or Batch 
GENERAL DIAGRAM “A” 
INDUSTRIAL MANUFACTURING PLANT 
FOR PHARMACEUTICAL LIQUID DOSAGE FORMS Decontamination 
Camera 
Restricted access area 
Pressure = Atmospheric pressure + 5 PSIG 
Bottling 
Equipment 
Packing 
Filters 
Compressor 
Homogenizator 
Main 
Pump 
Filters 
Mixer 
Dosing 
Pumps 
Primary Components Tanks 
Restriction 
Gate 
Compressor 
Purified 
Water 
Air 
recycle 
including drawings of the manufacturing and fi lling lines [6] , are especially important 
for clean - in - place (CIP) systems, as indicated in Figures 1 and 2 . 
Many companies have problems with standardizing operating procedures for 
cleaning steps and materials used [6] . Appropriate SOPs are necessary to determine 
the scope of the problem in investigations about possible cross - contaminations or 
mix - ups. The best approach to validate a SOP is to test it, use it as a training tool, 
and observe the results obtained by different persons. This includes the worst - case 
situation in order to enhance the step - by - step writing methodology as well as standardizing 
the materials used. A typical SOP contains a header to present the SOP 
title, date of issue, date of last review, total number of pages, responsible person, 
and approval signature. Typically, a SOP includes position of responsible person, 
SOP purpose and scope, defi nitions, equipment and materials, safety concerns, step - 
by - step procedure, explanation of critical steps, tables to keep data, copies of forms 
to fi ll, and references [26] . The forms to keep the records must show the date, time, 
product, and lot number of each batch processed. However, the most important 
points of the SOP are equipment identity, cleaning method(s) with documentation 
of critical cleaning steps, materials approved for cleaning that have to be easily 
removable, names and position of persons responsible for cleaning and inspection, 
inspection methods, and maintenance and cleaning history of the equipment [20] . 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 323 
Cleaning and Sanitizing Transfer Lines Pipes should be hard, easily cleaned, and 
sanitized. To avoid moisture collection and microbiological contamination, hoses 
should be stored in a way that allows them to drain rather than be looped. For 
example, transfer lines are an important source of contamination when fl exible 
hoses are handled by operators, lying on the fl oor, and after they are placed in 
transfer or batching tanks [6] . 
Heat is considered one of the most effi cient physical treatments for sanitizing 
pharmaceutical equipment and could be used for sanitizing hoses that have already 
been cleaned. The recirculation of hot water at a temperature of 95 o C for at least 
100 min allows bacteria elimination [14] . 
Due to the important amount of insoluble residues left on piping and transfer 
lines after emulsion manufacturing, such as topical creams and ointments, equipment 
cleaning becomes diffi cult to address. To avoid cross - contamination, some 
manufacturers have decided to dedicate lines and hoses to specifi c products. 
FIGURE 2 Mixing and fi lling lines for pharmaceutical dosage forms. Using this hydropneumatic 
system, instead of the mechanical system in Figure 1 , the liquid moves by the 
pressure generated in a compressed air tank. 
Hydropneumatic 
vessel 
UV Rays 
Restricted access area 
Pressure = Atmospheric pressure + 5 PSIG 
Compressor 
Collector Tank 
Continuous or Batch 
GENERAL DIAGRAM “B” 
INDUSTRIAL MANUFACTURING PLANT 
FOR PHARMACEUTICAL LIQUID DOSAGE FORMS 
OF LOW VISCOSITY 
Restriction 
Gate
Air 
Recycle 
Pressure 
pump 
Decontamination 
Camera 
Bottling 
Equipment 
Homogenizator Dosing 
Pumps 
Primary Components Tanks Purified 
Water 
Homogenizator
Mixing 
Control 
Booster 
Pump 
Mixer 
Packing 
Filters 
Compressor 
Restriction 
Gate 
Filters

324 LIQUID DOSAGE FORMS 
However, these decisions have to appear in the written production protocols and 
SOPs [20] . 
Sampling Cleaned Surfaces for Presence of Residues The cleaning method is 
validated by sampling the cleaned surfaces of the equipment for the existence of 
residues. The equipment characteristics and residue solubility are factors to support 
the selection of the sampling method to be used [6] . There are two acceptable 
general types of sampling methods: direct surface sampling by swabbing of surfaces 
and rinse sampling with a routine production in - process control. Although surface 
residues will not be identical on each part of the surface, statistically the most 
advantageous is direct surface sampling because it allows evaluation of the hardest 
areas to clean as well as insoluble or “ dried - out ” residues by physical removal. The 
type of sampling material and solvent used for extraction from the sampling material 
should be validated in order to determine their impact on the test data. The 
second method, rinse sampling, is used for larger surfaces or inaccessible systems. 
Contaminants that are physically occluded and insoluble residues are disadvantages 
of the rinse sampling method. To validate this cleaning process, direct measurement 
of the contaminant in the rinse water has to be tested instead of a simple 
test for water quality. Routine production in - process control is used as indirect 
testing for large equipment that has to be cleaned by the rinse sampling method. 
The uncleaned equipment has to give an unacceptable result for the indirect 
test [27] . 
Establishing Appropriate Limits on Levels of Postequipment Cleaning 
Residues Very low levels of residue are possible to be determined since technological 
advances offer more sensitive analytical methods. The manufacturer should 
know the toxicological information of the materials used and potential amounts of 
residues after exposure to the equipment surface. Accordingly, the manufacturer 
has to establish proper limits of residues after equipment cleaning and scientifi cally 
justify these limits. The established limits must be clinically and pharmaceutically 
safe, realistic, viable, and verifi able [20] . The sensitivity of the analytical method will 
determine the logic of the established limits since absence of residues could indicate 
a low sensitivity of the analytical method or a poor sampling procedure. Sometimes 
thin - layer chromatography (TLC) screening must be used in addition to chemical 
analyses. Some practical levels established by manufacturers include 10 ppm of 
chemicals, 1/1000 of the biological activity levels met on a normal therapeutic dose, 
and no visible residues of particles determined organoleptically [27] . 
Connections Connectors and manifolds should not be for common use. For 
example, sharing connectors in a water supply, premix, or raw material supply tanks 
may be a source of cross - contamination [6] . 
Time between Completion of Manufacturing and Initiation of Cleaning The time 
that may elapse from completion of a manufacturing operation to initiation of 
equipment cleaning should also be stated where excessive delay may affect the 
adequacy of the established cleaning procedure. For example, residual product may 
dry and become more diffi cult to clean [20] . 
SOPs are an example of defi ciency in many manufacturers regarding time limitations 
between batch cleaning and sanitization [6] . Lack of communication between 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 325 
departments responsible for the production at different levels is the main cause of 
time control problems. Typically each department, from human resources to fi nances, 
manufacturing, and warehouse, has its own computer system optimized for the 
particular ways that the department does its work. Therefore, time control becomes 
a primordial issue when labile materials are transferred from one department to 
another [28] . 
To facilitate communication between different departments, some useful softwares 
have been developed. For example, ERP is an integrated approach which may 
have positive payback if the manufacturer installs it correctly. An ERP is a type 
of software that can improve communication between planning and resources. The 
software attempts to integrate all departments and functions in a company onto a 
single computer system that can serve each particular need, such as fi nance, human 
resources, manufacturing management, process manufacturing management, inventory 
management, purchasing management, quality management, and sales management. 
Each department has its own software, except now the software is linked 
together, so that, for example, someone in manufacturing can look into the maintenance 
software to see if specifi c batch cleaning and sanitization have been scheduled 
or realized and someone in fi nance can review the warehouse software to see if a 
specifi c order has been shipped. The information is online and not in someone ’ s 
heads or on papers that can be misplaced. People in different departments may see 
the same information, update it if they are allowed to do, and make right decisions 
faster. However, the software is less important than the changes companies make 
in the ways they work. Reorganization and training are the keys of ERP ’ s success 
to fi x integration problems. There are three different ways to install an ERP: big 
bang, franchising strategy, and slam dunk. Big bang is the most ambitious way 
whereby companies install a single ERP across the entire company. By the franchising 
strategy, departments do not share many common processes across, whereas 
slam dunk is focused on just a few key processes [28] . 
Weight in Formulations Flow properties of liquids rarely vary due to their constant 
density at a constant temperature. Oral solutions and suspensions are formulated 
on a weight basis (gravimetry) in order to be able to measure the fi nal volume 
by weight before fi lling and packing. Volumetric measurements of liquid amounts 
to be used for manufacturing liquid dosage forms have shown greater variability 
than weighted liquids. For instance, the inaccurate measurement of the fi nal volume 
by using dip sticks or a line on a tank may cause further analytical errors and 
potency changes [6] . 
The importance of selecting gravimetry instead of volumetry to measure liquid 
amounts in the pharmaceutical industry of liquid dosage forms is well illustrated by 
the volume contraction of water – ethanol and volume expansion of ethyl acetate – 
carbon disulfi de liquid mixtures as well as a CS2 – ethyl acetate system. The National 
Formulary (NF) diluted alcohol is a typical example of the volume nonadditivity of 
liquid mixtures [29] . This solution is prepared by mixing equal volumes of alcohol 
[U.S. Pharmacopeia (USP)] USP and purifi ed water (USP). The fi nal volume of this 
solution is about 3% less than the sum of the individual volumes because of the 
contraction due to the mixing phenomenon [1] . In addition, molecular interactions 
of surfactants in mixed monolayers at the air – aqueous solution interface and in 
mixed micelles in aqueous media also cause some contraction of volume upon 
mixing [30] . 

326 LIQUID DOSAGE FORMS 
Location of Bottom Discharge Valve in Batching Tank The bottom discharge 
valve should be located exactly at the bottom of the tank. In some cases valves have 
been found to be several inches to a foot above the bottom of the tank [6] . 
For a tank suspected of having substantial deposits at the bottom, a fi ber - optic 
camera can be inserted in the tank to provide a view and positive confi rmation of 
the tank bottom condition. These camera and light vision systems are sanitary equipment 
able to provide a computational real - time visual inspection of the inside tank 
under process conditions or pressure vessel. In addition, they are used to control 
several parameters during the manufacturing process, such as product level and 
thickness, solids level, uniformity of suspensions, foam, and interface and/or cake 
detection [31] . 
Batching Equipment to Mix Solution Ingredients of solutions have to be completely 
dissolved. For instance, it has been observed that some low - solubility drugs 
or preservatives can be kept in the “ dead leg ” below the tank, and the initial samples 
have reduced potency [6] . When there is inadequate solubility of the drug in the 
chosen vehicle, the dose is unable to contain the correct amount of drug in a manageable 
size unit, that is, one teaspoonful or one tablespoonful. Thus, ingredients 
as well as handling and storage conditions should be chosen to manage the problem 
[14] . 
In solutions, the most important physical factors that infl uence the solubility of 
ingredients are type of fl uid, mixing equipment, and mixing operations. Generalized 
Newtonian fl uids are ideal fl uids for which the ratio of the shear rate to the shear 
stress is constant at a particular time. Unfortunately, in practice, usually liquid 
dosage forms and their ingredients are non - Newtonian fl uids in which the ratio of 
the shear rate to the shear stress varies. As a result, non - Newtonian fl uids may not 
have a well - defi ned viscosity [32] . 
When all the ingredients are miscible liquids, the combination and distribution 
of these components to obtain a homogeneous mixture are called blending. Whenever 
possible, ingredients should be added together and the impeller mixer often is 
located near the bottom of the vessel [21] . Mixing of high - viscosity materials requires 
higher velocity gradients in the mixing zone than regular blending operations. In 
fact, the fundamental laws of physics regarding the performance of Newtonian fl uids 
in the production process may be studied using computational tools. For example, 
VisiMix is a software that is routinely used to calculate shear rates [2] . 
Finally, if it is determined that there is a bigger problem of insolubility 
coming from the formulation, then addition of cosolvents, surfactants, as well as 
the preparation of the ionized form of an acid or base, drug derivatization, and 
solid - state manipulation are approaches to manipulating the solubility of the drug 
[14] . 
Batching Equipment to Mix Suspension In the case of suspensions, the fl ow necessary 
to overcome settling in a satisfactory suspension depends on the mixing 
equipment and is predicted by Stokes ’ s law. Thus, to use the Stokes ’ s law, suspensions 
are considered as Newtonian fl uids if the percentage of solids is below 50%. 
Mixing equipment uses a mechanical device that moves through the liquid at a given 
velocity. Dispersing and emulsifying equipment is categorized as “ high - shear ” mixing 
equipment. The maximum shear rate with such equipment occurs very close to the 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 327 
mixing impeller. Therefore, the diameter of the impeller and the impeller speed 
directly infl uence the power applied by the mixer to the liquid [21] . 
Batching Equipment to Mix Emulsion The most common problems of mixing 
emulsions are removing “ dead spots ” of the mixture and scrapping internal walls of 
the mixer. Dead spots are quantities of ingredients that are not mixed and become 
immobile. Where dead spots are present, that quantity of the formula has to be 
recirculated or removed and not used. If the inside walls of the mixer keep residual 
material, operators should use hard spatulas to scrape the walls; otherwise the 
residual material will become part of the next batch. In both cases, the result may 
be nonuniformity. Stainless steel mixers have to include blades made of hard plastic, 
such as Tefl on, to facilitate the scrapping of the mixer walls without damaging the 
mixer. Scrapper blades should be fl exible enough to remove internal material but 
not too rigid to avoid damaging the mixer [20] . The mixing will be successful if the 
macroscale mixing offers suffi cient fl ow of components in all areas in the mixing 
tank and the microscopic examination shows a correct particle size distribution 
[33] . 
4.3.4.3 Particle Size of Raw Materials 
Raw materials in Solution The types of raw materials used to be part of solutions 
are presented in Table 1 . They have different purposes and can be cosolvents, electrolytes, 
buffers, antioxidants, preservatives, coloring, fl avoring and sweetener agents, 
among others. 
Particle Size of Raw Materials in Solution Particle size is affected by the breaking 
process of the particle, crystal form, and/or salt form of the drug. The particle 
size can affect the rate of dissolution of raw materials in the manufacturing process. 
Raw materials of a fi ner particle size may dissolve faster because they have a larger 
surface area in contact with the solvent than those of a larger particle size when the 
product is compounded [6] . Mixing faster causes the particle to break down and 
dissolve more quickly. In addition, hydrated particles are less soluble than their 
anhydrous partners [37] . 
TABLE 1 Solutions: pharmaceutical excipients 
Purpose Agent 
Protecting the active product 
ingredients 
- Buffers 
- Antioxidants 
- Preservatives 
Maintaining the appearance - Colorings 
- Stabilizers 
- Cosolvents 
- Antimicrobial preservatives 
- Electrolytes 
Taste/Small Masking - Sweeteners 
- Flavorings 
Source : From ref. 4, 34, 35, 36 

328 LIQUID DOSAGE FORMS 
Solid drugs may occur as pure crystalline substances of defi nite identifi able shape 
or as amorphous particles without defi nite structure. In addition, when a drug particle 
is broken up, the total surface area is increased as well as its rate of dissolution. 
The amorphous form of a chemical is usually more soluble than the crystalline form 
while the crystalline form usually is more stable than the amorphous form [37] . 
Processing conditions used for providers to obtain raw materials can dramatically 
impact their quality and stability; for instance, the presence of different polymorphs 
may depend on the thermal history of freezing, concentration of solvents, and drying 
conditions [38] . The polymorphism of a crystalline form is the capacity of a chemical 
to form different types of crystals, depending on the conditions of temperature, 
solvents, and time followed for its crystallization. Among different polymorphs, only 
one crystalline form is stable at a given temperature and pressure. Over time, the 
other crystalline forms, called metastable forms, will be transformed into stable 
forms. Transformations longer than the shelf - life of metastable forms into stable 
forms of a drug are very common in fi nal products and compromise its stability and 
effi cacy to different extents depending on quality control [37] . 
While the metastable forms offer higher dissolution rates, many manufacturers 
use a particular amorphous, crystalline, salt, or ester form of a drug with the solubility 
needed to be dissolved in the established conditions, for instance, to prepare a 
chloramphenicol ophthalmic solution [39] . Thus, the selection of amorphous or 
crystalline form of a drug may be of considerable importance to facilitate the formulation, 
handling, and stability [37] . 
However, the dissolution rate of an equal sample of a slowly soluble raw material 
usually will increase with increasing temperature or rate of agitation as well as with 
reduce viscosity, changes of pH or nature of the solvent. In addition, other alternative 
mechanisms to enhance the solubility of insoluble drugs are: 1) hydrophilization: 
the reduction in contact angle or angle between the liquid and solid surface 
[40] , which can be accessed by intensive mixing of the hydrophobic drug with a small 
amount of methylcellulose solution [41] ; 2) the formation of microemulsions: by 
covering small particles with surfactants to obtain micromicelles that are visible only 
in the form of an opalescence; and, 3) the formation of complexing compounds: by 
adding a soluble substance to form soluble reversible complexes. However, the last 
method is used with some restrictions [42] . 
Raw Materials in Suspension The types of raw materials used to be part of suspensions 
are presented in Table 2 . They have different purposes and can be wetting 
agents, salt formation ingredients, buffers, polymers, suspending agents, fl occulating 
agents, electrolytes, antioxidants, poorly soluble Active Product Ingredients, preservatives, 
coloring, fl avoring and sweetener agents, among others. 
Particle Size of Drug in Suspension The physical stability of a suspension can be 
enhanced by controlling the particle size distribution [43] . Uncontrolled changes of 
drug particle size in a suspension affect the dissolution and absorption of the drug 
in the patient. Drug substances of fi ner particle size may be absorbed faster and 
bigger particles may not be absorbed. Aggregation or crystal growth is evaluated 
by particle size measurements using microscopy and a Coulter counter [21] or preferably 
techniques that allow samples to be investigated in the natural state. Allen 
[44] offers an academic and industrial discussion about particle characterization. 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 329 
Powder properties and behavior, sampling, numerous potential particle size measuring 
devices, available equipment as well as surface and pore size are his principal 
themes. 
Particles are usually very fi ne (1 – 50 . m). For instance, topical suspensions use 
less than 25 . m particle size [6] . The particle size of the drug is the most important 
consideration in the formulation of a suspension, since the sedimentation rate of 
disperse systems is affected by changes in particle size. Finer particles become interconnected 
and produce particle aggregation followed by the formation of nonresuspendable 
sediment, known as caking of the product. The two main causes of 
aggregation and caking are energetic bonding and bonding through shared material. 
A statistical wide distribution of particle sizes gives more compact packing and 
energetic bonding than narrower distributions. It has been observed that heat treatments 
can cause agglomeration of particles, not only due to energetic bonding but 
also by formation of crystal bridges. Also, when the application of shear forces to 
mix and homogenize the suspension uses too high energy inputs, then the probability 
for aggregation increases [43] . 
Examples of oral suspensions in which a specifi c and well - defi ned particle size 
specifi cation for the drug substance is important are phenytoin suspension, carbamazepine 
suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone 
suspension [6] . 
There are some useful methods to improve the physical stability of a suspension, 
such as decreasing the salt concentration, addition of additives to regulate the 
osmolarity, as well as changes in excipient concentrations, unit operations in the 
process, origin and synthesis of the drug substance, polymorphic behavior of 
the drug substance crystals, and other particle characteristics. However, methods 
based on changes of the particle properties and the surfactants used are the most 
successful [43] . 
TABLE 2 Suspensions: pharmaceutical excipients 
Purpose Agent 
Facilitating the connection between Active 
Product Ingredient and vehicle 
- Wetting agents particle size ( > 0.1 . m) 
- Salt formation ingredients 
- Sugars 
Protecting the Active Product Ingredients - Buffering – systems 
- Polymers 
- Antioxidants 
- Poorly soluble drugs 
Maintaining the suspension appearance - Colorings 
- Suspending agent 
- Flocculating agent 
- Antimicrobial preservatives 
- Electrolytes 
Masking the unpleasant taste/smell - Sweeteners 
- Flavorings 
- Poorly soluble Active Product Ingredient 
Source : From ref. 4, 34, 35, 36 

330 LIQUID DOSAGE FORMS 
To approach physical stability problems of suspensions, effectiveness and stability 
of surfactants as well as salt concentrations must be checked with accelerated aging. 
In addition, unit operations affecting particle size distribution, surface area, and 
surfactant effectiveness should be approached, taking into account that different 
types of distributions, for instance, volume or number weighted, give a different 
average diameter for an equal sample [43] . 
Raw Materials in Emulsions The types of raw materials used to be part of emulsions 
are presented in table 3 . They have different purposes and can be buffers, 
polymers, emulsifying agents, penetration enhancers, gelling agents, stabilizers, antioxidants, 
preservatives, coloring, fl avoring and sweetener agents, among others. 
Particle Size in Emulsions When a solid drug is suspended in an emulsion, the 
liquid dosage form is known as a coarse dispersion. In addition, a colloidal dispersion 
has solid particles as small as 10 nm – 5 . m and is considered a liquid between 
a true solution and a coarse dispersion [44] . 
4.3.4.4 Compounding: Effects of Heat and Process Time 
Oxygen Oxygen removal for processing materials that require oxygen to degrade 
is possible by methods such as nitrogen purging, storage in sealed tanks, as well 
as special instructions for manufacturing operations [6] . For instance, sealing glass 
ampules containing a liquid dosage form with heat under an inert atmosphere is a 
packing mechanism used to prevent oxidation. Some aspects of oxygen sensitiveness 
that should be taken into account are the necessity of water and headspace deoxygenation 
in ampules before sealing, the avoidance of multidose vials that facilitate 
oxygen contact with the product after opened, and rubber stoppers for vial sealing 
that are permeable to oxygen as well as release additives to catalyze oxidative reac- 
TABLE 3 Emulsions: pharmaceutical excipients 
Purpose Agent 
Particle Size - Solid particles (10 nanometers to 5 micrometers size) 
- Droplet particles (0.1 – 1.0 micrometers size) 
Protecting the Active Product 
Ingredients 
- Buffering - Systems 
- Polymers 
- Antioxidants 
- Distribution pattern (O/W, W/O) 
Maintaining the appearance - Colorings 
- Emulsifying agents 
- Penetration enhancers 
- Gelling agents 
- Stabilizers 
- Antimicrobial preservatives 
Taste/smell Masking - Sweeteners 
- Flavorings 
- Relation oil vs. water 
Source : From ref. 4, 34, 35, 36 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 331 
tions. Rubber stoppers soften and get sticky over time because all rubber products 
degrade as sulfur bonds induced during vulcanization revert. Connors et al. [45] 
present the oxygen content of water at different temperatures and an interesting 
discussion of calculations for the case of captopril as an oxygen - sensitive drug. 
Dissolution of Drugs in Solutions Although some compounds, such as poloxamers, 
decrease their aqueous solubility with an increase in temperature [46] , usually, 
drugs dissolve more quickly when the temperature increases because particle vibration 
is augmented and the molecules move apart to form a liquid. Chemical instabilities 
by oxidation due to high temperature or prolonged periods of heat exposure 
can occur when trying to increase the dissolution of poorly soluble raw materials. 
To control such instabilities, charts of time and amount of temperature treatments 
to dissolve materials as well as tests of dissolution are required [6] . In addition, 
precipitations and other reactions may occur between salts in solution and can be 
anticipated by using heat - of - mixing data and activation energy calculations for 
decomposition reactions. Connors et al. [45] provide examples of calculations about 
effects of temperature on chemical stability of pharmaceuticals in solution. Regarding 
the instability of the product, the reasons to limit temperature amounts can go 
from controlling fi nal concentration changes to controlling burn - on/fouling when 
too - high temperatures are applied [45] . Usually salts are more soluble in water and 
alcohol than weak acids or bases. The reason salts are not always the best choice to 
increase the solubility of a drug is its permeability. Oral drug absorption depends 
not only on solubility and dissolution but also on permeability through the cellular 
membrane. Drugs have to be able to dissolve not only in the aqueous fl uids of the 
body before reaching the intestinal wall but also in the lipophilic environment of 
the cellular membrane in order to reach the internal part of the cell and interfere 
with its functionability. Therefore, the cosolvent approach is essential if the drug 
presents problems in dissolving in the media. The dielectric constant of a solvent is 
a relative measure of its polarity. Comparing the hydroxyl – carbon ratio of the 
solvent molecule allows establishing the relative polarity of the cosolvent as determined 
by its dielectric constant [47] . Remington describes the formulations of some 
solutions, such as the ferrous sulfate syrup, amantadine hydrochloride syrup, phenobarbital 
elixir, and theophylline elixir [1] . 
Potency of Drugs in Suspension To avoid degradation of the suspended drug substance 
by high temperature or prolonged periods of heat exposure, it is necessary 
to record the time and amount of temperature treatments on charts [6] . The rate 
of dissolution of a suspended drug increases with the increase in temperature. The 
potency stability of a suspended drug depends on the concentration of the dissolved 
drug since drug decomposition occurs only in solution [48] . The goal is to avoid 
the dissolution of suspensions. Changing the pH of the vehicle or replacing the drug 
with a less soluble molecule may result in enhanced potency stability of the suspended 
drug [48] . 
For instance, when the chemical stability of a suspension of ibuprofen powder 
and other ibuprofen – wax microspheres was studied with a modifi ed HPLC procedure 
for three months, the amount of drug released from the microspheres was 
affected by the medium pH, type of suspending agent, and storage temperature 
without observing chemical degradation of the drug [49] . 

332 LIQUID DOSAGE FORMS 
Temperature Uniformity in Emulsions During the preparation of emulsions, heat 
may be increased as part of the manufacturing protocol or mixing operation system. 
Temperature measurements should be monitored and documented continuously 
using a recording thermometer if the temperature control is critical or using a hand - 
held thermometer if it is not a critical factor. Temperature may be critical in the 
manufacturing process depending on the thermosensitivity of the drug product and 
excipients as well as the type of mixer used. To guarantee the temperature uniformity 
during the mixing operation, manufacturers may consider the relation between 
the container size, mixer speed, blade design, viscosity of the contents, and rate of 
heat transfer [20] . 
Fong - Spaven and Hollenbeck [50] studied the apparent viscosity as a function 
of the temperature from 25 to 75 ° C of an oil – water emulsion stabilized with 5% 
triethanolamine stearate (TEAS) using a Brookfi eld digital viscometer. They 
observed that the viscosity decreased when the temperature reached about 48 ° C, 
but surprisingly viscosity increased to a small peak at 54 ° C and then continued 
decreasing after that peak. The viscosity peak was attributed to a transitional gellike 
arrangement molecular structure of TEAS that is destroyed as soon as the temperature 
continues increasing, the TEAS crystalline form reappears, and viscosity again 
decreases [36] . 
Microbiological Control To avoid chemical instabilities that yield microbiological 
and physical instabilities, as a result of high temperature or prolonged periods of 
exposure, it is necessary to record the time and amount of temperature treatments 
on charts [6] . 
Product Uniformity Charts of storage and transfer operation times for the bulk 
product are required to control the risk of segregation. Transfers to the fi lling line 
and during the fi lling operation are the most critical moments to keep the suspension 
uniformity [6] . The implementation of an ERP for time scheduling is the best 
solution for time control and organization of resources. However, it could be diffi - 
cult due to the reluctance of people to change [10] . The constant fl ow of the liquid 
through the piping, the constant mixing of the bulk product in the tank, as well as 
the transfer of small amounts near the end of the fi lling process to a smaller tank 
during the fi lling process may minimize segregation risks [6] . 
Final Volume Excess heating produces variations of the fi nal volume over time 
[6] . Although increasing solute concentration can elevate the boiling point and 
reduce evaporation of water, changes in drug concentration are undesirable because 
they yield different fi nal products. Regarding the instability of the product, the 
reasons to limit temperature amounts can go from controlling fi nal concentration 
changes to controlling burn - on/fouling when too - high temperatures are applied 
[36] . 
A solution is a liquid at room temperature that passes into the gaseous state when 
heated at very high temperature, forming a vapor with determined vapor pressure, 
through a process called vaporization. The kinetic energy is not evenly distributed 
between the molecules of the liquid. When the liquid is in a closed container at a 
constant temperature, the molecules with the highest kinetic energy leave the surface 
of the liquid and become gas molecules. Some of the gas molecules remain as gas 
and others condense and return to the liquid. When, at a determined temperature, 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 333 
the rate of condensation equals the rate of vaporization, the equilibrium vapor pressure 
is reached. However, vapor pressure increases with increases in liquid temperature, 
resulting in more molecules leaving the liquid surface and becoming gas 
molecules [51] . 
Storage Charts of time and temperature of storage are important to control the 
increased levels of degradedness [6] . Shelf life is defi ned as the amount of time in 
storage that a product can maintain quality and is equivalent to the time taken to 
reach 90% of the composition claim or have 10% degradation. The availability of 
an expiration date is assumed under specifi ed conditions of temperature. Based on 
zero - and fi rst - order reaction calculations, Connors et al. [45] show the estimation 
methods to determine the shelf life of a drug product at temperatures different from 
the one specifi ed under standard conditions. 
4.3.4.5 Uniformity of Oral Suspensions 
Keeping the particles uniformly distributed throughout the dispersion is an important 
aspect of physical stability in suspensions. Based on Stokes ’ s law for dilute 
suspensions where the particles do not interfere with one another, there are different 
factors that control the velocity of particle sedimentation in a suspension, for 
instance, particle diameter, densities of the dispersed phase and the dispersion 
medium, as well as viscosity of the dispersion medium [36] . Remington describes 
the formulation of trisulfapyrimidines oral suspension [1] . In addition, Lieberman 
et al. [42, 48] are also good sources of typical formulations for suspensions. 
Viscosity Depending upon the viscosity, many suspensions require continuous or 
periodic agitation during the fi lling process [6] . 
Segregation in Transfer Lines When the stored bulk of a nonviscous product is 
transferred to fi lling equipment through delivery lines, some level of segregation is 
expected. The manufacturer has to write the procedures and diagrams for line setup 
prior to fi lling the product [6] . Delivery lines of suspensions increase the tendency 
of particles of the same size to assemble together. However, slightly increasing the 
global mixing in the lines can easily reverse the segregation without enhancing the 
global mixing [52] . Shear stress versus rate of shear can be plotted to determine 
the fl ow pattern of a specifi c suspension as pseudoplastic, Newtonian, or dilatant. 
The type of fl ow is determined by the slope of the plot. While shaking increases the 
yield stress and causes particles fl ow, the cessation of shear and rest rebuilds the 
order of the system. A good - quality suspension is known as a thixotrophic system 
and is obtained when the particles at rest avoid or show reduced sedimentation. The 
rheogram of a thixotrope system presents a typical hysteresis or curve representing 
different shear stresses over time [33] . 
Quality Control The GMPs for suspensions include testing samples at different 
checkpoints in the procedure, at the beginning, middle, and end, as well as samples 
from the bulk tank. The uniformity will be successful only if, on microscopic analysis, 
the components are dispersed to the expected particle size distribution established 
by product development. Visual and microscopic examinations should consist of 
looking for verifi cation of foam formation, segregation, and settling, although testing 

334 LIQUID DOSAGE FORMS 
for viscosity is important to determine agitation during the fi lling process. Samples 
used for tests should not be combined again with the lot [6, 33] . 
4.3.4.6 Uniformity of Emulsions 
Remington describes the following three typical formulas of emulsions: type A 
gelatin, mineral oil emulsion (USP), and oral emulsion (O/W) containing an insoluble 
drug [1] . In addition, Lieberman et al. [42, 50] are also good sources of typical 
formulations for emulsions. The components of the emulsion system may present 
physical and chemical instabilities refl ected on the distribution of an active ingredient, 
component migration from one phase to another, polymorphic changes in 
components, and chemical degradation of components [33] . 
Solubility The soluble active ingredient should be added to the liquid phase that 
will be its carrier vehicle. Data of solubility have to be determined as part of the 
process validation. Potency uniformity has to be tested by demonstrating satisfactory 
distribution in the emulsifi ed mix [20] . 
Particle Size Regarding globule diameter in emulsions, the size – frequency distribution 
of particles in an emulsion over time may be the only method for determining 
stability [36] . Drug activity and potency uniformity of insoluble active ingredients 
depend upon control of particle size and distribution in the mix [6] . In addition, 
aggregation of the internal phase droplets, formation of larger droplets, and phase 
separation are categorized as emulsion system instabilities that are refl ected in the 
particle size distribution of the emulsion. The measurement of particle size distribution 
over time allows the characterization of the emulsion stability and determines 
the rheological behavior of the emulsion. Well - accepted approaches to determine 
particle size distribution include microscopy, sedimentation, chromatography, and 
spectroscopy. However, these analyses are problematic in a multiphase emulsion 
[33] . 
Crystalline Form Uncontrolled temperature or shear can induce changes in component 
crystallinity or solubility. For this reason, analytes originally present in each 
phase of the product should be counted as well possible interactions with the container 
or closure and the processing equipment analyzed. Some techniques used to 
obtain information about the emulsion system and its components are microscopic 
examination, macro - and microlaser Raman, and rheological studies [33] . The FDA 
guidance offers the following example: “ in one instance, residual water remaining 
in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in 
partial solubilization and subsequent recrystallization of the drug substance; the 
substance recrystallized in a larger particle size than expected and thereby raised 
questions about the product effi cacy ” [20] . 
4.3.4.7 Microbiological Quality 
Microbial Specifi cations These specifi cations are determined by the manufacturer. 
The USP Chapters 61, 62, and 1111 present the microbial limits to assess the 
signifi cance of microbial contamination in a dosage form [53] . However, the USP 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 335 
does not determine specifi c methods for water - insoluble topical products. The 
microbial specifi cations are presented as a manufacturer ’ s document that details the 
methods to isolate and identify the organisms as well as the number of organisms 
permitted and action levels to be taken when limits are exceed and the potential 
causes are investigated [6] . The Pharmaceutical Microbiology Newsletter (PMF) 
presents several articles to discuss topics such as microbial identifi cation, methods, 
data analysis, and preservation as well as topics related to USP and FDA regulations 
[54] . To minimize the differences about microbial limits and test methods, the USP 
is trying to harmonize the standards with the European Pharmacopoeia (EP) [55] . 
Microbial Test Methods The selected microbial test methods determine specifi c 
sampling and analytical procedures. When the product has a potential antimicrobial 
effect and/or preservative, the spread technique on microbial test plates must be 
validated. In addition, the personnel performing the analytical techniques have to 
be qualifi ed and adequately trained for this purpose [6] . 
Usually, total aerobic bacteria, molds, and yeasts are counted by using a standard 
plate count in order to test the microbial limits. The microbial limit test may be 
customized by performing a screening for the occurrence of Staphylococcus aureus, 
Pseudomonas aeruginosa, Pseudomonas cepacia, Escherichia coli, and Salmonella 
sp. [56] . 
Investigation of Exceeded Microbiological Limits A high number of organisms 
may indicate defi ciencies in the manufacturing process, such as excessive high 
temperature, component quality, inadequate preservative system, and/or container 
integrity. Information about the health hazards of all organisms isolated from the 
product has different meanings depending on the type of dosage form and group 
of patients to be treated. For instance, in oral liquids, pseudomonads are usually a 
high - risk contamination. Examples presented by the FDA are Nystatin antifungal 
suspension, used as prophylaxis in AIDS patients [57] ; antacids, with which P. aeruginosa 
contamination can promote gastric ulceration [58] ; and the presence of 
Pseudomona putida , which could indicate the presence of other signifi cant contaminants 
such as P. aeruginosa [6] . 
Deionizer Water - Monitoring Program Deionizing systems must be controlled in 
order to produce purifi ed water, required for liquid dosage forms and USP tests and 
assays [1] . The monitoring program has to include the manufacturer ’ s documentation 
about time between recharging and sanitizing, microbial quality and chlorine 
levels of feed water, establishment of water microbial quality specifi cations, conductivity 
monitoring intervals, methods of microbial testing, action levels when microbial 
limits are exceeded, description of sanitization and sterilization procedures for 
deionizer parts, and processing conditions such as temperature, fl ow rates, use 
and sanitization frequency, and regenerant chemicals for ion exchange resin beds 
[6, 59] . 
Effectiveness of Preservative Manufacturing controls and shelf life must ensure 
that the specifi ed preservative level is present and effective as part of the stability 
program [6] . Depending on the type of product, the selection of the preservative 
system is based on different considerations, such as site of use, interactions, 

336 LIQUID DOSAGE FORMS 
spectrum, stability, toxicity, cost, taste, odor, solubility, pH, and comfort. The 
USP and other organizations describe methods to validate the preservative 
system used in the dosage form. Compounds used as preservatives are alcohols, 
acids, esters, and quaternary ammonium compounds, among others. For instance, to 
preserve ophthalmic liquid dosage forms, these products are autoclaved or fi ltrated 
and require an antimicrobial preservative to resist contamination throughout 
their shelf life, such as chlorobutanol, benzalkonium chloride, or phenylmercuric 
nitrate [1] . 
4.3.4.8 Filling and Packing 
Constant Mixing during Filling Process Due to the tendency of suspensions to 
segregate during transport through transfer lines, special attention is required on 
suspension uniformity during the fi lling process. Appropriate constant mixing of the 
bulk to keep homogeneity during the fi lling process and sampling of fi nished products 
and other critical points are indispensable conditions to assure an acceptable 
quality level during the fi lling and packing process [20] . 
Mixing Low Levels of Bulk Near End of Filling Process Constant mixing during 
the fi lling process includes mixing low levels of bulk near the end of the fi lling 
process. Large - size batches of bulk suspension require the transfer of the residual 
material to a smaller tank in order to assure appropriate mixing of components 
before fi lling and packing the containers [20] . 
Potency Uniformity of Unit - Dose Products Products manufactured have to be of 
quality at least as good as the established acceptable quality level (AQL). The quality 
level should be based on the limits specifi ed by the USP. However, when the bulk 
product is not properly mixed during fi lling and packing processes, liquid dosage 
forms, and specially suspensions, are not homogeneous and unit - dose products 
contain very different amounts of the active component and potency. For these 
reasons, fi nished products have to be tested to assure that the fi nal volume and/or 
weight as well as the amount of active ingredient are within the specifi ed limits [6] . 
Calibration of Provided Measuring Devices Measuring devices consist of droppers, 
spoons for liquid dosage forms, and cups labeled with both tsp and mL. Measuring 
devices have to be properly calibrated in order to assure the right amount 
of ingredients per volume to be administered [6] . 
Container Cleanliness of Marketing Product The previous cleanliness of containers 
fi lled with the product will depend on their transportation exposure, composition, 
and storage conditions. Glass containers usually carry at least mold spores of 
different microorganisms, especially if they are transported in cardboard boxes. 
Other containers and closures made with aluminum, Tefl on, metal, or plastic usually 
have smooth surfaces and are free from microbial contamination but may contain 
fi bers or insects [45] . Some manufacturers receive containers individually wrapped 
to reduce contamination risks and others use compressed air to clean them. However, 
the cleanliness of wrapped containers will depend on the provider ’ s guarantee of 
the manufacturing process and compressed - air equipment may release vapors or 
oils that have to be tested and validated [6] . 

CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS 337 
4.3.4.9 Stability 
The typical stability problems are color change, loss of active component, and clarity 
changes for solutions; inability to resuspend the particles and loss of signifi cant 
amounts of the active component for suspensions; and creaming and breaking 
(or coalescence) for emulsions [1] . These instabilities are usually related to the 
following: 
Active and Primary Degradant. A liquid dosage form is stable while it remains 
within its product specifi cations. When chemical degradation products are 
known, for stability study and expiration dating, the regulatory requirements 
for the primary degradant of a active component are chemical structure, biological 
effect and signifi cance at the concentrations to be determined, mechanism 
of formation and order of reaction, physical and chemical properties, 
limits and methods for quantitating the active component and its degradant 
molecule at the levels expected to be present, and pharmacological action or 
inaction [45] . Examples of drugs in liquid dosage forms that are easily degraded 
are vitamins and phenothiazines [6] . 
Interactions with Closure Systems. Elastomeric and plastic container and closure 
systems release leachable compounds into the liquid dosage form, such as 
nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing 
agents [44] . Each type of container and closure with different composition 
and/or design proposed for marketing the drug or physician ’ s samples has to 
be tested and stability data should be developed. Containers should be stored 
upright, on their side, and inverted in order to determine if container – closure 
interactions affect product stability [6, 45] . 
Moisture Loss. When the containers are inappropriately closed, part of the 
vaporized solvent is released and the concentration and potency of the active 
component may be increased [6] . 
Microbiological Contamination. Inappropriate closure systems also increase the 
possibilities of microbial contamination when opening and closing containers 
[6] . 
4.3.4.10 Process Validation 
Objective Process validation has the objectives of identifying and controlling 
critical points that may vary product specifi cations through the manufacturing 
process [6] . 
Amount of Data To validate the manufacturing process, the manufacturer has to 
design and specify in the protocol the use of data sheets to keep information about 
the control of product specifi cations from each batch in - process as well as fi nished - 
product tests. Some formats are common to different products, though each type of 
product has some specifi c information to be kept on special sheets. Thus, the amount 
of data varies from one type of product to another [6] . 
Scale - Up Process Data obtained using special batches for the validation of the 
scale - up process are compared with data from full - scale batches and batches used 
for clinical essays [6] . 

338 LIQUID DOSAGE FORMS 
Product Specifi cations The most important specifi cations or established limits for 
liquid dosage forms are microbial limits and test methods, medium pH, dissolution 
of components, viscosity, as well as particle size uniformity of suspended components 
and emulsifi ed droplets. Effectiveness of the preservative system depends on 
the dissolution of preservative components and may be affected by the medium pH 
and viscosity. In addition, dissolved oxygen levels are important for components 
sensitive to oxygen and/or light [6] . 
Bioequivalence or Clinical Study In the patient, the general or systemic circulation 
is responsible for carrying molecules to different tissues of the body. To assure 
the expected bioactivity of a product, the amount of drug that reaches the systemic 
circulation per unit of time is analyzed and is known as bioavailability. Bioequivalence 
is the comparison of the bioavailability of a product with a reference product. 
While oral solutions may not always need bioequivalence studies because they are 
considered self - evidente, suspensions usually require bioequivalence or clinical 
studies in order to demonstrate effectiveness. However, OTC suspension products 
such as antacids are exempt from these studies [6] . 
Control of Changes to Approved Protocol The manufacturing process of a specifi c 
product is validated and approved internally by the quality control unit and externally 
by the FDA. Any change in the approved protocol has to be documented to 
explain the purpose and demonstrate that the change will not unfavorably affect 
product safety and effi cacy. Factors include potency and/or bioactivity as well as 
product specifi cations. However, the therapeutic activity and uniformity of the 
product are the main concerns after formulation and process changes [20] . 
4.3.5 LIQUID DOSAGE FORMS * 
Douche A liquid preparation, intended for the irrigative cleansing of the vagina, 
that is prepared from powders, liquid solutions, or liquid concentrates and 
contains one or more chemical substances dissolved in a suitable solvent or 
mutually miscible solvents. 
Elixir A clear, pleasantly fl avored, sweetened hydroalcoholic liquid containing 
dissolved medicinal agents; it is intended for oral use. 
Emulsion A dosage form consisting of a two - phase system comprised of at least 
two immiscible liquids, one of which is dispersed as droplets (internal or dispersed 
phase) within the other liquid (external or continuous phase), generally 
stabilized with one or more emulsifying agents. (Note: Emulsion is used as a 
dosage form term unless a more specifi c term is applicable, e.g. cream, lotion, 
ointment.). 
Enema A rectal preparation for therapeutic, diagnostic, or nutritive purposes. 
Extract A concentrated preparation of vegetable or animal drugs obtained by 
removal of the active constituents of the respective drugs with a suitable menstrua, 
evaporation of all or nearly all of the solvent, and adjustment of the 
residual masses or powders to the prescribed standards. 
* The defi nitions in this section are from ref. 11 . 

For Solution A product, usually a solid, intended for solution prior to 
administration. 
For Suspension A product, usually a solid, intended for suspension prior to 
administration. 
For Suspension, Extended Release A product, usually a solid, intended for suspension 
prior to administration; once the suspension is administered, the drug 
will be released at a constant rate over a specifi ed period. 
Granule, Effervescent A small particle or grain containing a medicinal agent in 
a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric 
acid which, when in contact with water, has the capability to release gas, resulting 
in effervescence. 
Inhalant A special class of inhalations consisting of a drug or combination of 
drugs, that by virtue of their high vapor pressure can be carried by an air 
current into the nasal passage where they exert their effect; the container from 
which the inhalant generally is administered is known as an inhaler. 
Injection A sterile preparation intended for parenteral use; fi ve distinct classes 
of injections exist as defi ned by the USP. 
Injection, Emulsion An emulsion consisting of a sterile, pyrogen - free preparation 
intended to be administered parenterally. 
Injection, Solution A liquid preparation containing one or more drug substances 
dissolved in a suitable solvent or mixture of mutually miscible solvents that is 
suitable for injection. 
Injection, Solution, Concentrate A sterile preparation for parenteral use which, 
upon the addition of suitable solvents, yields a solution conforming in all 
respects to the requirements for injections. 
Injection, Suspension A liquid preparation, suitable for injection, which consists 
of solid particles dispersed throughout a liquid phase in which the particles 
are not soluble. It can also consist of an oil phase dispersed throughout an 
aqueous phase, or vice - versa. 
Injection, Suspension, Liposomal A liquid preparation, suitable for injection, 
which consists of an oil phase dispersed throughout an aqueous phase in such 
a manner that liposomes (a lipid bilayer vesicle usually composed of phospholipids 
which is used to encapsulate an active drug substance, either within a 
lipid bilayer or in an aqueous space) are formed. 
Injection, Suspension, Sonicated A liquid preparation, suitable for injection, 
which consists of solid particles dispersed throughout a liquid phase in which 
the particles are not soluble. In addition, the product is sonicated while a gas 
is bubbled through the suspension and these result in the formation of microspheres 
by the solid particles. 
Irrigant A sterile solution intended to bathe or fl ush open wounds or body 
cavities; they ’ re used topically, never parenterally. 
Linament A solution or mixture of various substances in oil, alcoholic solutions 
of soap, or emulsions intended for external application. 
Liquid A dosage form consisting of a pure chemical in its liquid state. This 
dosage form term should not be applied to solutions. 
LIQUID DOSAGE FORMS 339

340 LIQUID DOSAGE FORMS 
Liquid, Extended Release A liquid that delivers a drug in such a manner to allow 
a reduction in dosing frequency as compared to that drug (or drugs) presented 
as a conventional dosage form. 
Lotion An emulsion, liquid dosage form. This dosage form is generally for 
external application to the skin. 
Lotion/Shampoo A lotion dosage form which has a soap or detergent that is 
usually used to clean the hair and scalp; it is often used as a vehicle for dermatologic 
agents. 
Mouthwash An aqueous solution which is most often used for its deodorant, 
refreshing, or antiseptic effect. 
Oil An unctuous, combustible substance which is liquid, or easily liquefi able, on 
warming, and is soluble in ether but insoluble in water. Such substances, 
depending on their origin, are classifi ed as animal, mineral, or vegetable oils. 
Rinse A liquid used to cleanse by fl ushing. 
Soap Any compound of one or more fatty acids, or their equivalents, with an 
alkali; soap is detergent and is much employed in liniments, enemas, and in 
making pills. It is also a mild aperient, antacid and antiseptic. 
Solution A clear, homogeneous liquid dosage form that contains one or more 
chemical substances dissolved in a solvent or mixture of mutually miscible 
solvents. 
Solution, Concentrate A liquid preparation (i.e., a substance that fl ows readily 
in its natural state) that contains a drug dissolved in a suitable solvent or 
mixture of mutually miscible solvents; the drug has been strengthened by the 
evaporation of its nonactive parts. 
Solution, for Slush A solution for the preparation of an iced saline slush, which 
is administered by irrigation and used to induce regional hypothermia (in 
conditions such as certain open heart and kidney surgical procedures) by its 
direct application. 
Solution, Gel Forming/Drops A solution, which after usually being administered 
in a drop - wise fashion, forms a gel. 
Solution, Gel Forming, Extended Release A solution that forms a gel when it 
comes in contact with ocular fl uid, and which allows at least a reduction in 
dosing frequency. 
Solution/Drops A solution which is usually administered in a drop - wise 
fashion. 
Spray A liquid minutely divided as by a jet of air or steam. 
Spray, Metered A non - pressurized dosage form consisting of valves which allow 
the dispensing of a specifi ed quantity of spray upon each activation. 
Spray, Suspension A liquid preparation containing solid particles dispersed in 
a liquid vehicle and in the form of coarse droplets or as fi nely divided solids 
to be applied locally, most usually to the nasal - pharyngeal tract, or topically 
to the skin. 
Suspension A liquid dosage form that contains solid particles dispersed in a 
liquid vehicle. 

Suspension, Extended Release A liquid preparation consisting of solid particles 
dispersed throughout a liquid phase in which the particles are not soluble; the 
suspension has been formulated in a manner to allow at least a reduction in 
dosing frequency as compared to that drug presented as a conventional dosage 
form (e.g., as a solution or a prompt drug - releasing, conventional solid dosage 
form). 
Suspension/Drops A suspension which is usually administered in a dropwise 
fashion. 
Syrup An oral solution containing high concentrations of sucrose or other 
sugars; the term has also been used to include any other liquid dosage form 
prepared in a sweet and viscid vehicle, including oral suspensions. 
Tincture An alcoholic or hydroalcoholic solution prepared from vegetable 
materials or from chemical substances. 
Notes : 
1. A liquid is pourable; it fl ows and conforms to its container at room temperature. 
It displays Newtonian or pseudoplastic fl ow behavior. 
2. Previously the defi nition of a lotion was “ The term lotion has been used to 
categorize many topical suspensions, solutions, and emulsions intended for 
application to the skin. ” The current defi nition of a lotion is restricted to an 
emulsion. 
3. A semisolid is not pourable; it does not fl ow or conform to its container at 
room temperature. It does not fl ow at low shear stress and generally exhibits 
plastic fl ow behavior. 
4. A colloidal dispersion is a system in which particles of colloidal dimension 
(i.e., typically between 1 nm and 1 . m) are distributed uniformly throughout a 
liquid. 
REFERENCES 
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The Science and Practice of Pharmacy , Lippincott Williams & Wilkins , Philadelphia , 
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Pharmaceutical Association (APhA) . Washington D.C. , 2002 . Pages 93, 95. 
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11 – 12. Available at: http://www.contractpharma.com/articles/2003/11/outsourcing - 
stability - services 
6. USA Department of Health and Human Services: Food and Drug Administration (FDA) . 
Guides to inspections. 

342 LIQUID DOSAGE FORMS 
7. Kourounakis , P. N. ( 1994 ), Advanced Drug Design and Development , Taylor and Francis , 
p. 141 . 
8. Papich , M. G. ( 2005 ), Drug compounding for veterinary patients , AAPS J. , 7 ( 2 ), 
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11. USA Department of Health and Human Services, Food and Drug Administration (FDA) . 
Center for Drug Evaluation and Research (CDER) Data Standards Manual: Dosage 
Form (4/92) available at: http://www.fda.gov/cder/dsm/DRG/drg00201.htm . 
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htm#L . 
13. DeLuca , P. P. ( 1992 ), Formulation of small volume parenterals , in Avis , K. E. , Lieberman , 
H. A. , and Lachman , L. , Eds., Pharmaceutical Dosage Forms: Parenteral Medications , Vol. 
1 , Marcel Dekker , New York . 
14. Allen , L. V. , Popovich , N. G. , and Ansel , H. C. , Ansel ’ s Pharmaceutical Dosage Forms and 
Drug Delivery Systems , Lippincott William & Wilkins , Baltimore , 2004 , Chapters 2 
and 5. 
15. SAP Information Center, Best practices for automotive: Pharmaceutical industry, Liquid 
dosage forms, available: http://help.sap.com/ . 
16. Sokoll , K. ( 2007 ), Optimizing drug development strategies: Exploring methods to improve 
the process, Contract Pharm . Marzo 2007. Available: http://www.contractpharma.com/ 
articles/2007/03/optimizing - drug - development - strategies 
17. Carleton , F. J. , and Agalloco , J. P. ( 1999 ), Validation of Pharmaceutical Processes: Sterile 
Products , Marcel Dekker , New York . 
18. Stacey , R. D. , Griffi n , D. , and Shaw , P. ( 2000 ), Complexity and Management: Fad or Radical 
Challenge to Systems Thinking? Taylor and Francis Group , Boca Raton, Fl . 
19. Hardman , J. G. , Limbrid , L. E. , Molinoff , P. B. , and Ruddon , R. W. Goodman and Gilman ’ s 
The Pharmacological Basis of Therapeutics , McGraw - Hill , New York , 2006 . 
20. Scott , R. R. ( 1989 ), A practical guide to equipment selection and operating techniques , 
in Lieberman , H. A. , Rieger , M. M. , and Banker , G. S. , Eds., Pharmaceutical Dosage Forms: 
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as an undeclared steroid in zinc pyrithione formulations by high - performance liquid 
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fi ltration systems, Pharmaceutical Industry Standard On - line, available: http://www. 
pharmaceuticalonline.com/downloads/detail.aspx?docid=74B77B1C - 0ED9 - 4E7B - A317 - 
5DD0D23124B3&VNETCOOKIE=NO . 
23. Biotrace International (2004), Air samplers. LIT055/002/29.06.04 . 
24. 3 - A Sanitary Standards, Technical Resource Center, resource papers, available: http:// 
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25. Cook , Jr. , J. L. ( 1998 ), Standard Operating Procedures and Guidelines , PennWell Books , 
Tulsa, OK , p. 318 . 

 
28. Thierauf , R. J. , and Hoctor , J. J. ( 2006 ), Optimal Knowledge Management: Wisdom Management 
Systems Concepts and Applications , Idea Group , Hershey, PA . 
29. Petru s evski , V. M. , and Metodija , Z. N. ( 2001 ), Volume non - additivity of liquid mixtures: 
Modifi cations to classical demonstrations , Chem. Ed. J. , 6 , 3 . 
30. Zhou , Q. , and Milton , R. ( 2003 ), Molecular interactions of surfactants in mixed monolayers 
at the air/aqueous solution interface and in mixed micelles in aqueous media: 
The regular solution approach , Am. Chem. Soc. , 19 ( 11 ), 4555 – 4562 . 
31. CANTY Process Technology ( 2007 ), CANTY Lighting Systems, available: http://www. 
jmcanty.com/images/overview/16pagermaster.pdf . 
32. Wikipedia, Non - Newtonian fl uid defi nition, available: http://en.wikipedia.org/wiki/Non - 
Newtonian_fl uid . 
33. Lieberman , H. A. , Rieger , M. M. , and Banker , G. S. ( 1988 ), Pharmaceutical Dosage Forms: 
Disperse Systems , Vol. 1 , Marcel Dekker , New York . 
34. Gibson , M. , Pharmaceutical Preformulation and Formulation: A Practical Guide from 
Candidate Drug Selection to Commercial Dosage Form , Interpharm , Boca Raton, FL , 
2004 , pp. 581 . 
35. Davidow , L. W. , Davidow , L. , and Thompson , J. E. , A Practical Guide to Contemporary 
Pharmacy Practice , Lippincott Williams & Wilkins , 2003. pp. 704. 
36. Sinko , P. J. Martin ’ s Physical Pharmacy and Pharmaceutical Sciences , Lippincott Williams 
& Wilkins , Baltimore, MD., 2005, pp. 795. 47. 
37. Nusim , S. ( 2005 ), Active Pharmaceutical Ingredients: Development, Manufacturing, and 
Regulation , Taylor and Francis Group , Boca Raton, FL . 
38. Chongprasert , S. , and Nail S. L. ( 1998 ), Infl uence of drug polymorphism on the 
physical chemistry of freeze - drying, Digital dissertations and theses, Purdue e - pubs, ETD 
Collection for Purdue University , available: http://docs.lib.purdue.edu/dissertations/ 
AAI9939331/ . 
39. Borka , L. ( 1971 ), The stability of chloramphenicol palmitate polymorphs. Solid and solution 
phase transformations , Acta Pharm. Suec. , 9 – 8 ( 4 ), 365 – 372 . 
40. Rosenholm , J. B. ( 2007 ), Wetting of surfaces and interfaces: A conceptual equilibrium 
thermodynamic approach , in Colloid Stability: The Role of Surface Forces, Part II , Tharwat 
F. Tadros Colloids and Interface Science Series, Vol. 2, Wiley-VCH, Weinheim. 
41. Lerk , C. F. , Lagas , M. , Lie - a - Huen , L. , Broersma , P. , and Zuurman , K. ( 1979 ), In vitro and 
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42. Rosoff , M. ( 1988 ), Specialized pharmaceutical emulsions , in Lieberman , H. A. , Rieger , 
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44. Allen , T. ( 1997 ), Particle Size Measurement , Chapmann and Hall , London . 
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A Handbook for Pharmacists , Wiley - Interscience , New York . 
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344 LIQUID DOSAGE FORMS 
46. Miller , S. C. , and Drabik , B. R. ( 1984 ), Rheological properties of poloxamer vehicles , Int. 
J. Pharm. , 18 , 269 . 
47. Millard , J. W. , Alvarez - Nunez , F. A. , and Yalkowsky , S. H. ( 2002 ), Solubilization by 
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153 – 166 (14). 
48. Nash , R. ( 1996 ), Pharmaceutical suspensions , in Lieberman , H. A. , Rieger , M. M. , and 
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49. Adeyeye , C. M. , and Price , J. C. ( 1997 ), Chemical dissolution stability and microscopic 
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59. Dreeszen , P. ( 2003 ), Biofi lm: Key to Understanding and Controlling Bacterial Growth in 
Automated Drinking Water Systems , Edstrom Industries , Waterford, WI , pp. 19 . 

SPECIAL/NEW DOSAGE FORMS 
SECTION 5


347 
5.1 
CONTROLLED - RELEASE 
DOSAGE FORMS 
Anil Kumar Anal 
Living Cell Technologies (Global) Limited, Auckland, New Zealand 
Contents 
5.1.1 Introduction 
5.1.2 Rationale 
5.1.3 General Design Principle for Controlled - Release Drug Delivery Systems 
5.1.4 Physicochemical and Biological Factors Infl uencing Design and Performance of 
Controlled - Release Formulations 
5.1.4.1 Physicochemical Factors 
5.1.4.2 Biological Factors 
5.1.5 Controlled - Release Oral Dosage Forms 
5.1.5.1 Anatomical and Physiological Considerations 
5.1.5.2 Fundamentals of Controlled - Release Oral Dosage Forms 
5.1.5.3 Factors Infl uencing Oral Controlled - Release Dosage Forms 
5.1.6 Design and Fabrication of Controlled - Release Dosage Forms 
5.1.6.1 Microencapsulation 
5.1.6.2 Nanostructure - Mediated Controlled - Release Dosage Forms 
5.1.6.3 Liposomes 
5.1.6.4 Niosomes 
5.1.7 Technologies for Developing Transdermal Dosage Forms 
5.1.8 Ocular Controlled - Release Dosage Forms 
5.1.9 Vaginal and Uterine Controlled - Release Dosage Forms 
5.1.10 Release of Drugs from Controlled - Release Dosage Forms 
5.1.10.1 Time - Controlled - Release Dosage Forms 
5.1.10.2 Stimuli - Induced Controlled - Release Systems 
5.1.11 Summary 
References 
Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad 
Copyright © 2008 John Wiley & Sons, Inc.

348 CONTROLLED-RELEASE DOSAGE FORMS 
5.1.1 INTRODUCTION 
Therapeutic value and pharmaeconomic value have in recent years become major 
issues in defi ning health care priorities under the pressure of cost containment [1] . 
The improvement in drug therapy is a consequence of not only the development of 
new chemical entities but also the combination of active substances and a suitable 
delivery system. The treatment of an acute disease or chronic illness is mostly 
accomplished by delivery of one or more drugs to the patient using various pharmaceutical 
dosage forms. Tablets, pills, capsules, suppositories, creams, ointments, 
liquids, aerosols, and injections are in use as drug carriers for many decades. These 
conventional types of drug delivery systems are known to provide a prompt release 
of the drug. Therefore, to achieve as well as to maintain the drug concentration 
within the therapeutically effective range needed for treatment, it is often necessary 
to take this type of drug several times a day, resulting in the signifi cant fl uctuation 
in drug levels [2] . For all categories of treatment, a major challenge is to defi ne the 
optimal dose, time, rate, and site of delivery. Recent developments in drug delivery 
techniques make it possible to control the rate of drug delivery to sustain the duration 
of therapeutic activity and/or target the delivery of drug to a specifi c organ or 
tissue. Many investigations are still going on to apply the concepts of controlled 
delivery for a wide variety of drugs [3] . 
5.1.2 RATIONALE 
The basic rationale for controlled drug delivery is to alter the pharmacokinetics and 
pharmacodynamics of pharmacologically active moieties by using novel drug delivery 
systems or by modifying the molecular structure and/or physiological parameters 
inherent in a selected route of administration. It is desirable that the duration 
of drug action become more a design property of a rate - controlled dosage form and 
less, or not at all, a property of the drug molecules ’ inherent kinetic properties. 
The rationale for development and use of controlled dosage forms may include 
one or more of the following arguments [4] : 
• Decrease the toxicity and occurrence of adverse drug reactions by controlling 
the level of drug and/or metabolites in the blood at the target sites. 
• Improve drug utilization by applying a smaller drug dose in a controlled - release 
form to produce the same clinical effect as a larger dose in a conventional 
dosage form. 
• Control the rate and site of release of a drug that acts locally so that the drug 
is released where the activity is needed rather than at other sites where it may 
cause adverse reactions. 
• Provide a uniform blood concentration and/or provide a more predictable drug 
delivery. 
• Provide greater patient convenience and better patient compliance by signifi - 
cantly prolonging the interval between administrations. 
However, there are also disadvantages attached to the use of controlled - release 
dosage forms. These include higher cost of manufacturing, unpredictability, poor in 

vitro/in vivo correlation, reduced potential, and poor systemic availability in general 
and the effective release period is infl uenced and limited by the gastrointestinal 
(GI) residence time [5] . The transit time of a dosage form through the GI tract is 
dependent on the physical characteristics of the formulation as well as on physiological 
factors such as stomach emptying time and effect of food on the absorption 
process. 
Only drugs with certain properties are suitable for controlled - release dosing. 
Characteristics that may make a drug unsuitable for controlled - release dosing 
include a long or short elimination half - life, a narrow therapeutic index, a large dose, 
low/slow solubility, extensive fi rst - pass clearance, and time course of circulating drug 
levels different from that of the pharmacological effect. The ideal drug delivery 
should be inert, biocompatible, mechanically strong, comfortable for the patient, 
capable of achieving high drug loading, simple to administer, and easy to fabricate 
and sterilize [6] . A range of materials have been employed to control the release of 
drugs and other active substances. Controlled - release dosage forms have been 
developed for over four decades. One of the fi rst practically used controlled - release 
oral dosage forms was the Spansule capsule, which was introduced in the 1950s. 
Spansule capsules were manufactured by coating a drug onto nonpareil particles 
and further coating with glyceryl stearate and wax. Subsequently, ion exchange 
resins were proposed for application as sustained - release delivery systems of 
ac cessible drug. Since then numerous products have been introduced and 
commercialized. 
5.1.3 GENERAL DESIGN PRINCIPLE FOR CONTROLLED - RELEASE 
DRUG DELIVERY SYSTEMS 
In the drug delivery system, the pharmacodynamics of active molecules becomes 
more a function of design and less one of inherent kinetic properties. Therefore, a 
deep understanding of the design of controlled - release systems of the pharmacokinetics 
and pharmacodynamics of the drug is required [7] . The conventional tablet 
or capsule provides only a single and transient burst of drug. A modifi cation introduced 
to the molecular structure of the drug (often used to decrease the elimination 
rate) or a system for modifi ed release rate is the common approaches used to 
increase the interval between two doses. The objective of both these approaches is 
to decrease the fl uctuations in plasma levels during multiple dosing. This allows the 
dosing interval to increase without compromising the required dosage levels. If the 
half - life of a drug is less than 6 h or the passage time in the smaller intestinal track 
is decreased, there might not be enough time to allow proper absorption, thus 
making frequent dosing compulsory. For other routes, where the residence time is 
not a constraint, dosing intervals can be as long as months or even years. 
A controlled - release drug delivery system serves primarily two functions [8] . 
First, it involves the transport of the drug to a particular part of the body. This may 
be accomplished in two ways, parenterally and nonparenterally. Second, the release 
of active ingredients occurs in a controlled manner, depending on the preparation 
of dosage forms. This determines the rate at which a drug is made available to the 
body once it has been delivered. Controlled drug delivery occurs when a biomaterial, 
either natural or synthetic, is judiciously combined with a drug or other active 
CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 349

350 CONTROLLED-RELEASE DOSAGE FORMS 
agent in such a way that the active agent is released from the material in a predesigned 
manner. To be successfully used in controlled drug delivery formulations, a 
material must be chemically inert and free of leachable impurities. It must also have 
an appropriate physical structure, with minimal undesired aging, and be readily 
processable. 
Controlled - release systems provide numerous benefi ts over conventional dosage 
forms. Conventional dosage forms are not able to control either the rate of drug 
delivery or the target area of administration and provide an immediate or rapid 
drug release. This necessitates frequent administration in order to maintain a therapeutic 
level. As a result, as shown in Figure 1 , drug concentrations in the blood 
fl uctuate widely. The concentrations of drug remain at a maximum value, which may 
represent a toxic level, or a level at which undersized side effects might occur, and 
a minimum value, below which the drug is no longer effective. The duration of 
therapeutic effi cacy is dependent upon the frequency of administration, the half - life 
of the drug, and the release rate of dosage forms. In contrast, controlled - release 
dosage forms not only are able to maintain therapeutic levels of drug with narrow 
fl uctuations but also make it possible to reduce the frequency of drug administration. 
The drug concentrations, as shown in Figure 1 , released from controlled - release 
dosage forms fl uctuate within the therapeutic range over a longer period of time. 
The plasma concentration profi le depends on the preparation technology, which 
may generate different release kinetics, resulting in different pharmacological and 
pharmacokinetic responses in the blood or tissues. 
The primary objectives of controlled drug delivery are to ensure safety and to 
improve effi cacy of drugs as well as patient compliance. This is achieved by better 
control of plasma drug levels and less frequent dosing. For conventional dosage 
forms, only the dose ( D ) and dosing interval ( . ) can vary above which undesirable 
or side effects are elicited. As an index of this window, the therapeutic index (TI) 
can be used. This is often defi ned as the ratio of lethal dose (LD 50 ) to median effective 
dose (ED 50 ). Alternatively, it can be defi ned as the ratio of maximum drug 
concentration ( C max ) in blood that can be tolerated to the minimum concentration 
( C min ) needed to produce an acceptable therapeutic response. 
FIGURE 1 Theoretical plasma concentration after administration of various dosage forms: 
( a ) standard oral dose; ( b ) oral overdose; ( c ) IV injection; ( d ) controlled - release system. 
Toxic level 
Minimum 
effective level 
c 
a 
b 
d 
Drug concentration in blood 
Time

Different types of modifi ed release systems can be defi ned [4, 8] : 
• Sustained release (extended release) that permits a reduction in dosing frequency 
as compared to the situation in which the drug is presented as a conventional 
form 
• Delayed release when the release of the active ingredient comes sometimes 
other than promptly after administration 
• Pulsatile release when the device actively controls the dosage released following 
predefi ned parameters 
In general, the sustained - release dosage form is designed to maintain therapeutic 
blood or tissue levels of the drug for an extended period of time. This is accomplished 
by attempting to obtain zero - order release from the designed dosage form. 
Zero - order release constitutes drug release from the dosage form that is independent 
of the amount of drug in the delivery system at a constant release rate. Systems 
that are designed for prolonged release can also be attributed as achieving 
sustained - release delivery systems. Repeat - action tablets are an alternative method 
of sustained release in which multiple doses of drugs are contained within a dosage 
form and each dose is released at a periodic interval, while delayed - release systems 
may not be sustaining, since often the function of these dosage forms is to maintain 
the drug within the dosage form. 
5.1.4 PHYSICOCHEMICAL AND BIOLOGICAL FACTORS 
INFLUENCING DESIGN AND PERFORMANCE OF 
CONTROLLED - RELEASE FORMULATIONS 
A number of variables, such as drug properties including stability, solubility, partitioning 
characteristics. charge and protein binding behavior, routes of drug delivery, 
target sites, acute or chronic therapy, the disease, and the patient, must be considered 
to establish the criteria for designing controlled - release products [9] . The performance 
of a drug in its release pattern from the dosage form as well as in the body 
proper is a function of its properties. These properties can at times prohibit placement 
if the drug is in a controlled - release form, restrict the route of drug administration, 
and signifi cantly modify performance for one reason or another. There is 
no clear distinction between physicochemical and biological factors since the biological 
properties of a drug are a function of its physicochemical properties while 
biological properties result from typical pharmacokinetic studies on the absorption, 
distribution, metabolism, and excretion (ADME) characteristics of a drug as well 
as those resulting from pharmacological studies. 
5.1.4.1 Physicochemical Factors 
Physicochemcial properties, such as aqueous solubility, partition coeffi cient and 
molecular size, drug stability, and protein binding, are those that can be determined 
from in vitro experiments. 
CONTROLLED-RELEASE FORMULATIONS 351

352 CONTROLLED-RELEASE DOSAGE FORMS 
Ionization, p K a 
, and Aqueous Solubility Most drugs are weak acids or bases. It 
is important to note the relationship between the p K a of the compound and the 
absorptive environment. Delivery systems that are dependent on diffusion or dissolution 
will likewise be dependent on the solubility of drug in the aqueous media. 
Since drugs must be in solution before they can be absorbed, compounds with very 
low aqueous solubility usually have the oral bioavailability problems because of 
limited GI transit time of the undissolved drug particles and they are limited at the 
absorption site. Unfortunately, for many of the drugs and bioactive compounds, the 
site of maximum absorption occurs at the site where solubility of these compounds 
is least. 
The drug (e.g., tetracycline) for which the maximum solubility is in the stomach 
but high absorption takes place in the intestinal region may be poor candidates for 
controlled - release systems, unless the system is capable of retaining the drug in the 
stomach and gradually releasing it to the small intestine or unless the solubility is 
made higher and independent of the external environment by encapsulating those 
compounds in a membrane system. Other compounds, such as digoxin [10] , with 
very low solubility, are inherently sustained, since their release over the time course 
of a dosage form in the gastrointestinal tract is limited by dissolution of the drug. 
Although the action of a drug can be prolonged by making it less soluble, this may 
occur at the expense of consistent and incomplete bioavailability. 
The choice of mechanism for oral sustained/controlled - release systems is limited 
by the aqueous solubility of the drug. Thus, diffusional systems are poor choices for 
low aqueous - soluble drugs since the driving force for diffusion, the concentration 
in aqueous solution, will be low. The lower limit for the solubility of a drug to be 
formulated in a controlled - release system has been reported to be 0.1 mg/mL [11] . 
Partition Coeffi cient and Molecular Size Following administration, drugs and 
other bioactive compounds must traverse a variety of membranes to gain access to 
the target area. The partition coeffi cient and molecular size infl uence not only the 
permeation of drug across biological membranes but also diffusion across or through 
a rate - controlling membrane or matrix. The partition coeffi cient is generally defi ned 
as the ratio of the fraction of drug in an oil phase to that of an adjacent aqueous 
phase. Drugs with extremely high partition coeffi cient (i.e., those that are highly oil 
soluble) readily penetrate the membranes but are unable to proceed further, while 
the excessive high aqueous - soluble compounds, having low oil/water partition coef- 
fi cients, cannot penetrate the membranes. A balance in the partition coeffi cient is 
needed to give an optimum fl ux for permeation through the biological and rate - 
controlling membranes. The ability of drugs to diffuse through membranes, also 
known as diffusivity, is related to its molecular size by the following equation: 
log log log D s V k s M k V V = . + = . + M M 
where D is the diffusivity, M is the molecular weight, V is the molecular volume, 
and s V , s M , k V , and k M are constants in a particular medium. Generally, there is smaller 
diffusivity with the denser medium. 
Drug Stability The stability of drug in the environment where it is to be exposed 
is an essential physicochemical factor to be considered before designing controlled 

dosage forms [12] . For example, orally administered drugs are subjected to both 
acid – base hydrolysis and enzymatic degradation [13] . For drugs that are unstable in 
the stomach, the dosage forms can be designed in so that they can be placed in a 
slowly soluble form or have their release delayed until they reach the intestine. This 
type of approach can be ineffective and the drug may be unstable in the small 
intestine or undergo extensive gut - wall metabolism. To obtain better bioavailability 
for such types of drugs, which are unstable even in the intestine, a different route 
of administration (e.g., transdermal with controlled - release dosage forms) can be a 
better option [14] . A transdermal patch of nitroglycerin is a good example. The 
details for transdermal dosage forms will be described later in this chapter. 
5.1.4.2 Biological Factors 
A drug, being a chemical/biological agent or a mixture of chemical and biological 
agents, is recognized as a xenobiotic by the human body. Subsequently, the drug will 
be prevented from entering the body and/or eliminated after its entry. As a result, 
the defense mechanisms of the human body become barriers to the delivery of 
drugs. A drug may encounter physical, physiological, enzymatic, or immunological 
barriers on its way to the site of action. Hence, the design of controlled - release 
product should be based on a comprehensive picture of drug disposition. This would 
entail a compl