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PHARMACEUTICAL MANUFACTURING HANDBOOK
Regulations and Quality

SHAYNE COX GAD, PH.D., D.A.B.T. 
Gad Consulting Services 
Cary, North Carolina 
A JOHN WILEY & SONS, INC., PUBLICATION




CONTENTS 
SECTION 1 GOOD MANUFACTURING PRACTICES (GMP) AND 
OTHER FDA GUIDELINES 1 
1.1 Good Manufacturing Practices (GMPs) and Related FDA 
Guidelines 3 
James R. Harris 
1.2 Enforcement of Current Good Manufacturing Practices 45 
Kenneth J. Nolan 
1.3 Scale-Up and Postapproval Changes (SUPAC) Regulations 67 
Puneet Sharma, Srinivas Ganta, and Sanjay Garg 
1.4 GMP-Compliant Propagation of Human Multipotent Mesenchymal 
Stromal Cells 97 
Eva Rohde, Katharina Schallmoser, Christina Bartmann, Andreas Reinisch, 
and Dirk Strunk 
SECTION 2 INTERNATIONAL REGULATIONS OF GOOD 
MANUFACTURING PRACTICES 117 
2.1 National GMP Regulations and Codes and International GMP 
Guides and Guildelines: Correspondences and Differences 119 
Marko Narhi and Katrina Nordstrom

x CONTENTS 
SECTION 3 QUALITY 163 
3.1 Analytical and Computational Methods and Examples for Designing 
and Controlling Total Quality Management Pharmaceutical 
Manufacturing Systems 165 
Paul G. Ranky, Gregory N. Ranky, Richard G. Ranky, and Ashley John 
3.2 Role of Quality Systems and Audits in Phatmaceutical 
Manufacturing Environment 201 
Evan B. Siegel and James M. Barquest 
3.3 Creating and Managing a Quality Management System 239 
Edward R. Arling, Michelle E. Dowling, and Paul A. Frankel 
3.4 Quality Process Improvement 287 
Jyh-hone Wang 
SECTION 4 PROCESS ANALYTICAL TECHNOLOGY (PAT) 311 
4.1 Case for Process Analytical Technology: Regulatory and Industrial 
Perspectives 313 
Robert P. Cogdill 
4.2 Process Analytical Technology 353 
Michel Ulmschneider and Yves Roggo 
4.3 Chemical Imaging and Chemometrics: Useful Tools for Process 
Analytical Technology 411 
Yves Roggo and Michel Ulmschneider 
SECTION 5 PERSONNEL 433 
5.1 Personnel Training in Pharmaceutical Manufacturing 435 
David A. Gallup, Katherine V. Domenick, and Marge Gillis 
SECTION 6 CONTAMINATION AND CONTAMINATION 
CONTROL 455 
6.1 Origin of Contamination 457 
Denise Bohrer 
6.2 Quantitation of Markers for Gram-Negative and Gram-Positive 
Endotoxins in Work Environment and as Contaminants in 
Pharmaceutical Products Using Gas ChromatographyTandem 
Mass Spectrometry 533 
Alvin Fox 
6.3 Microbiology of Nonsterile Pharmaceutical Manufacturing 543 
Ranga Velagaleti

CONTENTS xi 
SECTION 7 DRUG STABILITY 557 
7.1 Stability and Shelf Life of Pharmaceutical Products 559 
Ranga Velagaleti 
7.2 Drug Stability 583 
Nazario D. Ramirez-Beltran, Harry Rodriguez, and L. Antonio Estevez 
7.3 Effect of Packaging on Stability of Drugs and Drug Products 641 
Emmanuel O. Akala 
7.4 Pharmaceutical Product Stability 687 
Andrew A. Webster 
7.5 Alternative Accelerated Methods for Studying Drug Stability: 
Variable-Parameter Kinetics 701 
Giuseppe Alibrandi 
SECTION 8 VALIDATION 725 
8.1 Analytical Method Validation: Principles and Practices 727 
Chung Chow Chan 
8.2 Analytical Method Validation and Quality Assurance 743 
Isabel Taverniers, Erik Van Bockstaele, and Marc De Loose 
8.3 Validation of Laboratory Instruments 791 
Herman Lam 
8.4 Pharmaceutical Manufacturing Validation Principles 811 
E. B. Souto T. Vasconcelos D. C. Ferreira, and B. Sarmento 
INDEX 839



PREFACE 
This Handbook of Manufacturing: Regulations and Quality focuses on all regulatory 
aspects and requirements that govern how drugs are produced for evaluation (and, 
later, sale to and use in) humans. The coverage ranges from what the issues are at 
the early stages (when the amounts are small and the materials of limited sophistication) 
up to until the issue is reproducibly and continuously making large volumes 
of a highly sophisticated manufactured product. These 25 chapters cover the full 
range from preformulation of a product (the early exploratory work that allows us 
to understand how to formulate and deliver the drug) to identifi cation of sources 
of contamination and assessment of stability. 
The Handbook of Manufacturing: Regulations and Quality seeks to cover the 
entire range of available approaches to satisfying the wide range of regulatory 
requirements for making a highly defi ned product that constitutes a successful new 
drug and how to do so in as effective and as effi cient a manner as possible. 
Thanks to the persistent efforts of Michael Leventhal, these 25 chapters, which 
are written by leading practitioners in each of these areas, provide coverage of the 
primary approaches to the fundamental regulatory challenges that must be overcome 
to manufacture successfully a deliverable and stable new drug. 


GOOD MANUFACTURING PRACTICES 
( GMP ) AND OTHER FDA GUIDELINES 
SECTION 1


3 
1.1 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc. 
GOOD MANUFACTURING 
PRACTICES ( GMP ) AND RELATED 
FDA GUIDELINES 
James R. Harris 
James Harris Associates, Inc., Durham, North Carolina 
Contents 
1.1.1 FDA Regulations: Real and Imagined 
1.1.2 21 CFR 210 and 211: Current Good Manufacturing Practice for Finished 
Pharmaceuticals 
1.1.3 Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good 
Manufacturing Practice Regulations 
1.1.3.1 CGMPS and the Concepts of Modern Quality Systems 
1.1.3.2 Quality Systems Model 
1.1.4 Guidance for Industry: PAT  Framework for Innovative Pharmaceutical Development, 
Manufacturing, and Quality Assurance 
1.1.4.1 PAT Framework 
1.1.5 Guidance for Industry: Part 11. Electronic Records; Electronic Signatures  Scope and 
Application 
1.1.6 Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination 
Products 
1.1.7 Guidance for Industry: Powder Blends and Finished Dosage Units  Stratifi ed In - 
Process Dosage Unit Sampling and Assessment 
1.1.7.1 Validation of Batch Powder Mix Homogeneity 
1.1.7.2 Verifi cation of Manufacturing Criteria 
1.1.8 Guidance for Industry: Immediate - Release Solid Oral Dosage Forms Scale - Up and 
Postapproval Changes (SUPAC)  Chemistry, Manufacturing and Controls, In Vitro 
Dissolution Testing, and In Vivo Bioequivalence Documentation 
1.1.9 Other GMP - Related Guidance Documents 

4 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
1.1.1 FDA REGULATIONS: REAL AND IMAGINED 
A regulation is a law. In the United States, all federal laws have been arranged or 
codifi ed in a manner that makes it easier to fi nd a specifi c law. The Code of Federal 
Regulations (CFR) is a compilation of all federal laws published in the Federal 
Register by the executive departments and agencies of the federal government. This 
code is divided into 50 titles which represent broad areas of federal regulation. Each 
title is further divided into chapters. The chapters are then subdivided into parts 
covering specifi c regulatory areas. Changes and additions are fi rst published in the 
Federal Register . Both the coded law and the Federal Register must be used to determine 
the latest version of any rule. All food - and drug - related laws are contained 
in Title 21 of the CFR. Each title of the CFR is updated annually. Title 21 is updated 
as of April 1 of each year. 
Because virtually all of the drug regulations are written to state what should be 
done but do not tell how to do it, the Food and Drug Administration (FDA) also 
publishes guidance documents. These documents are intended to provide precisely 
what the name implies  guidance. In this context, guidance documents are not law 
and do not bind the FDA or the public . Manufacturers are not required to use the 
techniques or approaches appearing in the guidance document. In fact, FDA representatives 
have repeatedly stated that the regulations were not written to suggest 
how something should be done in order to encourage innovation. While following 
the recommendations contained in the guidance documents will probably assure 
acceptance (agency philosophy and interpretation may have changed since the guidance 
document was published), other approaches are encouraged. No matter how 
they choose to proceed, manufacturers should be prepared to show that their 
methods achieve the desired results. 
A method used by the FDA to  fl oat  new ideas is to discuss them at industry 
gatherings such as FDA - sponsored seminars or meetings of industry groups such as 
the Pharmaceutical Manufacturers Association (PMA), the Parenteral Drug Association 
(PDA), and the International Society of Pharmaceutical Engineering (ISPE). 
Again, it must be remembered that while these comments refl ect current FDA 
thinking, they are simply thoughts and recommendations. They are not law. 
Several industry groups also publish comments, guidelines, and so on, that put 
forth current thinking of the group writing the document. These publications are 
interesting and often bring out valuable information. However, it is important to 
remember that these publications are not regulations or even offi cial guidance documents. 
If a fi rm chooses to follow the recommendations of such documents, they are 
probably following good advice. However, since the advice comes from a nonoffi cial 
source, fi rms should still be prepared to defend their actions with good scientifi c 
reasoning. 
1.1.2 21 CFR 210 AND 211: CURRENT GOOD MANUFACTURING 
PRACTICE FOR FINISHED PHARMACEUTICALS 
Parts 210 and 211 of CFR Title 21 are the laws defi ning good manufacturing practices 
for fi nished pharmaceutical products. All manufacturers must follow these 
regulations in order to market their products in the United States. When a fi rm fi les 
an application to market a product in the United States through a New Drug Application 
(NDA), abbreviated NDA, (ANDA), Biological License Application (BLA), 

CURRENT GOOD MANUFACTURING PRACTICE 5 
or other product application, one of the last steps in approving the application is a 
preapproval inspection of the manufacturing facility. A major purpose of this inspection 
is to assure adherence to the GMP regulations. Preapproval inspections are a 
part of every application approval. Thus, if a fi rm has 10 applications pending, it 
should expect 10 inspections. The fact that the manufacturing facility has already 
been inspected will not alter the need for another inspection. 
The FDA also has the right to visit and inspect any manufacturing facility that 
produces a product or products sold in the United States. Such inspections are unannounced. 
A manufacturer must admit an inspector when he or she appears at that 
facility and must do so without undue delay. 
GMP requirements for manufacturers of pharmaceutical dosage forms are discussed 
below. This information should not be considered to be an exact statement 
of the law. We have attempted to show intent and, occasionally, add some comments 
that will clarify how that particular regulation is interpreted. For precise wording of 
a regulation, refer to the CFR and then check the Federal Register to determine if 
there have been any changes since the last update. 
General Provisions 
1. This section pertains to the manufacture of drug products for humans or 
animals. 
2. These requirements will not be enforced for over - the - counter (OTC) drug products 
if the products and all their ingredients are ordinarily marketed and considered 
as human foods and which products may also fall within the legal defi nition 
of drugs by virtue of their intended use. 
Organization and Personnel 
1. Responsibilities of quality control unit 
(a) A quality control unit must be a part of the facility organization. 
(b) This unit must be given responsibility and authority to approve or reject all 
components, drug product containers, closures, process materials, packaging 
material, labeling, and drug products, and the authority to review production 
records. 
(c) Adequate laboratory facilities for testing and approval or rejection of the 
above listed materials must be available. 
(d) The quality control unit is responsible for approving or rejecting all procedures 
or specifi cations that impact on the identity, strength, quality, and purity 
of the drug product. 
(e) Responsibilities and procedures applicable to the quality control unit must 
be written and these procedures must be followed. 
2. Personnel qualifi cations 
(a) Every person involved in the manufacture, processing, packing, or holding of 
a drug product must have education, training, and experience that enable 
that individual to perform their duties. Employees must be trained in the 
particular operations that they perform and in Current GMPs (CGMPs). The 
GMP training must be conducted by qualifi ed individuals and with suffi cient 
frequency to assure that workers remain familiar with the requirements 
applicable to them. 

6 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(b) Persons responsible for supervision must have the education, training, and 
experience to perform their assigned functions in such a manner as to assure 
that the drug product has the safety, identity, strength, quality, and potency 
that it is represented to possess. 
(c) There must be an adequate number of qualifi ed personnel to perform the 
needed tasks. 
3. Personnel responsibilities 
(a) Personnel shall wear clean clothing appropriate for the duties they perform. 
Protective apparel must be worn as necessary. 
(b) Personnel shall practice good sanitation and health habits. 
(c) Only personnel authorized by supervisory personnel shall enter those areas 
designated as limited - access areas. 
(d) Any worker considered to have an apparent illness or open lesions that may 
adversely affect safety or quality of drug products shall be excluded from 
direct contact with product, components, or containers. 
4. Consultants that advise on the manufacture, processing, packing, or holding of 
drug products must have suffi cient education, training, and experience to advise 
on the subject for which they are retained. The manufacturer must maintain 
records of name, address, and qualifi cations of any consultants and the type of 
service they provide. 
Buildings and Facilities 
1. Design and construction features 
(a) Buildings should be of suitable size, construction location to facilitate cleaning, 
maintenance, and proper operations. 
(b) Space should be adequate for the orderly placement of equipment and materials 
to prevent mix - ups between different components, drug product containers 
and closures, labeling, in - process materials, or drug products and to 
prevent contamination. 
(c) The movement of components and product through the building must be 
designed to prevent contamination. 
(d) Operations should be performed within specifi cally defi ned areas having 
adequate control systems to prevent contamination or mix - ups during each 
of the following procedures: 
(i) Receipt, identifi cation, storage, and withholding from use of components, 
drug product containers, closures, and labeling, pending the 
appropriate sampling, testing, and release for manufacturing or 
packaging. 
(ii) Holding rejected materials listed in (a) above. 
(iii) Storage of released components, drug product containers, closures, and 
labeling. 
(iv) Storage of in - process materials. 
(v) Manufacturing and processing operations. 
(vi) Packaging and labeling operations. 
(vii) Quarantine storage before release of drug products. 
(viii) Storage of drug products after release. 
(ix) Control and laboratory operations. 

CURRENT GOOD MANUFACTURING PRACTICE 7 
(x) Aseptic processing, which includes: 
(1) Floors, walls, and ceilings of smooth, hard surfaces that are easily 
cleanable. 
(2) Temperature and humidity controls. 
(3) An air supply fi ltered through High - Effi ciency Particulate Air 
(HEPA) fi lters under positive pressure regardless of whether fl ow 
is laminar or nonlaminar. 
(4) A system for monitoring environmental conditions. 
(5) A system for cleaning and disinfecting the room and equipment to 
produce aseptic conditions. 
(6) A system for maintaining any equipment used to control the aseptic 
conditions. 
(e) Operations relating to the manufacture, processing, and packing of penicillin 
must be performed in facilities separate from those used for other drug 
products for humans. Note : For all purposes of these GMP regulations, the 
FDA considers cephalosporins to be penicillin. 
2. Adequate lighting should be provided in all areas. 
3. Heating, ventilation, and air conditioning (HVAC) 
(a) Adequate ventilation is required in all areas. 
(b) Equipment for adequate control over air pressure, microorganisms, dust, 
humidity, and temperature must be provided when appropriate for the manufacture, 
processing, packing, or holding of a drug product. 
(c) When appropriate, air supplied to production areas should be fi ltered to 
avoid any possibility of contamination or cross - contamination. 
(d) Air - handling systems for the manufacture, processing, and packing of penicillin 
shall be completely separate from those for other drug products for 
humans. 
4. Plumbing 
(a) Potable water should be supplied in a continuous positive - pressure system 
free from defects that could contribute to contamination of any drug 
product. 
(b) Potable water must meet the standards prescribed in the Environmental 
Protection Agency (EPA) Primary Drinking Water Regulations defi ned in 
40 CFR Part 141. 
(c) Drainage must be of adequate size. Where connected directly to a sewer, an 
air break or other suitable mechanical device must be provided to prevent 
back - siphonage. 
5. Sewage, trash, and other refuse in and from the building and immediate premises 
must be disposed of in a safe and sanitary manner. 
6. Adequate washing facilities should be provided. This is to include hot and cold 
water, soap or detergent, air driers or single - service towels, and clean toilet facilities 
easily accessible to all work areas. 
7. Sanitation 
(a) Any building used for manufacture, processing, packing, or holding of a drug 
product should be maintained in a clean and sanitary condition. Such buildings 
should be free of infestation by rodents, birds, insects, and other vermin. 
(b) Trash and organic waste matter should be held and disposed of in a timely 
and sanitary manner. 

8 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(c) Written procedures assigning responsibility for sanitation and describing in 
suffi cient detail the cleaning schedules, methods, equipment, and materials 
to be used in cleaning the buildings and facilities are required. Such procedures 
must be followed. 
(d) Written procedures for use of suitable rodenticides, insecticides, fungicides, 
fumigating agents, and cleaning and sanitizing agents are required and must 
be followed. These written procedures should be designed to prevent the 
contamination of equipment, components, product containers, closures, packaging, 
labeling materials, or drug products. Agent may not be used unless 
registered and used in accordance with the Federal Insecticide, Fungicide, 
and Rodenticide Act (7 U.S.C. 135). 
(e) All sanitation procedures apply equally to contractors or temporary employees 
as to regular employees. 
8. All buildings used for GMP - related purposes must be maintained in a good state 
of repair. 
Equipment 
1. Equipment should be of appropriate design, adequate size, and suitably located 
to facilitate operations for its intended use and for cleaning and maintenance. 
2. Equipment construction 
(a) Equipment should be constructed so that surfaces that contact components, 
in - process materials, or drug products should not be reactive, additive, or 
absorptive so as to alter the safety, identity, strength, quality, or purity of the 
drug product beyond offi cial or other established requirements. 
(b) Any substance required for operation such as lubricants or coolants shall not 
come into contact with drug products, containers, and so on, so as to alter 
the safety, identity, strength, quality, or purity of the drug product beyond 
established requirements. 
3. Equipment cleaning and maintenance 
(a) Equipment and utensils should be cleaned, maintained, and sanitized at 
appropriate intervals to prevent malfunctions or contamination that would 
alter the drug product beyond the offi cial requirements. 
(b) Written procedures must be established and followed for cleaning and 
maintenance of equipment and utensils used in the processing of a drug 
product. These procedures must include but are not limited to the 
following: 
(i) Assignment of responsibility for cleaning and maintaining equipment. 
(ii) Maintenance and cleaning schedules, including sanitizing schedules if 
appropriate. 
(iii) A suffi ciently detailed description of the methods, equipment, and 
materials used in cleaning and maintenance operations and the methods 
of disassembling and reassembling equipment as a part of cleaning and 
maintenance. 
(iv) Removal or obliteration of previous batch identifi cation. 
(v) Protection of clean equipment from contamination prior to use. 
(vi) Inspection of equipment for cleanliness immediately before use. 

CURRENT GOOD MANUFACTURING PRACTICE 9 
(vii) Records should be kept of maintenance, cleaning, sanitizing, and inspection 
of all processing equipment. 
4. Automatic, mechanical, and electronic equipment 
(a) All such equipment, including computers or related systems that will perform 
a function to be used in any GMP - related activity, must be routinely calibrated, 
inspected, or checked according to a written program designed to 
assure proper performance. Written records must be maintained for all such 
activities. 
(b) Appropriate controls should be exercised to assure that changes in master 
production and control records or other similar records are made only by 
authorized personnel. Input to and output from such systems should be 
checked for accuracy. 
A backup fi le of data entered into a computer - related system must be 
maintained except where certain data such as calculations performed in connection 
with laboratory analysis are eliminated by computerization or other 
automated processes. In this situation, a written record of the program should 
be maintained along with validation data. 
5. Filters for liquid fi ltration used as a part of the manufacture, processing, or 
packing of injectable drug products intended for human use must not release 
fi bers into such products. Fiber - releasing fi lters may not be used unless it is not 
possible to manufacture the product without the use of such a fi lter. In this situation, 
an additional non - fi ber - releasing fi lter of 0.22 . m maximum must be used 
after the fi ber - releasing fi ltration. Use of an asbestos - containing fi lter is permissible 
only upon submission of proof to the appropriate FDA bureau that use of 
a non - fi ber - releasing fi lter will compromise the safety or effectiveness of the drug 
product. 
Control of Components and Drug Product Containers and Closures 
1. General requirements 
(a) There must be written procedures describing in suffi cient detail the receipt, 
identifi cation, storage, handling, sampling, testing, and approval or rejection 
of product components, containers, and closures. Of course, all such procedures 
must be followed. It is quite common and even more embarrassing to 
be cited for not following your own written procedures. Note: For the rest of 
this discussion, the term components will mean product ingredients, containers, 
closures, and so on. 
(b) All components listed above must be handled and stored in a manner that 
will prevent contamination. 
(c) Bagged or boxed components should be stored off the fl oor. Spacing should 
allow cleaning and inspection. 
(d) Every container of components must be identifi ed with a distinctive code or 
lot number for each receival of that product. Even if the next receival is the 
same vendor lot number, it must be a new identifying number by the pharmaceutical 
manufacturer. Each lot must be appropriately identifi ed as to its 
status (quarantined, approved, or rejected). 

10 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
2. Receipt and storage of untested components 
(a) Upon receipt each container of components must be visually examined for 
appropriate labeling and any damage or contamination to the component 
container. 
(b) Components must be stored under quarantine until they have been tested as 
appropriate and released for use. 
3. Testing and approval or rejection of components 
(a) Each lot of components shall be withheld from use until it has been sampled, 
tested, and released by the quality control unit. 
(b) Representative samples must be taken from every receival of every component. 
The number or amount of component to be sampled should be based 
on component appearance, statistical confi dence levels, the past history of 
the supplier, and the quantity needed to analyze and reserve samples if 
required. 
(c) Sampling procedures 
(i) The component containers should be cleaned where necessary. 
(ii) The containers should be opened, sampled, and resealed in a manner 
designed to prevent contamination of the sample and remaining contents 
of the container. 
(iii) If appropriate, sterile equipment and aseptic sampling techniques should 
be used. 
(iv) Where sampling is done from various parts of a container, samples 
should not be composited for testing. 
(v) Containers from which samples have been taken must be marked to 
show that samples have been removed. 
(d) Examination and testing of samples 
(i) At least one test should be conducted on each lot of component drug 
product to verify identity. 
(ii) Each component must be tested for conformity with all appropriate 
written specifi cations for purity, strength, and quality if an ingredient or 
for conformity with written specifi cations for containers or closures. 
(iii) In lieu of the above testing by the manufacturer, a report of analysis 
may be accepted from the supplier provided that at least one specifi c 
identity test is conducted on the component by the manufacturer and 
provided that the manufacturer has established the reliability of the 
supplier  s analyses through appropriate validation. 
(iv) When appropriate, components should be examined microscopically. 
(v) Each lot of a component that is liable to contamination with dirt, insect 
infestation, or other extraneous adulterant should be examined against 
established specifi cations for such contamination. 
(vi) Each lot of a component that is subject to microbial contamination that 
is contrary to its intended use should be subjected to microbiological 
tests before use. 
(e) If a lot of components meets the written specifi cations, it may be approved 
and released for use. Any lot of such material that does not meet such speci- 
fi cations must be rejected. 
4. Use of approved components (including drug product containers and closures) 
must be rotated to assure that the oldest approved stock is used fi rst. 

CURRENT GOOD MANUFACTURING PRACTICE 11 
5. Components must be retested and/or reexamined after storage for a long period 
of time or after exposure to the atmosphere, heat, or other condition that might 
adversely affect the component. 
6. Rejected components should be identifi ed and controlled under a quarantine 
system designed to prevent their use in manufacturing or processing. 
7. Containers and closures 
(a) Containers and closures must not be reactive, additive, or absorbent so as to 
alter the drug beyond established acceptance criteria. 
(b) Container closure systems must provide adequate protection against foreseeable 
external factors in storage that can cause deterioration or contamination 
of the product. 
(c) Containers and closures should be clean and, if necessary, sterile and processed 
to remove pyrogens. 
(d) Standards or specifi cation, methods of testing, and, if appropriate, sterilization 
and depyrogenation must be written and followed. 
Production and Process Controls 
1. Written procedures and procedure deviations 
(a) Written procedures for production and process control must be written and 
followed. These procedures should be designed to assure that the drug products 
have the identity, strength, quality, and purity they are represented to 
possess. These procedures must include all requirements given below and 
must be drafted, reviewed, and approved by the affected organizational units 
and reviewed and approved by the quality control unit. 
(b) When following the above identifi ed procedures, all actions must be documented 
at the time of performance. Any deviations from the written procedure 
must be recorded and justifi ed. 
2. Charge - in of components  Written production and control procedures must 
include the following, which are designed to assure that the drug products produced 
meet all specifi cations and standards. 
(a) The batch must be formulated with the intent to provide not less than 100% 
of the labeled amount of active ingredient. 
(b) Components used must be weighed, measured, or subdivided appropriately. 
If a component is removed from its original container and placed in 
another, the new container should be identifi ed with the following 
information: 
(i) Component name and/or item code. 
(ii) Receiving or control number. 
(iii) Weight or measure of material in the new container. 
(iv) Batch or lot number for which the component was dispensed, including 
its product name, strength, and lot number. 
(c) Weighing, measuring, or subdividing operations for all components must be 
adequately supervised. Each container of component dispensed to manufacturing 
must be examined by a second person to assure that: 
(i) The component was released by the quality control unit. 
(ii) The weight or measure is correct as stated in the batch production 
records. 

12 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(iii) The containers are properly identifi ed and contain the quantity stated 
on the label. 
(d) Addition of each component must be performed by one person and verifi ed 
by a second person. 
3. Actual yield and percentage of theoretical yield should be determined at the 
completion of each appropriate phase of manufacturing, processing, packaging, 
or holding. These calculations should be performed by one person and independently 
verifi ed by a second individual. 
4. Equipment identifi cation 
(a) All compounding and storage containers, processing lines, and major equipment 
used during the production of a batch of a drug product must be properly 
identifi ed at all times to indicate their contents and the phase of processing 
of the batch. 
(b) Major equipment should be identifi ed by a distinctive identifi cation that shall 
be recorded in the batch production record to indicate the specifi c equipment 
used. In cases where only one of a particular type of equipment exists in a 
given manufacturing facility, the name of the equipment may be used instead 
of creating a distinctive identifi cation. 
5. Sampling and testing of in - process materials and drug products 
(a) To assure batch uniformity and integrity, it is necessary to write and follow 
procedures that describe the in - process controls and tests or examinations 
that will be conducted on samples taken according to procedure. Procedures 
should be written to monitor the output and to validate the performance of 
those manufacturing processes that may be responsible for causing variability 
in the product being manufactured. These control procedures should 
include but are not limited to the following: 
(i) Tablet or capsule weight variation. 
(ii) Disintegraton time. 
(iii) Adequacy of mixing or blending to assure uniformity and 
homogeneity. 
(iv) Dissolution time and rate. 
(v) Clarity of solutions. 
(vi) pH of solutions. 
(b) In - process specifi cations for all characteristics must be consistent with the 
drug product fi nal specifi cations and must be developed from previous 
acceptable product average and process variability data. 
(c) In - process materials should be tested for identity, strength, quality, and purity 
as appropriate. As a part of the production process, they must be approved 
for continued use or rejected by the quality control unit before production 
continues. 
(d) Rejected in - process materials must be identifi ed and controlled under a 
quarantine system designed to prevent their use in manufacturing operations 
for which they have been found to be unsuitable. 
6. When appropriate, time limits should be established for the completion of each 
phase of production. The purpose of this is to assure the quality of the drug 
product. Deviation from the established time limits may be acceptable if this 
deviation does not compromise the quality of the product. Any deviation must 
be documented, including the justifi cation for such deviation. 

CURRENT GOOD MANUFACTURING PRACTICE 13 
7. Control of microbial contamination 
(a) To prevent the growth of objectionable microorganisms in products not 
required to be sterile, appropriate written procedures designed to prevent 
such growth should be written and followed. 
(b) If sterilization is a part of any procedure described in (a) above, this procedure 
must be validated. 
8. Reprocessing 
(a) Written procedures describing any system used to reprocess batches that do 
not conform to the established standards must be written and followed. 
(b) Reprocessing must not be performed without the review and approval of the 
quality control unit. 
Packaging and Labeling Control 
1. Materials examination and usage criteria 
(a) Written procedures describing in detail the receipt, identifi cation, storage, 
handling, sampling, examination, and/or testing of labeling and packaging 
materials must be developed, approved, and followed. These materials must 
be representatively sampled, examined, or tested on receipt and accepted by 
the quality control unit before use. 
(b) Any materials that do not fully meet acceptance criteria must be rejected to 
prevent their use. 
(c) Records of each receival of each different label and packaging material must 
be maintained indicating receipt, examination or testing, and whether 
accepted or rejected. 
(d) Labels and other labeling materials for each different drug product, strength, 
dosage form, or quantity of contents must be stored separately with suitable 
identifi cation. Access to the storage area must be limited to authorized 
personnel. 
(e) Obsolete and outdated labels, labeling, and other packaging materials must 
be quarantined and destroyed. 
(f) The use of gang - printed labels for different drug products or different 
strengths or different net contents is prohibited. The only exception to this 
rule is if labels from gang - printed sheets are adequately differentiated by 
size, shape, or color that will prevent mixing of labels. 
(g) If cut labeling is used, packaging and labeling operations must include one 
or more of the following special control procedures: 
(i) Dedication of a labeling and packaging line to each different strength 
of each different drug product. 
(ii) Use of appropriate electronic or electromechanical equipment to 
conduct a 100% examination for correct labeling during or after completion 
of the fi nishing operation. 
(iii) Use of visual inspection to conduct a 100% examination for correct 
labeling. If visual inspection is used, the inspection should be performed 
by one person and independently verifi ed by a second individual. 
(h) Printing devices on or associated with the manufacturing line used to imprint 
labeling upon the drug product unit label or case must be monitored to assure 

14 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
that the printing conforms to the print specifi ed in the batch production 
record. 
2. Issuance of labeling 
(a) Strict control should be exercised over the issuance of labeling for use in 
drug product labeling operations. 
(b) Labeling materials issued for a batch must be carefully examined for identity 
and conformity to the labeling specifi ed in the batch production record. 
(c) Procedures should be written and followed for reconciliation of the quantities 
of labeling issued, used, destroyed, and returned. Procedures should 
require evaluation of discrepancies found between the number of packages 
fi nished and the amount of labeling issued if discrepancies outside narrow 
preset limits occur. Limits should be established on the basis of historical 
operating data. Labeling reconciliation is waived for either cut or roll labeling 
if a 100% examination for correct labeling is performed. 
(d) All excess labeling bearing a lot or control number must be destroyed. 
(e) Returned labeling should be maintained and stored in a manner to prevent 
mix - ups. 
(f) Written procedures should describe the control procedures used for the issuance 
of labeling. 
3. There must be written procedures designed to assure that correct labels, labeling, 
and packaging materials are used. These procedures should incorporate the following 
features: 
(a) Prevention of mix - ups and cross - contamination by physical or spatial separation 
of operations on other drug products. 
(b) Identifi cation and handling of fi lled drug product containers that are set 
aside and held in unlabeled condition for future labeling operations. Such 
procedures should be designed to prevent mislabeling individual containers, 
lots, or portions of lots. It is not necessary to apply identifi cation to each 
individual container, but the procedure should be adequate to determine the 
name, strength, quantity of contents, and lot or control number of each 
container. 
(c) Identifi cation of the drug product with a lot or control number that permits 
determination of the history of the manufacture and control of the batch. 
(d) Examination of packaging and labeling materials for suitability and correctness 
before issuing for use and before packaging operations. These examinations 
must be documented in the batch production record. 
(e) Inspection of the packaging and labeling facility immediately before use to 
assure that all drug products and labeling materials from the previous operation 
have been removed. Inspection results must be documented in the batch 
production record. 
4. Tamper - evident packaging requirements for OTC human drug products 
(a) An OTC product (with the exception of a dermatological, dentifrice, insulin, 
or lozenge product) intended for retail sale is considered adulterated or 
misbranded or both if it is not packaged in a tamper - resistant package. 
(b) Requirements for a tamper - evident package 
(i) With the exceptions listed above, all OTC products must be packaged 
in a tamper - evident package if the product is accessible to the 
public while being held for sale. A tamper - evident package must have 

CURRENT GOOD MANUFACTURING PRACTICE 15 
one or more indicators or barriers to entry which, if breached or missing, 
can reasonably be expected to provide visible evidence to consumers 
that tampering has occurred: A tamper - evident package may involve an 
immediate container and closure system or a secondary container or 
carton system or a combination of systems intended to provide a visual 
indication of package integrity. The tamper - evident feature must be 
designed to and shall remain intact when handled in a reasonable 
manner during manufacture, distribution, and retail display. 
(ii) In addition to the tamper - evident packaging feature described above, 
any two - piece hard gelatin capsule covered by this regulation must be 
produced using an acceptable tamper - evident technology. 
(c) Labeling 
(i) In order to alert consumers to the specifi c tamper - evident features used, 
each retained package of an OTC drug product covered by this regulation 
is required to bear a statement that: 
(1) Identifi es all tamper - evident features and any capsule - sealing 
technologies. 
(2) Is prominently placed on the package. 
(3) Is so placed that it will be unaffected if the tamper - evident feature 
of the package is breached or missing. 
(ii) If the tamper - evident feature chosen to meet the requirement uses an 
identifying characteristic, that characteristic is required to be referred 
to in the labeling statement. For example, the labeling statement on a 
bottle with a shrink band could say For your protection, this bottle has 
an imprinted seal around the neck . 
(d) A manufacturer or packer may request an exemption from the tamper - 
evident requirement. A request for exemption is required to be submitted in 
the form of a petition and should be clearly identifi ed on the envelope as a 
 Request for Exemption from the Tamper - Evident Packaging Rule.  This 
petition is required to contain the following: 
(i) The name of the drug product or, if the petition seeks an exemption for 
a drug class, the name of the drug class and a list of products within that 
class. 
(ii) The reasons that the drug product  s compliance with the tamper - evident 
packaging and labeling requirements is unnecessary or cannot be 
achieved. 
(iii) A description of alternative steps that are available or that the petitioner 
has already taken to reduce the likelihood that the product or 
drug class will be the subject of malicious adulteration. 
(iv) Other information justifying an exemption. 
(e) Holders of approved new drug applications for OTC drug products are 
required to provide the FDA with notifi cation of changes in packaging and 
labeling to comply with the requirements of this section. Changes in packaging 
and labeling required by the regulation may be made before FDA 
approval. Manufacturing changes by which capsules are to be sealed require 
prior FDA approval. 
(f) This section does not affect any requirements for  special packaging  as 
required under the Poison Prevention Packaging Act of 1970. 

16 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
5. Drug product inspection 
(a) Packaged and labeled products must be examined during fi nishing operations 
to provide assurance that containers and packages in the lot have the 
correct label. 
(b) A representative sample of units should be collected at the completion of 
fi nishing operations and should be visually examined for correct labeling. 
(c) Results of these examinations must be recorded in the batch production 
records. 
6. Expiration dating 
(a) All packaged drug products must carry an expiration date that has been 
determined from appropriate stability testing. 
(b) Expiration dates must be related to the recommended storage conditions 
stated on the label as determined by stability studies. 
(c) If the drug product is to be reconstituted at the time of dispensing, its label 
must carry expiration information for both the reconstituted and unreconstituted 
forms. 
(d) Expiration dates must appear on labeling in accordance with the requirements 
stated elsewhere in this regulation. 
(e) Homeopathic drug products are exempt from the requirements of this 
section. 
(f) Allergenic extracts that are labeled  No U.S. Standard of Potency  are 
exempt. 
(g) New drug products for investigational use are exempt provided that they 
meet appropriate standards or specifi cations as demonstrated by stability 
studies during their use in clinical investigations. If new drug products for 
investigational use are to be reconstituted at the time of dispensing, their 
labeling must bear expiration information for the reconstituted product. 
(h) Pending consideration of a proposed exemption published in the Federal 
Register , September 29, 1978, the requirements in this section will not be 
enforced for human drug products if their labeling does not bear dosage 
limitations and they are stable at least three years as supported by stability 
data. 
Holding and Distribution 
1. Warehousing procedures 
(a) Written procedures describing the warehousing of drug products must be 
written and followed. These procedures should include: 
(i) Quarantine of drug products before release by the quality control 
unit. 
(ii) Storage of drug products under appropriate conditions of temperature, 
humidity, and light so that the quality of the drug products is not affected. 
2. Distribution procedures 
(a) Written procedures concerning the distribution of drug products must be 
established and followed. These procedures should include: 
(i) A procedure that assures the distribution of the oldest approved stock 
fi rst. Deviation from this procedure is acceptable if it is temporary and 
appropriate. 

CURRENT GOOD MANUFACTURING PRACTICE 17 
(ii) A system for documenting distribution so that distribution of each lot 
of drug product can be readily determined to facilitate its recall if 
required. 
Laboratory Controls 
1. General requirements 
(a) The establishment of any specifi cations, standards, sampling plans, test processes, 
or other laboratory control mechanism required by this part of the 
regulation, including any changes to the above must be drafted by the appropriate 
organizational unit and reviewed and approved by the quality control 
unit. All actions must be documented at the time of performance and any 
deviation must be recorded and justifi ed. 
(b) Laboratory controls must include the establishment of scientifi cally 
sound and appropriate specifi cations, standards, sampling plans, and test 
procedures designed to assure that all materials conform to appropriate 
standards of identity, strength, quality, and purity. Laboratory controls should 
include: 
(i) Determination of conformance to written specifi cations for the acceptance 
of each lot within each shipment of raw materials. The specifi cations 
should include a description of the sampling and testing procedures 
used. Samples must be representative and adequately identifi ed. These 
procedures must also require appropriate retesting of any material that 
is subject to deterioration. 
(ii) Determination of conformance to written specifi cations and a description 
of sampling and testing procedures for in - process materials. 
(iii) The calibration of instruments, apparatus, gauges, and recording devices 
at specifi ed intervals in accordance with an established written program 
containing specifi c directions, schedules, limits for accuracy and precision, 
and provisions for remedial action in the event that the limits are 
not met. Any such devices that do not meet the established specifi cations 
must not be used. 
2. Testing and release for distribution 
(a) Laboratory testing of each lot of drug product must be conducted to establish 
conformance to fi nal specifi cations for the product. Testing must include 
identity and strength of each active ingredient. Where sterility and/or pyrogen 
testing are required on short - lived radiopharmaceuticals, batches may be 
released prior to completion of this testing provided that such testing is 
completed as soon as possible. 
(b) Each batch of product required to be free of objectionable microorganisms 
must be tested appropriately. 
(c) All sampling and testing plans must be described in written procedures that 
include the method of sampling and the number of units to be tested. 
(d) Acceptance criteria for the sampling and testing conducted by the quality 
control unit must be adequate to assure that the batch being tested meets all 
specifi cations. Appropriate statistical quality control criteria should be used. 
The statistical quality control criteria must include acceptance levels and/or 
rejection levels. 

18 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(e) The accuracy, sensitivity, specifi city, and reproducibility of test methods used 
must be established and documented. Validation and documentation must 
be accomplished in accordance with this regulation. 
(f) Drug products failing to meet established standards or specifi cations and any 
relevant quality control criteria must be rejected. Reprocessing may be performed, 
however, prior to acceptance and use, and reprocessed material must 
meet all standards, specifi cations, and other relevant criteria. 
3. Stability testing 
(a) There must be a written testing program designed to assess the stability 
characteristics of every drug product. The results of such testing must be used 
to determine appropriate storage conditions and expiration dates. The written 
program must include: 
(i) Sample size and test intervals based on statistical criteria for each attribute 
examined. 
(ii) Storage conditions for sampled retained for testing. 
(iii) Reliable, meaningful and specifi c test methods. 
(iv) Testing of the product in the same container - closure system as the one 
in which the product is to be marketed. 
(v) Testing of drug products for reconstitution at the time of dispensing as 
well as after they are reconstituted. 
(b) An adequate number of batches of each drug product must be tested to 
determine appropriate expiration date. A record of such data must be maintained. 
Accelerated studies, combined with basic stability information on the 
components and drug product in its container - closure system may be used 
to project a tentative expiration date that is beyond the date supported by 
shelf life studies. However, there must be stability studies conducted including 
drug product testing at appropriate intervals until the tentative expiration 
date is verifi ed. 
(c) The requirements for homeopathic drug products are as follows: 
(i) There must be a written assessment of stability based on testing or 
examination of the drug product for compatibility of the ingredients, 
and based on marketing experience with the drug product to indicate 
that there is no degradation of the product for the normal or expected 
period of use. 
(ii) Evaluation of stability must be based on the same container - closure 
system as the one in which the drug product is to be marketed. 
(d) Allergenic extracts that are labeled  No U.S. Standard of Potency  are exempt 
from the requirements of this section. 
4. Special testing requirements 
(a) For each batch of drug product claimed to be sterile and/or pyrogen 
free, there must be appropriate laboratory testing to establish conformance 
to this claim. The test procedures must be in writing and must be followed. 
(b) For each batch of ophthalmic ointment, there must be appropriate testing to 
determine conformance to specifi cations regarding the presence of foreign 
particles and harsh or abrasive substances. The test procedures must be in 
writing and must be followed. 
(c) For each batch of controlled - release dosage form, there must be appropriate 
laboratory testing to determine conformance to the specifi cations for the rate 

CURRENT GOOD MANUFACTURING PRACTICE 19 
of release of each active ingredient. The test procedures must be in writing 
and must be followed. 
5. Reserve samples 
(a) An identifi ed reserve sample that is representative of each lot or of each 
shipment of each active ingredient must be retained. This reserve sample 
should contain at least twice the quantity needed for all tests required to 
determine whether the active ingredient meets its established specifi cations 
with the exception of sterility and pyrogen testing. The required retention 
time is as follows: 
(i) For an active ingredient in a drug product other than those described 
in paragraphs (b) and (c) below, the reserve sample must be retained 
for one year after the expiration date of the last lot of drug product 
containing that lot of active ingredient. 
(b) For an active ingredient in a radioactive drug product except for nonradioactive 
reagent kits, the reserve sample must be retained for: 
(i) Three months after the expiration date of the last lot of the drug product 
containing that lot of active ingredient if the expiration dating period 
of the drug product is 30 days or less. 
(ii) Six months after the expiration date of the last lot of the drug product 
containing that lot of active ingredient if the expiration dating period 
of the drug product is more than 30 days. 
(c) For an active ingredient in an OTC drug product that is exempt from bearing 
an expiration date, the reserve sample must be retained for three years after 
distribution of the last lot of drug product containing that lot of active 
ingredient. 
(d) A properly identifi ed reserve sample that is representative of each batch 
of drug product must be retained and stored under conditions consistent 
with the product labeling. The reserve sample must be stored in the 
same immediate container closure system in which the drug product is 
marketed or in one that has essentially the same characteristics. The 
reserve sample consists of at least twice the quantity needed to perform 
all the required tests except those for sterility and pyrogens. Reserve samples 
from representative sample lots or batches selected by acceptable statistical 
procedures must be examined visually at least once a year for evidence of 
deterioration unless visual examination would affect the integrity of 
the reserve sample. Any evidence of reserve sample deterioration must be 
investigated. The results of the examination must be recorded and maintained 
with stability data concerning that drug product. Retention times are 
as follows: 
(i) For a drug product other than the exceptions noted above, the reserve 
sample must be retained for one year after the expiration date of the 
drug product. 
(ii) For a radioactive drug product, except for nonradioactive reagent kits, 
the retention sample must be retained for: 
(1) three months after the expiration date of the drug product if the 
expiration date is 30 days or less or 
(2) six months after the expiration date of the drug product if the expiration 
date is more than 30 days. 

20 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(iii) For an OTC drug product that is exempt from bearing an expiration 
date, the reserve sample must be retained for three years after the batch 
of drug product is fully distributed. 
6. Animals used in testing components, in - process materials, or drug products for 
compliance with established specifi cations must be maintained and controlled in 
a manner that assures their suitability for their intended use. They must be identi- 
fi ed and adequate records must be maintained showing the history of their use. 
7. If a reasonable possibility exists that a nonpenicillin drug product has been 
exposed to cross - contamination with penicillin, the nonpenicillin drug product 
must be tested for the presence of penicillin. The drug product may not be 
marketed if a detectable level of penicillin is found when tested according to 
procedures specifi ed in  Procedures for Detecting and Measuring Penicillin contamination 
in Drugs  which is incorporated in the regulation by reference. 
Records and Reports 
1. General Requirements 
(a) Any production, control, or distribution record that is associated with a batch 
of a drug must be retained for at least one year after the expiration date of 
the batch OR, for OTC drug products that do not have expiration dates, three 
years after complete distribution of the batch. 
(b) Records must be retained for all components, containers, closures, and labeling 
for the same time periods shown in (a) above. 
(c) All retained records or copies of these records must be readily available for 
authorized inspection at any time in the required retention period. Records 
must be available for inspection where the activities described therein 
occurred. Photocopying or similar reproduction by investigators must be 
permitted. 
(d) Retained records may be original records or true copies such as photocopies, 
microfi lm, microfi che, or other accurate reproduction of the original. 
(e) Written records that must be retained must be maintained so that data contained 
therein can be used for evaluating the quality standards of each drug 
product to determine the need for changes in drug product specifi cations or 
manufacturing or control procedures. Such reviews should be conducted at 
least annually. Written procedures must be established and followed for these 
evaluations and must include provisions for: 
(i) A review of a representative number of batches, whether approved or 
rejected, and records associated with the batch. 
(ii) A review of complaints, recalls, returned or salvaged drug products, and 
investigations conducted under Section 211.192 of the GMP regulations 
for each drug product. 
(f) Procedures must be established to assure that the responsible offi cials of the 
fi rm are notifi ed in writing of any investigations conducted under Sections 
211.198, 211.204, or 211.208 of any recalls, reports of inspectional observations 
issued by the FDA, or any regulatory actions relating to GMP brought 
by the FDA. 
2. A written record of major equipment cleaning, maintenance (except routine 
maintenance), and use must be included in individual equipment logs that show 

CURRENT GOOD MANUFACTURING PRACTICE 21 
the date, time, product, and lot number of each batch processed. The persons 
performing and double checking the cleaning and maintenance should date and 
sign or initial the log indicating that the work was performed. Entries in the log 
must be in chronological order. 
3. Component, drug product container, closure, and labeling records must include 
the following: 
(a) The identity and quantity of each shipment of each lot of components, drug 
product containers, closures, and labeling. Also required are the identity of 
the supplier, the supplier  s lot number(s), the receiving code, the date of 
receipt, and name and location of the prime manufacturer if different from 
the supplier. 
(b) The results of any test or examination performed and any conclusions derived 
from these results. 
(c) An individual inventory record of each component and a reconciliation of 
the use of each lot of such component. The inventory record must contain 
suffi cient information to allow determination of any batch or lot of drug 
product associated with the use of each component. 
(d) Documentation of the examination and review of labels and labeling for 
conformance with established specifi cations. 
(e) The disposition of rejected materials. 
4. Master production and control records 
Batch production and control records should be prepared for each batch of 
drug product produced and must include complete information about the production 
and control of that batch. These records must include: 
(a) A full and complete reproduction of the appropriate master production or 
control record. The copy must be checked for accuracy, dated, and signed. 
(b) Documentation that each signifi cant step in the manufacture, processing, 
packaging, and holding of the batch was accomplished as prescribed, 
including: 
(i) Dates. 
(ii) Identity of individual major equipment used. This includes packaging 
lines. 
(iii) Complete and specifi c identifi cation of each batch of component or 
in - process material used. 
(iv) Weight and measures of components used in the course of 
processing. 
(v) In - process and laboratory control results. 
(vi) Inspection of the packaging and labeling area before and after use. 
(vii) Documentation of the actual yield and the percentage of theoretical 
yield that this represents at critical stages of processing. 
(viii) Complete labeling control records, including specimens or copies of all 
labeling used. 
(ix) A description of drug product containers and closures. 
(x) Any sampling performed. 
(xi) Identifi cation of the persons performing and directly supervising or 
checking signifi cant steps in the operation. 
(xii) Any investigations conducted. 
(xiii) Results of examinations made. 

22 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
5. All drug product production and control records, including those for packaging 
and labeling, must be reviewed and approved by the quality control unit to determine 
compliance with all established written procedures before a batch is released 
or distributed. Any unexplained discrepancy or the failure of a batch or any of 
its components to meet any of the established specifi cations must be thoroughly 
investigated. The investigation must be extended to other batches of the same 
drug product and other drug products that may have been associated with the 
specifi c fault or discrepancy. A written record of the investigation must be made 
and include the conclusions and any required follow - up. 
6. Laboratory records 
(a) Laboratory records must include complete data derived from all tests needed 
to assure compliance with established specifi cations and standards. This 
includes examinations and assays as follows: 
(i) A description of the sample received for testing with identifi cation of 
source. For example, location where the sample was obtained, quantity, 
lot number or other distinctive code, date the sample was taken, and 
the date that it was received for testing. 
(ii) A statement of each method used in the testing of the sample. The 
statement must indicate the location of data that establish that the 
methods used in the testing of the sample meet proper standards of 
accuracy and reliability as applied to the product tested. (If the method 
used is in the current revision of the U.S. Pharmacopeia (USP), National 
Formulary (NF), or other recognized standard reference or if it is 
detailed in an approved NDA, this statement will not be required.) 
(iii) A statement of the weight or measure of sample used for each test. 
(iv) A complete record of all data secured in the course of each test, including 
all graphs, charts, and spectra from laboratory instrumentation 
properly identifi ed to the specifi c component and lot tested. 
(v) A record of all calculations performed in connection with the test, 
including units of measure, conversion factors, and equivalency 
factors. 
(vi) A statement of the results of tests and how the results compare with 
established standards of identity, strength, quality, and purity for the 
component tested. 
(vii) The initials or signature of the person who performed each test and 
the date the tests were performed. 
(viii) The initials or signature of a second person showing that the original 
records have been reviewed for accuracy, completeness, and compliance 
with established standards. 
(b) Complete records must be maintained of any modifi cation of an established 
method employed in testing. These records must include the reason for the 
modifi cation and verify that the modifi cation produced results that are at 
least as accurate and reliable for the material being tested as the established 
method. 
(c) Complete records must be maintained of any testing and standardization of 
laboratory reference standards, reagents, and standard solutions. 
(d) Complete records must be maintained of the periodic calibration of laboratory 
instruments, apparatus, gauges, and recording devices. 

CURRENT GOOD MANUFACTURING PRACTICE 23 
(e) Complete records must be maintained of all stability testing performed in 
accordance with Section 211.166 of the regulation. 
7. Distribution records must contain the name and strength of the product and 
description of the dosage form, name and address of the consignee, date and 
quantity shipped, and lot or control number of drug product. For compressed 
medical gas products, distribution records are not required to contain lot or 
control numbers. 
8. Complaint fi les 
(a) Written procedures describing the handling of all written and oral complaints 
regarding a drug product must be established and followed. These procedures 
must include provisions for review by the quality control unit of any complaint 
involving the possible failure of a drug product to meet any of its 
specifi cations and a determination as to the need for an investigation. These 
procedures must include provisions for review to determine whether the 
complaint represents a serious and unexpected adverse drug experience 
which is required to be reported to the FDA. 
(b) A written record of each complaint must be maintained in a fi le designated 
for product complaints. The fi le may be maintained at another facility if the 
written records of such fi les are readily available for inspection at that other 
facility. Written reports involving a drug product must be maintained until 
at least one year after the expiration date of the drug product or one year 
after the date that the complaint was received, whichever is longer. In the 
case of certain OTC drug products lacking expiration dating because they 
meet the criteria for exemption, such written records must be maintained for 
three years after distribution of the drug product. 
(i) The written record must include the following information 
where known: the name and strength of the drug product, lot number, 
name of complainant, nature or complaint, and reply to the 
complainant. 
(ii) Where an investigation is conducted, the written record must include 
the fi ndings of the investigation and follow - up. The record or a copy 
of the record of investigation must be maintained at the location where 
the investigation occurred. 
(iii) Where an investigation is not conducted, the written record must include 
the reason that an investigation was not considered to be necessary and 
the name of the responsible person making the determination. 
Returned and Salvaged Drug Products 
1. Returned drug products  Returned drug products must be identifi ed as such 
and held. If the conditions under which returned drug products have been held, 
stored, or shipped before or during the return or the condition of the drug product, 
its container, carton, or labeling is a result of storage or shipping casts doubt on the 
safety, identity, strength, quality, or purity of the drug product, the returned drug 
product must be destroyed unless examination testing or other investigation proves 
the drug product meets appropriate standards. Records of returned drug products 
must be maintained and must include the name and label potency of the drug 

24 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
product dosage lot number, reason for the return, quantity returned, date of disposition, 
and ultimate disposition of the returned product. If the reason for a drug 
product being returned implicates associated batches, an investigation must be 
conducted. Procedures for the holding, testing, and reprocessing of returned drug 
products must be in writing and must be followed. 
2. Drug product salvaging  Drug products that have been subjected to improper 
storage conditions, including extremes in temperature, humidity, smoke, fumes, pressure, 
age, or radiation due to natural disasters, fi res, accidents, or equipment failures, 
must not be salvaged and returned to the marketplace. Whenever there is a question 
whether drug products have been subjected to such conditions, salvaging operations 
may be conducted only if there is (a) evidence from laboratory tests and assays that 
the drug products meet all applicable standards of identity, strength, quality, and 
purity and (b) evidence from inspection of the premises that the drug products and 
associated packaging were not subjected to improper storage conditions as a result 
of the disaster or accident. Organoleptic examinations are acceptable only as supplemental 
evidence that the drug products meet appropriate standards of identity, 
strength, quality, and purity. Records including name, lot number, and disposition 
must be maintained for drug products subject to this section. 
1.1.3 GUIDANCE FOR INDUSTRY: QUALITY SYSTEMS APPROACH 
TO PHARMACEUTICAL CURRENT GOOD MANUFACTURING 
PRACTICE REGULATIONS 
This guidance document was written by the FDA to help manufacturers implement 
what they consider to be modern quality systems and risk management approaches 
that will meet the requirements of the FDA  s GMP regulations. The guidance 
describes what the FDA considers a comprehensive quality systems (QS) model. It 
also explains how manufacturers can be in full compliance with the GMP regulations 
by implementing such quality systems. The FDA does not intend this guidance 
to place new expectations on manufacturers nor does this replace the GMPs. 
As is true with all guidance documents, this document does not establish legally 
enforceable responsibilities, but rather it describes the FDA  s current thinking. Thus, 
this guidance should be viewed as a set of recommendations unless a regulation is 
cited. 
The objective of this guidance is to describe a quality systems model and demonstrate 
how and where the elements of this model can fi t within the requirements 
of the CGMP regulations. The philosophy being put forward is that quality should 
be build into the product, and testing alone cannot be relied on to ensure product 
quality . 
1.1.3.1 CGMPS and the Concepts of Modern Quality Systems 
The FDA believes that several key concepts are critical for any discussion of modern 
quality systems. The following concepts are used throughout this guidance as they 
relate to the manufacture of pharmaceutical dosage forms: 

CURRENT GOOD MANUFACTURING PRACTICE 25 
Quality For the purposes of this guidance, the phrase achieving quality means 
achieving the identity, strength, purity, and other quality characteristics 
designed to ensure safety and effectiveness. 
Quality by Design and Product Development This means designing and developing 
a product and its associated manufacturing processes that will be used 
to ensure that the product consistently attains a predefi ned quality at the end 
of the manufacturing process. 
Quality Risk Management This component of a quality systems framework can 
help guide the setting of specifi cations and process parameters for dosage form 
manufacturing, assess and mitigate the risk of changing a process or specifi cation, 
and determine the extent of discrepancy investigations and corrective 
actions. 
Corrective and Preventative Action (CAPA) This is a regulatory concept that 
focuses on investigating, understanding, and correcting discrepancies while 
attempting to prevent their recurrence. This model separates CAPA into three 
separate concepts: 
 Remedial corrections of an identifi ed problem 
 Root cause analysis with corrective action to help understand the cause of 
the deviation and prevent recurrence of a similar problem 
 Preventative action to prevent recurrence of similar problems 
Change Control This process focuses on managing change to prevent unintended 
consequences. 
Quality Unit While the GMPs refer to a quality unit, current industry practice 
is to divide the responsibilities of this unit between two groups: 
 Quality control (QC) usually involves (a) assessing the suitability of incoming 
components and the fi nished products, (b) evaluating the performance 
of the manufacturing process, and (c) determining the acceptability of each 
batch for release and distribution 
 Quality assurance (QA) involves (a) review and approval of all procedures 
related to manufacturing and maintenance, (b) review of records, and 
(c) auditing and performing/evaluating trend analyses. 
Six - System Inspection Model The FDA  s instruction manual for its investigators 
is a systems - based approach to inspection consistent with this guidance. The 
FDA defi nes six interlocked systems: (1) the quality system which encompasses 
all the other systems, (2) a materials system, (3) a production system, 
(4) a packaging and labeling system, (5) a facilities and equipment system, and 
(6) a laboratory controls system. The agency believes that use of this overall 
system approach will help fi rms achieve better control. 
1.1.3.2 Quality Systems Model 
This section was written to describe a model for use in pharmaceutical manufacturing 
that can supply the controls to consistently produce a product of acceptable 
quality. The model is described by four major factors: 

26 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
 Management responsibilities 
 Resources 
 Manufacturing operations 
 Evaluation 
Management Responsibilities The FDA feels that a robust quality system model 
calls for management to play a key role in the design, implementation, and 
management of the quality system. 
Resources Suffi cient resources should be provided to create a robust quality 
system that complies with the GMP regulations. Senior management or a 
designee should be responsible for providing adequate resources. 
Facilities and Equipment The technical experts who have an understanding of 
pharmaceutical science, risk factors, and manufacturing processes related to 
the product are responsible for defi ning specifi c facility and equipment requirements. 
The equipment must be qualifi ed, calibrated, cleaned, and maintained 
to prevent contamination and product mix - ups. It is important to remember 
that the GMPs place as much emphasis on process equipment as on testing 
equipment while most quality systems focus only on testing equipment. 
Control Outsourced Operations Quality systems call for contracts with outside 
suppliers that clearly describe the materials or service, quality specifi cation 
responsibilities, and communication mechanisms. 
Manufacturing There is an overlap between the elements of a quality system 
and the GMP regulation requirements for manufacturing operations. One 
should always remember that the FDA  s enforcement programs and inspectional 
coverage are based on the GMPs. The FDA feels that the following 
factors are essential in a manufacturing quality system: 
1. Design, develop, and document product and processes 
2. Examine inputs 
3. Perform and monitor operations 
4. Address nonconformities 
Evaluation Activities This includes the following activities: 
1. Analyze data for trends 
2. Conduct internal audits 
3. Quality risk management 
4. Corrective action 
5. Preventative action 
6. Promote improvements 
1.1.4 GUIDANCE FOR INDUSTRY: PAT  FRAMEWORK FOR 
INNOVATIVE PHARMACEUTICAL DEVELOPMENT, 
MANUFACTURING, AND QUALITY ASSURANCE 
This guidance is intended to describe a regulatory framework that the FDA chooses 
to call process analytical technology , or PAT. It is the FDA  s hope that this will 

encourage the voluntary development and implementation of innovative pharmaceutical 
development, manufacturing, and quality assurance. The FDA intended this 
guidance for a broad audience in different organizational units. To a large extent, 
the guidance discusses principles with the goal of highlighting opportunities and 
developing regulatory processes that encourage innovation. 
Conventional pharmaceutical manufacturing is usually accomplished using batch 
processing with laboratory testing of samples at various stages of manufacturing to 
evaluate quality. The FDA believes that opportunities exist for improving the development, 
manufacturing, and quality assurance steps through innovation in product 
and process development, process control, and analysis. 
Typically, the pharmaceutical industry has been reluctant to try something new 
due to the fear that the new approach will not fi nd favor with the FDA. An FDA 
rejection would result in costly delays and processing revisions that industry is 
unwilling to risk. The FDA now says that this hesitancy is undesirable from a public 
health perspective and it would like to see more innovation introduced. According 
to the FDA, pharmaceutical manufacturing should be based on: 
 The design of effective and effi cient manufacturing manufacturing processes 
 Product and process specifi cations based on an understanding of how formulation 
and process factors affect product performance 
 Continuous real - time quality assurance 
 Relevant regulatory policies and procedures tailored to accommodate the most 
current level of scientifi c knowledge 
 Risk - based regulatory approaches that recognize: 
The level of scientifi c understanding of how formulation and manufacturing 
process factors affect product quality and performance 
The capability of process control strategies to prevent or mitigate the risk of 
producing a poor - quality product 
It is the intent of this guidance to facilitate progress to this state. So far, the FDA  s 
stated goal is not being met. FDA representatives have stated the agency  s concern 
about the failure of industry to rush to implement change. However, the economies 
of change continue to favor the status quo. 
1.1.4.1 PAT Framework 
Quality should be built into pharmaceutical products through a comprehensive 
understanding of: 
 Intended therapeutic objectives, patient population, route of administration, 
and pharmacokinetic characteristics of a drug 
 Chemical, physical, and biopharmaceutic characteristics of a drug 
 Design of a product and selection of product components and packaging based 
on drug attributes 
 Design of manufacturing processes using principles of engineering, material 
science, and quality assurance to ensure acceptable and reproducible product 
quality and performance throughout a product  s shelf life 
GUIDANCE FOR INDUSTRY 27 
0
0

28 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
Process Understanding A process is considered to be well understood when all 
critical sources of variability are identifi ed and explained, variability is managed by 
the process, and product quality attributes can be accurately and reliably predicted. 
Principles and Tools Pharmaceutical manufacturing often consists of a series of 
unit operations, each of which is intended to change certain properties of the materials 
being processed. To assure these changes are acceptable and reproducible, consideration 
should be given to the quality attributes of incoming materials and their 
acceptability for the given unit operation. Most current pharmaceutical processes 
are based on time - defi ned endpoints such as  blend for ten minutes.  In some cases, 
these time - defi ned endpoints do not consider the effects of physical differences in 
raw materials. Processing diffi culties can arise that result in the failure of a product 
to meet specifi cations even if the raw materials conform to established specifi cations. 
Use of PAT tools and principles can provide relevant information relating to 
physical, chemical, and biological attributes. The process understanding gained from 
this information will enable process control and optimization, address the limitation 
of the time - defi ned endpoints, and improve effi ciency. 
PAT Tools There are many tools available that enable process understanding. 
These tools, when used within a system, can provide effective and effi cient means 
for acquiring information to facilitate process understanding, continuous improvement, 
and development of risk mitigation strategies. Such tools are categorized as 
follows: 
 Multivariate tools for design, data acquisition, and analysis 
 Process analyzers 
 Process control tools 
 Continuous improvement and knowledge management tools 
Strategy for Implementation To enable successful implementation of PAT, fl exibility, 
coordination, and communication with manufacturers are critical. The FDA 
believes that current regulations are suffi ciently broad to accommodate these strategies. 
In the course of implementing the PAT framework, manufacturers may want 
to evaluate the suitability of a tool on experimental and/or production equipment 
and processes. It is recommended that risk analysis of the impact on product quality 
be conducted before installation. This can be accomplished within the facility  s 
quality system without prior notifi cation to the agency. Data collected using an 
experimental tool should be considered research data. If conducted in a production 
facility, it should be done under the facility  s quality system. The FDA does not 
intend to inspect research data collected on an existing product for the purpose of 
evaluating the suitability of an experimental PAT tool. Its routine inspection of a 
fi rm  s manufacturing process that incorporates a PAT tool for research purposes 
will be based on current regulatory standards. 
The FDA has posted much of the information that fi rms will need in order to 
implement a PAT program on the Web at http://www.fda.gov/cder/ops/pat.htm . 
All marketing applications, amendments, or supplements to an application should 
be submitted to the appropriate Center for Drug Evaluation and Research (CDER) 
or Center for Veterinary Medicine (CVM) division in the usual manner. In general, 

PAT implementation plans should be risk based. The FDA has suggested the following 
possible implementation plans, where appropriate: 
 PAT can be implemented under the facility  s own quality system. CGMP inspections 
by the PAT team or PAT - certifi ed investigator can precede or follow PAT 
implementation. 
 A supplement [Changes Being Expected (CBE), Changes Being Expected in 30 
Days (CBE - 30), or Prior Approval Supplement (PAS)] can be submitted to the 
agency prior to implementation, and, if necessary, an inspection can be performed 
by a PAT team or PAT certifi ed investigator before implementation. 
 A comparability protocol can be submitted to the agency outlining PAT research, 
validation and implementation strategies, and time lines. Following approval of 
this comparability protocol by the agency, one or a combination of the above 
regulatory pathways can be adopted for implementation. 
To facilitate adoption or approval of a PAT process, manufacturers may request 
a preoperational review of a PAT manufacturing facility and process by the PAT 
team by contacting the FDA Process Analytical Technology Team at PAT@cder.fda. 
gov . It should be noted that when certain PAT implementation plans neither affect 
the current process nor require a change in specifi cations, several options can be 
considered. Manufacturers should evaluate and discuss with the agency the most 
appropriate option for their situation. 
1.1.5 GUIDANCE FOR INDUSTRY: PART 11. ELECTRONIC RECORDS; 
ELECTRONIC SIGNATURES  SCOPE AND APPLICATION 
Of the many regulations written by the FDA, the least understood is undoubtedly 21 
CFR Part 11. Rather than review the regulation itself, which is under review and possible 
revision, we will review the guidance for industry that FDA published in August 
2003 to  aid  industry in their puzzlement. Depending on the source, it appears to be 
questionable as to whether this guidance document aids or confuses. It exists, however, 
and like it or not, understand it or not, the regulation must be followed. 
The guidance indicates that the FDA  s approach is based on three main 
components: 
 The regulation will be interpreted narrowly. Fewer records will be considered 
subject to Part 11. 
 Those records that are considered subject to Part 11 will be subject to enforcement 
discretion with regard to the requirements for validation, audit trails, 
record retention, and record copying in the manner described and with regard 
to all Part 11 requirements for systems that were operational before the effective 
date of this regulation. 
 All predicate rule requirements will be enforced. This includes record and 
record - keeping requirements. 
The FDA does intend to enforce all other provisions of Part 11, including certain controls 
for closed systems. The following controls and requirements will be enforced: 
GUIDANCE FOR INDUSTRY 29

30 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
 Limiting system access to authorized individuals 
 Use of operational system checks 
 Use of authority checks 
 Use of device checks 
 Determination that persons who develop, maintain, or use electronic systems 
have the education, training, and experience to perform their assigned tasks 
 Establishment of and adherence to written policies that hold individuals 
accountable for actions initiated under their electronic signatures 
 Appropriate controls over systems documentation 
 Controls for open systems corresponding to controls for closed systems 
 Requirements related to electronic signatures 
Part 11 Records Under the narrow interpretation, the FDA considers Part 11 to 
be applicable to the following records or signatures in electronic format: 
1. Records that are required to be maintained under predicate rule requirements 
and that are maintained in electronic format in place of paper format. 
2. Records that are required to be maintainer under predicate rules, that are 
maintained in electronic format in addition to paper format, and that are relied 
on to perform regulated activities. 
3. Records submitted to the FDA under predicate rules in electronic format. 
However, a record that is not itself submitted but is used in generating a submission 
is not a Part 11 record. 
4. Electronic signatures that are intended to be the equivalent of handwritten 
signatures, initials, and other general signings required. 
FDA s Approach to Specifi c Part 11 Requirements 
1. Validation With respect to validation, the agency intends to exercise enforcement 
discretion regarding specifi c Part 11 requirements. However, compliance 
with all applicable predicate rules for validation is still expected. The FDA 
suggests an approach to validation be based on a justifi ed and documented 
risk assessment and a determination of the potential of the system to affect 
product quality, safety, and record integrity. 
2. Audit Trail The agency also intends to exercise enforcement discretion 
regarding specifi c requirements related to computer - generated, time - stamped 
audit trails and any corresponding requirements in Part 11. Compliance with 
all applicable predicate rule requirements related to documentation of date, 
time, or sequencing of events is still expected. It is also required to comply 
with rules for ensuring that changes to records do not obscure previous 
entries. 
3. Legacy Systems The FDA intends to exercise enforcement discretion with 
respect to all Part 11 requirements for systems that otherwise were operational 
prior to August 20, 1997. Thus they do not intend to take enforcement action 
to enforce compliance with any Part 11 requirements if all of the following 
criteria are met for a specifi c system: 

 The system was operational before the effective date. 
 The system met all applicable predicate rule requirements before the effective 
date. 
 The system currently meets all applicable predicate rule requirements. 
 There is documented evidence and justifi cation that the system is fi t for its 
intended use. 
4. Copies of Records Enforcement discretion will be applied with respect to 
specifi c Part 11 requirements for generating copies of records and any corresponding 
requirements in this part. An investigator should be provided with 
reasonable and useful access to records during an inspection. All records held 
by a manufacturer are subject to inspection. 
5. Record Retention The FDA intends to exercise enforcement discretion with 
regard to the Part 11 requirements for the protection of records to enable their 
accurate and ready retrieval at any time throughout the records retention 
period. 
1.1.6 GUIDANCE FOR INDUSTRY AND FDA : CURRENT GOOD 
MANUFACTURING PRACTICE FOR COMBINATION PRODUCTS 
This document discusses the applicability of GMPs to combination products as 
defi ned under 21 CFR 3.2(e). Manufacturers must ensure that the product is not 
adulterated; the product possesses adequate strength, quality, identity, and purity; 
and the product complies with performance standards as appropriate. This guidance 
does not address technical manufacturing methods or make recommendations for 
manufacturers  selection of facilities used in manufacturing. 
A combination product is a product composed of a drug and a device, a biological 
product and a device, a drug and a biological product, or a drug, a device, and a 
biological product. For the purposes of this document, a constituent part of a combination 
product is an article in a combination product that can be distinguished by 
its regulatory identity as a drug, device, or biological product. 
For regulatory purposes, a combination product is assigned to an agency center 
or alternative organizational component that will have primary jurisdiction for its 
premarket review and regulation. Manufacturers will be required to use the applicable 
GMP for their products. Regulations that may apply are: 
 GMP regulations for fi nished pharmaceuticals (21 CFR Parts 210 and 211). 
 Quality system regulations for devices (21 CFR Part 820). 
 The biological product regulations (21 CFR Parts 600  680) may also apply to 
the manufacture of drugs that are also biological products along with the drug 
provisions. 
There are no GMP regulations specifi cally for combination products. Until such 
regulations are promulgated, the manufacture of each constituent part is governed 
by the regulations for that component. 
The Offi ce of Combination Products is available as a resource to sponsors 
throughout the lifecycle of a combination product. This offi ce can be reached at 
GUIDANCE FOR INDUSTRY AND FDA 31

32 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
(301) 427 - 1934 or by E - mail at combination@fda.cov . Updated guidance documents 
are available at the offi ce  s Internet website, http://www.fda/gov/oc/combination . 
1.1.7 GUIDANCE FOR INDUSTRY: POWDER BLENDS AND FINISHED 
DOSAGE UNITS  STRATIFIED IN - PROCESS DOSAGE UNIT SAMPLING 
AND ASSESSMENT 
This guidance is intended to assist manufacturers in meeting the GMP requirements 
for demonstrating the adequacy of mixing to ensure uniformity of in - process powder 
blends and fi nished dosage units. 
Stratifi ed Sampling In this process dosage units are sampled at predefi ned intervals 
and representative samples collected from specifi cally targeted locations in the 
compression/fi lling operations that have the greatest potential to yield extremes of 
drug concentration. 
This guidance describes methods of sampling that might be used to demonstrate 
active ingredient homogeneity. These methods are put forward as suggestions and 
are not intended to be the only methods for meeting FDA requirements for demonstration 
of the adequacy of a powder mix. 
Assessment of Powder Mix Uniformity The following procedures are 
recommended: 
1. Conduct blend analysis on batches by extensively sampling the mix in the 
blender and/or intermediate bulk containers. 
2. Identify appropriate blending time and speed ranges, dead spots in blenders, 
and locations of segregation in intermediate bulk containers (IBCs). 
3. Defi ne the effects of sample size (1  10 times the dosage unit range) while 
developing a technique capable of measuring the true uniformity of the blend. 
Sample quantities larger than 3 times the dosage size can be used with adequate 
scientifi c justifi cation. 
4. Design blend - sampling plans and evaluate them using appropriate statistical 
analyses. 
5. Quantitatively measure any variability that is present among the samples. 
Attribute the sample variability to either lack of uniformity of the blend or 
sampling error. Signifi cant variances in the blend data within a given location 
can be an indication of one factor or a combination of factors such as inadequacy 
of blend mix, sampling error, or agglomeration. Signifi cant between - 
location variance can indicate that the blending operation is inadequate. 
Correlation of Powder Mix Uniformity with Stratifi ed In -Process Dosage Unit 
Data The following steps are recommended for correlation: 
1. Conduct periodic sampling and testing of the in - process dosage units by sampling 
them at defi ned intervals and locations throughout the compression or 
fi lling process. Use a minimum of 20 appropriately spaced in - process dosage 

unit sampling points. There should be at least 7 samples taken from each of 
these locations for a total minimum of at least 140 samples. 
2. Take 7 samples from each additional location to further assess each signifi cant 
event, such as fi lling or emptying of hoppers and IBCs, start and end of the 
compression or fi lling process, and equipment shutdown. This may be accomplished 
by using process development batches, validation batches, or routine 
manufacturing batches for approved products. 
3. Signifi cant events may also include observations or changes from one batch 
to another (e.g., batch scale - up and observations of undesirable trends in previous 
batch data). 
4. Prepare a summary of the data and analysis used to correlate the stratifi ed 
sampling locations with signifi cant events in the blending process. 
5. Compare the powder mix uniformity with the in - process dosage unit data 
described above. 
6. Investigate any discrepancies observed between powder mix and dosage 
unit data and establish root causes. At least one troubleshooting guide is 
available that may be helpful with this task. Possible corrections may range 
from going back to formulation development to improve powder characteristics 
to process optimization. Sampling problems may also be negated by use 
of alternate state - of - the - art methods of in situ real - time sampling and 
analysis. 
Correlation of Stratifi ed In -Process Samples with Finished Product The following 
steps are recommended: 
1. Conduct testing for uniform content of the fi nished product using an appropriate 
procedure or as specifi ed in the ANDA or the NDA for approved 
products. 
2. Compare the results of stratifi ed in - process dosage unit analysis with uniform 
content of the fi nished dosage units from the previous step. This analysis 
should be done without weight correction. 
3. Prepare a summary of the data and analysis used to conclude that the stratifi ed 
in - process sampling provides assurance of uniform content of the fi nished 
product. 
1.1.7.1 Validation of Batch Powder Mix Homogeneity 
This section describes sampling and testing the powder mix of demonstration and 
process validation batches used to support implementing the stratifi ed sampling 
method described in this guidance. 
The guidance document recommends that during the manufacture of demonstration 
and process validation batches, the following uniformity characteristics be 
assessed: (1) the powder blend, (2) the in - process dosage units, and (3) the fi nished 
product. Each attribute should be determined independently. It is further recommended 
that the following steps be used to identify sampling locations and acceptance 
criteria prior to the manufacture of the exhibit and/or validation batches: 
GUIDANCE FOR INDUSTRY AND FDA 33

34 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
1. Carefully identify at least 10 sampling locations in the blender to represent 
potential areas of poor blending. For example, in tumbling blenders (such as 
V - blenders, double cones, or drum mixers), samples should be selected from 
at least two depths along the axis of the blender. For convective blenders (such 
as a ribbon blender), a special effort should be made to implement uniform 
volumetric sampling to include the corners and discharge area (at least 20 
locations are recommended to adequately validate convective blenders). 
2. Collect at least three replicate samples from each location. Samples should 
meet the following criteria: 
 Assay one sample per location (number of samples n = 10, or n = 20 for 
ribbon blender). 
 RSD (relative standard deviation) of all individual results is 5.0%. 
 All individual results are within 10.0% (absolute) of the mean of the 
results. 
It is also recommended that you not proceed any further with implementation 
of the methods described in this guidance until the criteria are met. 
Sampling errors may occur in some powder blends, sampling devices, and techniques 
that make it impractical to evaluate adequacy of mix using only the blend 
data. In such cases, it is recommended that in - process dosage unit data be used in 
conjunction with blend sample data to evaluate blend uniformity. 
Some powder blends may present an unacceptable safety risk when directly 
sampled. The safety risk, once described, may justify an alternate procedure. In such 
cases, process knowledge and data from indirect sampling combined with additional 
in - process dosage unit data may be adequate to demonstrate the adequacy of the 
powder mix. Data analysis used to justify using these alternate procedures 
should be described in a summary report that is maintained at the manufacturing 
facility. 
1.1.7.2 Verifi cation of Manufacturing Criteria 
The assessment of powder mix uniformity and correlation of stratifi ed in - process 
dosage unit sampling development procedures should be completed before establishing 
the criteria and controls for routine manufacturing. It is also recommend 
that the normality be assessed and that the RSD be determined from the results of 
stratifi ed in - process dosage unit sampling and testing that were developed. The RSD 
value should be used to classify the testing results as either readily pass (RSD 4.0%) , 
marginally pass (RSD 6.0%), or inappropriate for demonstration of batch homogeneity 
when RSD > 6.0%. 
The FDA recommends that routine manufacturing batches be evaluated 
against the following criteria after completing the procedures described above to 
assess the adequacy of the powder mix and uniform content in the fi nished dosage 
form: 
1. Standard criteria method (SCM)  This method is recommended when either of 
the following conditions is met: 
1.1. Results of establishing initial criteria are classifi ed as readily pass . 

1.2. Results of testing to the marginal criteria method (MCM) pass the criteria 
for switching to the SCM. 
1.2.1. Stage 1 Test To perform the stage 1 test, collect at least three dosage 
units from each sampling location, assay one dosage unit from each 
location, weight correct the results, and compare the results with the 
following criteria: 
1.2.1.1. RSD of all individual results is less than 5%. 
1.2.1.2. Mean of all results is 90  110% of target assay. 
If the results pass these criteria and the adequacy of mix and uniformity 
of dosage unit content for the batch are adequate, the SCM 
can be used for the next batch. If test results fail stage 1 criteria, 
extended testing to stage 2 is required. 
1.2.2. Stage 2 Test To perform the stage 2 test, assay the remaining two 
dosage units from stage 1 for each sampling location and compute the 
mean and RSD of data combined from both stage 1 and stage 2. 
Compare the results with the following criteria: 
1.2.2.1. For all individual results, the RSD should be less than 5.0%. 
1.2.2.2. Mean of all results is 90  110% of target assay. 
If results pass the above criteria, the adequacy of mix and uniformity 
of content for the batch are adequate and stage 1 can be used for 
the next batch. If test results fail the criteria, use the MCM described 
in the section below. 
2. Marginal criteria method  The MCM can be used when either of the following 
conditions is met: 
2.1. Results of initial criteria establishment qualifi ed as marginally pass . 
2.2. Results of initial criteria establishment qualifi ed as readily pass or a batch 
was tested according to SCM and the test results failed both stage 1 and 
stage 2 criteria. 
2.3. If either of the above two criteria apply, use the weight corrected 
results from the stage 2 SCM analysis and compare this with the MCM 
criteria: 
2.3.1. For al individual results, the RSD is less than 6.0% . 
2.3.2. The mean of all results is 90.0  110.0% of target assay. 
2.4. It is acceptable to switch to the SCM when fi ve consecutive batches pass the 
MCM criteria and result in RSD of less than 5.0%. 
1.1.8 GUIDANCE FOR INDUSTRY: IMMEDIATE - RELEASE SOLID 
ORAL DOSAGE FORMS SCALE - UP AND POSTAPPROVAL CHANGES 
( SUPAC )  CHEMISTRY, MANUFACTURING AND CONTROLS, 
IN VITRO DISSOLUTION TESTING, AND IN VIVO 
BIOEQUIVALENCE DOCUMENTATION 
This guidance provides recommendations to NDA and ANDA sponsors who intend 
to make changes to the product during the postapproval period. Changes include 
any change in components or composition of the product, the site of manufacture, 
the scale - up/scale - down of batch size, and/or the manufacturing process and/or 
equipment of an immediate - release oral formulation. 
GUIDANCE FOR INDUSTRY 35

36 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
Changes in Components (Excipients) and Composition Changes in the amount 
or source of drug substance are not addressed by this guidance. Changes in components 
or composition that have the effect of adding a new excipient or deleting an 
excipient are defi ned at level 3 except as described below: 
1. Level 1 changes 
1.1. Level 1 changes are those that are unlikely to have any detectable impact 
on formulation quality and performance. 
1.2. Allowed changes (changes that can be made without prior FDA 
approval) are shown below. This is based on the assumption that the drug 
substance in the product is formulated to 100% of label potency. To be considered 
a level 1 change, the total additive effect of all excipient changes 
should not be more than 5% relative to the target dosage form weight. 
Excipient 
Percentage of Excipient (W/W) 
Out of Total Target Dosage 
Form Weight 
Filler  5 
Disintegrant 
Starch  3 
Other  1 
Binder  0.5 
Lubricant 
Calcium or magnesium Stearate  0.25 
Other  1 
Glidant 
Talc  1 
Other  0.1 
Film coat  1 
1.3. Test documentation 
1.3.1. Chemistry  Application/compendial release requirements and stability 
testing. For stability testing, one batch should be on long - term stability 
testing with data being reported in the annual report. 
1.3.2. Filing documentation  All information must be included in the annual 
report (including long - term stability data). 
2. Level 2 changes 
2.1. Level 2 changes are those that could have a signifi cant impact on formulation 
quality and performance. Tests and fi ling documentation for a level 2 change 
depend on three factors: (1) therapeutic range, (2) solubility, and (3) permeability. 
Therapeutic range is defi ned as either narrow or nonnarrow. Drug 
solubility and drug permeability are defi ned as either low or high. Changes 
in excipients, expressed as percent (w/w) of total formulation, greater than 
those listed for a level 1 change but less than or equal to the following 
percent ranges are acceptable level 2 changes: 

Excipient 
Percentage of Excipient (w/w) of Total Target 
Dosage Form Weight 
Filler  10 
Disintegrant 
Starch  6 
Other  2 
Binder  1 
Lubricant 
Ca or Mg stearate  0.5 
Other  2 
Glidant 
Talc  2 
Other  0.2 
Film coat  2 
These percentages are based on the assumption that the drug substance in 
the fi nished product is formulated to 100% of labeled potency. The total 
additive effect of all excipient changes should not change by more than 
10%. 
All components in the formulation should have numerical targets that 
represent the nominal composition of the product on which any future 
changes in the composition of the product are based. Allowable changes in 
the composition should be based on the approved target composition and 
not on the composition based on previous level 1 or level 2 changes. 
2.2. Test documentation 
2.2.1. Chemistry 
2.2.1.1. Application/compendial release requirements and batch 
records. 
2.2.1.2. Stability testing  Test one batch with three months of accelerated 
stability data in supplement and on batch on long - term 
stability. 
2.2.2. dissolution 
2.2.2.1. High - permeability, high - solubility drugs  Dissolution of 85% 
in 15 min in 900 mL of 0/1 N HCl. If a drug product fails to 
meet this criterion, tests in 2.2.2.2 or 2.2.2.3 below should be 
performed. 
2.2.2.2. Low - permeability, high - solubility drugs  Multipoint dissolution 
profi le should be performed in the application/compendial 
medium at 15, 30, 45, 60, and 120 min or until an asymptote 
is reached. The dissolution profi le of the proposed and currently 
used product formulations should be similar. 
2.2.2.3. High - permeability, low - solubility drugs  Multipoint dissolution 
profi les should be performed in water, 0.1 N HCl, and 
USP buffer media at pH 4.5, 6.5, and 7.5 (fi ve different pro- 
fi les) for the proposed and currently accepted formulations. 
Adequate sampling should be performed at 15, 30, 45, 60, and 
120 min until either 90% of drug from the drug product is 
GUIDANCE FOR INDUSTRY 37

38 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
dissolved or an asymptote is reached. A surfactant may be 
used, but only with appropriate justifi cation. The dissolution 
profi le of the proposed and currently used product formulations 
should be similar. 
2.2.3. In vivo bioequivalence documentation is not required for level 2. If 
the product does not meet any of the level 1 cases above, refer to level 
3 changes. 
2.2.4. Filing documentation  A prior approval supplement with all data 
including the accelerated stability data is required. This change should 
also be documented in the annual report along with the long - term 
stability data. 
2.3. Level 3 changes 
2.3.1. Level 3 changes are those that are likely to have a signifi cant impact 
on formulation quality and performance. Tests and fi ling documentation 
vary depending on the following three factors: therapeutic range, 
solubility, and permeability. For example: 
2.3.1.1. Any qualitative and quantitative excipient changes to a narrow 
therapeutic drug beyond the ranges specifi ed in the level 1 
table. 
2.3.1.2. All other drugs not meeting the dissolution criteria under level 
2. 
2.3.1.3. Changes in the excipient ranges of low - solubility, low - 
permeability drugs beyond those listed in level 1. 
2.3.1.4. Changes in the excipient ranges of all drugs beyond those 
listed in the level 2 table. 
2.3.2. Test documentation 
2.3.2.1. Chemical 
(a) Application/compendial release requirements and batch 
records: 
 Information available  One batch with three months 
accelerated stability data reported in a supplement and 
one batch on long - term stability reported in the annual 
report. 
 Information NOT available  Up to three batches with 
three months accelerated stability data reported in the 
supplement and one batch on long - term stability data 
reported in annual report. 
(b) Dissolution documentation  Case B dissolution profi le as 
described in the table for level 2. 
(c) In vivo bioequivalence documentation  Full bioequivalence 
study. This requirement may be waived with a veri- 
fi ed acceptable in vivo/in vitro correlation. 
2.3.2.2. Filing documentation  Prior approval supplement including 
accelerated stability data plus an annual report showing long - 
term stability data. 
Site Changes Site changes are changes in the location of manufacture for both 
company - owned and contract manufacturing facilities. A site change does not 
include, for example, scale - up changes, changes in manufacturing equipment or a 
manufacturing process, and changes in Standard Operating Procedures (SOPs) or 
environmental changes. Each change must be considered separately. 
1. Level 1 changes  A level 1 change consists of a site change within a single facility 
where the same equipment, SOPs, environmental conditions, and personnel are 
used and where no changes are made to the manufacturing batch records other 
than location of the facility and administrative changes. 
1.1. Required documentation  No documentation is required beyond the usual 
application/compendial requirements. No in vivo bioequivalence documentation 
is required. 
1.2. Filing requirements  Annual report. 
2. Level 2 changes  A level 2 change is a site change within a contiguous campus 
or between facilities in adjacent city blocks where the same equipment, SOPs, 
environmental conditions and controls, and personnel common to both manufacturing 
sites are used. There must be no changes to the manufacturing batch 
records except for administrative information and the location of the facility. 
2.1. Required documentation 
2.1.1. ChemistryIdentify location of new site and updated batch records. 
No other documentation is required beyond application/compendial 
release requirements, although one batch produced at the new site 
should be placed on long - term stability and the data should be reported 
in the annual report. Dissolution data other than normal release requirements 
are not required nor is in vivo bioequivalence testing required. 
2.1.2. Filing documentation  A supplement should be fi led showing the 
changes being effected. Long - term stability test data should be included 
in the annual report. 
3. Level 3 changes  A level 3 change is a change in manufacturing site to a different 
campus. However, the same equipment, SOPs, environmental conditions, and 
controls should be used in the manufacturing process at the new site. No changes 
may be made to the manufacturing batch records except for administrative information, 
location, and language translation if needed. 
3.1. Documentation 
3.1.1. Chemistry  Location of new site and updated batch records. 
3.1.2. Stability 
3.1.2.1. If a signifi cant body of data is available, one batch with three 
months accelerated stability data must be reported in a supplement. 
One batch should be on long - term stability with the 
stability data reported in the annual report. 
3.1.2.2. If a signifi cant body of data is not available, up to three batches 
with three months accelerated stability data should be reported 
in the supplement. Up to three batches should be on long - term 
stability with these data being reported in the annual report. 
3.1.3. Dissolution  A multipoint dissolution profi le should be performed in 
the application/compendial medium at 15, 30, 45, 60, and 120 min or 
until an asymptote is reached. The dissolution profi le of the drug 
product at the current and proposed site should be similar. 
3.1.4. In vivo bioequivalence  None required. 
GUIDANCE FOR INDUSTRY 39

40 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
3.2. Filing documentation required  Changes being effected should be identifi ed 
in a supplement. Long - term stability data are reported in the annual 
report. 
Changes in Batch Size Postapproval changes in the size of a batch from the pilot 
scale used to manufacture product for clinical trials to larger or smaller commercial 
batch sizes require submission of additional information in the application. Scale - 
down below 100,000 dosage units is not covered by this guidance. All scale - up 
changes should be properly validated and, where needed, inspected by appropriate 
FDA personnel. 
1. Level 1 changes  A change in batch size, up to and including a factor of 10 times 
the size of the pilot batch, is considered a level 1 change. However, (1) the equipment 
used must be of the same design and operating principles, (2) the product 
is manufactured in full compliance with the prevailing GMPs, and (3) the same 
formulation and manufacturing procedures are used as well as the same SOPs 
and controls. 
1.1. Chemistry documentation  (1) Application/compendial release requirements, 
(2) notifi cation of change to the FDA and submission of updated 
batch records in the annual report, and (3) one batch should be on long - term 
stability with results being provided in the annual report. 
1.2. Dissolution documentation  None beyond application/compendial release 
requirements. 
1.3. In vivo bioequivalence  None. 
1.4. Filing documentation  Annual report with long - term stability data. 
2. Level 2 changes  Level 2 consists of changes in batch size beyond a factor of 10 
times the size of the pilot batch where (1) the equipment used to produce the 
pilot batches is of the same design and operating principles, (2) the product is 
manufactured in full compliance with the prevailing GMPs, and (3) the same 
formulation and manufacturing procedures are used as well as the same SOPs 
and controls. 
2.1. Chemistry  Application/compendial release requirements. Notifi cation of 
change in batch size and submission of updated batch records to the FDA. 
One batch must be placed on accelerated stability testing and one on long - 
term stability. 
2.2. Dissolution  None beyond application/compendial release requirements. 
2.3. In vivo bioequivalence  None. 
2.4. Filing requirements  Must submit changes being effected in the supplement. 
Long - term stability data are reported in the annual report. 
Manufacturing Manufacturing changes may be either the equipment used in the 
manufacturing process or the process itself: 
1. Equipment 
1.1. Level 1 equipment changes  This category includes change from the use of 
nonautomated or nonmechanical equipment to automated or mechanical 
equipment to move ingredients and a change to alternative equipment of 
the same design and operating principles of the same or different capacity. 

1.1.1. Chemistry documentation  Application/compendial release requirements, 
notifi cation of change, and submission of updated batch records. 
One batch should be placed on long - term stability. 
1.1.2. Dissolution documentation  None other than application/compendial 
release requirements. 
1.1.3. In vivo bioequivalence documentation  None. 
1.1.4. Filing documentationAnnual report with long-term stability data. 
1.2. Level 2 equipment changes  This type of change involves a change in equipment 
to a different design and different operating principles. 
1.2.1. Chemistry documentation  Application/compendial release requirements, 
notifi cation of change, and submission of updated batch 
records. 
1.2.1.1. If a signifi cant body of data are available, one batch with three 
months of accelerated stability data reported in the supplement 
and one batch on long - term stability with data reported 
in the annual report. 
1.2.1.2. If a signifi cant body of data are not available, submit up to 
three batches with three months accelerated stability data in 
the supplement and up to three batches on long - term stability 
with data reported in the annual report. 
1.2.2. Dissolution documentation  A multipoint dissolution profi le should 
be performed in the application/compendial medium at 15, 30, 45, 60, 
and 120 min or until an asymptote is reached. The dissolution profi le 
of the drug product at the current and proposed site should be 
similar. 
1.2.3. In vivo bioequivalence documentation  None. 
1.2.4. Filing documentation  Prior approval supplement with justifi cation 
for change; long - term stability data must be reported in the annual 
report. 
2. Process changes 
2.1. Level 1 process changes  This includes process changes such as changes in 
mixing times and operating speeds within application/validation ranges. 
2.1.1. Chemistry documentation  None beyond application/compendial 
release requirements. 
2.1.2. Dissolution documentation  None beyond application/compendial 
release requirements. 
2.1.3. In vivo bioequivalence documentation  None. 
2.1.4. Filing documentation  Annual report. 
2.2. Level 2 process changes  Level 2 changes include process changes such as 
mixing times and operating speeds outside of application/validation ranges. 
2.2.1. Chemistry documentation  Application/compendial release requirements; 
notifi cation of change and submission of updated batch records. 
One batch on long - term stability. 
2.2.2. Dissolution documentation  A multipoint dissolution profi le should 
be performed in the application/compendial medium at 15, 30, 45, 60, 
and 120 min or until an asymptote is reached. The dissolution profi le 
of the drug product at the current and proposed site should be 
similar. 
GUIDANCE FOR INDUSTRY 41

42 GOOD MANUFACTURING PRACTICES & RELATED FDA GUIDELINES 
2.2.3. In vivo bioequivalence documentation  None. 
2.2.4. Filing documentation  A supplement with changes being effected. 
Long - term stability data should be reported in the annual report. 
2.3. Level 3 process changes  Level 3 includes change in the type of process used 
in the manufacture of the product, such as a change from wet granulation to 
direct compression. 
2.3.1. Chemistry documentation  Application/compendial release requirements. 
Notifi cation of change and submission of updated batch records. 
Stability testing varies depending on the amount of data available: 
2.3.1.1. Signifi cant body of data available  One batch with three 
months accelerated stability data should be reported in the 
supplement; one batch should also be put on long - term stability 
with data being reported in the annual report. 
2.3.1.2. No signifi cant body of data available  Up to three batches 
with three months accelerated stability data should be reported 
in the supplement. Up to three batches should be on long - term 
stability with data being reported in the annual report. 
2.3.2. Dissolution documentation  A multipoint dissolution profi le should 
be performed in the application/compendial medium at 15, 30, 45, 60, 
and 120 min or until an asymptote is reached. The dissolution profi le 
of the drug product at the current and proposed site should be 
similar. 
2.3.3. In vivo bioequivalence documentation  An in vivo bioequivalence 
study should be performed. This may be waived if a suitable in vivo/in 
vitro correlation has been verifi ed. 
2.3.4. Filing documentation  A prior approval supplement must be fi led 
with justifi cation for the change. Long - term stability data should be 
submitted in the annual report. 
1.1.9 OTHER GMP - RELATED GUIDANCE DOCUMENTS 
This chapter has discussed the CGMP regulations and some of the more important 
guidances. There have been a number of additional guidance documents related to 
GMPs published by the FDA. These documents are all posted on the FDA website. 
They are listed below along with their URL: 
 Current good manufacturing practice for combination products: http://www. 
fda.gov/cder/guidance/OCLove1dft.pdf 
 Questions and answers on current good manufacturing practices (cGMP) for 
drugs: http://www.fda.gov/cder/guidance/cGMPs/default.htm 
 Powder blends and fi nished dosage units  Stratifi ed in - process dosage unit 
sampling and assessment 
 Sterile drug products produced by aseptic processing  Current good manufacturing 
practice: http

 Current good manufacturing practice for medical gases: http://www.fda.gov/ 
cder/guidance/3823dft.pdf 
 General principles of process validation
 SUPAC - IR: Immediate - release solid oral dosage forms: Scale - up and post - 
approval changes: Chemistry, manufacturing and controls, in vitro dissolution 
testing, and in vivo bioequivalence documentation: http://www.fda.gov/cder/ 
guidance/cmc5.pdf 
 SUPAC - IR/MR: Immediate release and modifi ed release solid oral dosage 
forms manufacturing equipment addendum
 SUPAC - MR: Modifi ed release solid oral dosage forms scale - up and postapproval 
changes: Chemistry, manufacturing, and controls; in vitro dissolution 
testing and in vivo bioequivalence documentation: http://www.fda.gov/cder/ 
guidance/1214fnl.pdf 
 SUPAC - SS: Nonsterile semisolid dosage forms; scale - up and post - approval 
changes: Chemistry, manufacturing and controls; in vitro release testing and in 
vivo bioequivalence documentation
 SUPAC - SS: Nonsterile semisolid dosage forms manufacturing equipment 
addendum 
OTHER GMP-RELATED GUIDANCE DOCUMENTS 43


45 
1.2 
ENFORCEMENT OF CURRENT GOOD 
MANUFACTURING PRACTICES 
Kenneth J. Nolan 
Nolan & Auerbach, P. A., Fort Lauderdale, Florida 
Contents 
1.2.1 Introduction and Background 
1.2.2 Enforcement Players 
1.2.3 FDA Enforcement Techniques 
1.2.3.1 Inspections 
1.2.3.2 After the Inspection: Form 483 
1.2.3.3 Recalls 
1.2.3.4 Warning Letter 
1.2.4 Judicial Enforcement: Beyond the Warning Letter 
1.2.4.1 Introduction 
1.2.4.2 Civil Proceedings 
1.2.4.3 Criminal Proceedings 
1.2.5 Conclusion 
1.2.1 INTRODUCTION AND BACKGROUND 
The legal authority for the Food and Drug Administration (FDA) to impose 
minimum manufacturing standards is set forth in the federal Food and Drug and 
Cosmetic Act (FDCA), 21 U.S.C. sec. 301 et seq. Section 351(a)(2)(B) of 21 U.S.C. 
requires manufacturers of drugs to operate in conformance with manufacturing 
regulations established by the FDA. The regulations are primarily contained in Title 
21 of the U.S. Code of Federal Regulations (CFR), Parts 210 and 211, and are called 
the current good manufacturing practice (cGMP) regulations. 
The cGMP regulations stem from congressional concern that impure and otherwise 
adulterated drugs might escape detection under a system predicated only on 
seizure of drugs shown to be in fact adulterated. That is, the U.S. Congress desired 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

46 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
to require manufacturers to utilize manufacturing practices designed to prevent 
pharmaceuticals from such defects as contamination, nonconforming bioavailability, 
or potency defects. 
Congress stated the rationale for imposing cGMP on the pharmaceutical industry 
this way 1 : 
The manufacturing of drugs is a business that requires highly qualifi ed and trained 
personnel, and special laboratory and other facilities and most careful internal manufacturing, 
packaging, and labeling controls. These requirements are necessary to the 
assurance that the drugs will be safe for the user and will have, and so far as possible 
retain, the identity, strength, quality, purity, and effectiveness that they purport to 
have. 
The purpose of the cGMP requirement is to prevent injury and death  by building 
quality into the design and production of pharmaceuticals,  2 so that substandard 
prescription drugs do not jeopardize the health and safety of the patients. 
The cGMPs require manufacturers to have adequately equipped manufacturing 
facilities, adequately trained personnel, precisely controlled manufacturing processes, 
appropriate laboratory controls, complete and accurate records and reports, 
appropriate fi nished product examination, and so on. Current GMPs are not  best 
practices  ; rather, they establish threshold or minimum standards which must be 
satisfi ed in order for a pharmaceutical manufacturing operation to be compliant. 
The cGMPs were modifi ed only once between 1963 and 2002 with changes made 
in 1978 to update them in light of the current technology and also to describe the 
requirements more explicitly and with more specifi city. Meanwhile, the intervening 
decades saw myriad advances in manufacturing science, engineering, and technology, 
including the development of better quality systems. These advances, combined with 
the desire to harmonize manufacturing standards in an increasingly globalized production 
environment, created the impetus to revamp the cGMPs again. 
In August 2002, the FDA announced a comprehensive review of the pharmaceutical 
cGMPs. The agency identifi ed its cGMP initiative  Pharmaceutical cGMPs for 
the 21st Century: A Risk - Based Approach.  The FDA  s articulated goals for the 
initiative, relevant to enforcement, were: 
 The submission review program and the inspection program operate in a coordinated 
and synergistic manner. 
 Regulation and manufacturing standards are applied consistently. 
 FDA resources are used most effectively and effi ciently to address the most 
signifi cant health risks. 
One of the major products of the cGMP initiative was issued by the FDA in 
September 2006 in a document entitled  Guidance for Industry  Quality Systems 
Approach to Pharmaceutical cGMP Regulations.  3 The FDA described the guid- 
1 H. R. Rep. No. 2464, 87th Cong., 2d Sess. 2 (1962). See also 1962 U.S. Cong. and Admin. News , p. 2884. 
2 FDA, Pharmaceutical cGMPs for the 21st century: A risk - based approach, Rockville, MD, August 21, 
2002. 
3 The FDA  s guidance documents advise the reader that they  do not establish legally enforceable responsibilities. 
Instead, guidances describe the [the FDA  s] current thinking on a topic and should be viewed 
only as recommendations, unless specifi c regulatory or statutory requirements are cited.  

ance as a comprehensive quality systems model which, if followed, would improve 
quality control and satisfy the requirements of the cGMP regulations. Quality 
systems and quality assurance are important parts of the cGMP modernization 
process because quality assurance problems have been the cGMP issues most frequently 
cited by FDA investigators in recent years. 
Drugs which are manufactured not in accordance with any cGMP requirement, 
including the quality control and quality process mandates, are  adulterated  under 
the FDCA. Section 351 of 21 U.S.C. defi nes a drug as adulterated 
[if] the methods used in, or the facilities or controls used for, its manufacture, processing, 
packing, or holding do not conform to or are not operated or administered in 
conformity with current good manufacturing practice to assure that such drug meets 
the requirement of the act as to safety and has the identity and strength, and meets the 
quality and purity characteristics, which it purports or is represented to possess. 
1.2.2 ENFORCEMENT PLAYERS 
The FDA is obviously one of the most important regulatory agencies in the United 
States. It may also be characterized as the most important consumer protection 
agency in the world. Its decisions involving approval of drugs have a direct effect 
on testing, approval, access, and distribution of prescription drugs worldwide. As a 
regulatory agency in a largely scientifi c role, it is involved in shaping pharmaceutical 
science and drug access throughout the world. As a scientifi c agency, the FDA 
employs physicians, pharmacists, biologists, biochemists, engineers, biostatisticians, 
and other highly educated and specialized professionals. 
But the FDA also has very important law enforcement responsibilities. The 
agency employs civil and criminal investigators, auditors, attorneys, and other 
enforcement professionals. One of the FDA  s many enforcement functions is investigation, 
remediation, and prosecution of cGMP violations. 
The FDA district offi ces operate under the auspices of the agency  s Offi ce of 
Regulatory Affairs (ORA). The ORA fi eld organization is divided into fi ve regional 
offi ces (northeast, central, southeast, southwest, Pacifi c). Each region includes district 
offi ces, of which there are 20 nationwide. Most district offi ces have three or 
four branches, including either a compliance branch or an enforcement branch. The 
branch offi ces are the primary regulatory contacts within the districts and act as the 
 eyes and ears  for FDA headquarters. 
The FDA  s Offi ce of Criminal Investigations (OCI) is responsible for reviewing 
allegations which if proven would violate the U.S. criminal code, including potential 
violations of the cGMPs. The OCI investigators conduct such investigations as is 
deemed appropriate, sometimes in connection with other federal investigative 
agencies, including the FBI and the Offi ce of Inspector General of the Department 
of Health and Human Services. If the OCI chooses not to recommend to the Department 
of Justice (DOJ) 4 that criminal indictment be pursued, then the district offi ce 
is at liberty to pursue the matter through administrative or civil proceedings. 
4 The DOJ is under the direction of the attorney general of the United States. Its mission, relevant to this 
chapter, is to enforce federal statutes and uphold the rule of the law. It pursues violations brought to its 
attention by the FDA as well as other federal agencies. 
ENFORCEMENT PLAYERS 47

48 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
Although the FDA  s Offi ce of General Counsel is involved with enforcement of 
both civil and criminal matters, cases involving court enforcement are handled by 
assistant U.S. attorneys (AUSAs), who are located in U.S. attorneys  offi ces located 
across the United States. U.S. attorneys are the local representatives of the DOJ; 
they are appointed by and serve at the discretion of the president, with advice 
and consent of the Senate. There are 93 U.S. attorneys, and they are located (by 
district) across the United States and its territories. Each U.S. attorney is the chief 
federal law enforcement offi cer of the United States within his or her particular 
district. 
The AUSAs are the principal trial attorneys for the U.S. government. Each U.S. 
attorney exercises wide discretion in the use of his or her resources to further the 
priorities of the local jurisdiction. Discretion and expertise are big factors in case 
decisions. There may be signifi cant disparity in the experience, interest, and capability 
of U.S. attorneys  offi ces with respect to their pursuit of cGMP violations. 
The impact of this disparity is mitigated or eliminated by the expertise of the 
DOJ  s Offi ce of Consumer Litigation (OCL), which is charged with coordinating 
and supporting FDCA prosecutions nationwide. The OCR  s attorneys exercise considerable 
infl uence over and discretion in deciding what to and what not to prosecute, 
thus fostering consistent prosecutive decision making. Many civil actions, 
particularly those seeking injunctive relief, cannot be brought by a U.S. attorney 
without OCL approval, minimizing the risk that an inconsistent policy position is 
taken by a U.S. attorney  s offi ce. 
1.2.3 FDA ENFORCEMENT TECHNIQUES 
1.2.3.1 Inspections 
The FDA has the right to conduct surveillance inspections of manufacturing facilities 
for the purpose of enforcement. The goal of inspections is  to minimize consumers 
exposure to adulterated products.  5 
The FDCA, 21 U.S.C. 374, provides that the FDA is authorized to enter and  to 
inspect, at reasonable times and within reasonable limits and in a reasonable manner 
 all pertinent equipment, fi nished and unfi nished materials, containers, and labeling 
 in the manufacturing or related facility. This statute further authorizes the 
inspection to  extend to all things therein (including records, fi les, papers, processes, 
controls, and facilities)  as long as the records, for example, are relevant to any 
potential adulteration or misbranding 6 or other FDCA violations. The statute denies 
the agency the right to review  fi nancial data, sales data, pricing data, personnel data 
(other than data as to qualifi cations of technical and professional personnel performing 
functions)  and certain other types of documents. 
Inspectors are required to notify the company that the inspection is occurring 
but need not provide their reasons. They may take samples and photographs related 
5 Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspection Program , 
7356.002, available: www.fda.gov . 
6 Misbranding involves labeling a pharmaceutical product in a misleading way. See 21 U.S.C. 331(k). 

FDA ENFORCEMENT TECHNIQUES 49 
to the subject of the inspection. It is a criminal offense to deny entry to FDA inspectors 
or other offi cials who have appropriately made attempts to conduct an inspection. 
[21 U.S.C. 331(f)] 
In addition to the for - cause inspections, the FDCA mandates that the FDA routinely 
inspect a manufacturer  s facilities for cGMP compliance every two years. 
This applies to domestic and foreign facilities which manufacture drugs for sale 
within the United States. 7 Unfortunately, this two - year mandate is rarely satisfi ed 
because the FDA  s district offi ces, which are charged with the responsibility for the 
inspections, lack suffi cient resources to conduct regular cGMP compliance 
inspections. 
The FDA conducts two categories of facility inspections  surveillance inspections 
and compliance inspections. Surveillance inspections are periodic. Whether 
and when to inspect a particular manufacturing facility is decided in part by application 
of an analytical model to determine high risk sites. In late 2004, the FDA issued 
a report entitled  Risk - Based Method for Prioritizing cGMP Inspections of Pharmaceutical 
Manufacturing Sites  A Pilot Risk Ranking Model,  which allows the 
agency to rank manufacturing plants  risk of noncompliance by using an analytical 
process to (1) pose a risk question, (2) identify potential hazards and risks, (3) 
characterize factors that can be used as variables for quantifying risk, and (4) mathematically 
combine the variables to yield an overall risk score. Since the publication 
of the report, the FDA has added adverse events reports data to the model. Surveillance 
inspections are supposed to involve audit coverage of two or more systems, 8 
with mandatory coverage of the quality system. 9 
Compliance inspections are for the purpose of evaluating or verifying compliance 
corrective actions after a problem has been identifi ed and regulatory action has 
been taken. Compliance inspections cover the areas found defi cient and subjected 
to corrective actions. One type of compliance inspection is a  for - cause  inspection, 
which is conducted to investigate a specifi c problem that has come to the attention 
of the FDA. The sources that trigger a compliance inspection include fi eld alert 
reports, industry complaints, and recalls. 
In fi scal year 2005, the FDA fi eld offi ce conducted 1437 cGMP inspections, resulting 
in 15 warning letters, six injunctions, and one seizure. These enforcement actions 
are discussed later in this chapter. Data for the years 2000  2005 are set forth in 
Figures 1 and 2 . 
1.2.3.2 After the Inspection: Form 483 
If the inspector determines that there are deviations from cGMP, he will complete 
a form FDA - 483 (Inspectional Observations) detailing the violations. The fi ndings 
are presented to the manufacturer, which is given an opportunity to respond. The 
FDA - 483 advises: 
7 The other cGMP basic enforcement strategy is collection and analysis of drug samples during factory 
inspections as well as collecting and analyzing drug products in distribution. 
8 The FDA has separated the cGMP regulation into six systems: quality, facilities and equipment, production, 
materials, packaging and labeling, and laboratory controls. 
9 Compliance Program Guidance Manual , 7356.002, February 1, 2002. 

50 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
This document lists observations made by the FDA representative(s) during the inspection 
of your facility. They are inspectional observations, and do not represent a fi nal 
Agency determination regarding your compliance. If you have an objection regarding 
an observation, or have implemented, or plan to implement, corrective action in 
response to an observation, you may discuss the objection or action with the FDA 
representative(s) during the inspection or submit this information to FDA at the 
address above. If you have any questions, please contact FDA at the phone number 
and address above. 
Most manufacturers provide a written response to the FDA - 483, either disputing 
the fi ndings or addressing how they will correct the issues and how problems are to 
be corrected. Negotiations typically proceed for months or years until the inspectional 
problems and issues are resolved or the FDA elects to pursue elevated 
enforcement. The agency retains discretion to pursue elevated enforcement if it 
concludes that there is a signifi cant risk of harm to patients, with such action being 
more likely where patient harm is more likely or more serious. 
In addition to providing a form FDA - 483, FDA investigators prepare an establishment 
inspection report (EIR), which is sent to FDA headquarters, which then 
evaluates the report and determines the corrective action, if any. The FDA then 
classifi es the inspection as  no action indicated,   voluntary action indicated,  or 
 offi cial action indicated.  The EIR contains much greater detail than contained in 
the 483 and is not provided to the manufacturer until after the inspection is deemed 
closed. 
FIGURE 1 CDER fi ve - year Inspection data. ( Source : FDA .) 
2610 
2529 
2585 
2627 
2682 
2450 
2500 
2550 
2600 
2650 
2700 
2001 2002 2003 2004 2005 
Inspections (Foreign & Domestic) 
FIGURE 2 Surveillance activity. ( Source : FDA .) 
2529 2585 2627 2600 2682 
1982 
1712 
2087 
1434 
1548 
174 
362 
180 260 
1183 
0 
500 
1000 
1500 
2000 
2500 
3000 
2001 2002 2003 2004 2005 
Inspections 
Domestic Samples 
Import Samples

FDA ENFORCEMENT TECHNIQUES 51 
When the FDA conducted an analysis of past FDA - 483 reports, 10 the two most 
reported violations were: 
1. Violations of 21 CFR 211.100(b) (failure to follow and/or document production 
and process control procedures), occurring in over half of all of the 
483  s 
2. Violations of 21 CFR 122d (failure to create adequate, written responsibilities 
and procedures for the quality control unit or failure to follow them), occurring 
in 42% of the 483  s 
The next eight violations, in order of prevalence, were as follows: 
 Failure to have written procedures for production and process controls. 
 Failure to have testing and release of drug product for distribution for determination 
of satisfactory conformance to the fi nal specifi cations/identity and 
strength of each active ingredient prior to release. 
 Batch production and control records were not prepared or are incomplete. 
 Control procedures are not established to monitor the output/validate the 
performance of manufacturing processes that may be responsible for causing 
variability in the characteristics of the drug product. 
 Employees were not given appropriate training. 
 Laboratory controls do not include the establishment of scientifi cally sound 
and appropriate specifi cations/standards/sampling plans/test procedures. 
 Drug product production and control records are not certifi ed by the quality 
control unit to assure compliance with all established, approved written procedures 
before a batch is released or distributed. 
 Procedures describing the handling of all written and oral complaints regarding 
a drug product either not established or not followed. 
1.2.3.3 Recalls 
Chapter 7 of the Regulatory Procedures Manual (March 2007, available at www.fda. 
gov ) provides detailed instructions to FDA personnel regarding recalls. The FDCA 
does not authorize the FDA to  order  a manufacturer to recall a drug product. 11 
In practice, however, the manufacturers or distributors of the drug products are 
encouraged to implement and carry out recalls voluntarily to fulfi ll their responsibility 
to protect the public. It is not uncommon for a company to discover that one of 
its products is defective and recall it entirely on its own; or the FDA informs a 
company of its fi ndings that one of its products is defective and suggests or requests 
10 The data for the analysis were compiled by the FDA and derived from 614 Turbo EIR reports completed 
from 2001 to 2003. (FDA investigators enter their inspections observations on the FDA  s Turbo 
EIR system. The Turbo  s electronic format prompts investigators to select the specifi c cGMP violation 
in question and then to explain their fi ndings uncovered during the inspection.) 
11 The FDCA gives authority to the FDA to order a recall in some cases involving infant formulas, 
biological products, and devices that present a  serious hazard to health,  but not involving 
pharmaceuticals. 

52 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
a recall. 12 Once a voluntary recall is initiated, the FDA generally follows the following 
protocol (Figures 3  5 ): 
1. Classify the Recall The FDA reviews relevant information and then assigns 
a recall classifi cation according to the level of health risk involved: 
Class I recalls involve drug products in which the reason for recall predictably 
could cause serious health problems or death. 
Class II recalls involve drug products which defect might cause a temporary 
health problem or pose only a slight threat of a serious nature. 
Class III recalls involve products that are unlikely to cause any adverse 
health reaction but that violate FDA labeling or manufacturing 
regulations. 
2. Monitor and Audit the Recall The FDA oversees a recall depending upon the 
health risk involved. For a class I recall, the FDA checks to make sure that the 
defective product has been recalled in full. In contrast, for a class III recall, 
FDA oversight may be to simply spot - check. 
FIGURE 3 2005 recall by class. [ Source : Centre for Drug Evaluation and Research (CDER) 
2005 Report to the Nation. ] 
Class I: 18 
Class II: 314 
Class III 170 
TOTAL: 502 
FIGURE 4 Drug recalls. One fi rm had over 100 recalls in 2005, which caused a spike in the 
2005 recall fi gures. ( Source : CDER 2005 Report to the Nation .) 
191 
226 
248 
176 
352 
316 
248 
354 
254 
215 
401 
60 53 
34 
88 
72 
156 
72 
83 88 
71 
101 
0 
50 
100 
150 
200 
250 
300 
350 
400 
450 
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 
Number of Recalls 
Rx 
OTC 
12 If the company does not comply, then FDA can seek judicial enforcement under the FDCA. 

FDA ENFORCEMENT TECHNIQUES 53 
3. Notifi cation and Public Warning Class I recalls almost always warrant a 
press release to the media. Classes II and III are not necessarily announced 
in the media, but all of them are included in the FDA  s weekly enforcement 
report, posted at www.fda.gov/opacom/Enforce.html on the FDA  s 
website. 
4. Termination The FDA provides written notice to the recalling manufacturer 
on when the recall should be terminated. 
5. Noncompliance If applicable, the FDA will take appropriate legal action if 
a manufacturer fails or refuses to timely complete a recall. 
1.2.3.4 Warning Letter 
A warning letter is intended to notify manufacturers about violations that the FDA 
has documented during its inspections or investigations. A warning letter will notify 
a responsible individual and/or fi rm that the FDA considers one or more products, 
practices, processes, or other activities to be in violation of the cGMPs. Warning 
letters should only be issued for violations of regulatory signifi cance, that is, those 
that may actually lead to an enforcement action if the documented violations are 
not promptly and adequately corrected. A warning letter is one of the FDA  s principal 
means of achieving prompt voluntary compliance. 
Examples of situations in which the FDA may be expected to issue a warning 
letter include: 
 An active pharmaceutical ingredient (API) batch fails to conform to established 
specifi cations and yet the manufacturer distributed it anyway. 
 Deliberately blending API batches to dilute or hide noxious contaminant or 
fi lth or failing to determine actual yield and percentages of expected yields. 
 Contamination of drugs with toxic chemicals, drug residues, airborne contaminants, 
or fi lth. 
 Failing to comply with commitments in drug applications. 
 Combining a batch that does not conform with critical attributes with a batch 
that does. 
 Failing to demonstrate water used in the manufacturing process is suitable. 
 Failing to validate water systems. 
FIGURE 5 Top 10 reasons for drug recalls in fi scal year 2005. ( Source : FDA .) 
 Miscellaneous cGMP deviations (other than below) 
 Failed USP dissolution test requirements 
 Microbial contamination of non-sterile products 
 Lack of efficacy 
 Impurities/degradation products 
 Lack of assurance of sterility 
 Lack of product stability 
 Labeling: Label error on declared strength 
 Misbranded: Promotional literature with unapproved therapeutic 
claims 
 Labeling: Correctly labeled product in incorrect carton or package

54 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
 Lacking a formal written program to validate an API validation process. 
 Failing to demonstrate homogeneity of fi nal blending operations. 
 Failing to keep adequate batch records. 
 Failing to have a formal process change control system in place. 
 Using inadequate or unvalidated laboratory test methods. 
 Packaging and labeling processes that could introduce a signifi cant risk of 
mislabeling. 
 Failing to test for residues of organic or inorganic solvents that may carry over 
to the API. 
 Using incomplete stability studies to establish API stability for the intended 
period of use. 
Warning letters detailing cGMP violations typically conclude with the following: 
 The article(s), (DRUG NAME), is (are) adulterated within the meaning of Section 
501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the 
facilities or controls used for, its manufacture, processing, packing, or holding fails 
to conform to, or is not operated or administered in conformity with, cGMP regulations 
[21 CFR 210, 211].  The number of warning letters issued by the FDA concerning 
prescription and over - the - counter drugs has ranged from 130 letters in 2000 to 
79 letters in 2005. 
A warning letter is distinguishable from a notice of violation, also called an 
untitled letter. An untitled letter cites violations that do not meet the threshold of 
regulatory signifi cance for a warning letter, but the FDA has a need nevertheless to 
communicate. Unlike a warning letter, an untitled letter does not include a warning 
statement that failure to take prompt correction may result in enforcement action 
and does not evoke a mandated FDA follow - up. Further, the untitled letter requests 
(rather than requires) a written response (from the manufacturer) within a reasonable 
amount of time (e.g.,  Please respond within 45 days  ). 
1.2.4 JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 
1.2.4.1 Introduction 
The FDA is likely to bypass sending a Warning Letter in certain circumstances. 
According to Chapter 4 of the FDA Regulatory Procedures Manual , the following 
violations are likely to result in an enforcement action without necessarily issuing 
a warning letter: 
1. The violation refl ects a history of repeated or continual conduct of a similar 
or substantially similar nature during which time the individual and/or fi rm 
has been notifi ed of a similar or substantially similar violation. 
2. The violation is intentional or fl agrant. 
3. The violation presents a reasonable possibility of injury or death. 
4. Adequate notice has been given by other means and the violations have not 
been corrected or are continuing. 

5. The violations, under Title 18 U.S.C. 1001, are intentional and willful acts that 
once having occurred cannot be retracted. Also, such a felony violation does 
not require prior notice. Therefore, Title 18 U.S.C. 1001 violations are not suitable 
for inclusion in warning letters. 
In addition, actively deceiving the FDA is almost guaranteed to bring judicial 
enforcement actions. This includes false representations in the written record - 
keeping requirements or in written communication with the FDA. Manufacturing 
record - keeping requirements which give exposure to fraud liability are summarized 
in Figure 6 . Potential violations include the following: 
FIGURE 6 Written record highlights. 
Written records are required to be kept as set forth in 211.180 to 211.208. Highlights are as follows: 
 211.182 Equipment cleaning and use log. 
A written record of major equipment cleaning, maintenance (except routine 
maintenance such as lubrication and adjustments), and use shall be included in 
individual equipment logs that show the date, time, product, and lot number of each 
batch processed. 
 211.184 Component, drug product container, closure, and labeling records. 
These records shall include the following: 
(a) The identity and quantity of each shipment of each lot of components, drug 
product containers, closures, and labeling; the name of the supplier; the supplier's 
lot number(s) if known; the receiving code as specified in  211.80; and the date 
of receipt. The name and location of the prime manufacturer, if different from the 
supplier, shall be listed if known. 
(b) The results of any test or examination performed (including those performed 
as required by  211.82(a),  211.84(d), or 211.122(a)) and the conclusions 
derived therefrom. 
 211.186 Master production and control records. 
To assure uniformity from batch to batch, master production and control records 
for each drug product, including each batch size thereof, shall be prepared, dated, 
and signed (full signature, handwritten) by one person and independently checked, 
dated, and signed by a second person. The preparation of master production and 
control records shall be described in a written procedure and such written 
procedure shall be followed. 
 211.188 Batch production and control records. 
Batch production and control records shall be prepared for each batch of drug 
product produced and shall include complete information relating to the production 
and control of each batch. 
 211.194 Laboratory records. 
Laboratory records shall include complete data derived from all tests necessary to 
assure compliance with established specifications and standards, including 
examinations and assays ... 
 211.198 Complaint files. 
A written record of each complaint shall be maintained in a file designated for drug 
product complaints 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 55

56 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
(a) Accepting and validating drug products that failed to meet established standards 
or specifi cations and any other relevant quality control criteria (i.e., 
dissolution rates, content uniformity, purity, potency) and then falsely recording 
the untruthful data as if the drug products did not fail 
(b) Accepting and validating the stability characteristics of drug products and 
then falsely recording the untruthful data as if the drug products did not 
fail 
(c) Documenting the examination and review of labels, when in truth and fact 
no review occurred (which results in inaccurate labels distributed with 
drugs) 
(d) Falsely documenting any components of master production and central 
records 
(e) Falsely documenting any component of the batch production and control 
records 
(f) Falsely describing testing methods when no (or inadequate) testing methods 
were performed 
(g) Failing to accurately make a written record of all written and oral complaints 
regarding a drug product and/or certifying that investigations were performed 
when they were not, falsely certifying that the fi ndings were negative 
when they were not, and so on 
(h) Falsifying records which would indicate manufacturing changes which require 
approval by the FDA 
(i) False representations that contain statements of fact in correspondence sent 
to the FDA addressing violations in an inspector  s form 483 
The FDA typically initiates progressive enforcement, as described in Figure 7 . 
Once the FDA and DOJ decide to bring enforcement action, the U.S. courts have 
held that the FDA  s interpretation of its cGMPs is entitled to substantial deference. 
As long as the FDA  s interpretation of its regulations are  reasonable  and  sensibly 
conforms to the purpose and wording of the regulations,  courts are required to 
follow the FDA  s interpretations. 
1.2.4.2 Civil Proceedings 
Seizures If during an inspection of a facility the FDA inspector or employee 
making the inspection has reason to believe that a drug found in such facility is 
adulterated, such inspector or employee may order the drug detained for a reasonable 
period which may not exceed 20 days (unless the FDA institutes an action 
under Subsection 334(a) or an injunction, in which case a longer detention period 
may be authorized). 
The FDCA expressly permits administrative seizure on the basis of an ex parte 
showing of reasonable belief [21 U.S.C. 334 (g)]. Seizure of a company  s inventory 
deprives the company of both capital investment and potential profi t. 
If the FDA pursues relief beyond detainment, the United States can fi le a complaint 
for forfeiture directing the U.S. marshall to  seize  the pharmaceuticals (or 
take possession or place in constructive custody of the court). The theory in a complaint 
for forfeiture is that there is a violation of the law by the pharmaceutical 

product itself. Accordingly, the government asks the court to condemn the article 
and declare forfeiture. Upon fi ling of the complaint, the clerk automatically issues 
a warrant. Thus, the FDA is able to obtain a warrant without review by a judicial 
offi cer or even a fi nding of probable cause. 
There are three types of seizures: mass, open ended, and lot specifi c. A mass 
seizure is the seizure of all FDA - regulated products at an establishment/facility. 
Mass seizures might be conducted when all of the products are produced under the 
same conditions (e.g., nonconformance with cGMPs). An open - ended seizure is the 
seizure of all units of a specifi c product or products, regardless of lot or batch 
number, when the violation is expected to be continuous. An open - ended seizure 
may be conducted when a specifi c product extends to all lots or batches of a product 
but not to all of the products in the facility. 
Following seizure of its drugs a manufacturer has three courses of action. First, 
it may do nothing, in which case the drug will be disposed of. Second, it can enter 
into a consent decree, admitting the violation, agreeing to pay costs, and seeking to 
destroy or rehabilitate the article. The consent decree will typically provide for 
(1) condemnation of the article as being in violation of the law; (2) a penal bond in 
approximately twice the retail value of the article under seizure; (3) provisions for 
payment of costs for storage and handling by the U.S. marshall and for supervision 
by the FDA before release of the product; and (4) a provision that the manufacturer 
will attempt to bring the article into compliance under the supervision of and to the 
satisfaction of the FDA. 13 
Third, it can contest the action. If the manufacturer contests the action, the case 
is then treated like any other civil case under the federal rules of civil procedure, 
and the government must prove its case by a preponderance of the evidence. The 
government must produce evidence, in support of its allegations, including proof of 
interstate shipment of the drug or its components. FDA employees may testify, but 
FIGURE 7 Progressive enforcement. 
FDA enforcement mechanisms are often utilized progressively. A good example is the 
enforcement action against Glaxo SmithKline (GSK), which began in July 2002, identifying 
numerous significant cGMP violations found during a February/April 2002 inspection. A Warning 
Letter requested that the violations be corrected and stated that failure to correct the violations may 
result in regulatory action, including seizure and/or injunction. Although a limited follow-up FDA 
inspection in October 2002, found that some specific corrections were acceptable, the subsequent 
FDA inspections in November/December 2003 and September/November 2004, revealed continuing 
significant cGMP violations. FDA concluded that the firms data and corrective plans were not 
adequate to correct the cGMP violations. GSK also initiated recall of some, but not all, lots of the 
two products. On March 4, 2005, in response to ongoing concerns about manufacturing quality, 
FDA and the DOJ initiated seizures of two GSK pharmaceuticals. The Agency initiated these 
seizures actions based on concerns that GSKs violation of manufacturing standards may have 
resulted in the production of poor quality drug products that could potentially pose risks to 
consumers. On April 28, 2005, FDA announced that GSK had signed a Consent Decree with FDA 
to correct manufacturing deficiencies at its Cidra, Puerto Rico, facility. The Consent Decree was 
initiated based on FDAs continued concerns that GSKs violation of manufacturing standards may 
have resulted in the production of drug products that could potentially pose risks to consumers. 
13 Regulatory Procedures Manual , Chapter 6 - 1 - 11, March 2007. This contemplates that seizure of a specifi c 
product(s) is the sole issue. More complex consent decrees are described hereinafter. 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 57

58 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
also outside experts testify such as to the signifi cance of failure to comply with 
cGMP requirements. If a decree of condemnation is entered (either after trial or by 
consent), the court may direct disposition of the article by destruction. 
Injunctions The FDCA expressly authorizes the courts to restrain and enjoin acts 
that are in violation of 21 U.S.C. 331, which includes prohibition of adulterated 
products. FDA policy provides that an injunction action is appropriate where: 
(a) there is a current and defi nite health hazard or a gross consumer deception 
requiring immediate action to stop the violative practice; 
(b) there are signifi cant amounts of violative products owned by the same person 
in many locations, voluntary recall by the fi rm was refused or is signifi cantly 
inadequate to protect the public, and seizures are impractical or uneconomical; 
or 
(c) there are long - standing (chronic) violative practices that have not produced 
a health hazard or gross consumer fraud, but which have not been corrected 
through use of voluntary or other regulatory approaches. 14 
A complaint for injunction is typically accompanied by a motion for preliminary 
injunction. 15 The court schedules a court hearing to determine whether to grant a 
preliminary injunction, often very quickly and on short notice. The government  s 
main focus at this preliminary stage will be to prove that there is a  substantial 
likelihood  that the defendant has been producing adulterated drugs in violation 
of 21 U.S.C. 331, by substantial noncompliance with the cGMPs. The government 
will also typically present evidence, if applicable, that the defendant has had 
a history of prior noncompliance with the FDCA and implementing regulations. 
No specifi c fi nding of irreparable harm is necessary as is required in the typical 
injunction, because the passage of the statute proscribing adulterated products has 
15 The government may also apply for a temporary restraining order (TRO) seeking immediate, temporary 
relief (for a period of 10 days, which may be extended for 10 additional days) prior to the hearing 
for preliminary injunction. The FDA will typically recommend a TRO when it believes that the violation 
is so serious that it must be controlled immediately . 
14 Regulatory Procedures Manual , March 2007. 
FIGURE 8 Disgorgement. 
Major recent consent decrees are United States v. Abbott Labs., Consent Decree of 
Permanent Injunction filed Nov. 2, 1999; United States v. Various Articles of Drug Identified in 
Attachment A & Wyeth-Ayerst Labs., Consent Decree of Condemnation and Permanent Injunction 
filed Oct. 4, 2000; and United States v. Schering-Plough Corp., Consent Decree of Permanent 
Injunction filed May 20, 2002. To avoid giving manufacturers the wrong message by allowing them 
to keep on the market what FDA had determined to be produced in violation of the cGMPs, the FDA 
included three separate types of disgorgement payments in the Abbott, Wyeth and Schering 
consent decrees: (1) a lump sum payment (Abbott, $100 million; Wyeth, $30 million; and Schering, 
$500 million) (2) if the remedial work was not achieved by the deadline established in the decree, 
(i) a percentage of sales (Abbott, 16%; Wyeth, 18.5%; and Schering, 24.6%) and (ii) daily payments 
of a certain flat amount. Both were to be paid until compliance was achieved.

been held itself to be an implied fi nding by Congress that violations will harm the 
public. 
United States courts are imbued with authority to enjoin present and future 
violations of Section 331 based upon proof by the FDA that such violations have 
occurred and could recur. Factors that courts consider when determining whether 
there is a reasonable chance of future infractions include (1) the degree of scienter 
involved on the part of the defendant; (2) the isolated or recurrent nature of the 
infraction; (3) the defendant  s recognition of the wrongful nature of his or her 
conduct; (4) the sincerity of the defendant  s assurances against future violations; 
and (5) the nature of the defendant  s violation. The court also considers whether 
the defendant voluntary ceased the challenged conduct, the genuineness of the 
defendant  s efforts to conform to the law, the defendant  s progress toward improvement, 
and the defendant  s compliance with any recommendations made by the 
government. 
Good faith is not a defense to the issuance of an injunction. Nor may a defendant 
successfully defend against the issuance of an injunction by asserting that the injunction 
would drive it out of business. 
Consent Decrees and Disgorgement A consent decree is a judgment (legal order) 
issued by the court that has been agreed to by the parties whereby the defendant 
agrees to stop illegal or improper activity as alleged by the government. Once court 
approval is obtained, the seizure or injunctive lawsuit, for instance, is dropped, and 
the government  s remedy is then based upon any breach of the consent decree, itself 
which is enforceable by the court. 
Consent decrees typically involve a defendant agreeing to address the areas of 
noncompliance in a manner satisfactory to the FDA within a certain amount of time. 
It can also provide for the hiring of an expert consultant to certify in detailed reports 
that the manufacturing facility, at periodic dates, is in full compliance with the 
cGMPs, and has adequate adverse - event controls, adequate training, and adequate 
recall procedures. It may also require the payment of money to the U.S. Treasury 
such as under the equitable remedy of  disgorgement,  as described in Figure 8 . 
As part of a court action, the FDA will sometimes pursue  disgorgement.  The 
purpose of disgorgement is to deprive the wrongdoer of ill - gotten gains as well as 
provide deterrence. The amount of disgorgement is not necessarily directly tied to 
restitution. In practice, the amount the FDA exacts is supposed to be enough to 
send a message but certainly does not provide for full disgorgement of profi ts of 
the drug product(s) at issue. 
False Claims Act The U.S. Civil False Claims Act, 31 U.S.C. 3729 et seq., is the 
government  s principal means of redressing fraud by government contractors. The 
act has implications for cGMP violations because the United States (funding as it 
does the Medicare program, the state Medicaid programs, the Veterans Administration, 
the TRICARE program, and others) is the world  s largest purchaser of prescription 
medications. 
Nonetheless, the government has yet to bring a False Claims Act case which seeks 
damages for cGMP. One reason may be that the government has multiple other 
remedies within which to recover damages from noncompliant manufacturers, such 
as criminal fi nes and penalties and disgorgement. 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 59

60 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
Qui tam whistleblowers, 16 however, have already begun bringing such cases. 
Because the False Claims Act imposes liability on any government contractor which 
knowingly submits false claims to the United States or which uses false documents 
to get a false claim paid, a pharmaceutical manufacturer which knew or was recklessly 
indifferent to the fact that the manufacturing process was compromised by 
cGMP violations is in the same position as any other contractor which is required 
to conform to contractual or regulatory standards. The basis of liability under the 
False Claims Act is that false records have been generated which caused (false) 
claims for drugs to be paid by the United States. 17 The monetary damages result 
because the payor (in this case, the United States) is potentially paying for substandard 
drugs due to the cGMP violations  later covered up by false statements in 
documents required to be completed under the cGMP. 
It makes sense, too: The cGMPs are a set of regulations which, by their very 
nature, are designed to ensure that drugs are manufactured in such a way that they 
meet the requirements of the federal Food, Drug and Cosmetic Act as to safety and 
have the identity and strength and meet the purity characteristics that they purport 
or are represented to possess. The major federally funded government health care 
programs, Medicare and Medicaid, operate under the express provisions that they 
will only pay for medical services and products that are  reasonable and necessary.  
Unsafe or ineffective drug products are neither reasonable nor necessary. Accordingly, 
as the theory goes, the United States suffers monetary damages if Medicare 
and Medicaid programs pay for unsafe or less effective products. These and other 
federally funded health care programs spend billions of dollars every year on 
pharmaceuticals. 
False representations concerning minor or technical violations will not be the 
basis for FCA liability. Distribution of products that are not totally cGMP compliant 
(but have been falsely documented to be) does not necessarily result in unsafe (or 
subpotent) products. Substantial violations of the cGMP, later covered up in writing, 
however, could very well be the basis for FCA liability. The common thread through 
each violation is that the violation is severe enough so that the drug product that 
16 Qui tam is shorthand for the Latin phrase, qui tam pro domino rege quam pro seipso , meaning  He 
who is as much for the king as for himself.  Qui tam statutes date back to thirteenth - century England. 
The actions were a means of enabling private parties to allege the king  s interest and therefore gain 
access to the royal courts. 
The qui tam provisions of the federal False Claims Act allow any citizen who has knowledge of fraud 
that has taken place against the government to bring a civil action in federal court in the name of the 
United States. In return for his or her efforts, the citizen is entitled to share in the proceeds of the recovery. 
The qui tam provisions raise the incentive for insiders to put the spotlight on the criminals, thereby 
providing the government with tangible and detailed evidence upon which to base an investigation and 
prosecution. 
In 1986, Congress enacted amendments to the False Claims Act which strengthened the law and 
increased monetary awards. When hearings were held in 1985 and 1986, the climate was favorable for 
strengthened antifraud legislation, and Congress expected that most qui tam cases would involve defense 
contractor fraud. In the last decade, the majority of cases have instead been against the health care 
industry. 
17 Even so, factual questions will be raised, including: (1) Even with the false representations, was a false 
claim  caused  to be submitted? (2) Had the FDA known about the falsities, would it have enjoined the 
manufacturer from any further production, etc? (3) What about the false record or statement made the 
claims for such drugs false? 

fi nally reaches the public is foreseeably and substantially less safe or less effective 
than if the cGMPs were not violated. 
1.2.4.3 Criminal Proceedings 
Introduction Criminal prosecutions of violations of the FDCA are intended to 
further the goal of protecting the health and safety of the public. The FDA historically 
has not pursued criminal charges unless the defendant shows a continuous or 
repetitive course of violative conduct, with the exception of intentional violations, 
fraud, or danger to health. 18 
While the FDCA contains various prohibitions and restrictions which a drug 
company could violate, the most common FDCA violation arising out of cGMPs 
is charged by using 21 U.S.C. 331(a), which specifi cally prohibits introducing an 
adulterated 19 drug into interstate commerce. In addition to introducing an adulterated 
drug into interstate commerce, some other acts prohibited by Section 331(a) 
which could be involved in manufacturing violations include 331(e), which prohibits 
the refusal to allow access to records mandated elsewhere in the act and 331(f), 
which prohibits the refusal to allow inspection of production facilities (21 U.S.C. 
374). 
Commission of any act prohibited by Section 331 is a federal misdemeanor (21 
U.S.C. 333). However, violations of Section 331(a) may be charged as felonies where 
there is intent to defraud or mislead or where the defendant previously has been 
convicted of a misdemeanor under the FDCA [21 U.S.C. 333(b)]. Federal misdemeanor 
charges are typically resolved in proceedings before U.S. magistrate judges, 
and federal felonies are resolved by U.S. district judges. 
Individual versus Corporate Liability Introducing an adulterated product into 
interstate commerce is a strict liability crime that can be enforced against individuals 
in positions of suffi cient authority and responsibility as well as their company. 
Persons at risk are those who, at minimum, 20 fail to take adequate measures to 
prevent the cGMP violations. As such, warning letters and other communications 
are often directed at presidents and CEOs as well as their companies. As stated by 
the U.S. Supreme Court 21 in 1964, just two years after the FDCA as we know it was 
passed: 
Food and drug legislation, concerned as it is with protecting the lives and health of 
human beings, under circumstances in which they might be unable to protect themselves, 
often  dispenses with the conventional requirement for criminal conduct  
awareness of some wrongdoing. In the interest of the larger good it puts the burden of 
acting at hazard upon a person otherwise innocent but standing in responsible relation 
to a public danger. . . .  
18 A government review of recent FDA enforcement has suggested that adequate FDA enforcement 
activity is lacking. See  Prescription for Harm: The Decline in FDA Enforcement Activity,  House Committee 
on Government Reform, June 2006. 
19 Failure to follow cGMP is the most common form of violating the prohibition against introducing an 
adulterated drug into interstate commerce. 
20 They may also be directly implicated in fraud and cover - ups. 
21 United States v. Wiesenfeld Warehouse Co. , 376 U.S. 86, 91 (1964). 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 61

62 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
In 1975, the Supreme Court made clear that individual responsibility is very 
important 22 : 
The [FDCA] imposes not only a positive duty to seek out and remedy violations when 
they occur but also, and primarily, a duty to implement measures that will insure that 
violations will not occur. The requirements of foresight and vigilance imposed on 
responsible corporate agents are beyond question demanding, and perhaps onerous, 
but they are no more stringent than the public has a right to expect of those who voluntarily 
assume positions of authority in business enterprises whose services and products 
affect the health and well - being of the public that supports them. 
Manufacturing executives therefore carry a great liability burden. The government 
only need establish that the individual defendant failed to act on his or 
her own authority and that such an action could have prevented or corrected 
the violation. The individual need not have formed any intent to break any laws in 
order to be found guilty. What is relevant is, did the executive have the power to 
prevent the acts or omissions complained of? This includes a consideration of 
whether the executive could have prevented the acts or omission by the systems 
and processes alone. The job is not made easier to the extent that the cGMP regulations 
are open to varying interpretations or that the technology is constantly 
changing. 
Section 305 Proceedings Due to the nature of the inspection process, a company 
that the FDA deems is in violation of the cGMPs should not be surprised when a 
warning letter or more elevated enforcement techniques are implemented. Even so, 
the FDA sometimes issues a formal form of notice that criminal charges will be 
brought by what is called a Section 305 notice. 
Section 305 of 21 U.S.C., the statutory basis for a 305 notice, seemingly requires 
that before any violation of the FDCA is reported to the DOJ for institution of a 
criminal proceeding, the target defendant must  be given appropriate notice and an 
opportunity to present his views, either orally or in writing, with regard to such 
contemplated proceeding.  The U.S. Supreme Court has watered down this provision, 
holding that a notice under Section 305 is not a legal prerequisite to government 
prosecution. 
In practice, then, the FDA only sometimes issues a 305 notice and conducts a 305 
hearing when it is considering a misdemeanor prosecution. A very informal process, 
the manufacturer can approach it with as much or as little of a defense as counsel 
deems appropriate, as there are pros and cons to providing the government with 
the company  s full defense at that juncture. 
A prototype Section 305 notice appears in Figure 9 . 
Grand Jury Proceedings If the government will be pursuing felony criminal 
charges against a manufacturing facility or persons associated with such facility, it 
will proceed by grand jury. The Fifth Amendment to the U.S. constitution requires 
that charges for all capital or  infamous  crimes be brought by an indictment 
22 United States v. Park , 421 U.S. 658 (1975). 

returned by a grand jury. This has been interpreted by the U.S. courts to require that 
an indictment be used to charge federal felonies. 
The activities, deliberations, or matters occurring before a grand jury are secret. 23 
Strict adherence to grand jury secrecy is important to the integrity of the investigative 
process and ensures that the grand jury will be able to deliberate without 
outside pressure, to encourage people with information about a crime to come 
forward without fear of disclosure, and to protect the rights of the accused, specifi - 
cally the innocent accused, from disclosure of the fact that he or she or it was 
investigated. Other than attorneys for the government, only the witness, interpreters 
when needed, and a court reporter are authorized persons permitted to be present 
while a grand jury is in session. 
A grand jury  s function is to determine whether there is probable cause to believe 
that a certain person(s) or company(ies) have committed a federal offense. 24 Prosecutors 
are permitted to appear before the grand jury and, in practice, conduct the 
grand jury proceedings. In general, the prosecutor is the one who makes the decision 
FIGURE 9 Section 305 notice. 
In reply refer to: 
Sample No. 
Product 
Firm Name and Individual Date 
Street Address 
City, State, Zip 
Investigation by this Administration indicates your responsibility for violations of the 
Federal Food, Drug, and Cosmetic Act, and other Federal Laws, as described in the 
attached Charge Sheet, with respect to the following: 
[describes specifics of cGMP violations] 
A meeting has been scheduled for (day, date, time) at (location), to give you an 
opportunity to present your views on this matter. The enclosed INFORMATION SHEET 
explains the purpose and nature of the meeting, and how you may reply. If no response 
is received on or before the date set, our decision on whether to refer the matter to the 
Department of Justice for prosecution will be based on the evidence in hand. 
By direction of the Secretary of the Department of Health and Human Services: 
Compliance Officer 
Enclosures: 
Legal Status Sheet (3) 
Charge Sheet 
Information Sheet 
Regulations 
23 See Rule 6(e) Fed. R. Crim. Pro. 
24 The grand jury system is not presently used by countries outside the United States. The United 
Kingdom, New Zealand, Canada, and Australia, for instance, all have abolished the use of grand juries. 
See http://enwikipedia.org/wiki/Grand_jury . 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 63

64 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
as to which witnesses to call and what evidence should come before the grand jury. 
The prosecutor asks the witness questions and subsequently members of the grand 
jury may also question witnesses directly or through the prosecutor. 
During the course of a grand jury investigation regarding cGMP violations/adulterated 
product allegations, for instance, the grand jury may hear testimony from 
not only federal investigators, federal agents, and federal inspectors but also former 
employees of the company (or current if a custodian of records) and/or experts in 
the pharmaceutical manufacturing fi eld. These persons are considered witnesses. 
Witnesses are typically subpoenaed and may not refuse to appear before the grand 
jury or be subject to contempt charges. 
In the federal grand jury system, a witness is not permitted to bring an attorney 
into the grand jury room. However, a witness is permitted to consult with his attorney 
outside the grand jury room even interrupting his own testimony. 25 It is typical 
for corporations such as pharmaceutical manufacturing companies to provide an 
attorney for any and all employees subpoenaed by a grand jury of which the manufacturer 
is a target. 
A target is the person who is the focus of the grand jury investigation and is likely 
to be indicted. This company or person may receive a  target letter  from the grand 
jury which offi cially advises them of their jeopardy and serves as a formal warning 
of their status. 
In practice, if a manufacturer is the target, the government will likely attempt 
to develop evidence by subpoena of persons and materials which will help 
prove culpability. It is likely the subpoenas will ask for correspondence, notes, 
and memos during a particular time period and involving a particular subject 
matter. 
The grand jury may also issue a subpoena to the manufacturer  s designated 
 custodian of records  for specifi c document production. The description of subpoenaed 
documents can include statements or charts of an organization, 
announcements, statements of policy and procedure, diaries, records of email, 
manufacturing logs, emails, travel vouchers, fi nancial records and statements, 
correspondence, notes of conversations, and any other documents that relate to the 
manufacturing of certain drugs. A document subpoena may also request every 
writing or record of whatever type and description in the possession, custody, or 
control of the company that relates to a particular element of the criminal violation 
the grand jury is investigating. The request typically includes all handwritten, typed, 
printed, recorded, or transcribed records, including computer records tapes or 
disks. 
The burden is on the government to prove that the crime was committed in the 
district in which the prosecution is brought. The grand jury should not consider a 
case unless venue lies in the district where the grand jury is sitting. 26 In the case of 
adulterated drugs, courts have generally held that it is proper to have venue in a 
district from which the defendant caused the unlawful introduction of goods into 
commerce, even though the physical shipment commenced from a different 
district. 
25 See Rule 6(d) Fed. R. Crim. Pro.; 28 U.S.C. secs. 515, 542, 547. 
26 See Rule 18 Fed. R. Crim. Pro. 

Form of Charges and Penalties A grand jury investigation may culminate in the 
return of an indictment. This means that the grand jury found probable cause to 
believe that a violation of law occurred. While the focus of the initial inquiry can 
surround adulterated drugs by virtue of failure to abide by the cGMPs, additional 
criminal violations may be charged, as, for instance, where there are actions to evade 
or mislead a grand jury. The end result could, for instance, include accusations of 
making false statements to the FDA and obstructing the FDA  s or DOJ  s investigation, 
in addition to the  adulterated  drug charges. 
An indictment consists of a statement describing the time, place, and manner 
through which the defendant violated the law. Each violation of the law is set out 
in a separate count. A defendant charged by an indictment is entitled to a trial by 
jury, although this right can be waived. A defendant has the right to a trial by 
jury for any criminal offense punishable by imprisonment for more than six 
months. 27 
If the matter only involves a misdemeanor violation, the prosecutor charges 
 by information.  The information is often referred to as a complaint. An information, 
like an indictment, is simply a pleading that accuses the defendant of committing 
crimes. The distinction between an information and an indictment is that a 
prosecutor can issue and fi le an information without the grand jury  s participation 
or fi nding of probable cause but a grand jury must approve and return an 
indictment. 28 
The penalty for a violation of 21 U.S.C. 331(b) by violating the cGMPs resulting 
in the adulteration of drug products in interstate commerce is set forth in 21 U.S.C. 
sec. 333(a). Each separate count for violating the cGMPs (where a misdemeanor is 
charged) carries with it a possible imprisonment of not more than one year or a fi ne 
not to exceed $ 1000 or both. If the government charges a felony for violation of the 
cGMPs, then the penalties are imprisonment of not more than three years or a fi ne 
not to exceed $ 10,000 or both. Of course, there may be other charges with greater 
or lesser penalties which are not related to the adulterated drug charges. 
The criminal fi ne amounts (but not the imprisonment durations), however, are 
superceded by the criminal fi ne amounts contained in a different federal statute 
enacted later. Section 3571 of 18 U.S.C. provides for much greater fi nes than those 
provided for within the FDCA itself. For a manufacturer convicted of a felony, the 
fi ne can be as much as $ 500,000; for a misdemeanor (not resulting in death), it could 
be $ 200,000. Fines for individuals include a maximum up to $ 150,000 for a felony 
and an amount up to $ 100,000 for a conviction of a misdemeanor not resulting in 
death. The statute also provides for a multiplier of 2 based upon a fi nding that the 
defendant derived a pecuniary gain from the offense. The FDA and DOJ are able 
to elevate the monetary recoveries against the manufacturers for violations of the 
cGMP under a civil disgorgement theory explained infra. Recoveries have been in 
the hundreds of millions in recent years, typically agreed to in a negotiated consent 
decree. 
27 See Sixth Amendment, U.S. Constitution. 
28 Sometimes, prosecutors are in communication with defendants and their counsel during the investigatory 
stage. If there are negotiations concerning a plea to a felony and they are successful, a defendant 
can waive his or her right to be indicted by a grand jury, and the prosecutor can charge them by 
information. 
JUDICIAL ENFORCEMENT: BEYOND THE WARNING LETTER 65

66 ENFORCEMENT OF CURRENT GOOD MANUFACTURING PRACTICES 
1.2.5 CONCLUSION 
The diligent enforcement of good manufacturing practices is a cornerstone of the 
safety net for drugs in the United States. Congress, the courts and, manufacturers, 
most importantly, expect a degree of consistency and responsibility in enforcement 
policy over a statute as powerful and central to public health and safety as the 
FDCA. To the extent there is consistency and effective and evenhanded enforcement, 
it not only protects the public, but it provides a level playing fi eld for those 
manufacturers who operate in accordance with the cGMPs. 

67 
1.3 
SCALE - UP AND POSTAPPROVAL 
CHANGES (SUPAC) REGULATIONS 
Puneet Sharma , Srinivas Ganta , and Sanjay Garg 
University of Auckland, Auckland, New Zealand 
Contents 
1.3.1 Introduction 
1.3.2 Scientifi c and Regulatory Rationale for SUPAC 
1.3.2.1 Supporting Documents and Extent of Change 
1.3.2.2 Supporting Documents for Change in Specifi cations 
1.3.2.3 Comparability Protocols 
1.3.2.4 In Vitro  In Vivo Requirements 
1.3.3 Regulatory Agencies and Guidelines 
1.3.3.1 FDA SUPAC Regulations 
1.3.3.2 Regulatory Guidance on SUPAC by Pharmaceutical Unit of EU 
1.3.3.3 Regulatory Guidance on SUPAC by Agencia Nacional de Vigilancia 
Sanitaria 
1.3.4 Harmonization 
1.3.5 GMP Issues: Change Control and Process Validation 
1.3.5.1 Change Control 
1.3.5.2 Process Validation 
1.3.6 Conclusion 
1.3.1 INTRODUCTION 
Product development aims at formulating active drug ingredient in a palatable form. 
Technology transfer of a pharmaceutical product from research to the production 
fl oor (referred to as  shop fl oor  ) with simultaneous increase in production outputs 
is commonly known as scale - up. In simple terms, the process of increasing batch size 
is termed as scale - up. Conversely, scale - down refers to decrease in batch size in 
response to reduced market requirements. 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

68 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
Often, changing of scale from the research lab to the shop fl oor is fraught with 
problems. The basic reason for such problems is the usage of different processing 
equipment in research and on the shop fl oor. Moreover, insuffi cient information 
about the equipment, various requirements of process control, complexity of a particular 
pharmaceutical process which may have a several different unit operations, 
limited information about the behavior of ingredients at different scales, and adoption 
of trial - and - error methodology also add signifi cantly to scale - up issues. Every 
product coming from research should be manufacturable and the process should be 
capable to demonstrate its ruggedness at the shop fl oor level. This statement points 
toward the criticality and signifi cance of scale - up and technology transfer in a pharmaceutical 
development process. After successful accomplishment of technology 
transfer and validation activity, a product usually has a smooth run on large - scale 
production machines. Changes are being made in the manufacturing process and 
chemistry of a drug product following approval and continue throughout its life. 
Depending upon foreseen (or unforeseen) requirements, there can be changes in 
the raw materials, process, equipment or manufacturing site, and batch size which 
ultimately affect quality attributes of a drug or fi nished product. Therefore, there is 
a need to anticipate and fully evaluate the impact of any kind of change on the 
quality of a drug or fi nished product. There can be several reasons for these changes, 
such as changed market requirement affecting batch size, new source of raw material, 
change in manufacturing process, upgrades of packaging material, or shifting 
to a new analytical methodology. 
The intensity of the adverse effect produced by a particular change depends on 
the type of dosage form. For example, a change in the inactive ingredient beyond a 
certain range will have more effect on a modifi ed - release (MR) dosage form than 
it would on an immediate - release (IR) dosage form, where bioavailability is not rate 
limiting. Likewise, a change in the primary packaging of liquid parenteral may have 
more pronounced effect on its effectiveness than it would have on a solid dosage 
form. Hence, depending upon the intensity of change or the adverse effect it may 
have on the critical parameters of a dosage form, reporting requirements to regulatory 
authorities also vary. 
A drug or drug product may experience many changes during its life cycle. These 
changes may have an adverse effect on the overall safety and effectiveness of the 
drug or drug product. After a number of changes over a long time period, the 
product coming to market may be completely different from the one that was 
approved. Hence, data submitted to regulatory authorities in support of a change 
must have a comparison record of the drug or drug product to the one that was 
approved initially. Documentation generated in support of any change to the 
approved drug or drug product is submitted to regulatory authority for review, and 
based on the benefi t - to - risk ratio, the drug or drug product is approved. Depending 
upon the intensity of change, supporting documents are provided to the regulatory 
agency. 
Regulatory authorities such as the U.S. Food and Drug Administration (FDA), 
the European Commission, the Agencia Nacional de Vigilancia Sanitaria (ANVISA) 
(in english the National Health Surveillance Agency  Brazil, and others require the 
pharmaceutical industries in respective countries to follow guidelines on scale - up 
and postapproval changes (SUPAC) to maintain the quality of the pharmaceutical 
produced. From time to time these guidelines are assessed so as to keep pace with 

SCIENTIFIC AND REGULATORY RATIONALE FOR SUPAC 69 
the technological advances and new guidelines are developed to reduce the burden 
on the pharmaceutical industry and regulatory authorities. Apart from these guidelines, 
there are other checkpoints within an industry to assure production of quality 
products, such as change control and validation exercises, which will be discussed in 
detail in this chapter. These operations are controlled through the principles of good 
manufacturing practices issued by regulatory authorities. 
This chapter describes the regulations imposed by different regulatory authorities 
and measures taken by a pharmaceutical industry to assure quality and performance 
of pharmaceuticals. The FDA guidelines, being most descriptive, have been 
discussed at length. Other guidelines have been described in general terms and the 
interested reader is referred to the references or the regulatory websites for more 
specifi c details. 
1.3.2 SCIENTIFIC AND REGULATORY RATIONALE FOR SUPAC 
Guidelines pertaining to postapproval changes classify these changes in various 
categories depending upon the effect a particular change may have on the quality 
and performance of a drug or drug product. Irrespective of the terminologies used 
by regulatory agencies, in general terms, changes can be described as mild, moderate , 
and major and the extent of supporting document varies with the nature of the 
change. For example, U.S. FDA guideline  Changes to an Approved NDA or ANDA  
describe these changes as mild changes that can be implemented immediately and 
fi led in the next periodic report, moderate changes that can be implemented immediately, 
moderate changes that require 30 days notice before implementation, and 
major changes that require FDA approval before implementation [1] . Similarly, any 
changes in an approved drug or drug product under European Union (EU) domain 
type I (type IA and type IB) and II variation are fi led prior to marketing products 
[2] . The therapeutics Good Administration  Australia (TGA) describes postapproval 
changes in three categories: nonassessable, self - assessable, and changes 
requiring prior approval [3] . 
1.3.2.1 Supporting Documents and Extent of Change 
As per FDA guidelines, changes in excipients (%w/w) of total formulation not 
greater than 5% are considered minor and all information is provided in the annual 
report. However, changes likely to have signifi cant effect on the quality and performance 
of a drug product calls for submission of a prior approval supplement on all 
information (in vitro dissolution and in vivo dissolution), including accelerated stability 
and long - term stability testing in the annual report [4] . Similarly, in EU guidelines, 
a change in the batch size of the fi nished product up to10 - fold compared to 
the original batch size approved at the grant of the marketing authorization (or 
downscaling to 10 - fold) has been defi ned as type IA and requires batch analysis 
data (in a comparative tabulated format) on a minimum of one production batch 
manufactured to both the currently approved and the proposed sizes. Batch data 
on the next two full production batches should be made available upon request and 
reported by the marketing authorization holder if outside specifi cations (with proposed 
action). However, for type IB (more than 10 - fold), in addition to the above 

70 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
data, a copy of an approved release and end - of - shelf - life specifi cations as well as 
the batch numbers ( . 3) used in the validation study should be indicated or a validation 
protocol (scheme) be submitted and the number of batches used in the stability 
studies should be indicated. 
1.3.2.2 Supporting Documents for Change in Specifi cations 
Changes in any type of specifi cation also need to be supported by documentation. 
In all the guidelines, relaxing an acceptance criterion or deleting any part of the 
specifi cation is classifi ed as a major change and hence extensive documentation is 
required, for example, submission of a prior approval supplement to the FDA or 
comparative table of current and proposed specifi cations and details of any new 
analytical method and validation data and batch analysis data on two production 
batches of the fi nished product for all tests in the new specifi cation to EU. The 
specifi cations are benchmarks for comparison of performance of any product. For 
example, content uniformity specifi cation of 90  110% assay limit of a 20 - mg (average 
weight) tablet of a potent drug signifi es the challenge in maintaining the uniformity 
of such a low - dose drug during the blending operation. Any relaxation in specifi cation 
of this potent drug should be justifi ed with extensive documentation to assure 
the performance. However, tightening of an acceptance criterion is considered as a 
minor level change and to have minimal potential for an adverse effect on the 
identity, quality, purity, or potency of a product. 
1.3.2.3 Comparability Protocols 
The FDA has introduced the concept of comparability protocols to expedite the 
process of approval after submission of supporting document for a particular change 
[5] . The protocol covers anticipated changes a product may experience during 
it shelf life. Its recently published draft guidance  Comparability Protocols  
Chemistry, Manufacturing, and Controls (CMC) Information  describes the general 
principles and procedures to prepare comparability protocols. The FDA suggests a 
less stringent reporting category for any future change, where appropriate. Additionally, 
if a detailed comparability protocol is provided, the FDA is less likely to 
request additional supporting documents while comparing pre - and postapproval 
change, and this could also help in implementing a particular CMC change, thereby 
moving the product in the distribution line sooner. According to the FDA: 
A comparability protocol is a well - defi ned, detailed, written plan for assessing the effect 
of specifi c CMC changes in the identity, strength, quality, purity, and potency of a specifi 
c drug product as these factors relate to the safety and effectiveness of the product. 
A comparability protocol describes the changes that are covered under the protocol 
and specifi es the tests and studies that will be performed, including the analytical procedures 
that will be used, and acceptance criteria that will be achieved to demonstrate 
that specifi ed CMC changes do not adversely affect the product. The submission of a 
comparability protocol is optional. 
A comparability protocol may be submitted with a new drug application (NDA), 
abbreviated new drug application (ANDA), or supplements to these applications. 

SCIENTIFIC AND REGULATORY RATIONALE FOR SUPAC 71 
Comparability protocols can have single or multiple changes provided that each 
change is discrete and specifi cation of the acceptance criteria for a change is well 
defi ned. 
1.3.2.4 In Vitro  In Vivo Requirements 
Stability of a drug product, in vitro dissolution, and in vivo bioequivalence are prerequisites 
for performance of a drug product and play a key role in establishing the 
quality of a drug product after a postapproval change has been implemented. Any 
type of major change, for example, in the manufacturing process from dry granulation 
to wet granulation could affect the bioavailability and stability of a drug 
product. Careful selection of the dissolution condition can obviate the need for a 
costly bioequivalence study. Guidelines by the FDA [4] and ANVISA [6] take into 
consideration the solubility and permeability of a drug substance for selection of 
dissolution criteria for a particular drug product (immediate release or modifi ed 
release) whereas guidelines by the EU and TGA recommend submitting comparison 
records between a particular number of manufacturing batches pre - and 
postapproval. 
While categorizing a change or variation for its effect, suffi cient consideration 
should be given to those parameters of a drug product which could affect its bioavailability. 
Critical parameters like the particle size of active ingredient or excipients, 
solid - state characteristics, and surface wettability may change during the 
process variation and could adversely affect product performance resulting in an 
altered dissolution profi le. The effect would be more pronounced in drug products 
containing poorly soluble potent drugs and could have a deleterious effect on bioavailability. 
The FDA guideline considers recommendation of the Biopharmaceutic 
Classifi cation System (BCS) regarding solubility and permeability characteristics to 
see whether any in vivo bioequivalence study is needed along with an in vitro dissolution 
study. In the same pattern, ANVISA places drugs in three categories for 
solid TM dosage form: case A, active substances with high permeability and high 
solubility; case B, active substances with low permeability and high solubility; and 
case C, active substances with high permeability and low solubility. As per the 
guideline, for alteration of registration due to excipient change, for level 2 alterations 
(that could cause signifi cant impact on quality and performance) the following 
requirements should be met: 
Case A  The required documentation must include the undertaking of the 
technical report and assessment of the results of the dissolution test, carried 
out as described in the Brazilian Pharmacopoeia and, in its absence, other 
codes authorized by the legislation in force. There must be dissolution of at 
least 85% of the active substance in up to 15 minutes, using 900 ml of HCl 
0.1 M . In case this criterion is not complied with, the tests described for Cases 
B or C must be carried out.  
Case B  The required documentation must include the undertaking of the 
technical report and assessment of the results of the dissolution profi le employing 
Pharmacopeial conditions and removing samples from the medium at 
appropriate time points until the plateau is reached. The dissolution profi le 
obtained must be similar to the profi le of the unaltered formulation.  

72 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
Case C  The required documentation must include the undertaking of the 
technical report and assessment of the results of the dissolution profi le in fi ve 
different conditions: distilled water, HCl 0.1 M and phosphate buffer pH 4.5, 
6.5 and 7.5 for the proposed formulation and the previous formulation, without 
change. Samples of the dissolution medium must be removed at appropriate 
time points until 90% of the active substance is dissolved or the plateau is 
reached. A tensoactive may be used only when appropriately justifi ed. The 
profi le obtained must be similar to the profi le of the unaltered formulation.  
In addition, for level 2 change, no additional bioequivalence study is required if 
the proposed alteration matches with the situation for cases A, B, and C. However, 
if there is any deviation, then documentation containing the results and assessment 
of a new bioequivalence and/or bioavailability study [if proper in vitro/in vivo correlation 
( ivivc ) has not been established] should be submitted as per the conditions 
mentioned in the level 3 alteration. 
1.3.3 REGULATORY AGENCIES AND GUIDELINES 
1.3.3.1 FDA SUPAC Regulations 
The Food and Drug Administration Modernization Act (FDAMA) of 1997 (the 
Modernization Act) was passed on November 21. With FDAMA in effect, another 
Section 506A was added to the federal Food, Drug, and Cosmetic Act (the act) and 
Section 314.70 (21 CFR 314.70) and the section included recommendations for 
reporting categories (in terms of defi ned words) for any type of manufacturing 
changes to an approved application (NDA or ANDA). In accordance with the act, 
the FDA issued  Guidance for Industry: Changes to an Approved NDA or ANDA  
(fi nalized in 2004). This guidance is a current standard for pharmaceutical manufacturers 
for making and reporting manufacturing changes to an approved application 
and for distributing a drug product made with such changes. 
 SUPAC - IR: Immediate - Release Solid Oral Dosage Forms: Scale - Up and Post - 
Approval Changes: Chemistry, Manufacturing and Controls, In vitro Dissolution 
Testing, and In vivo Bioequivalence Documentation  (issued 1995) was the fi rst 
attempt to provide the pharmaceutical industry with a clear - cut guideline covering 
the requirements for notifi cation and submission of documentation to regulatory 
authorities pertaining to postapproval changes. This guideline was an outcome of 
(a) a workshop on the scale - up of IR products conducted by the American Association 
of Pharmaceutical Scientists with the U.S. Pharmacopoeia (USP) Convention 
and the FDA; (b) research conducted by the University of Maryland at Baltimore 
on the CMC of IR products; (c) drug categorization research on the permeability 
of drug substances at the University of Michigan and the University of Uppsala; 
and (d) SUPAC task force set up by the Centre for Drug Evaluation and Research 
(CDER) CMC coordination committee. Following the issuance, it became a benchmark 
for the industry. Two more guidances have been published on the same format 
(level of changes as defi ned by SUPAC IR) as of SUPAC for MR drug products 
(issued in 1997) [7] and nonsterile semisolid drug products (issued in 1997) [8] . 
 Guideline for Changes to Approved NDA or ANDA  supersedes any previous 

guidelines which have information on reporting categories that is inconsistent with 
this guideline. 
Guideline to Industry: Changes to Approved NDA or ANDA  Guideline for 
Industry: Changes to Approved NDA or ANDA  provided reporting categories for 
various postapproval changes and relaxed certain requirements that were considered 
to have minimal or no impact on the drug product [1] . Moreover, it lessened 
the burden on regulatory authorities and companies as well. Four reporting categories 
provided in this guideline are as follows: 
1. Prior Approval Supplement For a major change (substantial potential to 
have effect on quality and performance), a supplement has to be submitted to 
the FDA for approval before a product made with the change is distributed. 
There is also a provision for  Prior Approval Supplement: Expedite Review 
Requested  for public health reasons and if the delay in approval may cause 
any substantial concerns for the applicant. 
2. Supplement: Changes Being Effected (CBE) in 30 Days For a moderate 
change (moderate potential to have effect on quality and performance), a 
supplement has to be submitted to the FDA for approval 30 days before a 
product made with the change is distributed. 
3. Supplement: Changes Being Effected in 0 Days For some changes a supplement 
has to be submitted to the FDA and simultaneously the product made 
with the change can be distributed. 
4. Annual Report For a minor change (minimal potential to have effect on 
quality and performance), all information has to be submitted to the FDA in 
the next annual review and the product made with the change can be 
distributed. 
All three types of changes under this guidance have been categorized as 
follows: 
(a) Changes in Components and Composition Any qualitative or quantitative 
changes in the components and composition of a drug product is considered 
as major changes. The current Guideline to Industry: Changes to Approved 
NDA or ANDA does not mention these in detail because of the complexity 
involved in the recommendations and therefore the SUPAC guideline has to 
be followed for any such type of changes and regarding documentation 
requirements for regulatory submission. 
(b) Changes in Manufacturing Sites A change in a manufacturing site (for 
manufacturing, packaging, labeling of drug products, testing components, 
drug product containers, closures, packaging materials), either owned or 
contract site, of drug products from the one that is approved requires prior 
approval from the CDER. A prior approval supplement has to be submitted 
for a change to a site that does not have a satisfactory CGMP inspection for 
the type of operation to be performed. Further, changes in sites related to 
operations like labeling, secondary packaging, and testing are considered to 
have effect independent of drug product dosage form and therefore the 
REGULATORY AGENCIES AND GUIDELINES 73

74 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
reporting categories for any of type of manufacturing site changes will be the 
same. However, changes in sites related to operations like manufacturing and 
primary packaging are considered to have effect that is dependent on dosage 
form and hence reporting categories may be different. 
(c) Changes in Manufacturing Process Changes in the manufacturing process 
can have substantial effect on the identity, strength, quality, purity, or potency 
of a drug product and there may be a change in the effi cacy of the drug 
product regardless of the testing of drug product for conformance for the 
approved specifi cation. 
(d) Changes in Specifi cations Specifi cation, acceptance criteria, and regulatory 
analytical procedure are a part of every dossier submitted to regulatory 
agencies. Specifi cations are the standards, acceptance criteria are the limits 
for specifi cations, and the regulatory analytical procedure is used for testing 
a specifi cation  s acceptance criteria for the test substance that is approved 
by the regulatory authority. Alternative analytical procedure may be 
included in the application simultaneously with the main analytical 
procedure. 
(e) Changes in the Container Closure System Effects related to changes in the 
container closure system are largely dependent on route on administration, 
the operation in which the container closure system is involved, and contact 
with the drug product. In some cases, there may be an effect in spite of the 
conformance of drug product with the approved specifi cation. 
(f) Changes in Labeling Changes in the package insert and package container 
label are included in the labeling changes and applicant must immediately 
revise all promotional labeling and drug advertisement in accordance with 
the change in the approved labeling. 
(g) Miscellaneous Changes Apart from categories mentioned above, changes 
like stability protocol, expiration period, and addition of stability protocol 
or comparability protocol have been included in the miscellaneous 
category. 
(h) Multiple Related Changes One change may lead to advertent or inadvertent 
incorporation of another change, for example, a change in the manufacturing 
site may lead to a change in the manufacturing equipment and manufacturing 
process or changes in packaging material may cause changes in stability 
protocol. For such combination changes, the CDER recommends submitting 
documents in accordance with the most stringent reporting category for the 
individual change. 
Scale - up and Postapproval Changes: Immediate - Release and Modifi ed - Release 
Dosage Forms SUPAC guidelines categorized postapproval changes in terms of 
 levels  [4] . Three levels were defi ned depending upon the intensity of the adverse 
effect on the formulation. Level 1 signifi es that the resulting effect on the quality 
would be minimal and less extensive documentation should be presented to the 
FDA in an annual review. Changes in accordance with level 2 could have signifi cant 
effect on the quality and performance of the dosage form. Level 3 changes are most 
likely to affect the quality and performance of the dosage form and hence extensive 

documentation justifying those changes should be submitted to the FDA prior to 
distribution of the products made with these changes. Apart from describing these 
levels, recommendations were also made on the extent of CMC documentation, in 
vitro dissolution, and in vivo bioequivalence tests that need to be submitted. Each 
section in the guideline [(a) components and compositions, (b) site change, (c) scale - 
up/scale - down; and (d) manufacturing equipment and process] was categorized in 
terms of these three levels. Further, SUPAC IR also takes into consideration the 
therapeutic range, solubility, and permeability of the drug for defi ning any particular 
change. As per the guideline, three cases have been defi ned for the dissolution 
testing (as mentioned in Table 1 ). Moreover, changes in excipient limits for a narrow 
therapeutic range drug beyond that mentioned in level 1 have been recommended 
as level 3 changes and extensive documentation is required for justifi cation. In the 
SUPAC guideline for MR dosage forms, changes have been described at the same 
three levels [7] . 
However, dissolution conditions have been distinguished quite reasonably 
between extended - and delayed - release dosage form (Table 2 ). For reporting any 
level 3 change, three - month accelerated stability data of three batches (signifi cant 
body of information not available) or three - month accelerated stability data for one 
batch (signifi cant body of information available) have to be submitted in a supplement 
along with long - term stability data for one batch in an annual review. A signifi 
cant body of information has been defi ned in the guideline as availability of 
suffi cient stability information of the product (stability data of fi ve commercial 
batches). To provide a comparative outline, the guidelines for MR and IR dosage 
forms are described in Tables 3  8 : 
TABLE 1 Different Cases and Respective Dissolution Conditions for Immediate - Release 
Solid Dosage Form 
Case A a Case B b Case B c 
Dissolution of 85% in 
15 min in 900 mL of 0.1 N 
HCl. If a drug product fails 
to meet this criterion, the 
applicant should perform 
the tests described for case 
B or C. 
Multipoint dissolution 
profi le should be 
performed in the 
application/compendial 
medium at 15, 30, 45, 60, 
and 120 min or until an 
asymptote is reached. 
Multipoint dissolution profi les 
should be performed in water, 
0.1 N HCl, and USP buffer 
media at pH 4.5, 6.5, and 7.5 
(fi ve separate profi les) for the 
proposed and currently accepted 
formulations. Adequate sampling 
should be performed at 15, 30, 
45, 60, and 120 min until either 
90% of drug from the drug 
product is dissolved or an 
asymptote is reached. A 
surfactant may be used, but only 
with appropriate justifi cation. 
a High - permeability, high - solubility drugs. 
b Low - permeability, high - solubility drugs. 
c High - permeability, low - solubility drugs. 
REGULATORY AGENCIES AND GUIDELINES 75

76 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
TABLE 2 Dissolution Conditions for Modifi ed - Release Dosage Form 
Extended Release Delayed Release 
In addition to application/compendial 
release requirements, multipoint 
dissolution profi les should be 
obtained in three other media, for 
example, in water, 0.1 N HCl, and 
USP buffer media at pH 4.5 and 6.8 
for the changed drug product and the 
biobatch or marketed batch 
(unchanged drug product). Adequate 
sampling should be performed, for 
example, at 1, 2, and 4 h and every 2 
hours thereafter until either 80% of 
the drug from the drug product is 
released or an asymptote is reached. 
A surfactant may be used with 
appropriate justifi cation. 
In addition to application/compendial release 
requirements, dissolution tests should be 
performed in 0.1 N HCl for 2 h (acid stage) 
followed by testing in USP buffer media, in 
the range of pH 4.5  7.5 (buffer stage) under 
standard (application/compendial) test 
conditions and two additional agitation speeds 
using the application/compendial test apparatus 
(three additional test conditions). Multipoint 
dissolution profi les should be obtained during 
the buffer stage of testing. Adequate sampling 
should be performed, for example, at 15, 30, 45, 
60, and 120 min (following the time from which 
the dosage form is placed in the buffer) until 
either 80% of the drug from the drug product is 
released or an asymptote is reached. The above 
dissolution testing should be performed using 
the changed drug product and the biobatch or 
marketed batch (unchanged drug product). 
(a) Changes in Components and Compositions (Table 3 ) The guideline for 
changes to approved NDA or ANDA does not defi ne these changes in detail, and 
thus the SUPAC guideline has to be followed for reference and reporting. Changes 
in excipient levels are submitted as a prior approval supplement (with accelerated 
stability data) whereas any changes in the levels of colors or fl avors are submitted 
in an annual review (long - term stability data). In MR dosage forms these changes 
have been logically categorized as (a) changes in excipient levels not affecting the 
release profi le and (b) changes in excipient levels affecting the release profi le. In 
level 2 changes for IR product and MR dosage forms for a non - narrow therapeutic 
drugs, three - month accelerated stability data of one batch (in MR dosage form for 
narrow therapeutic drugs three - month accelerated stability data of three batches) 
in a supplement and long - term stability data of one batch in an annual review should 
be submitted. Additionally, for delayed - release MR dosage forms of a narrow therapeutic 
range drug, the multipoint dissolution profi le in the buffer stage of testing 
should be generated for changed and commercial product using the medium that is 
approved or in pharmacopeia. For extended - release MR dosage forms of a narrow 
therapeutic range drug, the multipoint dissolution profi le should be generated for 
changed and commercial product using the medium that is approved or in 
pharmacopeia. 
(b) Changes in Manufacturing Site (Table 5 ) A change in the manufacturing 
or packaging site (or a contract manufacturing location) that has been approved by 
the FDA in the original application has to be evaluated for its effect on the product 
quality and performance. These changes have been described in detail in current 
guideline changes to approved NDA or ANDA. 

TABLE 3 Changes in Nonrelease Controlling Components and Composition 
Level Classifi cation 
Therapeutic 
Range/Type of 
Drug Test Documnetation 
Filing 
Documentation 
I 
Complete or partial 
deletion 
of color/fl avor 
Change in inks, 
imprints 
SUPAC - IR level 1 
excipient ranges 
No other changes 
All drugs Stability 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Change in technical 
grade and/or 
specifi cations 
Higher than 
SUPAC - IR level 
1 but less than 
level 2 excipient 
ranges 
No other changes 
All drugs for 
MR 
Depending upon 
therapeutic 
range 
solubility and 
permeability 
(as per BCS) 
for IR 
MR (ER): 
Notifi cation and updated 
batch record 
Stability 
Application/ 
compendial 
requirements plus 
multipoint dissolution 
profi les in three other 
media (e.g., water, 
0.1 
N HCl, and USP 
buffer media at pH 4.5 
and 6.8) until . 80% of 
drug released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing dissolution 
profi les 
No biostudy 
MR (DR): 
Notifi cation and updated 
batch record 
Stability 
Application/compendial 
requirements 
plus multipoint 
dissolution profi les in 
additional buffer stage 
testing (e.g., USP 
buffer media at pH 
4.5  7.5) under 
standard and increased 
agitation conditions 
until . 80% of drug 
released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing dissolution 
profi les 
No biostudy 
IR: 
Notifi cation and 
updated batch 
record 
Stability 
Dissolution 
requirements: 
case A, case B, or 
case C 
Apply some 
statistical test (f2 
test) for comparing 
dissolution profi les 
No biostudy 
Prior approval 
supplement 
Change in technical 
grade and/or 
specifi cations 
Higher than 
SUPAC - IR 
level 1 
No other changes 
77

Level Classifi cation 
Therapeutic 
Range/Type of 
Drug Test Documnetation 
Filing 
Documentation 
III 
Higher than 
SUPAC - IR level 
2 excipient ranges 
for MR and IR, 
change in 
excipient range 
for low solubility 
and low 
permeability 
drugs beyond 
level 1 
All drugs for 
MR and all 
drugs failing 
dissolution 
criteria for 
level 2 for IR 
Updated batch record 
Application/compendial (profi le) requirements and as 
mentioned for level II 
Stability 
Biostudy or ivivc 
Updated batch 
record 
Dissolution profi le as 
for level II 
Stability 
Biostudy or ivivc 
Prior approval 
supplement 
Note : 
MR, 
Modifi ed - release dosage form; ER, extended - release dosage form; DR, delayed - release dosage form; IR, immediate - release dosage form. 
TABLE 3 Continued 
78

TABLE 4 Changes in Release Controlling Components and Composition 
Level Classifi 
cation Therapeutic Range Test Documentation 
Filing Documentation 
I 
. 5% w/w change based 
on total release 
controlling excipient 
(e.g., controlled - 
release polymer, 
plasticizer) content 
No other changes 
All drugs Stability 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Change in technical 
grade and/or 
specifi cations 
. 10% w/w change based 
on total release 
controlling excipient 
(e.g., controlled - 
release polymer, 
plasticizer) content 
No other changes 
Nonnarrow 
MR (ER): 
MR (DR): 
Prior approval 
supplement Notifi cation and updated 
batch record 
Stability 
Application/compendial 
requirements plus 
multipoint dissolution 
profi les in three other 
media (e.g., water, 0.1 N 
HCl, and USP buffer media 
at pH 4.5 and 6.8) until 
. 80% of drug released or 
an asymptote is reached 
Apply some statistical test (f2 
test) for comparing 
dissolution profi les 
No biostudy 
Notifi cation and updated 
batch record 
Stability 
Application/compendial 
requirements plus 
multipoint dissolution 
profi les in additional 
buffer stage testing (e.g., 
USP buffer media at pH 
4.5  7.5) under standard 
and increased agitation 
conditions until . 80% of 
drug released or an 
asymptote is reached 
Apply some statistical test 
(f2 test) for comparing 
dissolution profi les 
No biostudy 
Narrow Updated batch record 
Stability 
Application/compendial (profi le) requirements 
Biostudy or ivivc 
Prior approval 
supplement 
III 
> 10% w/w change 
based on total release 
controlling excipient 
(e.g., controlled - 
release polymer, 
plasticizer) content 
All drugs Updated batch record and stability 
Application/compendial (profi le) requirements 
Biostudy or ivivc 
Prior approval 
supplement 
79

TABLE 5 Site Changes 
Level Classifi cation 
Therapeutic 
Range Test Documentation Filing Documentation 
I Single facility 
Common 
Personnel 
No other changes 
All drugs 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Same contiguous 
campus 
Common personnel 
No other changes 
All drugs MR (ER): 
MR (DR): 
IR: 
Changes being effected 
supplement 
(accelerated stability 
data for MR and no 
stability data for IR) 
Annual report (long - 
term stability data for 
MR and IR) 
Identifi cation and 
description of site 
change and updated 
batch record 
Notifi cation of site 
change 
Stability 
Application/ 
compendial 
requirements plus 
multipoint 
dissolution profi les 
in three other media 
(e.g., water, 0.1 N 
HCl, and USP buffer 
media at pH 4.5 and 
6.8) until . 80% of 
drug released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing 
dissolution profi les 
No biostudy 
Identifi cation and 
description of site 
change, and updated 
batch record 
Notifi cation of site 
change 
Stability 
Application/ 
compendial 
requirements plus 
multipoint 
dissolution profi les 
in additional buffer 
stage testing (e.g., 
USP buffer media at 
pH 4.5  7.5) under 
standard and 
increased agitation 
conditions until 
. 80% of drug 
released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing 
dissolution profi les 
No biostudy 
Identifi cation and 
description of site 
change and 
updated batch 
record 
Notifi cation of site 
change 
Stability 
Application/ 
compendial 
requirements 
No biostudy 
III 
Different campus 
Different personnel 
All drugs Notifi cation of site change 
Updated batch record 
Application/compendial (profi le) requirements 
(as for level II) 
Stability 
Biostudy or ivivc 
Notifi cation of site 
change 
Updated batch 
record 
Case B dissolution as 
for excipient 
change (level II) 
Stability 
No biostudy 
Prior approval 
supplement 
(accelerated stability 
data) for MR and 
changes being 
effected supplement 
for IR 
Annual report 
80

TABLE 6 Changes in Batch Size: 
Scale - Up/Scale - Down 
Level Classifi 
cation Change Test Documentation 
Filing 
Documentation 
I 
Scale - up of biobatch(s) 
or pivotal clinical 
batch(s) 
No other changes 
. 10 . (all drugs) Updated batch record 
Stability 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Scale - up of biobatch(s) 
or pivotal clinical 
batch(s) 
No other changes 
> 10 . (all drugs) 
MR (ER): 
MR (DR): 
IR: 
Changes being 
effected 
supplement 
(accelerated 
stability data) 
Annual report 
(long - term 
stability data) 
Updated batch record 
Stability 
Application/ 
compendial 
requirements plus 
multipoint 
dissolution profi les 
in three other 
media (e.g., water, 
0.1 
N 
HCl, 
and 
USP buffer media 
at pH 4.5 and 6.8) 
until . 80% of drug 
released or an 
asymptote is 
reached 
Apply some statistical 
test (f2 test) for 
comparing 
dissolution profi les 
No biostudy 
Updated batch record 
Stability 
Application/compendial 
multipoint dissolution 
profi les in additional 
buffer stage testing 
(e.g., USP buffer 
media at p H 
4.5  7.5) 
under standard and 
increased agitation 
conditions until . 80% 
of drug released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing dissolution 
profi les 
No biostudy 
Updated batch 
record 
Stability 
Case B dissolution 
as for excipient 
change (level II) 
No biostudy 
81

TABLE 7 Changes in Manufacturing: equipment 
Level Classifi cation Change Test Documentation Filing Documentation 
I Equipment 
changes 
No other changes 
(all drugs) 
Alternate 
equipment of 
same design 
and principle 
Automated 
equipment 
Updated batch record 
Stability 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Equipment 
changes 
No other changes 
(all drugs) 
Change to 
equipment of 
a different 
design and 
operating 
principle 
MR (ER): 
MR (DR): 
IR: 
Prior approval 
supplement 
(accelerated 
stability data) 
Annual report (long - 
term stability data) 
Updated batch record 
Stability 
Application/ 
compendial 
requirements plus 
multipoint 
dissolution profi les 
in three other media 
(e.g., water, 0.1 N 
HCl, and USP 
buffer media at pH 
4.5 and 6.8) until 
. 80% of drug 
released or an 
asymptote is 
reached 
Apply some statistical 
test (f2 test) for 
comparing 
dissolution profi les 
No biostudy 
Updated batch 
record 
Stability 
Application/ 
compendial 
requirements plus 
multipoint 
dissolution 
profi les in 
additional buffer 
stage testing (e.g., 
USP buffer media 
at ph 4.5  7.5) 
under standard 
and increased 
agitation 
conditions until 
. 80% of drug 
released or an 
asymptote is 
reached 
Apply some 
statistical test 
(f2 test) for 
comparing 
dissolution 
profi les 
No biostudy 
Updated batch 
record 
Stability 
Case C dissolution 
as for excipient 
change (level II) 
No biostudy 
82

TABLE 8 Changes in Manufacturing: Processes 
Level Classifi cation Change Test Documentation 
Filing 
Documentation 
I 
Processing changes 
affecting the 
nonrelease/release 
controlling excipients 
for MR 
Changes within 
validation ranges (IR) 
No other changes 
Adjustment of 
equipment 
operating 
conditions (mixing 
times, operating 
speeds)  within 
approved 
application ranges 
Updated batch record 
Application/compendial requirements 
No biostudy 
Annual report 
II 
Processing changes 
affecting the 
nonrelease controlling 
excipients and/or the 
release controlling 
excipients 
Processing changes 
outside validation 
ranges for IR 
No other changes 
Adjustment of 
equipment 
operating 
conditions (e.g. 
mixing times, 
operating speeds, 
etc.) 
Beyond approved 
application ranges 
MR (ER): 
MR (DR): 
IR: 
Changes being 
effected 
supplement 
(accelerated 
stability data 
for MR) 
Annual report 
(long - term 
stability data 
for MR and 
IR) 
Updated batch record 
Stability 
Application/compendial 
requirements plus 
multipoint dissolution 
profi les in three other 
media (e.g. water, 
0.1 
N HCl, and USP 
buffer media at pH 
4.5 and 6.8) until 
. 80% of drug 
released or an 
asymptote is reached 
Apply some statistical 
test (f2 test) for 
comparing dissolution 
profi les 
No biostudy 
Updated batch record 
Stability 
Application/compendial 
requirements plus 
multipoint dissolution 
profi les in additional 
buffer stage testing (e. 
g., USP buffer media at 
pH 4.5  7.5) under 
standard and increased 
agitation conditions 
until . 80% of drug 
released or an 
asymptote is reached 
Apply some statistical test 
(f2 test) for comparing 
dissolution profi les 
No biostudy 
Notifi cation of change 
Updated batch record 
Stability 
Case B dissolution as 
for excipient 
change (level II) 
No biostudy 
III 
Processing changes 
affecting the 
nonrelease controlling 
excipients and/or the 
release controlling 
excipients 
Change in the type 
of process used 
(e.g. from wet 
granulation to 
dry) 
Updated batch record 
Stability 
Application/compendial (profi le) requirements 
Biostudy or ivivc 
Updated batch 
record  stability 
Case B dissolution as 
for excipient 
change (level II) 
No biostudy 
Prior approval 
supplement 
(accelerated 
stability data 
for MR) 
Annual report 
(long - term 
stability data 
for MR and 
IR) 
83

84 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
The FDA should be notifi ed of the new location. For any type of moderate 
changes, accelerated stability data of one batch should be submitted with the CBE 
supplement for MR dosage forms and long - term stability data of one batch should 
be submitted in the annual review for IR as well as MR dosage forms. Additionally, 
the CBE should be submitted to the FDA in case of any moderate change. Stability 
requirements for any major change are the same as those mentioned in the previous 
section, that is, three - month accelerated stability data of three batches (signifi cant 
body of information not available) or three - month accelerated stability data for one 
batch (signifi cant body of information available) have to be submitted in a prior 
approval supplement along with long - term stability data for one batch in the annual 
review. 
(c) Scale - Up/Scale-Down (Table 6 ) A change in the batch size of a drug product, 
either scale - up or scale - down, is likely to induce some changes in the operation 
parameters. This in turn can adversely affect product quality. 
(d) Changes in Manufacturing Equipment (Table 7 ) and Process (Table 8 ) Any 
manufacturing changes in equipment and process are included in this section. For 
example, a change in the blending equipment from octagonal blender to double 
cone blender or a change in the granulation process from wet to dry granulation 
calls for submission of proper validation documentation for FDA approval. All 
these changes along with reporting categories have been described in current guidelines 
for changes to approved NDA or ANDA. 
Biowaivers In vitro and in vivo approaches are commonly used for establishment 
of bioavailability and bioequivalence. Dissolution studies are used as in vitro 
approaches and also serve as quality control tools for pharmaceuticals. Under 
certain circumstances, in vitro dissolution may also act as a surrogate marker 
for in vivo biostudy and enable the establishment of in vitro and in vivo 
bioequivalence. 
 CDER Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence 
Studies for IR Solid Dosage Form Based on Biopharmaceutic Classifi cation 
System (BCS)  recommends waiving an in vivo biostudy under specifi c circumstances. 
For example, a waiver of the in vivo biostudy of one or more lower strengths 
is acceptable based on the correlation data and in vivo bioequivalence of the higher 
strength, provided all strengths are proportionally equivalent in terms of active and 
inactive ingredients. A biostudy on a lower strength may also be requested based 
on safety reasons (as for mitrazapine tablets) and a biowaiver for highest strength 
is acceptable provided elimination kinetics is linear over a dose range, strengths are 
proportional, and comparative dissolution data of all strengths are acceptable. 
The BCS classifi es drugs in four classes: 
Class I: high solubility, high permeability 
Class II: low solubility, high permeability 
Class III: high solubility, low permeability 
Class IV: low solubility, low permeability 
Dissolution, solubility, and permeability are the three fractors that control the 
bioavailability of a drug for an IR drug product. Provided the inactive excipient 

does not control or modify the release and absorption of the active ingredient, the 
biostudy may be waived. According to the guideline, the solubility class is determined 
for the highest dose strength of a drug product for which a biowaiver has 
been requested. When the highest dose strength of a solid dosage form is soluble in 
250 mL of water or less across a pH range of 1  7.5, it is considered as highly soluble. 
For determination of permeability class various in vivo methods like mass balance, 
absolute bioavailability, and intestinal perfusion approaches and in vitro methods 
like permeation studies using excised tissue or monolayer of cultured epithelial cells 
are used. When extent of absorption is greater than 90% of the administered dose 
in humans, it is considered as highly permeable. For a dissolution study, drug release 
should be evaluated in three media that are 0.1 N HCl or USP - simulated gastric 
fl uid without enzymes, pH 4.5 buffer, and pH 6.8 buffer or USP - simulated intestinal 
fl uid without enzymes. Rapidly dissolving drug products are those that dissolve 
more than 80% in 900 mL of the above - mentioned media in less than 30 min using 
USP apparatus at 100 rpm (or USP II apparatus of 50 rpm). 
A biowaiver can be requested for the postchange products if it falls under class 
I of the BCS and displays a rapidly dissolving profi le and there is a similarity (as 
determined by f2 test) between the pre - and postchanged drug product in all three 
media. For BCS class II drugs, a meaningful correlation (level A, B, or C correlation) 
between in vitro drug release and in vivo absorption also may be used for requesting 
the biowaiver. Deconvolution techniques are used for prediction of in vivo dissolution 
and absorption. 
1.3.3.2 Regulations Guidance on SUPAC by Pharmaceutical Unit of EU 
The pharmaceutical market in European countries is one of the largest in the world. 
To ensure that the EU promotes pharmaceutical trade and ensures safety, effi cacy, 
and quality of medicinal products within the European member states, the pharmaceutical 
unit of the EU runs a series of information and communication projects, 
collectively called EUDRA projects. Out of these projects, the EUDRALEX pharmaceutical 
unit is responsible for making community pharmaceutical legislation, 
guidelines, and notices for applicants [9] . Under Volume 2, Section C, of Regulatory 
Guidelines (Pharmaceutical Legislation: Notice to Applicants) of Eudralex,  Guideline 
on Dossier Requirements for Type IA and Type IB Notifi cations  has been 
provided [2] . 
Regulations were introduced to lessen the administrative load on the authority 
and to simplify the procedure for granting a postapproval variation without negotiating 
any quality attribute of drug product [10] . Under these regulations, type IA 
and type IB were defi ned; also, clearcut terms were introduced for extension application, 
parallel/consequential notifi cation/variation, and urgent safety restriction. 
For streamline operation of these regulations, four documents have been 
prepared: 
(a) A procedural guidance for the member states (reference or concerned) and 
the applicant for notifi cations/variations in the mutual recognition procedure 
(b) A procedural guidance for the applicant for notifi cations/variations in the 
centralized procedure 
REGULATORY AGENCIES AND GUIDELINES 85

86 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
(c) A common application form which may be used for type IA and type IB 
notifi cations or type II variations in both the centralized and mutual recognition 
procedures 
(d) A guideline on the documentation to be submitted for type IA and type IB 
notifi cations 
All member states of the EU follow the same regulations for a change or  variation 
 in an already approved medical product. As per the guidance, three types of 
variations or changes have been identifi ed  type I variation, which is further classi- 
fi ed into types IA and IB and type II variations. The guidelines classify some specifi c 
changes in type IA or IB. It also provides specifi c data analysis required for variation 
and the types of document that need to be submitted to the regulatory authority. 
Any change that is not listed in this section is classifi ed as type II variation. 
According to Commission Regulation (EC, No. 1084/2003), type I variation has 
been defi ned as  A  minor variation  of type IA or type IB means a variation listed 
in Annex I, which fulfi ls the conditions, set out therein.  Annex I of the regulation 
provides a list of changes and conditions (to be satisfi ed) to be classifi ed as type IA 
or type IB variation and Annex II provides changes falling under the extension 
application category. Type II variations in proposed documentation are not type I 
or extension application. There is also a provision for  urgent safety restrictions.  
These are any temporary or provisional changes in the product summary characteristics, 
such as indications, posology, contraindications, warnings, target species, and 
withdrawal periods, as result of a new information that may cause signifi cant safety 
concerns about the medicinal product [11] . 
Any change arising from the primary change has to be notifi ed separately. Consequential 
changes form part of the same notifi cation whereas parallel changes do 
not. A consequential change to type IA can only be another type IA whereas a 
consequential change to type IB can be type IA or type IB. All other variations 
should be submitted as Type II variations.  Guideline on Dossier Requirements for 
Type IA and Type IB Notifi cations  provides a complete list of all changes, conditions 
required to be met for the particular change, and documentation required by 
the regulatory authority [10] . 
1.3.3.3 Regulatory Guidance on SUPAC by Agencia Nacional de 
Vigilancia Sanitaria 
Agencia Nacional de Vigilancia Sanitara (ANVISA) issues Brazil  s generic drug 
policy. Under legislation for industry, Resolution RE N  893, of May 29, 2003, is 
described in  Guide for Making Post - Registration Alterations, Inclusions and Noti- 
fi cations of Drug Products  [6] . This guideline describes postregistration changes as 
 alterations  and  inclusions  and also tells about the documentation and assays 
that need to be submitted in support of any type of change. As per the guideline, 
each type of alteration or inclusion has to be submitted separately and approved 
by the ANVISA before it can be implemented. Table 9 presents some examples for 
each category. 
Under each category, certain requirements have to be met before its implementation. 
For example, for inclusion in the batch size, the company should notify, in 
alteration, if the included batch size is more than 10 times. The documentation that 
needs to be submitted includes the original proof of payment of fee or of exemption; 

a copy of the certifi cate of good manufacturing and control practices (CBPFC) 
issued by ANVISA; technical justifi cation; production and quality control records 
of one batch of each strength of the product; a technical report; and a technical 
report and assessment of the dissolution profi le. 
1.3.4 HARMONIZATION 
It is essential to evaluate the safety and quality of new or changed medical products 
before they reach the market. However, the need to set specifi c guidelines has been 
recognized at different times in different countries. For example, in the United 
States a tragic incident with a junior paracetamol formulation was the alarm to initiate 
guidelines for authorization of medical products. European countries followed 
this trend in the 1960s after the thalidomide incident. Since then there have been a 
large number of guidelines that have been put into place to evaluate medical products 
in terms of their quality, safety, and effi cacy [12] . However, with the pharmaceutical 
industries becoming international and aiming for a worldwide market, there 
is a move toward internationally accepted guidelines and approval systems. In order 
for medical products to be marketed internationally, companies have found it necessary 
to duplicate many tests and studies that are time consuming and broad. 
TABLE 9 Examples of Different Categories 
Postregistration 
Alterations 
Postregistration 
Inclusions 
Postregistration 
Notifi cations 
Postregistration 
Cancellation 
Labeling alteration Inclusion of new 
commercial 
presentation 
Temporary 
suspension of 
manufacture 
Cancellation upon 
request of 
registration of 
drug 
presentation 
Alteration of corporate 
name 
Inclusion of new 
packing 
Resumption 
of drug 
manufacture 
Cancellation of 
drug registration 
Alteration of date of 
expiry 
Inclusion of new 
concentration 
already approved in 
country 
Alteration of 
preservation 
conditions 
Inclusion of new 
dosage form already 
approved in country 
Alteration of synthesis 
path of drug 
Inclusion of new 
therapeutic 
indication in country 
Alteration of 
manufacturer of 
drug 
Inclusion of 
manufacture site 
Alteration of 
manufacturing site 
Inclusion of 
manufacturer of 
drug 
Alteration of excipient Inclusion in the batch 
size 
HARMONIZATION 87

88 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
Table 10 shows examples of documentation required by different countries when 
a postapproval change is made during the manufacturing process of medical products. 
When there are changes in the specifi cation of an excipient, the documents 
required by the TGA and European Agency for Evaluation of Medicinal Products 
(EMEA) are variable. Furthermore this would indicate that the benefi t of a patent/ 
medical product might not reach globally. There are also many chances of making 
an error. For example, the 2003 recall of clotrihexal 100 - mg vaginal tablets in New 
Zealand pharmacies was due to the fact that clotrihexal was packed according to 
TGA guidelines and thus its sale was prohibited in New Zealand. This resulted in 
much confusion and problems among patients and medical professionals. Harmonization 
is the process by which the pharmaceutical industries worldwide adopt 
the same laws and regulations. Harmonization is intended to assure the safety, 
quality, and effi cacy of a medical product globally. The main goal of harmonization 
is to recognize and minimize the differences in the scientifi c requirements for 
medical product development within different regulatory agencies in different 
countries. 
Harmonization activities focus on reducing and simplifying the types of studies 
that the pharmaceutical industries need to carry out in order to register a medical 
product in another country, protocols to be followed when performing these studies, 
techniques used to validate supporting data, and techniques used to perform risk 
assessment. 
Harmonization reduces replications and unnecessary production and registration 
of new and changed products. The concept of harmonization was explored by 
European countries in the 1980s. The success of harmonization in these countries 
has demonstrated that it is practical and possible. Following harmonization in 
Europe the International Conference on Harmonization (ICH) was set up in 1990 
[13] . Table 11 shows some of the harmonized rules that have been successfully 
developed by ICH. 
TABLE 10 Changes in Specifi cation of Excipients (Addition of New Test Limit): 
Comparison between Guidelines 
Guidelines Documentation Type of Change 
TGA Details of the test method must be provided. 
Appropriate validation data have been generated for 
the test method. 
The limits proposed are based on batch analytical data 
and are in compliance with offi cial standard and/or 
relevant accepted guidelines if applicable. 
Self - assessable 
changes 
EMEA Comparative table of current and proposed 
specifi cations. 
Batch analysis data on two production batches for all 
tests in the new specifi cation. 
Where appropriate, comparative dissolution profi le 
data for the fi nished product on at least one pilot 
batch containing the excipient complying with the 
current and proposed specifi cation. For herbal 
medicinal products, comparative disintegration data 
may be acceptable. 
Minor change 
type IB 
requires 
approval 

1.3.5 GMP ISSUES: CHANGE CONTROL AND PROCESS VALIDATION 
Changes are unavoidable in a manufacturing setup. Manufacturers make changes 
at some stage of manufacturing during and after approval of a product. However, 
consistent quality of a drug product can only be assured through well - defi ned validation 
procedures. When a change is made in the manufacturing process of a drug 
product, sponsors are responsible for evaluating the effect of any change on the 
safety, effi cacy, quality, stability, and potency of a drug product and ensuring that 
these properties are not infl uenced by the change. In a manufacturing setup, 
various disciplines like sales, marketing, medical, regulatory affairs, manufacturing, 
electrical, and technical services work together. Hence, any kind of change in one 
discipline will have direct consequences on other disciplines. Each company should 
have a procedure with regard to handling a change. Quality control and quality 
assurance departments usually keep track of various changes occurring in a 
GMP environment. Therefore, it is required that personnel performing the job are 
trained enough to assess the effect of any kind of change or variation and take 
appropriate action for its evaluation or control. Supporting data should be generated 
and once evaluated can confi rm whether further clinical or nonclinical studies 
are required. 
1.3.5.1 Change Control 
When a change is made in a manufacturing setup, it is important to assess its impact. 
As a change can have impact on regulatory fi ling, manufacturing parameters, speci- 
fi cations, and technical services, it is important to consider the concerns and objections 
of various disciplines involved and only through well - defi ned standard 
operating procedures should it be properly validated, evaluated, and fi nally implemented. 
A properly defi ned order of evaluation of a change with strategic input of 
trained personnel is key to delivering a consistent quality product (Figure 1 ). 
When a change is the processed, the manufacturer should have protocols in place 
with regard to assessing the change. Therefore,  control of change  is important. 
Control can be implemented effectively only through well - defi ned standard operating 
procedures. The main purpose of  change control  exercise is to have a 
TABLE 11 Example of Quality Guidelines Harmonized by ICH 
Quality Topic Example of Guideline 
Q1: Stability Q1B: Photostability testing 
Q2: Validation of analytical procedure Q2A: Methodology 
Q3: Impurity testing Q3A: Impurities in new drug 
substances 
Q4: Pharmacopoeias Q4: Pharmacopoeial harmonization 
Q5: Quality of biotechnological products Q5A: Viral safety evaluation of 
biotechnological products 
Q6: Specifi cations for new drug substance and 
products 
Q6A: Acceptance criteria for new drug 
substances 
Q7: GMP for pharmaceutical ingredients Q7A: GMP for active pharmaceutical 
ingredients 
GMP ISSUES: CHANGE CONTROL AND PROCESS VALIDATION 89

90 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
systematic process in place to accurately evaluate a change using specifi c tests. 
Moreover, it aims to measure the effects on quality safety and effi cacy before a 
change is implanted. Change control and its evaluation through proper documentation 
should include [14] : 
(a) Description and purpose of change 
(b) Inputs from research and development (R & D) department 
(c) Evaluation steps for impact assessment, such as evaluation of stability, validation 
requirements, and in vivo bioequivalence requirement 
(d) Need and extent of regulatory documentation and approval 
(e) Implementation schedule 
(f) Clear defi nition of personnel authorized for change approval 
(g) Monitoring protocol for change implementation and periodic review of 
impact 
Following the informal proposal of a change, it should be reviewed by the responsible 
initiator, who will then generate a formal proposal [15] . The proposal should 
describe accurately what the change is concerned with, how to validate the change, 
and the time frame within which the change should be implemented. The fi nal proposal 
should be reviewed and assessed by all functional groups involved. Once the 
change is approved, it can be implemented and the change cycle is completed. Figure 
2 describes responsibilities of different departments of a pharmaceutical company, 
FIGURE 1 Change control cycle for change in manufacturing process. 
Comments 
And Signature 
Comments 
And Signature 
Comments 
And Signature 
Comments 
And Signature 
Change 
Implement 
Initiator 
Approved by 
Quality 
Assurance 
Approved by 
Production 
Department 
Approved by 
Regulatory 
Department 
Approved by 
Head of 
Department 
Change Control Cycle 

in the change control procedure. Standard operating procedures (SOPs) for change 
control are an important part of any GMP audit. Hence it is important that it is 
implemented by trained and qualifi ed personnel from appropriate disciplines. 
After a change has been approved by all functional groups within the manufacturing 
setup and if it has no regulatory concerns, it can be implemented immediately. 
However, if the impact comes under any regulatory domain, the company may have 
to wait for regulatory approval. 
1.3.5.2 Process Validation 
Process validation is an important part in the implementation of a postapproval 
change. It establishes the documented evidence of conformance of a pharmaceutical 
operation in accordance with specifi cations. FDA  Guideline on General Principles 
of Process Validation  describes in detail the principles and practices of process 
validation and documentation required by the regulatory authority [13] . In general 
terms, process validation may be defi ned as the procedure which generates suffi cient 
assurance and documented evidence that a particular operation is operating 
and producing drug products in accordance with the specifi cations and process 
controls. 
FIGURE 2 Responsibilities of different disciplines of a pharmaceutical company in a 
change control procedure ( modifi ed from ref. 15 ). 
INITIATION OF 
CHANGE CONTROL 
PROOFREADING 
CONFORMANCE TO CGMP AND 
APPLICABILITY TO OTHER SYSTEMS 
REVIEW AND APPROVAL 
REGULATORY IMPACT AND 
WORLDWIDE FILING STRATEGY 
VALIDATION 
Quality assurance, Quality control, 
Manufacturing, Process Engineering, 
Technical services, Regulatory affairs, 
Owner of system or procedure being 
changes 
Quality assurance 
Quality assurance 
Regulatory affairs 
Quality assurance, Quality control, 
Manufacturing, Process Engineering, 
Technical services, Regulatory affairs, 
Owner of system or procedure being 
changes 
Quality assurance 
GMP ISSUES: CHANGE CONTROL AND PROCESS VALIDATION 91

92 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
Prospective validation, retrospective validation, concurrent validation, and revalidation 
are the four validation components. Prospective validation is performed 
before the distribution of drug products in the market or after the manufacturing 
of a drug product using revised changes that can affect product quality and characteristics. 
Retrospective validation is conducted for an established drug product 
whose manufacturing process is stable to ensure that the current pharmaceutical 
operation is performing as per the protocols and specifi cation and yielding satisfactory 
product. Concurrent validation is conducted by monitoring in - process critical 
manufacturing parameters and end - product testing to ensure that the current manufacturing 
process is per the in - process control specifi cations. Revalidation is performed 
after changes to an approved drug product are implemented to ascertain 
that there is no adverse effect on the quality and performance of a drug product 
[16] . 
During a validation process, the products and processes are subjected to testing 
at extreme conditions of in - process limits and their performance is evaluated against 
the acceptance criteria. The parameters of different pharmaceutical operations are 
varied and product properties are recorded and evaluated (Figure 3 ). When it is 
found that adjustment is required, necessary actions are taken in consultation with 
R & D personnel. Generally, validation data of three production scale batches are 
compared to generate a high level of quality assurance. 
Systematic documentation of the effect on the product attributes by varying 
various process parameters is very important in the validation process. The product 
development team, engineering and technical services, and production and regulatory 
departments are also consulted while making any process change or before 
fi nalizing any validation protocol or report. Depending on the  level  of change or 
degree of effect to be produced, the extent of the validation is determined. 
Based on the validation requirements, samples are collected at different stages 
and submitted for analysis per the validation protocol. The data are fi nally compiled 
in the form of a validation report. A systematic validation protocol and validation 
report are the backbone of the validation process. Table 12 gives key components 
of any validation activity [16] . These protocols and reports should be verifi ed and 
approved by the relevant functions. 
Some changes are often made in the manufacturing process without prior notifi - 
cation, and hence it is advisable to consider revalidation at predetermined frequencies 
(or whenever an unusual behavior is noted). 
When new equipment is purchased or there is a change in the manufacturing site, 
qualifi cation exercises are performed as part of the validation process. Qualifi cation 
(installation qualifi cation, operation qualifi cation, and performance qualifi cation) 
for any equipment or facility is an extreme process which involves testing, verifi cation, 
and documentation to assure that the particular equipment or facility is per 
the specifi cation and meets the appropriate standards as defi ned by vendor and 
required by manufacturing and engineering personnel [14] . 
1.3.6 CONCLUSION 
The global pharmaceutical industry is continuously growing in a rapidly changing 
and dynamic environment of the health care sector. New drugs and delivery systems 

FIGURE 3 Various process parameters and product characteristics associated with validation 
activity of typical coated tablet. 
Wet Granulation 
Drying 
Milling 
Blending 
Tabletting 
Coating 
Process Parameters Product Characteristics 
Premix time, Binder addition 
time, Impeller/Chopper Speed, 
Inlet air temperature, Bed Temperature, 
Airflow rate, Raking frequency 
Screen size, Hammer/knives 
direction and speed 
Compression speed, force (hardness 
and thickness), tablet weight 
Pan capacity, inlet/exhaust 
temperatures, Pan Speed, spray 
rate, Air flow rate, Bed temperature 
Capacity of Blender, Mixing 
time, mixing speed 
Granule hardness and size 
distribution 
Moisture content of Granules, 
Amount of residual solvent 
Size distribution, Bulk/ Tapped 
density of granules 
Content uniformity in blender 
and drum, Bulk/ Tapped density 
of final blend 
Tablet weight, hardness, thickness, 
content uniformity, friability, 
dissolution, disintegration, Assay/ 
potency 
Dissolution, disintegration, coating 
weight gain, mottling, assay/ potency 
CONCLUSION 93 
TABLE 12 Key Components of Validation Activity 
Validation Protocol Validation Report 
Purpose of study Aim of study 
Personnel responsibility List of raw material used in study 
Critical process steps List of manufacturing equipment 
Critical process parameters Critical steps studied 
Critical product parameters Collected data and its analysis 
Sampling plan Acceptance criteria evaluation 
Testing plan Statistical analysis 
Acceptance criteria Recommendations by validation department 

94 SCALE-UP AND POSTAPPROVAL CHANGES (SUPAC) REGULATIONS 
surface each year in the market. To maintain the quality of new and existing drugs 
and delivery technologies, pharmaceutical operations are controlled by regulatory 
guidelines. The purpose of developing guidelines is to keep the health and safety of 
a person on the highest priority by delivering quality pharmaceuticals. Implementation 
of these guidelines and systematic follow - up of the effect of postapproval 
changes in the form of documentation are essential to safeguard against any possible 
failure of the whole system. Change control and validation ensure that there is no 
deleterious impact on the drug product characteristics. Anticipated changes incorporated 
in comparability protocols reduce signifi cant risk of experiencing unpredictable 
adverse effects and help to introduce the product in less time. When an impact 
is anticipated, it should be properly discussed with R & D, process development, 
and other concerned departments for appropriate regulatory fi ling by following 
regulatory guidelines. Provided that these guidelines are followed properly, quality 
and performance of a drug product can be ensured. 
REFERENCES 
1. U.S. Department of Health and Human Services, Food and Drug Administration, Centre 
for Drug Evaluation and Research (CDER) , Guidance for industry: Changes to an 
approved NDA or ANDA, available, 
accessed Apr. 15, 2006 . 
2. European Commission , Guideline on dossier requirements for type IA and type IB 
notifi cations: Pharmaceuticals: Regulatory framework and market authorizations, available: 
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol - 2/c/gdvartypiab_rev0_ 
200307.pdf , accessed Apr. 20, 2006 . 
3. Department of Health and Ageing , Therapeutic Goods Administration, Australian regulatory 
guidelines for prescription medicines. Appendix 12: Changes to the quality information 
of registered medicines: Notifi cation. Self - assessment and prior approval, available: 
http://www.tga.gov.au/pmeds/argpmap12.pdf , accessed Apr. 12, 2006 . 
4. Food and Drug Administration, Centre for Drug Evaluation and Research (CDER) , 
Guidance for industry: SUPAC - IR: Immediate - release solid oral dosage forms: Scale - up 
and post - approval changes: Chemistry, manufacturing and controls, in vitro dissolution 
testing, and in vivo bioequivalence documentation, available: http://www.fda.gov/cder/ 
guidance/cmc5.pdf , accessed May 11, 2006 . 
5. Food and Drug Administration, Centre for Drug Evaluation and Research (CDER) , 
Guidance for industry: Comparability protocols  Chemistry, manufacturing, and controls 
information (draft), available, accessed Apr. 15, 2006 . 
6. Brazilian Sanitary Surveillance Agency (ANVISA) , Resolution: Guide for making post - 
registration alterations, inclusions and notifi cations of drug products, Brazil  s generic drug 
policy, industry legislation, available: http://www.anvisa.gov.br/hotsite/genericos/legis/ 
resolucoes/893_03re_e.htm , accessed Apr. 11, 2006 . 
7. U.S. Department of Health and Human Services, Food and Drug Administration, Centre 
for Drug Evaluation and Research (CDER) , Guidance for industry: SUPAC - MR: Modi- 
fi ed release solid oral dosage forms scale - up and postapproval changes: Chemistry, 
manufacturing, and controls; in vitro dissolution testing and in vivo bioequivalence documentation, 
, accessed May 5, 
2006 . 

8. U.S. Department of Health and Human Services, Food and Drug Administration, Centre 
for Drug Evaluation and Research (CDER) , Guidance for industry: SUPAC - SS: Nonsterile 
semisolid dosage forms; scale - up and post - approval changes: Chemistry, manufacturing 
and controls; in vitro release testing and in vivo bioequivalence documentation. 
9. Pharmaceutical Unit of European Commission at EUROPA, available: http://ec.europa. 
eu/enterprise/pharmaceuticals/pharmacos/docs/brochure/pharmaeu.pdf , accessed May 
21, 2006 . 
10. Variations. Pharmaceuticals: Regulatory framework and market authorizations, Chapter 
5, in Procedures for Marketing Authorisation , Vol. 2A, European Commission, available: 
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol - 2/a/v2a_chap5_r1_2004 - 02. 
pdf , accessed Apr. 16, 2006 . 
11. Commission regulation (EC) No. 1084/2003 of June 3, 2003, concerning the examination 
of variations to the terms of a marketing authorisation for medicinal products for human 
use and veterinary medicinal products granted by a competent authority of a member 
state (Offi cial Journal L 159, 27/6/2003, pp. 1  23), available: http://ec.europa.eu/ 
enterprise/pharmaceuticals/eudralex/homev1.htm , accessed Apr. 10, 2006 . 
12. The ICH process for harmonisation of guidelines, available: http://www.ich.org/cache/ 
compo/276 - 254 - 1.html , accessed May 15, 2006 . 
13. Food and Drug Administration, Centre for Drug Evaluation and Research (CDER) , 
Guideline on general principles of process validation, available: http://www.fda.gov/cder/ 
guidance/pv.htm , accessed Apr. 26, 2006 . 
14. Willig , S. H. ( 2001 ), Production and process controls , in Swarbrick , J. , Ed., Good Manufacturing 
Practices for Pharmaceuticals: A Plan for Total Quality Control from Manufacturer 
to Consumer , Marcel Dekker , New York , pp. 99  138 . 
15. Waterland , N. H. , and Kowtna , C. C. ( 2003 ), Change control and SUPAC , in Nash , R. A. , 
and Wachter , A. H. , Eds., Pharmaceutical Process Validation , Marcel Dekker , New York , 
pp. 699  748 . 
16. Ahmed , S. U. , Naini , V. , and Wadgaonkar , D. ( 2005 ), Scale - up, process validation and 
technology transfer , in Shargel , L. , and Kanfer , I. , Eds., Generic Drug Product Development: 
Solid Oral Dosage Form , Marcel Dekker , New York , pp. 95  136 . 
REFERENCES 95


97 
1.4 
GMP - COMPLIANT PROPAGATION 
OF HUMAN MULTIPOTENT 
MESENCHYMAL STROMAL CELLS 
Eva Rohde , Katharina Schallmoser , Christina Bartmann , 
Andreas Reinisch , and Dirk Strunk 
Medical University of Graz, Graz, Austria 
Contents 
1.4.1 Introduction 
1.4.2 Acronyms and Defi nitions 
1.4.2.1 Mesenchymal Stromal Cells 
1.4.2.2 Somatic Stem Cell Therapy 
1.4.2.3 Good Manufacturing Practice 
1.4.2.4 Cell - Based Medicinal Products 
1.4.2.5 Human Platelet Lysate 
1.4.3 Approaches 
1.4.3.1 Adherence to Principles of GMP in a Preclinical Developmental Process 
1.4.3.2 Effi cient Standardized MSC Propagation Using Low Cell Seeding Density 
1.4.3.3 Superior MSC Proliferation Resulting from HPL - Driven as Compared to 
FBS - Driven Cultures 
1.4.3.4 Contamination Risks Can Be Minimized in Rational MSC Propagation 
Procedures 
1.4.4 Testing Methods 
1.4.4.1 Safety and Effi cacy of CBMP in Preclinical Stage 
1.4.4.2 Quality Controls During Cell Culture (In - Process Controls) and Final Product 
Release Criteria 
1.4.4.3 MSC Functionality and Potency Assays 
1.4.5 Conclusion 
References 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

98 GMP-COMPLIANT PROPAGATION 
1.4.1 INTRODUCTION 
Somatic stem cell therapy (SCT) is a rapidly growing fi eld that opens a broad spectrum 
of therapeutic options. The concept of regenerative SCT is based on the 
assumption that transplantation of adult human stem cells may support organ regeneration, 
modulate immunity, and regulate hematopoiesis. Transplantation of bone 
marrow (BM)  derived hematopoietic stem cells (SCs) for blood and immune system 
regeneration has been a clinical reality for almost 40 years. The existence of detectable 
numbers of mesenchymal and endothelial progenitors within blood and BM 
has promoted the readily harvestable hematopoietic tissue as a source of SCs for 
nonhematopoietic regenerative SCT (Figure 1 ). 
Multipotent mesenchymal stromal cells (MSCs) are currently undergoing evaluation 
in a number of clinical trials ( www.clinicaltrials.gov ). These nonhematopoietic 
cells have been fi rst described by Friedenstein et al. in a fi broblast colony - forming 
unit assay (CFU - F) based on low - density culture of adherent BM - derived cells 
[1  3] . Alternative sources for MSCs have been identifi ed in a number of studies 
showing the successful isolation of fi broblast precursors from umbilical cord blood, 
placenta, umbilical cord, amniotic fl uid, and adipose tissue [4  13] . To date, most 
experimental and clinical experience has been accumulated with BM - MSC [14  21] . 
Ex vivo expansion of these rare BM constituents (representing less than 1% of 
aspirated BM nucleated cells) is a prerequisite to achieve a reasonable MSC application 
dose of at least 2 . 10 6 MSCs/kg of the recipients  body weight. The majority 
of expansion procedures are currently based on the use of fetal bovine serum (FBS), 
which carries the risk of xenoimmunization and transmission of known (e.g., prions 
transmitting bovine spongiforme encephalopathia, BSE) and unknown pathogens. 
These risks could be avoided by developing MSC expansion protocols that use 
human alternatives which replace FBS. 
The preclinical development of medicinal products in general bears high complexity 
due to the lack of fi xed routines. Long term manipulations of cell - based 
medicinal products (CBMPs) may enhance the risks for undesirable effects in the 
course of ex vivo cell expansions. Safety concerns regarding the clinical application 
of ex vivo generated MSCs require a logistic environment providing an established 
good manufacturing practice (GMP) background embedded in a highly effective 
quality system. Demonstration of manufacturing and product consistency is achieved 
by applying rational in - process controls. Release criteria should ideally emerge from 
successful product development and optionally include the sterility, safety, purity, 
identity, and potency. 1 They must to be rapid, sensitive, and reliable and should 
retain some fl exibility in type and timing of testing. The complexity and function of 
different CBMPs require an array of analytical procedures to adequately characterize 
the particular product (potency assays). Personalized (patient - specifi c) CBMPs 
differ from large drug batches in the pharmaceutical industry in terms of practicability 
in fi nal product release in that they may require process - oriented rather than 
single - product potency testing. U.S. regulations demand that  tests for potency 
shall consist of either in vitro or in vivo tests, or both, which have been specifi cally 
1 U.S. legislation: 21 CFR 610, General biological products standards, CFR 610.10 Potency, CFR 
600.3(s). 

FIGURE 1 Hematopoietic tissue - derived SC and progenitors. Hematopoietic tissue contains 
( a ) mesenchymal and ( b ) endothelial in addition to ( c ) hematopoietic progenitor cells. 
( a ) Adult human BM - derived MSCs were stained to visualize the actin cytoskeleton, mitochondria, 
and nuclei. ( b ) The periphery of an umbilical cord blood  derived endothelial progenitor 
cell (EPC) colony is depicted demonstrating typical cobble stone  like morphology. 
The entire colony was derived from a single UCB - EPC indicating impressive proliferation 
potential (more than 70,000 cells were obtained by harvesting single EPC - derived colonies 
indicating the completion of at least 16 population doublings). Less than 10 mL of adult BM 
[( a ) and ( c )] but at least 40 mL of UCB ( b ) were suffi cient to generate appropriate numbers 
of cells for therapeutic purposes. 
(c) 
(b) 
(a) 
INTRODUCTION 99

100 GMP-COMPLIANT PROPAGATION 
designed for each product so as to indicate its potency in a manner adequate to 
satisfy the interpretation of potency given by the defi nition in 21 CFR 600.3(s).  
Functional analyses accompanying the expansion process development leading to 
a full product characterization and optimization of manufacturing steps are prerequisites 
that allow for the creation of a safe and effective CBMP. 
This chapter demonstrates that rapid and standardized expansion of human 
MSCs to achieve a reasonable cell dose (i.e., . 2 . 10 6 /kg body weight of a 75 - kg 
person corresponding to . 1.5 . 10 8 MSCs) is feasible within less than four weeks. 
Replacing FBS with human platelet lysate (HPL) provides one strategy toward a 
safer CBMP (Figure 2 ). Appropriate preclinical development adhering to GMP 
principles will enhance safety in the course of a consecutive clinical evaluation of 
MSCs as a therapeutic agent. 
1.4.2 ACRONYMS AND DEFINITIONS 
1.4.2.1 Mesenchymal Stromal Cells 
Adhesion of mononuclear cells from human bone marrow aspirates (BM - MNC) to 
tissue culture plastic and removal of nonadherent cells during the fi rst days of 
culture selects for a population of proliferating spindle - shaped fi broblast - like non- 
FIGURE 2 GMP - compliant propagation of human MSCs. The summary of a 
two - step MSC production procedure shows seeding and harvest numbers of BM - MNC and 
resulting numbers of MSC HPL as compared to MSC FBS . ( Reproduced with permission from 
ref. 23 .) 
4 x 2.5mL heparinized BM Aspiration diluted 
immediately (without density gradient) in 
.-MEM / 10% FBS .-MEM / 10% HPL 
1 x 107 MNC / 60mL / 225cm 2 in 
10 - 20 x T225 or 1 -2 CF-4 ( < 105 BM-MNC/cm 2) 
8 x 106 MSC / 225cm 2 1 x 106 MSC / 225cm 2 
STORE: n x 3x10 5 
MSCHPL aliquots 
STORE: n x 1x10 6 
MSCFBS aliquots 
.-MEM / 10% HPL 
3 x 105 MSC / 1m 2 
.-MEM / 10% FBS 
3 x 105 MSC / 1m 2 
STEP II 
STEP I 
1 SEEDING 
day 0 
1 HARVEST 
. 10 - 16 days 
BM aspiration 
day 0 
2 HARVEST 
. 11 - 15 days 
2 SEEDING 
day 0 
3.0 - 5.4 x 10 8 MSCHPL 0.5  1.1 x 10 8 MSCFBS

hematopoietic multipotent MSCs. Mesenchymal stromal cells can also be obtained 
from umbilical cord blood, umbilical cord, placenta, adipose tissue, and several fetal 
tissues. The minimum criteria for MSCs are defi ned in an ISCT (International 
Society for Cellular Therapy) position paper published in 2006 [22] . The MSCs have 
a high self - renewal potential and the capacity to be differentiated in vitro into 
progeny displaying an osteo - , chondro - , or adipogenic phenotype. 
1.4.2.2 Somatic Stem Cell Therapy 
The concept of regenerative SCT is based on experimental and early clinical observations 
indicating that the application of adult stem cells can improve organ regeneration 
after ischemic, toxic, or metabolic injury. Bone marrow harbors hematopoietic 
and mesenchymal stem cells and endothelial progenitor cells and is an easily accessible 
but not the sole, source of candidate cells to promote organ repair after systemic 
or local application. Regulation of hematopoiesis and immune modulation 
are the two established applications in the broad fi eld of SCT with autologous and 
allogeneic stem and progenitor cells. 
1.4.2.3 Good Manufacturing Practice 
Good manufacturing practice is that part of the quality management system (QMS) 
that is concerned with the production and quality control of medicinal products 
(drugs) for human and veterinary use. It includes documentation, personnel training, 
facility, equipment, and process controls for the manufacture of pharmaceuticals. 
1.4.2.4 Cell - Based Medicinal Products 
Medicinal products containing viable cells are summarized under the umbrella term 
cell - based medicinal products . The term CBMP does not cover products containing 
nonviable cells or cellular fragments. The CBMPs may have much potential in the 
treatment of various diseases that to date have no cure. They are heterogeneous in 
terms of origin and type of cells and with regard to the complexity of the product. 
Cells may be self - renewing stem cells, more committed progenitors, or terminally 
differentiated cells exerting a specifi c regenerative function. Cells may be of autologous 
or allogeneic origin. Cells may be used alone or in combination with biomolecules, 
chemical substances, or structural materials that possibly potentiate their 
desired effects. 
1.4.2.5 Human Platelet Lysate 
Human platelet lysate can be obtained from buffy coat  derived platelet rich plasma. 
The platelet fraction is separated from the plasma and the white and red blood cell 
fraction by centrifugation steps and concentrated to a density of at least 1 . 10 9 platelets/
mL. Platelets can either be activated with thrombin or lysed by repeated freeze  
thaw cycles. Both mechanisms result in the release of growth factors and mitogens 
that are stored in intact platelets. Mediators released from platelets include, among 
others, epidermal growth factor (EGF), basic fi broblast growth factor (bFGF), platelet 
- derived growth factors (PDGFs), transforming growth factor (TGF - . 1), and 
insulinlike growth factor (IGF) [23, 24] . Perhaps HPL may replace FBS in many 
ACRONYMS AND DEFINITIONS 101

102 GMP-COMPLIANT PROPAGATION 
cell culture systems that have previously been thought to strictly depend on the 
presence of FBS. 
1.4.3 APPROACHES 
1.4.3.1 Adherence to Principles of GMP in a Preclinical Developmental Process 
The standardized MSC propagation should be conducted as a well - planned, consistently 
documented, and optimized procedure that also minimizes risks of microbiological, 
particulate and pyrogen contamination by reducing manipulation steps and 
manipulation time. According to current European legislation, 2 the principles of 
GMP should be applied to CBMP when they are manufactured for use in human 
subjects in phase 1 studies. These requirements do not apply to cellular or tissue - 
based medicinal products used in phase 1 studies according to U.S. legislation 3 or 
to products in the preclinical developmental phase. If it is expected that preclinical 
fi ndings are to be translated into clinical use rather rapidly, it may be recommended 
to establish GMP - compliant technology during the preclinical developmental 
phase of any cell product. As a result, this ensures that products are consistently 
produced and controlled to meet the quality standards appropriate for their intended 
use or product specifi cation. The GMP requirements are well described in  PIC/S 
Guide to Good Manufacturing Practice for Medicinal Products  and include 
the implementation of an effi ciently running quality management system, dedi - 
cated areas for manufacture of sterile medicinal products complying with GMP, 
appropriately qualifi ed and trained personnel, suitable equipment, correct materials, 
containers and labels, approved procedures and instructions, suitable storage and 
transport facilities, and a record - keeping system that allows the complete history of 
a medicinal product to be traced (See http://www.picscheme.org ). It is a challenge 
to conduct preclinical research and development complying to GMP as procedures 
routinely turn out to be much more time and cost intensive than common laboratory 
- scale research. These circumstances can advance either the developmental 
progress at the expense of quality standards or vice versa. It should therefore be 
decided on a case - by - case basis how closely to adhere to GMP standards depending 
on the more or less stringent time schedule for the considered clinical use of a 
CBMP. 
1.4.3.2 Effi cient Standardized MSC Propagation Using Low Cell 
Seeding Density 
The future use of MSCs in clinical studies may require very high absolute MSC 
numbers to gain appropriate cell doses ( > 5 . 10 6 /kg body weight) per patient compared 
to in vivo experimental models with small animals [20] . It is consequently 
advantageous to develop large - scale MSC expansion protocols that allow for the 
2 European legislation: Directive 65/65/EEC, Directive 75/318/EEC, Directive 75/318/EEC, Commission 
Communication on the Community marketing authorisation procedures for medicinal products 
(98/C229/03); Directive 2001/20/EC, EMEA/CHMP/410869/2006. 
3 U.S. legislation: 21 CFR 210; 21 CFR 211; 21 CFR 312.21; 21 CFR 312.22(a) and 21 CFR 
312.23(a)(7)(i). 

APPROACHES 103 
generation of up to 5 . 10 8  10 . 10 8 MSCs from the limited starting volume of 
primary material. 
The cell seeding density is of critical importance for the expansion rate of MSCs 
and must be defi ned for the primary seeding and the following passaging steps. Most 
experimental and clinical expansions described to date were started with a 
high seeding density of more than 1 . 10 5 BM - MNC/cm 2 [2, 14, 16] . For further passages 
pioneering studies showed that a very low seeding density between 0.5 and 
10 MSCs/cm 2 selects for the expansion of a rapidly proliferating subpopulation of 
recycling SCs, termed RS cells [25  28] . This seeding density, referred to as  clonal 
density,  would necessitate a theoretical growth area of from 2,000,000 to 100,000 cm 2 
(from 200 to 10 m 2 ) to obtain a clinical quantity of > 1 . 10 8 MSCs from 1 . 10 6 starting 
MSCs within one passage. Plating 30  100 MSCs/cm 2 therefore is a reasonable 
compromise density requiring a more realistic growth area between 10,000 and 
25,000 cm 2 (1 and 2.5 m 2 ). We have recently shown that the primary seeding of only 
10 mL bone marrow aspirates on approximately 0.2 m 2 culture area for two weeks 
(culture step 1; BM diluted immediately after aspiration in culture medium without 
density gradient separation; removal of nonadherent cells at day 3) followed by an 
expansion on 2.5 m 2 (step 2) is suffi cient to consistently generate at least 1.5 . 
10 8 MSCs in FBS - supplemented medium within less than four weeks (Figure 2 ) [29] . 
This study furthermore corroborated earlier data on the inverse correlation of the 
seeding density to MSC proliferation (Figure 3 ) [25  28] . 
1.4.3.3 Superior MSC Proliferation Resulting from HPL - Driven as Compared 
to FBS - Driven Cultures 
The most commonly used basic cell culture medium compositions for MSC propagation 
are minimum essential medium alpha ( . - MEM) and low - glucose (1 g/L) Dulbecco 
 s modifi ed Eagle medium (DMEM - LG) supplemented with l - glutamin, 
antibiotics, and 5  20% FBS [14, 16, 19, 24, 25, 30] . Our experience with MSC propagation 
relates to the use of . - MEM supplemented with either FBS or HPL. In 
contrast to HPL that has been recognized only recently as a potent culture medium 
supplement [24] , FBS is a well - known key medium supplement for cell culture and 
its role has been unchallenged for more than 50 years [31] . The common use of FBS 
in MSC cultures as a source of growth factors and mitogens bears the risk of transmission 
of known and unknown pathogens as well as xenoimmunization against 
bovine pathogens and should therefore be avoided for clinical use [32, 33] . 
In a recent study we analyzed the capacity of HPL to replace FBS in large - scale 
(clinical) MSC expansions and were able to demonstrate a superior propagation of 
MSC cultured with HPL (MSC HPL ) as compared to MSC derived from FBS - driven 
cultures (MSC FBS ) [23] . Figure 4 illustrates superior MSC proliferation at low plating 
density and higher population doublings (PDs) with HPL after a culture period of 
less than 14 days. 
1.4.3.4 Contamination Risks Can Be Minimized in 
Rational MSC Propagation Procedures 
Cell expansion is mainly performed according to labor - intensive time - consuming 
protocols using open systems that increase the risks of microbiological or particulate 
contamination and supplementation with potent antibiotics to control these prob

104 GMP-COMPLIANT PROPAGATION 
lems. Avoiding the use of penicillin during clinical - scale cell propagation follows the 
rationale to reduce the risk of sensitization as well as anaphylactic precipitation. 
Thus, it may be worthwhile not using other antibiotics for the GMP - compliant MSC 
propagation. One approach to minimize potential contamination risks is to rigorously 
reduce handling in the course of MSC propagation to the absolute minimum 
of necessary steps. In our experience, the commonly used density gradient centrifugation 
step can be skipped prior to the primary cell seeding of the bone marrow 
aspirate. Immediate dilution of limited volumes (e.g., 10  20 mL) of heparinized BM 
aspirate into supplemented . - MEM medium for direct cell seeding does not result 
in a loss of MSC recovery [23] . Furthermore, the aforementioned low cell seeding 
density and the employment of an increased growth area in a simplifi ed procedure 
together with the use of HPL in fact allow for an effi cient production of high MSC 
numbers within one to two harvest - replating cycles. The relatively short ex vivo 
expansion time of less than three to four weeks may be helpful in reducing the 
cumulative risk of contamination. 
1.4.4 TESTING METHODS 
1.4.4.1 Safety and Effi cacy of CBMP in Preclinical Stage 
The preclinical developmental period should be used for the extensive characterization 
of the CBMP. Release criteria have to be defi ned and reasonable time frames 
1000/cm2 
day 1 
day 3 
day 5 
day 10 
100/cm2 10/cm2 1/cm2 
P+1 P+1 
FIGURE 3 Inverse correlation of seeding density to MSC proliferation. BM - derived MSCs 
derived from passage 2 were seeded at log fold deescalated density of 1000, 100, 10, and 1 cm . 2 . 
Photographs were taken after 1, 3, 5, and 10 days of culture in . - MEM/10% FBS (original 
magnifi cation 40 . ). In the case of MSC seeded at 100 and 1000 cells/cm 2 confl uence necessitated 
trypsinisation between days 5 and 10 followed by reseeding at 100 and 1000 cells/cm 2 , 
respectively, and is therefore indicated as P + 1. 

must be set to allow for a high safety and quality standard of the fi nal cellular 
product. On the other hand, the logistic background should allow for a rapid release 
of the CBMP within a few hours due to the potential short shelf life of many cellular 
products. Ranges of cell purity, sterility, and absence of pyrogens and endotoxins 
are factors of utmost importance which must be determined. It is an inherent feature 
of CBMPs that product specifi cations must be adapted to the individual application. 
The challenge in the preclinical developmental phase is to fi nd satisfactory answers 
to unresolved questions in terms of cell type, source, dose, and mode of application 
according to the particular target disease. Thus, in - process controls and defi nitive 
release criteria must be met by each CBMP. Since many CBMPs are personalized 
medicine, potency assays must be performed for selected representative products 
(e.g., before initiating a study and consecutively once per year). 
1.4.4.2 Quality Controls During Cell Culture (In - Process Controls) and Final 
Product Release Criteria 
General Safety According the Food and Drug Administration (FDA), cellular 
therapy products are exempt from general safety testing [21 CFR 610.11(g)(1)]. 
Cell Dose The preclinical stage can be used to determine the specifi cations for the 
minimum effective and maximum tolerable number of viable and functional cells. 
The optimum dose of cells to be administered still needs to be established [20] . 
FIGURE 4 MSC proliferation capacity depends on seeding density in xenogeneic FBS and 
HPL - supplemented cultures. The inverse correlation of MSC proliferation to their seeding 
density resulted in the formation of a confl uent MSC layer in cultures starting with 1 MSC/cm 2 
in . - MEM/10% FBS and cultures starting with 1  10 MSCs/cm 2 in . - MEM/10% HPL but not 
when initiating cultures with the respective higher seeding densities within less than two 
weeks. The calculated fold increase of the cell number and corresponding population doublings 
from a representative experiment harvested at day 13 are shown. 
0
2
4
6
8 
10 
1/cm2 10/cm2 100/cm2 
FBS HPL 
FBS HPL 
1/cm2 1/cm2 
10/cm2 10/cm2 
100/cm2 100/cm2 
0 
200 
400 
600 
800 
1/cm2 10/cm2 100/cm2 
FBS HPL 
PD (d 13) Fold increase 
MSC cultured for 13 days 
TESTING METHODS 105

106 GMP-COMPLIANT PROPAGATION 
Viability Viability of MSCs can easily be determined immediately after trypsinization 
via trypan blue or 7 - amino - actinomycin D (7 - AAD) exclusion. According 
to the specifi cations developed from our cell culture studies, viability should be 
> 90%. In selected exceptional cases a lower limit of 70% viability of total harvested 
cells may be acceptable. 
Microbiological Testing Sterility testing that detects fungal, anaerobic, and aerobic 
bacterial and mycoplasma contamination should be performed after each critical 
manipulation step during MSC culture that is prone to microbiological contamination 
[34] . The crucial bacterial sterility check at the end of last harvesting step cannot 
be evaluated prior to in vivo application if MSCs need to be applied immediately 
after propagation due to the duration of the cultures. Mycoplasma polymerase chain 
reaction (PCR) results can be obtained at the day of harvest within less than 6 h. 
MycoAlert  results are available within less than 1 h at the day of harvest. Defi nitive 
culture results to exclude mycoplasma contamination are available within two to 
three weeks and therefore are not applicable for CBMPs with a short shelf life that 
are planned to be administered immediately after production. 
Endotoxin and Pyrogenicity Testing Endotoxin measurement using the Limulus 
amebocyte lysate (LAL) assay is typically done as an alternative to pyrogenicity 
testing for early phase trials. For any parenteral drugs, except those administered 
intrathecally, the FDA recommends that the upper limit for endotoxin be 5 EU/kg 
body weight/dose. The LAL assay method can be applied to the safety evaluation 
of biological preparations according to existing regulations. 4 We use the LAL assay 
to substitute for the lengthy delay in microbiological data availability to obtain 
results prior to the clinical application of the fi nal product within less than 2 h after 
harvest. 
Phenotypic Identity of MSC In addition to morphological identifi cation by microscopy, 
the immunophenotypic characterization of MSCs can be done using a broad 
panel of fl uorescence - conjugated antibodies directed against surface molecules. To 
date there is no specifi c marker uniquely defi ning MSCs. Therefore a profi le is used 
to show the expression of certain markers and to exclude the contamination by cells 
expressing other marker profi les. Flow cytometry is recommended by the ISCT to 
reveal that MSCs stain positive for CD73, CD90, and CD105 and negative for HLA - 
DR, CD14, CD31, CD34, and CD45 (Figure 5 ) [22, 23] . Much more extensive phenotypic 
analyses have been performed without retrieving additional information 
about MSC type or function [35] . Gene expression profi ling will hopefully result in 
a better defi nition of human MSCs [35  42] . 
1.4.4.3 MSC Functionality and Potency Assays 
Clonogenicity The self - renewal capacity of cells and the proportion of proliferating 
cells within a heterogeneous cell mixture can be evaluated using the CFU assay. 
4 Endotoxin testing, LAL, according to Eur. Pharm. 2.6.14 and Guideline on Validation of the Limulus 
Amebocyte Lysate Test as an End - Product Endotoxin Test for Human and Animal Parenteral Drug, 
Biological Products and Medical Devices, 1987, Sections I  IV, http://www.fda.gov/cber/gdlns/lal.pdf . 

A tissue culture method allowing for the clone counting of cells was fi rst describend 
in 1956 [43] . The introduction of bone marrow CFU assays led to the discovery of 
hematopoietic stem cells [44] . Fibroblast precursors existing within the hematopoietic 
system also have been evaluated with another specifi c CFU assay method 
introduced by Friedenstein in 1974 (CFU - F) [2] . We analyzed the clonal expansion 
capacity of MSC with the CFU - F method. Figure 6 shows differences in CFU - F 
appearance between MSC HPL and MSC FBS . In the case of primary BM appropriate 
dilution is necessary to determine the CFU - F frequency (Figure 7 ). Once MSCs are 
enriched, the appropriate MSC seeding density recommended for CFU - F enumeration 
may range from 1 to 5 MSCs/cm 2 [2, 29] . 
Osteo - , Chondro - , and Adipogenic Differentiation Isolated BM - derived MSCs 
were shown to differentiate along multiple mesechymal lineages in 1999 [45] . Evidence 
suggests MSCs can also express phenotypic characteristics of endothelial, 
neural, smooth muscle, skeletal myoblast, and cardiac myocyte cells [46] . The prototype 
pathways of MSC differentiation occur along osteogenic, chondrogenic, and 
adipogenic lineages and have been extensively demonstrated in a large number of 
publications [47] . This kind of potency assay may be performed regularly if bone or 
connective tissue repair is intended, although time limits do not enable immediate 
product release. 
FIGURE 5 Immune phenotype of human MSCs. Flow cytometric analysis of at least 10,000 
viable MSCs was used to determine antibody reactivity (gray - fi lled histograms) compared to 
appropriately diluted isotype controls (black line). Phenotypic criteria require positivity 
( . 90%) for CD73, CD90, and CD105 and negativity ( . 2%) for HLA - DR, CD14 (or CD11b), 
CD19 (or CD79 . ), CD34, and CD45. Absence of CD3+ T cells may be desirable in the case 
of GvHD treatment. Depending on the culture conditions, MSCs share reactivity with the 
anti-disialoganglioside antibody GD2 with neuroblastoma cells, melanoma, and small - cell 
lung cancer cells. 
HLA-AB CD 13 CD 29 CD 73 CD 90 CD105 CD 146 
CD 45 CD 3 HLA-DR CD 31 CD 14 CD 34 
FBS 
FBS 
HPL 
HPL 
GD-2 
CD 19 CD 133 
TESTING METHODS 107

108 GMP-COMPLIANT PROPAGATION 
Immune Modulatory Effects Mesenchymal stromal cells inhibit T - cell alloreactivity 
in mixed lymphocyte cultures (MLCs) or lymphocyte proliferation induced by 
mitogens, such as phytohemaglutinin (PHA) or concanavalin A [29, 48  51] . It is of 
note that high concentrations of MSCs (representing 10  40 MSCs per 100 responder 
lymphocytes) have an inhibitory effect while low MSC concentrations (0.1  1%) 
may stimulate lymphocyte proliferation in mixed lymphocyte cultures [50] . If MSCs 
are used for immunosuppressive therapies, these fi ndings may imply that high doses 
of MSCs are needed to inhibit T - cell proliferation in patients with graft - versus - host 
disease following allogeneic bone marrow transplantation. The application of low 
MSC numbers could stimulate lymphocyte proliferation in vivo and hence result in 
an undesirable boost to graft - versus - host disease as an adverse reaction of the MSC 
therapy. It is not clear so far whether the precise number of T cells in a 
given MSC transplant needs to be determined to exclude a potential boost to 
alloreactivity. Immune modulation can be measured with carboxyfl uorescein diacetate 
N - succinimidyl ester (CFSE) labeling of cells to quantify proliferation in 
response to allogeneic or mitogenic stimuli [52] . We analyzed the loss of CFSE fl uorescent 
intensity indicating cell proliferation by fl ow cytometry after culturing 
CFSE - labeled MNCs in the absence or presence of different numbers of MSCs [53] . 
The immune regulatory capacity of MSC HPL and MSC FBS was studied by measurement 
of allogenic MNC proliferation after co - culturing pairs of MNC from three 
different donors with two independent MSC HPL and two other MSC FBS (Figure 8 ). 
Hematopoiesis Regulation Regulation of the behavior of early hematopoietic 
progenitor cells (HPCs) can be analyzed by MSC - HPC cocultures in vitro [54] . 
FIGURE 6 Morphological evaluation of MSCs. CFU - F of MSC HPL compared to MSC FBS 
differ in size, morphology, and density (scale bar identifi es magnifi cation in the upper panel; 
colony photographs taken on day 12, 40 . original magnifi cation). 
HPL 
500.m 
FBS 
500.m

Liquid cultures of purifi ed CD34 + (HPC) with a preestablished MSC feeder layer 
result in the expansion of CD34 + /38 + HPC and CD34 + /38 . hematopoietic SCs and 
support the growth of mature hematopoietic total nucleated cell (TNC) progeny 
(Figure 9 ). 
Genetic Stability and Potential Tumorigenicity Genetic analysis of human MSCs 
is not well established. The signifi cance of standard metaphase chromosome G 
banding is limited due to the low number of metaphases recovered during standard 
analyses. Advances in multicolor fl uorescence in situ hybridization (FISH) and high - 
resolution array - based techniques may also soon be translated into practicable 
diagnostic tools in relation to CBMP safety in regenerative medicine [55] . 
Genetic instability can occur as a rare event after extended culture of mouse and 
human MSCs in FBS - supplemented medium [56, 57] . To test for potential in vivo 
tumor formation, MSCs derived from short - term clinical - scale expansions in FBS - 
or HPL - supplemented media were injected into immunocompromised athymic 
nude mice subcutaneously. Putative tumor formation was evaluated by histological 
analyses three months after injection of 2 . 10 6 and 2 . 10 4 MSCs and compared to 
controls that were injected 48 h prior to euthanasia. A primary cell deposit was 
visible immediately and 48 h after injection and MSCs could be recovered by conventional 
microscopic evaluation. However, none of 12 animals tested developed a 
macroscopic or microscopic detectable tumor over the 90 - day observation period 
[23] . In this situation, genetic testing may be encouraged for prospective data acqui- 
FIGURE 7 CFU - F Evaluation of MSCs depends on BM seeding density. An appropriate 
dilution of the heparinised BM aspiration is needed for accurate enumeration of the primary 
CFU - F frequency as indicated in this representative experiment where whole heparinized 
BM was seeded corresponding to the respective measured BM - MNC number per square 
centimeters of growth area, cultured for 11 days at 37  C/humidifi ed atmosphere/3% O 2 /5% 
CO2 . Nonadherent cells were removed at day 3. CFU - F are visualized by Harris hematoxylin 
staining. 
2.23 x 104 4.46 x 103 0.89 x 103 0.18 x 103 
Seeded MNC / cm2 
Day 11 
TESTING METHODS 109

110 GMP-COMPLIANT PROPAGATION 
FIGURE 8 MSC-mediated Immune Modulation. Allogeneic MNC proliferation (mean 
cell number  SEM) was measured after co - culturing pairs of MNC from three different 
donors with two independent MSC HPL and two other MSC FBS as shown in the bar chart. MSC 
were added in a 1 : 10 (3 . 10 4 MSC to 3 . 10 5 MNC/well; MNC[+PHA]:MSC = 10 : 1) or 1 : 100 
(MNC[+PHA]:MSC = 10 : 1) ratio to test their infl uence on PHA - driven proliferation of 
MNC. MNC numbers were measured by fl ow cytometric MNC count using BD Truecount TM 
tubes. As a control numbers of mitogen stimulated MNC without additional MSC 
(MNC[+PHA] only) and background proliferation without PHA stimulation (MNC w/o 
PHA) are shown. MSC did not induce MNC proliferation (MNC + MSC w/o PHA). Signifi - 
cant differences are marked by asterisks ( *p < 0.05 and * * p < 0.01). (Figure reproduced with 
permission from reference 53 ) 
MNC[+PHA]:MSC = 100:1 
MNC[+PHA] only 
MNC[+PHA]:MSC = 10:1 
MNC + MSC w/o PHA 
MNC w/o PHA 
0 
2x105 
4x105 
6x105 
8x105 
1x106 
1.2x106 
1.4x106 
CELL NUMBER 
HPL FBS

200 
CD34+ No 
0 
4x105 
8x105 
1,2x106 
1,6x106 
2x106 
50 
100 
150 
250 
0 
(b) 
(c) 
CD34+ FOLD INCREASE 
0 
3x106 
6x106 
8x106 
1,2x107 
1,5x107 
300 
1,8x107 
2,1x107 
TNC N o 
FOLD INCREASE 
20 
5
10 
15 
25 
0 
CD34 only CD34 
+ 
MSCFBS 
(a) 
FOLD INCREASE 
CELL NUMBER 
CD34 
+ 
MSCHPL 
CD34 only CD34 
+ 
MSCFBS 
CD34 
+ 
MSCHPL 
CD34+/CD38- No 
0 
1x105 
2x105 
3x105 
4x105 
12 
6
8 
10 
14 
0
4
2 
CD34 only CD34 
+ 
MSCFBS 
CD34 
+ 
MSCHPL 
CD34+/CD38- FI vs. CTRL 
FIGURE 9 MSC - mediated hematopoiesis regulation. ( a ) Umbilical cord blood (UCB) - 
derived sorted CD34 + cells were expanded in cytokine - supplemented medium [Roswell Park 
Memorial Institue (RMPI) - 1640/10% Fetal Bovine Serum (FBS)/Granulocyte and Macrophage 
Colony Stimulating Factor (GM - CSF)/Interleukin 3(IL - 3)/Stem Cell Factor (SCF)/ 
FMS-like tyrosin kinase 3 ligand (Flt - 3L)] in the absence or presence of clinical - scale 
expanded MSCs. Gray bars show harvested total nucleated cell number (TNC N  .) and black 
bars show the fold increase (FI) of the TNC N  . compared to the starting CD34 + cell number. 
( b ) Harvested number of CD34 + cells (gray bars) and fold increase (black bars) of CD34 + 
cells after liquid culture with or without MSC support. ( c ) Harvested number (gray bars) and 
fold increase (black bars) of CD34 + /CD38 . hematopoietic stem cells after liquid culture of 
CD34 + cells with MSC FBS or MSC HPL support compared to cytokine - supplemented liquid 
cultures in the absence of MSCs. (Mean  Standard Error of the Mean (SEM) of two independent 
expansions.) ( Reproduced with permission from ref. 53 .) 
TESTING METHODS 111

112 GMP-COMPLIANT PROPAGATION 
sition but is not considered as mandatory for product release in current MSC clinical 
trials. 
1.4.5 CONCLUSION 
There are considerable limitations of common pharmacological techniques used in 
determining the safety and effi cacy of CBMPs at the preclinical stage. Conventional 
methods used in the pharmaceutical industry to develop pharmacological profi les 
and to determine the acute toxicity of drugs in animals as well as toxicity studies 
may not directly be translated to ex vivo generated cellular products. Nevertheless, 
it is inevitable that preclinical research and development of cellular products will 
be conducted under the guidance of either individual or consensus specifi cations 
and defi nitions that will continuously be improved. This approach will be helpful in 
developing successful therapeutic cellular agents. 
ACKNOWLEDGMENTS 
This work was supported in part by The Adult Stem Cell Research Foundation 
(TASC RF ; C.B. and A.R.) and a young investigator fellowship of the Austrian Federal 
Ministry for Education, Science and Culture, bm:bwk (A.R.). The Austrian Nano - 
Initiative co - fi nanced this work as part of the Nano - Health project (no. 0200), the 
sub-project NANO - STEM being fi nanced by the Austrian Science Fund (FWF 
Project no. N211 - NAN). 
REFERENCES 
1. Luria , E. A. , Panasyuk , A. F. , and Friendenstein , A. Y. ( 1971 ), Fibroblast colony formation 
from monolayer cultures of blood cells , Transfusion , 11 ( 6 ), 345  349 . 
2. Friedenstein , A. J. , Deriglasova , U. F. , Kulagina , N. N. , et al. ( 1974 ), Precursors for fi broblasts 
in different populations of hematopoietic cells as detected by the in vitro colony 
assay method , Exp. Hematol. , 2 ( 2 ), 83  92 . 
3. Kuznetsov , S. A. , Friedenstein , A. J. , and Robey , P. G. ( 1997 ), Factors required for bone 
marrow stromal fi broblast colony formation in vitro , Br. J. Haematol. , 97 ( 3 ), 561  570 . 
4. Erices , A. , Conget , P. , and Minguell , J. J. ( 2000 ), Mesenchymal progenitor cells in human 
umbilical cord blood , Br. J. Haematol. , 109 ( 1 ), 235  242 . 
5. Kogler , G. , Sensken , S. , Airey , J. A. , et al. ( 2004 ), A new human somatic stem cell from 
placental cord blood with intrinsic pluripotent differentiation potential , J. Exp. Med. , 
200 ( 2 ), 123  135 . 
6. Bieback , K. , Kern , S. , Kluter , H. , and Eichler , H. ( 2004 ), Critical parameters for the isolation 
of mesenchymal stem cells from umbilical cord blood , Stem Cells , 22 ( 4 ), 625  634 . 
7. Romanov , Y. A. , Svintsitskaya , V. A. , and Smirnov , V. N. ( 2003 ), Searching for alternative 
sources of postnatal human mesenchymal stem cells: Candidate MSC - like cells from 
umbilical cord , Stem Cells , 21 ( 1 ), 105  110 . 
8. Miao , Z. , Jin , J. , Chen , L. , et al. ( 2006 ), Isolation of mesenchymal stem cells from human 
placenta: Comparison with human bone marrow mesenchymal stem cells , Cell. Biol. Int. , 
30 ( 9 ), 681  687 . 
9. In  t Anker , P. S. , Scherjon , S. A. , Kleijburg - van der Keur , C. , et al. ( 2004 ), Isolation of 
mesenchymal stem cells of fetal or maternal origin from human placenta , Stem Cells , 
22 ( 7 ), 1338  1345 . 

10. In  t Anker , P. S. , Scherjon , S. A. , Kleijburg - van der Keur , C. , et al. ( 2003 ), Amniotic fl uid 
as a novel source of mesenchymal stem cells for therapeutic transplantation , Blood , 
102 ( 4 ), 1548  1549 . 
11. Gronthos , S. , Franklin , D. M. , Leddy , H. A. , Robey , P. G. , Storms , R. W. , and Gimble , J. M. 
( 2001 ), Surface protein characterization of human adipose tissue - derived stromal cells , 
J. Cell Physiol. , 189 ( 1 ), 54  63 . 
12. Zuk , P. A. , Zhu , M. , Ashjian , P. , et al. ( 2002 ), Human adipose tissue is a source of multipotent 
stem cells , Mol. Biol. Cell , 13 ( 12 ), 4279  4295 . 
13. Kern , S. , Eichler , H. , Stoeve , J. , Kluter , H. , and Bieback , K. ( 2006 ), Comparative analysis 
of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue , 
Stem Cells , 24 ( 5 ), 1294  1301 . 
14. Lazarus , H. M. , Haynesworth , S. E. , Gerson , S. L. , Rosenthal , N. S. , and Caplan , A. I. ( 1995 ), 
Ex vivo expansion and subsequent infusion of human bone marrow - derived stromal 
progenitor cells (mesenchymal progenitor cells): Implications for therapeutic use , Bone 
Marrow Transplant. , 16 ( 4 ), 557  564 . 
15. Koc , O. N. , Peters , C. , Aubourg , P. , et al. ( 1995 ), Bone marrow - derived mesenchymal stem 
cells remain host - derived despite successful hematopoietic engraftment after allogeneic 
transplantation in patients with lysosomal and peroxisomal storage diseases . Exp. 
Hematol. , 27 ( 11 ), 1675  1681 . 
16. Koc , O. N. , Gerson , S. L. , Cooper , B. W. , et al. ( 2000 ), Rapid hematopoietic recovery after 
coinfusion of autologous - blood stem cells and culture - expanded marrow mesenchymal 
stem cells in advanced breast cancer patients receiving high - dose chemotherapy , J. Clin. 
Oncol. , 18 ( 2 ), 307  316 . 
17. Lee , S. T. , Jang , J. H. , Cheong , J. W. , et al. ( 2002 ), Treatment of high - risk acute myelogenous 
leukaemia by myeloablative chemoradiotherapy followed by co - infusion of T cell - 
depleted haematopoietic stem cells and culture - expanded marrow mesenchymal stem 
cells from a related donor with one fully mismatched human leucocyte antigen haplotype , 
Br. J. Haematol. , 118 ( 4 ), 1128  1131 . 
18. Koc , O. N. Day , J. , Nieder , M. , Gerson , S. L. , Lazarus , H. M. , and Krivit , W. ( 2002 ), 
Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy 
(MLD) and Hurler syndrome (MPS - IH) , Bone Marrow Transplant. , 30 ( 4 ), 
215  222 . 
19. Le Blanc , K. , Rasmusson, I. , Sundberg , B. , et al. (2004), Treatment of severe acute graft- 
versus - host disease with third party haploidentical mesenchymal stem cells , Lancet , 1, 
363 ( 9419 ), 1439  1441 . 
20. Lazarus , H. M. , Koc , O. N. , Devine , S. M. , et al. ( 2005 ), Cotransplantation of HLA - identical 
sibling culture - expanded mesenchymal stem cells and hematopoietic stem cells in hematologic 
malignancy patients , Biol. Blood Marrow Transplant. , 11 ( 5 ), 389  398 . 
21. Ringden , O. , Uzunel , M. , Rasmusson , I. , et al. ( 2006 ), Mesenchymal stem cells for 
treatment of therapy - resistant graft - versus - host disease , Transplantation , 81 ( 10 ), 1390  
1397 . 
22. Dominici , M. , Le Blanc , K. , Mueler , I. , et al. ( 2006 ), Minimal criteria for defi ning multipotent 
mesenchymal stromal cells. The International Society for Cellular Therapy position 
statement , Cytotherapy , 8 ( 4 ), 315  317 . 
23. Schallmoser , K. , Bartmann , C. , Rohde , E. , et al. ( 2007 ), Human platelet lysate can replace 
fetal bovine serum for clinical scale expansion of functional MSC , Transfusion . 2007 Aug; 
47 ( 8 ), 1436  1446 . 
24. Doucet , C. , Ernou , I. , Zhang , Y. Z. , et al. ( 2005 ), Platelet lysates promote mesenchymal 
stem cell expansion: A safety substitute for animal serum in cell - based therapy applications 
. J. Cell. Physiol. , 205 ( 2 ), 228  236 . 
REFERENCES 113

114 GMP-COMPLIANT PROPAGATION 
25. Digirolamo , C. M. , Stokes , D. , Colter , D. , Phinney , D. G. , Class , R. , and Prockop , D. J. 
( 1999 ), Propagation and senescence of human marro stromal cells in culture: A simple 
colony - forming assay identifi es samples with the greatest potential to propagate and differentiate 
, Br. J. Haematol. , 107 ( 2 ), 275  281 . 
26. Colter , D. C. , Class , R. , DiGirolamo , C. M. , Prockop , D. J. ( 2000 ), Rapid expansion of 
recycling stem cells in cultures of plastic - adherent cells from human bone marrow , Proc. 
Nat. Acad. Sci. USA , 97 ( 7 ), 3213  3218 . 
27. Colter , D. C. , Sekiya , I. , and Prockop , D. J. ( 2001 ), Identifi cation of a subpopulation of 
rapidly self - renewing and multipotential adult stem cells in colonies of human marrow 
stromal cells , Proc. Nat. Acad. Sci. USA , 98 ( 14 ), 7841  7845 . 
28. Sekiya , I. , Larson , B. L. , Smith , J. R. , Pochampally , R. , Cui , J. G. , and Prockop , D. J. ( 2002 ), 
Expansion of human adult stem cells from bone marrow stroma: Conditions that maximie 
the yields of early progenitors and evaluate their quality , Stem Cells , 20 ( 6 ), 530  541 . 
29. Bartmann , C. , Rohde , E. , Schallmoser , K. , et al. ( 2007 ), Two steps to functional MSC for 
clinical application , Transfusion . 2007 Aug; 47 ( 8 ), 1426  1435 . 
30. Horwitz , E. M. , Gordon , P. L. , Koo , W. K. , et al. ( 2002 ), Isolated allogeneic bone marrow - 
derived mesenchymal cells engraft and stimulate growth in children with osteogenesis 
imperfecta: Implications for cells therapy of bone , Proc. Natl. Acad. Sci. USA , 99 ( 13 ), 
8932  8937 . 
31. Pollard , J. W. ( 1989 ), Basic cell culture , in Pollard , J. W. , Ed., Animal Cell Culture , Human , 
Clifton, NJ , pp. 1  2 . 
32. WHO ( 1997 ), Medicinal and other products and human and animal transmissible spongiform 
encephalopathies: Memorandum from a WHO meeting , Bull. World Health Org. , 
75 ( 6 ), 505  513 . 
33. European Union ( 2004 ), Note for guidance on minimising the risk of transmitting animal 
spongiform encephalopathy agents via human and veterinary medicinal products 
(EMEA/410/01 Rev. 2  October 2003) adopted by the Committee for Proprietary Medicinal 
Products (CPMP) and by the Committee for Veterinary Medicinal Products (CVMP) , 
Off. J. Europ. Union , C24/26  C24/19 . 
34. Schallmoser , K. , Rosin , C. , Vormittag , R. , et al. ( 2006 ), Specifi cities of platelet autoantibodies 
and platelet activation in lupus anticoagulant patients: A relation to their history 
of thromboembolic disease , Lupus , 15 ( 8 ), 507  514 . 
35. Wagner , W. , Wein , F. , Seckinger , A. , et al. ( 2005 ), Comparative characteristics of mesenchymal 
stem cells from human bone marrow, adipose tissue, and umbilical cord blood , 
Exp. Hematol. , 33 ( 11 ), 1402  1416 . 
36. Ramalho - Santos , M. , Yoon , S. , Matsuzaki , Y. , Mulligan , R. C. , and Melton , D. A. ( 2002 ), 
 Stemness  : Transcriptional profi ling of embryonic and adult stem cells , Science , 298 ( 5593 ), 
597  600 . 
37. Boquest , A. C. , Shahdadfar , A. , Fronsdal , K. , et al. ( 2005 ), Isolation and transcription 
profi ling of purifi ed uncultured human stromal stem cells: Alteration of gene expression 
after in vitro cells culture , Mol. Biol. Cell , 16 ( 3 ), 1131  1141 . 
38. Shahdadfar , A. , Fronsdal , K. , Haug , T. , Reinholt , F. P. , and Brinchmann , J. E. ( 2005 ), In 
vitro expansion of human mesenchymal stem cells: Choice of serum is a determinant of 
cell proliferation, differentiation, gene expression, and transcriptome stability , Stem Cells , 
23 ( 9 ), 1357  1366 . 
39. Silva , W. A. , Jr. , Covas , D. T. , Panepucci , R. A. , et al. ( 2003 ), The profi le of gene expression 
of human marrow mesenchymal stem cells , Stem Cells , 21 ( 6 ), 661  669 . 
40. Panepucci , R. A. , Siufi , J. L. , Silva , W. A. , Jr. , et al. ( 2004 ), Comparison of gene expression 
of umbilical cord vein and bone marrow - derived mesenchymal stem cells , Stem Cells , 
22 ( 7 ), 1263  1278 . 

41. Jeong , J. A. , Hong , S. H. , Gang , E. J. , et al. ( 2005 ), Differential gene expression profi ling 
of human umbilical cord blood - derived mesenchymal stem cells by DNA microarray , 
Stem Cells , 23 ( 4 ), 584  593 . 
42. Monticone , M. , Liu , Y. , Tonachini , L. , et al. ( 2004 ), Gene expression profi le of human bone 
marrow stromal cells determined by restriction fragment differential display analysis , 
J. Cell. Biochem , 92 ( 4 ), 733  744 . 
43. Puck , T. T. , and Marcus , P. I. ( 1956 ), Action of x - rays on mammalian cells . J. Exp. Med. , 
103 ( 5 ), 653  666 . 
44. Tepperman , A. D. , Curtis , J. E. , and McCulloch , E. A. ( 1974 ), Erythropietic colonies in 
cultures of human marrow , Blood , 44 ( 5 ), 659  669 . 
45. Pittenger , M. F. , Mackay , A. M. , Beck , S. C. , et al. ( 1999 ), Multilneage potential of adult 
human mesenchymal stem cells , Science , 284 ( 5411 ), 143  147 . 
46. Pittenger , M. F. , and Martin , B. J. ( 2004 ), Mesenchymal stem cells and their potential as 
cardiac therapeutics , Circ. Res. , 95 ( 1 ), 9  20 . 
47. Delorme , B. C. S. , and Charbord , P. ( 2006 ), The concept of mesenchymal stem cells , Regenerative 
Med. , 1 ( 4 ), 497  509 . 
48. Di Nicola , M. , Carlo - Stella , C. , Magni , M. , et al. ( 2002 ), Human bone marrow stromal 
cells suppress T - lymphocyte proliferation induced by cellular or nonspecifi c mitogenic 
stimuli , Blood , 99 ( 10 ), 3838  3843 . 
49. Bartholomew , A. , Sturgeon , C. , Siatskas , M. , et al. ( 2002 ), Mesenchymal stem cells suppress 
lymphocyte proliferation in vitro and prolong skin graft survival in vivo , Exp. 
Hematol. , 30 ( 1 ), 42  48 . 
50. Le Blanc , K. , Tammik , L. , Sundberg , B. , Haynesworth , S. E. , and Ringden , O. ( 2003 ), 
Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic 
responses independently of the major histocompatibility complex , Scand. J. Immunol. , 
57 ( 1 ), 11  20 . 
51. Tse , W. T. , Pendleton , J. D. , Beyer , W. M. , Egalka , M. C. , and Guinan , E. C. ( 2003 ), Suppression 
of allogeneic T - cell proliferation by human marrow stromal cells: Implications 
in transplantation , Transplantation , 75 ( 3 ), 389  397 . 
52. Muller , I. , Kordowich , S. , Holzwarth , C. , et al. ( 2006 ), Animal serum - free culture conditions 
for isolation and expansion of multipotent mesenchymal stromal cells from human 
BM , Cytotherapy , 8 ( 5 ), 437  444 . 
53. Reinisch , A. , Bartmann , C. , Rohde , E. S. K. , Bjelic - Radisic , V. , Lanzer , G. , Linkesch , W. , 
and Strunk , D. ( 2007 ), A humanized system to propagate cord blood - derived mesenchymal 
stem cells for clinical application , Regen. Med. 2007 Jul; 2 ( 4 ), 371  382 . 
54. Robinson , S. N. , Ng , J. , Niu , T. , et al. ( 2006 ), Superior ex vivo cord blood expansion following 
co - culture with bone marrow - derived mesenchymal stem cells , Bone Marrow 
Transplant. , 37 ( 4 ), 359  366 . 
55. Speicher , M. R. , and Carter , N. P. ( 2005 ), The new cytogenetics: Blurring the boundaries 
with molecular biology , Nat. Rev. Genet. , 6 ( 10 ), 782  792 . 
56. Rubio , D. , Garcia - Castro , J. , Martin , M. C. , et al. ( 2005 ), Spontaneous human adult stem 
cell transformation , Cancer Res. , 65 ( 8 ), 3035  3039 . 
57. Tolar , J. , Nauta , A. J. , Osborn , M. J. , et al. ( 2007 ), Sarcoma derived from cultured mesenchymal 
stem cells , Stem Cells , 25 ( 2 ), 371  379 . 
REFERENCES 115


INTERNATIONAL REGULATIONS OF 
GOOD MANUFACTURING PRACTICES 
SECTION 2


119 
2.1 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc. 
NATIONAL GMP REGULATIONS AND 
CODES AND INTERNATIONAL GMP 
GUIDES AND GUIDELINES: 
CORRESPONDENCES AND 
DIFFERENCES 
Marko N a rhi and Katrina Nordstr o m 
Helsinki University of Technology, Helsinki, Finland 
Contents 
2.1.1 Introduction 
2.1.2 National GMP Regulations and Codes 
2.1.2.1 United States 
2.1.2.2 Canada 
2.1.2.3 European Union 
2.1.2.4 East Asian Countries 
2.1.2.5 India 
2.1.2.6 Australia 
2.1.2.7 New Zealand 
2.1.2.8 South Africa 
2.1.3 International GMP Guides and Harmonization 
2.1.3.1 World Health Organization 
2.1.3.2 Pharmaceutical Inspection Cooperation Scheme 
2.1.3.3 International Conference on Harmonization 
2.1.3.4 Association of Southeast Asian Nations (ASEAN) 
2.1.3.5 Mercado Comun del Sur (MERCOSUR) 
2.1.4 Correspondences of the U.S. GMP Regulations with GMP Codes and Guidelines 
2.1.4.1 General Issues 
2.1.4.2 Organization and Personnel 
2.1.4.3 Buildings and Facilities 
2.1.4.4 Equipment 
2.1.4.5 Control of Components and Drug Product Containers and Closures 
2.1.4.6 Production and Process Controls 

120 CORRESPONDENCES AND DIFFERENCES 
2.1.4.7 Packaging and Labeling Control 
2.1.4.8 Holding and Distribution 
2.1.4.9 Laboratory Controls 
2.1.4.10 Records and Reports 
2.1.4.11 Returned and Salvaged Drug Products 
References 
2.1.1 INTRODUCTION 
The fi rst predecessors of manufacturing and quality requirements, which later 
evolved into good manufacturing practices (GMPs), were issued in the 1940s in the 
United States by the Food and Drug Administration (FDA) [1] . In the general 
meeting of the World Health Organization (WHO) held in 1969, the World Health 
Assembly issued a recommendation for the introduction of GMPs [2] . Since then, 
most industrialized countries have passed laws on control procedures essential for 
the manufacture of drug products. In some countries GMPs are integrated into 
national legislation as a part of laws or regulations on production, distribution, 
marketing, and use of drug products (GMP regulations). In other countries, GMPs 
are separate guidelines outside the national drug legislation (GMP codes). In addition 
to national GMPs, also some international organizations and trade blocks have 
issued their own international GMP guidelines to harmonize the requirements for 
drug production in different countries. However, regardless of their origin, the main 
purpose of GMPs is to ensure that manufactured drug products have the safety, 
identity, potency, purity, and quality that they are presented to have [3] . To fulfi ll 
this aim, most GMPs usually cover quality management, personnel, premises, equipment, 
documentation, materials management, production and in - process controls, 
packaging and labeling of intermediate and fi nished products, laboratory controls, 
validation, and change controls [4] . 
2.1.2 NATIONAL GMP REGULATIONS AND CODES 
2.1.2.1 United States 
In the United States the production of drug products is controlled under the federal 
Food, Drug and Cosmetic Act, which states that a drug product will be deemed to 
be adulterated unless the methods used in or the facilities or controls used for its 
manufacture, processing, packaging, or holding conform to or are operated or 
administered in conformity with current GMP [5] . The actual GMP regulations are 
issued as a part of the Code of Federal Regulations and as such they are a federal 
law. The current set of GMP regulations is based on the 1978 revision [6, 7] of the 
original GMP regulations, which were fi rst promulgated in 1963. The GMP regulations 
are updated every year in April [8] ; however, no major changes have been 
implemented since 1978. As an addition to GMP regulations, the FDA also publishes 
other GMP - related guidance documents covering various issues of drug manufacturing 
[9] . On the other hand, although these documents refl ect current views and 

NATIONAL GMP REGULATIONS AND CODES 121 
expectations of the agency, they only provide guidance on principles and practices 
that are not legal requirements [1] . As a member of the International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceutical 
for Human Use (ICH), the United States has adopted the ICH guidance document 
Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, and 
published it as a guidance for industry document [10] . 
The U.S. GMP regulations are divided into two parts: 210 [6] and 211 [7] . Part 
210,  Current Good Manufacturing Practice in Manufacturing, Processing, Packing 
or Holding of Drugs  General,  provides the framework for the regulations [6] , and 
Part 211,  Current Good Manufacturing Practice for Finished Pharmaceuticals,  
states the actual requirements. Part 211 is further divided into 11 subparts, which 
cover the requirements for personnel, premises, equipment, control of materials, 
production and process controls, packaging and labeling control, holding and distribution, 
laboratory controls, documentation, and returned and salvaged products [7] . 
The contents of Part 211 are presented in Table 1 . 
2.1.2.2 Canada 
The production of drug products (drugs) in Canada is controlled under the Food 
and Drugs Act, which states that distributors and importers are not allowed to sell 
a drug product unless it has been manufactured according to the requirements of 
GMP. The principles of GMP are laid down by Division 2 in Part C of the Food and 
Drug Regulations, which is a part of the Food and Drugs Act [11] . The Health 
Products and Food Branch Inspectorate has also issued a guidance document (GMP 
code), which has been prepared to assist in the interpretation of GMP regulations. 
The current set of the Canadian GMP code was issued in 2002 and has not been 
revised since. It has been written with a view to harmonization with GMP standards 
of other countries and international organizations [WHO, Pharmaceutical Inspection 
Cooperation Scheme (PIC/S), ICH]. Canadian Healthcare authorities have also 
published several annexes to the basic GMP code covering topics such as GMP for 
medical gases, biological drug products, blood products, and production of investigational 
new drugs. In addition to the GMP code and its annexes, the Canadian 
TABLE 1 Contents of Part 211 of U . S . GMP Regulations [7] 
Section Subject 
Subpart A General provisions 
Subpart B Organization and personnel 
Subpart C Buildings and facilities 
Subpart D Equipment 
Subpart E Control of components and drug product containers and closures 
Subpart F Production and process controls 
Subpart G Packaging and labeling control 
Subpart H Holding and distribution 
Subpart I Laboratory controls 
Subpart J Records and reports 
Subpart K Returned and salvaged drug products 

122 CORRESPONDENCES AND DIFFERENCES 
authorities have also issued several other specifi c guidelines dealing with issues 
related to GMP and manufacturing methods [12] . 
As shown in Table 2 the Canadian GMP code can be divided into four chapters 
and three annexes. The fi rst three chapters cover general issues such as scope and 
applicability of the code, defi nitions of used terms, and issues concerning quality 
management and GMP in general. GMP regulations and their application are presented 
in the fourth chapter (  Regulation  ), which is divided into 14 subchapters 
covering the requirements for premises, equipment, personnel, sanitation, testing of 
components and packaging materials, testing of fi nished product, production control, 
quality control department, documentation, reserve samples, stability testing, and 
manufacture of sterile drug products and medical gases. Each subchapter contains 
the corresponding regulation according to regulations in Division 2 [11] issued with 
a rationale and interpretation to assist in their application. The annexes include 
requirements for batch certifi cation, application form for alternate sample retention 
site, and references such as hyperlinks to Canadian laws concerning drug products 
and other GMP - related national and international guidelines [12] . 
2.1.2.3 European Union 
The production of drug products (medicinal products) in the European Union (EU) 
is controlled under Directive 2001/83/EC of the European parliament and of the 
Council, which states that the holder of a manufacturing authorization for medicinal 
products is obliged to comply with good manufacturing practices as laid down by 
European Community law [13] . The principles and guidelines of GMP for medicinal 
products are stated by the Commission directive 2003/94/EC, which provides the 
TABLE 2 Contents of Canadian GMP Code [12] 
Introduction 
Quality management 
Glossary of terms 
Regulation 
Premises 
Equipment 
Personnel 
Sanitation 
Raw material testing 
Manufacturing control 
Quality control department 
Packaging material testing 
Finished product testing 
Records 
Samples 
Stability 
Sterile products 
Medical gases 
Annex A: Internationally Harmonized Requirements for 
Batch Certifi cation 
Annex B: Application for Alternate Sample Retention 
Annex C: References 

NATIONAL GMP REGULATIONS AND CODES 123 
legal basis for GMP in the EU [14] . The actual GMP code with detailed written 
procedures is published in The Rules Governing Medicinal Products in the European 
Union , volume 4. The current set of the EU GMP code was fi rst introduced in 1989 
consisting of nine chapters covering the general requirements of GMP and one 
annex on the manufacture of sterile drug products. Since then the EU GMP code 
has been revised many times and several new annexes have been issued [15] . In 
addition to the GMP code, the EU has also published several other guidelines concerning 
the quality issues of drug production in The Rules Governing Medicinal 
Products in the European Union , volume 3A [16] . 
As shown in Tables 3  5 , the EU GMP code is presented in two parts of basic 
requirements and 18 annexes. Part I,  Basic Requirements for Medicinal Products,  
covers GMP principles for the manufacture of drug products. It consists of nine 
chapters covering the requirements for quality management and control, personnel, 
premises, equipment, documentation, production, contract services, complaints, 
product recall, and self - inspection. Part II,  Basic Requirements for Active Substances 
Used as Starting Materials,  covers GMPs for active substances used as 
starting materials. It is based on the ICH document Q7, Good Manufacturing Practice 
Guide for Active Pharmaceutical Ingredients , and was originally introduced in 
2001 as Annex 18 of the EU GMP code. In the restructured revision of the EU 
GMP code issued in October 2005, Annex 18 was replaced with Part II. It consists 
of 19 chapters, which cover basic GMP issues related to quality management, personnel, 
premises, equipment, documentation, materials, production and process controls, 
packaging and labeling, storage and distribution, laboratory controls, validation, 
change control, complaints, recalls, contract services, co - operators, active pharmaceutical 
ingredients (APIs) manufactured by cell culture/fermentation, and APIs 
used in clinical trials. The annexes give more detailed specifi c guidance on the 
manufacture of sterile drug products, biological drug products, radiopharmaceuticals, 
veterinary drug products, medical gases, herbal drug products, oral liquids, 
external preparations (creams, ointments), aerosols, investigational new drugs, and 
blood and blood products. They also cover sampling of materials, computerized 
systems, use of ionizing radiation, qualifi cation and validation, batch release, parametric 
release, reference, and retention samples [15] . 
TABLE 3 Contents of Part I of EU GMP Code Covering 
Basic Requirements for Manufacture of Drug Products [15] 
Section Subject 
Introduction 
Chapter 1 Quality management 
Chapter 2 Personnel 
Chapter 3 Premises and equipment 
Chapter 4 Documentation 
Chapter 5 Production 
Chapter 6 Quality control 
Chapter 7 Contract manufacture and analysis 
Chapter 8 Complaints and product recall 
Chapter 9 Self - inspection 
Glossary 

124 CORRESPONDENCES AND DIFFERENCES 
TABLE 4 Contents of Part II of EU GMP Code Covering Basic Requirements for 
Manufacture of Active Substances Used as Starting Materials [15] 
Section Subject 
1 Introduction 
2 Quality management 
3 Personnel 
4 Buildings and facilities 
5 Process equipment 
6 Documentation and records 
7 Materials management 
8 Production and in - process controls 
9 Packaging and identifi cation labeling of APIs and intermediates 
10 Storage and distribution 
11 Laboratory controls 
12 Validation 
13 Change control 
14 Rejection and reuse of materials 
15 Complaints and recalls 
16 Contract manufacturers (including laboratories) 
17 Agents, brokers, traders, distributors, repackers, and relabelers 
18 Specifi c guidance for APIs manufactured by cell culture/fermentation 
19 APIs for use in clinical trials 
20 Glossary 
TABLE 5 Annexes of EU GMP Code Covering Specifi c Guidance [15] 
Section Subject 
Annex 1 Manufacture of sterile medicinal products 
Annex 2 Manufacture of biological medicinal products for human use 
Annex 3 Manufacture of radiopharmaceuticals 
Annex 4 Manufacture of veterinary medicinal products other than immunological 
veterinary medicinal products 
Annex 5 Manufacture of immunological veterinary medicinal products 
Annex 6 Manufacture of medicinal gases 
Annex 7 Manufacture of herbal medicinal products 
Annex 8 Sampling of starting and packaging materials 
Annex 9 Manufacture of liquids, creams, and ointments 
Annex 10 Manufacture of pressurised metered - dose aerosol preparations for inhalation 
Annex 11 Computerized systems 
Annex 12 Use of ionizing radiation in manufacture of medicinal products 
Annex 13 Manufacture of investigational medicinal products 
Annex 14 Manufacture of products derived from human blood or human plasma 
Annex 15 Qualifi cation and validation 
Annex 16 Certifi cation by a qualifi ed person and batch release 
Annex 17 Parametric release 
Annex 19 Reference and retention samples 

NATIONAL GMP REGULATIONS AND CODES 125 
2.1.2.4 East Asian Countries 
Japan In Japan the production of drug products (drugs) is regulated under the 
Pharmaceuticals Affairs Law (PAL), which states that any drug manufacturer who 
plans to manufacture a drug product for sale in Japan must have a Japanese drug 
manufacturing license and comply with Japanese GMP requirements. The fi rst regulations 
of Japanese GMP were introduced in 1974 as The Standards for Manufacturing 
Control and Quality Control . In 1979 PAL was partially revised and GMPs 
became legally binding [2] . 
PAL is managed and enforced via ministerial ordinances and notices, which are 
detailed regulations prepared by the Japanese government. The requirements for 
premises for drug manufacture are given in Ministry of Health, Labor and Welfare 
(MHLW) Ministerial Ordinance No. 73, 2005 Regulations for Buildings and Facilities 
for Pharmacies, etc. [originally Ministry of Health and Welfare (MHW) Ministerial 
Ordinance No. 2, 1961] [17] , and the requirements for manufacturing and quality 
controls in MHLW Ministerial Ordinance No. 95, 2003 Regulations for Manufacturing 
Control and Quality Control of Drugs (originally MHW Ministerial Ordinance 
No. 3, 1994). As a member of the ICH Japan has adopted the ICH guidance 
document Q7, Good Manufacturing Practice Guide for Active Pharmaceutical 
Ingredients , and published it as Pharmaceutical and Food Safety Bureau (PFSB) 
Director - General Notifi cation No. 1200, 2001 Guidelines on GMP for Drug Substances 
, which states the requirements for the manufacture of APIs. The requirements 
concerning imported drug products are given in MHLW Ministerial Ordinance 
No. 97, 2003 Regulations for Importing/Retail Management and Quality Control of 
Drugs and Quasi - Drugs (originally MHW Ministerial Ordinance No. 62, 1999). The 
requirements specifying manufacture of investigational products are given in PAB 
Notifi cation No. 480, 1997 Products and Standards for the Buildings and Facilities of 
Manufacturing Plants for Investigational Products (Investigational Product GMP) 
[2] . 
South Korea The production of drug products (drugs) in South Korea is regulated 
under the Pharmaceutical Affairs Law, which was fi rst enacted in 1953 and has since 
been revised several times [18] . New drug approval and related activities are regulated 
in much the same way as in the United States and Japan. Korean GMP, which 
is often called KGMP, was initiated in 1984 and became mandatory in 1995 [19] . A 
drug manufacturer who intends to manufacture a drug product for sale in Korea 
must have approval from the Commissioner of the Korea Food and Drug Administration 
(KFDA). In order to require the license for manufacturing business the 
manufacturer has to prove the compliance of facility standards with KGMP [20] . 
China China regulates the production of drug products (drugs) under the Drug 
Administration Law of the People  s Republic of China, which states that a drug 
manufacturer has to conduct drug manufacture according to the GMP for pharmaceutical 
products formulated by the Drug Regulatory Department under the State 
Council on the basis of the Drug Administration Law [21] . In June 2004 GMP 
became mandatory in China and the State Drug Administration announced that 
local drug manufacturing establishments lacking approved GMP certifi cation would 
not be allowed to continue the production of pharmaceuticals [22] . 

126 CORRESPONDENCES AND DIFFERENCES 
2.1.2.5 India 
The production of drug products (drugs) in India is controlled under the Drugs and 
Cosmetics Rules (1945, last amended in 2005), which states that the holder of the 
license to manufacture drugs has to comply with the requirements of GMP as laid 
down in Schedule M [23] . Schedule M is a part of the Drugs and Cosmetics Rules 
and embodies the Indian GMP regulations [24] , which are based on the 1982 version 
of WHO GMP guidelines [25] . 
As shown in Tables 6  8 the Indian GMP regulations consists of eight parts: I, IA, 
IB, IC, ID, IE, IF, and II. Part I covers the general requirements of GMP. It is divided 
into 29 chapters, which deal with the requirements for personnel, premises, equipment, 
sanitation, production and process controls, materials, documentation, quality 
management, validation, reserve samples, recalls, complaints, and self - inspection. 
Parts IA to IE cover specifi c requirements for the manufacture of different dosage 
forms regarding premises, equipment, and methods. Part IA deals with the require- 
TABLE 6 Contents of Part I of Indian GMP Regulations 
Covering Good Manufacturing Practices for Premises and 
Materials [24] 
Section Subject 
1 General requirements 
2 Warehousing area 
3 Production area 
4 Ancillary areas 
5 Quality control area 
6 Personnel 
7 Health, clothing, and sanitation of workers 
8 Manufacturing operations and control 
9 Sanitation in the manufacturing premises 
10 Raw materials 
11 Equipment 
12 Documentation and records 
13 Labels and other printed materials 
14 Quality assurance 
15 Self - inspection and quality audit 
16 Quality control system 
17 Specifi cation 
18 Master formula records 
19 Packing records 
20 Batch packaging records 
21 Batch processing records 
22 Standard operating procedures (SOPs) and records 
23 Reference samples 
24 Reprocessing and recoveries 
25 Distribution records 
26 Validation and process validation 
27 Product recalls 
28 Complaints and adverse reactions 
29 Site master fi le 

NATIONAL GMP REGULATIONS AND CODES 127 
ments for the manufacture of parenteral preparations; Part IB with the requirements 
for the manufacture of oral solid dosage forms such as tablets and capsules; 
Part IC with the requirements for the manufacture of oral liquids such as syrups, 
elixirs, emulsions, and suspensions; Part ID with the requirements for the manufacture 
of external preparations such as creams, ointments, pastes, emulsions, and 
lotions; and Part 1E with the requirements for the manufacture of inhalers. Part 1F 
covers specifi c requirements for the manufacture of APIs regarding buildings and 
facilities, utilities, equipment, controls, and containers. Part II of the Indian GMP 
regulations consist of detailed recommendations for the process equipment to be 
used in the manufacture of different dosage forms and requirements for the partition 
of the production area [24] . 
TABLE 7 Contents of Parts IA , IB , IC , ID , IE , and IF of Indian GMP Regulations 
Covering Specifi c Guidance [24] 
Section Subject 
Part IA Specifi c requirements for manufacture of sterile products, parenteral 
preparations (small - volume injectables and large - volume parenterals) and 
sterile ophthalmic preparations 
Part IB Specifi c requirements for manufacture of oral solid dosage forms (tablets and 
capsules) 
Part IC Specifi c requirements for manufacture of oral liquids (syrups, elixirs, 
emulsions, and suspensions) 
Part ID Specifi c requirements for manufacture of topical products, i.e., external 
preparations (creams, ointments, pastes, emulsions, lotions, solutions, dusting 
powders, and identical products) 
Part IE Specifi c requirements for manufacture of metered - dose inhalers (MDIs) 
Part IF Specifi c requirements of premises, plant, and materials for manufacture of 
active pharmaceutical ingredients (bulk drugs) 
TABLE 8 Contents of Part II of Indian GMP Regulations 
Covering Requirements of Plant and Equipment [24] 
Section Subject 
1 External preparations 
2 Oral liquid preparations 
3 Tablets 
4 Powders 
5 Capsules 
6 Surgical dressing 
7 Ophthalmic preparations 
8 Pessaries and suppositories 
9 Inhalers and vitrallae 
10 Repacking of drugs and pharmaceutical chemicals 
11 Parenteral preparations 

128 CORRESPONDENCES AND DIFFERENCES 
2.1.2.6 Australia 
In Australia the production of drug products (medicinal products) is controlled 
under the Therapeutics Goods Act, which provides the Minister for Health and 
Aged Care the right to determine written principles including codes of GMP to be 
observed in the production of drug products for use in humans [26] . The Therapeutic 
Goods (Manufacturing Principles) Determination No. 2 of 2002 given by the 
minister states that drug products must be manufactured in compliance with the 
Australian Code of Good Manufacturing Practice for Medicinal Products , dated 
August 16, 2002 [27] . The current set of the Australian GMP code is based entirely 
on the PIC/S GMP guide version PH 1/97 (Rev. 3) published in 2002 with some 
minor modifi cations [28] . 
As shown in Table 9 , the Australian GMP code consists of 9 chapters and 13 
annexes. The chapters present the general requirements of GMP for the manufacture 
of drug products, the requirements for quality management and control, 
personnel, premises, equipment, documentation, production, contract services, complaints, 
product recall, and self - inspection. The annexes give specifi c guidance on 
the manufacture of sterile drug products, biological drug products, radiopharmaceuticals, 
medical gases, herbal drug products, oral liquids, external preparations (creams, 
ointments), aerosols, investigational new drugs, blood, and blood products. They also 
TABLE 9 Contents of Australian GMP Code [28] 
Section Subject 
Introduction 
Interpretation 
Chapter 1 Quality management 
Chapter 2 Personnel 
Chapter 3 Premises and equipment 
Chapter 4 Documentation 
Chapter 5 Production 
Chapter 6 Quality control 
Chapter 7 Contract manufacture and analysis 
Chapter 8 Complaints and product recall 
Chapter 9 Self - inspection 
Annex 1 Manufacture of sterile medicinal products 
Annex 2 Manufacture of biological medicinal products for human use 
Annex 3 Manufacture of radiopharmaceuticals 
Annex 6 Manufacture of medicinal gases 
Annex 7 Manufacture of herbal medicinal products 
Annex 8 Sampling of starting and packaging materials 
Annex 9 Manufacture of liquids, creams, and ointments 
Annex 10 Manufacture of pressurised metered - dose aerosol preparations for 
inhalation 
Annex 11 Computerized systems 
Annex 12 Use of ionizing radiation in the manufacture of medicinal products 
Annex 13 Manufacture of investigational medicinal products 
Annex 15 Qualifi cation and validation 
Annex 17 Parametric release 
Glossary 

NATIONAL GMP REGULATIONS AND CODES 129 
cover sampling of materials, computerized systems, use of ionizing radiation, quali- 
fi cation, and validation and parametric release [28] . 
Australia has not adopted Annexes 4, 5, 14, 16, and 18 of the PIC/S GMP guide. 
Annexes 4 and 5 cover the manufacture of veterinary drug products. Annex 14 
covers the manufacture of products derived from human blood or human plasma, 
which is excluded from the Australian GMP code. Annex 16 is specifi c to the EU 
GMP code and Annex 18 is the ICH GMP guide for the manufacture of APIs, which 
Australia has adopted separately as a manufacturing principle [28] . 
2.1.2.7 New Zealand 
The production of drug products (medicines) in New Zealand is controlled under 
the Medicines Act 1981, which states that a drug manufacturer is not allowed to 
manufacture drug products without a manufacturing license issued by the licensing 
authority. In order to obtain a manufacturing license the applicant must satisfy the 
licensing authority with respect to the proposed manufacturing premises and equipment, 
which must be suitable and adequate for the manufacture of drugs. Moreover, 
the applicant must show that adequate arrangements have been made or are to be 
made for the making, maintaining, and safekeeping of adequate records with reference 
to the drug products that are to be manufactured [29] . The authorities (Medsafe) 
require that any drug manufacturer who plans to manufacture drug products for 
sale in New Zealand must deliver evidence of GMP compliance for the manufacturing 
site. Copies of appropriate certifi cates, manufacturing licenses, or reports issued 
by a regulatory authority whose competence is recognized by Medsafe are accepted 
as proof of GMP compliance [30] . 
As shown in Table 10 New Zealand  s own GMP code consists of fi ve parts. The 
fi rst part covers the manufacture of drug products and the second part the manufacture 
of blood products. Part 3 covers compounding and dispensing, including 
compounding of sterile drug products. Part 4 deals with wholesaling and Part 5 with 
product recalls. Parts 4 and 5 are combined in one document [31] . 
2.1.2.8 South Africa 
South Africa controls the production of drug products (medicines) under the Medicines 
and Related Substances Control Act (Act 101 of 1965), which states that the 
Medicines Control Council may issue to a drug manufacturer a license to manufacture 
a drug product upon such conditions as to the application of such acceptable 
TABLE 10 Contents of New Zealand  s GMP Code [31] 
Section Subject 
Part 1 Manufacture of pharmaceutical products 
Part 2 Manufacture of blood and blood products 
Part 3 Compounding and dispensing 
Part 4 Wholesaling of medicines and medical devices 
Part 5 Uniform recall procedure for medicines and 
medical devices 

130 CORRESPONDENCES AND DIFFERENCES 
quality assurance principles and GMPs as the council may determine [32] . As a part 
of the license application the manufacturer must provide acceptable documentary 
proof of the ability to comply with GMP as determined by the council [33] . The 
current set of South African GMP code determined by the council is entirely based 
on the PIC/S GMP guide version PE 009 - 2, published in 2004 with some minor 
modifi cations [34] . 
As shown in Table 11 the South African GMP code consists of 9 chapters and 17 
annexes. The chapters present the general requirements of GMP for the production 
of drug products covering the requirements for quality management and control, 
personnel, premises, equipment, documentation, production, contract services, complaints, 
product recall, and self - inspection. The annexes give specifi c guidance on 
the manufacture of sterile drug products, biological drug products, radiopharmaceuticals, 
veterinary drug products, medical gases, herbal drug products, oral liquids, 
external preparations (creams, ointments), aerosols, investigational new drugs, and 
blood and blood products. They also cover sampling of materials, computerized 
systems, use of ionizing radiation, qualifi cation and validation, organization, and 
TABLE 11 Contents of South African GMP Code [34] 
Section Subject 
Introduction 
Chapter 1 Quality management 
Chapter 2 Personnel 
Chapter 3 Premises and equipment 
Chapter 4 Documentation 
Chapter 5 Production 
Chapter 6 Quality control 
Chapter 7 Contract manufacture and analysis 
Chapter 8 Complaints and product recall 
Chapter 9 Self - inspection 
Annex 1 Manufacture of sterile medicinal products 
Annex 2 Manufacture of biological medicinal products for human use 
Annex 3 Manufacture of radiopharmaceuticals 
Annex 4 Manufacture of veterinary medicinal products other than 
immunologicals 
Annex 5 Manufacture of immunological veterinary medical products 
Annex 6 Manufacture of medicinal gases 
Annex 7 Manufacture of herbal medicinal products 
Annex 8 Sampling of starting and packaging materials 
Annex 9 Manufacture of liquids, creams, and ointments 
Annex 10 Manufacture of pressurized metered - dose aerosol preparations for 
inhalation 
Annex 11 Computerized systems 
Annex 12 Use of ionizing radiation in the manufacture of medicinal products 
Annex 13 Manufacture of investigational medicinal products 
Annex 14 Manufacture of products derived from human blood or human plasma 
Annex 15 Qualifi cation and validation 
Annex 16 Organisation and personnel 
Annex 17 Parametric release 
Glossary 

personnel and parametric release. The original Annex 16, which is specifi c to the 
EU GMP code, has been replaced in South African GMP code with an annex covering 
organization and personnel. Nor has South Africa adopted Annex 18, which 
covers the ICH GMP guide for the manufacture of APIs, as it has been adopted 
separately as a manufacturing principle [34] . 
2.1.3 INTERNATIONAL GMP GUIDES AND HARMONIZATION 
2.1.3.1 World Health Organization 
The WHO was established in 1948 as a specialized agency of the United Nations 
(UN). Its purpose is to serve as the directing and coordinating authority for international 
health matters and public health. One of the main functions of the WHO 
is to provide objective and reliable information and advice in the fi eld of human 
health, a task that it partly fulfi lls through WHO publications [35] . The fi rst WHO 
draft text on GMP was prepared in 1967 and a revised version was published in 
1968 as an annex of the twenty - second report of the WHO expert committee on 
specifi cations for pharmaceutical preparations. Over the years the WHO has issued 
several versions of its GMP guidelines as well as other guidelines related to the 
GMP and quality issues of the production of therapeutic products. The latest version 
of the WHO GMP guideline was published in 2003 as an annex of the WHO Technical 
Report 908 [36] . 
As shown in Table 12 the WHO GMP guideline is divided into fi ve parts: introduction, 
general considerations, glossary, quality management in the drug industry, 
and references. The actual GMP guidelines are presented in the fourth part, which 
consists of 17 chapters covering the requirements for quality assurance and control, 
personnel, premises, equipment, sanitation, materials, validation, documentation, 
production, contract services, complaints, recalls, and self - inspection [36] . In addition 
to this guideline laying down the main principles of GMP, the WHO has also published 
several other guidelines covering specifi c requirements for components, 
quality of water for pharmaceutical use, APIs, excipients, sterile drug products, 
biological drug products, investigational drug products, herbal drug products, and 
radiopharmaceuticals (Table 13 ). 
2.1.3.2 Pharmaceutical Inspection Cooperation Scheme 
The Pharmaceutical Inspection Convention (PIC), which is the predecessor of 
PIC/S, was founded in 1970 by the European Free Trade Area (EFTA). The initial 
members comprised of the 10 EFTA member countries at that time. From the beginning 
one of the main goals has been the harmonization of GMP requirements as 
well as the promotion of mutual recognition of inspections and uniformity of inspection 
systems by training the inspectors, improving the exchange of information, and 
mutual confi dence [46] . Originally PIC was a formal treaty between member countries 
and as such it also had a legal status. When countries outside Europe were 
seeking to join PIC, it became evident that, according to European law, individual 
EU countries that were members of PIC were not permitted to sign agreements 
with countries outside Europe. Only the European Commission, which itself was 
INTERNATIONAL GMP GUIDES AND HARMONIZATION 131

132 CORRESPONDENCES AND DIFFERENCES 
not a member of PIC, was permitted to sign agreements. Consequently, a less formal 
and more fl exible PIC/S was developed to continue the work of PIC. The PIC/S, 
which became operational in November 1995, is an informal arrangement without 
legal status between regulatory authorities instead of countries. The PIC and the 
PIC Scheme, operating together as PIC/S, provide an active and constructive cooperation 
in the fi eld of GMP [47] . 
The current members of PIC/S are Australia, Austria, Belgium, Canada, Czech 
Republic, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, 
TABLE 12 Contents of WHO GMP Guideline Covering General Requirements of GMP 
for Manufacture of Drug Products [36] 
Introduction 
General considerations 
Glossary 
Quality management in the drug industry: philosophy and essential elements 
Section Subject 
1 Quality assurance 
2 Good manufacturing practices for pharmaceutical products (GMP) 
3 Sanitation and hygiene 
4 Qualifi cation and validation 
5 Complaints 
6 Product recalls 
7 Contract production and analysis 
8 Self - inspection and quality audits 
9 Personnel 
10 Training 
11 Personal hygiene 
12 Premises 
13 Equipment 
14 Materials 
15 Documentation 
16 Good practices in production 
17 Good practices in quality control 
References 
TABLE 13 GMP -Related WHO Documents Covering Specifi c Guidance 
Document Subject 
TRS 929, Annex 2 [37] Requirement for the sampling of starting materials 
TRS 823, Annex 1 [38] Active pharmaceutical ingredients (bulk drug substances) 
TRS 885, Annex 5 [39] Pharmaceutical excipients 
TRS 902, Annex 6 [40] Sterile pharmaceutical products 
TRS 834, Annex 3 [41] Biological products 
TRS 863, Annex 7 [42] Investigational pharmaceutical products for clinical trials 
in humans 
TRS 863, Annex 8 [43] Herbal medicinal products 
TRS 908, Annex 3 [44] Radiopharmaceutical products 
TRS 929, Annex 3 [45] Water for pharmaceutical use 

Italy, Latvia, Liechtenstein, Malaysia, Netherlands, Norway, Poland, Portugal, 
Romania, Singapore, Slovak Republic, Spain, Sweden, Switzerland, and the United 
Kingdom. In addition, Estonia, the European Agency for the Evaluation of Medicinal 
Products (EMEA), UNICEF, and the WHO participate in PIC/S activities as 
observers [48] . Also many other regulatory authorities have shown interest in joining 
PIC/S, in particular Argentina, Brazil, Cyprus, Indonesia, Israel, Philippines, 
Slovenia, Thailand, the United States, Bulgaria, Estonia, Lithuania, Oman, Russia, 
South Africa, and the Ukraine [49] . 
To become a PIC/S member, a joining regulatory authority is required to go 
through a detailed assessment to prove that the authority has the arrangements and 
competence necessary to apply an inspection system equivalent to inspection 
systems of existing PIC/S members. To ensure that both new applicants and older 
members fulfi ll the same requirements, also existing members are reassessed on a 
regular basis. One of the main functions of PIC/S is to develop GMP guidance documents, 
which it carries out in close cooperation with the EU and relevant agencies 
thereof. Under this cooperation both parties have been able to adopt each others  
documents, thus minimizing the duplication of effort in development of GMP - 
related documents. Among other highly informative guides on various aspects of 
GMP and quality issues [49] , PIC/S has also published its own GMP guide ( Guide 
to Good Manufacturing Practice for Medicinal Products ), which is harmonized with 
the EU GMP code [50] . 
The latest revision of the PIC/S GMP guide (version PE 009 - 3) was issued in 
January 2006. As shown in Table 14 , it consists of 9 chapters and 16 annexes. Chapters 
present the general requirements of GMP for the production of drug products 
covering the requirements for quality management and control, personnel, premises, 
equipment, documentation, production, contract services, complaints, product recall, 
and self - inspection. The annexes give specifi c guidance on the manufacture of sterile 
drug products, biological drug products, radiopharmaceuticals, veterinary drug products, 
medical gases, herbal drug products, oral liquids, external preparations (creams, 
ointments), aerosols, investigational new drugs, and blood and blood products. In 
addition, there are annexes covering the sampling of materials, computerized 
systems, use of ionizing radiation, qualifi cation and validation, and parametric 
release [50] . 
Although the PIC/S GMP guide is harmonized with the EU GMP code and their 
contents are similar, there are some minor differences between them. Instead of the 
term qualifi ed person , the PIC/S GMP guide uses the term authorized person . Furthermore, 
all references to EU directives have been deleted from the PIC/S GMP 
guide. Moreover, PIC/S has not adopted Annexes 16 and 18 of the EU GMP code. 
Annex 16 is specifi c to the EU GMP code covering the status of a qualifi ed person 
in batch release and Annex 18 is the ICH GMP guide for the manufacture of APIs, 
which the PIC/S Committee has adopted as a stand - alone document (PE 007) 
[50] . 
2.1.3.3 International Conference on Harmonization 
The ICH was established in 1990. Its main aim is to improve the effi ciency of the 
drug development process and the registration of new drug products in its member 
countries through harmonization of national guidelines. This is a joint initiative 
INTERNATIONAL GMP GUIDES AND HARMONIZATION 133

134 CORRESPONDENCES AND DIFFERENCES 
involving both regulators and industry as equal partners. The founders and current 
members of ICH, which represent the regulatory bodies and the research - based 
industry in the member countries, are the EU, European Federation of Pharmaceutical 
Industries and Associations (EFPIA), MHLW, Japan Pharmaceutical Manufacturers 
Association (JPMA), FDA, and Pharmaceutical Research and Manufactures 
of America (PhRMA). In addition to the actual member countries there are also 
observers who act as a link between ICH and non - ICH countries and regions. 
Current observers are the WHO, EFTA, Swissmedic (representing Switzerland), and 
Health Canada (representing Canada) [51] . 
Among other guidelines, ICH has also published a guide on GMP for APIs (Q7: 
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients ). It is 
intended to provide guidance regarding GMP for the manufacture of APIs and to 
help ensure that APIs meet the quality and purity requirements that they are presented 
to possess. This covers APIs that are manufactured by chemical synthesis, 
extraction, cell culture/fermentation, recovery from natural sources, or any combination 
of these processes. Excluded are vaccines, medical gases, bulk - packaged drug 
TABLE 14 Contents of PIC / S GMP Guide [50] 
Section Subject 
Introduction 
Chapter 1 Quality management 
Chapter 2 Personnel 
Chapter 3 Premises and equipment 
Chapter 4 Documentation 
Chapter 5 Production 
Chapter 6 Quality control 
Chapter 7 Contract manufacture and analysis 
Chapter 8 Complaints and product recall 
Chapter 9 Self - inspection 
Annex 1 Manufacture of sterile medicinal products 
Annex 2 Manufacture of biological medicinal products for human use 
Annex 3 Manufacture of radiopharmaceuticals 
Annex 4 Manufacture of veterinary medicinal products other than 
immunologicals 
Annex 5 Manufacture of immunological veterinary medical products 
Annex 6 Manufacture of medicinal gases 
Annex 7 Manufacture of herbal medicinal products 
Annex 8 Sampling of starting and packaging materials 
Annex 9 Manufacture of liquids, creams, and ointments 
Annex 10 Manufacture of pressurised metered - dose aerosol preparations for 
inhalation 
Annex 11 Computerized systems 
Annex 12 Use of ionizing radiation in manufacture of medicinal products 
Annex 13 Manufacture of investigational medicinal products 
Annex 14 Manufacture of products derived from human blood or human plasma 
Annex 15 Qualifi cation and validation 
Annex 17 Parametric release 
Glossary 

products, radiopharmaceuticals, whole cells, whole blood and plasma, blood and 
plasma derivatives, and gene therapy APIs. However, APIs that are produced 
using blood or plasma as raw materials are included [52] . All ICH member countries 
have adopted this guideline: the EU in November 2000, Japan in November 
2001, and the United States in September 2001 [53] . In addition, it has also been 
adopted by several other non - ICH countries such as Australia [28] and South Africa 
[34] . 
The basic structure of the ICH GMP guideline for API production is shown in 
Table 15 . It consists of 19 chapters, which cover the requirements for quality management, 
personnel, premises, equipment, documentation, materials, production and 
process controls, packaging and labeling, storage and distribution, laboratory controls, 
validation, change control, complaints, recalls, contract services, cooperators, 
APIs manufactured by cell culture/fermentation, and APIs used in clinical trials 
[52] . 
2.1.3.4 Association of Southeast Asian Nations ( ASEAN ) 
ASEAN was established in 1967 by Indonesia, Malaysia, Philippines, Singapore, and 
Thailand. Current members include also Brunei and Darussalam (joined in 1984), 
Vietnam (joined in 1995), Laos and Myanmar (joined in 1997), and Cambodia 
(joined in 1999). The aims and purposes of ASEAN involve cooperation in the 
economic, social, cultural, technical, educational, and other fi elds [54] . Among other 
cooperation schemes the ASEAN countries have also developed their own GMP 
guidelines, which were issued in 1984 [55] . 
TABLE 15 Contents of ICH GMP Guideline for API Production [52] 
Section Subject 
1 Introduction 
2 Quality management 
3 Personnel 
4 Buildings and facilities 
5 Process equipment 
6 Documentation and records 
7 Materials management 
8 Production and in - process controls 
9 Packaging and identifi cation labeling of APIs and intermediates 
10 Storage and distribution 
11 Laboratory controls 
12 Validation 
13 Change control 
14 Rejection and reuse of materials 
15 Complaints and recalls 
16 Contract manufacturers (including laboratories) 
17 Agents, brokers, traders, distributors, repackers, and relabelers 
18 Specifi c guidance for APIs manufactured by cell culture/fermentation 
19 APIs for use in clinical trials 
20 Glossary 
INTERNATIONAL GMP GUIDES AND HARMONIZATION 135

136 CORRESPONDENCES AND DIFFERENCES 
2.1.3.5 Mercado Comun del Sur ( MERCOSUR ) 
MERCOSUR was established in 1991 by Argentina, Brazil, Paraguay, and Uruguay 
to develop a common market between its member countries. Current members 
include also Bolivia and Chile (joined in 1996). One of the original aims was to 
harmonize the pharmaceutical legislation of the member countries. As a part of 
these harmonization activities MERCOSUR has developed its own GMP guidelines, 
which are based on WHO recommendations. In addition to the GMP guideline, 
MERCOSUR has also issued other GMP - related guides covering inspections, 
requirements for facilities, and quality control [56] . 
2.1.4 CORRESPONDENCES OF THE U . S . GMP REGULATIONS WITH 
GMP CODES AND GUIDELINES 
The following sections deal with the correspondences and differences between the 
U.S. GMP regulations and the Canadian and EU GMP codes and the WHO GMP 
guideline. As the EU GMP code is harmonized with the PIC/S GMP guide, the 
correspondences between the EU GMP code and the U.S. GMP regulations cover 
also the correspondences between the U.S. GMP regulations and the PIC/S GMP 
guide as well as all other national GMPs that are based on the PIC/S GMP guide. 
Differences between the EU GMP code and the PIC/S GMP guide have been presented 
in Section 2.1.3.2 . 
2.1.4.1 General Issues 
In the U.S. GMP regulations general issues related to the use and applicability of 
GMP regulations are presented in Part 210 [6] , which consists of regulations 210.1, 
210.2, and 210.3 and in Subpart A of Part 211 [7] , which consists of regulations 211.1 
and 211.3. Contents of Part 210 and Subpart A of Part 211 are presented in Table 
16 . Regulation 210.1 defi nes the status, 210.2 deals with the applicability, and 211.1 
states the scope of the regulations. Defi nitions of terms used in the regulations are 
provided in regulation 210.3 and in regulation 211.3, which states that the defi nitions 
provided in regulation 210.3 apply also in Part 211. 
Correspondences in Canadian GMP Code In the Canadian legislation general 
issues related to the use and applicability of the GMP regulations and code are 
covered in the introduction of the GMP code [12] and in Divisions 1A [57] and 2 
TABLE 16 Contents of Part 210 and Subpart A of Part 211 of US GMP Regulations 
Covering General Issues Related to Use and Applicability of Regulations [6, 7] 
Section Subject 
CFR 210.1 Status of current good manufacturing practice regulations 
CFR 210.2 Applicability of current good manufacturing practice regulations 
CFR 210.3 Defi nitions 
CFR 211.1 Scope 
CFR 211.3 Defi nitions 

of the Part C of the Food and Drug Regulations [11] . Defi nitions for the GMP regulations 
are covered in regulation C.01A.001 of Division 1A [57] and in regulation 
C.02.002 of Division 2 [11] . Defi nitions for the GMP code are covered in the glossary 
of terms of the code [12] . 
Correspondences in EU GMP Code In the EU legislation general issues related 
to the use and applicability of the GMP regulations and the code are covered in the 
Commission Directive 2003/94/EC [14] and in the introduction of the GMP code 
[15] . Defi nitions for the directive are covered in Article 2 of the directive [14] and 
defi nitions for the code in the glossary of the GMP code [15] . 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
general issues related to the use and applicability of the GMP guide are covered in 
section  General Considerations.  Defi nitions for the GMP guide are covered in the 
glossary of the guideline. 
2.1.4.2 Organization and Personnel 
For GMP regulations in the United States issues related to organization and personnel 
are covered in Subpart B [7] , which consists of regulations 211.22, 211.25, 211.28, 
and 211.34. The contents of Subpart B is presented in Table 17 . Regulation 211.22 
states the responsibilities and authorities of the quality control unit, including 
requirements for the resources. Regulation 211.25 deals with personnel qualifi cations 
covering the requirements for their education and experience and it also states 
the requirements for the training of the personnel. Regulation 211.28 states the 
responsibilities of personnel covering the requirements for the clothing and other 
protective apparel, personal sanitation and health habits, as well as personal health 
conditions. Furthermore, it states the requirements for the authorization for limited 
access. Regulation 211.34 deals with consultants and lays down the requirements 
for their education, training, and experience, including the requirements for 
documentation. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to organization and personnel are mainly covered in the interpretation of 
regulation C.02.006 (Personnel) and partly in the interpretations of regulations 
C.02.004 (Premises), C.02.008 (Sanitation), C.02.011 (Manufacturing Control), 
C.02.013 (Quality Control Department), C.02.015 (Quality Control Department), 
and C.02.024 (Records). Correspondences to regulation 211.22 are covered in 
TABLE 17 Contents of Subpart B of Part 211 of U. S . 
GMP Regulations Covering Organization and Personnel [7] 
Section Subject 
CFR 211.22 Responsibilities of quality control unit 
CFR 211.25 Personnel qualifi cations 
CFR 211.28 Personnel responsibilities 
CFR 211.34 Consultants 
CORRESPONDENCES 137

138 CORRESPONDENCES AND DIFFERENCES 
Sections 1  5 of the interpretation of regulation C.02.015 and in Section 2 of the 
interpretation of regulation C.02.013. Sections 1  5 of the interpretation of regulation 
C.02.015 state the responsibilities of the quality control unit (quality control 
department), and Section 2 of the interpretation of regulation C.02.013 covers the 
requirements for resources. Correspondences to regulation 211.25 stating the 
requirements for the education, training, and experience of the personnel are 
covered in Sections 1  5 of the interpretation of regulation C.02.006. Correspondences 
to regulation 211.28 are covered in Section 6.3 of the interpretation of regulation 
C.02.004, Sections 1  2 of the interpretation of regulation C.02.008, Section 8 
of the interpretation of regulation C.02.011, and Section 4 of the interpretation of 
regulation C.02.013. Section 1 of the interpretation of regulation C.02.008 states the 
health requirements and Section 2 the requirements for clothing, other protective 
apparel, and personal hygiene. Section 6.3 of the interpretation of regulation 
C.02.004, Section 8 of the interpretation of regulation C.02.011, and Section 4 of the 
interpretation of regulation C.02.013 cover the requirements regarding limited 
access. Correspondences to regulation 211.34 are covered in Section 6 of the interpretation 
of regulation C.02.006 and in Subsection 1.3.2 of the interpretation of 
regulation C.02.024. Section 6 of the interpretation of regulation C.02.006 states the 
requirements for the education, training, and experience of consultants and contractors 
and Subsection 1.2.3 of the interpretation of regulation C.02.024 the requirements 
for documentation. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
organization and personnel are mainly covered in Chapter 2 (Personnel) and partly 
in Chapters 3 (Premises and Equipment), 5 (Production), and 6 (Quality Control). 
Correspondences to regulation 211.22 are covered in Subchapters 2.6, 2.7, 6.1, and 
6.2. Subchapters 2.6 and 2.7 deal with the responsibilities of the head of the quality 
control unit (quality control department) and 6.2 with the responsibilities of 
the quality control unit as a whole. Requirements for resources are covered in 
Subchapter 6.1. Correspondences to regulation 211.25 are covered in Subchapters 
2.1, 2.4, and 2.8  2.12. Subchapters 2.1 and 2.4 deal with the requirements for personnel 
and Subchapters 2.8  2.12 with the requirements for their training. Correspondences 
to regulation 211.28 are covered in Subchapters 2.15, 2.16, 3.5, 3.21, 5.16, and 
6.4. Subchapter 2.15 deals with requirements for personal health conditions and 2.16 
with requirements for clothing and protection. Access limitations are covered in 
Subchapters 3.5, 3.21, 5.16, and 6.4. In the EU GMP code there is no correspondence 
to regulation 211.34, which covers the requirements for the use of consultants. 
However, Chapter 7 of the code deals with the requirements for the contract services 
in general. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to organization and personnel are mainly covered in Chapter 9 (Personnel) 
and partly in Chapters 10 (Training), 11 (Personal Hygiene), 16 (Good 
Practices in Production), and 17 (Good Practices in Quality Control). Correspondences 
to regulation 211.22 are covered in Subchapters 9.8, 9.10, 17.3, and 17.4. 
Subchapters 9.8 and 9.10 state the responsibilities of the head of the quality control 
unit and Subchapter 17.4 the responsibilities of the quality control unit as a whole. 
Subchapter 17.3 covers the requirements for resources. Correspondences to regula

tion 211.25 are covered in Subchapters 9.2, 9.4, 9.7, and 10.1  10.4. Subchapters 9.2, 
9.4, and 9.7 state the requirements for the personnel covering their education and 
experience and Subchapters 10.1  10.4 the requirements for the training. Correspondences 
to regulation 211.28 are covered in Subchapters 11.1  11.8, 9.5, and 16.7. 
Subchapters 11.1  11.5 state the requirements for the health conditions and personal 
hygiene and Subchapters 11.6  11.8 the requirements for the clothing and other 
protective apparel. Subchapters 9.5 and 16.7 cover the requirements for the limited 
access. Correspondences to regulation 211.34 are covered in Subchapter 10.6, which 
covers the requirements for the use of consultants. 
2.1.4.3 Buildings and Facilities 
In the United States GMP regulations on issues related to buildings and facilities 
are covered in Subpart C [7] , which consists of regulations 211.42, 211.44, 211.46, 
211.48, 211.50, 211.52, 211.56, and 211.58. Contents of Subpart C are presented in 
Table 18 . Regulation 211.42 deals with design and construction features covering 
the requirements for the size, construction, and location of buildings used in the 
production. Furthermore, it states the requirements for the placement of equipment 
as well as the fl ow of materials and products and specifi es operations, which have 
to be performed in separate or defi ned areas to prevent contamination or mix - ups. 
It also covers the special requirements for the facilities used in aseptic processing 
and facilities used in the production of penicillin. Regulation 211.44 states the 
requirements for lighting and 211.46 for ventilation, including the requirements for 
controls and air - handling systems. Furthermore, it states the special requirements 
for ventilation in the production of penicillin. Regulation 211.48 deals with plumbing 
covering requirements for the plumbing system, drains, and the quality of potable 
water. Regulation 211.50 deals with sewage, trash, and other refuse stating the 
requirements for their disposal. Regulation 211.52 covers the requirements for 
washing and toilet facilities. Regulation 211.56 deals with sanitation stating the 
requirements for the conditions to be maintained in the manufacturing facilities. It 
also states the requirements for handling of trash and organic waste. Furthermore, 
it states the requirements for the written procedures for sanitation operations 
and use of biocides, fumigating, cleaning, and sanitizing agents. It also states the 
TABLE 18 Contents of Subpart C of Part 211 of U. S . 
GMP Regulations Covering Buildings and Facilities [7] 
Section Subject 
CFR 211.42 Design and construction features 
CFR 211.44 Lighting 
CFR 211.46 Ventilation, air fi ltration, air heating and 
cooling 
CFR 211.48 Plumbing 
CFR 211.50 Sewage and refuse 
CFR 211.52 Washing and toilet facilities 
CFR 211.56 Sanitation 
CFR 211.58 Maintenance 
CORRESPONDENCES 139

140 CORRESPONDENCES AND DIFFERENCES 
requirements for the use of biocides and the scope of sanitation procedures. Regulation 
211.58 states the requirements for the maintenance of the buildings used in the 
production. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to buildings and facilities are mainly covered in the interpretation of regulation 
C.02.004 (Premises) and partly in the interpretations of regulations C.02.005 
(Equipment), C.02.007 (Sanitation), C.02.009 (Raw Material Testing), C.02.011 
(Manufacturing Control), and C.02.029 (Sterile Products). Correspondences to regulation 
211.42 are covered in Sections 1, 2, 2.3, 6, 6.2, and 6.4 of the interpretation 
of regulation C.02.004, in Section 15 of the interpretation of regulation C.02.011, 
and in section  Premises  of the interpretation of regulation C.02.029. Sections 1 
and 2 of the interpretation of regulation C.02.004 cover the requirements for the 
size, construction, and location of buildings used in the production. Section 6.2 of 
the interpretation of regulation C.02.004 and Section 15 of the interpretation of 
regulation C.02.011 state the requirements for the placement of equipment. Requirements 
for the fl ow of materials and products are covered in Section 6 of the interpretation 
of regulation C.02.004 and operations, which have to be performed in 
separate or defi ned areas in Sections 2.3 and 6.4 of the interpretation of regulation 
C.02.004. The requirements for the facilities used in aseptic processing are covered 
in section  Premises  of the interpretation of regulation C.02.029 and the requirements 
for the facilities used in the production of penicillin in Section 11.1 of the 
interpretation of regulation C.02.004. Correspondences to regulation 211.44 stating 
the requirements for the lighting are covered in Section 6.5 of the interpretation of 
regulation C.02.004. Correspondences to regulation 211.46 are covered in Sections 
3.6 and 4 of the interpretation of regulation C.02.004. Section 3.6 of the interpretation 
of regulation C.02.004 states the requirements for the air - handling systems and 
Section 4 the requirements for the control of temperature and humidity. The specifi c 
requirements regarding the production of penicillin are covered in Section 11.1. 
Correspondences to regulation 211.48 are covered in Sections 3.5 and 7 of the 
interpretation of regulation C.02.004, Section 3.7 of the interpretation of regulation 
C.02.005, Section 4 of the interpretation of regulation C.02.009, and section  Water 
Treatment Systems  of the interpretation of regulation C.02.029. Section 7 of the 
interpretation of regulation C.02.004 states the requirements for the utilities and 
support systems, including supplies of purifi ed water. Section 3.7 of the interpretation 
of regulation C.02.005 states the requirements for the operation of water puri- 
fi cation, storage, and distribution equipment. Requirements for the quality of water 
are covered in Section 4 of the interpretation of regulation C.02.009 and in section 
 Water Treatment Systems  of the interpretation of regulation C.02.029. The requirements 
for drains are covered in Section 3.5 of the interpretation of regulation 
C.02.004. Correspondences to regulation 211.50 stating the requirements for the 
handling of sewage and refuse are covered in Section 2.6 of the interpretation of 
regulation C.02.007. Correspondences to regulation 211.52 stating the requirements 
for washing and toilet facilities are covered in Section 5 of the interpretation of 
regulation C.02.004. Correspondences to regulation 211.56 stating the requirements 
for sanitation are covered in Sections 1 and 2 of the interpretation of regulation 
C.02.007. The Canadian GMP code does not state any separate requirements for 
the handling of organic waste. General requirements for the handling of waste 

materials are covered in Section 2.6 of the interpretation of regulation C.02.007. 
Correspondences to regulation 211.58 stating the requirements for the maintenance 
of the premises are covered in Section 9 of the interpretation of regulation 
C.02.004. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
buildings and facilities are mainly covered in Chapter 3 (Premises and Equipment) 
and partly in Annex 1 (Manufacture of Sterile Medicinal Products). Correspondences 
to regulation 211.42 are covered in the foreword of Chapter 3 and in Subchapters 
3.6  3.8, 3.13, 3.22, 3.23, 3.26, and 3.33. The requirements for the size, 
construction and location of buildings used in the production are covered in the 
foreword of Chapter 3. Subchapter 3.8 states the requirements for the placement 
of equipment and Subchapter 3.7 for the fl ow of materials and products. Operations, 
which have to be performed in separate or defi ned areas, are specifi ed in Subchapters 
3.6, 3.13, 3.22, 3.23, 3.26, and 3.33. Annex 1 covers the requirements for facilities 
used in aseptic processing and Subchapter 3.6 the requirements for the facilities 
used in the production of penicillin. Correspondences to regulation 211.44 are 
covered in Subchapters 3.3 and 3.16, which state the requirements for lighting. Correspondences 
to regulation 211.46 are covered in Subchapters 3.3 and 3.12, which 
state the requirements for ventilation. The specifi c requirements for the production 
of penicillin are covered in Subchapter 3.6. Correspondences to regulation 211.48 
are covered in Subchapters 3.10 and 3.11 and in Subsections 35 and 44 of Annex 1. 
Subchapter 3.10 states the requirements for the plumbing and Subchapter 3.11 the 
requirements for drains. Section 35 of Annex 1 covers the requirements for water 
treatment plants and distribution systems and Section 44 the requirements for the 
monitoring of water sources and water treatment equipment. More guidance on the 
quality of water is given in the EU guidance document Note for Guidance on Quality 
of Water for Pharmaceutical Use [58] . The EU GMP code does not have correspondence 
to regulation 211.50, which covers the requirements for the handling of 
sewage and other refuse. Correspondences to regulation 211.52 are covered in Subchapter 
3.31, which covers the requirements for the facilities for washing and toilet 
purposes. Correspondences to regulation 211.56 are covered in Subchapters 3.2, 3.4, 
3.43, and 4.26. Subchapters 3.2 and 3.4 cover the requirements for the conditions to 
be maintained in the manufacturing facilities. Subchapter 4.26 covers the procedures 
for cleaning and sanitization and Subchapter 3.43 the requirements for the sanitization 
of water pipes. The EU GMP code does not cover any separate requirements 
for the handling of organic waste. Correspondences to regulation 211.58 are covered 
in Subsection 3.2, which covers the requirements for the maintenance of the buildings 
used in the production. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to buildings and facilities are mainly covered in Chapter 12 (Premises) 
and partly in Chapters 3 (Sanitation and Hygiene), 14 (Materials), and 15 (Documentation). 
Correspondences to regulation 211.42 are covered in Subchapters 12.1, 
12.2, 12.4, 12.5, 12.10, 12.14, 12.17, 12.19, 12.22  12.26, and 12.33. The requirements 
for the size, construction, and location of buildings are stated in Subchapters 12.1, 
12.4, and 12.5. Subchapters 12.2 and 12.26 cover the requirements for the placement 
of equipment and Subchapters 12.10 and 12.25 the requirements for the fl ow of 
CORRESPONDENCES 141

142 CORRESPONDENCES AND DIFFERENCES 
materials and products. Operations, which have to be performed in separate or 
defi ned areas, are specifi ed in Subchapters 12.14, 12.17, 12.19, 12.22  12.24, and 12.33. 
The requirements for the facilities used in aseptic processing are covered in Chapter 
9 of Annex 6 of the WHO TRS 902 [40] and the requirements for the facilities used 
in the manufacture of penicillin are in Subchapter 12.24. Correspondences to regulation 
211.44 are covered in Subchapters 12.8 and 12.32, which state the requirements 
for lighting. Correspondences to regulation 211.46 are covered in Subchapters 12.8 
and 12.30, which state the requirements for ventilation. The specifi c requirements 
for the production of penicillin are covered in Subchapter 12.24. Correspondences 
to regulation 211.48 are covered in Subchapters 12.28, 12.29, and 14.6 and in Annex 
3 of the WHO TRS 929 [45] . Subchapter 12.28 states the requirements for the 
plumbing and Subchapter 14.6 for the quality of water used in the production of 
drug products. More guidance on the quality of water is given in Annex 3 of the 
WHO TRS 929 [45] . The requirements for the drains are stated in Subchapter 12.29. 
Correspondences to regulation 211.50 are covered in Subchapters 14.44 and 14.45, 
which state the requirements for the handling of sewage and other refuse. Correspondences 
to regulation 211.52 are covered in Subchapter 12.12, which states the 
requirements for the facilities for washing and toilet purposes. Correspondences to 
regulation 211.56 are covered in Subchapters 3.1, 12.7, 12.9, 14.44  14.46, and 15.48. 
Subchapters 12.7 and 12.9 state the requirements for the conditions to be maintained 
in the manufacturing facilities and Subchapter 3.1 the general requirements 
for sanitation and hygiene. In the WHO GMP guideline there is no separate guidance 
on the handling of organic waste. General requirements for the handling of 
waste materials are stated in Subchapters 14.44 and 14.45. Subchapter 15.48 states 
the requirements for the written procedures for sanitation operations and Subchapter 
14.46 for the use of rodenticides, insecticides, fumigating agents, and sanitizing 
materials. Correspondences to regulation 211.58 are covered in Subchapter 12.6, 
which states the requirements for the maintenance of the buildings used in drug 
production. 
2.1.4.4 Equipment 
For GMP regulations in the United States issues related to equipment are covered 
in Subpart D [7] , which consists of regulations 211.63, 211.65, 211.67, 211.68, and 
211.72. Contents of Subpart D are presented in Table 19 . Regulation 211.63 states 
the requirements for the production equipment covering design, size, and location. 
Regulation 211.65 states the requirements for the construction of equipment cover- 
TABLE 19 Contents of Subpart D of Part 211 of U. S . 
GMP Regulations Covering Equipment [7] 
Section Subject 
CFR 211.63 Equipment design, size, and location 
CFR 211.65 Equipment construction 
CFR 211.67 Equipment cleaning and maintenance 
CFR 211.68 Automatic, mechanical, and electronic 
equipment 
CFR 211.72 Filters 

ing the characteristics of used materials and special requirements for the structure 
of the equipment. Regulation 211.67 deals with cleaning, maintenance, and sanitizing 
of equipment and utensils covering the requirements for the procedures for 
cleaning and maintenance operations. Regulation 211.68 deals with automatic, 
mechanical, and electronic equipment covering requirements for their calibration 
and inspection, including the requirements for the documentation of checks and 
inspections. Furthermore, it covers the requirements for the controls for computer 
or related systems, including the requirements for the maintenance of backup data. 
Regulation 211.72 covers the requirements for the fi lters for liquid fi ltration used 
in the manufacture of injectable products, including the specifi c requirements for 
the use of fi ber - releasing and asbestos - containing fi lters. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to equipment are mainly covered in the interpretation of regulation C.02.005 
(Equipment) and partly in the interpretation of regulation C.02.007 (Sanitation) 
and C.02.024 (Records). Correspondences to regulation 211.63 stating the requirements 
for the design, construction, and location of equipment used in the manufacture 
of drug products are covered in Sections 1 and 5 of the interpretation of 
regulation C.02.005. Correspondences to regulation 211.65 stating the requirements 
for the construction of equipment are covered in Sections 2.1  2.3 of the interpretation 
of regulation C.02.005. Correspondences to regulation 211.67 stating the 
requirements for the sanitation are covered in Sections 1, 2, and 3 of the interpretation 
of regulation C.02.007. Correspondences to regulation 211.68 are covered in 
Section 5.4 of the interpretation of regulation C.02.005 and in the foreword of the 
interpretation of regulation C.02.024. Section 5.4 of the interpretation of regulation 
C.02.005 states the requirements for the use of automatic, mechanical, and electronic 
equipment, including computerized systems, and the foreword of the interpretation 
of regulation C.02.024 the requirements for the maintenance of backup data. The 
Canadian GMP code does not have correspondence to regulation 211.72, which 
states the requirements for the fi lters for liquid fi ltration used in the manufacture 
of injectable products. Nor does it cover requirements for the use of fi ber - releasing 
or asbestos - containing fi lters. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
equipment are mainly covered in Chapter 3 (Premises and Equipment) and partly 
in Chapter 4 (Documentation) and Annexes 1 (Manufacture of Sterile Medicinal 
Products) and 11 (Computerised Systems). Correspondences to regulation 211.63 
are covered in Subchapter 3.34, which states the requirements for the design and 
location of equipment used in the manufacture of drug products. Correspondences 
to regulation 211.65 are covered in Subchapters 3.38 and 3.39, which state the 
requirements for the construction of equipment. Correspondences to regulation 
211.67 are covered in Subchapters 3.36, 3.37, and 3.43, which cover the requirements 
for cleaning and sanitizing the manufacturing equipment. Correspondences to regulation 
211.68 are covered in Subchapters 3.41 and 4.9 and Annex 11. Subchapter 
3.41 states the requirements for the maintenance of measuring, weighing, recording, 
and control equipment and Subchapter 4.9 the requirements for the use of electronic 
data processing systems and the maintenance of backup data. Additional 
guidance on the use of computerized systems is given in Annex 11. Correspondences 
CORRESPONDENCES 143

144 CORRESPONDENCES AND DIFFERENCES 
to regulation 211.72 stating the requirements for fi lters for liquid fi ltration used in 
the sterile fi ltration are covered in Sections 84  87 of Annex 1. The EU GMP code 
does not have any separate guidance for the use of fi ber - releasing or asbestos - 
containing fi lters. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to equipment are mainly covered in Chapter 13 (Equipment) and 
partly in Chapters 14 (Materials), 15 (Documentation), and 16 (Good Practices in 
Production). Correspondences to regulation 211.63 are covered in Subchapters 13.1 
and 13.2, which state the requirements for the design, location, and installation of 
equipment used in the manufacture of drug products. Correspondences to regulation 
211.65 are covered in Subchapters 13.9 and 14.3, which state the requirements 
for the construction of equipment. Correspondences to regulation 211.67 are covered 
in Subchapters 13.6, 13.8, 13.12, 16.17, 16.18, and 16.22, which state the requirements 
for cleaning and sanitizing the equipment. Correspondences to regulation 211.68 
are covered in Subchapters 16.23 and 15.9. The requirements for the maintenance 
of measuring, weighing, recording, and control equipment and instruments 
are covered in Subchapter 16.23. Subchapter 15.9 states the requirements for the 
use of electronic data - processing systems, including the requirements for the maintenance 
of backup data. Correspondences to regulation 211.72 stating the requirements 
for the use of fi lters are covered in Subchapters 7.6  7.9 of Annex 6 of the 
WHO TRS 902 [40] . Subchapter 7.6 covers the requirements for asbestos - containing 
fi lters. 
2.1.4.5 Control of Components and Drug Product Containers and Closures 
In the United States issues related to control of components and drug product 
containers and closures are covered in Subpart E [7] , which consists of regulations 
211.80, 211.82, 211.84, 211.86, 211.87, 211.89, and 211.94. Contents of Subpart E are 
presented in Table 20 . Regulation 211.80 defi nes the requirements for the procedures 
for the control of components, containers, and closures. It also states the 
requirements for their handling, storing, and identifi cation. Regulation 211.82 covers 
the requirements for receipt and storage of untested components, containers, and 
TABLE 20 Contents of Subpart E of Part 211 of U . S . GMP Regulations Covering 
Control of Components and Drug Product Containers and Closures [7] 
Section Subject 
CFR 211.80 General requirements 
CFR 211.82 Receipt and storage of untested components, drug product containers, 
and closures 
CFR 211.84 Testing and approval or rejection of components, drug product 
containers, and closures 
CFR 211.86 Use of approved components, drug product containers, and closures 
CFR 211.87 Retesting of approved components, drug product containers, and 
closures 
CFR 211.89 Rejected components, drug product containers, and closures 
CFR 211.94 Drug product containers and closures 

closures. Regulation 211.84 deals with testing and approval or rejection of components, 
containers, and closures covering the requirements for sampling, testing, and 
release. Regulation 211.86 deals with the use of approved components, containers, 
and closures stating the requirements for the rotation of the storage. Regulation 
211.87 states the requirements for the retesting of approved components, containers, 
and closures. Regulation 211.89 covers the requirements for the handling of rejected 
components, containers, and closures. Regulation 211.94 deals with drug product 
containers and closures covering the requirements for materials and the cleanliness 
of containers and closures. Furthermore, it states the requirements for container 
closure systems, standards and methods. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to control of components and drug product containers and closures are 
covered in interpretations of regulations C.02.009 (Raw Material Testing), C.02.010 
(Raw Material Testing), C.02.011 (Manufacturing Control), C.02.014 (Quality 
Control Department), C.02.016 (Packaging Material Testing), and C.02.017 (Packaging 
Material Testing). Correspondences to regulation 211.80 stating the general 
requirements for the handling, storing, and identifi cation of components (raw materials) 
and drug product containers and closures (packaging materials) are covered 
in Sections 1, 20, and 21 of the interpretation of regulation C.02.011. Correspondences 
to regulation 211.82 stating the requirements for the receipt, testing, and 
storage of untested components and drug product containers and closures are 
covered in Sections 16, 18, and 19 of the interpretation of regulation C.02.011. Correspondences 
to regulation 211.84 stating the requirements for testing and approval 
of components and drug product containers and closures are covered in Sections 6 
and 7 of the interpretation of regulation C.02.009, Sections 1  8 of the interpretation 
of regulation C.02.010, Sections 1 and 2 of regulation C.02.016, Section 4 of its 
interpretation, and Section 1 of the interpretation of regulation C.02.017. Interpretations 
6 and 7 of regulation C.02.009 and interpretations 1  8 of regulation C.02.010 
cover the requirements for components. Sections 1 and 2 and interpretation 4 of 
regulation C.02.016 and interpretation 1 of regulation C.02.017 state the requirements 
for drug product containers and closures. In the Canadian GMP code there 
is no correspondence to regulation 211.86, which covers the requirements for the 
rotation of the storage. Correspondences to regulation 211.87 stating the requirements 
for the retesting of approved components are covered in Sections 8  10 of the 
interpretation of regulation C.02.009. For the retesting of drug product containers 
and closures the Canadian GMP code has no guidance. Correspondences to regulation 
211.89 stating the requirements for the handling of rejected components and 
drug product containers and closures are covered in Section 14 of the interpretation 
of regulation C.02.011 and in Section 5 of the interpretation of regulation C.02.014. 
The Canadian GMP code does not have correspondence to regulation 211.94, which 
covers the requirements for containers and closure systems. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
control of components and drug product containers and closures are mainly covered 
in Chapter 5 (Production) and partly in Chapter 6 (Quality Control). Correspondences 
to regulation 211.80 are covered in Subchapters 5.2, 5.7, 5.10, 5.29, and 
5.40  5.42, which cover the requirements for the handling, storing, and identifi cation 
CORRESPONDENCES 145

146 CORRESPONDENCES AND DIFFERENCES 
of components (starting materials) and drug product containers and closures 
(primary packaging materials). Correspondences to regulation 211.82 are covered 
in Subchapters 5.5, 5.27, and 5.40, which state the requirements for the receipt, 
testing, and storage of untested components and drug product containers and closures. 
Correspondences to regulation 211.84 are covered in Subchapters 5.31, 5.40 
and 6.11  6.22 and Annex 8. The general requirements for sampling and testing are 
covered in Subchapters 6.11  6.22. More guidance on sampling is given in Annex 8. 
The requirements for the approved use of components and drug product containers 
and closures are stated in Subchapters 5.31 and 5.40. Correspondences to regulation 
211.86 are covered in Subchapter 5.7, which states the requirements for the storage 
conditions and rotation. Correspondences to regulation 211.87 are covered in 
Subchapters 5.29 and 5.40, which deal with the retesting of components and drug 
product containers and closures. Correspondences to regulation 211.89 are covered 
in Subchapter 5.61, which states the requirements for the handling of rejected components 
and drug product containers and closures. Correspondences to regulation 
211.94 are covered in Subchapter 5.48, which states the requirements for drug 
product containers and closures. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to control of components and drug product containers and closures 
are covered in Chapters 14 (Materials), 16 (Good Practices in Production), and 17 
(Good Practices in Quality Control). Correspondences to regulation 211.80 are 
covered in Subchapters, 14.5, 14.13, 14.14, 14.19  14.21, and 16.2, which state the 
requirements for the handling, storing, and identifi cation of components (starting 
materials) and drug product containers and closures (primary packaging materials). 
Correspondences to regulation 211.82 are covered in Subchapters 14.4, 14.9  14.11, 
and 14.19, which state the requirements for receipt, testing, identifi cation, and 
storage of untested components and drug product containers and closures. Correspondences 
to regulation 211.84 are covered in Subchapters 14.12, 14.15, and 17.7  
17.17. The requirements for sampling and testing are covered in Subchapters 
17.7  17.17 and 14.12. Subchapter 14.15 states the requirements for the approved 
use of components and drug product containers and closures. Correspondences to 
regulation 211.86 are covered in Subchapter 14.5, which states the requirements for 
the storage conditions and the rotation of the storage. Correspondences to regulation 
211.87 are covered in Subchapter 14.13, which states the requirements for the 
retesting of approved components. The WHO GMP guideline does not cover the 
requirements for the retesting of drug product containers and closures. Correspondences 
to regulation 211.89 are covered in Subchapter 14.28, which states the 
requirements for the handling of rejected components and drug product containers 
and closures. Correspondences to regulation 211.94 are covered in Subchapter 16.19, 
which states the requirements for the drug product containers and closures. 
2.1.4.6 Production and Process Controls 
In the United States GMP regulations on issues related to production and process 
controls are covered in Subpart F [7] , which consists of regulations 211.100, 211.101, 
211.103, 211.105, 211.110, 211.111, 211.113, and 211.115. Contents of Subpart F are 
presented in Table 21 . Regulation 211.100 states the requirements for procedures 

regarding production and process controls, including the requirements for the documentation 
and handling of deviations. Regulation 211.101 deals with the requirements 
for the charge - in of components. Regulation 211.103 states the requirements 
for the determination of yields. Regulation 211.105 covers requirements for the 
identifi cation of processing equipment such as containers, processing lines, and 
major equipment used during manufacture. Regulation 211.110 states the requirements 
for in - process controls, including the testing and approval of in - process 
materials and handling of rejected in - process materials. Regulation 211.111 covers 
the requirements for the time limitations on production, including the handling of 
deviations from established limits. Regulation 211.113 covers the control of microbiological 
contaminations. Regulation 211.115 states the requirements for the reprocessing 
of batches that do not conform to standards or specifi cations. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to production and process controls are mainly covered in the interpretation 
of regulation C.02.011 (Manufacturing Control) and partly in the interpretations of 
regulations C.02.005 (Equipment), C.02.014 (Quality Control Department), and 
C.02.029 (Sterile Products). Correspondences to regulation 211.100 are covered in 
Sections 1  5 of the interpretation of regulation C.02.011. Interpretations 1  4 state 
the requirements for manufacturing processes and interpretation 5 for the handling 
of deviations. Correspondences to regulation 211.101 stating the requirements for 
charge - in of components are covered in Section 22 of the interpretation of regulation 
C.02.011. Correspondences to regulation 211.103 stating the requirements for 
the determination of yields including the handling of deviations from the expected 
yield are covered in Sections 6 and 7 of the interpretation of regulation C.02.011. 
Correspondences to regulation 211.105 stating the requirements for the identifi cation 
of piping, containers, equipment, and rooms used in the manufacturing of drug 
products are covered in Section 3.5 of the interpretation of regulation C.02.005 and 
in Section 13 of the interpretation of regulation C.02.011. Correspondences to regulation 
211.110 are covered in Sections 11 and 14 of the interpretation of regulation 
C.02.011 and in Section 5 of the interpretation of regulation C.02.014. Section 11 of 
the interpretation of regulation C.02.011 states the requirements for the in - process 
controls. The Canadian GMP code does not cover requirements for the testing of 
in - process materials. The handling of rejected materials is covered in Section 14 
of the interpretation of regulation C.02.011 and in Section 5 of the interpretation 
TABLE 21 Contents of Subpart F of Part 211 of U . S . GMP Regulations Covering 
Production and Process Controls [7] 
Section Subject 
CFR 211.100 Written procedures, deviations 
CFR 211.101 Charge - in of components 
CFR 211.103 Calculation of yield 
CFR 211.105 Equipment identifi cation 
CFR 211.110 Sampling and testing of in - process materials and drug products 
CFR 211.111 Time limitations on production 
CFR 211.113 Control of microbiological contamination 
CFR 211.115 Reprocessing 
CORRESPONDENCES 147

148 CORRESPONDENCES AND DIFFERENCES 
of regulation C.02.014. Correspondences to regulation 211.111 dealing with the 
requirements for the time limitations on production are covered in Section 24.7 of 
the interpretation of regulation C.02.011. Correspondences to regulation 211.113 
are covered in the interpretation of regulation C.02.029, which deals with the manufacture 
of sterile products. Correspondences to regulation 211.115 stating the 
requirements for the reprocessing of batches that do not conform to specifi cations 
are covered in Sections 7  9 of the interpretation of regulation C.02.014. 
Correspondences in EU GMP In the EU GMP code [15] issues related to production 
and process controls are mainly covered in Chapter 5 (Production) and partly 
in Chapters 3 (Premises and Equipment), 4 (Documentation), and 6 (Quality 
Control). Correspondences to regulation 211.100 are covered in Subchapters 5.2, 
5.15, and 5.22  5.24. The requirements for manufacturing processes are covered in 
Subchapters 5.2 and 5.22  5.24. Subchapter 5.15 states the requirements for handling 
of deviations from instructions or procedures. Correspondences to regulation 
211.101 are covered in Subchapters 5.28  5.34, which state the requirements for the 
charge - in of components. Correspondences to regulation 211.103 are covered in 
Subchapters 5.8 and 5.39, which state the requirements for determination of yields, 
including the handling of deviations from the expected yield. Correspondences to 
regulation 211.105 are covered in Subchapters 3.42 and 5.12, which state the requirements 
for identifi cation of piping, containers, equipment, and rooms used in the 
manufacture of drug products. Correspondences to regulation 211.110 are covered 
in Subchapters 3.17, 4.10, 4.12, 5.38, 5.61, and 6.18. The requirements for in - process 
controls are covered in Subchapters 3.17, 5.38, and 6.18. Subchapters 4.10 and 4.12 
state the requirements for the specifi cations for in - process materials (intermediate 
products) and Subchapter 5.61 for handling of rejected materials. The EU GMP 
code does not cover separate guidance on testing and approval of in - process materials. 
General guidance on sampling and testing is given in Subchapters 6.11  6.22. 
Correspondences to regulation 211.111, which deals with the time limitations on 
production, are covered in Chapter 4.15. Correspondences to regulation 211.113 are 
covered in Subchapter 5.10 and in Annex 1, which cover the requirements for the 
control of microbiological contaminations. Correspondences to regulation 211.115 
are covered in Subchapters 5.62 and 5.64, which state the requirements for the 
reprocessing of rejected batches. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to production and process controls are covered in Chapters 13 (Equipment), 
14 (Materials), 15 (Documentation), 16 (Good Practices in Production), and 
17 (Good Practices in Quality Control). Correspondences to regulation 211.100 are 
covered in Subchapters 16.1  16.3. Subchapters 16.1 and 16.2 state the requirements 
for the manufacturing operations and Subchapter 16.3 for the handling of deviations 
from instructions or procedures. Correspondences to regulation 211.101 are covered 
in Subchapters 14.12  14.18, which state the requirements for the charge - in of components. 
Correspondences to regulation 211.103 are covered in Subchapters 16.4 
and 16.20, which state the requirements for the determination of yields, including 
the handling of deviations from the expected yield. Correspondences to regulation 
211.105 are covered in Subchapters 13.3, 13.4, and 16.6, which state the requirements 
for the identifi cation of piping, containers, equipment, and rooms used during pro

duction. Correspondences to regulation 211.110 are covered in Subchapters 14.28, 
15.20, 16.9, 16.16, and 17.8. Subchapters 16.9, 16.16, and 17.8 cover the requirements 
for the in - process controls and Subchapter 15.20 for the specifi cations for in - process 
materials (intermediate products). The requirements for the handling of rejected 
materials are stated in Subchapter 14.28. Correspondences to regulation 211.111, 
which deals with the time limitations on production, are covered in Chapter 15.23. 
Correspondences to regulation 211.113 are covered in Subchapters 16.10  16.14 and 
in Annex 6 of the WHO TRS 902 [40] . Subchapters 16.10  16.14 cover general 
requirements for the prevention of cross - contamination and bacterial contamination 
during production and Annex 6 general requirements for the manufacture of 
sterile drug products. Correspondences to regulation 211.115 are covered in Subchapters 
14.29, 14.31, and 15.40, which state the requirements for the reprocessing 
of rejected batches. 
2.1.4.7 Packaging and Labeling Control 
For GMP regulations in the United States issues related to packaging and labeling 
control are covered in Subpart G [7] , which consists of regulations 211.122, 211.125, 
211.130, 211.132, 211.134, and 211.137. The contents of Subpart G is presented in 
Table 22 . Regulation 211.122 deals with materials examination and usage criteria 
covering the requirements for the receipt, identifi cation, storage, handling, sampling, 
testing, and approval of labeling and packaging materials, including documentation. 
Furthermore, it covers the requirements for the control of labeling, handling of 
obsolete and outdated labeling and packaging materials, and special requirements 
for different labeling methods. Regulation 211.125 states the requirements for the 
labeling issuance covering the testing of labeling materials, the control of discrepancy 
between the quantities of labeling issued, used, and returned, and the handling 
of excess and returned labeling. Regulation 211.130 states the requirements for the 
packaging and labeling operations covering the written procedures. Regulation 
211.132 states the requirements for the tamper - evident packaging. Regulation 
211.134 states the requirements for the inspections of packaged and labeled 
products covering sampling, examination, and documentation. Regulation 211.137 
states the requirements for the expiration dates, including exemptions from the 
requirements. 
TABLE 22 Contents of Subpart G of Part 211 of U . S . GMP Regulations Covering 
Packaging and Labeling Control [7] 
Section Subject 
CFR 211.122 Materials examination and usage criteria 
CFR 211.125 Labeling issuance 
CFR 211.130 Packaging and labeling operations 
CFR 211.132 Tamper - evident packaging requirements for over - the - counter (OTC) 
human drug products 
CFR 211.134 Drug product inspection 
CFR 211.137 Expiration dating 
CORRESPONDENCES 149

150 CORRESPONDENCES AND DIFFERENCES 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to packaging and labeling control are covered in the interpretations of regulations 
C.02.011 (Manufacturing Control), C.02.017 (Packaging Material Testing), 
C.02.016 (Packaging Material Testing), C.02.019 (Finished Product Testing), and 
C.02.027 (Stability). Correspondences to regulation 211.122 are covered in Sections 
1, 16, 40, and 43  48 of the interpretation of regulation C.02.011, Sections 1, 8, and 9 
of the interpretation of regulation C.02.017, and Sections 1 and 4  7 of the interpretation 
of regulation C.02.016. Sections 1, 16, 43, and 48 of the interpretation of regulation 
C.02.011 state the general requirements for the handling of packaging and 
labeling materials covering receipt and storage. Section 8 of the interpretation of 
regulation C.02.017 states the requirements for the identifi cation of the packaging 
and labeling materials. The requirements for the testing of the packaging and labeling 
materials are covered in Sections 1 and 9 of the interpretation of regulation 
C.02.017. Sections 1 and 4 of the interpretation of regulation C.02.016 and Sections 
6 and 7 of the interpretation of regulation C.02.017 state the requirements for the 
approval of packaging and labeling materials. Sections 44  47 of the interpretation 
of regulation C.02.011 cover requirements for the use of roll - fed labels, cut labels, 
gang printing, and the monitoring of the performance of printing. The requirements 
for the handling of obsolete and outdated packaging and labeling materials are 
covered in Section 40 of the interpretation of regulation C.02.011 and in Section 5 
of the interpretation of regulation C.02.016. Correspondences to regulation 211.125 
are covered in Sections 39 and 42 of the interpretation of regulation C.02.011 
and in Section 8 of the interpretation of regulation C.02.017. Section 8 of the interpretation 
of regulation C.02.017 states the requirements for the examination of 
packaging and labeling materials. The requirements for the control and handling of 
discrepancy between the quantities of labeling issued, used, and returned are covered 
in Section 42 and the requirements for the handling of unused batch - coded packaging 
and labeling materials in Section 39 of the interpretation of regulation C.02.011. 
Correspondences to regulation 211.130 stating the requirements for the packaging 
and labeling operations are covered in Sections 29  38 of the interpretation of regulation 
C.02.011. In Canadian GMP code there is no correspondence to regulation 
211.132 stating the requirements for the tamper - evident packaging. Correspondences 
to regulation 211.134 stating the requirements for the inspections of packaged 
and labeled products are covered in Section 1 of the interpretation of regulation 
C.02.019. Correspondences to regulation 211.137 stating the requirements for the 
expiration dates are covered in regulation C.02.027 and in Section 1 of its 
interpretation. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
packaging and labeling control are mainly covered in Chapter 5 (Production) and 
partly in Chapters 4 (Documentation) and 6 (Quality Control). Correspondences 
to regulation 211.122 are covered in Subchapters 4.11, 4.19, 4.21  4.23, 5.2, 5.40  5.43, 
and 5.50  5.52. Subchapters 4.19, 4.21  4.23, 5.2, and 5.40  5.42 cover the requirements 
for purchase, handling, control, storage, and identifi cation of packaging and labeling 
materials. Specifi cations for packaging and labeling materials are stated in Subchapter 
4.11 and the requirements for handling of outdated or obsolete packaging and 
labeling materials in Subchapter 5.43. Subchapter 5.51 covers the requirements for 
the use of cut - labels, off - line overprinting, and roll - feed labels. The requirements for 

the control of the printing and labeling operations are stated in Subchapters 5.50 
and 5.52. Correspondences to regulation 211.125 are covered in Subchapters 5.2, 
5.56, and 5.57. Subchapter 5.2 states the general requirements for the handling of 
packaging and labeling materials. The requirements for the control of discrepancy 
between the quantities of labeling issued, used, and returned are covered in Subchapter 
5.56 and the requirements for the handling of unused batch - coded packaging 
and labeling materials in Subchapter 5.57. Correspondences to regulation 211.130 
are covered in Subchapters 5.2 and 5.44  5.49. Subchapter 5.2 states the general 
requirements for the handling of packaging and labeling materials and Subchapters 
5.44  5.49 cover the requirements for the packaging and labeling operations. The 
European Community GMP code does not have correspondence to regulation 
211.132, which covers the requirements for the tamper - evident packaging. Correspondences 
to regulation 211.134 are covered in Subchapters 5.54 and 6.3, which 
state the requirements for the control of packaged and labeled products. The EU 
GMP code does not have correspondence to regulation 211.137, which covers the 
requirements for expiration dates. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to packaging and labeling control are covered in Chapters 6 (Product 
Recalls), 12 (Premises), 14 (Materials), 15 (Documentation), 16 (Good Practices in 
Production), and 17 (Good Practices in Quality Control). Correspondences to regulation 
211.122 are covered in Subchapters 12.21, 14.19  14.23, 15.18, 16.2, 17.14, and 
17.16. Subchapters 6.2, 12.21, 14.19  14.21, 14.23, and 17.16 state the requirements 
for the purchase, handling, control, storage, and identifi cation of packaging and 
labeling materials. The requirements for the approval of packaging and labeling 
materials are covered in Subchapters 17.14 and 15.18. Subchapter 14.20 states the 
requirements for the use of roll - feed and cut labels and Subchapter 14.22 the 
requirements for the handling of outdated and obsolete packaging and labeling 
materials. Correspondences to regulation 211.125 are covered in Subchapters 16.2, 
16.34, and 16.35. Subchapter 16.2 states the general requirements for the handling 
of packaging and labeling materials and Subchapter 16.34 the requirements for the 
handling of discrepancy between the quantities of labeling issued, used, and returned. 
The requirements for the handling of unused batch - coded packaging and labeling 
materials are covered in Subchapter 16.35. Correspondences to regulation 211.130 
are covered in Subchapters 16.25  16.30, which state the requirements for the packaging 
and labeling operations. The WHO GMP guideline does not cover correspondence 
to regulation 211.132, which covers the requirements for tamper - evident 
packaging. Correspondences to regulation 211.134 are covered in Subchapter 16.32, 
which states the requirements for the control of packaged and labeled products. 
Correspondences to regulation 211.137 are covered in Subchapter 17.24, which 
states the requirements for the determination of expiration dates and shelf - life 
specifi cations. 
2.1.4.8 Holding and Distribution 
In the United States GMP regulations on issues related to holding and distribution 
are covered in Subpart H [7] , which consists of regulations 211.142 and 211.150. The 
contents of Subpart H is presented in Table 23 . Regulation 211.142 states the 
CORRESPONDENCES 151

152 CORRESPONDENCES AND DIFFERENCES 
requirements for the warehousing procedures covering quarantine and storage and 
regulation 211.150 for the distribution procedures covering distribution order and 
recalls. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to holding and distribution are covered in the interpretations of regulations 
C.02.004 (Premises), C.02.011 (Manufacturing Control), C.02.012 (Manufacturing 
Control), and C.02.019 (Finished Product Testing). Correspondences to regulation 
211.142 stating the requirements for the quarantine and storage of products are 
covered in Sections 1 and 49 of the interpretation of regulation C.02.011, Section 
11.4 of the interpretation of regulation C.02.004, and Section 2 of the interpretation 
of regulation C.02.019. Correspondences to regulation 211.150 stating the requirements 
for distribution and recalls are covered in Section 1 of the interpretation of 
regulation C.02.011 and Section 1 of the interpretation of regulation C.02.012. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
holding and distribution are covered in Chapters 4 (Documentation), 5 (Production), 
and 8 (Complaints and Product Recall). Correspondences to regulation 
211.142 are covered in Subchapters 5.2, 5.58, and 5.60, which state the requirements 
for the storage and quarantine of products. Correspondences to regulation 211.150 
are covered in Subchapters 4.25, 5.2, and 8.8  8.15, which state the requirements for 
distribution and recalls. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to holding and distribution are covered in Chapters 6 (Product 
Recalls), 14 (Materials), 15 (Documentation), and 16 (Good Practices in Production). 
Correspondences to regulation 211.142 are covered in Subchapters 14.4, 14.26, 
and 16.2, which state the requirements for the storage and quarantine of products. 
Correspondences to regulation 211.150 are covered in Subchapters 6.1  6.8, 15.45, 
and 16.2, which state the requirements for distribution and recalls. 
2.1.4.9 Laboratory Controls 
In the United States GMP regulations [7] issues related to laboratory controls are 
covered in Subpart I, which consists of regulations 211.160, 211.165, 211.166, 211.167, 
211.170, 211.173, and 211.176. The contents of Subpart I is presented in Table 24 . 
Regulation 211.160 states the requirements for the establishment of laboratory 
controls such as specifi cations, standards, sampling plans, and test procedures. 
Furthermore, it covers the requirements stated for the calibration of instruments, 
apparatus, gauges, and recording devices. Regulation 211.165 states the require- 
TABLE 23 Contents of Subpart H of Part 211 of U . S . 
GMP Regulations Covering Holding and Distribution [7] 
Section Subject 
CFR 211.142 Warehousing procedures 
CFR 211.150 Distribution procedures 

ments for the laboratory testing of batches prior to release covering the requirements 
for sampling, testing, and approval. Furthermore, it states the requirements 
for the handling of rejected drug products. Regulation 211.166 states the requirements 
for stability testing, including the requirements for the determination of 
expiration dates and the requirements for stability testing of homeopathic drug 
products. Regulation 211.167 deals with special testing requirements covering sterile 
products, ophthalmic ointments, and controlled - release dosage forms. Regulation 
211.170 states the requirements for reserve samples covering identifi cation, quantity, 
retention time, and storage. Furthermore it covers the requirements for the deterioration 
investigations. Regulation 211.173 deals with laboratory animals covering the 
requirements for their maintenance and control. Regulation 211.176 states the 
requirements for the testing of penicillin contamination and the handling of penicillin 
contaminated drug product. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to laboratory controls are covered in the interpretations of regulations 
C.02.004 (Premises), C.02.009 (Raw Material Testing), C.02.011 (Manufacturing 
Control), C.02.014 (Quality Control Department), C.02.015 (Quality Control 
Department), C.02.016 (Packaging Material Testing), C.02.017 (Packaging Material 
Testing), C.02.018 (Finished Product Testing), C.02.025 (Samples), C.02.026 
(Samples), C.02.027 (Stability), and C.02.028 (Stability). Correspondences to regulation 
211.160 stating the general requirements for laboratory controls are covered in 
regulation C.02.009 and Sections 1  3 and 5  6 of its interpretation, regulation 
C.02.016 and Sections 1  3 of its interpretation, Section 1 of the interpretation of 
regulation C.02.017, regulation C.02.018 and Sections 1  5 of its interpretation, and 
Section 6.4 of the interpretation of regulation C.02.015. Correspondences to regulation 
211.165 stating the requirements for the release for distribution including the 
testing of fi nished drug products and the handling of rejected drug products are 
covered in Sections 7 and 14 of the interpretation of regulation C.02.011, Sections 
2 and 5 of the interpretation of regulation C.02.014, Section 3 of the interpretation 
of regulation C.02.015, and Section 2 of regulation C.02.018 and Sections 1 and 4 of 
its interpretation. Correspondences to regulation 211.166 stating the requirements 
for stability testing are covered in Section 1 of the interpretation of regulation 
C.02.027 and Sections 1 and 2 of the interpretation of regulation C.02.028. The 
Canadian GMP code does not cover separate requirements for the stability testing 
TABLE 24 Contents of Subpart I of Part 211 of U . S . GMP 
Regulations Covering Laboratory Controls [7] 
Section Subject 
CFR 211.160 General requirements 
CFR 211.165 Testing and release for distribution 
CFR 211.166 Stability testing 
CFR 211.167 Special testing requirements 
CFR 211.170 Reserve samples 
CFR 211.173 Laboratory animals 
CFR 211.176 Penicillin contamination 
CORRESPONDENCES 153

154 CORRESPONDENCES AND DIFFERENCES 
of homeopathic drug products. Correspondences to regulation 211.167 stating the 
requirements for sterility testing are covered in Sections 1  4 of the interpretation 
of regulation C.02.029 (Sterile Products). The Canadian GMP code does not have 
any guidance covering the testing of ophthalmic ointments and controlled - release 
dosage forms. Correspondences to regulation 211.170 stating the requirements for 
reserve samples are covered in Section 1 of regulation C.02.025 and in regulation 
C.02.026 and Sections 1 and 3  5 of their interpretation. Correspondences to regulation 
211.173 stating the requirements for laboratory animals are covered in Section 
2.4 of the interpretation of regulation C.02.004. The Canadian GMP code does not 
have correspondence to regulation 211.176, which covers the requirements for the 
testing and handling of penicillin contamination. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
laboratory controls are covered in Chapters 1 (Quality Management), 4 (Documentation), 
5 (Production), and 6 (Quality Control) and in Annexes 1 (Manufacture of 
Sterile Medicinal Products), 9 (Manufacture of Liquids, Creams, and Ointments), 
and 19 (Reference and Retention Samples). Correspondences to regulation 211.160 
are covered in Subchapters 1.4, 4.2, 4.3, 4.10  4.13, 5.15, 6.7, and 6.18, which cover 
the general requirements for laboratory controls. Correspondences to regulation 
211.165 are covered in Subchapters 4.22, 4.23, 5.61, 5.62, 6.3, 6.11, and 6.15, which 
state the requirements for the release for distribution, the testing of fi nished drug 
products, and the handling of rejected drug products. The EU GMP code does not 
have correspondence to regulation 211.166, which states the requirements for stability 
testing. However, there is a separate guideline, Stability Testing on Active Ingredients 
and Finished Products [59] , which provides guidance on issues related to 
stability testing. Furthermore, Subchapters 6.23  6.33 cover the requirements for the 
on - going stability program. Correspondences to regulation 211.167 are covered in 
Annexes 1 and 9. Section 93 of Annex 1 covers the requirements for sterility testing 
and Annex 9 the requirements for ointments. In the EU GMP code there is no 
guidance on the testing of the controlled - release dosage forms. Correspondences to 
regulation 211.170 are covered in Subchapters 1.4 and 6.12 and Annex 19, which 
state the requirements for reserve samples. Correspondences to regulation 211.173 
are covered in Subchapters 3.33 and 6.22, which state the requirements for the 
maintenance of animals. The EU GMP code does not have correspondence to regulation 
211.176, which covers the requirements for the testing and handling of penicillin 
contaminations. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to laboratory controls are covered in Chapters 14 (Materials), 15 
(Documentation), 16 (Good Practices in Production), and 17 (Good Practices in 
Quality Control). Correspondences to regulation 211.160 are covered in Subchapters 
15.14  15.16, 15.18  15.21, 16.3, and 16.23, which state the general requirements 
for laboratory controls. Correspondences to regulation 211.165 are covered in 
Subchapters 14.28, 14.29, 15.13, 15.42, 17.7  17.13, 17.19, and 17.20, which state the 
requirements for the release for distribution covering the testing of fi nished drug 
products and the handling of rejected drug products. Correspondences to regulation 
211.166 are covered in Subchapters 17.23  17.26, which state the requirements for 
stability testing. The WHO GMP guideline does not cover separate requirements 

for the stability testing of homeopathic drug products. Correspondences to regulation 
211.167 are covered in Annex 6 of the WHO TRS 902 [40] , which states the 
requirements for sterility testing. The WHO GMP guideline does not cover any 
requirements for the testing of ophthalmic ointments or controlled - release dosage 
forms. Correspondences to regulation 211.170 are covered in Subchapter 17.22, 
which states the requirements for reserve samples. The WHO GMP guideline does 
not have correspondence to regulation 211.173, which covers the requirements 
for the maintenance of laboratory animals. Nor does it have correspondence to 
regulation 211.176, which covers the requirements for the testing of penicillin 
contaminations. 
2.1.4.10 Records and Reports 
In the United States issues related to records and reports are covered in Subpart J 
[7] , which consists of regulations 211.180, 211.182, 211.184, 211.186, 211.188, 211.192, 
211.194, 211.196, and 211.198. The contents of Subpart J is presented in Table 25 . 
Regulation 211.180 states the general requirements for documentation covering 
maintenance, retention times, and availability of the records. Furthermore, it states 
the requirements for the annual quality standards evaluation. Regulation 211.182 
states the requirements for individual equipment logs. Regulation 211.184 states the 
requirements for component, drug product container, closure, and labeling records. 
Regulation 211.186 states the requirements for master production and control 
records. Regulation 211.188 states the requirements for batch production and control 
records. Regulation 211.192 states the requirements for the review and approval of 
production and control records, including the requirements for the investigation of 
any unexplained discrepancies. Regulation 211.194 states the requirements for laboratory 
records, including the requirements for the documentation of modifi cations. 
Furthermore, it covers the requirements for the documentation of the testing and 
standardization of reference standards, reagents, and standard solutions; calibration 
of laboratory instruments and recording devices; and stability tests. Regulation 
211.196 states the requirements for the distribution records. Regulation 211.198 
states the requirements for the handling of complaints, including the maintenance 
and retention times of complaint fi les. 
TABLE 25 Contents of Subpart J of Part 211 of U . S . GMP Regulations Covering 
Records and Reports [7] 
Section Subject 
CFR 211.180 General requirements 
CFR 211.182 Equipment cleaning and use log 
CFR 211.184 Component, drug product container, closure, and labeling records 
CFR 211.186 Master production and control records 
CFR 211.188 Batch production and control records 
CFR 211.192 Production record review 
CFR 211.194 Laboratory records 
CFR 211.196 Distribution records 
CFR 211.198 Complaint fi les 
CORRESPONDENCES 155

156 CORRESPONDENCES AND DIFFERENCES 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to records and reports are mainly covered in regulations C.02.021, C.02.022, 
C.02.023, and C.02.024 (Records) and in their interpretations and partly in the 
interpretations of regulations C.02.005 (Equipment), C.02.010 (Raw Material 
Testing), C.02.011 (Manufacturing Control), C.02.012 (Manufacturing Control), 
C.02.014 (Quality Control Department), C.02.015 (Quality Control Department), 
and C.02.017 (Packaging Material Testing). Correspondences to regulation 211.180 
stating the general requirements for the maintenance of records, including periodic 
quality evaluation (self - inspection) and the retention time of the records are covered 
in regulations C.02.021, C.02.022, C.02.023, and C.02.024 and their interpretations 
and in Section 2 of the interpretation of regulation C.02.012. Correspondences 
to regulation 211.182 stating the requirements for individual equipment logs are 
covered in Section 5.5 of the interpretation of regulation C.02.005. Correspondences 
to regulation 211.184 stating the requirements for records to be kept on components, 
drug product containers, closures, and labeling are covered in Sections 4 and 5 of 
the interpretation of regulations C.02.020  24, Section 5 of the interpretation of 
regulation C.02.010, and Section 7 of the interpretation of regulation C.02.017. 
Correspondences to regulation 211.186 stating the requirements for the master 
production and control records (manufacturing and packaging master formulas) are 
covered in Sections 23  25 of the interpretation of regulation C.02.011 and Section 
1.1 of the interpretation of regulations C.02.020  24. Correspondences to regulation 
211.188 stating the requirements for the batch production and control records 
(manufacturing and packaging batch document) are covered in Sections 26, 27, 29, 
and 30 of the interpretation of regulation C.02.011 and Section 1.2 of the interpretation 
of regulations C.02.020  24. Correspondences to regulation 211.192 stating the 
requirements for review and approval of production and control records including 
investigation of batch deviations are covered in Section 2 of the interpretation of 
regulation C.02.014. Correspondences to regulation 211.194 stating the requirements 
for laboratory records are covered in Sections 6.4, 6.6, and 6.7 of the interpretation 
of regulation C.02.015. Correspondences to regulation 211.196 stating the 
requirements for distribution records are covered in Section 1.6 of the interpretation 
of regulation C.02.012 and Section 2.1 of the interpretation of regulations 
C.02.020  24. Correspondences to regulation 211.198 stating the requirements for 
the maintenance of complaint fi les including retention times are covered in Section 
4 of the interpretation of regulation C.02.015, Section 3.1 of the interpretation of 
regulations C.02.020  24, and regulation C.02.023. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
records and reports are mainly covered in Chapter 4 (Documentation) and partly 
in Chapters 1 (Quality Management), 5 (Production), 6 (Quality Control), 8 (Complaints 
and Product Recall), and 9 (Self Inspection). Correspondences to regulation 
211.180 are covered in Subchapters 4.1  4.9, 6.8, and 9.1  9.3, which state the general 
requirements for the maintenance of the records, including periodic quality evaluation 
(self - inspection) and retention times. Correspondences to regulation 211.182 
are covered in Subchapters 4.28 and 4.29, which state the requirements for individual 
equipment logs. Correspondences to regulation 211.184 are covered in Subchapters 
4.19 and 4.20, which state the requirements for the records to be kept on the 
receipt of components, drug product containers, closures, and labeling. Correspon

dences to regulation 211.186 are covered in Subchapters 4.14  4.16, which state the 
requirements for the master production and control records (manufacturing formula, 
processing, and packaging instructions). Correspondences to regulation 211.188 are 
covered in Subchapters 4.17 and 4.18, which state the requirements for the batch 
production and control records (batch processing and packaging record). Correspondences 
to regulation 211.192 are covered in Subchapters 1.4, 4.3, 4.24, 5.8, and 
5.39, which state the requirements for review and approval of production and 
control records, including the investigation of unexplained discrepancies. Correspondences 
to regulation 211.194 are covered in Subchapters 3.41, 6.7, 6.17, 6.20, 
and 6.21, which state the requirements for laboratory records. Correspondences to 
regulation 211.196 are covered in Subchapter 4.25, which states the requirements 
for distribution records. Correspondences to regulation 211.198 are covered in 
Subchapters 4.26 and 8.1  8.8, which state the requirements for the handling of 
complaints. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to records and reports are covered in Chapters 5 (Complaints), 
8 (Self - Inspection and Quality Audits), 13 (Equipment), 14 (Materials), 15 
(Documentation), 16 (Good Practices in Production), and 17 (Good Practices in 
Quality Control). Correspondences to regulation 211.180 are covered in Subchapters 
8.1  8.6 and 15.1  15.9, which state the general requirements for the maintenance 
of the records, including periodic quality evaluation (self - inspection) and retention 
times. Correspondences to regulation 211.182 are covered in Subchapters 15.46 
and 15.47, which state the requirements for individual equipment logs. Correspondences 
to regulation 211.184 are covered in Subchapters 15.32 and 15.33, which state 
the requirements for the records to be kept on the receipt of components, 
drug product containers, closures, and labeling. Correspondences to regulation 
211.186 are covered in Subchapters 15.22  15.24, which state the requirements for 
the master production and control records (master formula and packaging instructions). 
Correspondences to regulation 211.188 are covered in Subchapters 15.25  
15.30, which state the requirements for the batch production and control records 
(batch processing and packaging records). Correspondences to regulation 211.192 
are covered in Subchapters 16.4, 16.20, and 17.21, which state the requirements for 
review and approval of production and control records covering also the requirements 
for the investigation of unexplained discrepancies. Correspondences to regulation 
211.194 are covered in Subchapters 13.5, 14.34, 14.35, 14.41, 15.12, 15.42, 15.43, 
and 16.23, which states the requirements for laboratory records. Correspondences 
to regulation 211.196 are covered in Subchapter 15.45, which states the requirements 
for the distribution records. Correspondences to regulation 211.198 are 
covered in Subchapters 5.1  5.10, which state the requirements for the handling of 
complaints. 
2.1.4.11 Returned and Salvaged Drug Products 
In the United States GMP regulation [7] issues related to returned and salvaged 
drug products are covered in Subpart K, which consists of regulations 211.204 and 
211.208. The contents of Subpart K is presented in Table 26 . Regulation 211.204 
states the requirements for the handling of returned drug products, including repro- 
CORRESPONDENCES 157

158 CORRESPONDENCES AND DIFFERENCES 
cessing and documentation. Regulation 211.208 states the requirements for drug 
product salvaging. 
Correspondences in Canadian GMP Code In the Canadian GMP code [12] issues 
related to returned and salvaged drug products are covered in the interpretation of 
regulation C.02.014 (Quality Control Department). Correspondences to regulation 
211.204 stating the requirements for the handling of returned drug products are 
covered in Section 4 of the interpretation of regulation C.02.014. The Canadian 
GMP code does not have correspondence to regulation 211.208, which covers the 
requirements for drug product salvaging. 
Correspondences in EU GMP Code In the EU GMP code [15] issues related to 
returned and salvaged drug products are covered in Chapters 4 (Documentation) 
and 5 (Production). Correspondences to regulation 211.204 are covered in Subchapters 
4.26 and 5.26, which state the requirements for the handling of returned drug 
products. The EU GMP code does not have correspondence to regulation 211.208, 
which covers the requirements for drug product salvaging. 
Correspondences in WHO GMP Guideline In the WHO GMP guideline [36] 
issues related to returned and salvaged drug products are covered in Chapter 14 
(Materials). Correspondences to regulation 211.204 are covered in Subchapter 
14.33, which states the requirements for the handling of returned drug products. The 
WHO GMP guideline does not have correspondence to regulation 211.208, which 
covers the requirements for drug product salvaging. 
REFERENCES 
1. Immel , B. K. ( 2001 ), A brief history of the GMPs for pharmaceuticals , Pharm. Technol. 
No. Am. , 25 ( 7 ), 44  48 . 
2. Anonymous Pharmaceutical Administration and Regulations in Japan , Japan Pharmaceutical 
Manufacturers Association, available: http://www.jpma.or.jp/english/library/pdf/2005. 
pdf . 
3. Vesper , J. L. ( 2003 ), So what are GMPs, anyway? BioProcess Int. , 1 ( 2 ), 24  29. 
4. Rosin , L. J. ( 2006 ), Regulatory affairs: If you didn  t write it down, it didn  t happen , 
BioProcess Int. , 4 ( 3 , Suppl), 16  23 . 
5. Anonymous ( 2002 ), Sec. 351: Adulterated drugs and devices, in United States Code , 
Title 21, Chapter 9, Subchapter V, Part A, U.S. Government Printing Offi ce, Washington, 
DC, available: http://frwebgate.access.gpo.gov/cgi - bin/getdoc.cgi?dbname=browse_ 
usc&docid=Cite:+21USC351 . 
TABLE 26 Contents of Subpart K of Part 211 of U . S . 
GMP Regulations Covering Returned and Salvaged Drug 
Products [7] 
Section Subject 
CFR 211.204 Returned drug products 
CFR 211.208 Drug product salvaging 

6. Anonymous ( 2005 ), Part 210: Current good manufacturing practice in manufacturing, 
processing, packing, or holding of drugs: General, in Code of Federal Regulations , Title 
21, Chapter I, U.S. Government Printing Offi ce, Washington, DC, pp. 118  119, available: 
http://www.access.gpo.gov/nara/cfr/waisidx_05/21cfr210_05.html . 
7. Anonymous ( 2005 ), Part 211: Current good manufacturing practice for fi nished pharmaceuticals, 
in Code of Federal Regulations , Title 21, Chapter I, U.S. Government 
Printing Offi ce, Washington, DC, pp. 120  141, available: http://www.access.gpo.govnara/ 
cfr/waisidx_05/21cfr211_05.html . 
8. Grazal , J. G. , and Earl , D. S. ( 1997 ), EU and FDA regulations: Overview and comparison , 
Qual. Assur. J. , 2 , 55  60 . 
9. Anonymous ( 2006 ), Guidance page, available: http://www.fda.gov/cder/guidance/index. 
htm . 
10. Anonymous ( 2001 ), Guidance for industry: Q7A Good manufacturing practice guidance 
for active pharmaceutical ingredients, Offi ce of Training and Communications, available: 
http://www.fda.gov/cber/gdlns/ichactive.pdf . 
11. Anonymous ( 2005 ), Division 2: Good manufacturing practices, in Consolidated 
Statutes and Regulations , Food and Drugs Act, Food and Drug Regulations, Part C, 
Department of Justice, Canada, available: http://laws.justice.gc.ca/en/f - 27/c.r.c. - c.870/ 
230079.html . 
12. Anonymous ( 2002 ), Good manufacturing practices guidelines, Version 2, Health Products 
and Food Branch Inspectorate, available: http://www.hc - sc.gc.ca/dhp - mps/alt_formats/ 
hpfb - dgpsa/pdf/compli - conform/2002v2_e.pdf . 
13. Anonymous ( 2001 ), Directive 2001/83/EC of the European Parliament and of the Council , 
Off. J. Eur. Union , 44 ( L311 ), 67  128 , available: http://europa.eu.int/eur - lex/pri/en/oj/ 
dat/2001/l_311/l_31120011128en00670128.pdf . 
14. Anonymous ( 2003 ), Commission directive 2003/94/EC , Off. J. Eur. Union , 
46 ( L262 ), 22  26 , available: http://europa.eu.int/eur - lex/pri/en/oj/dat/2003/l_262/ 
l_26220031014en00220026.pdf . 
15. Anonymous ( 2005 ), EU guidelines to good manufacturing practice, in The Rules Governing 
Medicinal Products in the European Union , Vol. 4, European Commission Enterprise 
and Industry Directorate - General, available: http://pharmacos.eudra.org/F2/eudralex/ 
vol - 4/home.htm . 
16. Anonymous ( 1998 ), Quality and biotechnology, in The Rules Governing Medicinal Products 
in the European Union , Vol. 3A, European Commission Directorate General III, 
available: http://pharmacos.eudra.org/F2/eudralex/vol - 3/home.htm . 
17. Anonymous ( 2005 ), Regulations for Buildings and Facilities of Pharmacies , etc., MHLW 
Ministerial Ordinance, Yakuji Nippon Ltd. , Tokyo , No.73. 
18. Kim , Y. - O. , Ha , K. - W. , and Choi , K. - S. ( 2001 ), Safety evaluation for new drug approval in 
Korea , Drug Info. J. , 35 ( 1 ), 285  291 . 
19. Shin , S. - G. ( 1998 ), Current status of clinical trials in the Republic of Korea , Drug Info. J. , 
32 (Suppl), 1217S  1222S . 
20. Anonymous ( 2000 ), Competition in the Pharmaceutical Industry  Republic of Korea , 
Working Party No. 2 on Competition and Regulation, Committee on Competition Law 
and Policy, OECD Publishing , Paris . 
21. Anonymous ( 2001 ), Drug Administration Law of the People  s Republic of China , Order 
of the President of the People  s Republic of China No. 45, available: http://www.sfda.gov. 
cn/cmsweb/webportal/W45649037/A48335975.html . 
22. Deng , R. , and Kaitin , K. I. ( 2004 ), The regulation and approval of new drugs in China , 
Drug Info. J. , 38 ( 1 ), 29  39 . 
REFERENCES 159

160 CORRESPONDENCES AND DIFFERENCES 
23. Anonymous ( 2005 ), The Drugs and Cosmetics Act and Rules, Ministry of Health 
and Family Welfare, Department of Health, available: http://cdsco.nic.in/html/ 
Drugs&CosmeticAct.pdf . 
24. Anonymous ( 2005 ), Schedule M: Good manufacturing practices and requirements of 
premises, plant and equipment for pharmaceutical products, in The Drugs and Cosmetics 
Act and Rules, Ministry of Health and Family Welfare, Department of Health, pp. 386  
436, available: http://cdsco.nic.in/html/Drugs&CosmeticAct.pdf . 
25. Venkateswarlu , M. ( 2006 ), Why do we need revision of schedule M, available: http://www. 
pharmabiz.com , 2006. 
26. Anonymous ( 2006 ), Section 36: Manufacturing principles, in Therapeutic Goods Act 1989 , 
Offi ce of Legislative Drafting and Publishing, pp. 96  97, available: http://www.tga.gov.au/ 
legis/index.htm#instruments . 
27. Slater , T. ( 2002 ), Therapeutic goods (manufacturing principles) determination no 2 of 
2002 , Commonwealth Austral. Gaz. , GN 34, 2306  2307 . 
28. Anonymous ( 2002 ), Australian code of good manufacturing practice for medicinal 
products, Therapeutic Goods Administration, available: http://www.tga.gov.au/docs/pdf/ 
gmpcodau.pdf . 
29. Anonymous ( 2005 ), Medicines Act 1981, Parliamentary Counsel Offi ce, available: http:// 
www.legislation.govt.nz/browse_vw.asp?content - set=pal_statutes . 
30. Anonymous ( 2001 ), Guidance notes for applicants for consent to distribute new and 
changed medicines and related products, in New Zealand Regulatory Guidelines for 
Medicines , Vol. 1, 5th ed., MedSafe, available: http://www.medsafe.govt.nz/downloads/ 
vol1.doc . 
31. Anonymous ( 2005 ), New Zealand code of good manufacturing practice for manufacture 
and distribution of therapeutic goods, available: http://www.medsafe.govt.nz/Regulatory/ 
Guideline/code.htm . 
32. Anonymous ( 2002 ), Medicines and Related Substances Control Act 101 of 1965, 
Medicines Control Council, available: http://www.mccza.com/showdocument. 
asp?Cat=27&Desc=Acts%20and%20Regulations . 
33. Anonymous ( 2003 ), General regulations made in terms of the Medicines and Related 
Substances Act 1965 (Act no. 101 of 1965) as Amended, Government Notice, Department 
of Health, available: http://www.mccza.com/showdocument.asp?Cat=27&Desc= 
Acts%20and%20Regulations . 
34. Anonymous ( 2005 ), Guide to Good Manufacturing Practice for Medicines in South 
Africa, Medicines Control Council, available: http://www.mccza.com/showdocument. 
asp?Cat=21&Desc=Guidelines%20 - %20Good%20Manufacturing%20Practices . 
35. Anonymous ( 2002 ), WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 
37th Report, WHO Technical Report Series 908, World Health Organization, 
Singapore, available: http://whqlibdoc.who.int/trs/WHO_TRS_908.pdf . 
36. Anonymous ( 2002 ), Annex 4: Good manufacturing practices for pharmaceutical products: 
Main principles, in WHO Expert Committee on Specifi cations for Pharmaceutical 
Preparations: 37th Report, WHO Technical Report Series 908, World Health Organization, 
Singapore, pp. 36  89, available: http://whqlibdoc.who.int/trs/WHO_TRS_908.pdf . 
37. Anonymous ( 2005 ), Annex 2: Good manufacturing practices: Requirement for the sampling 
of starting materials (Amendment), in WHO Expert Committee on Specifi cations 
for Pharmaceutical Preparations: 39th Report, WHO Technical Report Series 929, 
World Health Organization, Singapore, pp. 38  39, available: http://whqlibdoc.who.int/trs/ 
WHO_TRS_929_eng.pdf . 
38. Anonymous ( 1992 ), Annex 1: Good manufacturing practices for pharmaceutical products: 
Good manufacturing practices for active pharmaceutical ingredients (bulk drug 

substances), in WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 
32th Report, WHO Technical Report Series 823, World Health Organization, 
Geneva, pp. 72  79, available: http://whqlibdoc.who.int/trs/WHO_TRS_823.pdf . 
39. Anonymous ( 1998 ), Annex 5: Good manufacturing practices: Supplementary guidelines 
for the manufacture of pharmaceutical excipients, in WHO Expert Committee on Speci- 
fi cations for Pharmaceutical Preparations: 35th Report, WHO Technical Report Series 
885, World Health Organization, Madrid, Spain, pp. 50  71, available: http://whqlibdoc. 
who.int/trs/WHO_TRS_885.pdf . 
40. Anonymous ( 2002 ), Annex 6: Good manufacturing practices for sterile pharmaceutical 
products, in WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 
36th Report, WHO Technical Report Series 902, World Health Organization, Singapore, 
pp. 76  93, available: http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf . 
41. Anonymous ( 1993 ), Annex 3: Good manufacturing practices for biological products, in 
WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 33th Report, 
WHO Technical Report Series 834, World Health Organization, Geneva, pp. 20  30, 
available: http://whqlibdoc.who.int/trs/WHO_TRS_834.pdf . 
42. Anonymous ( 1995 ), Annex 7: Good manufacturing practices: Supplementary guidelines 
for the manufacture of investigational pharmaceutical products for clinical trials in 
humans, in WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 
34th Report, WHO Technical Report Series 863, World Health Organization, Geneva, pp. 
97  108, available: http://whqlibdoc.who.int/trs/WHO_TRS_863_(p1 - p98).pdf (pp. 97  98); 
http://whqlibdoc.who.int/trs/WHO_TRS_863_(p99 - p194).pdf (pp. 99  108). 
43. Anonymous ( 1995 ), Annex 8: Good manufacturing practices: Supplementary guidelines 
for the manufacture of herbal medicinal products, in WHO Expert Committee on Speci- 
fi cations for Pharmaceutical Preparations: 34th Report, WHO Technical Report Series 
863, World Health Organization, Geneva, pp. 109  113, available: http://whqlibdoc.who. 
int/trs/WHO_TRS_863_(p99 - p194).pdf . 
44. Anonymous ( 2002 ), Annex 3: Guidelines on good manufacturing practices for radiopharmaceutical 
products, in WHO Expert Committee on Specifi cations for Pharmaceutical 
Preparations: 37th Report, WHO Technical Report Series 908, World Health 
Organization, Singapore, pp. 26  35, available: http://whqlibdoc.who.int/trs/WHO_TRS_ 
908.pdf . 
45. Anonymous ( 2005 ), Annex 3: WHO Good manufacturing practices: Water for pharmaceutical 
use, in WHO Expert Committee on Specifi cations for Pharmaceutical Preparations: 
39th Report, WHO Technical Report Series 929, World Health Organization, 
Singapore, pp. 40  58, available: http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf . 
46. Anonymous ( 2006 ), Background to PIC, available: http://www.picscheme.org/ 
indexnofl ash.php?p=backg . 
47. Anonymous ( 2006 ), Introduction, available: http://www.picscheme.org/indexnofl ash. 
php?p=intro . 
48. Anonymous ( 2006 ), List of PIC/S participating authorities ( & observers), available: http:// 
www.picscheme.org/indexnofl ash.php?p=members . 
49. Brunner , D. ( 2004 ), Pharmaceutical inspection co - operation scheme (PIC/S) , Qual. Assur. 
J. , 8 , 207  211 . 
50. Anonymous ( 2006 ), Guide to good manufacturing practice for medicinal products, PE 
009  3, Pharmaceutical inspection co - operation scheme, available: http://www.picscheme. 
org/guides.php# . 
51. Anonymous ( 2006 ), Structure of ICH, available: http://www.ich.org/cache/html/ 
510 - 272 - 1.html . 
REFERENCES 161

162 CORRESPONDENCES AND DIFFERENCES 
52. Anonymous ( 2000 ), Good manufacturing practice guide for active pharmaceutical ingredients 
Q7, ICH harmonised tripartite guideline, ICH Steering Committee, available: 
http://www.ich.org/LOB/media/MEDIA433.pdf . 
53. Anonymous ( 2006 ), Quality guidelines, available: http://www.ich.org/cache/compo/ 
363 - 272 - 1.html . 
54. Anonymous ( 2006 ), The founding of ASEAN, available: http://www.aseansec.org/ 
7069.htm . 
55. Anonymous ( 2006 ), Pharmaceuticals, available: http://www.aseansec.org/8657.htm . 
56. Vernengo , M. J. ( 1998 ), Advances in pharmaceutical market integration in MERCOSUR 
and other Latin American countries , Drug Info. J. , 32 ( 3 ), 831  839 . 
57. Anonymous ( 2005 ), Division 1A establishment licences, in Consolidated Statutes and 
Regulations , Food and Drugs Act, Food and Drug Regulations, Part C, Department of 
Justice Canada, available: http://laws.justice.gc.ca/en/f - 27/c.r.c. - c.870/230049.html . 
58. Anonymous ( 2002 ), Note for guidance on quality of water for pharmaceutical use, CPMP/ 
QWP/158/01, Committee for Proprietary Medicinal Products, Quality Working Party, 
London, available: http://www.emea.eu.int/pdfs/human/qwp/015801en.pdf . 
59. Anonymous ( 1998 ), Stability testing on active ingredients and fi nished products, in The 
Rules Governing Medicinal Products in the European Union , Vol. 3A, European Commission 
Directorate General III, pp. 143  151, available: http://pharmacos.eudra.org/F2/ 
eudralex/vol - 3/pdfs - en/3aq16aen.pdf . 

QUALITY 
SECTION 3


165 
3.1 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc. 
ANALYTICAL AND COMPUTATIONAL 
METHODS AND EXAMPLES FOR 
DESIGNING AND CONTROLLING 
TOTAL QUALITY MANAGEMENT 
PHARMACEUTICAL 
MANUFACTURING SYSTEMS 
Paul G. Ranky, 1 Gregory N. Ranky, 2 Richard G. Ranky, 1 and 
Ashley John 1 
1 New Jersey Institute of Technology, Newark, New Jersey 
2 Public Research University of New Jersey, Newark, New Jersey 
Contents 
3.1.1 Introduction 
3.1.2 Flexible Pharmaceutical Manufacturing and Assembly System Design 
3.1.3 Flexible Manufacturing Model Integrated with Design 
3.1.4 Real - Time Operation Control 
3.1.5 Innovative Design 
3.1.6 Open Innovation Architecture 
3.1.7 Generic, Object - Oriented Innovation Process Modeling Method and Sample 
Model 
3.1.8 Systems Approach to Pharmaceutical Manufacturing Systems Management 
3.1.9 Requirements Analysis for System Product, Process, and Service Design 
Innovation 
3.1.10 Innovation Risk Analysis and Opportunity Method and Tool with Pharmaceutical 
Manufacturing System Applications 
3.1.11 Open - Source Computational Statistical and Three - Dimensional Multimedia for 
Pharmaceutical Manufacturing System Innovation and Project Communication 
3.1.12 RFID Applications 
3.1.13 RFID Examples 

166 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
3.1.14 RFID Integration Models for Digital Pharmaceutical Manufacturing and Assembly 
Supply Chains 
3.1.15 Evaluation of Network Simulation Results 
3.1.16 Summary 
3.1.17 Complimentary Video on DVD 
References 
3.1.1 INTRODUCTION 
Total quality management (TQM) and operation control in pharmaceutical manufacturing 
system design engineering is essential. TQM - focused pharmaceutical 
manufacturing system engineering involves the continual satisfaction of customer 
requirements at lowest cost by harnessing the efforts of everybody in the company. 
Quality assurance means sustaining a system that prevents defects. This includes 
quality control and quality engineering. Quality control means establishing and 
maintaining specifi ed quality standards of products; quality engineering is the establishment 
and execution of tests to measure product quality and adherence to acceptance 
criteria. 
This chapter explains the importance of reducing variation for the purpose of 
implementing total quality in every process of the pharmaceutical design and manufacturing 
enterprise. Furthermore, it represents a modular product, process, service 
design, implementation, and management approach to the introduction of various 
TQM methods, tools, technologies, and their management issues within a variety of 
small, medium, and large enterprises for the purpose of designing and controlling 
pharmaceutical manufacturing systems. 
These aspects are very important, clearly illustrated by the fact that the U.S. Food 
and Drug Administration (FDA) has three classifi cation levels for medical 
products: 
 Class I products are passive devices that do not enter the patient  s body or 
contact only the skin. 
 Class II products are active devices or devices that are used to administer fl uids 
to the patient  s body. 
 Class III products are implanted inside the patient  s body. 
The FDA is familiar with the complexity of designing pharmaceutical systems. To 
support this activity, there are several software tools that help product/process and 
system designers to achieve the above. 
It should also be noted that the FDA expects design validation results to accompany 
some submissions. This is particularly true of class II and III devices. The 
agency expects such analysis results to match those obtained with established experimental 
methods. A number of software tools, including fi nite element analysis 
(FEA), motion and actuation simulation, computational fl uid dynamics (CFD), in 
conjunction with the computer - aided design (CAD) used for the designs themselves 
and other solutions are available that help today  s pharmaceutical/medical designer/ 
medical manufacturing/assembly system designer to meet the complex requirements 
of the industry as well as the FDA. (The key, here, is to accept the important 

principle that pharmaceutical design and manufacturing/assembly and even packaging 
must be an integrated approach.) 
The main problems when applying a traditional quality management philosophy 
to any pharmaceutical design/manufacturing/assembly challenge include the 
following: 
 This philosophy focuses on correcting mistakes after they have been made, 
rather than preventing them in the fi rst place. 
 It allows mistakes to be made. It actually builds them into every aspect of the 
system, typically costing around 20% of the turnover. 
 It accepts that quality has to be sacrifi ced as the volume and the productivity 
go up. 
 As viewed by accountants, it is an expensive add on item of the value chain. 
However, modern thinking claims that, because TQM involves every person, 
aspect, and machine of the organization, it requires a total commitment. It is not a 
 test - and - fi x  approach. It is a preventive system designed into every aspect of the 
world - class design, manufacturing, and service enterprise, including product design, 
manufacture, and management (and even in accounting terms costing somewhat 
less than conventional quality systems, i.e., typically around 10% of the turnover). 
The fundamental goal of TQM and TQC (total quality management and control) 
is to program, measure, and keep process variability under control. Some of these 
methods discussed in this chapter are as follows: 
 Pharmaceutical manufacturing system design methods and tools with 
examples 
 Process modeling for designing and running pharmaceutical manufacturing 
systems 
 Requirements analysis modeling for pharmaceutical manufacturing systems 
 Risk analysis modeling for pharmaceutical manufacturing systems 
 Dynamic modeling and network simulation for globally distributed pharmaceutical 
manufacturing systems and other methods and tools 
3.1.2 FLEXIBLE PHARMACEUTICAL MANUFACTURING AND 
ASSEMBLY SYSTEM DESIGN 
A fl exible pharmaceutical manufacturing/assembly system, (FMS) is a highly automated, 
distributed feedback - controlled system of data, information, and physical 
processors, such as computer and manually controlled machines, cells, workstations, 
and robots, in which decisions have to be made often in real time. This is only possible 
if all information processors (including the human resources of such systems) 
are  well informed  and lean/fl exible, meaning that they have the exact information 
at the exact time, format, and mode they need to allow responsible decision making 
within given time constraints. Note that this is a fundamentally different system 
design concept than that of the transfer line, operating on a fi xed cycle time, and 
designed for large batch production [1  8] . 
When designing a fl exible manufacturing/assembly system (FMS/FAS), the design 
team should consider the following steps: 
FLEXIBLE PHARMACEUTICAL MANUFACTURING 167

168 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
1. Collect all current and possible future user and system requirements. 
2. Analyze the system (i.e., the data processing and the FMS/ FAS hardware and 
software constraints). 
3. Design an appropriate data structure and database for describing processors 
and their resources, such as machines, robots, and tools (and/or robot hands, 
probes, sensory - based inspection and assembly tools, etc.). 
4. Specify and design programs and query routines and dialogues that are capable 
of accessing this database as well as communicating with the real - time production 
planning and control system of the FMS/FAS. 
5. Design and integrate the system with the rest of the hardware and software, 
including on - line manuals, education, and training packages, preferably in 
interactive, engineering multimedia format. 
6. Maintain the system and continuously learn for the benefi t of the existing as 
well as future system designs. 
Probably the most important questions to be answered before starting to design 
such a system are: Who is going to use it? For what purposes? With what data? How 
will it be used? 
As an example, consider that tooling data in FMSs will typically be used by 
several subsystems as well as by human beings are as follows: 
 Production planning subsystem 
 Process control 
 Part programming 
 Tool preset and tool maintenance 
 Tool assembly (manual or robotized) 
 Stock control and material storage 
By employing the above subsystems, the production planning system has to be 
informed in real time about the availability of tools in stock as well as about the 
current contents of the tool magazines of the machine tools (in the case of FASs 
the robot hands in the end - of - arm - tool magazines); otherwise it will not be able to 
generate a proper production schedule. 
It must be noted that the real - time aspect is important because tools are changed 
in the magazines of machines (or cells), not only because they wear, but also because 
different part programs may need different sets of tools. (The actual tool - changing 
operation is done in most cases by manipulators or by robots. The tool magazine 
loading/unloading procedure is performed mostly by human operators, sometimes 
by robots or special - purpose mechanisms, such as a tool shuttle.) 
Both the process control and the production planning systems have to update 
any changes and act in real time; otherwise the operation of the system can be 
disrupted. 
From the FMS/FAS tooling and tool management points of view one must 
emphasize the links between the CAD system, in which the parts are designed 
(using design for manufacturing principles), and the computer - aided manufacturing 
(CAM) system, where the FMS part programs are written. Typically, an FMS part 
programmer analyzes the CAD output (i.e., the design drawings of the pharmaceuti

cal products to be manufactured/assembled on the FMS), the fi xturing, the different 
setup (i.e., work - mounting) tasks, as well as the necessary operations, their alternatives, 
the required tools, and fi nally a precedence list of the resources (i.e., the possible 
candidates of processing stations, or cells, or machines). 
Real - time databases and software systems are also important, since they provide 
the reports and status information that are needed for the smooth operation of the 
FMS (in particular, its dynamic scheduler and other subsystems such as maintenance 
should be emphasized here) [4, 9  14] . 
3.1.3 A FLEXIBLE MANUFACTURING MODEL 
INTEGRATED WITH DESIGN 
The output of the CAM system is a production rule base. This is the knowledge the 
FMS needs to produce each pharmaceutical product. In this production rule base, 
among others, tools are assigned to each operation. The tool codes are selected by 
the FMS process planner or automatically assigned by a process planning system 
and are obtained from the tool database. 
On the basis of the requested tools a list is sent via the network to the tool 
preparation facility, or station, where the actual tools are prepared (i.e., assembled 
and preset) and stored in an appropriate way such that the material - handling system 
of the FMS can pick them up [12  21] . 
The tool preparation station also deals with other activities, among which the 
most important are as follows: 
 Tool service and maintenance 
 Tool assembly to orders (as it is necessary to replace worn tools) 
 Tool preset, tool inspection and adjustment 
 Real - time tool pickup and tool transportation organized to serve the needs of 
the real - time FMS 
The tool preparation station receives its orders, initially originated by the CAD 
data processing system, via the FMS network and technically specifi ed by the CAM 
system in the form of a production rule base. Order data arriving at the tool preparation 
station include the following: 
 Part orders (consisting of part codes and quantities). Note that this is a very 
important data set for the real - time FMS dynamic scheduler too. 
 Notifi cation of when the parts are physically available for FMS processing, 
representing a due date for tool preparation. 
 A priority order (note that this can change because of some real - time changes 
in the system, and thus this station must be able to cope with this task too). 
 The portion of the production rule base describing the requirements regarding 
tool preparation. 
The tool preparation station keeps in touch with the real - time FMS system, as well 
as with the rest of the system, by feeding back important tooling system - related 
data: 
A FLEXIBLE MANUFACTURING MODEL INTEGRATED WITH DESIGN 169

170 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
 Stock reviews (regarding tools) 
 FMS status report (regarding tools) 
 Part priority status reports (in case dynamic changes must be performed in the 
FMS which have an effect on tooling needs and tool preparation due dates) 
3.1.4 REAL - TIME OPERATION CONTROL 
The real - time part of the FMS operation control and management system must deal 
with the following tasks: 
 It must handle the application of tools for a variety of processes as defi ned in 
the production rule base and assigned in real time to the FMS/FAS resources 
by the dynamic scheduler. 
 It must provide data to control the transportation of tools and tool magazines 
within the FMS. 
 It must provide information to perform and supervise tool changes and tool 
magazine changes at all levels. 
 It must be notifi ed of tool inspection results (e.g., if it fi nds a worn - out tool as 
a result of an inspection procedure, it must generate a command that instructs 
the tool magazine update system to change the tool in question in the appropriate 
tool magazine). 
 It must provide information in the case of emergency. 
 It must provide the necessary interfaces and data to perform diagnostic/recovery 
operations, preferably using diagnostic expert systems. 
Finally, let us underline an important feedback loop starting at the real - time 
system and ending at the tool preparation station, which contains the real - time tool 
status, wear, and part priority information. These data are often useful to those 
people and/or system software systems that deal with the generation of the production 
rule base. It is also a very useful data set for FMS designers, since a lot of data 
which would previously have been lost will be saved in this way. 
The most important operation control activities in FMS/FAS identify three levels 
at which simulation and optimization are required prior to or during FMS/FAS part 
manufacturing: 
1. The factory level or business level handled by the business system of the 
computer integrated manufacturing (CIM) or, even broader, the enterprise 
resource management system 
2. The FMS off - line level representing scheduling, simulation, and optimization 
activities prior to loading a batch or a single component on the FMS (handled 
sometimes by the CAM system, sometimes by the FMS part programming 
computer) 
3. The real - time controlled level handled by the FMS/FAS operation control 
system, a dynamic scheduler with integrated tool management and multimedia 
support, representing a situation where the parts are already physically as well 
as logically in the real - time controlled environment 

Due to its complexity, a truly integrated approach is required in designing a 
production rule base to provide the job description for the FMS dynamic scheduler. 
This is because the dynamic system relies heavily on the knowledge base as represented 
by the rule base, and an overly restrictive rule base will lead to ineffi cient, 
at times even wrong, decisions. In other words, such a structure should represent all 
the multilevel interactions and their possible precedence rules that relate to the 
manufacturing process planning and processing decisions in an FMS. This turns out 
to be a diffi cult task. 
It should be underlined that the application of multimedia at this level is extremely 
benefi cial in terms of part program preparation, teaching/training operators on 
setting up parts, fi xtures, tools, machines, for troubleshooting, for regular maintenance, 
at the computer numerical control (CNC) level programming, robot programming, 
placement machine programming, programmable logic controller (PLC) 
programming, quality control, maintenance, and other tasks. 
Most FMSs have some part - buffering capability. This may be not for scheduling 
reasons, but for technological, that is, process - planning, reasons (e.g., the part must 
cool before an accurate inspection procedure is performed). Some level of buffering 
is useful and necessary because of reliability reasons. (The actual number of buffer 
store locations should be established on the basis of simulation and experience.) 
Cells often have some buffers too. The reason for this is that, by providing a part 
in the input queue of the cell just before the currently processed part is fi nished at 
the particular cell, the cell is kept running at its highest effi ciency level, since time 
is only  wasted  for part changing. The other important point to note is that well - 
designed part buffers offer a direct access pickup/load facility, making the rescheduling 
process in the queues short, simple, and dynamic [18, 19, 21  27] . 
3.1.5 INNOVATIVE DESIGN 
The key objective of this chapter is to describe a generic and systematic pharmaceutical 
manufacturing/assembly system design method that includes product, 
process, service systems, and even innovation project management architecture 
aspects of such systems. 
This architecture must be simultaneously novel as well as compliant with set 
guidelines by the product/process design industry and the PMI (Project Management 
Institute), following International Organization for Standardization (ISO) 
9000:2000 quality standards. Our tested pharmaceutical manufacturing system 
design solution integrates object - oriented process modeling, requirements and risk 
analysis, statistical methods, design of experiments, and three - dimensional (3D) 
interactive multimedia methods and tools which are 100% Web compatible. 
Furthermore, our methods and software tools are generic in that they can be 
applied not only to systems such as the pharmaceutical industries or automobile 
manufacturing but also to processes such as the oil business or services such as 
education. 
A pharmaceutical manufacturing system design requires signifi cant level of innovation. 
The broadest defi nition of innovation is the act of introducing something 
new to a society or community, whether a product or process. This is often confused 
with invention, which focuses more on specifi c objects. Within pharmaceuticals 
innovation can therefore include new business structures within the company, 
INNOVATIVE DESIGN 171

172 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
manufacturing processes and quality control for the medications, and product materials. 
Process and service improvements can also qualify as innovation, but note that 
in this case services are usually counted as processes [4, 13, 21, 23, 28  32] . 
Discoveries such as the charting of new planets, land masses, or forms of life are 
not classifi ed as innovations as they had existed before being observed by humans. 
When new species are introduced into a society and fi nd a specifi c use, it can be 
classifi ed as innovation. A pharmaceutical example of this is the antibiotic penicillin. 
Although it had existed as a fungal secretion, it was only within the past century 
that it was used to actively eliminate infectious bacteria. In initial analysis, however, 
it was not thought to survive long enough within the human body to be effective. 
This brings a vital aspect of innovation, namely the ability to recognize alternative 
uses for existing processes or tools. This is diffi cult as unexpected changes within a 
system are usually labeled as mistakes or anomalies. The development of the Post - It 
note is an example of this. The original goal was to create a high - strength adhesive, 
and an extremely weak one was created by accident. Nonetheless, instead of simply 
disposing of it, the possibilities of this new substance were examined by technicians 
and managers alike, allowing the use of easily placed reminders for everyday usage. 
Possessing an ultraweak adhesive allows Post - It notes to be removed without damaging 
the surfaces that they are placed on, and they are available in a variety of 
colors and sizes. 
The former example is a radical innovation, not only because it allowed signifi - 
cant changes in message reminders and adhesives, but also because it was completely 
unexpected. The diversifi cation of Post - It notes into different sizes and colors 
is an example of incremental innovation, which involves step - by - step changes and 
improvements to existing products or processes. Radical innovations are far less 
common, though their effects are farther reaching over both society and history. 
The general trend through human history has been one of learning to consciously 
recognize and direct innovation, particularly through combining science and technology. 
Human societies have often worked with certain processes even without 
fully understanding their effects or underlying ideas. Metallurgy shows this clearly, 
as iron, bronze, and gold have been used for millennia before the molecular structure 
could be seen and analyzed. Note also that, although our ancestors could not 
describe their chemical composition, these metals served a great many successful 
purposes. In these cases, the goals of innovation are highly pragmatic, as successful 
solutions are passed down and taught to future generations. 
Those who innovate can therefore learn from working, viable solutions to begin 
their own practices. Those who continuously work with a fi xed set of designs must 
be willing to experiment, test, and diversify their practices to avoid stratifi cation, as 
innovation not only allows survival but also encourages prosperity. 
The ability to innovate also involves learning from past mistakes, not just one  s 
own. Mistakes and errors in practices can be both costly and dangerous but can be 
prevented from occurring successively if their causes are determined. This can be 
diffi cult because a near - miss scenario can be seen either as an infrequent event or 
as an averted disaster. The fi rst reaction to this is usually to continue without changing 
current practices, allowing for similar mistakes to occur. Learning requires all 
levels of an organization to participate and create channels of communication to 
innovate effectively, as the inability to share experience denies new opportunities 
[13, 29  40] . 

3.1.6 OPEN INNOVATION ARCHITECTURE 
Innovation as a process and the related research - and - development (R & D) project 
management are considered to be two of the most complex information systems 
and engineering architectures due to the large number of attributes, processes, and 
dynamic changes projects go through during their life cycle. 
Following our integrated and simultaneously open architectural approach, we 
look at every innovation process and project as a system built of objects and classes 
of objects. 
Then we look at the way the components of these systems interact with each 
other. Once we understand these behaviors, we follow our integrated system 
approach in terms of looking at the project management system as processes, trying 
to satisfy customer requirements and also representing risks. 
We then embed this system model into a statistical analysis and 3D interactive 
multimedia framework (Figure 1 ). We use statistical methods to capture processes 
before they go out of control as well as to perform trend analysis, a great opportunity 
for innovation, and use 3D interactive multimedia and 3D visualization methods 
over the Web for communication purposes with global innovation team members. 
The emphasis on collaboration in today  s competitive medical drug fi eld requires 
these virtual environments to streamline team interaction. (Note that the active 
FIGURE 1 When designing lean and fl exible pharmaceutical manufacturing/assembly/ 
packaging systems, one needs to analyze the required processes, customer, user, maintenance, 
quality, reliability, fl exibility, lean, design requirements, and risks involved with any of the 
listed processes, all in a statistical framework. (Note that our 3D interactive multimedia and 
simulation framework supports integrated digital design and digital manufacturing system 
design principles, meaning that one should test all designs and systems fi rst on the screen, 
and only if everything looks fi ne, in the real world.) 
Process analysis 
Risk analysis 
statistical analysis, design of experiments, 
Web-base 3D interactive multimedia, DVD full-screen 
vidoeos and just-in-time iPod videos for 
knowledge managemet 
Requirements analysis 
OPEN INNOVATION ARCHITECTURE 173

174 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
code spreadsheets and 3D objects referred to in this presentation are all part of 
Ranky  s eLibrary and are available at http://www.cimwareukandusa.com .) 
To illustrate the importance of the  openness  of our architecture, consider 
modern simulation/analysis tools by Parametric Technology Corporation (PTC) 
(Figure 2 ), and PLM (product life - cycle management) tools, such as the IBM/Dassault 
Systemes Delmia tools for pharmaceutical manufacturing system modeling 
and design (Figure 3 ) with sensory feedback processing (Figure 4 ). 
Since these models can be designed, edited, run, and driven even over the limits, 
they can be extremely valuable sources for modeling in the digital domain, process 
analysis, requirements modeling, risk analysis, and even collecting statistical data 
and modeling breakdowns of complex systems. 
Observe the FEA in Figure 2 a . This is a torsional test of a pharmaceutical manufacturing 
machine element on the assembly line of a new medication packaging line. 
The line is still being tested and improved in the virtual environment, which greatly 
streamlines the refi nement process. As can be seen by the von Mises stress distribution, 
the sharp edges of the shaft will need to be rounded with a fi llet. These would 
also increase the distribution of the same stress and thus reduce the majority of the 
red zones (high stress) to blue or even green (low stress). Without using the virtual 
assembly line to test ideas before for the physical, the unexpected failure of this 
part could create delays or contamination of product or even harm human 
operators. 
As can be seen, digital pharmaceutical manufacturing/assembly/packaging and 
factory design tools include not only machines but also advanced sensors, actuators, 
controls, material - handling systems, labeling machines, and even ergonomically realistic 
human models and operators performing real - world tasks in extremely realistic 
model factories. Simulations like these are not just pretty models; they actually save 
huge investments because the factories are not built until the models are satisfactory. 
Keep in mind that making changes in a physical factory costs time, money, and 
possibly production effi ciency, even to just check a possible improvement. Virtual 
models can be simultaneously run thousands of times over a period of days, with 
hundreds of variables being optimized until the appropriate combination is chosen 
[30  36, 38, 40  44] . 
3.1.7 GENERIC, OBJECT - ORIENTED INNOVATION PROCESS 
MODELING METHOD AND SAMPLE MODEL 
Understanding, modeling, and then following processes, procedures, and best practice 
reusable processes are essential for every business to stay at the top. The pharmaceutical 
manufacturing system  innovation business  is not exception. 
Major international product/process design standards written and reviewed by 
thousands of leading researchers and companies around the world always help to 
create a model for complex problem - solving challenges such as innovation. Therefore 
this section discusses two of the eight quality management principles of the 
ISO 9000:2000 international quality standard and the way these rules should be 
applied to pharmaceutical manufacturing system designs. 
We do this for the purpose of developing systematic innovation (with related 
project modeling skills) and reusable, tested pharmaceutical system design 

FIGURE 2 Finite element torsional test of pharmaceutical manufacturing machine element 
on assembly line of new medication packaging line. The line is still being tested and improved 
in the virtual environment, which greatly streamlines the refi nement process. As can be seen 
by the von mises stress distribution, the sharp edges of the shaft will need to be rounded with 
a fi llet. These would also increase the distribution of the same stress and thus reduce the 
majority of the red zones (high stress) to blue or even green (low stress). 
Von Mises stress distribution plot Displacement distribution plot 
(a) 
max_disp_mag 
(mm) 
P_Pass 
Scale 1.0000E + 00 
Loadset: LoadSet1 
max_disp_mag 
max_disp_mag 
0.00 
0.25 
0.20 
0.15 
0.10 
0.05
0 2 3
PLoop Pass
4 5 6 
strain_energy 
(mm N) 
P_Pass 
Scale 1.0000E + 00 
Loadset: LoadSet1 
strain_energy 
strain_energy 
2.00 
4.00 
6.00 
10.00 
8.00 
12.00 
14.00 
16.00 
18.00
0 2 3
PLoop Pass
4 5 6 
max_strees_vm 
(N/mm^2) 
P_Pass 
Scale 1.0000E + 00 
Loadset: LoadSet1 
max_strees_vm 
max_strees_vm 
40.00 
50.00 
60.00 
70.00 
80.00 
90.00 
100.00 
110.00 
120.00 
130.00 
140.00
0 2 3
PLoop Pass 
4 5 
(b)

176 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
FIGURE 3 Modern simulation/analysis and PLM tool: IBM/Dassault Systemes Delmia for 
pharmaceutical manufacturing system modeling and design. The benefi ts are huge, since the 
system can be built and tested in the digital domain. (Courtesy of IBM/Dassault Systemes 
Delmia, Inc.) 
processes. We use our own object - oriented process modeling method, called CIMpgr. 
The nature of this method tansforms into UML models [the Unifi ed Modeling 
Language of information technology (IT)] and also complies with international 
process modeling standards used in complex system modeling environments. 
First, we will discuss a few important defi nitions that closely relate to ISO 
9000:2000 (quality process modeling) standard principle 4: 
 A process, or activity, can be defi ned as a transfer function with one or more 
inputs, outputs, controls, and resources that together all enable the variables to 
gain data and then fi re. 
 Transfer functions, when fi red, create a transformation process. A transformation 
process in a project is made up of methods, steps, tasks, and various algorithms 
and processes that acquire and manipulate data and then turn it into 
system output(s). Note that the input data can describe material, human knowledge, 
technological standing, fi scal information, and others. 
 The output of the process is a product that consists of specifi c technical and/or 
social products and services that conform to the sponsor  s requirements. 
 Processes, in terms of quality project management, have visibility, documentation, 
and traceability. 
 In this context visibility, relates to whether we know and transparently (or 
graphically) see what methods and techniques, system process steps, and technologies 
are involved when creating the desired output. Do we know the 

FIGURE 4 Advanced sensors working in pharmaceutical assembly systems help real - time 
operation control and quality assurance system to test every product. (This is often referred 
to as the zero - defect policy designed into a system.) The luminescence sensor illustrated will 
detect a wide variety of invisible targets. This STEALTH - UV sensor was designed to sense 
the presence of invisible fl uorescent materials contained in or added to many products. Users 
can detect the most diffi cult targets, including clear tamper - proof seals, clear labels, and invisible 
registration marks. This unique sensor is also ideal for solving many of today  s toughest 
problems in product orientation, inspection, and verifi cation. (Courtesy of TRI - TRONICS 
Co., Inc., www.ttco.com .) 
sequence of these steps and the possible parallel process relationships? How 
does one process affect the other? 
 Documentation means that the methods, steps, processes, and technologies are 
well specifi ed and recorded according to agreed - upon standard specifi cations. 
 Traceability means that the process steps as well as the output(s) can be traced 
back to actual customer requirements. 
 Process capability can be defi ned as the ability of the production process to 
meet certain specifi cations and tolerances. 
 Process discrepancy is the deviation of process settings from specifi cations. 
 Process variability is the variation in dimensional or other measurable characteristics 
of output from a production process. (Note that in any project the 
ultimate goal is to stay within the predefi ned limits of process variability and, 
if possible and feasible, to reduce process variability, because this typically 
reduces risk too.) 
 Variability can be expressed in terms of average range of standard deviation. 
 A process variable is a process parameter that fl uctuates in the manner of a 
random variable and hence requires surveillance. 
 Process management means getting the activities and procedures that highly 
skilled and experienced managers carry in their heads into the open by means 
of a well - documented model, often referred to as the process model [40  46] . 
GENERIC, OBJECT-ORIENTED INNOVATION PROCESS MODELING METHOD 177

178 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
3.1.8 SYSTEMS APPROACH TO PHARMACEUTICAL 
MANUFACTURING SYSTEMS MANAGEMENT 
Identifying, understanding, and managing interrelated processes as a system contribute 
to the organization  s effectiveness and effi ciency in achieving its objectives. 
(Note that every one of the key drivers listed below embed one or more innovation 
opportunities!) 
Key drivers and achievable gains include the following: 
 Processes that will achieve the desired results will become better integrated 
and aligned. 
 Management and process owners will have the ability to focus their efforts on 
the key processes. 
 Since the consistency, effectiveness, and effi ciency of the organization will grow, 
the confi dence of interested parties and collaborators in the organization will 
grow too. 
 System structuring and fi ne - tuning will become possible to achieve the organization 
 s objectives in the most effective and effi cient way. 
 Understanding the interdependencies between the processes of the system will 
yield good results. 
 Structured (and object/component - oriented) modeling approaches that harmonize 
and integrate processes will become reality. Employees will understand 
them, follow them, and therefore reduce waste and increase quality in every 
process. 
 The resistance created by cross - functional barriers will be reduced, providing 
a better understanding of the roles and responsibilities necessary for achieving 
common objectives. 
 Organizational capabilities and the establishment of resource constraints prior 
to action will be better understood by all involved (and mostly by all those who 
have created the models). 
 Targeting and defi ning how specifi c activities within a system should operate 
will become reality. 
 Continually improving the system through measurement and feedback - 
controlled evaluation becomes possible due to the analytical and quantifi able 
approach of the process models. (Note that at its ultimate level this will lead 
to a real - time, feedback - controlled enterprise capable of reacting to dynamically 
changing market needs.) 
After this introduction, let us show our object - oriented system components, 
following the above described ISO 9000:2000 principles, and how we can 
model complex innovation and related project management processes using them 
[40  54] . 
As a simple example, consider, that you are packaging a pharmaceutical product 
using a line that performs various process steps. Figure 5 a illustrates one of 
these steps. It has input(s), output(s), control(s), and resource(s). These data 

types help to identify under what conditions the process should be executed by 
the pharmaceutical manufacturing system. (Defi nitions are offered in the diagrams.) 
We can also see the way the CIMpgr process maps into a UML diagram. 
This is important, since UML is the modeling language of the IT professionals 
who will program the PLCs and control systems for the lines. Figure 5 b shows 
how the CIMpgr process maps into a UML diagram. We can see in Figure 5 a how 
multiple processes have to interact as we design a pharmaceutical assembly 
system. 
FIGURE 5 Object - oriented process modeling method (CIMpgr) as applicable to pharmaceutical 
manufacturing/assembly/packaging system design. 
This box represents the process. We can 
identify a process by naming it A0 (as a 
parent), and its children (a A1, A2, etc.) 
CIMpgr Process Model A0 
This is the control side to our process. This is where data 
somehow limits, or controls the process. (As an example for 
controls, imagine the international emission control 
regulations that automotive designers must follow). We can 
identify each control by a variable name, such as C1A0. 
A0 
DBI_A0: 
This identifies a data 
storage, a file, or a 
database for the process. 
This is the resource side to our process. This is where 
data describes the available manpower, hardware, 
software, and other available resources for executing the 
process. We can identify each resource by a variable 
name, such as R1A0. 
This is the administrative 
section of out model. 
Purpose: Why are we doing this? What is the fundamental purpose of this model? 
Viewpoint: As is System Analyst, System Designer; To be System Analyst, System Designer 
Authoring Team Members: Ranky, with 
Key Contact: Paul G. Ranky, Email: cimware@earthink.net, USA Tel: (201) 493 0521 
Client Ref: Company ABC Inc. 
Data: January 21, 2004, Version: ver. 1.0 
Confidential! Public Release: OK; Object / Class inheritance: ON 
R1A0: 
R2A0:
C3A0: 
C4A0: 
C2A0: 
C1A0: 
I1A0: 
I2A0: 
I3A0: 
I4A0: 
I5A0: 
I6A0: 
C5A0: 
C6A0: 
R3A0: 
R4A0: 
R5A0: 
O5A0: 
O4A0: 
O2A0: 
O1A0: 
This is the 
output side to 
our process. 
This is where 
data leaves 
the process. 
We can 
identify each 
output by a 
variable 
name, such 
as O1A0. 
This is the 
input side 
to our 
process. 
This is 
where data 
enters the 
process. 
We can 
identify input 
by a 
variable 
name, such 
as I1A0. 
(a) 
PHARMACEUTICAL MANUFACTURING SYSTEMS MANAGEMENT 179

180 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
Class NameL ClassA0 
Attributes in detail (also in CIMpgr model): 
Input(s): 
I1A0= , 
I2A0= , 
Output(s): 
O1A0= , 
O2A0= , 
Control(s): 
C1A0= , 
C2A0= , 
Resource(s): 
R1A0= , 
R2A0= , 
Link to 
Requirements Analysis Model Filename: 
Risk Analysis Model Filename: 
Attributes 
Attributes 
Operations 
Operations 
Operations (Mathematical TR functions, pseudo code for 
proc. descr., etc., using the attributes, as above=CIMpgr 
model attributes) 
Class Name: 
ClassA1 
Attributes 
Attributes 
Operations 
Operations 
Class Name: 
ClassA2 
(b) 
I1A1: New 
need from 
the customer 
/project 
sponsor 
C1A1: 
I2A1: 
I1A2: 
I3A1: 
I4A1: 
I5A1: 
I6A1: 
I7A1: 
C6A1: 
C1A3: 
I1A3: 
C2A3: 
C2A4: 
C1A4: 
C1A5: 
C2A5: 
I1A4: 
R2A4: 
C2A4: 
I1A4: 
C2A2: 
C1A2: 
C5A1: 
C2A1: 
Project time, budget and quality control. (Note that there are many other types of control, that relate to environmental 
issues, specific design, material, manufacturing, assembly, test, service, IT, and other processes and sub-systems.) 
Conception, or Conceptual, 
or Requirements Analysis 
Phase, or Process A1
A1 
A2 
A3 
A4 
O1A1: The results of the requirements analysis study. (This data-set offers valuable information for this future projects, 
for data mining, and for knowledge management.) O2A1: Project 
specification: What? 
When? How much? 
etc. 
R1A1: CORA 
software tool, 
and 
experienced 
CORA 
consultant R2A1: 
Requirements 
analysis team 
R3A1: PFRA 
risk analysis 
tool,project 
time and cost 
management 
software and 
consultant Definition, or Planning, or 
System Analysis Phase, or 
Process A2 
O1A2: Project specification results (This is n important data-set in case of multiple projects with precedence constraints. 
Also, this data-set offers valuable information for data mining, and for knowledge management.) O2A2: 
Detailed 
project 
specification 
DBI_A1: 
Process A1 
related 
requirements 
analysis 
results are 
stored here 
(e.g. results 
of a CORA 
study) 
DBI_A2: 
The 
system 
analysis 
documents 
and data 
are stored 
here 
R1A2: CIMpgr 
process 
model 
drawing tools, 
optional 
dynamic 
simulation 
software, and 
experienced 
consultant 
R2A2: Project 
time 
management 
and budget 
management 
software, and 
experienced 
planning team Design, or Acquisition, or 
System Design Phase, or 
Process A3 
O1A3 Project design result. (This data-set offers valuable information for 
data mining, and for knowledge management.) O2A3: 
Detailed 
project 
design 
DBI_A3: 
The 
system 
design 
blueprints 
are stored 
here 
R1A3: Project 
time 
management 
and budget 
management 
software, and 
experienced 
project design 
team 
R2A3: 
Specific 
CORA 
requirements 
analysis and 
PFRA risk 
analysis, and 
product/ 
process 
experts 
Operation, or Integration, 
or System Implementation 
and Test Phase, or 
Process A4 
A5 
O1A4: Project implementation results. (This data-set 
offers valuable information for data mining, and 
for knowledge management.) 
O2A4: 
Operational 
parameters of 
the 
implemented 
project 
Design-To-Analysis Feedback Loop 
Design-To-Requirements Feedback Loop 
Generic Project Management Model in CIMpgr for A1 to A5 Processes 
Key Contact: Paul G. Ranky, Email: cimware@earthlink.net, USA Tel: (201)493 0521 
Client Ref: Company ABC Inc., Date: June 09, 2004, Version: Ver. 5.0 
Detailed Project Management eBook Template Build-up. 
Object/Class Inheritance: ON 
Notation: Example: Conception, or Conceptual, or Requirements Analysis Phase, or 
Process A1, meaning, that this is a process, typically called by one or more of the listed 
names, for our purposes meaning exactly the same. 
DBI_A4: 
The system 
integration, 
implementation 
and test data 
are stored here 
R1A4: Project 
time 
management 
and budget 
management 
software, and 
experienced 
project 
implementation 
team 
DBI_A5: The 
post project 
review data is 
stored here 
based on longterm 
test and 
maintenance 
results 
Post Project Review, or 
Long Term System Test, or 
Maintenance phase, or 
Process A5 
O1A5: 
Test 
results 
O2A5: 
R2A5: 
R1A5: 
Continuous 
improvement 
team 
Implementation-To-Design Feedback Loop 
Long Term Test/Maintenance-To-Design Feedback Loop 
(c) 
FIGURE 5 Continued

3.1.9 REQUIREMENTS ANALYSIS FOR SYSTEM PRODUCT, PROCESS, 
AND SERVICE DESIGN INNOVATION 
Processes in a successful innovation project must satisfy requirements set by the 
market, the sponsors, and/or the inventor  s own dreams. Requirements analysis is 
considered to be one of the most important features of any innovative pharmaceutical 
manufacturing system project, because if done professionally, it helps to specify, 
research, and develop appropriate features and processes that customers need. 
In our innovation project examples we have focused on generic needs and 
requirements, and our associated  customers  are the pharmaceutical R & D team 
members, managers, and operators in various industries. 
In terms of our research approach, we have followed a proven method: Analyze 
the needs and the requirements, the demonstrated processes, and the methods and 
systems they try to or have to satisfy, and if you fi nd a  gap  , you have found an 
innovation opportunity. Note that when we search for this gap, it will simultaneously 
appear as a missing process in our CIMpgr model or as an existing process but 
missing attributes as well as a requirement in our CORA model (component - 
oriented requirements analysis) model: 
 Analyze the actual methods presented. Find the core methodologies, the 
mathematical models, and the underlying engineering and/or other science 
foundation. 
 Analyze the technologies involved. (How is science turned into a practical 
solution/engineering and/or computing technology?) Is there a need for a new, 
novel technology that has not been invented yet or applied in this fi eld? 
 Analyze and review the actual processes and the way the process fl ow is integrated. 
(Follow an object - oriented process analysis method, i.e., from concept 
to product.) Focus on the attributes of the processes. Note that by adding a new 
attribute you create new data types, with new information, and if your process 
can reason over this in a new way, new knowledge; therefore your combined 
CIMpgr and UML model becomes a new knowledge representation model too. 
This is important because innovation is formalized this way and can be communicated 
among global teams. 
 Analyze potential alternative solutions. (A pharmaceutical manufacturing/ 
assembly/packaging system must be very fl exible these days, due to dynamically 
changing customer requirements and even operating conditions.) 
 Analyze the benefi ts and the disadvantages of each process/solution. 
 Design alternative methods, processes based on what you have experienced/ 
seen and learned. 
 Design an integrated system, based on what you have analyzed in this case. 
 Work in a multidisciplinary team and exchange ideas. 
 Understand the boundaries as well as the tremendous potential of new ideas 
and developments by working on this case (realize that in order to survive and 
win, you must add value) [54  57] . 
After this short introduction, we demonstrate our CORA spreadsheet solution 
with a real - world example (Figure 6 ). 
REQUIREMENTS ANALYSIS 181

182 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
Object / Component Oriented Requirements Analysis Program for 
Networked Lean Manufacturing by Paul G. Ranky  19922006 
 Paul G. Ranky. 20002002 
Engineering / Software Solutions 
Responding to Customer 
Requirements 
Lean Manufacturing Manager: 
Customer Requirements 
( Reflecting component object 
behavior related to customer needs) 
S.No Describe the Requirement 
Reliability of data transfer for realtime 
access should be high 
Reliability of reporting process failure 
to the line managers computer 
Ease of integration into a system (plug 
and play networking): important! 
Ease of machine programming (CNC 
machining / inspection) 
Ease of changng CNC part programs 
(locally, and via the network) 
Ease of adding new sensors to a 
workstation, CNC, or cell: high 
safety of operation: critical! 
Cost of change/extenaion/system 
expansion should be low 
Operator training needs and costs 
should be low 
Network installation complexity and 
cost should be low 
1
2
3 
3 
3 3 3 3 
3
3 3 
3 
4 
4
4
4
4 
5 
5
5 
6
7
8
9 
9 9 9 9 3 9 
9 9 9 9 
9 9 9 9 
9 
9 9 9 9 9 9 
9 9 9 9 
9 9 9 
9 
3 9 
3 
3
9 
3 3 
3 3 
3 9 
9 
9 9 
9 
9 9 9 9 
9 3 3 
9 3 3 
9 9 9 
9 9 9 
9 9 9 
9 3 3 
9 9 9 9 9 
9 9 9 
9 9 9 
9 3 3 10 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 
Importance Rating (15) 
Fieldbus Network 
Profibus Network 
DeviceNet Network 
Ethemet 
Graphical CNC Progr. 
On-site maint. Support 
Off-site maint. Support 
On-site Redundant Server 
Off-site Redundant Server 
Link to Factory prod. contr. 
Link to Factory TQM/TQC 
2D videos/3D multimedia 
Cell-based web Camera 
PC-based CNC Controller 
PC based workkstation 
contr. 
PC based Cell controller 
(a) 
FIGURE 6 CORA method. This is a spreadsheet - based tool, designed to analyze customer 
requirements. (A  customer  here can mean a pharmaceutical manufacturing line vendor, 
user, operators, maintenance engineers, and many others.) The key approach is that we create 
a correlation matrix and then evaluate the results using a quantitative, computational 
approach. This is much more accurate than just a simple structured list. Our method offers 
a list of all key requirements as well as the priorities for the pharmaceutical manufacturing 
system design team they should follow during the design process. (For more about this software 
tool, see http://www.cimwareukandusa.com . 
0 
Competitor Cs product 
Competitor Bs product 
Competitor As product 
Our product 
0
1
2
3
4
5
6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Enter Competitor Cs ratings (1-5); Graph 
Enter Competitor Bs ratings (1-5); Graph 
Enter Competitor As ratings (1-5); Graph 
Enter Our Product ratings 
(1 = low, 5 = High) 
Relative Importance Rating 
Absolute Importance Rating 
3
3 3
3 3 
3 3 
3 3
3 
3 
3 3 3 
3 
3 
5 5 5 
5 
5 
5 5 5 5 
2 3 3 2 2 2 
2 2 
2 2 
2 1 1 4 4 
4 4
4 4 4 
4 
4 
4 
4 
4 4 4 4 4 4 4 
4 
4 4 
4 4 
4 4 5 
416 416 416 489 207 147 111 186 107 144 135 87 87 567 0 0 0 0
0 0 0 0 13 8.5 13 1.9 1.9 3 3.2 2.4 4.1 2.5 3.3 4.6 11 9.3 9.3 9.3 
381 588 
Target Values (List here the parameters 
that specify engineering solutions 
accurately. If you dont know the range of 
the acceptable values, use our Taguchi 
Calculator Program for Designing an 
Experiment) 
The system history database should 
be on the network 20 5 3 3 3 3 3 3 3 3 9 9 9 9 9 
Within 27 m sec 
Within 27 m sec 
Within 27 m sec 
Within 27 m sec 
GUI, iconized, 
multimedia 
Less than 3 
minutes 
Less than 24 hrsr 
0 sec switch 
Less than 30 sec 
switch 
Retresh every 2 
minutes 
Refresh every 2 
minutes 
320 240 pxels 
or better 
320 240 pxels 
or better 
Win, Linux, 
Solans, or OSX 
Response within 
12 m sec 
Response within 
24 m sec 
4 0 
(b)

3.1.10 INNOVATION RISK ANALYSIS AND OPPORTUNITY METHOD 
AND TOOL WITH PHARMACEUTICAL MANUFACTURING 
SYSTEM APPLICATIONS 
Our failure risk analysis and opportunity method and iterative software tool, as part 
of our New Product & Process Innovation (NPPI) Tool Library, promotes systematic 
collaboration and team - oriented engineering thinking when a new pharmaceutical 
manufacturing system process and/or product are developed. (We call it  opportunity 
method  too, since most risks, if not all, offer new opportunities for innovation.) 
It is based on our generic process failure risk analysis method that could be applied 
to literally any process that involves risk  and innovation is a very risky process. 
We follow a rule - based method when we analyze risk objects and components 
and their attributes. These plug - and - play rules can be different for different subjects, 
research areas, and industries. They can be designed and standardized for different 
industry sectors, enabling an analytical approach, systematic standardization, and 
accurate and predictable results. 
Our risk analysis method and tools help the engineering management team to 
understand some of the following concerns: 
 What could go wrong with the processes involved during the innovation 
project? 
 How badly might it go wrong and what could the fi nancial loss be? 
 Which are the highest risk processes/operations when working on the product/ 
process/service - related innovative design and project? 
 What needs to be done to prevent failures? 
 Which processes must be changed to reduce the risk of failure? 
 What tools and fi xtures are required to prevent failures and reduce the risk? 
 What education is needed for participants, innovators, engineers, and process 
owners, such as line management and operators, to reduce or prevent 
failures? 
After this introduction, we show the risk analysis system components, following 
the already described ISO 9000:2000 principles, and how we can model complex 
project management risks using them (Figure 7 ) (note that the active code spreadsheets 
and 3D objects are part of Ranky  s eLibrary) [50  55] . 
3.1.11 OPEN - SOURCE COMPUTATIONAL STATISTICAL 
AND THREE - DIMENSIONAL MULTIMEDIA FOR 
PHARMACEUTICAL MANUFACTURING SYSTEM INNOVATION 
AND PROJECT COMMUNICATION 
Since we follow an analytical, quantitative, and open - source computational approach, 
our pharmaceutical product/process and project management method and software 
toolset are implemented as (Internet browser readable) MS - Excel spreadsheets, 
integrated with several hyperlinks to the rule base and to optional 2D video and 
3D virtual - reality objects for visualization. 
OPEN-SOURCE COMPUTATIONAL STATISTICAL 183

184 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
FIGURE 7 The process failure risk analysis (PFRA) tool is an analytical and computational 
tool using rule bases for evaluating process risks. It is an ideal method and tool for reducing 
costly failures. (For more about this software tool, see http://www.cimwareukandusa.com . 
Rev.2.1.3. by Ranky 
9/19/01 
11/16/01 
Ranky 111601/DFRA_Ver.5 
List/Identify the Parts/Components Retrieved 
in Each Disassembly Process Step 
Painted metal PC cover (File: 3DMetalCover. 
mov) 
Floppy drive, hard drive, mounted in a solid 
sheet metal bracket inside the PC 
(File: 3DFloppyHDassy. mov) 
Floppy drive (File: 3DFloppyDrive. mov) 
Hard drive (File: 3DHDobj. mov) 
Metal bracket holding the floppy and the hard 
drive (File: 3DFloppyHDBracket. mov) 
Disassembly Process Code 
Engineering Rerease Date or Process Methodology 
Type of Product Disassembled 
Product Group Classifier 
Engineering Release Date of the Product 
Process 
Time 
Process 
Cost 
Accumulated 
Process Cost 
Ranky PC DisassyCode: 05/07/97 
5/7/97 
Electro-mechanical 
Desktop PC 
Estimated: 1993 
The DFRA Team Describes/Illustrates the Potential Disassembly 
Failure Mode and the Effect; the Risk of Failure 
Failure Mode(s) and Effect(s) 
Metal Cover scratched by slipped screwdriver 
As PC Metal Cover is removed, internal parts are cratched 
Floppy drive assy. screw removal can damage nother board 
Movie, illustrating floppy/HD assy. removal risks 
Can damage Floppy Drive if assy. Is dropped 
Can damage Hard Drive if assembly is dropped 
Can damage Hard Drive if assembly is dropped 
Proc. ID 
ID 5.1 
ID 5.2 
ID 5.3 
ID 4.1 
ID 4.2 
ID 4.3 
ID 3.1 
ID 3.2 
ID 3.3 
ID 2.1 
ID 2.2 
ID 2.3 
ID 1.1 
ID 1.2 
ID 1.3 
[sec] [USD] [USD] 
16.40 
45 0.21 
137 0.62 
35 0.16 
65 0.30 
12 0.05 
0.21 
0.83 
0.99 
0.28 
1.34 
(a) 
Ranky PC DisassyCode: 05/07/97 
5/7/97 ss 
Electro-mechanical 
Desktop PC 
Estimated: 1993 oduct 
ed 
ost 
This DFRA Study Prepared By 
DFRA Team 
Responsible Organization/Department 
Paul 
NJIT 
NJIT 
RPN 
Pr 
Nu 
Comments 
The DFRA Team Describes/Illustrates the Potential Disassembly 
Failure Mode and the Effect; the Risk of Failure 
Proc.ID 
ID 1.1 
ID 1.2 
ID 1.3 
ID 2.1 
ID 2.2 
ID 2.3 
ID 3.1 
ID 3.2 
ID 3.3 
ID 4.1 
ID 4.2 
ID 4.3 
ID 5.1 
ID 5.2 
ID 5.3 
Metal Cover scratched by slipped screwdriver 
As PC Metal Cover is removed, internal parts are cratched 
Floppy drive assy, screw removal can damage mother board 
Movie, illustrating floppy/HD assy. removal risks 
Can damage Floppy Drive if assy. Is dropped 
Can damage Hard Drive if assembly is dropped 
Can damage Hard Drive if assembly is dropped 
Severity 
Rating 
Detection 
Rating 
Occurrence 
Rating 
(1-10) (1-10) (1-10) 
3
3
3 
3
5
5 
4
2 
2 
2
2
2
9 
9
8
8 
1
1 
Failure Mode(s) and Effect(s) 
(b) 
The reason for this is because we would like to offer our users the opportunity 
not just to understand the method and the coded logic, but also to be able to enjoy 
the 3D interactive graphics, the digital videos, the color images, and most importantly 
the active code spreadsheets. Along with any other imaginable visualization, 
this can be executed and experimented with using their own data. 
In terms of statistical methods, our NPPI Tool Library has several statistical 
analysis tools to capture innovation opportunities at processes that are likely to drift 
and become out of control or processes that execute with random failure. 

This DFRA Study Prepared By 
OFRA Team 
Responsible Organization/Department 
Comments 
Paul G Ranky NJIT/MERC 
NJIT/MERC CFRA Team 
NJIT/MERC 
Severity 
Rating 
Detection 
Rating 
Occurrence 
Rating 
RPN (Risk 
Priority 
Number) 
Max. RPN Tooling 
Factor 
Clamping/ 
Fixturing 
Factor 
Skill Factor 
Any Other 
Factor You 
Define 
Accumulated 
RPN 
Risk 
Associated 
(1-10) (1-10) (1-10) 0.1-2.1=100% 0.1-2.1=100% 0.1-2.1=100% 0.1-2.1=100% 
3 
3
3
3 
2
2
2
2 
2 
5
5
8
8
9 
9
4 1
1 
18 
20 20 
0
0
0
0
0
0 
0 
0
0
0 
90 
90 
16 
48 48 
54 
54 
1.40 
1.40 
1.40 
1.40 
1.40 
1.40 
1.60 
1.20 1.20 
1.20 
1.20 
1.00 1.00 
1.00 
1.00 
1.00 
1.00 1.00 1.00 1.00 
33.60 
282.24 
96.77 
127.01 
0.00 
Low 
Low 
Low 
Low 
HIGH 
Mc 
Ha 
(c) 
(d) 
FIGURE 7 Continued 
OPEN-SOURCE COMPUTATIONAL STATISTICAL 185

186 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
For capturing such critical opportunities for innovation and process improvement, 
we use a range of control charts for drifting data analysis, Taguchi DOE 
(design of experiments) methods for developing the desired list of parameters for 
our engineering solutions in our requirements analysis method, and Weibull methods 
for process reliability analysis. As we progress, we plan to introduce further statistical 
and other tools to our NPPI Tool Library [56  70] . 
3.1.12 RFID APPLICATIONS 
Radio - frequency identifi cation (RFID) technologies are being adopted in the 
United States at a fast pace in pharmaceutical/assembly and packaging, in general 
manufacturing, warehousing, distribution, and global supply chain management. The 
market size for this technology is expected to rise from around $ 500 million in 2005 
to about $ 4 billion in 2010. In this section we outline some of the main application 
areas with a focus on the pharmaceutical applications. 
We also deal with the R & D opportunities and some digital pharmaceutical 
manufacturing systems with RFID information system modeling results . Furthermore 
we offer a generic factory assembly and tracking digital model for RFID 
integration, the most complicated task manufacturing systems engineers, industrial 
engineers, and IT experts have faced due to the mixed real - time as well as global 
traceability and messaging challenges one faces with RFID - tagged parts and shipments. 
RFID opportunities are great since with the appropriate IT infrastructure 
they help both major distributors and manufacturers as well as other logistics operations, 
such as in the health care system, defense industries, and others, dealing with 
complex, global supply chains in which products and product shipments must be 
traced and identifi ed in a noncontact, wireless fashion using a computer network, 
because of cost, security, or safety or because parts are subject to corrosion or medicine 
is subject to quality degradation. 
All of these requirements point to an automated, wireless - readable sensory - 
based identifi cation method and network that offers more functionalities and is 
signifi cantly  smarter  than the well - known bar code or the unifi ed product code 
(UPC). 
RFIDs are available as passive and/or active radio read/write sensor packages 
with active read (and often write) capabilities in relatively large areas (e.g., a large 
distribution center warehouse or a containership), all performed automatically, 
supervised by computers, and communicated in a wireless fashion over secure 
intranets. The attraction to a pharmaceutical assembly factory or a supply chain 
manager is that when the RFID network is integrated with the factories  material 
resource IT management systems, accurate information can be obtained on all 
tagged parts in close to real time throughout the entire supply chain. This can 
include the globally distributed factories as well as information about parts and 
assemblies during shipment, including in transit. This is why RFID represents great 
research and technology as well as huge business opportunities. 
We introduce here some of the most important engineering and information 
systems management principles and challenges that RFID researchers, implementers, 
and users should keep in mind when developing such systems and/or planning 

for such applications as well as offer an RFID digital factory integration model in 
UML [60  64, 70, 73] . 
3.1.13 RFID EXAMPLES 
To set the scene, consider a large storage house for a variety of medications or their 
distribution center with thousands of boxes, parts, and assemblies that range from 
low cost to high value, on occasion even highly sensitive technology or perishable 
drugs that must be kept in certain environmental conditions, such as temperature, 
humidity, or pressure, for the entire period of the shipment and/or production/packaging 
operations. 
Just - in - time delivery in an environment like this means that in order to build an 
order with variety or a new combination of treatments in a medical drug, every 
component must be in place on time and in good condition, which is a very diffi cult 
criterion to satisfy. 
Obviously supply chains are global these days, and shipments are typically made 
by a variety of means, including cargo ships, air, rail, and trucks; all of these can be 
late or can get in trouble because of the weather, traffi c, industrial disputes, or other 
reasons. Supply chain systems like this are very complex, because of the uncertainties 
in deliveries, parts and shipments are lost and/or stolen, goods get damaged 
during shipment, or the number of international ports and customs often take 
unpredictable time to check shipments with different levels of safety/security, and 
many other reasons. 
There are many valid reasons why wireless, computer - networked, sensory - based 
part identifi cation methods, tools, and technologies are being researched and 
deployed in industry. The application fi elds and opportunities are vast. The key 
driver is that even in chaotic, largely distributed, more stochastic than deterministic 
business environments, adaptive organizations and enterprises must react to 
demands quickly, else a competitor will take the business. Therefore they must 
reduce waste and improve effi ciency at all fronts. The most important aspect of this 
strategy is to know exactly what parts they have in stock, exactly where these parts 
are, and in what condition/state of assembly or preparedness they are. Furthermore, 
major distributors dealing with complex, global supply chains must be able to trace 
their shipments in detail because of cost, security, safety, quality degradation (as in 
the case of temperature - , humidity - , and/or shock - sensitive components or drugs), 
or other reasons. 
RFID technologies with the appropriate IT infrastructure help major distributors 
and manufacturers as well as other logistics operations such as the health care 
system, defense industries, and others deal with complex, global supply chains in 
which products and product shipments must be traced and identifi ed in a noncontact, 
wireless fashion using a computer network. 
All of the above - listed requirements point to an automated, wireless - readable, 
sensory - based identifi cation method and network that offer more functionalities, 
and are signifi cantly  smarter  than the well - known bar code or the UPC  hence 
the new popularity of RFID technology. 
RFID tags carry a serialized tag data construct. As an example, a 64 - bit class 0 
tag offered by a supplier includes 64 bits of total user memory on the tag itself, 
RFID EXAMPLES 187

188 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
including a unique serial number. This number is encoded by the manufacturer and 
uniquely identifi es up to 264 = 18,446,744,073,709,551,616 tagged items. 
RFIDs are available as passive and/or active radio read/write sensor packages 
with active read (and often write) capabilities in relatively large areas (like a large 
distribution center warehouse or a containership), all performed automatically, 
supervised by computers, and communicated in a wireless fashion. The attraction to 
an assembly factory or a supply chain manager here is that when the RFID network 
is integrated with the factories  material resource IT management systems, accurate 
information can be obtained on all tagged parts at close to real time, all throughout 
the entire supply chain. This can include the globally distributed factories as well as 
information about parts and assemblies in shipment/in transit. 
This is why RFID represents excellent research, technology, as well as big business 
opportunities. To illustrate this, consider research challenges such as remotely 
scanning and tracing products and parts in boxes on a cargo ship as it approaches 
national waters from international waters; tracing parts that are subject to corrosion 
and being used in agricultural or military equipment; medical drugs that are being 
counterfeited and repackaged and then shipped and imported illegally; or laptop 
computers that are dropped and damaged by accident. As a clear sign of the business 
opportunity, consider that according to a U.S. Department of Defense published 
presentation, RFID - enabled supply chain savings reached over U.S. $ 460 
million in 2004 and the projections for 2010 are in excess of $ 4 billion! 
3.1.14 RFID SYSTEM INTEGRATION MODELS FOR DIGITAL 
PHARMACEUTICAL MANUFACTURING AND ASSEMBLY 
SUPPLY CHAINS 
In the U.S. manufacturing and assembly industry, many of the RFID pilot projects 
focus on achieving 100% read rates at speeds set by the widely used bar code technology. 
The focus for these projects is to achieve proper tag placement on cases and 
pallets as well as the proper confi guration of pallets to enable 100% RFID tag 
read rates. This is a huge issue in pharmaceutical manufacturing and assembly 
in the fi ght to eliminate fake products and packages reaching the market! (See 
Figures 8  15 .) 
Based on the above - described requirements analysis, network planning, and 
server balancing reasoning, for our purposes, we have decided to follow a simple 
but powerful network architecture. In this architecture, we have included subnetworks. 
In terms of the way OPNET IT - Guru handles subnetworks, a subnetwork 
contains other network objects and abstracts them into a single object. A subnetwork 
can encompass a set of nodes and links to represent a physical grouping of 
objects (this can be a local - area network of CNC machines or robot PC controllers) 
or it can contain other subnetworks (e.g., including the material - handling system 
control of the line) [32, 34, 63, 66, 69  77] . 
Subnetworks within other subnetworks form the hierarchy of the network model. 
This hierarchy can then be extended as required to model the structure of the 
network. A subnetwork is considered the parent of the objects inside of it, and 
the objects are the children of the subnetwork. The highest level subnetwork in the 
network hierarchy does not have a parent, and therefore it is the top subnetwork, 

FIGURE 8 UML model segment illustrating the way the stock fi le is integrated with the 
routing and tooling fi les, assuming that all parts and all tools are RFID tagged. UML models 
like this should be used prior to any implementation work to assess requirements, technology 
needs, and RFID integration challenges with the rest of the factory  s IT infrastructure. 
FIGURE 9 Simulation network for distributed pharmaceutical manufacturing systems and 
their warehouses in U.S., Europe, India, and Asia. Model focuses on information and data 
management, the way the servers can cope with the task of tracking pharmaceutical product, 
and RFID data on a world wide basis. As a modeling tool we use OPNET, a professional 
network simulation tool. 
RFID SYSTEM INTEGRATION MODELS FOR DIGITAL PHARMACEUTICAL 189

FIGURE 10 Segment of simulation model illustrating corporate headquarters in New York. 
This is where we have our main servers in our distributed system. Modeling tool is OPNET. 
FIGURE 11 Segment of simulation model illustrating New Delhi campus network. This is 
where the business process outsourcing team and related servers in our distributed system 
are located. Modeling tool is OPNET. 

FIGURE 12 Pharmaceutical company portals as a wireless network of a pharmaceutical 
manufacturing system. The power of the model is that we can simulate a shop - fl oor request, 
comment, or warning throughout the entire international network of globally distributed 
pharmaceutical companies, with all important functions and processes. This means that before 
any pharmaceutical manufacturing system is actually built, we can simulate the entire system 
in the digital domain, saving huge expense and time. Modeling tool is OPNET. 
FIGURE 13 Simulation diagram illustrating and confi rming that the network system design 
from an ATM variation  response time point of view can cope with the demand. Modeling 
tool is OPNET. 

192 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
or global subnetwork. Subnetworks can be created and interconnected within this 
top level or within other subnetworks. Subnetworks provide a powerful mechanism 
for manipulating complex networks by breaking down the system  s complexity 
through abstraction. 
Since in our pharmaceutical network simulation models we deal with packets, let 
us explain a few aspects of packet formats. Packets carry information and can be 
sent between transmitters and receivers. In our example, packets can carry robot 
programs when uploaded from the design/programming offi ce servers to the robot 
lines and then to the individual CNCs, or robots, or parts of them if there is a need 
for an update, edit, quality control, production control, maintenance, and other data. 
(Packets can include mission - critical,  panic  related real - time data between the 
robot controller PCs and the line servers.) 
Packets are data structures consisting of storage areas called fi elds and can either 
be formatted or unformatted. Formatted packets have fi elds designed according to 
a packet format which specifi es the packets  fi eld names, data types, sizes, and default 
values. Formatted packets can be read by corresponding communication protocols 
only. Unformatted packets have no predefi ned fi elds. In IT - Guru, packet formats 
are predefi ned and typically named according to the model in which they are 
intended to be used. 
FIGURE 14 Simulation diagram illustrating and confi rming that the server balancing 
aspects of the network system design can cope with the demand. Modeling tool is OPNET. 

3.1.15 EVALUATION OF NETWORK SIMULATION RESULTS 
The goal of most simulation scenarios is to evaluate some aspect of a system  s 
behavior or performance and to quantify, typically in terms of statistics, the results 
and then use the results for decisions. This requires a simulation environment with 
software tools that provide insight into a model  s dynamic operation. 
Based on IT - Guru  s in - depth analysis, the pharmaceutical manufacturing system 
network engineering analyst can collect object, scenariowide, and global statistics 
as follows: 
 Object statistics are collected from individual objects. They allow the network 
engineering analyst to evaluate the performance of specifi c network nodes or 
links (a single hub  s Ethernet delay or a server balancing change, as in our 
example). 
 Scenariowide object statistics are collected from all relevant objects in a network 
(e.g., Ethernet delay for every node). They allow the network engineering 
analyst to easily monitor the performance of all objects of a specifi c type. 
EVALUATION OF NETWORK SIMULATION RESULTS 193 
FIGURE 15 Simulation diagram illustrating and confi rming that the network system design 
from an object variation  response time point of view can cope with the demand. As an 
example, this is important if a pharmaceutical manufacturing system line manager in India 
wants to notify a manager in New York by sending an image object, a sound object, or a 
multimedia object of a machine in the line for quality evaluation. Modeling tool is OPNET. 

194 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
 Global statistics are collected from the entire network. They represent results 
that apply to the network as a whole (such as global end - to - end delay) and let 
the designers and management analyze aspects of the network  s overall 
performance. 
 More specifi cally, IT - Guru offers the following types of statistics when analyzing 
networks: 
Queue size 
Available space 
Overfl ow occurrences 
Delay 
Interarrival times 
Packet sizes 
Throughput 
Utilization 
Error rates 
Collisions 
Application - specifi c statistics defi ned by a model developer 
Because there are many possible statistics to collect, the data fi les would quickly 
grow past practical use if the simulation program recorded them all. Therefore, the 
analyst must specifi cally select the statistics that are valuable for the particular study 
before running a simulation [71  79]. 
3.1.16 SUMMARY 
In this chapter, we have presented the foundations of an analytical and simultaneously 
computational lean and fl exible pharmaceutical manufacturing system design 
approach based on total quality standards. We have discussed why this approach is 
essential for pharmaceutical product, process, and manufacturing system designs. 
As illustrated, based on simulation results, using the plotted graphs and screens, 
management can easily evaluate different design alternatives, machine and human 
behavior models, control systems, sensory feedback processing, and the need of a 
balanced server architecture, and even investigate  what if  scenarios further, 
without committing to major upfront investment. 
We can clearly state that the time has come when pharmaceutical manufacturing 
systems can be designed and built in an entirely digital domain, saving huge amounts 
of capital and other related cost, and simultaneously increasing quality. 
3.1.17 COMPLIMENTARY VIDEO ON DVD 
To show real - world high - technology examples of pharmaceutical product, process, 
manufacturing, assembly, and packaging system designs, in action, something we 
cannot do in static, printed books, we have created a supplementary video, in high 
defi nition, and compressed onto a DVD. This professionally edited DVD supports 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 

this chapter as an independent, self - contained publication illustrating advanced 
pharmaceutical and medical product, process, and manufacturing system designs, 
related quality assurance processes and solutions, and others, explained by industry 
experts. To fi nd out more about this DVD, refer to Ranky, P. G., Ranky, G. N., and 
Ranky, R. G. (2006), Design Principles and Examples of Pharmaceutical Manufacturing 
Systems (Product, Process, Lean and Flexible Manufacturing, Assembly and 
Packaging System Designs) , Video on DVD, available: www.cimwareukandusa. 
com . 
REFERENCES 
1. Ranky , P. G. , A generic, analytical method to assess process - related risk with case studies, 
The Project Management Institute (PMI) Risk SIG and the Institute for International 
Research (IIR), paper presented at the Annual US National Project Risk Symposium, 
Houston, TX, May 22  May 26, 2006. 
2. Ashley , S. ( 2004 ), Penny - wise smart labels , Sci. Am . 291 ( 2 ), 30  31 . 
3. Ashton , P. , and Ranky , P. G. , ( 1999, Feb. ), An advanced concurrent engineering research 
toolset and its application at Rolls - Royce motor cars, ADAM (Adv. Des. Manufacturing), 
available: http://www.cimwareukandusa.com , listed and indexed by the Association of 
Research Libraries , Washington, DC, and the Edinburgh Engineering Virtual Library, 
United Kingdom, Vol. 1. 
4. Bradbrook , R. ( 2004 ), Wal - Mart and RFID, folding carton industry , Printing News , 31 ( 4 ), 
30  33 . 
5. Bradbrook , R. ( 2004 ), Procter and Gamble aim to be among the world leaders in RFID 
implementation , Int. Paper Board Ind ., 47 ( 8 ), 20  23 . 
6. Brzozowski , C. ( 2004 ), Tags, tickets & labels: New technologies emerge , Printing News , 
153 ( 3 ). 
7. Ranky , P. G. , An integrated PM approach, including: Process modeling, requirements 
analysis, risk analysis, statistical tools and 3D multimedia, presented at the Project Management 
Institute (PMI), New Jersey Chapter. Jan. 2006. 
8. Ranky , P. G. , Focus on RFID (radio frequency identifi cation) methods, technologies and 
education, presented as part of the NCME Mission (National Center for Manufacturing 
Education), sponsored by NSF (National Science Foundation, USA) and industry, Jan. 
2006. 
9. Flaherty , M. , Ranky , P. G. , Ranky , M. F. , Sands , S. , and Stratful , S. ( 1999, Mar. ), An 
engineering multimedia approach to servo pneumatic positioning, ADAM (Adv. Des. 
Manufacturing), available: http://www.cimwareukandusa.com , listed and indexed by the 
Association of Research Libraries, Washington DC, and the Edinburgh Engineering 
Virtual Library, United Kingdom, Vol. 1. 
10. Glidden , R. , Bockorick , C. , etal . ( 2004 ), Design of ultra - low - cost UHF RFID tags for 
supply chain applications , IEEE Commun. Mag . 42 ( 8 ), 140  151 . 
11. Graham-Rowe , D. (2004), Tags to banish forgetfulness , New Scientist , 183 ( 2460 ), 19 . 
12. Graham - Rowe , D. ( 2004 ), Who  s keeping tabs on your tags? New Scientist , 183 ( 2462 ), 
22 . 
13. Ho , K. L. , and Ranky , P. G. ( 1999, Mar. ), An object oriented approach to fl exible 
conveyor system design, ADAM (Adv. Des. Manufacturing), available: http://www. 
cimwareukandusa.com , listed and indexed by the Association of Research Libraries, Washington 
DC, and the Edinburgh Engineering Virtual Library, United Kingdom, Vol. 1. 
REFERENCES 195

196 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
14. Knights , P. F. , Henderson , E. , and Daneshmend , L. K. ( 2004 ), Drawpoint control using 
radio frequency identifi cation systems , CIM Bull ., 89 ( 1003 ), 53  58 . 
15. Loose , D. C. , and Ranky , P. G. ( 2007 ), A Case - Based Introduction to IBM  s Telematics 
Solutions , interactive multimedia eBook with 3D objects, text, and videos in a browser - 
readable format on CD - ROM/intranet, available: http://www.cimwareukandusa.com , 
CIMware USA, Inc., and CIMware Ltd., United Kingdom; multimedia design and programming 
by P. G. Ranky and M. F. Ranky. 
16. Mongeon , D. G. ( 2005, Feb. ), RFID: A tool for the 21st century distribution, USA Department 
of Defense Conference Presentation, RFID Media Briefi ng, Washington DC. 
17. Nadler , S. F. , Ranky , P. G. , and Ranky , M. ( 2002  2003 ), A 3D multimedia approach to the 
diagnosis of low back pain (Vol. 1, 18 - and 40 - year - old males), interactive 3D multimedia 
presentation on CD - ROM with off - line Internet support (650 Mbytes, approx. 150 interactive 
screens, 50 minutes of digital videos, 3D internal and external body tour, animation, 
and 3DVR objects), by CIMware (IEE and IMechE Approved Professional Developer); 
also in Multimedia design and programming by P. G. Ranky and M. F. Ranky. 
18. Ranky , G. N. , and Ranky , P.G. ( 2005 ), Japanese service robot R & D trends and examples , 
Ind. Robot , 32 ( 6 ), 460  467 . 
19. Ranky , P. G. , Caudill , R. J. , Limaye , K. , Alli , N. , ChamyVelumani , S. , Bhatia , A. , and 
Lonkar , M. ( 2002, May ), A Web - enabled virtual disassembly manager (web - VDM) for 
electronic product/process designers, disassembly line managers and operators, a UML 
(Unifi ed Modeling Language) model of our generic digital factory, and some of our 
electronic support system analysis tools, ADAM with IT (Adv. Des. Manufacturing), 
available: http://www.cimwareukandusa.com , listed and indexed by the Association of 
Research Libraries, Washington DC, and the Edinburgh Engineering Virtual Library, 
United Kingdom, Vol. 3. 
20. Ranky , P. G. ( 2006 ), Introduction to RFID  Radio frequency identifi cation methods and 
solutions , Assembly Automation , 26 ( 1 ), 28  33 . 
21. Ranky , P. G. ( 1999, Apr. ), New trends in fl exible, lean and agile manufacturing cells and 
systems, ADAM (Adv. Des. Manufacturing) , available: http://www.cimwareukandusa.com , 
listed and indexed by the Association of Research Libraries, Washington DC, and the 
Edinburgh Engineering Virtual Library, United Kingdom, Vol. 1. 
22. Ranky , P. G. ( 2002 ), A method for planning industrial robot networks for automotive 
welding and assembly lines , Ind. Robot: Int. J ., 29 ( 6 ), 530  537 . 
23. Ranky , P. G. ( 2003 ), A real - time manufacturing/assembly system performance evaluation 
and control model with integrated sensory feedback processing and visualization , Assembly 
Automation . 
24. Ranky , P. G. ( 2003 ), A simulation method and distributed server balancing results of networked 
industrial robots for automotive welding and assembly lines , Ind. Robot: Int. J ., 
30 ( 2 ), 192  197 . 
25. Ranky , P. G. ( 2002 ), Advanced digital automotive sensor applications , Sensor Rev.: Int. J ., 
22 ( 3 ), 213  217 . 
26. Ranky , P. G. ( 2003 ), Advanced machine vision systems and application examples , Sensor 
Rev.: Int. J ., 23 ( 3 ), 242  245 . 
27. Ranky , P. G. ( 2003 ), Collaborative synchronous robots serving machines and cells , Ind. 
Robot: Int. J ., 30 ( 3 ), 213  217 . 
28. Ranky , P. G. ( 2004 ), Digital, Internet - enabled assembly line and factory modeling , Assembly 
Automation , 24 ( 3 ), 247  253 . 
29. Ranky , P. G. ( 2004 ), Novel automated inspection methods, tools and technologies , Assembly 
Automation: Int. J ., 23 ( 3 ), 252  257 . 

30. Ranky , P. G. ( 2003 ), Reconfi gurable robot tool designs and integration applications , Ind. 
Robot: Int. J ., 30 ( 4 ), 338  344 . 
31. Ranky , P. G. ( 2002 ), Smart sensors , Sensor Rev.: Int. J ., 22 ( 4 ), 312  318 . 
32. Ranky , P. G. ( 1999, Jan. ,) Some generic algorithmic solutions to the problem of dynamic 
scheduling in fl exible manufacturing systems that operate globally, ADAM (Adv. Des. 
Manufacturing), available: http://www.cimwareukandusa.com , listed and indexed by the 
Association of Research Libraries, Washington DC, and the Edinburgh Engineering 
Virtual Library, United Kingdom, Vol. 1. 
33. Ranky , P. G. ( 2001 ), Trends and R & D in virtual and robotized product disassembly , Ind. 
Robot , 28 ( 6 ), 454  456 . 
34. Ranky , P. G. ( 2000, May ), Some analytical considerations of engineering multimedia 
system design within an object oriented architecture , Int. J. CIM , 13 ( 2 ), 204  214 . 
35. Ranky , P. G. , and ChamyVelumani , S. ( 2003 ), A method, a tool (CORA), and application 
examples for analyzing disassembly user interface design criteria , Int. J. CIM , 16 ( 4  5 ), 
317  325 . 
36. Ranky , P. G. , and ChamyVelumani , S. ( 2003 ), An analytical approach, a tool (DFRA) and 
application examples for assessing process - related failure risks , Int. J. CIM , 16 ( 4  5 ), 
326  333 . 
37. Ranky , P. G. , and Nadler , S. F. , A novel multimedia approach to low back pain diagnosis 
with internal and external 3D interactive body tours, paper presented at the 29th Annual 
Northeast Bioengineering Conference, New Jersey Institute of Technology, University 
Heights, Newark, NJ, Mar. 2003. 
38. Ranky , P. G. , and Nadler , S. F. , A new, Web-enabled multimedia approach with 3D virtual 
reality internal and external body tours to support low back pain diagnosis, paper presented 
at the 4th Annual Faculty Best Practices Showcase in Kean University, NJ, Mar. 2003. 
39. Ranky , P. G. , and Ranky , M. F. ( 2000 ), A Dynamic Operation control algorithm with 
multimedia objects for fl exible manufacturing systems , Int. J. CIM , 13 ( 2 ), 245  263 . 
40. Ranky , P. G. , Lonkar , M. , and ChamyVelumani , S. ( 2003 ), eTransition models of collaborating 
design and manufacturing enterprises , Int. J. CIM , 16 ( 4  5 ), 255  266 . 
41. Ranky , P. G. , Morales , C. , and Caudill , R. J. , Lean Disassembly line layout, process and 
network simulation models and cases, based on real - world data, paper presented at the 
IEEE (USA) International Symposium on Electronics and the Environment and the 
IAER Electronics Recycling Summit, Boston, MA, May 19  22, 2003. 
42. Ranky , P. G. , Ranky , G. N. , and Ranky , R.G. ( 2006 ), Examples of pharmaceutical product/ 
process/manufacturing/assembly and packaging system designs, video on DVD, available: 
www.cimwareukandusa.com . 
43. Ranky , P. G. , Subramanyam , M. , Caudill , R. J. , Limaye , K. , and Alli , N. , A dynamic scheduling 
and balancing method and software tool for lean and reconfi gurable disassembly 
lines, paper presented at the IEEE (USA) International Symposium on Electronics and 
the Environment and the IAER Electronics Recycling Summit, Boston, MA, May 19  22, 
2003. 
44. Ranky , P. G. , 3D engineering multimedia cases. A customizable 3D Web - enabled library 
with reusable objects, paper presented at the ASEE (American Society of Engineering 
Educators) Mid - Atlantic Conference, Kean University, NJ, Apr. 2003. 
45. Ranky , P. G. , A 3D multimedia approach to biomedical engineering: Low back analysis, 
paper presented at the ASEE, American Society of Engineering Educators, U.S. National 
Meeting, Biomedical Engineering Division, Nashville, TN, June 2003. 
46. Ranky , P. G. , Ranky , G. N. , and Ranky , R. G. ( 2006 ), Design principles and examples of 
pharmaceutical manufacturing systems (product, process, lean & fl exible manufacturing, 
REFERENCES 197

198 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
assembly and packaging system designs), video on DVD, available: www.cimwareukandusa.
com . 
47. Ranky , P. G. ( 2001  2006 ), A 3D multimedia case: Component oriented disassembly failure 
risk analysis, an interactive multimedia publication with 3D objects, text and videos in a 
browser - readable format on CD - ROM/intranet available: http://www.cimwareukandusa. 
com , CIMware USA, Inc., and CIMware Ltd., United Kingdom; Multimedia design and 
programming by P. G. Ranky and M. F. Ranky (published 6 volumes of this main title 
with different risk analysis challenges explained). 
48. Ranky , P. G. ( 2001  2005 ), A 3D multimedia case: component oriented disassembly user 
requirements analysis, an interactive multimedia eBook publication with 3D objects, text 
and videos in a browser - readable format on CD - ROM/intranet available: http://www. 
cimwareukandusa.com , CIMware USA, Inc., and CIMware Ltd., United Kingdom, Multimedia 
design and programming by P. G. Ranky and M. F. Ranky (published 7 volumes 
of this main title with different requirements analysis challenges explained). 
49. Ranky , P. G. , A 3D Web collaborative concurrent automotive engineering Method Based 
on our  distributed digital factory  and  digital car  models, paper presented at the 
Society of Automotive Engineers World Congress, Detroit, MI, Mar. 2003. 
50. Ranky , P. G. ( 2003 ), A 3D Web - enabled, case based learning architecture and knowledge 
documentation method for engineering, information technology, management, and 
medical science/biomedical engineering , Int. J. CIM , 16 ( 4  5 ). 346  356 . 
51. Ranky , P. G. , A Biomedical Engineering case with 3D lower back interactive virtual 
anatomy tours inside and outside the human body with automated post - test student 
assessment, paper presented at the ASEE (American Society of Engineering Educators) 
Mid - Atlantic Conference, Kean University, NJ, Apr. 2003. 
52. Ranky , P. G. , A new approach for teaching and learning about engineering process failure 
risk analysis with IE (industrial engineering) case studies, paper presented at the ASEE, 
American Society of Engineering Educators, US National Meeting, Industrial Engineering 
Division, Nashville, TN, June 2003. 
53. Ranky , P. G. , A novel 3D Internet - based multimedia method for teaching and learning 
about engineering management requirements analysis, paper presented at the ASEE, 
American Society of Engineering Educators, US National Meeting, Engineering Management 
Education Division, Nashville, TN, June 2003. 
54. Ranky , P. G. , An interactive 3D multimedia problem - based library for manufacturing 
engineering technology education with Internet support, paper presented at the ASEE, 
American Society of Engineering Educators, US National Meeting, Engineering Technology 
Division, Nashville, TN, June 2003. 
55. Ranky , P. G. ( 2003  2005 ), An introduction to alternative energy sources: Hybrid & fuel 
cell vehicles; an interactive multimedia eBook publication with 3D objects, text, and 
videos in a browser - readable format on CD - ROM/intranet, available: http://www. 
cimwareukandusa.com , CIMware USA, Inc., and CIMware Ltd.; United Kingdom, Multimedia 
design and programming by P. G. Ranky and M. F. Ranky, (2003  2005), Customer 
needs, wants & requirements analysis: Automotive exterior rearview mirror, an interactive 
multimedia eBook publication with 3D objects, text, and videos in a browser - readable 
format on CD - ROM/intranet, available: http://www.cimwareukandusa.com , CIMware 
USA, Inc., and CIMware Ltd., United Kingdom. 
56. Ranky , P. G. ( 2003  2005 ), An introduction to digital factory & digital telematic car modeling 
with R & D and industrial case studies, an interactive multimedia eBook publication 
with 3D objects, text, and videos in a browser - readable format on CD - ROM/intranet, 
available: http://www.cimwareukandusa.com , CIMware USA, Inc. and CIMware Ltd., 
United Kingdom, Multimedia design and programming by P. G. Ranky and M. F. Ranky. 

57. Ranky , P. G. (2005), An introduction to RFID, radio frequency identifi cation methods and 
applications, DVD video, available: www.cimwareukandusa.com (approximately 30 min). 
58. Ranky , P. G. ( 2005  2006 ), An introduction to RFID, radio frequency identifi cation 
methods and applications with a total quality management and control focus, interactive 
browser - readable 3D eBook, available: www.cimwareukandusa.com , (approximately 
30 min). 
59. Ranky , P. G. ( 1999, Apr. ), An object oriented system analysis and design method (CIMpgr) 
and an R & D case study, Adv. Des. Manufacturing, available: http://www.cimwareukan 
dusa.com , listed and indexed by the Association of Research Libraries, Washington DC, 
and the Edinburgh Engineering Virtual Library, United Kingdom, Vol. 1. 
60. Ranky , P. G. , Computerized engineering assessment method based on 3D interactive 
multimedia, That students enjoy, paper presented at the ASEE, American Society of 
Engineering Educators, US National Meeting, Continuing Professional Development 
Division, Nashville, TN, June 2003. 
61. Ranky , P. G. ( 1999 ), Design, manufacturing and assembly automation trends and strategies 
in China , Assembly Automation , 19 ( 4 ), 301  305 . 
62. Ranky , P. G. ( 2003 , Feb.), Designing a lean infrastructure; advanced machining cell design 
concepts, methods, architectures and cases , Manuf. Eng., J. IEE , 22  24 . 
63. Ranky , P. G. ( 2000 ), Engineering multimedia in CIM (computer integrated manufacturing) 
, Int. J. CIM , 13 ( 2 ), 169  171 . 
64. Ranky , P. G. ( 2003 ), eTransition in the multi - lifecycle CIM (computer integrated manufacturing) 
context , Int. J. CIM , 16 ( 4  5 ), 229  234 . 
65. Ranky , P. G. , Interactive 3D multimedia cases for engineering education with Internet 
support, ASEE, American Society of Engineering Educators, paper presented at the 
U.S. National Meeting, Computers in Education Division, Nashville, TN, June 2003. 
66. Ranky , P. G. , Interactive 3D multimedia cases for manufacturing engineering education 
with Internet support, paper presented at the ASEE, American Society of Engineering 
Educators, US National Meeting, Manufacturing Engineering Education Division, 
Nashville, TN, June 2003. 
67. Ranky , P. G. ( 2002, Dec. ), Introduction to concurrent engineering, an NSF (National 
Science Foundation, USA) sponsored Gateway Coalition streamed multimedia narrated 
web presentation, New Jersey Intitute of Technology, Public Research University, Newark, 
New Jersey . 
68. Ranky , P. G. ( 2003  2005 ), Key R & D and eTransition trends in US and international collaborative 
design & manufacturing enterprises, an interactive multimedia eBook publication 
with 3D objects, text, and videos in a browser - readable format on CD - ROM/intranet, 
available: http://www.cimwareukandusa.com , CIMware USA, Inc., and CIMware Ltd., 
United Kingdom; Multimedia design and programming by P. G. Ranky and M. F. Ranky . 
69. Ranky , P. G. ( 2000, Jan. ), Modular fi eldbus designs and applications , Assembly Automation 
, 20 ( 1 ), 40  45 . 
70. Ranky , P. G. ( 2003 ), Network simulation models of lean manufacturing systems in digital 
factories and an intranet server balancing algorithm , Int. J. CIM , 16 ( 4  5 ), 267  282 . 
71. Ranky , P. G. , Rapid prototyping cases for integrated design and manufacturing engineering 
education with 3D Internet support, paper presented at the ASEE, American Society 
of Engineering Educators, US National Meeting, Design in Engineering Education Division, 
Nashville, TN, June 2003. 
72. Roman , H. T. , and Ranky , P. G. ( 2003  2005 ), A case - based Introduction to Service robotics, 
an interactive multimedia eBook publication with 3D objects, text, and videos in a 
browser - readable format on CD - ROM/intranet, available: http://www.cimwareukandusa. 
REFERENCES 199

200 ANALYTICAL AND COMPUTATIONAL METHODS AND EXAMPLES 
com , CIMware USA, Inc., and CIMware Ltd., United Kingdom. Multimedia design and 
programming by P. G. Ranky and M. F. Ranky. 
73. Romero , C. , Department of logistics passive RFID initial implementation, paper presented 
at the USA Department of Defense Conference, RFID Media Briefi ng, 
Washington DC, Feb. 2005. 
74. Sangoi , R. , Smith , C. G. , et al . ( 2004 ), Printing radio frequency identifi cation (RFID) tag 
antennas using inks containing silver dispersions , J. Dispersion Sci. Technol . 25 ( 4 ), 
513  521 . 
75. Smith , K. , Enabling the supply chain, paper presented at the USA Department of Defense 
Conference, RFID Media Briefi ng, Washington, DC, Feb. 2005. 
76. Sugimoto , M. , Kusunoki , F. , Inagaki , S. , Takatoki , K. , and Yoshikawa , A. ( 2004 ), A system 
for supporting collaborative learning with networked sensing boards , Syst. Comput. Jpn ., 
35 ( 9 ), 39  50 . 
77. Wilke , P. , and Braunl , T. ( 2001 ), Flexible wireless communication network for mobile 
robot agents , Ind. Robot , 28 ( 3 ), 220  233 . 

201 
3.2 
ROLE OF QUALITY SYSTEMS AND 
AUDITS IN PHARMACEUTICAL 
MANUFACTURING ENVIRONMENT 
Evan B. Siegel and James M. Barquest 
Ground Zero Pharmaceuticals, Inc., Irvine, California 
Contents 
3.2.1 cGMP Regulations 
3.2.1.1 Duties of Quality Control Unit under cGMP Regulations 
3.2.2 Quality Assurance Function 
3.2.3 Quality Systems Approach 
3.2.4 Management Responsibilities 
3.2.5 Resources 
3.2.6 Manufacturing Operations 
3.2.6.1 Design, Develop, and Document Product and Processes 
3.2.6.2 Inputs 
3.2.6.3 Perform and Monitor Operations 
3.2.6.4 Address Nonconformities 
3.2.7 Evaluation Activities 
3.2.7.1 Trend Analysis 
3.2.7.2 Conduct Internal Audits 
3.2.7.3 Quality Risk Management 
3.2.7.4 Corrective and Preventive Actions 
3.2.7.5 Promote Improvement 
3.2.8 Transitioning to Quality Systems Approach 
3.2.9 Audit Checklist for Drug Industry 
3.2.9.1 Instructions for Using Audit Checklist 
References 
By regulation, appropriate practice, and common sense, quality assurance (QA) is 
a critical function in the pharmaceutical manufacturing environment. The need for 
an independent unit to audit and comment on the appropriate application of 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

202 ROLE OF QUALITY SYSTEMS AND AUDITS 
standard operating procedures, master batch records, procedures approved in 
product applications, and the proper functioning of the quality control (QC) unit is 
paramount. This helps assure that products are manufactured reliably, with adherence 
to approved specifi cations, and that current good manufacturing practices 
(cGMP) are maintained in conformance to regulation, both in the facility in general 
and the microenvironment of each product  s manufacturing sequence. 
Quality assurance personnel must have the appropriate training, experience, 
familiarization with the manufacturing facility and products, enforced independence 
from the production chain of command, and the ability to review adherence to 
procedures, policies, and agreed - upon approaches to manufacturing quality pharmaceuticals. 
This helps to provide both an environment and a manufactured product 
that can withstand Food and Drug Administration (FDA) inspection and support 
a fi rm  s reputation for quality products. 
The cGMP regulations establish requirements that are intended to provide a high 
level of assurance that the pharmaceutical products produced satisfy the strength, 
purity, potency, and other quality requirements established for the fi nished product 
to assure that it is fi t for its intended use. Manufacturers must establish a quality 
control unit that is responsible for many of the quality - related activities required 
by the regulations. These regulations have not been substantially updated since 1978. 
Since then, the science and practice of quality assurance have substantially evolved 
to include the development of quality management systems and risk management 
approaches to better assure product quality and fi tness for use. Pharmaceutical 
product manufacturers are increasingly interested in implementing a comprehensive 
quality management system (QMS) and employing risk management approaches 
because they allow them to apply newer quality management principles that they 
believe enable them to more effectively assure product quality and better allow 
harmonization with evolving international regulatory quality system requirements. 
The FDA has not changed the cGMP regulations but, as part of its Pharmaceutical 
CGMPs for the 21st Century Initiative, encourages this quality systems approach to 
cGMP compliance. 
This Chapter describes outlines and discusses the regulations applicable to the 
QA function and unit, structure, function, charter, and application of the unit in the 
pharmaceutical manufacturing environment. In addition, it discusses additional 
quality - related responsibilities that may result when manufacturers move toward a 
quality systems approach to quality that incorporates current quality system models 
to further improve quality and harmonize with international quality system 
requirements. 
The justifi cation for, and execution of, the QA audit are also described, including 
preparation, key items of interest, a typical checklist of the audit itself, corrective 
and preventive actions following the audit, and suggested measures for assuring 
successful operation of the unit. 
3.2.1 c GMP REGULATIONS 
The cGMP regulations for the manufacture of pharmaceutical products are contained 
in Parts 210 and 211 of Title 21 of the Code of Federal Regulations (CFR) 
[1] . These regulations, as well as guidance documents and other FDA documents 

pertaining to the regulation and FDA inspection of pharmaceutical product manufacturers, 
may be accessed on the FDA website at www.fda.gov . Part 210 specifi es 
the scope and applicability of the cGMP regulations and defi nes terms used in the 
regulations. Part 210 also indicates that the regulations establish  minimum  cGMP 
requirements and that products that are not manufactured under cGMP are adulterated. 
Adulterated products and the persons responsible for the adulteration are 
subject to regulatory action by the FDA. 
Part 211 contains specifi c good manufacturing practice requirements for fi nished 
pharmaceuticals and is divided into Subparts A  K as follows: 
A. Scope 
B. Organization and Personnel 
C. Buildings and Facilities 
D. Equipment 
E. Control of Components and Drug Product Containers and Closures 
F. Production and Process Controls 
G. Packaging and Labeling Control 
H. Holding and Distribution 
I. Laboratory Controls 
J. Records and Reports 
K. Returned and Salvaged Drug Products 
The cGMP regulations are written to address the primary potential sources of 
product variability. Subpart B establishes the quality control unit and the duties of 
that unit, establishes personnel requirements and addresses personnel practices 
(e.g. sanitation) intended to reduce the likelihood of product contamination. Subparts 
C and D establish requirements for buildings and facilities and equipment 
used in the manufacture, processing, packing, or holding of a drug product. Subparts 
E through H establish controls over the major processes associated with the production 
of a fi nished and packaged drug product that is ready to be shipped for distribution 
to users. Controls are established for incoming raw materials and components 
and continue through manufacturing, packaging, labeling, holding, and distribution 
of fi nished, packaged, labeled, and released drug product. Subpart I requires the 
establishment of scientifi cally sound and appropriate specifi cations, standards, sampling 
plans, and test procedures; requires instrument specifi cations and calibration; 
and establishes lot or batch testing and release requirements. Subpart J establishes 
documentation requirements including master and batch records, and Subpart K 
addresses the control and disposition of returned drug products and places limitations 
on the salvage of drug products that have been subjected to improper storage 
conditions (e.g., smoke, heat, fi re, moisture). 
3.2.1.1 Duties of Quality Control Unit under c GMP Regulations 
The cGMP regulations assign specifi c duties to the quality control unit. The unit is 
required to have the responsibility and authority to approve or reject all components, 
drug product containers, closures, in - process materials, packaging material, 
cGMP REGULATIONS 203

204 ROLE OF QUALITY SYSTEMS AND AUDITS 
labeling, and drug products and the authority to review production records to assure 
that no errors have occurred or, if errors have occurred, that they have been fully 
investigated. The responsibilities of the unit extend to approving or rejecting drug 
products manufactured, processed, packed, or held by contract manufacturers. The 
organization must assure that the quality control unit has adequate laboratory 
facilities for the testing and approval (or rejection) of components, drug product 
containers, closures, packaging materials, in - process materials, and drug products. 
In addition to duties associated with the approval of materials and fi nished products, 
the unit is also responsible for approving or rejecting all procedures or speci- 
fi cations impacting on the identity, strength, quality, and purity of the drug product. 
This includes review and approval of procedures for production and process control, 
including any changes to these procedures. These procedures, and the responsibilities 
and procedures applicable to the quality control unit within the organization, 
must be written and followed. 
All specifi cations, standards, sampling plans, test procedures, or other laboratory 
control mechanisms, including any changes, must be in writing and reviewed and 
approved by the quality control unit. 
Written procedures describing the handling of all written and oral complaints 
regarding a drug product are required. The quality control unit is responsible for 
reviewing any complaint involving the possible failure of a drug product to meet 
any of its specifi cations and, for such drug products, making a determination as to 
the need for an investigation in accordance with cGMP requirements. The review 
should include a determination if the complaint represents a serious and unexpected 
adverse drug experience, which is required to be reported to the FDA. A written 
record of each complaint must be maintained in a complaint fi le. 
3.2.2 QUALITY ASSURANCE FUNCTION 
The term quality is used in many industries and in everyday life and can have various 
meanings depending on context. For the purposes of discussion here quality means 
the product requirements or attributes that have a bearing on the product  s specifi ed 
requirements. Quality assurance activities are those processes and activities conducted 
to assure that a product or service consistently satisfi es its requirements and 
is fi t for its intended use. In the pharmaceutical manufacturing environment, this 
means the activities conducted to assure that the pharmaceutical product  s identity, 
strength, purity, potency, and other quality attributes conform to approved 
specifi cations. 
In the United States, cGMP requirements for the manufacture of drugs were 
established by regulation in 1978 and have not been substantially updated since 
then. The science and practice of quality assurance has substantially evolved since 
then to include the development of quality systems [2, 3] and risk management 
approaches [4] to better assure product quality and fi tness for use. Pharmaceutical 
product manufacturers are increasingly interested in implementing these approaches 
because they allow the manufactures to apply newer quality management principles 
that they believe enable them to more effectively assure product quality and 
better allow harmonization with evolving international regulatory quality system 
requirements. 

QUALITY SYSTEMS APPROACH 205 
3.2.3 QUALITY SYSTEMS APPROACH 
The systems approach to quality involves a coordinated approach to the management 
of quality - related activities as processes that work in conjunction with one 
another to provide assurance that the product meets its specifi ed requirements. It 
involves: 
 A management commitment to quality that is communicated throughout the 
organization 
 Identifying quality requirements using risk management and other methods as 
appropriate 
 Developing a quality policy, plan, objectives 
 Establishing an organizational structure with identifi ed responsibilities and 
authorities that allows quality objectives to be met 
 Providing the resources needed to meet quality objectives 
 Developing the required systems and processes 
 Establishing methods for the ongoing objective evaluation of the performance 
of systems and processes including quality auditing 
 Initiating corrective and preventive actions as needed to assure that quality 
objectives are consistently and reliably met 
The use of risk management techniques in identifying product requirements, establishing 
processes and process control and monitoring methods, evaluating quality 
data, identifying appropriate corrective and preventive actions to address quality 
problems, and for other quality - related activities can increase the overall effi ciency 
and effectiveness of the quality system. 
The FDA has recognized the value of and encourages a risk based quality systems 
approach for the manufacture of pharmaceutical products. This is refl ected in its 
Pharmaceutical CGMPs for the 21st Century Initiative. In association with this initiative 
the FDA has published reports and guidance documents that collectively 
provide information that can be used by pharmaceutical product manufacturers in 
implementing a quality systems and risk management approach to pharmaceutical 
cGMP regulations compliance [5  8] . In implementing this initiative, the FDA has 
made it clear that it does not impose new regulatory requirements on manufacturers. 
The FDA has provided information and guidance that is intended to serve as a 
bridge between the 1978 regulations and current quality systems by explaining how 
manufacturers implementing such systems can do so in full compliance with the 
cGMP regulations. This approach differs from that used by the FDA when it updated 
the cGMP regulations for medical devices to employ a quality systems approach. 
The 1996 Quality System Regulation updated the GMP requirements for fi nished 
medical device manufacturers to reduce the risk of inadequate device design and 
to harmonize them with international quality system standards that were in effect 
at that time [9] . These international standards have since been updated [10] ; however 
the device quality system regulation remains consistent with modern quality system 
models. 
In a modern quality system, the organizational unit responsible for quality - 
related activities within the organization generally has a central role in the 

206 ROLE OF QUALITY SYSTEMS AND AUDITS 
development and management of the overall quality system. These activities can 
include quality control, quality assurance, quality planning, and quality improvement. 
The cGMP regulations do not defi ne or employ these terms, but the activities 
the regulations assign to the quality control unit fall within these defi nitions as currently 
defi ned [2, 8, 11] . 
Current quality system models involve quality - related activities and terms that 
are not included in the cGMP regulations. Further, quality as a professional discipline 
is evolving. It is, therefore, important for organizations adopting a quality 
systems approach to unambiguously defi ne the terms and quality concepts they will 
be using and to include these defi nitions as appropriate in training all staff in the 
organization who will be involved in quality - related activities. This will help assure 
effective communication throughout the organization and with vendors and others 
(e.g., regulatory agencies, third - party auditors) who interact with the organization 
on quality - related matters. Regulatory defi nitions should be recognized, and the use 
of nonstandard or outdated terminology should be avoided to the extent possible. 
Incorporating terms and defi nitions by reference from pertinent standards and FDA 
guidance documents may be helpful. FDA guidance on the quality systems approach 
to pharmaceutical cGMP regulations (pharmaceutical QS guidance) includes the 
following defi nitions: 
Quality Assurance (QA) Proactive and retrospective activities that provide con- 
fi dence that requirements are fulfi lled. 
Quality Control (QC) The steps taken during the generation of a product or 
service to ensure that it meets requirements and that the product or service is 
reproducible. 
Quality Management (QM) Accountability for the successful implementation 
of the quality system. 
Quality System (QS) Formalized business practices that defi ne management 
responsibilities for organizational structure, processes, procedures, and 
resources needed to fulfi ll product/service requirements, customer satisfaction, 
and continual improvement. 
Quality Unit (QU) A group organized within an organization to promote quality 
in general practice. 
The FDA notes in its pharmaceutical QS guidance document that many current 
quality system concepts correlate very closely with the cGMP regulations and that 
the activities required by the regulations are generally consistent with a quality 
systems approach. In this and other guidance documents, the FDA uses the 
term quality unit rather than quality control unit as defi ned in the cGMP regulations 
to refer to the organizational unit with responsibility for quality - related 
activities. In a modern quality systems model these quality - related activities may go 
beyond, but are not necessarily inconsistent with, those required by the cGMP 
regulation. 
Use of the term quality unit is consistent with current quality management system 
models [2, 10] , which are intended to assure that the various operations associated 
with all systems are appropriately planned, approved, conducted, and monitored, 
and because the cGMP regulations specifi cally assign the QU the authority to create, 

QUALITY SYSTEMS APPROACH 207 
monitor, and implement a quality system. The FDA cautions that such activities do 
not substitute for, or preclude, the daily responsibility of manufacturing personnel 
to build quality into the product. The FDA has specifi cally indicated that the overarching 
philosophy articulated in both the cGMP regulations and in robust modern 
quality systems is that quality should be built into the product, and testing alone 
cannot be relied on to ensure product quality. 
Other cGMP - assigned responsibilities of the QU that are consistent with modern 
quality system approaches include the following: 
 Ensuring that controls are implemented and completed satisfactorily during 
manufacturing operations 
 Ensuring that developed procedures and specifi cations are appropriate and 
followed, including those used by a fi rm under contract to the manufacturer 
 Approving or rejecting incoming materials, in - process materials, and drug 
products 
 Reviewing production records and investigating any unexplained 
discrepancies 
The FDA has stressed that the release of the pharmaceutical QS guidance document 
does not impose new regulatory requirements on manufacturers but encourages 
manufactures to adopt a quality systems approach to cGMP compliance 
because of the potential benefi ts. An appropriately designed and implemented 
quality system can do the following: 
 Reduce the number of (or prevent) recalls, returned or salvaged products, and 
defective products entering the marketplace 
 Harmonize the cGMP regulations to the extent possible with other widely used 
quality management systems, which is desirable because of the globalization of 
pharmaceutical manufacturing, and the increasing prevalence of drug  device 
and biologic  device combination products 
 When coupled with manufacturing process and product knowledge and the use 
of effective risk management practices, handle many types of changes to facilities, 
equipment, and processes without the need for prior approval regulatory 
submissions 
 Potentially result in shorter and fewer FDA inspections by lowering the risk of 
manufacturing problems 
 Provide the necessary framework for implementing quality by design (building 
in quality from the product development phase and throughout a product  s life 
cycle), continual improvement, and risk management in the drug manufacturing 
process 
This suggests that even without making changes in the cGMP regulations, the 
FDA may be looking at them from a  new  quality systems perspective. The regulations 
include terms such as adequate and appropriate that may be subject to interpretation 
based on relevant technical or scientifi c capabilities and state - of - the - art 
knowledge. As these improve, the interpretation of what is adequate or appropriate 

208 ROLE OF QUALITY SYSTEMS AND AUDITS 
can change as well. Practically, most manufacturers are more than willing to adopt 
methods that can improve the quality and safety of their pharmaceutical products 
because it is cost effective in the long run [11] but may be reluctant to do so for 
fear of being considered out of compliance with the cGMP regulations. Current 
FDA efforts in this regard should serve to allay manufacturers  concerns in this 
area. 
The major elements of the quality system model described in the FDA  s 
pharmaceutical QS guidance document are consistent with existing quality 
system standards. These elements are as follows: 
 Management responsibilities 
 Resources 
 Manufacturing operations 
 Evaluation activities 
3.2.4 MANAGEMENT RESPONSIBILITIES 
Current quality system models assign management a major role in the deployment 
and operation of a successful quality system. In such systems, major management 
responsibilities include the following: 
 Provide leadership by establishing a commitment to quality that is supported 
by all levels of management and is communicated throughout the 
organization 
 Create an organizational structure with clearly defi ned responsibilities and 
authorities to perform quality functions associated with achieving quality 
objectives 
 Building and documenting a quality system to meet specifi ed quality and 
regulatory requirements and achieve quality objectives 
 Establishing a quality policy and objectives, and quality plans that are aligned 
with the organization  s strategic plans and communicate this throughout the 
organization 
 Reviewing the system by establishing appropriate accountability systems within 
the organization to monitor and report quality data and system status to management 
and assure that appropriate corrective and preventive actions are 
taken in response to quality problems using effective change control procedures 
and documented 
The cGMP does not specifi cally assign management responsibility for these 
actions, although actions of this nature are required by the regulation. Table 1 from 
the pharmaceutical QS guidance document shows this relationship. 
Under a comprehensive quality system the QU can expect an expanded and more 
visible role within the organization with greater accountability to and interaction 
with upper management. The QU should ideally be independent of the other organizational 
units to assure clear delineation of responsibility and authority and avoid 
confl icts. In certain instances, such as auditing, independence or objectivity is central 

to the effectiveness of the audit process, and auditors therefore should not have 
direct responsibility over the areas being audited. 
The cGMP regulations do not specify how the QU should be integrated into the 
overall organization but, in general, the QU should be structured to refl ect management 
 s strong commitment to quality and to facilitate achieving quality objectives. 
The structure (e.g., organizational relationship to other organizational units, reporting 
relationships) should provide clear lines of responsibility and authority that 
support the production, quality, and management activities necessary to achieve 
quality objectives. Different organizations may accomplish this in different ways; 
however, experience has been that placement of the quality function on the same 
level within the organizational hierarchy as other major organizational units (e.g., 
production) sends a clear message both within and outside the organization that 
top management has a strong commitment to quality. 
The cGMP regulations require quality - related activities to be conducted during 
all phases of manufacturing from the acceptance of raw materials through batch 
release, packaging, and labeling. The regulations also require that all personnel, 
including those engaged in quality - related activities, have suffi cient education, training, 
and experience or any combination thereof to enable them to perform their 
assigned functions. In a quality systems approach to cGMP compliance, the role of 
quality personnel can be signifi cantly expanded to include internal quality auditing, 
expanded review and analysis of quality data, investigation of nonconformance, root 
cause analysis, risk analysis, and other quality - related activities. Many of these activities 
are likely to be conducted with personnel from other organizational elements 
such as manufacturing, material control, facilities, product development, or engineering 
staff. Quality staff should have suffi cient scientifi c and technical knowledge 
and training (e.g., statistical methods, risk analysis) and knowledge of the product 
and manufacturing processes to effectively perform their assigned functions 
TABLE 1 21 CFR cGMP Regulations Related to Management Responsibilities 
Quality System Element Regulatory Citations 
1. Leadership 
2. Structure Establish quality function:  211.22(a) [see defi nition 
 210.3(b)(15)[ 
Notifi cation:  211.180(f) 
3. Build QS QU procedures:  211.22(d) 
QU procedures, specifi cations:  211.22(c), with reinforcement 
in:   211.100(a), 211.160(a) 
QU control steps:  211.22(a), with reinforcement in 
  211.42(c), 211.84(a), 211.87, 211.101(c)(1), 211.110(c), 
211.115(b), 211.142, 211.165(d), 211.192 
QU quality assurance; review/investigate:   211.22(a), 
211.100(a  b) 211.180(f), 211.192, 211.198(a) 
Record control:   211.180(a  d), 211.180(c), 211.180(d), 
211.180(e), 211.186, 211.192, 211.194, 211.198(b) 
4. Establish policies, 
objectives, and plans 
Procedures:   211.22(c  d), 211.100(a) 
5. System review Record review:   211.100, 211.180(e), 211.192, 211.198(b)(2) 
MANAGEMENT RESPONSIBILITIES 209

210 ROLE OF QUALITY SYSTEMS AND AUDITS 
and competently interact with personnel from other organizational elements as 
necessary. 
3.2.5 RESOURCES 
The appropriate assignment of resources is essential to the success of any endeavor, 
and this is particularly critical in a pharmaceutical manufacturing environment. 
Inadequate staffi ng, training, manufacturing equipment and facilities, environmental 
controls, analytical equipment, and other resources can be sources of variability 
leading to the production of product that does not meet specifi ed requirements. 
Modern quality system standards specifi cally address the issue of resources by 
requiring the organization to determine and provide the human, infrastructure, and 
work environment resources necessary for the quality system. The cGMP regulations 
address the resource issue in provisions that are intended to assure the 
adequacy of personnel (including consultants), manufacturing facilities including 
contract facilities, equipment, and laboratory facilities. The QU has signifi cant 
responsibility in this regard. 
The FDA, in its pharmaceutical QS guidance document, discusses the need for 
adequate resources in developing, implementing, and managing a quality system 
that complies with the cGMP regulations. Management is responsible for identifying 
resource requirements and providing resources accordingly, including providing 
training that is appropriate to the assigned activities. Personnel should understand 
the impact of their activities on their assigned duties and be familiar with cGMP 
requirements and the organization  s quality system. This is consistent with the 
generally accepted idea that a culture of quality within an organization requires 
personnel to understand quality concepts, the organization  s quality and regulatory 
objectives, and how their assigned activities contribute to the achievement of these 
objectives and fi t into the overall quality system. Management should establish a 
working environment that encourages problem solving and communication in 
identifying and acting upon quality - related issues. While the provision of resources 
is generally considered a management function, the QU and other organizational 
units should be involved in the identifi cation of the resources required to achieve 
quality objectives, including regulatory compliance, the assessment of the adequacy 
of existing resources, evaluating the effect of personnel, facility, product, process, 
regulatory, and other changes on resource needs, and generally providing management 
the information needed to make necessary and appropriate resource 
decisions. 
Current quality system models employ a risk - based and data - driven approach to 
the development of QS system requirements to assure their adequacy. The FDA 
notes that the cGMP regulations place as much emphasis on processing equipment 
as testing equipment and contain specifi c requirements for the qualifi cation, calibration, 
cleaning, and maintenance of production equipment that may be a higher 
standard than most nonpharmaceutical quality system models. Organizations should 
always keep in mind that, while the FDA may be encouraging the adoption of a 
comprehensive quality system, any system developed must satisfy the requirements 
of the cGMP regulations. 

Under a quality system model, the specifi cation of facility and equipment requirements 
may be performed by technical experts (e.g., engineers, development scientists) 
who have an understanding of the pharmaceutical science, manufacturing 
processes, and risk factors associated with the product and its manufacture. The 
cGMP regulations require the QU to be responsible for reviewing and approving 
all initial design criteria and procedures pertaining to facilities and equipment and 
any subsequent changes. These requirements are not mutually exclusive; while they 
place ultimate responsibility for review and approval of these activities with the QU, 
the regulations do not preclude a cross - functional review involving persons with 
relevant expertise from multiple areas of the organization. A requirement of both 
the cGMP and current quality system models is that such review and approval be 
conducted by persons who are qualifi ed by education, training and experience to 
do so. 
In the control of outsourced operations, the cGMP regulations require that the 
QU approve or reject products or services provided under a contract. Under current 
quality system models, the organization must follow a formal vendor qualifi cation 
process to qualify outsource providers and verify through inspection or other appropriate 
means that the provider is capable of meeting the requirements of the organization. 
To comply with the regulation, these operations should be conducted by 
the QU. 
Table 2 compares the major elements of a quality systems approach to addressing 
resource issues with corresponding requirements in the CGMP regulations. 
3.2.6 MANUFACTURING OPERATIONS 
There is signifi cant commonality between the requirements contained in current 
quality system models such as ISO 9001 - 2000 and the cGMP regulation requirements 
for manufacturing operations. The FDA has identifi ed four major elements 
of a QS approach to manufacturing operations. These are identifi ed and compared 
to the cGMP requirements in Table 3 . 
TABLE 2 21 CFR cGMP Regulations Related to Resources 
Quality System Element Regulatory Citation 
1. General arrangements 
2. Develop personnel Qualifi cations:  211.25(a) 
Staff number:  211.25(c) 
Staff training:  211.25(a  b) 
3. Facilities and equipment Buildings and facilities:   211.22(b), 211.28(c), 
211.42  211.58, 211.173 
Equipment:   211.63  211.72, 211.105, 211.160(b)(4), 
211.182 
Lab facilities:  211.22(b) 
4. Control outsourced operations Consultants:  211.34 
Outsourcing:  211.22(a) 
MANUFACTURING OPERATIONS 211

212 ROLE OF QUALITY SYSTEMS AND AUDITS 
3.2.6.1 Design, Develop, and Document Product and Processes 
In a modern quality systems manufacturing environment, the signifi cant characteristics 
of the product being manufactured should be defi ned and verifi ed as meeting 
requirements from design to delivery, and control should be exercised over all 
changes. This is consistent with the requirements of the cGMP regulation that 
require quality and manufacturing processes and procedures, and changes to them, 
to be defi ned, approved, and controlled. The idea of controlling the design of both 
product and process is consistent with concepts included in the FDA Pharmaceutical 
cGMPs for the 21st Century Initiative to assure product safety that focus on the 
entire product life cycle. No amount of  downstream  control and testing can compensate 
for a design that results in a product or production process that is incapable 
of meeting the requirements necessary to assure that the product is safe and 
effective for its intended use. Documentation is required and can include 
the following: 
 Resources and facilities used 
 Procedures to carry out the process 
 Identifi cation of the process owner who will maintain and update the process 
as needed 
 Identifi cation and control of important variables 
 Quality control measures, necessary data collection, monitoring, and appropriate 
controls for the product and process 
 Any validation activities, including operating ranges and acceptance criteria 
 Effects on related process, functions, or personnel 
The cGMP regulations include specifi c packaging and labeling controls, so packaging 
and labeling requirement, processes, and controls should be included in a QS - 
based approach to product and process design and development. 
TABLE 3 21 CFR cGMP Regulations Related to Manufacturing Operations 
Quality System Element Regulatory Citation 
1. Design and develop product and 
processes 
Production:  211.100(a) 
2. Examine Inputs Materials:   210.3(b), 211.80  211.94, 211.101, 
211.122, 211.125 
3. Perform and monitor operations Production:   211.100, 211.103, 211.110, 
211.111, 211.113 
QC criteria:   211.22(a  c), 211.115(b), 
211.160(a), 211.165(d), 211.188 
QC checkpoints:   211.22 (a), 211.84(a), 
211.87, 211.110(c) 
4. Address nonconformities Discrepancy investigation:   211.22(a), 
211.100, 211.115, 211.192, 211.198Recalls: 
21 CFR Part 7 

Manufacturers and the FDA have expressed concern that existing regulatory 
requirements (e.g., the need to effect manufacturing process changes through 
the regulatory submission process) may be excessively rigid and not conducive 
to innovation regardless of the potential benefi ts. The FDA acknowledges that 
the reluctance to pursue potentially innovative changes in pharmaceutical manufacturing 
can be undesirable from a public health perspective and has published a 
process analytical technology (PAT) guidance document that is intended to address 
this by promoting the use of analytical tools to gain process understanding 
and meet regulatory requirements for validating and controlling manufacturing 
processes [7] . 
The PAT guidance document describes a voluntary approach to the design, 
analysis, and control of manufacturing processes that involves the timely (e.g., in - 
process) measurement of critical quality and performance attributes of raw and 
in - process materials and processes, with the goal of ensuring fi nal product quality. 
The term analytical in PAT is broadly interpreted to include the integrated application 
of chemical, physical, microbiological, mathematical, and risk analysis as 
appropriate. One goal of PAT is to design and develop well - understood processes 
that will consistently ensure predefi ned quality at the end of the manufacturing 
process. This is consistent with a quality systems approach. PAT should ideally 
be initiated during the development stage and is intended to be integrated into 
existing regulatory processes with timely communication with the FDA a key 
element. The FDA has published the guidance document and other pertinent PAT 
information on its website at www.fda.gov . Companies interested in PAT methods 
should contact the FDA. FDA internal implementation of PAT includes the 
following: 
 A PAT team approach of CMC review and cGMP inspections 
 Joint training and certifi cation of FDA PAT review, inspection, and compliance 
staff 
 Scientifi c and technical support for the PAT review, inspection, and compliance 
staff 
Process analytical technology is consistent with the quality systems approach in 
that it is based on science and engineering principles for assessing and mitigating 
risks related to poor product and process quality. In the PAT guidance, the FDA 
indicates that the desired state for pharmaceutical manufacturing may be characterized 
as follows: 
 Product quality and performance are ensured through the design of effective 
and effi cient manufacturing processes 
 Product and process specifi cations are based on a mechanistic understanding 
of how formulation and process factors affect product performance 
 Continuous real - time quality assurance 
 Relevant regulatory policies and procedures are tailored to accommodate the 
most current level of scientifi c knowledge 
 Risk - based regulatory approaches recognize the following: 
MANUFACTURING OPERATIONS 213

214 ROLE OF QUALITY SYSTEMS AND AUDITS 
The level of scientifi c understanding of how formulation and manufacturing 
process factors affect product quality and performance 
The capability of process control strategies to prevent or mitigate the risk of 
producing a poor - quality product 
Process analytical technology is consistent with a modern risk - based data - driven 
quality systems approach to cGMP compliance. 
3.2.6.2 Inputs 
Current QMS models adopt a process - oriented approach to the design and operation 
of a QMS as a system of interrelated processes, each with inputs and outputs, 
which are designed to function in a defi ned way. Some process outputs are inputs 
to other processes. This concept is easily applied and understood within the manufacturing 
environment because it is process oriented. Inputs to manufacturing processes 
include any material that goes into the fi nal product, including materials 
purchased from vendors for use in manufacturing and in - process materials. Manufacturing 
operations generally involve multiple processes conducted in a defi ned 
manner to produce the fi nished product. Each process has a set of inputs and produces 
one or more outputs that may, in turn, be an input to a subsequent process. 
Each process has an input  output relationship such that changes or variation in one 
or more inputs will produce an attendant change in the output. Input specifi cations 
are established to assure that the fi nal product meets its requirements. A robust 
quality system will ensure that all inputs to the manufacturing process are suitable 
for use by establishing quality controls for the receipt and acceptance from qualifi ed 
vendors, production, storage, and use of all inputs. 
The cGMP regulations require either testing or use of a certifi cate of analysis 
(COA) plus an identity analysis for the release of materials for manufacturing. The 
quality systems approach additionally calls for initial supplier qualifi cation based 
on an objective evaluation and periodic auditing of suppliers based on risk assessment 
to verify the adequacy of suppliers  quality systems. During the audit, a manufacturer 
can observe the testing or examinations conducted by the supplier to help 
determine the reliability of the supplier  s COA. Under a QMS model, the QU would 
normally be responsible for auditing suppliers as part of its overall responsibility 
for materials acceptance. 
Change control involves the evaluation of proposed changes in a systematic way 
to determine how they would affect process outputs and ultimately the fi nished 
product and is an important element of current quality system models. The cGMP 
regulations require the QU to approve specifi cations, and certain changes require 
review and approval by the QU. Under a quality system model, changes to materials 
(e.g., specifi cation, supplier, or materials handling) should be implemented through 
a formal change control system involving the documented competent review and 
approval of the proposed change prior to implementation and communication of 
changes as appropriate throughout the organization. Manufacturers should also 
consider how best to assure that changes made by suppliers in supplied materials 
that may affect the quality of the fi nished product can be identifi ed and appropriately 
evaluated by the manufacturer. Such provisions should be included in supplier 
agreements where possible. 
0 
0 

3.2.6.3 Perform and Monitor Operations 
Both the cGMP regulations and quality system models call for the monitoring of 
critical processes that may be responsible for causing variability during production. 
The cGMP regulations require written production and process control procedures 
and specify process control activities that must be performed and documented. 
Current quality system models also require written procedures, process verifi cation 
and validation as appropriate, the establishment of appropriate process control 
measures and documentation. Risk analysis methods and design and development 
data may be used to establish process control and monitoring requirements. A 
quality systems approach allows the manufacturer to more effi ciently and effectively 
validate, perform, and monitor operations and ensure that the controls are scientifi - 
cally sound and appropriate. Production and process controls should be designed 
to ensure that the fi nished products have the identity, strength, quality, and purity 
they purport or are represented to possess. A systems approach will consider all 
sources of variability from inputs, through manufacturing processes, packaging, 
labeling, and shipping to assure that the product that is delivered to the user meets 
quality requirements. 
One important aspect of the quality systems approach is the ongoing collection 
and analysis of quality data to continuously evaluate quality system effectiveness. 
Historical data, process knowledge, and risk analysis methods can be applied to 
identify specifi c data requirements. Trending and other data analysis methods can 
allow identifi cation of actual and potential sources of nonconformity so that appropriate 
corrective and preventive actions can be taken in accordance with established 
change control procedures. 
The entire product life cycle should be addressed by the establishment of monitoring 
and continual improvement mechanisms in the quality system. Even well - 
defi ned or mature manufacturing processes may  drift  due to a host of factors 
including equipment and facility aging, changes or variation in raw materials, electrical 
power fl uctuations, and environmental changes. Thus, process validation is not a 
one - time event but an activity that continues throughout a product  s life. One 
major quality system objective should be to identify emerging quality problems 
before nonconformities occur. Trending of periodically collected environmental 
monitoring data may, for example, identify a slow but steady increase in airborne 
particulate levels that, if left unaddressed and the trend continues, could exceed a 
fi rm  s internal environmental standards and adversely affect the product. Early 
identifi cation of such problems allows an investigation to be initiated to identify the 
cause so that appropriate corrective and preventive actions can be taken in accordance 
with established change control procedures. After a change is implemented, 
its effectiveness should be objectively verifi ed and affected processes revalidated if 
necessary. 
3.2.6.4 Address Nonconformities 
A key component in any quality system is appropriately responding to nonconformities 
(i.e., deviations from requirements established under the quality system for 
in - process material or fi nal product quality attributes, process control parameters, 
records, procedures, etc.). Nonconformities may be detected during any stage of the 
MANUFACTURING OPERATIONS 215

216 ROLE OF QUALITY SYSTEMS AND AUDITS 
manufacturing process or during quality control activities. The cGMP regulations 
require an investigation to be initiated and that the investigation, conclusion, and 
follow - up be documented. A primary objective of any manufacturing quality system 
is to prevent nonconforming product from being produced and distributed. The 
complete response to nonconformities should be risk based and can include the 
following components: 
 Assessment of how the nonconformity will affect the quality of the fi nished 
product (i.e., determination if the nonconformity has resulted, or could result, 
in product that does not meet its specifi ed purity, potency, and quality 
characteristics). 
 Determine any actions necessary to assure that product that does not meet its 
specifi ed requirements is not produced and that appropriate steps are taken 
with regard to any nonconforming product that has been produced to assure 
that consumers are not harmed and that regulatory requirements are 
satisfi ed. 
 Determine the cause of the nonconformity. 
 Identify any actions needed to correct the cause and to prevent recurrence. 
 Document the investigation, fi ndings, and follow - up actions. 
 Assess the effectiveness of follow - up actions. 
 Repeat the cycle as needed. 
A nonconformity may not result in the fi nished product failing to meets its 
requirements; however, investigation of the nonconformity may identify process or 
quality system defi ciencies that require attention. For example, a small but unexpected 
deviation from a process control requirement (e.g., temperature, blending 
time) may not exceed the limit for which the process was initially validated and 
thus not be expected to adversely effect the fi nished product but could suggest an 
emerging process control or equipment issue that if not corrected could result in 
future product nonconformities. Similarly, nonconformities in the form of errors or 
omissions in production records or deviations from written procedures may not 
always result in product nonconformity but could suggest training, process design, 
or other issues that ought to be addressed. Thus the response to nonconformities 
should not be limited to a determination of the immediate impact on the fi nished 
product, but also consider its implications regarding overall quality system 
performance. 
3.2.7 EVALUATION ACTIVITIES 
The evaluation component of a QMS is intended to provide objective information 
and data that allow the organization to assess the conformity of the product, 
evaluate the performance of its quality system, and maintain and improve its effectiveness 
[10] . The cGMP regulations similarly require evaluation activities as shown 
in Table 4 . 

3.2.7.1 Trend Analysis 
The cGMP regulations require review and analysis of certain quality data annually 
at least. Current quality system models emphasize data - based decision making and 
the use of appropriate statistical analysis methods [2, 11] . Trend analysis is one statistical 
tool specifi cally recommended by the FDA in its pharmaceutical QS guidance 
document that can be very valuable in monitoring processes and quality system 
performance to identify emerging problems and to assess the effectiveness of 
improvement efforts. Traditional statistical process control and other methods also 
provide valuable support in the objective and ongoing analysis of quality data and 
can be helpful in implementing real - time quality assurance practices as recommended 
by the FDA [7] . 
3.2.7.2 Conduct Internal Audits 
Internal auditing is not specifi cally required by the cGMP regulations, but manufacturers 
have traditionally used internal audits as a self - assessment tool and to 
prepare for FDA inspections. The FDA has for some time recognized the value of 
internal auditing and encourages fi rms to conduct audits by, as a matter of policy, 
not reviewing internal audit results during inspections [12] . 
Current quality system models call for audits to be conducted at planned intervals 
to evaluate effective implementation and maintenance of the quality system and to 
determine if processes and products meet established parameters and specifi cations. 
International standards provide guidance on auditing [13] . Audit procedures should 
be developed and documented to ensure that the planned audit schedule takes into 
account the relative risks of the various quality system activities. Factors that can 
be incorporated into a risk - based approach to planning audit frequency and scope 
include the following [6] : 
 Existing legal requirements (e.g., cGMPs) 
 Overall compliance status and history of the company or facility 
 Robustness of a company  s quality risk management activities 
 Complexity of the site 
 Complexity of the manufacturing process 
 Complexity of the product and its therapeutic signifi cance 
 Number and signifi cance of quality defects (e.g., recall) 
TABLE 4 21 CFR cGMP Regulations Related to 
Evaluation Activities 
Quality System Element Regulatory Citation 
1. Analyze data for trends Annual review:  211.180(e) 
2. Conduct internal audits 
3. Risk assessment 
4. Corrective action Discrepancy investigation: 
  211.22(a), 211.192 
5. Preventive action 
6. Promote improvement  211.110 
EVALUATION ACTIVITIES 217

218 ROLE OF QUALITY SYSTEMS AND AUDITS 
 Results of previous audits/inspections that can include prior internal audit 
results as well as regulatory (e.g., state, federal, or other regulatory agencies) 
and third - party audits 
 Major changes of building, equipment, processes, and key personnel 
 Experience with manufacturing of a product (e.g., frequency, volume, number 
of batches) 
 Test results of offi cial control laboratories 
In general, auditors should not have direct responsibility over the matters being 
audited. Auditors should be trained in auditing methods and have suffi cient technical 
knowledge to be able to evaluate the systems being audited using objective audit 
criteria [14] . Audit criteria may be based on applicable regulatory requirements, 
standards to which the quality system is intended to conform (e.g., ISO 9001 - 2000), 
and the specifi c requirements of the quality system being audited as indicated in 
quality system documents. Auditing criteria should be defi ned prior to the initiation 
of the audit. 
Different audit approaches may be applied depending on the intended purpose 
and scope of the audit. A top - down approach fi rst evaluates the overall structure of 
the quality system and its subsystems. Selected subsystems may be chosen for review. 
Systems identifi ed and developed by the FDA in a six - system inspection model for 
the inspection of drug manufacturers [15] include the following: 
 Overall quality system 
 Facilities and equipment 
 Materials system 
 Production system 
 Packaging and labeling 
 Laboratory controls 
Subsystems must be pertinent to the specifi c quality system being audited and may 
coincide with major elements of a standard to which the quality system is intended 
to conform or the major elements identifi ed in the FDA pharmaceutical QS guidance. 
When using the top - down approach, the auditor will fi rst review each subsystem 
to determine if the requirements that apply to that subsystem (e.g., 
regulatory requirements, the requirements of the standard) are met by defi ning, 
documenting, and implementing appropriate procedures. Once the auditor has 
verifi ed that the requisite procedures are in place, he or she will review the associated 
records and other documents to verify that the procedures have been followed 
and documented and that the quality system is functioning effectively as designed 
and conforms to applicable regulatory requirements and standards. This approach 
allows for a systematic evaluation of each subsystem and can be as detailed as 
needed. 
A bottom - up approach may be used to follow up on a specifi c quality problem 
identifi ed from trend analyses, product nonconformities, adverse experiences, customer 
complaints, or other sources of quality data. Starting with quality records 
associated with the problem, the auditor will work his or her way up through the 

quality system, examining the quality processes having a bearing on the quality 
problem. This approach is helpful in identifying quality system issues that may be 
associated with specifi c quality problems but does not readily allow evaluation of 
the entire quality system. 
A combination approach may also be used that employs elements of top - down 
and bottom - up audits. This allows some level of assessment of the effectiveness of 
the overall quality system while evaluating the cause of specifi c quality problems. 
Auditors should select the audit method most appropriate for their intended 
audit purpose. Initial quality system audits or regularly scheduled audits are likely 
candidates for the top - down approach, while audits conducted as part of a root 
cause analysis, for example, may best employ a bottom - up approach. The FDA 
employs a similar approach to inspections. Regular scheduled biennial inspections 
are more likely to employ a top - down methodology. For cause inspections conducted 
in response to a specifi c product issue such as a recall are more likely to 
employ a bottom - up approach. FDA investigators may employ a combination 
approach during biennial inspections if investigators are aware of specifi c quality 
problems that they wish to include in the inspection. 
Auditing as described in QMS models is intended to assess the effectiveness of 
the overall quality system as designed and conformance to applicable standards. The 
overall quality system does not have to be covered in a single audit. Manufacturers 
may choose to employ a rolling audit approach in which specifi cally identifi ed subsystems 
are chosen for evaluation in accordance with an approved audit schedule. 
Audit plans should be designed to effectively perform this assessment. 
Compliance with cGMP requirements is also a major concern, and audit planning 
should include assessment of conformance to cGMP requirements and readiness 
for FDA inspections. Existing FDA guidance documents and compliance policy 
guides describe FDA inspectional approaches and policy and can be used for reference 
in developing audit plans [15  17] . It can be helpful to include mock FDA audits 
as part of an overall auditing regimen. Some fi rms prefer to use outside auditors for 
mock audits to better simulate the FDA inspection process. Mock audits are also 
useful for training purposes to prepare the organization for FDA inspections. 
The audit plan should be consistent with written quality auditing procedures 
included in the quality manual or other quality system documentation. The plan 
should include or refer to the objective criteria to be used to evaluate conformance 
to requirements. The plan should include or refer to other documents that will be 
used during the audit, including previous audit reports. If the audit is to include the 
review of batch or production records, such review should be conducted in accordance 
with a specifi ed sampling plan or other appropriate statistical rationale as 
specifi ed in a fi rm  s quality system procedures. 
Manufacturers implementing a quality system that conforms to an existing standard 
may fi nd it helpful to create a table or some other document that shows the 
relationship between cGMP requirements, requirements of the standard, and the 
element(s) of the manufacturer  s quality system. Such a tool can help assure that 
all pertinent requirements are covered in the quality system design and that audit 
plans designs include assessment of all pertinent requirements. 
Since current quality system models employ a systems approach, an audit checklist 
that is organized by subsystem may be helpful, as described in Table 5 . The 
form would include appropriate document control information such as form 
EVALUATION ACTIVITIES 219

220 ROLE OF QUALITY SYSTEMS AND AUDITS 
identifi cation, revision, and approval information. Companies may also wish to 
include reference information used in planning the audit such as previous audit 
reports, completed FDA Form 483 Inspectional Observations, third - party audit 
reports, and pertinent internal QS documents (e.g., audit procedures). Depending 
on the purpose of the audit, the subsystems may correspond to the six subsystems 
identifi ed by the FDA for use by investigators in conducting cGMP inspections (i.e., 
quality, production, facilities and equipment, laboratory controls, materials, packaging 
and labeling) or the major elements of a quality system standard. Cross references 
between elements of the standard being used and the pertinent sections of 
the cGMP regulations may be included as appropriate. The audit form should allow 
entry of information regarding conformance or nonconformance to each requirement 
and have space for a description of pertinent fi ndings. 
The QMS models require periodic audits but do not specify audit frequency. 
Audit frequency must be determined based on the risk associated with the matters 
to be audited and other factors including results of previous audits and other quality 
data. Periodic audits should be conducted over the entire product life cycle and 
follow - up audits conducted as appropriate to verify that previously identifi ed quality 
problems have been corrected in accordance with applicable quality system and 
regulatory requirements. 
3.2.7.3 Quality Risk Management 
The FDA has endorsed quality risk management as part of an overall quality 
systems approach to compliance with the cGMP regulations and achieving overall 
TABLE 5 Example Audit Checklist 
[Company Name] Quality System Audit Checklist 
Form: Rev: Date: Approved: 
Audit Date(s): Refs: 
Auditor: Title Signature: 
Requirement cGMP Section Cross 
Reference 
Conforms (Y/N/NA) Objective Evidence 
and Comments 
Subsystem 1 
Requirement 1.1 
Requirement 1.2 
Subsystem 2 
Requirement 2.1 
Requirement 2.2 
Subsystem 3 
Requirement 3.1 
Requirement 3.2 
Subsystem N 

quality system objectives [6] . Risk management methodologies permit management 
to assign priorities to activities or actions based on an assessment of the risk including 
both the probability of occurrence of harm and the severity of that harm. 
Implementation of quality risk management includes assessing the risks, selecting 
and implementing risk management controls commensurate with the level of risk, 
and evaluating the results of the risk management efforts. In a manufacturing quality 
systems environment, risk management is used as a tool in the development of 
product specifi cations and critical process parameters. Used in conjunction with 
process understanding, quality risk management helps manufacturers effectively 
manage and control change. 
A formal risk management process consists of several components: 
 Risk assessment 
Risk identifi cation 
Risk analysis 
Risk evaluation 
 Risk control 
Risk reduction 
Risk acceptance 
 Risk communication 
 Risk review 
Risk assessment starts with risk identifi cation , a systematic use of available information 
to identify hazards (i.e., events or other conditions that have the potential 
to cause harm). Information can be from a variety of sources including stakeholders, 
historical data, information from the literature, and mathematical or scientifi c analyses. 
Risk analysis is then conducted to estimate the degree of risk associated with 
the identifi ed hazards. This is estimated based on the likelihood of occurrence and 
resultant severity of harm. In some risk management tools, the ability to detect the 
hazard may also be considered. If the hazard is readily detectable, this may be considered 
a factor in the overall risk assessment. Risk evaluation determines if the risk 
is acceptable based on specifi ed criteria. In a quality system environment, criteria 
would include impact on the overall performance of the quality system and the 
quality attributes of the fi nished product. The value of the risk assessment depends 
on how robust the data used in the assessment process is judged to be. The risk 
assessment process should take into account assumptions and reasonable sources 
of uncertainty. Risk assessment activities should be documented. 
Risk control starts with risk reduction, which includes any actions taken to eliminate 
or reduce the risk. Actions taken should be commensurate with the signifi cance 
of the risk. If the risk has been reduced to an acceptable level, an affi rmative decision 
can be made to accept the risk (risk acceptance). One question to ask is if new 
risks have been introduced as a result of the identifi ed risks being controlled. Risk 
control measures should generally be conducted in accordance with change control 
procedures and documented. 
Risk communication involves the communication of appropriate information 
about the risk to stakeholders (e.g., others involved in or affected by the quality 
EVALUATION ACTIVITIES 221 
0 
0 
0 
0 
0 

222 ROLE OF QUALITY SYSTEMS AND AUDITS 
system including management, users, regulatory agencies). Risk communication 
should be documented. The included information might relate to the existence, 
nature, form, probability, severity, acceptability, control, treatment, detectability, or 
other aspects of risks to quality. Communication should be as appropriate and does 
not necessarily need to be carried out for each and every risk acceptance. 
Risk review should be conducted to evaluate the outputs of the risk management 
process and repeated as necessary, based on new quality data or if there are process 
or product changes. 
The Q9 Quality Risk Management guidance document [6] identifi es a number 
of risk management tools that manufacturers can apply, including failure mode 
effects and criticality analysis (FMECA), hazard analysis and critical control 
points (HAACP), and preliminary hazard analysis (PHA), and provides examples 
of how quality risk management might be applied to quality management, development, 
materials management, production, and other operations within the 
organization. 
3.2.7.4 Corrective and Preventive Actions 
Corrective and preventive action (CAPA) is the term commonly used to describe 
the subsystem of a comprehensive quality system that deals with the systematic 
investigation, understanding, and response to quality issues including nonconformities. 
A corrective or preventive action may be initiated based on review and analysis 
of quality data from a variety of sources including adverse experiences, product 
complaints, quality audits, FDA inspections, third - party inspections, nonconforming 
materials reports, process control information, trend analyses, and other sources. 
A corrective action is initiated to correct the cause of an identifi ed nonconformity 
and to prevent it or similar problems from reoccurring. It may include initial and 
follow - up actions (e.g., conducted after root cause analysis). Current quality system 
models and the cGMP regulations emphasize corrective actions and require that 
actions be documented. Under current quality system models, preventive actions 
include actions taken in response to quality data to address the cause of potential 
nonconformities to prevent their occurrence. An effective CAPA system therefore 
includes both reactive and proactive components. The effectiveness of corrective 
and preventive actions should be evaluated using objective criteria when possible 
and the evaluation documented. 
A fi rm  s CAPA system and processes should be designed to analyze and respond 
to quality issues in a systematic way that is commensurate with the risk. The system 
should provide for the verifi cation or validation of corrective and preventive actions 
to assure their effectiveness and to assure that actions do not adversely affect the 
fi nished product. The system should also assure that pertinent CAPA information 
is appropriately disseminated throughout the organization as necessary to assure 
the effective operation of the quality system and for management review. 
3.2.7.5 Promote Improvement 
Continual improvement is a requirement of existing quality system models such as 
ISO 9001 - 2000 in which the organization is required to continually improve the 
effectiveness of the quality management system through the use of the quality 

policy, quality objectives, audit results, analysis of data, corrective and preventive 
actions, and management review. In adapting the ISO 9001 - 2000 standard to serve 
as a regulatory standard for medical device quality management systems, drafters 
of the ISO 13485 standard altered the requirement slightly to require the organization 
to  identify and implement any changes necessary to ensure and maintain the 
continued suitability and effectiveness of the quality management system through 
the use of the quality policy, quality objectives, audit results, analysis of data, corrective 
and preventive actions, and management review.  The word improvement 
was deleted as not an objective of current regulatory standards, but the concept of 
continually monitoring the performance of the quality system and appropriately 
responding to quality data was retained. 
The cGMP regulation does not specifi cally require continual improvement; 
however, the regulations are specifi c with regard to the sampling and testing of in - 
process materials and drug products, and failure to take reasonable action to reduce 
identifi ed sources of variability may be of concern to FDA investigators. The FDA 
in its pharmaceutical QS guidance document encourages organizations to promote 
improvement through quality system activities and notes that it is critical for senior 
management to be involved. Process improvement, along with improvement of in - 
process controls, can render a manufacturing process more effi cient and more 
robust. The end result can reduce costs and further prevent product failures and 
defects from occurring. 
3.2.8 TRANSITIONING TO QUALITY SYSTEMS APPROACH 
The cGMP regulations assign signifi cant responsibilities to the organizational unit 
responsible for quality - related activities. Organizations implementing a quality 
system model will be responsible for additional quality - related activities including, 
but not necessarily limited to, conducting quality audits, analysis of quality data, 
risk assessment, and preventive actions based on review and analysis of quality data 
to prevent the occurrence of product nonconformities. In addition, management 
is required to provide requisite leadership by actively participating in the 
quality system and assuring that the quality system functions as intended. This is 
accomplished by establishing a quality policy and associated objectives, planning 
for quality, establishing an appropriate organization structure with designated 
responsibilities and authorities to appropriately carry out quality system requirements, 
providing appropriate resources and training, and periodically reviewing 
quality information and data, and assuring that the organization responds 
appropriately. 
The organizational unit responsible for quality - related activities will in all likelihood 
have an even greater role within the organization, and roles and responsibilities 
throughout the organization are likely to change. Careful planning will be 
required to assure that the transition is effected smoothly with no adverse impact 
on product quality. Following are some points to consider in planning the 
transition: 
 Create a transition team: A cross - functional team should be developed involving 
key managers and staff from throughout the organization to plan and 
TRANSITIONING TO QUALITY SYSTEMS APPROACH 223

224 ROLE OF QUALITY SYSTEMS AND AUDITS 
execute the transition. The transition team should have a clear understanding 
of its mission and the organizational objectives associated with the transition. 
 Train the transition team: The decision to make the transition must come from 
management and management should assure that all individuals on the transition 
team receive proper training on quality systems requirements, risk management, 
and FDA  s recommended approach to quality systems. 
 Develop a transition plan: A transition plan, based on clearly defi ned objectives, 
should be developed by the transition team. 
 Identify staffi ng requirements: The transition will likely affect individual job 
descriptions and create additional duties that will have to be addressed through 
the reassignment of staff, hiring new staff, and providing necessary training to 
all affected staff. 
 Identify other resource needs: The plan should include a defi nition of resource 
requirements for planning and executing the plan. 
 Defi ne roles and responsibilities: the plan should clearly defi ne the roles and 
responsibilities of those responsible for development and execution of the plan 
for quality system implementation as well as staff roles and responsibilities 
under the quality system. 
 Consider organizational structure requirements: In order to function properly, 
persons responsible for quality - related activities must have the responsibility 
and associated authority defi ned and appropriately communicated within the 
organization. 
 Conduct a gap analysis: The plan should conduct a gap analysis that identifi es 
how the quality system model chosen can be effectively integrated with existing 
processes to create a quality system that conforms to the organization  s quality 
objectives, meets regulatory requirements, and is consistent with other organizational 
requirements. The quality systems approach is intended to be somewhat 
fl exible in application and can be tailored to specifi c organizational 
requirements. In order to function properly the quality system must be effectively 
integrated into the organization so that it is not viewed as an  add - on  
or a set of extra requirements that prevent the  real  work from getting 
done. 
 Consider benchmarking: If possible, arrange with other organizations that have 
successfully made the transition to meet with them, review their system, and 
discuss transition issues and how they were solved. 
 Consult with experts: In addition to benchmarking, seeking assistance from 
persons familiar with quality systems can be very helpful, particularly when 
existing staff are relatively inexperienced with quality systems. It may be useful 
for one or more outside experts to work with the transition team on a regular 
basis as a coach or facilitator. 
 Communicate regularly: Clear and ongoing communication within the transition 
team and with management is essential to effectively coordinate plan 
activities, report progress, resolve issues, and identify evolving resource 
needs. 
 Sell the system: Successful implementation of a QS requires the active and 
informed participation of many individuals within the organization. Manage

ment commitment should be clearly communicated and training provided so 
that affected staff understand basic quality system concepts and their role in 
the quality system. 
 Validate the system. 
 Maintain regulatory compliance. 
3.2.9 AUDIT CHECKLIST FOR DRUG INDUSTRY 
The checklist provided in Table 6 [15] is intended to aid in the systematic GMP audit 
of a facility that manufactures drug components or fi nished products. 
The adequacy of any procedures is subject to the interpretation of the auditor. 
Therefore, the author accepts no liability for any subsequent regulatory observations 
or actions stemming from the use of this audit checklist. 
3.2.9.1 Instructions for Using Audit Checklist 
Before starting an on - site audit, plan the audit. Review past audits, note indications 
of possible problem areas and items, if any, that were identifi ed for corrective action 
in a previous audit. If you are not already familiar with this facility, learn the type 
of product produced and how it is organized by personnel and function. What does 
your  customer,  that is, your superior or senior facility management, expect to learn 
from this audit? 
1. The checklist is to be used with a notebook into which detailed entries can be 
made during the audit. 
2. While the checklist is to guide the auditor, it is not intended to be a substitute 
for knowledge of the GMP regulations. 
3. Although a single question may be included about any requirement, the 
answer will usually be a multipart one since the auditor should determine the 
audit trail for several products that may use many different components. Enter 
details in you notebook and cross reference your comments with the 
questions. 
4. At least three production batches should be selected for thorough analysis to 
include: (a) traceability of all components or materials used in the subject 
batches, (b) documentation of raw material or component, in - process, and 
fi nished goods testing for the subject product batches, and (c) warehousing 
and distribution records as they would relate to a possible recall. 
5. Responses entered on the checklist should be consistent.  X  is recommended 
for  No  ; a checkmark for  Yes  ;  N/A  for not applicable to questions that 
do not apply. An asterisk and notebook page number should be entered on 
the checklist to identify where relevant comments or questions are recorded 
in your notebook. 
6. The notebook used should be a laboratory - type notebook with bound pages. 
The notebook should be clearly labeled as to the audit type, date, and auditor(s). 
Many auditors prefer to use a notebook for a single audit so it may be fi led 
with the checklist and the fi nal report. 
AUDIT CHECKLIST FOR DRUG INDUSTRY 225

226 ROLE OF QUALITY SYSTEMS AND AUDITS 
TABLE 6 Audit Checklist 
Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
1.0 General Controls 
Does the facility and its departments (organizational units) 
operate in a state of control as defi ned by the GMP 
regulations? 
1.1 Organizational & Management Responsibilities 
1.101 Does this facility/business unit operate under a facility or 
corporate quality policy? 
1.102  211.22(a) Does a Quality Assurance unit (department) 
exist as a separate organizational entity? 
1.103  211.22(a) Does the Quality Assurance unit alone have 
both the authority and responsibility to approve or reject 
all components, drug product containers and closures, in - 
process materials, packaging materials, labeling, and drug 
products? 
1.104  211.22 Does the QA department or unit routinely review 
production records to ensure that procedures were 
followed and properly documented? 
1.105  211.22(b) Are adequate laboratory space, equipment, and 
qualifi ed personnel available for required testing? 
1.106 If any portion of testing is performed by a contractor, has 
the Quality Assurance unit inspected the contractor  s site 
and verifi ed that the laboratory space, equipment, 
qualifi ed personnel, and procedures are adequate? 
1.107 Date of last inspection:  
1.108  211.22(c) Are all QA procedures in writing? 
1.109  211.22(c) Are all QA responsibilities in writing? 
1.110 Are all written QA procedures current and approved? 
(Review log of procedures) 
1.111 Are the procedures followed? (Examine records to ensure 
consistent record - keeping that adequately documents 
testing.) 
1.112  211.25 Are QA supervisory personnel qualifi ed by way of 
training and experience? 
1.113  211.25 Are other QA personnel (e.g., chemists, analysts, 
laboratory technicians) qualifi ed by way of training and 
experience? 
1.2 Document Control Program 
1.201  211.22(a) Does the QA unit have a person or department 
specifi cally charged with the responsibility of designing, 
revising, and obtaining approval for production and 
testing procedures, forms, and records? 
1.202  211.22(d) Does a written SOP, which identifi es how the 
form is to be completed and who signs and countersigns, 
exist for each record or form? 
1.203  211.165(a)(b)(c) Is the production batch record and 
release test results reviewed for accuracy and 
completeness before a batch/lot of fi nished product is 
released?

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
1.3 Employee Orientation, Quality Awareness, and Job 
Training 
1.301 Circle the types of orientation provided to each new 
employee: (1) Company brochure. (2) Literature 
describing GMP regulations and stressing importance of 
following instructions. (3) On - the - job training for each 
function to be performed ( before the employee is allowed 
to perform such tasks). (4) Other: enter in notebook. 
1.302  211.25(a) Does each employee receive retraining on an 
SOP (procedures) if critical changes have been made in 
the procedure? 
1.303 Indicate how ongoing, periodic GMP training is 
accomplished. 
1.304  211.25 is all training documented in writing that indicates 
the date of the training, the type of training, and the 
signature of both the employee and the trainer? 
1.305  211.25 Are training records readily retrievable in a manner 
that enables one to determine what training an employee 
has received, which employees have been trained on a 
particular procedure, or have attended a particular 
training program? 
1.306 Are GMP trainers qualifi ed through experience and 
training? 
1.307  211.25(a) Are supervisory personnel instructed to prohibit 
any employee who, because of any physical condition 
(as determined by medical examination or supervisory 
observation) that may adversely affect the safety or 
quality of drug products, from coming into direct contact 
with any drug component or immediate containers for 
fi nished product? 
1.308  211.28(d) Are employees required to report to supervisory 
personnel any health or physical condition that may have 
an adverse effect on drug product safety and purity? 
1.309  211.25(a) Are temporary employees given the same 
orientation as permanent employees? 
1.310  211.34 Are consultants, who are hired to advise on any 
aspect of manufacture, processing, packing or holding, of 
approval for release of drug products, asked to provide 
evidence of their education, training, and experience? 
1.311  211.34 Are written records maintained stating the name, 
address, qualifi cations, and date of service for any 
consultants and the type of service they provide? 
1.4 Plant Safety and Security 
1.401 Does this facility have a facility or corporate safety 
program? 
1.402 Are safety procedures written? 
1.403 Are safety procedures current? 
TABLE 6 Continued 
AUDIT CHECKLIST FOR DRUG INDUSTRY 227

228 ROLE OF QUALITY SYSTEMS AND AUDITS 
Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
1.404 Do employees receive safety orientation before working in 
the plant area? 
1.405 Is safety training documented in a readily retrievable 
manner that states the name of the employee, the type of 
training, the date of the training, and the name of the 
trainer and the signature of the trainer and the 
participant? 
1.406 Does this facility have a formal, written security policy? 
1.407 Is access to the facility restricted? 
1.408 Describe how entry is monitored/restricted: 
1.409 Is a security person available 24 hours per day? 
1.5 Internal Quality/GMP Audit Program 
1.501 Does this business unit/facility have a written quality 
policy? 
1.502 Is a copy of this quality policy furnished to all employees? 
1.503 If  yes  to above, when provided?  
1.504 Is training provided in quality improvement? 
1.505 Does a formal auditing function exist in the Quality 
Assurance department? 
1.506 Does a written SOP specify who shall conduct audits and 
qualifi cations (education, training, and experience) for 
those who conduct audits? 
1.507 Does a written SOP specify the scope and frequency of 
audits and how such audits are to be documented? 
1.508 Does a written SOP specify the distribution of the audit 
report? 
1.6 Quality Cost Program 
1.601 Does this facility have a periodic and formal review of the 
cost of quality? 
1.602 Does this facility have the ability, through personnel, 
software, and accounting records, to identify and capture 
quality costs? 
1.603 Does this facility make a conscious effort to reduce quality 
costs? 
2.0 Design control 
Not directly related to the drug regulation 
3.0 Facility control 
3.1 Facility Design and Layout 
3.101  211.42(a) Are all parts of the facility constructed in a way 
that makes them suitable for the manufacture, testing, 
and holding of drug products? 
3.102  211.42(b) Is there suffi cient space in the facility for the 
type of work and typical volume of production? 
3.103 Does the layout and organization of the facility prevent 
contamination? 
3.2 Environmental Control Program 
3.201 The facility is NOT situated in a location that potentially 
subjects workers or product to particulate matter, fumes, 
or infestations? 
TABLE 6 Continued

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
3.202 Are grounds free of standing water? 
3.203  211.44 Is lighting adequate in all areas? 
3.204  211.46 Is adequate ventilation provided? 
3.205  211.46 Is control of air pressure, dust, humidity, and 
temperature adequate for the manufacture, processing, 
storage, or testing of drug products? 
3.206  211.46 If air fi lters are used, is there a written procedure 
specifying the frequency of inspection and replacement? 
3.207 Are drains and routine cleaning procedures suffi cient to 
prevent standing water inside the facility? 
3.208  211.42(d) Does the facility have separate air - handling 
systems, if required, to prevent contamination? 
(MANDATORY IF PENICILLIN IS PRESENT!) 
3.3 Facility Maintenance and Good Housekeeping Program 
3.301  211.56(a) Is this facility free from infestation by rodents, 
birds, insects, and vermin? 
3.302  211.56(c) Does this facility have written procedures for 
the safe use of suitable (e.g., those that are properly 
registered) rodenticides, insecticides, fungicides, and 
fumigating agents? 
3.303 Is this facility maintained in a clean and sanitary condition? 
3.304 Does this facility have written procedures that describe 
in suffi cient detail the cleaning schedule, methods, 
equipment, and material? 
3.305 Does this facility have written procedures for the safe and 
correct use of cleaning and sanitizing agents? 
3.306  211.58 Are all parts of the facility maintained in a good 
state of repair? 
3.307  211.52 Is sewage, trash, and other refuse disposed of in a 
safe and sanitary manner (and with suffi cient frequency)? 
3.4 Outside Contractor Control Program 
3.401  211.56(d) Are contractors and temporary employees 
required to perform their work under sanitary 
conditions? 
3.402 Are contractors qualifi ed by experience or training to 
perform tasks that may infl uence the production, 
packaging, or holding of drug products? 
4.0 Equipment control 
4.1 Equipment Design and Placement 
4.101  211.63 Is all equipment used to manufacture, process, or 
hold a drug product of appropriate design and size for its 
intended use? 
4.102 Are the following pieces of equipment suitable for their 
purpose: blender(s), conveyor(s), tablet, presses, capsule 
fi llers, bottle fi llers, other (specify)? 
4.103 Are the following pieces of equipment suitable in their size/ 
capacity: blender(s), conveyor(s), tablet, presses, capsule 
fi llers, bottle fi llers, other (specify)? 
TABLE 6 Continued 
AUDIT CHECKLIST FOR DRUG INDUSTRY 229

230 ROLE OF QUALITY SYSTEMS AND AUDITS 
Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
4.104 Are the following pieces of equipment suitable in their 
design: blender(s), conveyor(s), tablet, presses, capsule 
fi llers, bottle fi llers, other (specify)? 
4.105 Are the locations in the facility of the following pieces of 
equipment acceptable: blender(s), conveyor(s), tablet, 
presses, capsule fi llers, bottle fi llers, other (specify)? 
4.106 Are the following pieces of equipment properly installed: 
blender(s), conveyor(s), tablet, presses, capsule fi llers, 
bottle fi llers, other (specify)? 
4.107 Is there adequate space for the following pieces of 
equipment: blender(s), conveyor(s), tablet, presses, 
capsule fi llers, bottle fi llers, other (specify)? 
4.108  211.65(a) Are machine surfaces that contact materials 
or fi nished goods nonreactive, nonabsorptive, and 
nonadditive so as not to affect the product? 
4.109  211.65(b) Are design and operating precautions taken to 
ensure that lubricants or coolants or other operating 
substances do NOT come into contact with drug 
components or fi nished product? 
4.110  211.72 Fiber - releasing fi lters are NOT used in the 
production of injectable products. 
4.111  211.72 Asbestos fi lters are NOT used in the production of 
products. 
4.112 Is each idle piece of equipment clearly marked  needs 
cleaning  or  cleaned; ready for service  ? 
4.113 Is equipment cleaned promptly after use? 
4.114 Is idle equipment stored in a designated area? 
4.115  211.67(a)(b) Are written procedures available for each 
piece of equipment used in the manufacturing, processing, 
or holding of components, in - process material, or fi nished 
product? 
4.116 Do cleaning instructions include disassembly and drainage 
procedure, if required, to ensure that no cleaning solution 
or rinse remains in the equipment? 
4.117 Does the cleaning procedure or startup procedure ensure 
that the equipment is systematically and thoroughly 
cleaned? 
4.2 Equipment Identifi cation 
4.201  211.105 Are all pieces of equipment clearly identifi ed with 
easily visible markings? 
4.202  211.105(b) Are all pieces of equipment also marked with 
an identifi cation number that corresponds with an entry 
in an equipment log? 
4.203 Does each piece of equipment have written instructions for 
maintenance that includes a schedule for maintenance? 
4.204 Is the maintenance log for each piece of equipment kept on 
or near the equipment? 
TABLE 6 Continued

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
4.3 Equipment Maintenance & Cleaning 
4.301  211.67(b) Are written procedures established for the 
cleaning and maintenance of equipment and utensils? 
4.302 Are these procedures followed? 
4.303  211.67(b)(1) Does a written procedure assign responsibility 
for the cleaning and maintenance of equipment? 
4.304  211.67(b)(2) Has a written schedule been established 
and is it followed for the maintenance and cleaning of 
equipment? 
4.305 Has the cleaning procedure been properly validated? 
4.306  211.67(b)(2) If appropriate, is the equipment sanitized 
using a procedure written for this task? 
4.307  211.67(b)(3) Has a suffi ciently detailed cleaning and 
maintenance procedure been written for each different 
piece of equipment to identify any necessary disassembly 
and reassembly required to provide cleaning and 
maintenance? 
4.308  211.67(b)(3) Does the procedure specify the removal or 
obliteration of production batch information from each 
piece of equipment during its cleaning? 
4.309 Is equipment cleaned promptly after use? 
4.310 Is clean equipment clearly identifi ed as  clean  with a 
cleaning date shown on the equipment? 
4.311  211.67(b)(5) Is clean equipment adequately protected 
against contamination prior to use? 
4.312  211.67(b) Is equipment inspected immediately prior to 
use? 
4.313  211.67(c) Are written records maintained on equipment 
cleaning, sanitizing, and maintenance on or near each 
piece of equipment? 
4.4 Measurement Equipment Calibration Program 
4.401  211.68(a) Does the facility have approved written 
procedures for checking and calibration of each piece of 
measurement equipment? (Verify procedure and log for 
each piece of equipment and note exceptions in notebook 
with cross reference.) 
4.402  211.68(a) Are records of calibration checks and inspections 
maintained in a readily retrievable manner? 
4.5 Equipment Qualifi cation Program 
4.501  211.63 Verify that all pieces of equipment used in 
production, packaging, and quality assurance are capable 
of producing valid results. 
4.502  211.68(a) When computers are used to automate 
production or quality testing, have the computer and 
software been validated? 
4.503 Have on - site tests of successive production runs or tests 
been used to qualify equipment? 
4.504 Were tests repeated a suffi cient number of times to ensure 
reliable results? 
TABLE 6 Continued 
AUDIT CHECKLIST FOR DRUG INDUSTRY 231

232 ROLE OF QUALITY SYSTEMS AND AUDITS 
Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
4.505  211.63 Is each piece of equipment identifi ed to its 
minimum and maximum capacities and minimum and 
maximum operating speeds for valid results? 
4.506 Have performance characteristics been identifi ed for each 
piece of equipment? (May be provided by the 
manufacturer but must be verifi ed under typical 
operations conditions.) 
4.507 Have operating limits and tolerances for performance been 
established from performance characteristics? 
5.0 Material/component control 
5.1 Material/Component Specifi cation and Purchasing Control 
Although purchasing is not specifi cally addressed in the 
current GMP regulation, incumbent upon user of 
components and materials to ensure quality of product, 
material, or component. 
5.101 Has each supplier/vendor of material or component been 
inspected/audited for proper manufacturing controls? 
(Review suppliers and audits and enter names, material 
supplied, and date last audited in notebook.) 
5.2 Material/Component Receipt, Inspection, Sampling, and 
Laboratory Testing 
5.201  211.80(a) Does the facility have current written procedures 
for acceptance/rejections of drug products, containers, 
closures, labeling, and packaging materials? (List selected 
materials and components in notebook and verify 
procedures.) 
5.202  211.80(d) Is each lot within each shipment of material or 
components assigned a distinctive code so material or 
component can be traced through manufacturing and 
distribution? 
5.203  211.82(a) Does inspection start with visual examination of 
each shipping container for appropriate labeling, signs of 
damage, or contamination? 
5.204  211.82(b) Is the number of representative samples taken 
from a container or lot based on statistical criteria and 
experience with each type of material or component? 
5.205  211.160(b) Is the sampling technique written and followed 
for each type of sample collected? 
5.206 Is the quantity of sample collected suffi cient for analysis 
and reserve in case retesting or verifi cation is required? 
Verify that the following steps are included in written 
procedures unless more specifi c procedures are followed: 
5.207  211.84(c)(2) Containers are cleaned before samples are 
removed. 
5.208  211.84(c)(4) Stratifi ed samples are not composited for 
analysis. 
5.209  211.84(c)(5) Containers from which samples have been 
taken are so marked indicating date and approximate 
amount taken. 
TABLE 6 Continued

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
5.210 Each sample container is clearly identifi ed by material or 
component name, lot number, date sample taken, name 
of person taking sample, and original container 
identifi cation. 
5.211  211.84(d)(1)(2) At least one test is conducted to confi rm 
the identity of a raw material (bulk chemical or 
pharmaceutical) when a Certifi cate of Analysis is 
provided by supplier and accepted by QA. 
5.212 If a Certifi cate of Analysis is not accepted for a lot of 
material, then additional testing is conducted by a written 
protocol to determine suitability for purpose. 
5.213  211.84(d)(6) Microbiological testing is conducted where 
appropriate. 
5.3 Material Component Storage and Handling 
Verify that materials and components are stored and 
handled in a way that prevents contamination, mixups, 
and errors. 
5.301  211.42(b) Are incoming material and components 
quarantined until approved for use? 
5.302 Are all materials handled in such a way to prevent 
contamination? 
5.303 Are all materials stored off the fl oor? 
5.304 Are materials spaced to allow for cleaning and inspection? 
5.305  211.122(d) Are labels for different products, strengths, 
dosage forms, etc., stored separately with suitable 
identifi cation? 
5.306 Is label storage area limited to authorized personnel? 
5.307  211.89 Are rejected components, material, and containers 
quarantined and clearly marked to prevent their use? 
5.4 Inventory Control Program 
5.401  211.142 Are inventory control procedures written? 
5.402 Does the program identify destruction dates for obsolete 
or out - dated materials, components, and packaging 
materials? 
5.403  211.150(a) Is stock rotated to ensure that the oldest 
approved product or material is used fi rst? 
5.404  211.184(e) Is destruction of materials documented in a 
way that clearly identifi es the material destroyed and the 
date on which destruction took place? 
5.5 Vendor (Supplier) Control Program 
5.501 Are vendors periodically inspected according to a written 
procedure? 
5.502 Is the procedure for confi rming vendor test results written 
and followed? 
6.0 Operational control 
TABLE 6 Continued 
AUDIT CHECKLIST FOR DRUG INDUSTRY 233

234 ROLE OF QUALITY SYSTEMS AND AUDITS 
Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
6.1 Material/Component/Label Verifi cation, Storage, and 
Handling 
6.101  211.87 Do written procedures identify storage time beyond 
which components, containers, and closures must be 
reexamined before use? 
6.102  211.87 Is release of retested material clearly identifi ed for 
use? 
6.103 Are retesting information supplements originally obtained? 
6.104 Do written procedures identify steps in the dispensing of 
material for production? 
6.105 Do these procedures include (1) release by QC, (2) 
documentation of correct weight or measure, and (3) 
proper identifi cation of containers? 
6.106 Does a second person observe weighing/measuring/ 
dispensing and verify accuracy with a second signature? 
6.107  211.101(c) Is the addition of each component documented 
by the person adding the material during manufacturing? 
6.108  211.101(d) Does a second person observe each addition of 
material and document verifi cation with a second 
signature? 
6.109  211.125(a) Does a written procedure specify who is 
authorized to issue labels? 
6.110  211.125(a) Does a written procedure specify how labels 
are issued, used, reconciled with production, returned 
when unused, and the specifi c steps for evaluation of any 
discrepancies? 
6.111  211.125(d) Do written procedures call for destruction of 
excess labeling on which lot or control numbers have 
been stamped or imprinted? 
6.2 Equipment/Line/Area Cleaning, Preparation, and Clearance 
6.201  211.67(b)(5) Do written procedures detail how equipment 
is to be checked immediately prior to use for cleanliness, 
removal of any labels, and labeling from prior print 
operations? 
6.202  211.67(b)(3) Do written procedures detail any 
disconnection and reassembly required to verify readiness 
for use? 
6.3 Operational Process Validation and Production Change 
Order Control 
6.301 Have production procedures been validated? (Review 
selected procedures for validation documentation. 
Adequate?) 
6.302  211.100(a) Does the process control address all issues to 
ensure identity, strength, quality, and purity of product? 
6.303   211.101(a) Does the procedure include formulation that 
is written to yield not less than 100% of established 
amount of active ingredients? 
TABLE 6 Continued

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
6.304  211.101(c) Are all weighing and measuring preformed by 
one qualifi ed person and observed by a second person? 
6.305  211.101(d) Have records indicated preceding policy been 
followed by presence of two signatures? 
6.306  211.103 Are actual yields calculated at the conclusion of 
appropriate phases of the operation and at the end of the 
process? 
6.307  211.103 Are calculations performed by one person? Is 
there independent verifi cation by a second person? 
6.4 In - Process Inspection, Sampling, and Laboratory Control 
6.401  211.110(a) Are written procedures established to monitor 
output and validate the performance of manufacturing 
procedures that may cause variability in characteristics of 
in - process materials and fi nished drug products? 
6.402  211.110(c) Are in - process materials tested at appropriate 
phases for identity, strength, quality, purity, and are they 
approved or rejected by Quality Control? 
6.403  211.160(b) Are there laboratory controls including 
sampling and testing procedures to assure conformance 
of components, containers, closures, in - process materials, 
and fi nished product specifi cations? 
6.5 Reprocessing/Disposition of Materials 
6.501  211.115(a) Do written procedures identify steps for 
reprocessing batches? 
6.502  211.115(b) Are quality control review and approval 
required for any and all reprocessing of material? 
6.503 Does testing confi rm that reprocessed batches conform to 
established specifi cation? 
6.504 Does a written procedure outline steps required to 
reprocess returned drug products (if it can be determined 
that such products have not been subjected to improper 
storage conditions)? 
6.505 Does Quality Control review such reprocessed returned 
goods and test such material for conformance to 
specifi cations before releasing such material for resale? 
7.0 Finished product control 
7.1 Finished Product Verifi cation, Storage, and Handling 
7.101  211.30 Do written procedures indicate how and who 
verifi es that correct containers and packages are used for 
fi nished product during the fi nishing operation? 
7.102  211.134(a) In addition, do written procedures require that 
representative sample of units be visually examined upon 
completion of packaging to verify correct labeling? 
7.103  211.137(a) Are expiration dates stamped or imprinted on 
labels? 
7.104  211.137(b) Are expiration dates related to any storage 
conditions stated on the label? 
TABLE 6 Continued 
AUDIT CHECKLIST FOR DRUG INDUSTRY 235

Question 
Instructions/Questions 
(note any exceptions and comments in notebook) Yes, No, or NA 
7.105  211.142(a) Are all fi nished products held in quarantine 
until QC has completed its testing and releases product 
on a batch - to - batch basis for sale? 
7.106  211.142(o) Is fi nished product stored under appropriate 
conditions of temperature, humidity, light, etc. 
7.2 Finished Product Inspection, Sampling, Testing, and 
Release for Distribution 
7.201  211.166 Has the formulation for each product been tested 
for stability based on a written protocol? (Containers 
must duplicate those used in fi nal product packaging.) 
7.202  211.166 Are written sampling and testing procedures and 
acceptance criteria available for each product to ensure 
conformance to fi nished product specifi cations? 
7.203  211.170(a) Is a quantity of samples equal to at least twice 
the quantity needed for fi nished product release testing 
maintained as a reserve sample? 
7.204  211.167(a) Are sterility and pyrogen testing performed as 
required? 
7.205  211.167(b) Are specifi c tests for foreign particles or 
abrasives included for any ophthalmic ointments? 
7.206  211.167(c) Do controlled release or sustained release 
products include tests to determine conformance to 
release time specifi cation? 
7.3 Distribution Controls 
7.301  211.150(a) Does a written procedure manage stocks to 
ensure that oldest approved product is sold fi rst? 
7.302  211.150(a) Are deviations to the policy above 
documented? 
7.303  211.150(a) Does a written procedure identify the steps 
required if a product recall is necessary? 
7.304 Is the recall policy current and adequate? 
7.4 Marketing Controls 
7.401 The current regulation does not address marketing controls 
per se except that all fi nished products must meet their 
specifi cations. 
7.5 Complaint Handling and Customer Satisfaction Program 
7.501  211.198(a) Are complaints, whether received in oral or 
written form, documented in writing, and retained in a 
designated fi le? 
7.502  211.198(a) Are complaints reviewed on a timely basis by 
the Quality Control unit? 
7.503  211.198(b)(1) Is the action taken in response to each 
complaint documented? 
7.504  211.198(b)(3) Are decisions not to investigate a complaint 
also documented and the name of the responsible person 
documented? 
7.505  211.198(b)(2) Are complaint investigations documented 
and do they include investigation steps, fi ndings, and 
follow - up steps, if required? Are dates included for each 
entry? 
TABLE 6 Continued 
236

7. The references to sections in the GMP regulation are for your convenience 
should a question arise. In some instances, two or more sections within the 
GMP regulation may have bearing on a specifi c subject. The headings in the 
GMP regulation will usually offer some guidance on the areas covered in each 
section. 
8. A general suggestion for a successful audit is to spend most of your time on 
major issues and a smaller portion of your time on small issues. There may be 
observations that you may wish to point out to supervisory personnel that 
deserve attention but do not belong in an audit report because they are relatively 
insignifi cant. By the same token, too many small items suggests a trend 
of noncompliance and deserve attention as such. When citing these, be 
specifi c. 
REFERENCES 
1. U.S. Code of Federal Regulations (CFR) , Title 21, Part 211, Current good manufacturing 
practice for fi nished pharmaceuticals, available: http://www.accessdata.fda.gov/scripts/ 
cdrh/cfdocs/cfcfr/CRFSearch.cfm?CFRPart=211 , accessed Dec. 5, 2006 . 
2. American National Standards Institute (ANSI) ( 2000 ), Quality management system  
Requirements, ANSI/ISO/ASQ Q9001 - 2000, ANSI, New York. 
3. American National Standards Institute (ANSI) ( 2000 ), Quality management system  
Fundamentals and vocabulary, ANSI/ISO/ASQ Q9000 - 2000, ANSI, New York. 
4. International Organization for Standardization (ISO) , Application of risk management 
of medical devices, ISO 14971:2000, ISO, Geneva. 
5. U.S. Department of Health and Human services, U.S. Food and Drug Administration , 
Pharmaceutical cGMPs for the 21st century  A risk - based approach, Final Report  
Fall 2004, September 2004 , available: http://www.fda.gov/cder/gmp/gmp2004/GMP_ 
fi nalreport2004.htm , accessed Dec. 5, 2006. 
6. U.S. Department of Health and Human Services (DHHS) , Food and Drug Administration 
( 2006 , June), Guidance for industry: Q9 Quality risk management, DHHS, Rockville, 
MD. 
7. U.S. Department of Health and Human Services (DHHS) , Food and Drug Administration 
( 2004 , Sept.), Guidance for industry: PAT  A framework for innovative pharmaceutical 
development, manufacturing, and quality assurance, DHHS, Rockville, MD. 
8. U.S. Department of Health and Human Services (DHHS) , Food and Drug Administration 
( 2006 , Sept.), Guidance for industry: Quality systems approach to pharmaceutical 
CGMP regulations, DHHS, Rockville, MD. 
9. U.S. Code of Federal Regulations (CFR) , Title 21, Part 820, Quality system regulation 
for medical devices, available: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ 
CFRSearch.cfm?CFRPart=820 , accessed Dec. 5, 2006 . 
10. International Organization for Standardization (ISO) , ( 2003 ), Medical devices  Quality 
management systems  Requirements for regulatory purpose, ISO 13485:2003, ISO, 
Geneva. 
11. Juran J. M. , and Godfrey , A. B. , Eds. ( 1999 ), Juran  s Quality Handbook , 5th ed. , McGraw - 
Hill , New York . 
12. FDA compliance policy guide section 130.000, FDA access to results of quality assurance 
program audits and inspections (CPG 7151.02), available: http://www.fda.gov/ora/ 
compliance_ref/cpg/cpggenl/cpg130 - 300.html , accessed Dec. 5, 2006 . 
REFERENCES 237

238 ROLE OF QUALITY SYSTEMS AND AUDITS 
13. International Organization for Standardization (ISO) , ( 2002 ), Guidelines for quality 
and/or environmental management systems auditing, ISO 19011:2002, ISO, Geneva. 
14. The Global Harmonization Task Force, SG4, Training requirements for auditors (guidelines 
for regulatory auditing of quality systems of medical device manufacturers  Part 1: 
General requirements  Supplement 3), available: http://www.ghtf.org/sg4/inventorysg4/ 
trainingfi nal.pdf , accessed Dec. 5, 2006 . 
15. FDA compliance program guidance manual for FDA staff: Drug manufacturing inspections 
program (7356.002), 2/1/ 2002 , available: http://www.fda.gov/cder/dmpq/compliance_ 
guide.htm , accessed Dec. 5, 2006. 
16. U.S. Department of Health and Human Services (DHHS) , Food and Drug Administration 
( 2004 , Sept.), Guidance for industry: Sterile drug products produced by aseptic processing 
 Current good manufacturing practice, DHHS, Rockville, MD. 
17. U.S. Department of Health and Human Services (DHHS) , Food and Drug Administration 
( 2001 , Aug.), Guidance for industry: Q7A good manufacturing practice guidance for 
active pharmaceutical Ingredients, DHHS, Rockville, MD. 

239 
3.3 
CREATING AND MANAGING A 
QUALITY MANAGEMENT SYSTEM 
Edward R. Arling , Michelle E. Dowling , and Paul A. Frankel 
Amgen, Inc., Thousand Oaks, California 
Contents 
3.3.1 Introduction 
3.3.2 Understanding a Quality Management System 
3.3.2.1 Defi ning Quality Management Systems 
3.3.2.2 Synthesis versus Analysis 
3.3.2.3 System versus Process 
3.3.2.4 Business Benefi ts of Establishing a Robust Quality Management System 
3.3.2.5 Industry and Regulatory Expectations 
3.3.3 Management and Staff: Leadership and Support 
3.3.3.1 Outlining Benefi ts to the Enterprise 
3.3.3.2 Speaking Management Language 
3.3.3.3 Translating Benefi ts to Staff 
3.3.3.4 Ensuring Staff Support and Management Leadership 
3.3.3.5 Traps to Avoid 
3.3.4 Establishing Quality Management System Scope 
3.3.4.1 Defi ning Business Requirements 
3.3.4.2 Integrating Quality Management System into Quality Plans 
3.3.4.3 Determining Process Resolution Requirements 
3.3.4.4 Scalability to Enterprise 
3.3.5 System and Process Ownership: Roles and Responsibilities 
3.3.5.1 Quality Management System Ownership and Management 
3.3.5.2 Process Ownership 
3.3.5.3 Process Owner Selection 
3.3.5.4 Stakeholder/Process Owner Integration 
3.3.5.5 Decision Authority 
3.3.5.6 Industry Knowledge 
3.3.5.7 Regulatory Inspection and Audit Lead 
3.3.5.8 Subject Matter Expert 
3.3.5.9 Metric Ownership 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

240 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
3.3.5.10 Documentation Ownership 
3.3.5.11 Training 
3.3.5.12 Risk Management 
3.3.5.13 Continuous Improvement and Project Management 
3.3.5.14 Nonconformance / CAPA / Planned Deviation Ownership 
3.3.6 Change Management/Communication 
3.3.6.1 Managing Organizational Change 
3.3.6.2 Communication 
3.3.6.3 Feedback and Alignment 
3.3.6.4 Training 
3.3.7 Measuring Success through Meaningful Metrics 
3.3.7.1 Performance Metric Development 
3.3.7.2 Metric Review 
3.3.7.3 Maturity Model 
3.3.7.4 Meeting Process Maturity Requirements 
3.3.8 Driving Continuous Improvement: Projects 
3.3.8.1 Process Improvements 
3.3.8.2 Process Improvement Proposal 
3.3.8.3 Task versus Project 
3.3.8.4 Project Metrics 
3.3.9 Ensuring Ongoing Success 
3.3.9.1 Establishing Mutual Goals 
3.3.9.2 Rewards and Recognition 
3.3.9.3 Ensuring Ongoing Program Continuity 
3.3.9.4 Program Institutionalization 
References 
3.3.1 INTRODUCTION 
The world  s population continues to grow and the average life expectancy continues 
to increase. Pharmaceutical and biopharmaceutical products are more in demand 
as the population expands, requiring novel and specialized medications to treat 
common and debilitating diseases. The industry is challenged to rapidly discover 
and commercialize products to treat existing unmet medical needs and emerging 
threats as viruses mutate into new diseases that threaten the stability of the world 
as we know it. 
At the same time, the global marketplace continues to increase its demand on 
the industry. Government, consumer, and wholesale buying pressures demand lower 
prices. Higher quality standards are expected by regulators and consumers. Competition 
continues to increase from generic, biosimilar, and counterfeit producers. 
Developing nations, with lower cost overheads, are developing economical production 
capabilities. Meanwhile, research and development costs are increasing. 
This chapter will outline the concepts, benefi ts, and practical implementation 
steps for developing a comprehensive quality management system (QMS) that supports 
pharmaceutical and biopharmaceutical manufacturing operations. The material 
presented is universal in its utility, applicable to small and large companies, 
development, and commercial enterprises. A QMS is a proactive, structured approach 

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 241 
to supporting development and manufacturing operations. It includes all processes, 
metrics, management review, and continuous improvement activities. The QMS, as 
described in this chapter, is further supported through an active change management 
program and application of annual quality plans to ensure ongoing system 
sustainability. 
A well - designed QMS, with mature, developed processes, provides the required 
infrastructure and support necessary for successful manufacturing operations. Integrated 
processes, proactively managed, that can be quickly modifi ed to meet changing 
business and regulatory demands will support ongoing manufacturing operations 
and provide competitive advantage. This chapter provides guidance on creating and 
managing a robust QMS that supports manufacturing operations in the pharmaceutical 
and biopharmaceutical industry. 
3.3.2 UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 
Every development, testing, manufacturing, packaging, warehouse, or distribution 
facility has its own unique role in producing an output or product for consumption 
by a customer somewhere in the pharmaceutical or biopharmaceutical supply chain. 
Each facility and organization is critically dependent upon several different processes 
that function interdependently producing the desired output. Organizations  
survival and profi tability are directly linked to the effi ciency of design, execution, 
performance, and interrelational attributes of these processes. Throughout a product 
life cycle, from early discovery through development, scale up, clinical testing, 
product technology transfer, registration, approval, commercialization, and eventually 
product discontinuance, robust processes are the foundation supporting the 
successful enterprise. 
Manufacturing support processes are discrete in their output, but interrelated in 
their overall effect. Weak or ill - defi ned processes have a diminishing overall effect 
on the organization and its product. It manifests itself as increased rework, rejected 
material, extended cycle times, delayed disposition, high nonconforming performance 
metrics, complaints, recalls, or other inabilities to meet customer or market 
demands. A comprehensive QMS may encompass all the processes supporting 
development and manufacturing. It includes the standards, policies, and procedures 
required to measure those processes for performance and maturity. It provides 
metrics necessary for leadership to perform risk - based prioritization and focus 
resources for business improvement and regulatory compliance. 
Robust processes will have owners that have defi ned roles, responsibilities, and 
accountabilities. These process owners must be fully dedicated to their process. They 
must know their process capabilities and expectations, the interrelationship between 
their process and other processes and manage them like a business unto themselves. 
Functional management must support process owners, and leadership must understand 
and lead the QMS effort as an ongoing program, treating it as the integral 
part of the business that it is. 
A QMS is an organizational approach consisting of people, interrelated processes, 
process inputs and outputs, and structured review programs that lead to 
ongoing continuous improvement. This complexity of processes requires a programmatic 
organization and management to effectively interrelate its components. A 

242 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
QMS program offi ce is required to provide the organizational benefi ts expected 
from well - managed processes and should be one of the fi rst elements established 
when instituting the program. 
A QMS and the processes comprising it are not the sole responsibility of the 
quality function or a single functional group. Inherently, these processes have no 
bounds in the organization. The concept must be owned, managed, or executed by 
all staff from leadership to the most entry - level manufacturing associate. A quality 
mindset must be part of every employee that contributes to the discovery, manufacture, 
packaging, testing, warehousing, and shipping of a product or output. A 
culture of quality and understanding of the processes in which personnel work are 
essential to advance the QMS to maximize benefi ts to the enterprise and remain 
competitive. 
Instituting a QMS through a holistic approach that supports manufacturing operations 
has the potential to meet and exceed customer, patient, shareholder, and 
employee expectations. It requires a cross - functional team approach, with proactive 
management of all the processes responsible for manufacture, including functional 
support from development, manufacturing, analytical, engineering, and quality 
assurance. The development and maintenance of a tested, robust QMS requires time 
and resources. Full maturation of processes and organizational culture change may 
take, in some cases, years to fully implement and realize benefi ts, but worth the effort 
and time. Signifi cant QMS issues should not be addressed as one - off fi xes. Rather, 
action taken to remediate defi cient processes should be approached as long - term 
corrections, addressing the root cause of the failed process, so they do not repeatedly 
plague the organization. 
The ultimate responsibility for a robust, functional QMS lies with top management. 
The organization follows the leadership, and therefore, leadership must 
support a QMS that is specifi cally designed for the organization, be aware of and 
monitor its progress and contribution to the organization, and frequently support, 
guide, and maintain it. Doing so ensures viability of the QMS, and in turn the QMS 
will provide leadership the data and guidance necessary to effectively manage the 
organization. 
3.3.2.1 Defi ning Quality Management Systems 
The term system or quality system is used with surprising inconsistency throughout 
the pharmaceutical and biopharmaceutical industry and by government regulators. 
Even within a single company or within a department, the terms can be nebulous 
in their use and interpretation. System is often used to describe an individual process 
or unit operation. Often, the term system is used so narrowly as to describe an 
individual policy, standard, or even a single procedure. 
Recent initiatives by global organizations such as ISO (International Organization 
for Standardization, www.iso.org ) and ICH (International Conference on 
Harmonization, www.ich.org ) are attempting to bring consistency in concept and 
standardization in defi nition to the QMS. In 2004, the Pharmaceutical Inspection 
Co - Operation Scheme (PIC/S, www.picscheme.org ) issued its recommendation on 
Quality System Requirements for Pharmaceutical Inspectorates. The U.S. Food and 
Drug Administration (FDA) initiated inspection surveillance approaches based 
upon QMS organization and is another source of defi nition and interpretation. 

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 243 
Inconsistency in language and expectations continues to exist; however, efforts are 
progressing to minimize distinctions and globally harmonize efforts, structure, and 
language concerning quality systems. 
According to Webster  s dictionary, system is defi ned as a regularly interacting or 
interdependent group of items forming a unifi ed whole; a group of interacting 
bodies under the infl uence of related forces . . . an assemblage of substances that is 
in or tends to equilibrium . . . a group of organs that, when together, perform one or 
more vital functions . . . an organization forming a network especially for distributing 
something or serving a common purpose . . . an organized set of doctrines, ideas, 
or principles usually intended to explain the arrangement or working of a systematic 
whole [1] . 
The vocabulary and defi nitions used in this chapter defi nes a quality management 
system as the compilation of all the processes required to support the manufacture, 
packaging, testing, release, and distribution of an active pharmaceutical ingredient 
(API) or drug product. It is aligned with that of the FDA Center for Drug Evaluation 
and Research (CDER) compliance program 7356.002, issued to investigators 
for the inspection of pharmaceutical and biopharmaceutical manufacturing plants 
( www.fda.gov/IOM 7356.002). The CDER inspection program subdivides the processes 
comprising the QMS into six subsystems: quality, facilities/equipment, production, 
materials control, laboratory controls, and packaging and labeling. 
There are no specifi c CDER requirements as to which processes belong under 
each subsystem; however, one can easily follow the outline provided in 21 CFR Part 
211, the regulations applicable to human drug product manufacture, to aid in the 
determination of processes likely to be inspected during a regulatory inspection 
( www.fda.gov ). The FDA subdivides all the processes comprising a company  s QMS 
into six subsystems to ensure adequate and varied coverage during inspections. See 
Figure 1 . Using the same process organization structure and vocabulary as regulators 
provides an enterprise the advantage of more effi cient inspection preparation 
and avoidance of miscommunication during and after regulatory inspections. 
The CDER subsystem organization provides regulators and management the 
ability to focus attention to specifi c functional areas. Table 1 is an example of the 
processes, organized under appropriate subsystems, supporting a typical API or drug 
fi ll - and - fi nish operation. These subsystems are organized according requirements 
found in regulations used by investigators during inspections, 21 CFR Part 210, 211, 
and the unit operations and support processes necessary for production. 
One size does not fi t all situations. Each enterprise has the responsibility and 
latitude to design a QMS to meet its specifi c needs. Even facilities with very similar 
manufacturing operations may require different processes to support the business. 
Each manufacturing organization requires a customized set of processes which will 
comprise its QMS. The management group responsible for the QMS should be able 
to identify and justify the processes comprising the system. There is not a single set 
of processes that can be universally applied to all operations, as each organization 
is unique in its business, product output, organization, culture, as well as local and 
global regulatory and customer requirements. 
Processes identifi ed as part of the QMS can be organized into the appropriate 
CDER subsystems for the purpose of aligning with the methodology used during 
inspections. It also provides management the ability to determine areas of strength 
or opportunities for improvement within the QMS. Regulators will always include 

244 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
FIGURE 1 Subsystems and management relationship. 
TABLE 1 Quality Management System Subsystems and Processes 
Quality Facilities/equipment 
Audits and inspections Facility and equipment design 
Management review Equipment maintenance 
Risk management Equipment cleaning 
Organization and personnel Calibration 
Training Materials control 
Document management Supplier quality management 
Change control Sampling and inspection 
Nonconformances Receiving, warehouse, and storage 
Corrective and preventative actions Inventory management 
Biological product deviation Transport 
Product disposition Return and salvage 
Validation Laboratory controls 
Production Laboratory testing 
Manufacturing Sample management and sample plans 
Process monitoring Stability program 
Environmental and gowning monitoring Packaging and labeling 
In - process controls Labeling controls and approvals 
Gowning Package development 

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 245 
a focus on the processes within the quality subsystem. Other subsystems will be 
reviewed during inspections based upon the type of inspection and compliance 
history of the enterprise. More information on how the FDA focuses inspections 
based on quality system and subsystem organization is available at the FDA website 
( www.fda.gov ) or articles written on this subject [2] . 
To maximize the effect of a QMS, it should be designed to be scalable and transferable 
throughout the enterprise and easy to understand and execute. An adequately 
designed QMS results in increased effi ciency, a compliant operation, and 
staff satisfaction. 
3.3.2.2 Synthesis versus Analysis 
With systems thinking, the whole is greater than the sum of its parts. Systems rely 
upon the interaction of several processes. An individual process has limited value 
on its own, regardless of the level of development it has achieved. Processes provide 
value to the system through synthesis with other processes. 
In the early twentieth century, researchers began to recognize the existence of 
interdependent relationships and organizational patterns among seemingly discrete 
parts. It is the relationships that allow parts to function as a whole. The  perceived 
whole  is a system. Systems thinking involves considering the parts in the context 
of that whole. In systems thinking: 
 Everything in a system is related to everything else in the system. 
 The parts of a system work together to achieve the overall objective of the 
whole system. 
 In addition to the immediate effects of an action, there will be other consequences 
that ripple through the system. 
 Every change brings benefi ts and consequences. 
 Changing or reinforcing patterns and relationships within a system is as necessary 
to achieving the goals of the system as changing or retaining the parts of 
the system. 
 Systems are  living  entities that sustain themselves through self - regulating 
dynamic equilibrium and organize to respond to externally imposed change. 
Viewing a QMS in this context is benefi cial to organizational leadership and management 
responsible for the system. It puts into perspective the overall effect on an 
organization that is achievable by individual processes alone and what can be 
achieved and sustained through active management and the interaction between 
those processes. 
3.3.2.3 System versus Process 
Traditional industry paradigm has the Quality Department responsible for quality 
and the Manufacturing Department responsible for producing product. Inherent 
confl ict exists in this model due to competing functional priorities. By building 
quality concepts and accountabilities into production processes responsible for 
production, quality becomes infused into the organization. Both Quality and 

246 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
Manufacturing therefore share the common goal of supplying high - quality product 
through the effi cient execution of their processes. 
Historically, very few processes were regarded as  quality systems,  and they were 
viewed as something owned by the Quality Department. These  systems  were in 
fact ill defi ned and nonrelated processes used to monitor or detect individual actions 
and activities occurring in the manufacturing environment. These systems were 
based on quality control (QC) type of responsibilities for testing quality into the 
product. Examples include raw material testing, in - process and fi nished - product 
testing, nonconforming material review, environmental monitoring, and release and 
distribution. Few were interrelated with other processes, actively supported by 
management, or reviewed by leadership for performance or compliance. 
The QC monitoring processes described above, if supported, were limited in their 
ability to support improvements and could only lead to action that was reactive in 
nature. Process integration is weak or nonexistent. Neither process maturity and 
development nor proactive system management is achievable. In the past, QMS 
enhancement was viewed as an expense and not seen as a relational contributor to 
the value chain. Aware management now realizes, through regulatory action, penalty 
and fi nes, delayed product approvals, recalls, and the like that establishment of a 
comprehensive QMS is essential to survive in the current regulatory environment 
and remain competitive in the business environment. 
With the advancement of quality assurance (QA) principles and concepts at the 
end of the last century, QMSs have evolved to be more proactive to include change 
control, supplier and internal auditing, risk management, lagging and leading metric 
collection, and review. Review of predictive metrics has become the basis for preventive 
action and continuous improvement programs. Today  s competitive environment 
obligates leading manufacturers and world - class organizations to apply 
proactive system thinking to expand their focus to include all processes that support 
product quality, irregardless of the stage of development or manufacture. Early 
implementation of appropriate processes supports quality - by - design concepts and 
practice, within the framework of a QMS and ensures quality in all processes and 
provides the foundation for good investigations and continuous improvement. 
A QMS should be comprised of all the processes supporting that business and 
include an effective management review of those process metrics. Management 
needs to be aware of and understand process performance through structured 
metrics review programs in order to take appropriate action, providing resources 
and capital to improve the QMS. This hierarchy is illustrated in Figure 2 . 
Processes supporting and applicable to pharmaceutical and biopharmaceutical 
manufacturing are easily determined by examining the business needs of the organization 
and the regulations governing them. A carefully designed QMS will consider 
the needs of the enterprise as a whole, as well as that of the individual unit 
operations comprising the enterprise. If the QMS design is comprehensive, it will 
provide signifi cant value to global and local management. It will support staff by 
standardizing processes, requirements, and expectations and provide leadership 
meaningful and comparable metrics on system and process performance. Changes 
can be quickly facilitated and implemented when process modifi cations are required. 
A consistent representation of processes to regulators builds confi dence and trust 
that the enterprise is capable to produce the product for which approval has been 
granted. 

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 247 
3.3.2.4 Business Benefi ts of Establishing a Robust Quality Management System 
The competitive nature of the pharmaceutical business demands capable and effi - 
cient processes supporting discovery, development, technology transfer and scale - 
up, and commercial manufacturing and distribution. Execution of effi cient processes 
is the foundation for new and ongoing enterprises to be successful. It is the basis 
for successful manufacture and the bedrock upon which management and regulators 
can gauge the capability level of the enterprise. Providing patients with needed 
medicines in a timely, cost - effi cient manner, without delay due to manufacturing or 
compliance issues, should be a primary driving force behind the pharmaceutical and 
biopharmaceutical industry. 
Leadership may ask the question: Why implement a quality management system? 
The answer is that a well - designed system is necessary to establish a state of control 
to ensure that a high quality, safe, and effi cacious product is produced and available 
for patients. Quality systems as described in the forthcoming ICH Q10 guidance is 
the logical complement to its predecessors, ICH Q8 (Product Development) and 
ICH Q9 (Risk Management) ( www.ich.org ). These three guidance documents build 
upon each other from quality - by - design activities in development through the entire 
product life cycle. When used together, the guidance documents maximize their 
benefi ts to the enterprise through better process understanding, less regulatory 
scrutiny, and increased freedom to operate. Together, these guidance  s support more 
effi cient product life - cycle management from discovery through development and 
commercialization. 
Ineffi cient operations cost businesses untold amounts in fi nancial and human 
capital. A poorly designed system coupled with ineffi cient processes may result in 
rework of development and commercialization activities, data integrity issues, inef- 
fi cient use of resources, and delay in approval. Poorly designed processes may also 
FIGURE 2 Quality management system hierarchy. 

248 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
lead to loss of future revenue with business partners and have a negative regulatory 
consequence. 
A recent study conducted by the Pharmaceutical Manufacturing Research 
Project, a joint venture by Georgetown University and Washington University in St. 
Louis business schools, collected data from 42 manufacturing facilities owned by 19 
companies to determine factors that affected industry performance. The Final 
Benchmarking Report assessed performance in terms of manufacturing times, frequency 
of deviations from manufacturing standards, reasons for deviations, manufacturing 
yield, and rates of improvement for those metrics. 
The study determined that improvements in manufacturing process could save 
industry more than $ 50 billion in manufacturing costs, which the researchers believe 
could result in lower drug prices and more money for R & D. The report received no 
industry or government funding [3] . 
Leadership is both challenged and rewarded for supporting the development of 
a robust QMS. On one hand, it takes time and resources to design and develop a 
comprehensive program. Immediate return on this investment is not usually forthcoming. 
Management is typically under pressure to deliver aggressive results in a 
short time period, which is counterintuitive to careful planning and long - range 
development. Conversely, proactively formalizing and supporting a robust QMS 
will, in the long run, ensure the operations freedom to operate (regulatory compliance) 
and deliver business effi ciencies. 
In the pharmaceutical and biopharmaceutical manufacturing industry, the perception 
of quality has dramatically changed over the past several years, and loss of 
market capitalization can be a direct correlation to this perception. Large pharmaceutical 
companies have gone from some of the world  s most admired companies to 
losing signifi cant percentage of their value, based on consumer, media, and investor 
perceptions of quality and ethics. Speaking at a recent Parenteral Drug Association 
(PDA)/FDA joint regulatory conference, Daniel Diermeier, IBM Distinguished Professor 
of Regulation and Competitive Practice, Northwestern University stated:  The 
perception of quality on the pharmaceutical value chain is greater than in other 
industries (auto, furniture, etc.). Patients cannot assess the quality of drugs as they 
can a car or hotel room. In healthcare, the  value proposition  is higher than other 
industries and the Quality [Management] System is a critical subset of that perception 
 [4] . Dr. Diermeier goes on to suggest a QMS include processes for decision 
and detection to further protect the  value proposition  of the enterprise. 
Enterprises lacking individual capable processes experience degrees of negative 
effects throughout the organization. This is true for processes that support discovery, 
development, manufacturing, or marketing. Recent examples of fi nes imposed by 
regulators for poor processes supporting the QMS are increasing (see Table 2 ). 
These costs are only indicative of the fi ne itself and do not include lost revenue, cost 
of consultancy for remediation, decreased shareholder value, and diminished staff 
morale and support. These costs are typically an order of magnitude or more greater 
than the fi ne itself. 
A common misconception of pharmaceutical and especially smaller biopharmaceutical 
companies is that the implementation of a robust QMS is not required in 
areas other than commercial manufacturing. Small, biotech start - up companies also 
tend to delay the implementation of well - designed processes until they near the 
approval stage, focusing the organization instead for product approval or sale. This 

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 249 
can become a costly miscalculation, as speed to market and limited capital demand 
processes supporting effi cient development, clinical and regulatory submission processes 
be executed with minimal waste or rework. 
Although QMSs are routinely identifi ed with commercial manufacturing, it is 
critical to establish process parameters for discovery, development, and technology 
transfer, including scale - up, characterization of process, analytical methodology, and 
validation. Development activities are executed more effi ciently through the application 
of robust processes and ultimately become the foundation for robust manufacturing. 
Failed development studies, inadequate comparability reports, clinical 
studies requiring repeated, or poorly supported analytical and process characterization 
contribute to delayed submissions and weak regulatory submission and inspection 
presentation. The identifi cation of processes supporting these activities, owner 
identifi cation and accountability and support will ensure success of the enterprise 
and reduce the anxiety and uncertainty that is inherent in development and approval 
activities. 
Several opportunities exist for pharmaceutical and biopharmaceutical manufacturing 
plants to improve effi ciency and cost savings, which ultimately validate the 
program  s benefi ts and supports leadership in achieving their fi nancial goals. Traditionally, 
the industry environment is heavily regulated and has been very risk 
adverse. These two elements combine to offer countless opportunities to improve 
ineffi cient and ill - defi ned processes, clarify process scope, defi ne process owner 
accountabilities and responsibilities, and remediate process duplication or gaps. 
Performing ineffi cient processes for the sake of avoiding regulatory scrutiny or 
attempting to defend poorly characterized processes without adequate data and 
interpretation becomes self - defeating to the industry. Poor prioritization of work, 
ill - defi ned process relationships, and functional management interference or neglect 
may also contribute to ineffi ciency. Staff requires processes that are easy to execute, 
well integrated, and result in value - added activities. This can only be accomplished 
through the design and execution of effi cient processes that are interrelated, bringing 
value to the enterprise, process owners, and stakeholders. 
An example of a robust process is the design, development, and operation of a 
nonconformance process. Regulations require an operational process to identify, 
document, and correct nonconformances occurring in licensed pharmaceutical manufacturing 
facilities for approved products. Companies spend signifi cant human 
TABLE 2 Potential Financial Impacts 
Company Compliance Issue Type of Impact 
Cost to Business 
( $ Mil) 
A Failure to follow procedure 
Inadequate training 
Multiple 483 
observations 
< 1 
B Inadequate process defi nition, 
controls, and oversight 
Warning letter > 1 
C Repeat observations  direct product 
impact Failure to meet warning 
letter commitments 
Consent decree > 100 
D Plant shutdown Direct fi nes product 
stock - out 
> 500 

250 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
capital identifying, documenting, and tracking nonconformances. But how much is 
actually being done to remediate these nonconformances? Can the nonconformances 
be related to previously completed development or commercialization 
studies? Is the nonconformance process suffi ciently related to an effective corrective 
or preventive action (CAPA) process? Does the preventive action interrelate 
effi ciently with an effi cient change control process to ensure proposed changes 
remain in compliance with registrations? Are the documentation and training processes 
suffi cient to support approved changes? An adequately designed QMS will 
ensure the supporting processes are present and that functional and interrelationships 
established. A systems implementation provides a holistic approach, which 
results in both building effective individual processes and interrelating those processes 
to maximize their effect on the business, driving effi cient and science - based 
activities. 
Maintaining good manufacturing practice (GMP) compliance is essential for 
pharmaceutical and biopharmaceutical companies. Results of noncompliance are 
costly fi nes, loss of revenue, higher overhead costs, delayed approvals, and poor 
customer and regulatory perceptions. Poor compliance results from an inadequately 
designed QMS that lacked the processes and management review required to 
support the enterprise. Processes supporting compliance include self - audits, change 
control, document revision and approval, and staff training programs. Regular management 
review of these processes will ensure resources are allocated to appropriate 
initiatives and there should be no surprises during inspections. A well - designed 
QMS should prevent negative regulatory consequences. Effi cient and compliant 
processes support lean manufacturing efforts through the documentation and 
understanding of processes. Management review of these processes ensures that 
leadership awareness, support, and action is taken by the organization when 
appropriate. 
Figures 3 and 4 illustrate how a biennial document review process and document 
processing cycle time metrics faltered in their early stages due to lack of process 
ownership, defi nition, and management review. This situation presented a compliance 
risk to the organization and resulted in poor business effi ciencies. Improve- 
FIGURE 3 Biennial document review process. 
11% 
19% 
15% 
55% 
87% 
92% 
84% 
88% 
0% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
100% 
Q1/05 Q2/05 Q3/05 Q4/05 Q1/06 Q2/06 Q3/06 Q4/06 
Reviews complete 
Actual 
Target

UNDERSTANDING A QUALITY MANAGEMENT SYSTEM 251 
ment was attained by assigning a process owner who defi ned and improved each 
process, developed meaningful metrics, and presented those metrics to management. 
Management became aware of process performance, understood the compliance 
risk and business impact and took appropriate action to focus staff efforts to meet 
process requirements. Results were improved document review cycles, proactive 
compliance with internal procedures and regulatory requirements, and the satisfaction 
of knowing that no additional effort was required to achieve better business 
results and regulatory compliance. 
3.3.2.5 Industry and Regulatory Expectations 
While there are no requirements for a  quality system  in current FDA regulations 
applicable to pharmaceutical and biopharmaceutical manufacturing, regulatory 
agencies and industry trade organizations are increasingly recognizing the importance 
of robust, functioning quality systems in support of manufacturing the world  s 
medicinal products. The FDA realizes not all quality principles are represented in 
current GMP regulations for drug products (21 CFR Part 211), which were last 
updated in 1978. 
Quality management system issues and their association with risk management 
are common topics discussed in trade and regulatory seminars and conferences. 
Recent guidelines such as FDA  Quality Systems Approach to Current Good Manufacturing 
Practice Regulations  found on the FDA website and part of FDA  s initiative 
titled  GMP  s for the 21st Century  was written to complement existing 
regulations. While the FDA guidance may change or even become redundant with 
the issuance of ICH Q10, there is common intent among industry and government 
to advance quality management systems. According to Joe Famulare, Director 
DMPQ, FDA, the  FDA wanted to write a comprehensive Quality System model 
that would support and correlate with CGMP regulations. The guidance is consistent 
with defi ning a state of control; facilitate quality efforts, change control, Quality by 
Design, and risk management  [4] . 
In discussing quality systems at a recent industry conference on GMPs, Chris 
Joneckis of the FDA CBER (Center for Biological Evaluation and Research) had 
FIGURE 4 Document review cycle time. 
0 
10 
20 
30 
40 
50 
60 
Q1/05 Q2/05 Q3/05 Q4/05 Q1/06 Q2/06 Q3/06 Q4/06 
Month 
Number of days 
Actual 
Target

252 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
this to say:  A robust Quality Management System makes a strong case for quality 
product. It is a win, win, win  for patient, industry and regulators. It benefi ts technology 
transfer, process control, monitoring, capability, improves manufacturing, 
fewer nonconformances and better quality of investigations. Regulatory benefi ts 
include enhanced Chemistry, Manufacturing, Controls (CMC) review, change 
control, and submission of postapproval changes  [5] . 
Regulatory and industry guidance documents have been generated in support of 
developing and organizing quality systems. In the late 1990s, the system - based 
inspection approach was formalized by the Center for Devices & Radiological 
Health (CDRH) of the FDA [6] . These regulations were codifi ed as QSR, Quality 
Systems Regulations, and are included in Part 820 of the Code of Federal Regulations 
(CFR). 
The CDER and CBER soon followed the CDRH approach and issued their own 
Compliance Program Guidance Manuals, 7356.002 [7] and 7345.848 [8] , respectively, 
which were modeled on the CDRH QSR approach. The CDER and CBER are 
responsible for ensuring the biennial inspection of pharmaceutical and biopharmaceutical 
manufacturing facilities. The guidelines listed here are used by investigators 
during manufacturing inspections. Process owners and stakeholders as well as management 
and leadership should be familiar with these compliance manuals and how 
investigators plan to use them during inspections. 
Current FDA inspectional surveillance, based on the models described above, 
requires investigators evaluate the processes within the subsystems defi ned by the 
QMS to determine compliance and risk to patient safety. This is different than the 
traditional approach of reviewing individual products during inspections. There is 
subtle, yet signifi cant advantage to both the regulating agencies and compliant 
companies by using a system approach, as the inspections are designed to be faster 
and cover many product types during one inspection. Companies with compliant 
histories can benefi t with nominal inspections, whereas companies with noncompliant 
histories will receive more regulatory scrutiny and possible regulatory action. 
The movement by industry groups such as the ISO, which attempts to provide 
recognized standards for many industries, was also grounded in a systems approach 
with the publication and certifi cation of ISO 9000 series and later with ISO 2000:9004 
( www.iso.org ), which is based on QMS establishment and eventually continuous 
improvements once processes become stable. 
The ICH, a joint regulatory  industry initivative on international harmonization 
for drug development and approval, also recognizes the value and contribution of 
a quality systems approach through its guidance development on this topic (ICH 
Q10). The pharmaceutical and biopharmaceutical industry and regulatory agencies 
are collaborating to fi nalize the guidance sometime in 2008. ICH Q10 is focused on 
pharmaceuticals and is intended to align GMP requirements with a quality system 
approach. It will be applicable to drug substance and drug product, large and small 
molecule products, and harmonize one approach to quality systems. It also will 
complement ICH Q8 and ICH Q9. ICH Q10 contains a pharmaceutical context 
emphasizing a comprehensive approach; key elements included are management 
response and continuous improvement. Several ICH guidance documents are 
already adopted by regulatory agencies, such as ICH Q7A, for the manufacture of 
APIs. As these guidance documents are adopted, they often become the basis for 
regulatory expectations and inspections. 

3.3.3 MANAGEMENT AND STAFF: LEADERSHIP AND SUPPORT 
All manufacturing operations operate, to some extent, with elements and components 
of a quality management system. Those elements and processes may not be 
recognized or managed as though they are an integral part of a larger system and 
may be primarily reactive in nature. Signifi cant time and resources are required to 
change an organization  s culture and practices to move existing elements from a 
fragmented, reactive program to a defi ned structure that is proactively managed. 
The degree to which a program is proactively managed and supported by its leadership 
is directly related to the benefi ts experienced by the organization. 
Three distinct levels of support are required for successful implementation of a 
QMS program: executive leadership, functional management, and operational staff. 
All three levels of the organization must support the effort to attain success. Delivering 
program understanding and benefi ts to each should be a priority to ensure 
acceptance and continuity. Motivating staff and leadership, through benefi ts and 
business results, is important to ongoing program sustainability. 
Leadership requires capable and dedicated staff to design and maintain a dynamic 
QMS program. Leadership must embrace the program and support it throughout 
the organization. Functional management must understand the program in order to 
support it and direct its staff in execution of the program. Staff must understand 
what the program means to them and experience and realize the benefi ts in order 
to support it. 
The quality organization must be seen as a partner in assuring product quality, 
not the department that disseminates quality. Within a QMS, certain processes are 
owned by the quality function, just as manufacturing, engineering, development, 
technical support, and facilities own processes within the system. All functional 
groups should have defi ned roles and responsibilities to ensure quality product is 
produced. Cross - functional support and delineation of responsibilities ensure quality 
is built into every process, and each process owner is ultimately responsible for his 
or her process output. Leadership that understands and embraces this concept will 
support and infuse a culture of quality throughout the organization, maximizing the 
probability of success and competitive advantage. 
The organizations leadership, management, staff, and QMS program group must 
work together to develop and progress the QMS. A successful program should detail 
expected benefi ts for all stakeholders in the organization and provide ongoing 
results demonstrating functionality and utility. 
3.3.3.1 Outlining Benefi ts to the Enterprise 
Establishing a formal, structured QMS for an organization requires leadership 
approval, resources, and capital. Leadership support and approval is the place to 
initiate the program to ensure all program efforts are supported and the proposed 
system meets the business needs. This includes having dedicated resources that can 
focus their efforts to design and manage the program and operate and manage the 
processes. 
Leadership has visibility to present business needs and budget and the vision and 
insight for the organizations  future. Quality management system design needs to 
fulfi ll present and future needs to be robust and value added. A gap analysis on 
MANAGEMENT AND STAFF: LEADERSHIP AND SUPPORT 253

254 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
current business processes can help leadership understand where opportunities exist 
for improving processes. These gaps can be determined by analyzing the purpose of 
the organization and its ability to deliver quality results on time and on budget. 
Manufacturing areas to examine for operational improvement are regulatory 
compliance, audit fi ndings, rework, nonconformances, document revisions, disposition 
timeliness, complaints received, inventory on hand, equipment failures, manufacturing 
cycle times, employee turnover, and training opportunities. Additional 
areas targeted for improvement may come from benchmarking key manufacturing 
parameters against industry peers. Results of a gap analysis begin the dialogue 
regarding process performance and the need for process improvements. Leadership 
must be convinced there is opportunity for fi nancial and competitive gain, and the 
resource investment to operate the QMS will be outweighed by the program bene- 
fi ts received. 
Management at the highest level in the organization must understand, support, 
and lead the strategy to implement systems across the enterprise. More often than 
not, this requires some level of business transformation, a cultural and behavioral 
shift, and a certain level of risk. The risk associated in implementing change is 
minimal compared to that of not having a robust system, as outlined in the benefi ts 
section. 
3.3.3.2 Speaking Management Language 
Without upper management championing the establishment of systems, midlevel 
management will not support the effort, dedicate the time required, nor practice the 
behaviors essential to establish and maintain the processes. Leadership needs to be 
cognizant of the benefi ts and consequences of nonimplementation and be clear and 
unwavering in its support, delivering frequent consistent messaging to management 
and staff. Leadership requires tangible and intangible benefi ts to be convinced that 
the efforts are worthwhile and working and to regularly convey results to staff. 
Tangible benefi ts should include metrics and improvements demonstrating 
process and system cost savings, compliant inspections and customer audits, faster 
product approvals and manufacturing throughput, less rejected material, reduced 
nonconformance issues, and more effi cient continuous improvement and project 
implementation. Intangible benefi ts include improved staff morale, faster, more 
accurate transparent decision making, less employee turnover, increased staff 
accountability, and an enhanced culture of quality throughout the organization. The 
 feeling  conveyed by an organization that is reactive, stressed, and without well - 
structured processes is much different than that of a proactive organization with 
simple processes that are easily and successfully executed by trained staff. 
Systems thinking allows decision making and process management to occur at 
the process owner level, not the functional management level. This is a cultural shift 
for many organizations but brings with it many benefi ts. Faster decision making, by 
subject matter experts is valuable to organizations. It can benefi t both on a day - to - 
day, lot - to - lot basis as well as provide long - term strategic direction to leadership. 
Taking the burden off functional management and defi ning process owner responsibilities 
allows functional management to manage resource and personnel issues 
and not split time and attention between resources, personnel, technical, and process 
issues. 

3.3.3.3 Translating Benefi ts to Staff 
Similar to leadership and management requirements regarding system understanding 
and benefi ts, staff requires understanding prior to accepting the cultural changes 
that a system - based approach will bring to the organization. Once the program is 
initiated, tangible and intangible benefi ts must be realized and appreciated in order 
for staff to continually support the program. Staff support, through benefi t realization 
and management direction, will ensure program execution, ultimately delivering 
the expected business results. 
Transforming disparate processes into processes that are simple to understand, 
easy to execute, and provide a sense of accomplishment meet one of management  s 
obligations to staff. Staff interest lies in the ability to perform their work, contribute 
to continuous improvement, and have a reasonable work  life balance. Finally, they 
want to be able to contribute to their careers, have defi ned career paths, and have 
attainable development goals for advancement. A well - designed quality management 
system can contribute to provide all these employee benefi ts. 
Staff benefi ts should be designed into the QMS. An outline of expected benefi ts 
should be presented to staff to gain their support of the system initiative. Accomplishments 
should be advertised and rewarded. Establishing well - defi ned processes 
empowers employee involvement, participation, and contribution to the organization. 
It reinforces a culture of quality throughout the organization, and provides a 
conduit for their contribution. 
3.3.3.4 Ensuring Staff Support and Management Leadership 
Management  s responsibility includes providing staff robust tools and processes 
necessary to accomplish their jobs effi ciently. Complex, missing, or fragmented 
processes do not allow for easy operational execution, the ability to leave work at 
reasonable times, and may result in poor - quality output or rework. This type of 
environment quickly becomes dissatisfying to employees and results in poor morale, 
low effi ciency, and ultimately lack of interest and loss of staff. 
Staff empowerment allows pride in workmanship. Well - designed quality systems 
make clear to staff where decision authority and process accountability lies, provide 
clear expectations of the process and process owners, and provide personnel a clear 
development path to process ownership. 
Clearly identifi ed process attributes provide organizations more than tribal 
knowledge to pass onto the next process owner. They provide clear structure, process, 
and other attributes critical to the ongoing success of the enterprise. The organization 
becomes reliant on their system and processes not people  s personal knowledge, 
which can be lost with staff turnover. 
Ensuring leadership and staff support requires that a well - defi ned plan be 
designed and shared throughout the organization. A long - range plan, spanning 
several years may benefi t the organization to maintain perspective and govern 
expectations. An annual quality plan should encompass all aspects of the QMS and 
contain detailed periodic goals and objectives. Progress against the quality plan 
needs to be advertised and celebrated. Quality plan leadership should be recognized 
for its efforts and accomplishments. Advertising wins and accomplishments in both 
small group and large settings should be designed into the communication and 
change management program. 
MANAGEMENT AND STAFF: LEADERSHIP AND SUPPORT 255

256 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
Table 3 provides an outline of a long - term vision and goals for a quality management 
system. A long - term strategy provides leadership, management, and staff with 
an understanding of the program and anticipated timelines for implementation and 
benefi t expectations. Annual quality plans become the short - term strategic milestone 
vehicle to achieve the long - term strategic vision. 
3.3.3.5 Traps to Avoid 
Several challenges and requirements present themselves when establishing a formal 
QMS. A primary requirement is a skilled team that understands the needs of the 
organization, regulatory, and customer requirements. It should have the skill, experience, 
and expertise to design a robust system and identify processes that support 
the enterprise. A mismatch of team skills with enterprise needs may result in a 
nonviable system that is not supported by leadership and staff, leading to failure 
and disuse over time. 
Quality management system design must be well thought out and tested. Pilot 
programs are crucial to test system robustness and reliability, staff and management 
acceptance, and the ability to produce the desired results. Time spent in system 
design will pay dividends for years to come and increase staff support and critical 
mass throughout the enterprise supporting the program efforts. Avoid implementing 
any system or process design that has not been well thought out, does not have input 
from the stakeholders using the system, or has not been piloted prior to a full - scale 
implementation. Typically, a single opportunity exists to introduce a new program 
before staff and management either accept it or reject the ideas and concepts. 
Rebuilding interest and trust of a failed system is diffi cult. The probability for successful 
reintroduction is minimized. Taking suffi cient precaution for correct implementation 
the fi rst time is important. 
TABLE 3 Long - Term Strategic Vision 
Year 1 Year 2 Year 3 Year 4 Year 5 
Gain 
management 
support 
Create QMS 
offi ce 
Identify site 
processes and 
resources 
Develop 
communication 
and change 
management 
plan 
Implement 
program 
Train 
management, 
process 
owners, QA, 
and support 
staff 
Focus on 
maturing 
high - risk/ 
impact 
processes 
Reward and 
recognize 
QMS efforts 
Indoctrinate 
remaining 
processes into 
program 
Document and 
communicate 
cost/resource 
savings 
Begin 
integrating 
processes 
across the 
organization 
Focus on key 
projects based 
on QMS 
portfolio and 
management 
review 
Provide ongoing 
training, 
communications, 
and change 
management 
Adapt to changing 
business and 
regulatory 
environment 
Provide leadership to 
industry on QMS 
paradigm

Change management is another very important consideration when implementing 
a QMS because of the culture change required from the organization. Several 
resources can assist in managing change, and these should be incorporated into the 
system design. It is important to be cognizant that successful implementation 
requires change at all three levels of the organization; leadership, functional management, 
and operational staff. Each will need different messages, encouragement, 
rewards, and benefi ts. Consideration to deliver both tangible and intangible benefi ts 
to stakeholders is necessary. 
Leadership support from the highest level is required. Middle management will 
not support an effort that is not supported by its leadership. Leadership must 
provide unwavering support, not provide mixed messages, continue to advertise and 
celebrate success, and support the program through rough times. Consistency in 
language and deeds from management supports understanding and appropriate risk 
taking by management and staff. 
Functional management must also support system efforts and long - term strategies, 
to ensure that staff, who are critical to execution of the processes, know that 
their support and efforts are expected. Functional management send powerful messages 
to staff, and their support of the long - term plan and annual quality plan are 
essential. Specifi c system objectives, included in leadership, management, and staff 
goals reinforce the commitment and help ensure success of the program. 
The system needs to remain fl exible. Having a long - term plan and vision is necessary 
to provide a roadmap to the future. That roadmap may need to change as the 
business environment and enterprise needs change. The long - term plan and vision 
should be written at the level that it changes very little, but fl exibility is maintained 
through the preparation of an annual quality plan that is capable of addressing 
temporal issues and business needs. 
Prior to implementing any QMS initiative, one must understand what leadership, 
management, staff, and customers require. Knowing which processes are required 
to support customer needs and the impact of those processes upon each other is 
essential to system design. Developing process owners that understand their roles 
and deliverables in the organization, eliminating constraints so they may meet their 
goals is essential for success. Process owners must understand product and process 
priorities so signifi cant benefi ts may be realized. These are important considerations 
in designing system and processes that support the organization, produce meaningful 
metrics, and demonstrate progress. Consideration of these important points 
prevents system initiatives from failing and interpreted as another burden to the 
already overburdened work and demands placed upon the organization. 
3.3.4 ESTABLISHING QUALITY MANAGEMENT SYSTEM SCOPE 
In many pharmaceutical and biopharmaceutical manufacturing operations, duplicity 
exists in some processes and gaps are present between others. Often it is unclear 
exactly what boundaries or scope constitute a process, the expected outputs, who 
are the customers, who is the owner, and who is responsible for continuous improvement. 
Duplicity is ineffi cient and costly. Examples include multiple layers of an 
organization performing data reviews as documentation or information moves 
through the value chain. Regulatory submissions for analytical validation are an 
ESTABLISHING QUALITY MANAGEMENT SYSTEM SCOPE 257

258 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
example, where raw data may be checked at the laboratory, supervisor, quality assurance, 
compliance, and regulatory group levels. On the other hand, gaps may exist 
where each functional group listed above assumes data verifi cation is occurring with 
another group, and in fact there are gaps in data integrity. In this case, the result can 
be tremendously expensive if, upon regulatory inspection, errors are found and it 
appears data integrity issues are ubiquitous in a submission. 
This section will discuss the importance of defi ning business requirements to 
ensure processes comprising the QMS are designed to support the enterprise, integrated 
into a quality plan, suffi ciently defi ned to provide adequate resolution and 
are transferable and scalable throughout the enterprise. 
3.3.4.1 Defi ning Business Requirements 
The QMS and the processes that comprise it must be custom designed for the needs 
of the business. One size does not fi t all situations. The requirements of an enterprise 
vary across sites and the phases of a product life cycle. A comprehensive system will 
ensure a holistic programmatic approach in its support to the enterprise. This does 
not mean that every phase of the product life cycle (discovery, development, commercial 
manufacturing) will utilize all the processes that comprise the system. Nor 
does it require that all commercial manufacturing sites will necessarily implement 
all processes. It does, however, provide a common platform and expectation for all 
processes, owners, metrics review programs, continuous improvement efforts, and 
the like when they are implemented. 
The fi rst step in designing a QMS is determining business needs and the processes 
required to support the enterprise. Important consideration must be given to ensure 
that all processes are included in the assessment. The assessment must include all 
activities that affect product quality at corporate, business, manufacturing, distribution, 
contractors, or joint venture sites. Processes controlling incoming materials 
from vendors, laboratory services, contractual support, and other inputs should also 
be included in the initial assessment. 
Upon identifi cation of the processes required to support the enterprise, the next 
step is to defi ne exactly what is in and out of scope for each process. Mapping all 
the processes and their inter relationship with other processes will determine if any 
gaps or duplication exists in the system. Duplication may be warranted or eliminated. 
Gaps between processes require remediation. For example, a nonconformance 
process should have direct linkage into a corrective action process. A 
well - operating nonconformance process without an active, integrated corrective/ 
preventive action process will yield little benefi t to the organization and efforts 
expended on the nonconformance process will be nominal in their overall positive 
business impact. 
This comprehensive approach allows for effi cient integration between processes, 
different phases of product life cycle, and integration between different sites in the 
supply chain. This integration provides opportunity for effi ciency in that process 
owners are integrated with each other  s needs and expectations. Duplication of 
effort is avoided and effi ciencies gained. Quality outputs from one process become 
reliable inputs into the next process. Management and leadership will have access 
and insight into compliance, infrastructure, and performance metrics of all processes 
on a comparable basis. This provides leadership the opportunity for risk - based 
resource allocation to appropriate areas of the enterprise. 

Process mapping of the enterprise  s requirements to supply product enables 
design of the processes required for the system. Staff, management, and leadership 
input into the business needs provide additional guidance into processes 
attributes. 
3.3.4.2 Integrating Quality Management System into Quality Plans 
A quality plan is required by the regulations governing medical devices (QSR) but 
can readily be adopted as a useful tool for pharmaceutical and biopharmaceutical 
manufacturing operations. A quality plan is the documented plan and goals for 
enhancing and advancing the QMS. It can provide the outline and requirements of 
the organization  s purpose, mission, product, and business practices used to produce 
a quality product. A quality plan can detail the processes that comprise the QMS, 
the maturity level required for each process, organizational structure, and other 
requirements needed to meet the organization  s purpose. Included in the quality 
plan are the elements of the business including location, size, products, and expectations. 
It also includes its structure and support functions, values, and other attributes 
of the organization. 
An annual quality plan can be the detailed execution plan of the organization  s 
long - term quality vision for the QMS. It provides staff and management the outline 
and goals for improving the QMS. It enables employees to see the big picture, how 
they fi t into the organization, and the organization  s expectations. Within the quality 
plan attributes of the QMS should be described, including functional management 
responsibility. This then becomes the foundation for further defi nition of processes, 
description of management review and responsibility, and continuous improvement 
programs. The preparation of a quality plan begins defi ning what is assumed to be 
known by all levels of the organization. It is the mechanism for ensuring requirements 
are addressed and gaps in the organization do not exist. 
A quality plan may outline the organization  s long - term (several years) and 
short - term (annual) goals through a risk - based approach to improving product 
quality. It is the foundation for the manufacturing structure and support processes. 
A quality plan ensures integration of personnel, their qualifi cations, product requirements, 
quality management system, and regulatory and compliance infrastructure. 
An example of an outline of a quality plan is in Table 4 . Leadership review and 
approval of the quality plan is required to ensure that mission, scope, expectations, 
and division of labor in the organization is consistent and supported. 
In larger organizations, site or suborganization - based quality plans can be 
designed to support the scaling of the QMS across all components of the enterprise. 
The individual site plans provide focus on process challenges that are more critical 
than at other sites due to variations in business and compliance environments. While 
the specifi c plans emphasize goals based on site priorities, they also connect 
the members of an organization to the mission of the greater QMS, as shown in 
Figure 5 . 
3.3.4.3 Determining Process Resolution Requirements 
Leadership expects cost - effi cient reliable results from their manufacturing operations. 
Management requires a capable workforce, equipment, facilities, and materials 
to manufacture the product. Employees require robust processes that are easy to 
ESTABLISHING QUALITY MANAGEMENT SYSTEM SCOPE 259

260 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
execute to perform their jobs. All this needs to be considered in the design of the 
processes that comprise the quality management system. 
Complex processes may need to be managed as distinct subprocesses in order to 
provide process owners the ability to accomplish their work with specifi c focus and 
expertise. Management and leadership may require data and metrics on specifi c 
areas of the process that are not available if the process is too complex and large. 
Dividing a complex process into simpler, more manageable processes also allows 
for scalability and transferability throughout the organization. 
Once processes have been defi ned for the enterprise, suffi cient system resolution 
should be determined. This is accomplished by evaluating the ability of the process 
owner to manage and execute the process requirements. Another factor in this 
determination is the data and metrics needed from the process by management and 
leadership. An example of a complex process that benefi ts the organization by being 
managed through distinct subprocesses is validation. 
Validation is a regulatory requirement and has become an industry standard for 
ensuring product consistently meets quality attributes and regulatory requirements. 
Validation requirements are woven throughout the manufacturing supply chain 
encompassing many different subprocesses. The validation process may best be 
TABLE 4 Elements of QMS Annual Plan 
Element Defi nition 
Introduction Purpose of plan and defi nitions for clarity 
Plan Planned activities for the calendar year 
Goals Specifi c/cascading goals of the site 
Projects Major projects in support of the goals 
Metrics Key metrics with defi ned targets 
Approvals Site/plant management 
FIGURE 5 Scaling the QMS through site quality plans. 
Site 2 
Quality 
plan 
Site 6 
Quality 
plan 
Site 5 
Quality 
plan 
Site 7 
Quality 
plan 
Site 4 
Quality 
plan 
Site 3 
Quality 
plan 
Site 8 
Quality 
plan 
Site 1 
Quality 
plan 
Corp. 
Quality 
Plan

managed by dividing it into manageable subprocesses. This allows for effi cient management 
and execution of the subprocesses, and the metrics reported for those 
subprocesses are meaningful and specifi c. See Figure 6 , which illustrates one potential 
organization of the validation subprocesses. Subprocesses contained within the 
validation system could be cleaning, computers, automation, analytical, packaging, 
process, transport validation, etc. Manufacturing is another example of a large, 
complex process that may best be subdivided to support better management and 
more meaningful metrics to management. 
By dividing a larger process into manageable and specifi c subprocesses, management 
can assign appropriate subject matter expertise to lead and manage each 
subprocess. The metrics measuring subprocess performance can be uniquely 
reviewed, evaluated, and compared to similar subprocess metrics at other sites or 
companies. Valuable, meaningful comparisons can be obtained for process and subprocess 
performance that would otherwise be blinded or diluted, if they were summarized 
within the higher level process metrics. 
An additional advantage of establishing subprocesses is that it affords the opportunity 
for rapid assimilation and transfer of the subprocess at various sites within 
the enterprise. An example of this is the comparison of a bulk manufacturing facility 
with that of a distribution center. Both will need to implement aspects of the subprocess 
 transport validation,  however, the distribution center will not need to 
implement other subprocesses such as process or packaging validation. As the subprocess 
transport validation is designed and implemented at one site, that infrastructure 
and knowledge transfer to the other site is rapid, avoiding duplication of efforts. 
Sharing of information and expectations of the two sites becomes a common goal 
and format. Management can, therefore, compare transport validation needs and 
maturity levels between sites equally. 
Once all the processes and subprocesses supporting an operation have been 
defi ned, another gap analysis may be conducted to ensure that there are no assumptions, 
and all required processes and subprocesses required to support the business 
are included in the scope of the QMS. This can easily be accomplished by listing all 
the business drivers for an operation and comparing that against the processes 
FIGURE 6 Validation subprocesses. 
Computer 
validation 
Transport 
validation 
Packaging 
validation 
Analytical 
validation 
Automation 
validation 
Process 
validation 
Cleaning 
validation 
ESTABLISHING QUALITY MANAGEMENT SYSTEM SCOPE 261

262 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
established. Written defi nition of the process and subprocess scope is required. 
Stakeholders, owners, and users of the processes should be involved to ensure clear 
defi nition and understanding of process scope. Questions to be asked are: Are all 
the business needs addressed? Have all our activities and operations been included 
in the assessment? Is there any duplication in process expectations? Are there any 
gaps between process outputs and inputs? Once this evaluation has been concluded, 
it can be easily determined if any existing work process have been overlooked and 
the system requires further modifi cation. 
3.3.4.4 Scalability to Enterprise 
Well - designed processes and subprocesses are scalable to the enterprise. A comprehensive 
design will allow for replication and comparison of processes and subprocesses 
between multiple sites. This allows for rapid implementation of new technology, 
sharing of best practices, and comparison of similar metrics to determine compliance, 
infrastructure, and performance. A comprehensive system allows for each unit 
operation or site within the enterprise to have the fl exibility to apply applicable 
processes and subprocesses, yet continue operating within the defi ned structure of 
the QMS. For example, a manufacturing site may utilize almost all of the processes 
discussed in the validation process, whereas a distribution site may only utilize the 
transport process. Both sites, however, implement the same structure for the transport 
process, allowing for meaningful comparison of data and metrics and rapid 
implementation of any required changes to that process. 
Well - designed quality management systems support structured organic growth 
and are valuable in evaluating and integrating manufacturing acquisition opportunities. 
Business and manufacturing management should utilize the QMS and its standards 
whenever evaluating external facilities for appraisal, approval, integration, or 
expansion. Meaningful metrics obtained from a QMS provides the standard to 
make critical decisions affecting multiple internal or external manufacturing 
capabilities. 
Documented process structure provides rapid employee assimilations when 
transferring employees between sites. New employees, replacing existing process 
owners, are enabled to rapidly execute process responsibilities due to the abbreviated 
learning curve when processes have been well defi ned and documented. Systems 
designed as described here provide meaningful and comparable metrics for leadership 
to evaluate progress, compliance, and performance. 
3.3.5 SYSTEM AND PROCESS OWNERSHIP: 
ROLES AND RESPONSIBILITIES 
A well - designed QMS and the processes that comprise it require competent ownership 
with defi ned roles and responsibilities for program success. This combination 
ensures that the system and processes are established, maintained, improved, and 
remain current with industry practices and business expectations. Operational 
execution of the QMS and the processes comprising it will engage stakeholders, 
management, and leadership, provide business results, and support and ensure 
compliance. 

3.3.5.1 Quality Management System Ownership and Management 
The QMS is best owned at the highest level in the organization. At a minimum it 
should be owned at a level in the organization above manufacturing and quality. 
The owners  main responsibility is to champion the program and ensure organizational 
alignment. Regulatory investigators expect processes supporting manufacture 
are fully incorporated into the QMS. They also expect leadership to have signifi cant 
knowledge of the operations and interact with investigators during inspections with 
some degree of familiarity with the processes supporting manufacture. At the conclusion 
of an inspection, regulators issue inspectional fi ndings and, if appropriate, 
take regulatory action against the most senior member of the leadership group. 
Through high - level leadership  s active involvement and ownership, the QMS 
program and enterprise will be successful. 
As mentioned previously, the QMS is best managed by a group dedicated to the 
program. The QMS program offi ce should have defi ned roles and responsibilities. 
In the FDA regulation 21 CFR Part 211.22, the responsibility of the quality unit is 
described. It is the only functional group in a manufacturing organization that has 
its job description codifi ed in federal regulations. These responsibilities should not 
enable or dilute the responsibility for ensuring quality of other functional groups in 
the organization. All functional groups supporting manufacture should be applying 
their trade to the GMP world. Regulators expect the Quality Department to have 
oversight and approval of all processes affecting product quality. Program management 
is important because of the need for coordination and accountability to bring 
individual processes, long - term system strategy, yearly quality plans, and goals 
together to accomplish the program  s objectives. These activities and benefi ts cannot 
be realized from individual process owners. 
The program management of the QMS can be managed just as a process, with 
predefi ned expectations, metric collection, and management review, culminating in 
risk management application to continuous improvement programs. These metrics 
and improvement initiatives need to be vetted through leadership review and input 
to ensure alignment throughout the organization. 
An outline for the roles and responsibilities for the QMS program offi ce is illustrated 
in Table 5 . By establishing the roles and responsibilities of the program offi ce 
a defi ned point of contact and accountability is established for program execution. 
It establishes strong linkage and focus on the program objectives for process owners, 
training, functional management, and leadership. Similar program management 
structures are required at manufacturing sites and corporate functions to maximize 
benefi ts of the program through establishing common and specifi c goals and 
TABLE 5 QMS Program Offi ce Roles and Responsibilities 
Subject matter expert for QMS program 
Develop and execute communication plan 
Initial and ongoing training 
Facilitate management review process 
Identify process maturity goals and metrics 
Develop long - term strategic vision 
Create and execute annual action plan 
SYSTEM AND PROCESS OWNERSHIP: ROLES AND RESPONSIBILITIES 263

264 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
providing a platform for sharing best practices and knowledge. As organizations 
grow in complexity, additional management may be required to ensure that the 
elements of the QMS are integrated, functioning, and delivering the results 
expected. 
3.3.5.2 Process Ownership 
Designing a QMS that mandates and assigns process ownership to designated individuals 
is a signifi cant strategic decision in the establishment of a successful quality 
management system. It provides effi ciency, expertise, dedication to the process, and 
focused ownership for documentation, improvements, benchmarking, and compliance. 
Without defi ned and assigned process ownership functional management 
becomes the de facto process owner. This is problematic in that functional management 
is already overburdened with personnel and business management issues, 
unable to adequately focus and deliver the demanding process owner requirements 
required in today  s manufacturing environment. Several processes typically are 
organized under an individual functional manager, further diluting focus, attention, 
and expertise if functional management is relied upon as a process owner. 
3.3.5.3 Process Owner Selection 
Process owner selection requires program management to establish defi ned criteria 
for the selection process. Criteria include the capability to perform process owner 
roles and responsibilities, including self - development and decision making. Empowered 
process owners are accountable for maintaining and executing the processes 
that management relies upon to deliver business results. This accountability ensures 
that staff, management, and leadership know who to solicit for answers to process - 
related questions and issues. It also provides the best representation to regulators, 
clients, and customers. Effi ciencies are gained and current trends maintained with 
an active owner, with defi ned responsibilities. 
Selection criteria may include attributes of technical, interpersonal, and management 
skills. The capabilities needed for different process will vary and should be 
considered in the selection process. At the end of the selection process, functional 
management and the process owner may consider inclusion of the process owner  s 
roles and responsibilities into the process owner  s job description. Personal goals 
and development activities should be based on improving the process owner  s capabilities 
to manage the process and develop future process owners through active 
mentoring and talent development programs. 
Process owners need to be dedicated to their process. They must be empowered 
and held accountable for all the attributes listed in their roles and responsibilities. 
Process owners may have ownership of more than one process and may have other 
job responsibilities, but it must be clear throughout the organization as to who has 
full authority for the process. 
Process owners require a defi ned set of responsibilities to maintain a vibrant and 
effective process that continues to support product quality deliverables. Having 
roles and responsibilities defi ned provides owners with the structure and parameters 

needed to be effective. Examples of owner responsibilities include identifi cation of 
stakeholders, defi ned decision authority, document ownership, nonconformance 
ownership, knowledge of regulations and industry trends, subject matter expertise, 
training content, metric ownership, and representation to internal auditors and 
external regulators. Identifying, training, and development of the process owner on 
his or her roles and responsibilities is similar to assembling the piece of a puzzle. If 
one piece is missing, the effectiveness of the process owner will be minimized (see 
Figure 7 ). Developing a sound methodology for process owner selection ensures 
objectivity and is critical to the success of the program. A brief discussion on each 
process owner roles and responsibilities follows. 
3.3.5.4 Stakeholder/Process Owner Integration 
Process owners must identify the stakeholders of their process and ensure design 
and output of the process meets stakeholder needs. Regular communication, interaction, 
and support are maintained with stakeholders through scheduled meetings 
to discuss process status and improvements. Any changes to the process are vetted 
through the stakeholder group. Typical stakeholders include the QA unit that is 
responsible for review and approval of the process components, suppliers to and 
receivers of the process (i.e., owners of other processes that interact with the 
process), customers, management, and leadership. Each stakeholder roles and 
responsibilities also require defi nition. 
Including the key stakeholders in decisions affecting process design or changes 
ensures efforts by the process owner are applied correctly. Process robustness is 
dependent upon meeting business and customer needs, and the process owners 
require input and support from the stakeholder group. 
FIGURE 7 Process owner roles and responsibilities. 
Accountable 
ownership 
Risk 
management 
Nonconformance 
& corrective 
action 
ownership 
Inter/Intra 
process 
expertise 
Metrics 
& process 
improvements 
Inspection 
& audit 
point of contact 
Stakeholder 
management 
Document 
& training 
content 
Decision 
authority 
SYSTEM AND PROCESS OWNERSHIP: ROLES AND RESPONSIBILITIES 265

266 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
3.3.5.5 Decision Authority 
Each process owner requires a defi ned level of decision authority. This authority 
level delineates the bounds of decision making granted by the organization to the 
process owner. Business needs and risk assessment must be incorporated into the 
design of the decision authority granted to a process owner. Table 6 is an example 
of a decision authority matrix design for a process owner. It requires cross - functional 
management support to be effective. 
Preparing a decision matrix that is shared and agreed upon by the stakeholder 
group and functional management ensures decisions are made and communicated 
quickly by appropriate persons. It removes the burden of making every technical 
process decision from functional management. It is important to outline the process 
owner  s role in the decision - making process, as well as conditions for escalation. 
Effective process management is realized when the culture of an organization can 
support the outline of the decision matrix and not continually rely upon functional 
TABLE 6 Decision Authority Matrix 
Decision 
Category Defi nition 
Decision 
Maker 
Decision 
Support 
Required 
Informed of 
Decision 
Company 
standards 
Process - related 
global 
standards 
relevant to all 
manufacturing 
sites 
Corporate 
process 
owner 
Site process 
owners 
Site quality 
assurance 
counterpart 
Process 
stakeholders 
Impacted staff 
Standard 
operating 
procedures 
SOPs related to 
the specifi c 
process 
Site process 
owner 
Process 
stakeholders 
Site quality 
assurance 
counterpart 
Management 
review 
Corporate 
quality 
assurance 
counterpart 
Impacted staff 
Training Training on 
processes or 
procedures 
Corporate and 
site process 
owners 
Training 
Technical 
system 
matter expert 
Process 
stakeholders 
Corporate 
quality 
assurance 
counterpart 
Impacted staff 
Site projects All projects 
related to the 
existing 
process or the 
projected 
improved 
state of the 
process at a 
specifi c site 
Site head Process owner 
Leadership 
team 
Site project 
portfolio 
manager 
Process 
stakeholders 
Corporate 
quality 
assurance 
counterpart 
QMS offi ce 

management. If functional management continues to be relied upon and seen as the 
process decision makers, efforts and progress by the process owner will be nominal. 
The organization  s culture must support the process owner at all levels of the enterprise 
for the owners to be successful. 
3.3.5.6 Industry Knowledge 
The c in c GMP represents the notion of current industry practices. Process owners 
must work to remain current with industry and regulatory trends affecting their 
process and its overall effect on the QMS and the business. Awareness of process 
capability and comparability with other like processes within and outside the pharmaceutical 
and biopharmaceutical industry is essential. Regulators will compare an 
owner  s process against other similar processes in which they have experience when 
formulating value judgments. Benchmarking against similar processes provides 
process owners the data needed to determine adequacy of their process with industry 
peer groups. 
Where technology, effi ciency, performance, or compliance can be enhanced, it 
should be considered by an aware and informed process owner. Functional management 
cannot keep pace with the changes occurring with all the processes supporting 
manufacturing. Ensuring process owners dedicate suffi cient time to keeping current 
with process - related external events will ensure process success. This may include 
review of industry periodicals, attendance at seminars and regulatory presentations, 
and routine self - evaluation and benchmarking against relative processes. 
Often, the best examples of process effi ciency can be found outside the pharmaceutical 
and biopharmaceutical industries. Other fi elds such as electronics, space, 
and software industries have evolved their documentation, training, quality, and 
change control systems to the point of best in class. These industries are more time 
sensitive to get product to market and have often evolved their processes to be 
effi cient and decision processes to be very quick. Process owners may expand their 
knowledge by investigating other industries to fi nd best practices and apply them 
internally. 
3.3.5.7 Regulatory Inspection and Audit Lead 
Process owners play a critical role during regulatory inspections and customer 
audits. Process owners are the best choice to represent process attributes and performance 
to interested parties. Process owners provide regulators and auditors with 
a capable, knowledgeable resource to represent the process and answer detailed 
questions. The process owner should be aware of process history, requirements, 
operations, exceptions, changes, and nonconformances. The process owner will have 
detailed knowledge of process operations, compliance, and be able to defend the 
process. Providing an accurate answer the fi rst time to regulators and auditors is 
essential in building trust and representing competence. 
Each process owner is required to work closely with his or her QA counterpart. 
This ensures design and operational issues are clearly reviewed and approved by a 
representative from the quality assurance function, a regulatory expectation. The 
quality assurance counterpart must be familiar with the process, understand documentation 
supporting the process, and able to convey what approval the Quality 
SYSTEM AND PROCESS OWNERSHIP: ROLES AND RESPONSIBILITIES 267

268 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
Department has conveyed on the process and meaning of that approval. The QA 
counterpart to a process should also have defi ned and documented roles and 
responsibilities. 
When teamed together, the process owner and the quality assurance counterpart 
for a process will make a favorable impression upon regulators, be able to 
explain all operations involving the process, supporting documentation, and any 
ongoing projects or process improvements. This pair is the best to evaluate and 
consider any deviations to the process or recommendations for continuous 
improvement. 
In most all cases, the process owner and QA contact will posses more information 
about the process than regulators and be capable to defend the process design and 
operation. Should regulators have suggestions on process design or functionality, 
the process owner may consider them. If appropriate, any recommendations or 
observations made by regulators or auditors can be incorporated into the process 
design. However, it is critical for the process owner and stakeholders to evaluate 
proposed changes to avoid reactive management commitments, which could be 
deleterious to the effi cient operation and output of the process. 
3.3.5.8 Subject Matter Experts 
Process owners, through their selection and development, become the subject matter 
experts for the process. It is more effi cient for an enterprise to focus its expertise 
on individuals that have the authority and accountability described in this section, 
rather than dilute those attributes and accountabilities, thereby risking poor process 
execution and management. 
As a subject matter expert on the process, the owner has the capacity to deliver 
results outlined in the list of owner responsibilities, mentor future process owners, 
assist in staff development, and accurately guide management in its strategy related 
to the process. The process owner  s personal development of his or her process 
expertise is essential in delivering operational results and providing direction for 
future strategic changes to the process. 
3.3.5.9 Metric Ownership 
Process owners  responsibilities include determining appropriate metrics for their 
process. These metrics should include lagging and leading metrics that are meaningful 
to the process owner and management in determining performance, compliance, 
and infrastructure of the process. 
The process owner should represent and interpret these metrics to the organizations 
leadership. The metric output from a process is the basis for management 
and leadership  s action in resource deployment and approval of continuous improvement 
projects. Key operating parameters such as number of nonconformances and 
regulatory observations against the process should be tracked and factored into the 
maturity of the process. 
Every process owner needs to base their continuous improvement plan for the 
process based upon metrics collected from the process output. The metrics must be 
designed to assist in these decisions and be readily available for review, presentation, 
and interpretation. 

3.3.5.10 Documentation Ownership 
Process owners are the most appropriate owners for all documentation supporting 
their processes. This includes having either direct ownership or controlling infl uence 
over guidance and execution documentation such as corporate policies and standards, 
local requirements and standard operating procedures (SOPs), logs, and 
records. 
For the manufacturing process owner, this means owning the master manufacturing 
records and executed batch records, SOPs, use logs, and related training documents 
for their process. Combining responsibilities for process management and 
process ownership results in true accountability for the process owner. It also allows 
for progress and continuous improvement of the QMS. Removing questions 
of responsibility and accountability ensures integration between requirements 
(standards, policies, procedures) and execution (training, performance, and 
documentation). 
3.3.5.11 Training 
Assurance of adequate training for process users is an important responsibility of 
a process owner. Process owners must have a clear understanding of the requirements 
of their process and its operation. This understanding requires translation 
into executable training. Users must be able to understand and apply the training. 
Complicated processes coupled with ambiguous training will lead to confusion and 
an inability to properly execute a process, which eventually constitutes failure for 
the organization. A simple process, with easy to understand process steps, that are 
consistent with instructions and documentation requirements will support success, 
reduce production costs, minimize nonconforming events, and allow for employee 
satisfaction. 
Process owners are subject matter experts and should infl uence and provide 
consulting for training on the process. They may also participate in training delivery. 
Ensuring adequate training on a process is a key goal for system effi ciency and 
regulatory compliance. Process owners, capable of explaining the reasoning behind 
the process requirements, enhance the training experience for process users. Process 
owners should include effective presentation and training skill development into 
their personal development programs. 
3.3.5.12 Risk Management 
Process owners require basic understanding of risk management and its application 
to process design and continuous improvement prioritization. Several industry and 
regulatory resources exist, such as ICH Q9, that provide understanding on risk 
assessment, identifi cation, control, methodology, and the overall risk management 
process. Process owners should be familiar with risk management techniques and 
tools and apply them to their process management when designing, executing, or 
managing improvement efforts for their process. 
Risk management is especially important for the presentation of process improvement 
proposals to management where resources are required. The ability to quantify 
risk and demonstrate continuous improvement benefi ts is essential to project 
SYSTEM AND PROCESS OWNERSHIP: ROLES AND RESPONSIBILITIES 269

270 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
and resource approval. Risk analysis, management, and presentation constitute 
guiding leadership to work on the right things at the right time and then improve 
it. 
3.3.5.13 Continuous Improvement and Project Management 
Instituting quality - by - design efforts early in the design of a process should negate 
the need for major process improvements. However, over time, due to business 
needs, regulatory changes, or technology improvements, processes will require some 
form of change to ensure compliance or performance enhancement. As part of 
executing and maintaining their processes, owners need to collect and report performance 
metrics to management and staff. These metrics will inevitably direct 
attention to opportunities for improvement that require capital and human resources. 
Process owners are the best leaders of continuous improvement projects due to their 
intimate knowledge of the process and accountability for process output. 
Managing or leading a continuous improvement project requires process owners 
be knowledgeable in project management and team - leading skills. Improvement 
projects typically require cross - functional support and expertise from areas such as 
information systems, project management, manufacturing, engineering, and development. 
It is essential that continuous improvement efforts name the process owner 
as the project lead to ensure the required output of the project meets the process 
owner, stakeholders, and enterprise needs. Often, projects are completed and 
declared a success, delivering a substandard result that the process owner, users, and 
stakeholders fi nd inadequate to meet process requirements. 
Upon completion of continuous improvement projects, process owners  responsibilities 
include monitoring the changes made to the process to determine the 
impact of improvements. Metrics monitoring changes to the process, pre - and postimplementation, 
should be incorporated into existing performance metrics and 
reported during regular management reviews. 
3.3.5.14 Non Conformance/ CAPA /Planned Deviation Ownership 
An important barometer of process performance is the number of nonconformances, 
corrective and preventive actions taken, and planned deviations initiated 
against a process. These types of process artifacts must be known and owned by the 
process owner and stakeholders. The process owner must consider these process 
metrics for evaluation of and changes to process design, training, documentation, 
and performance. 
Nonconformances may fall into the category of manpower, machinery methods, 
materials, etc. Employees not following procedures or unable to execute required 
steps of the process indicate a poorly designed process requiring modifi cation and/or 
improved training. Machinery failures often indicate poor qualifi cation, validation, 
calibration, or maintenance programs. Unexpected results or outcomes are 
indicative of poor process design, characterization, or a break down between 
processes. 
Although planned deviations are frowned upon by many in the industry and 
regulators, there are times when temporary changes to a process must be employed 
to support the business. Permanent changes must be made through a formal change 

control process. When the use of a planned deviation is required, the affected 
process owner should be aware of and own the change. This provides owner control 
over the duration and extent of the change to the process and provides data for 
possible consideration in making a permanent change to the process. A planned 
deviation should be rare and monitored closely as it affects previously established 
standards, expectations, and training. 
Process owners must be capable to evaluate and interpret the effect of nonconformances 
and planned deviations on their systems. Process owners can evaluate 
the need and lead efforts for corrective or preventive action, ensuring adequate 
corrections and improvements are implemented. An effective QMS ensures deviations 
from approved processes are owned and adequately investigated by the process 
owner  s and ultimately approved by their quality assurance counterpart. The knowledge 
of these events is the basis and foundation for the process owners to make a 
risk - based evaluation on whether or not process changes are required, documentation 
or training require modifi cation, or continuous improvement efforts are 
warranted. 
A well - designed QMS will include identifi ed process owners with defi ned roles 
and responsibilities. Process owners require support from management, their customers, 
stakeholders, and quality assurance. Accountability and decision - making 
parameters will empower process owners to drive execution and improvements to 
their process, delivering the business results expected. Without these process owner 
attributes and support, minimal results will be achieved, and functional management 
will be burdened with and assume the responsibility for making decisions that 
should be in the hands of capable process owners. 
3.3.6 CHANGE MANAGEMENT/COMMUNICATION 
Establishing and maintaining an effective QMS, as this chapter describes, 
requires a signifi cant cultural shift. Many employees and functional management 
will fi nd the business transformation of defi ning processes, assigning ownership, 
delegating authority, and responsibility for process performance within the QMS 
is a signifi cant change in business conduct. The most signifi cant change results 
from the shift of control in process expertise and decision - making authority 
from functional management to process owner. Signifi cant business transformation 
may result by assigning responsibility and accountability to the process owner, 
and management  s support of process owners who drive continuous process 
improvement. 
In The Second American Revolution , Rockefeller describes the conservatism of 
organizations:  An organization is a system, with a logic of its own, and all the weight 
of tradition and inertia. The deck is stacked in favor of the tried and proven way 
of doing things and against the taking of risks and striking out in new directions  
[9 ]. If an organization is not already practicing principles of delegation, process 
ownership, established metric collection, management review, and continuous 
improvement, barriers within the organization will need to be addressed and broken 
down in order to establish new behaviors. These barriers to change will exist within 
and between functions, functional management and staff, and possibly between 
companies and regulators. 
CHANGE MANAGEMENT/COMMUNICATION 271

272 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
Although expected benefi ts are signifi cant when implementing a QMS and the 
end result desirable for employees and management, describing the desired 
state and motivating personnel to change and implement new behaviors contains 
signifi cant challenges. A successful business transformation requires a robust 
change management and communication plan that includes support for all staff 
affected. 
3.3.6.1 Managing Organizational Change 
Integration of the skill sets of human resources, training, and change management 
groups will signifi cantly augment efforts toward cultural change and acceptance. 
Often personality profi ling tools are effective to gauge the organization  s preferences, 
learning styles, and adoption tendencies. These types of tools should be considered 
in the overall change management program, used where applicable, and 
program modifi cations made based upon their results. 
The fi rst and critical step in developing a successful change management plan is 
to obtain initial support from the corporation  s leadership and functional management. 
Without this support the QMS will not gain critical mass and may not deliver 
the desired effects or changes. To acquire this support, the implementation team 
must put together a strong business case that speaks to the leadership  s needs and 
wants. The business case must include a risk assessment against compliance and the 
benefi ts of the fi nancial gains. It is important to be honest, consider current system 
status and future requirements, and include a long - term strategy that addresses costs 
and benefi ts. The change management plan must include frequent and repetitive 
communications, to all levels of the organization, of the cost/benefi ts and successes 
expected and realized by the program. 
Functional management support is also critical to the success of a new program 
such as a quality management system. Any time a staff member is asked to take on 
a new role or responsibility, he or she needs to be supported by the functional 
manager as well as leadership within the organization. Corporations are resource 
limited and necessarily need to continually prioritize where to allocate resources. 
Staff will only take on roles or responsibilities that they believe are supported by 
their functional manager in an effort to successfully meet their perceived immediate 
goals. Quantifi able support from leadership and functional management can be 
directly correlated to the success or failure of the QMS program. 
Signifi cant work is involved in training new process owners, functional managers, 
leadership, support organizations, and actualizing their new behaviors. A support 
system must be in place for the process owners, stakeholders, and management to 
guide and reinforce the new behaviors and maintain the process effectiveness. It is 
preferable that this support system be established through a dedicated team 
that can be fully attentive to all their needs. Without a single source to lead the 
efforts, diversity in interpretation and implementation will dilute the program, 
within different functions and sites, and its effectiveness and outcomes will be 
diminished. 
Establishing an organization to lead the systems initiative is important. That 
organization requires management, standards, and parameters similar to managing 
an individual quality process. It requires roles and responsibilities be established, 

metrics be determined, collected, reviewed and acted upon, and receive management 
and leadership visibility and support. The QMS program is best organized as 
a function within the Quality Department and be regarded as an ongoing program, 
not a short - term project or effort with limited shelf life. The group must be led by 
competent persons who are familiar with quality concepts and applications, regulatory 
expectations and requirements, needs of the enterprise, good communication 
and infl uencing skills, and are fl exible and enduring. 
3.3.6.2 Communication 
Trying to get people to comprehend a vision of an alternative future is also a communications 
challenge of a completely different magnitude from organizing them 
to fulfi ll a short - term plan. It is much like the difference between a football quarterback 
attempting to describe to his team the next two or three plays versus his 
trying to explain to them a totally new approach to the game to be used in the 
second half of the season. Aligning the organization to accept and implement a 
system - based approach requires careful messaging coupled with management 
support and results. 
Messages are not necessarily accepted just because they are understood. Another 
big challenge for leadership is credibility and getting people to believe the message. 
Aligning words and deeds supports the worthiness and credibility of the messaging. 
People have learned from experience that even if they correctly perceive important 
external changes and then initiate appropriate actions, they are vulnerable to 
someone higher up who does not like what they have done. Reprimands can take 
many forms:  That  s against policy,  or  We can  t afford it,  or  Shut up and do as 
you  re told  [10] . 
Having established a dedicated team that provides overall program management, 
it is imperative that the team outline a strategic plan for presentation to leadership. 
Without a vision and long - term plan, which is supported by the enterprise leadership, 
quality system initiatives will become diffi cult. The plan needs to be comprehensive 
in nature, yet broad enough to convey purpose, mission, and benefi ts at a 
high enough level to be understood and supported. An outline such as this provides 
framework and direction for the program management team and leadership. It 
also guides the program management team to developing annual goals and quality 
plans that fi t into the overall strategy and provide momentum and results to the 
organization. 
Annual quality plans should be prepared by the QMS program offi ce that 
address the long - term strategy and intermediate goals that come to surface during 
program implementation. Training, changes in regulatory requirements, metric - 
driven projects, and special circumstances warranting process changes such as implementation 
of new technology or programs should be included into the annual 
quality plan. 
Long - term strategy documents and annual quality plans require leadership and 
functional management support and approval. These documents must be reviewed 
and discussed with the leadership of the organization, modifi ed to meet the business 
and regulatory requirements, and then have full support through upper management 
approval. In this way, the goals are being led by top leadership and management 
and not any individual group in the organization. Once top leadership signs 
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274 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
onto the program, it can be shared throughout the organization in a number of 
ways. 
If leadership can support the long - term strategy and annual quality plans to 
accomplish the vision, then the foundation for change management and cultural 
shift is in place. Leadership will need to continually discuss the need for systems 
implementation, in front of a variety of audiences. This includes leadership staff 
meetings, management, and employee meetings. The importance of leadership 
support cannot be overlooked. Without consistent visible leadership and management 
support process owners and staff will revert to old behaviors, become reactive, 
and perhaps unrelated in their process integration efforts. Leadership needs to 
require aspects of the program be included into functional management annual 
objectives with defi ned deliverables outlined and evaluated. Likewise, functional 
management should require staff to include appropriate aspects and objectives of 
the QMS program into their individual goals and work to accomplish them. 
3.3.6.3 Feedback and Alignment 
Managing the changes required to fully implement a QMS can include several forms 
of communication and feedback. A detailed annual communications plan can aid 
the QMS  s group in identifying specifi c target groups, methods, and frequencies of 
communications, messaging types, and feedback mechanisms to monitor progress 
for program modifi cations. Table 7 is an example of an annual communications plan 
that supports efforts to keep internal audiences informed, aligned, and engaged. 
Each target audience requires specifi c messaging that connects with its needs. 
Failure to get the appropriate message, that is, what is the program bringing to them, 
will minimize support for the program. This plan should include face - to face and 
written communications addressing multiple audiences and media types. Face - to - 
face meetings can include presentations to steering committees, process owners, 
functional departments, and all staff meetings. Written communications can include 
sitewide communications, poster sessions, and newsletters. The communications 
should speak to all audiences   what  s in it for me?  Topics can include leadership  s 
commitment (direct quotes or actions taken); spotlight on successes (real - life stories 
from process owners); impact to the site (process improvements or risk mitigation); 
and progress to the program (metrics and successes). The progress and success of 
the QMS cannot be overcommunicated. 
Another useful tool to help the message and modify the program is the use 
of a feedback survey. If properly designed and distributed to a defi ned set of stake- 
TABLE 7 Communication Plan 
Vehicle Communication Type Frequency Date 
Functional metrics meeting Face to face Monthly First week of month 
Management interviews Face to face Annually January 1  31 
QMS newsletter Written Quarterly First week of 
quarter 
All staff meeting Presentation Semiannually March & September 
Poster session Written/face to face Annually July 

holders and employees, the survey can provide valuable insight into how staff and 
management view the program, its progress, and suggestions for modifi cations. 
If surveys are distributed electronically and offer only one - way communication, 
the benefi ts may be limited as the respondents are limited in their ability to fully 
convey their impressions or offer effective feedback. An electronic feedback survey 
may be a fi rst good step in understanding the thoughts and concerns of the 
stakeholders. 
Another suggestion or follow - up to the electronic survey is to utilize focus groups 
that have the ability to interact with the program questioners. This two - way conversation, 
verbal dialogue, allows further understanding of the program by the participants 
that follows with more meaningful feedback to the program administrators. 
Focus groups should be selected at different levels within the organization, including 
process owners, stakeholders and users of the system, leadership, functional management, 
and the general populace of employees. Focus groups provide valuable 
input into programs that the program administrators may be unaware of and can 
provide program redirection. 
Once suggestions are received on the program, it is essential to consider and 
incorporate those ideas and modifi cations that make sense to implement. Those 
changes need to be communicated and seen by the focus group members to ensure 
that their time and effort has not been wasted and their suggestions have been 
heard. This is one of the best ways to spread the word about the QMS program and 
garner grassroots support. 
3.3.6.4 Training 
A training plan should be developed to identify the needs of the staff and affected 
functional areas required to support the successful implementation of a QMS. It is 
the responsibility of the corporation to adequately support staff with training and 
tools when staff is expected to take on new roles, responsibilities, or behaviors. The 
training plan should consist of targeted training for general staff, process owners, 
and functional management of the process owners. 
At a minimum, all staff should be introduced to the purpose, goals, and requirements 
of the QMS. This training should be a high level explanation of the program 
looking to gain understanding and support for the program by communicating why 
it is important and what are the risks of not adopting the program. This can be 
accomplished by instructor - led training or an electronic, Web - based learning module 
depending on the size of the corporation. 
Process owners require more comprehensive levels of training to fully understand 
their role and responsibilities within the program. Process owner training 
should teach key concepts and tools that owners will need to evaluate and support 
their processes. This training can be done in a phased approach to support the elevation 
and advancement of a process within the organization  s chosen maturity 
model. 
Training should be provided to offer functional managers supervising process 
owners a thorough understanding of the QMS. Training should address new roles 
and responsibilities of staff, time demands on process owners, overall program 
timelines, and impact to functional areas. The acceptance and support of functional 
management is critical to successful implementation of a QMS. 
CHANGE MANAGEMENT/COMMUNICATION 275

276 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
Managing organizational change demands a well - written strategy, skill set, and 
resources to ensure changes that come with system implementation are understood, 
supported, and maintained. Starting with high - level overviews of system design, 
benefi ts and timelines for implementation are the foundation for management 
understanding and support. Detailed annual quality plans can be the tactical vehicle 
for program implementation. Leadership support through understanding and 
approval of the annual quality plan, inclusion of program objectives into management 
goals, and frequent verbal and visual support of the program are essential to 
success. Building the program infrastructure is a signifi cant undertaking. Inclusion 
of a comprehensive training, communication, and change management plan should 
be built into the overall goals of the program and routinely evaluated and 
delivered. 
3.3.7 MEASURING SUCCESS THROUGH MEANINGFUL METRICS 
Successful implementation of a comprehensive QMS can be determined by the 
establishment of a meaningful metrics program. The purpose of a metrics program 
is twofold: fi rst, to allow an organization to evaluate its progress toward meeting its 
goals in an objective, data - driven manner and, second, to monitor the performance 
of each process to ensure continuous improvement. By evaluating metrics for the 
QMS and its processes, the enterprise has the knowledge and understanding of the 
overall health of its system and processes and can develop strategies based on risk 
for continuous improvement of the system and processes. 
Once the metrics program is in place, the system and process metrics require 
visibility to process owners, upper management, and stakeholders. Process owners 
require understanding of the metrics  trends, issues, and associated risks. Stakeholders 
must work with the process owner to identify and propose process improvement 
opportunities. Leadership is accountable to understand the issues and associated 
risks and responsibly apply resources for remediation efforts. 
3.3.7.1 Performance Metric Development 
Quality and business indicating metrics should also be reviewed on a routine basis. 
These may include the following: 
 Quality indicating: ability to meet quality standards and procedures 
 Supply: ability to meet demand 
 Cost: savings as well as avoidance 
 Safety: near misses and incidents against process 
The guiding principle of metric development is to have a stable system or process 
to collect, review, and draw conclusions. All metrics should be developed with stakeholders 
input taking into account the requirements and needs of the customers. This 
includes the touch points of the downstream quality processes. Without this input 
and understanding metrics may be developed within a silo and hold little value, 
causing both frustration at the leadership as well as the staff level. Without proper 

design, metrics may become a check box activity that results in minimal or no action 
by management to support efforts by a process owner. 
Metrics can either fall into one of two categories: lagging or leading indicators. 
Both types are important to the process owner and management. Lagging indicators 
are metrics that represent the process  s ability to deliver results or outputs. They 
indicate the performance of the system in the past. They can assist process owners, 
management, and leadership in determining if goals have been met, objectives 
attained, or existing standards or expectations have been met. Leading metrics focus 
on the inputs and suppliers of a process. These metrics are important indicators to 
proactively allow owners and management to take action on a process prior to violating 
a standard, objective, or goal. A successful process owner will understand the 
relationship of leading metrics and their affect on the lagging metrics and process. 
Metrics need to be designed to meet the needs of the organization, be simple to 
track and present, and be regularly reviewed. 
3.3.7.2 Metric Review 
Ignorance of system and process performance leads to ineffi ciency, poor compliance, 
and low employee morale. It is good business practice to have regular review of 
process metrics to gauge the health and output of the system and processes that 
drive the organization. 
Process owners should be aware of all the metrics affecting their process and 
have a conduit to present the critical metrics to upper management. There are 
examples in the industry where process owners responsible for execution of a 
process are not aware of the metrics being collected, if any are, and have no basis 
for judging the adequacy of their process or its performance. 
Regulatory agencies hold management accountable for the operations of an 
organization. It is the fi duciary responsibility for process owners to share the output 
and performance of the operation with management and be able to explain and 
interpret those metrics. Management has the responsibility to know the operations, 
its performance, and take appropriate action to ensure compliance with government, 
industry, and company policies and regulations. 
Regulations require an annual product review be conducted of pharmaceutical 
products to determine and assess changes made to processes that may affect product 
quality. However, good industry practices would mandate quarterly or monthly 
review for faster detection, decision, and action. Reviews need to include metrics on 
key operating parameters and critical quality attributes to ensure product safety and 
effi cacy. Several other key business metrics also benefi t the organization and should 
be included in the metrics review program. The metrics collected should easily 
provide the process owner and management with an indication if the process is in 
control and delivering the desired results. If not, the process owner needs to present 
management a proposal to pursue continuous improvement opportunities and be 
able to describe required changes necessary to realize process enhancement. 
3.3.7.3 Maturity Model 
A maturity model is a useful management tool to determine process status and 
provides a standard in which to value processes. It provides a standard in determin- 
MEASURING SUCCESS THROUGH MEANINGFUL METRICS 277

278 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
ing the overall robustness and progression of a process and assists in the determination 
of resource prioritization. It provides the basic framework to apply risk 
management in determination of process development. For example, development 
of high - risk systems, such as aseptic fi lling where high patient and business risk exist, 
should be developed to a higher maturity than other processes with less patient or 
regulatory risk. Business demands placed on the pharmaceutical and biopharmaceutical 
industry limit resources in development, quality, and manufacturing requiring 
wise deployment of these resources to the areas that can best benefi t the 
organization. 
An example of a maturity model can be seen in Figure 8 . This example provides 
the QMS program group and leadership the ability to evaluate processes based on 
an objective standard. It is divided into fi ve general levels, moving from informal, 
unstructured to best in class. It includes specifi c deliverables for each level of the 
model to be completed before a process can be considered to have achieved that 
level. This model can also be divided into distinct subcategories, for instance, infrastructure, 
performance, and compliance, which are depicted in Table 8 . Each subcategory 
can be designed to provide meaningful information to the process owners 
FIGURE 8 Maturity model overview. ( Source : Adapted from Capability Maturity Model 
Integration, www.sei.cmu.edu . ) 
TABLE 8 Example Maturity Model 
Theme 
Level 1 (No 
Formal 
Approach) 
Level 2 
(Process 
Defi ned) 
Level 3 
(Proactively 
Managed) 
Level 4 
(Continuous 
Improvement) 
Level 5 (Best 
in Class) 
Compliance 
Infrastructure 
Performance 
Source : Adapted from Capability Maturity Model Integration, www.sei.cmu.org . 

and management. The maturity model is an excellent metric to measure development 
of the QMS and focus leadership in deployment of resources. 
The subcategories of the model demonstrate, through defi ned attributes that 
must be in place, specifi c areas required of a robust process. The infrastructure category 
includes a capable owner of the process is in place and a quality assurance 
counterpart is identifi ed, the process owner has a strong understanding of the 
process fl ow, scope, process boundaries, suppliers, customers, and roles and responsibilities. 
The goal is to develop a highly integrated process that is fully transferable 
and scalable. 
Compliance is a key process attribute for a process in the pharmaceutical and 
biopharmaceutical industry. Process maturity determination related to compliance 
can include documentation such as standards and SOPs, number of observations 
written against the process from internal audits, supplier audits, regulatory inspections, 
nonconformances, and a risk assessment on the process against patient safety 
and effi cacy. Training programs are also required as part of the process compliance. 
Audit and inspection observations written against a process are key metrics indicating 
maturity. Processes that can meet high maturity level for compliance represents 
a well - managed process that is consistently delivering a compliant and quality 
output. 
Performance metrics determine process performance, preferably against 
predetermined standards or expectations. Performance metrics should be indicators 
as to the health and robustness of the system. Performance metrics may include 
cycle turn around time, time to disposition from end of manufacture, and a risk 
assessment against business drivers. The purpose is to raise target performance 
objectives, developing a strategic approach, reducing variability, and improving 
effi ciencies. Effi ciencies gained in process performance contribute to the business 
needs. 
Advantages to utilizing a maturity model are that it provides a useful methodology 
for the QMS program group and leadership to evaluate, grade and provide 
process owners a goal for process development. Again, using a risk - based mindset, 
the entire inventory of process can be evaluated by leadership to determine where 
to place resources and to what maturity level each process is best positioned to 
support the enterprise. 
Maturity - level goals are best made by process owners, the QMS program group, 
and leadership. It is recommended that all processes are assessed against risk to the 
customer and the business. This allows the QMS to prioritize the processes and 
identify which of the processes need to be elevated to a higher maturity level in the 
maturity model. Upon completion of the risk assessment, results should be reviewed 
by leadership to determine if the processes have been prioritized appropriately and 
meet the corporation  s goals. This feedback forum will ensure that leadership supports 
process owners as they endeavor to achieve a higher level of process maturity. 
A well - designed QMS will allow for two - way conversation between the leadership 
and the process owners. It is as important for the leadership to communicate priorities 
to the process owners as well as having the process owners communicate issues 
and concerns that need to be addressed to the leadership. This will improve the 
alignment of priorities between the leadership and process owners. This integration 
ensures that the corporation is working on the right things at the right time with 
the right people. 
MEASURING SUCCESS THROUGH MEANINGFUL METRICS 279

280 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
3.3.7.4 Meeting Process Maturity Requirements 
A dedicated team or review board should be developed to review and approve all 
maturity - level deliverables upon completion of the attributes for the current level. 
This review board  s purpose is to ensure that all deliverables meet a consistent level 
of quality and documentation. This board can provide feedback to process owners 
or QMS program group to communicate best practices and lessons learned. 
A well - designed metric review program is essential to the success of the QMS. 
The program should include metrics for the QMS, process maturity - level assessment 
and process performance, infrastructure, and compliance metrics. These metrics are 
the basis for evaluating system progress against long - term vision and annual quality 
plans. The metrics provide leadership and process owners specifi c and objective data 
to determine program goal achievement. Leadership will have visibility and comparability 
of process performance within and between sites and have risk - based data 
to support their deployment of resources in addressing business issues. 
3.3.8 DRIVING CONTINUOUS IMPROVEMENT: PROJECTS 
Pharmaceutical and biopharmaceutical companies are under signifi cant pressure to 
deliver consistent quality product as well as drive the overall product cost down. 
The goal of implementing ICH Q8, Q9, and ultimately Q10 is to characterize processes 
based on risk assessments and improve them through a well - designed QMS. 
There are regulatory and business drivers to continually improve the QMS processes 
by building in quality and improve process effi ciency. The regulatory agencies 
are now focused on ensuring systems are in place that protect the public health by 
assuring both the safety and effi cacy of products. Understanding manufacturing 
processes, through well - designed characterization studies, is one of the most effi cient 
and effective methods to ensure process effi ciency. To meet business and consumer 
demands as well as regulatory guidance and expectations, the implementation of 
continuous improvement through risk - managed evaluations of manufacturing processes 
is expected. 
3.3.8.1 Process Improvements 
A quality management system  s process should follow a standard Six Sigma process 
improvement life cycle that includes the following steps: defi ne (process and metrics), 
measure and control (identify problems and issues), analyze (analyze problems and 
issues), and improve (implement) circling back to measure and control [11] . An 
example of a process improvement life cycle can be seen in Figure 9 . 
The basic foundation of continuous improvement begins with a process owner 
who fully understands the process and recognizes how the process impacts other 
processes within the QMS. Understanding this cause - and - effect relationship between 
processes requires close integration between process owners and stakeholders. This 
integration is critical throughout the entire life cycle of a process, from design 
through development and management. 
Prior to process improvements the process must be well - defi ned and predictable. 
This does not mean that the process or output is desirable but instead well under

stood and predictable. It is through metrics, trends, and risk assessments that issues 
and concerns should be evident. Process owners can use the management review 
forum to present a proposal for process improvements. 
3.3.8.2 Process Improvement Proposal 
The process owner with stakeholders will need to provide a process improvement 
proposal if the issue or change requires prioritization due to funds or additional 
resources from the enterprise. The proposal should include, at minimum, the problem 
and or opportunity statement, impact to the site based on risk, and proposal of an 
action and/or project, including both cost and resource requirements. 
During the development of the proposal, the process owner should consider 
requesting subject matter experts to assist with the development of the problem 
statement, risk assessment, and cost avoidance or savings. Many times a process 
owner  s core competencies align closely with the process but may lack business or 
project management skills. The process owner may need assistance to clearly articulate 
to the leadership what the benefi ts are to accept the proposed change versus 
the risks for not adopting the proposal. 
Risk assessment tools such as a nine - block risk assessment (Table 9 ) or a failure 
mode and effect analysis (FMEA) are available to assist the process owner with 
the evaluation of the process or issue to better understand and communicate the 
FIGURE 9 Continuous improvement process. 
Monitor / 
control Analyze 
problem 
Improve / 
implement 
Identify 
problems/ 
opportunities 
Define process 
and metrics 
TABLE 9 Nine - Block Risk Assessment Matrix 
Severity 
Minor Major Severe 
Frequency 
Probable Medium High High 
Occasional Low Medium High 
Remote Low Low Medium 
DRIVING CONTINUOUS IMPROVEMENT: PROJECTS 281

282 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
probability of failure and the severity of a process issue. These analyses assist with 
the prioritization of issues and identifi cation of specifi c actions required to mitigate 
risks or the identifi cation of contingency plans for issues that are not mitigated. In 
a pharmaceutical and biopharmaceutical environment it is important that all risk 
tools are completed assessing impact to product safety and effi cacy as well as the 
business drivers. Any steps or issues in the process that can negatively impact the 
safety and effi cacy of the product require immediate elevation to leadership and 
must be addressed immediately. If the proposal requires prioritization, the process 
owners should clearly identify potential cost savings or avoidance through a cost of 
quality model to further engage senior leadership. The combination of risk and costs 
is an effective way to gain leadership support and attention. 
Leadership  s role in the process improvement proposal is to understand the issue 
or opportunity, understand associated risk(s), and approve or redirect a proposed 
action or project and provide appropriate funding and or resources. As action items 
and proposals are approved and initiated, the progress should be monitored on a 
routine basis to ensure appropriate progress is made. 
3.3.8.3 Task versus Project 
Process improvements may be conducted by the completion of a task or a project. 
A task is an activity that can be completed by the process owner with minimal cost 
and/or resources over a short period of time. A project is defi ned as temporary work 
to provide a product or service that is beyond the process owner  s support. In 
general, a project requires more than one full - time equivalent (FTE), crosses over 
multiple functional organizations, and the duration of the effort spans over a longer 
period of time. Improvement status, updates, and issues should be discussed on a 
regular basis by a management forum or steering committee. Tasks and projects 
should be prioritized based on the risk against patient safety and effi cacy and 
compliance. 
If the process improvement meets the requirements of a project, a project 
manager should be identifi ed. Formal project management allows for a holistic and 
integrated approach to the change. The project manager should not replace the 
process owner but ensure that the issues are identifi ed, prioritized, and resources 
are applied, milestones are met, issues escalated and resolved, and progress reported. 
The process owner needs to be the project lead with the stakeholders or steering 
committee, providing support and guidance. This allows the process owner to focus 
on the issues and improvements (their core competencies) and allows the project 
manager to move the project forward in a methodical manner. During the project 
it is critical that success is defi ned and measured. 
3.3.8.4 Project Metrics 
Project metrics should be identifi ed to measure the actual benefi t of the change 
versus the expected result following the implementation. Many times, corporations 
implement a change and move on to the next project without fully understanding 
whether or not the changes achieved the desired result. A project that does not 
achieve the expected benefi ts can lead to an ineffective process, confl icts with associated 
touch points with other processes, or frustration from staff and customers. 

Applying a systems - based approach to continuous improvement of the QMS, 
utilizing formal risk management tools benefi ts the overall effi ciency of the organization. 
Process owners are accountable and empowered to drive continuous improvements. 
Metrics are utilized to identify trends, issues, and opportunities. Stakeholders 
are engaged throughout the process, and management is involved in the prioritization 
and staffi ng of the task or project. The processes are continually managed and 
evaluated. Continuous improvements based on risk allow the organization to apply 
resources and money to the most critical projects that will make the most impact. 
As process improvements are implemented, staff will benefi t from a predictable, 
lean process allowing them to focus on the proactive nature of their work as 
opposed to the high stress of reacting to the issue of the day. The process owner will 
gain credibility as he or she demonstrate the ability to ensure that the right people 
are making the right decisions in a timely manner and that process improvements 
are addressing systemic process problems and not superfi cially addressing issues 
that will resurface again. 
3.3.9 ENSURING ONGOING SUCCESS 
Building infrastructure to establish and maintain a quality management system 
requires resources and resolve from leadership and staff. The current pharmaceutical 
and biopharmaceutical global and regulatory environment requires an organization 
invested in developing and maintaining a robust system and processes meeting 
the organization  s requirements for producing quality product. Future competition, 
shorter time to market, effi cient development, and fi rst - pass approval expectations 
exacerbate the need for robust processes. The global marketplace continues its pressure 
on industry to deliver lifesaving and life - style changing medicines faster and 
cheaper. 
3.3.9.1 Establishing Mutual Goals 
Companies that have designed, developed, and established QMSs and processes 
that are simple to execute, easy to understand, and deliver the business and regulatory 
results will have competitive advantage over their industry peers. They will be 
faster and more effi cient at adapting new technologies, assimilating new organizations 
through merger and acquisitions, able to apply adequate resources to appropriate 
business needs, and most importantly quickly modify and adapt to changing 
marketplace demands. Dependence on people, fragmented procedures, or tribal 
knowledge, rather than integrated, functional processes, will bring undesirable 
results to all levels of the organization. 
Ensuring ongoing success requires establishing mutual goals for the organization 
from the beginning. These goals must satisfy the needs of the business, the employees, 
and the shareholders. Well - designed processes with accountable ownership that 
have been established through discussion, design, and support of leadership, 
functional management, operational stakeholders, and general staff provide the 
foundation for common shared needs (Figure 10 ). If anyone of these groups is not 
considered, nominal support and eventually failure of the program can be 
expected. 
ENSURING ONGOING SUCCESS 283

284 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
These shared goals need to be memorialized through documentation of the 
program. This includes outlining the long - term objectives of the program, benefi ts 
required to be achieved for stakeholders, and annual quality plans for achieving 
milestone goals and success. Program success comes from leadership support, robust 
system design, adequate training for employees, and meaningful metrics to measure 
performance and continuous improvement efforts. 
Mechanisms to determine stakeholder feedback on program acceptance, clarity, 
and improvement opportunities need incorporation into the ongoing maintenance 
of the QMS. Focus groups are one method of obtaining this type of information. 
Another opportunity exists with regulatory inspections and customer audits. Taking 
appropriate action to implement program changes and enhancements while recognizing 
contributors will ensure stakeholder support and participation. 
Mutual goals will drive success of the program and provide the reference for why 
the system approach is needed and the benefi ts it can bring. There is no better situation 
than having an entire organization aligned around the business design, and 
executing against it, while supporting each other. 
3.3.9.2 Rewards and Recognition 
Process owners  responsibilities are signifi cant. Owners need to be selected from 
predetermined criteria that are discriminatory in nature. Process owners are the 
drivers of the operations and therefore need to be recognized for their special 
efforts and responsibilities. This recognition can take many forms. A signifi cant distinction 
in base qualifi cations and rewards is a valuable incentive to becoming a 
process owner. Ongoing development for process owners is another incentive and 
reward for the process owner. In addition to the fi nancial and tangible rewards, 
being recognized by the organization to have the confi dence of management is also 
another form of reward and recognition. Inevitably, processes contain waste and 
FIGURE 10 Process owner support model. 

ineffi ciencies, thereby providing another opportunity for owners to improve their 
process and be recognized for that improvement. 
Public recognition of system program and process owner accomplishments is 
essential. This can easily be accomplished through regular review sessions, at metric 
review meetings, through staff meetings and updates, poster sessions, newsletters, 
and departmental meetings. Simple recognition and small gifts are appreciated and 
reinforce management  s support and commitment to the program. Process owners 
and stakeholders are the most infl uential group to spread the word on the usefulness 
of the program and must be cultured to ensure ongoing success. 
Studies indicate fi nancial rewards alone cannot provide employee satisfaction 
and retention. High employee turnover costs companies tremendous fi nancial and 
competitive resources. Many employees faced with equal or higher pay but unsatisfying 
work will move onto another company or position. A poorly integrated QMS 
with complicated processes is often the foundation for that dissatisfaction. To repeat 
work, lose valuable time, or deliver substandard product does not satisfy today  s 
highly educated and competitive worker in the pharmaceutical and biopharmaceutical 
industry. The cost to recruit, replace, relocate, and retrain employees is signifi - 
cant. Avoidance of these costs can be used as a partial basis for support of the 
program. 
3.3.9.3 Ensuring Ongoing Program Continuity 
Accomplishments of a comprehensive QMS program should be shared between 
locations and be consistent. Common, competent leadership for the enterprise will 
ensure consistency. A consistent QMS program also allows for transfer of staff 
between sites with little or no training and assimilation requirements. Divergent 
evolution will dilute the QMS effort and support. Flexibility to execute is important, 
however, caution must be exercised to restrict diverging language, interpretation, 
and philosophy. Within a short time of a global execution, effi ciencies will be quickly 
realized. Ensuring consistency also increases the number of process users with 
similar experiences and leverages focus for process improvements and therefore 
support. 
Regulators and customers require assurance in consistency of pharmaceutical 
and biopharmaceutical manufacturing operations. Today  s manufacturing supply 
chains require multiple sites in varying locations to produce a product. Quality 
systems must be perceived as an integral part of the value chain. This requires that 
all sites be compliant in their operations and systems. Strong areas in one location 
do not make up for weak or absent systems in another location. Fines are levied 
and business is made or lost based on the individual site or weakest link in the 
supply chain. Management must have a mechanism to measure its processes, and a 
comprehensive QMS is the mechanism to demonstrate capability. 
3.3.9.4 Program Institutionalization 
Program institutionalization is realized with time. All levels of the organization 
need to recognize and verbalize that the quality management system approach is 
the way business is conducted. This way of doing business will become part of 
the culture to the point at which it is second nature to leadership, management, 
ENSURING ONGOING SUCCESS 285

286 CREATING AND MANAGING A QUALITY MANAGEMENT SYSTEM 
and staff. Regulators and customers will recognize the benefi ts, as do the shareholders 
and patients. 
REFERENCES 
1. Webster  s New Collegiate Dictionary , ninth edition, 1986 , p. 1199 . 
2. Arling , E. R. ( 2004 ), Integrating QSIT into quality plans , Biopharm. Int. , June, 44  46, 48 , 
50  52 . 
3. Drug Industry Daily , Oct. 12, 2006, Vol. 5, No. 200, Washington Business Information. 
4. 2006 PDA/FDA joint regulatory conference , Sept. 11, 2006, Washington, DC. 
5. Joneckis , C. ( 2006 ), Ph.D. presentation at 11th Annual GMP by the Sea, Aug. 28  30, 
Cambridge, MD. 
6. Quality systems regulations CDRH , available: www.fda.gov . 
7. CPGM 7356.002, CDER, available: www.fda.gov . 
8. IOM biological inspections 7345.848 CBER, available: www.fda.gov . 
9. Rockefeller , J. D. , III ( 1973 ), The Second Revolution , Harper - Row , New York . 
10. Kotter , J. P. ( 2001 ), Leadership insights , Harvard Bus. Re. , p. 29 . 
11. George , M. (2004), Lean Six Sigma Pocket Tool Book , McGraw - Hill Professional , New 
York , p. 4 . 

287 
3.4 
QUALITY PROCESS IMPROVEMENT 
Jyh-hone Wang 
University of Rhode Island, Kingston, Rhode Island 
Contents 
3.4.1 Diagnosing a Process 
3.4.1.1 Introduction 
3.4.1.2 Basic Tools for Diagnosing a Process 
3.4.2 Stabilizing and Improving a Process 
3.4.2.1 Introduction 
3.4.2.2 Control Charts for Attributes 
3.4.2.3 Control Charts for Variables 
3.4.2.4 Special Control Charts 
3.4.3 Improving Performance of a Process 
3.4.3.1 Introduction 
3.4.3.2 Process Capability and Improvement Studies 
Bibliography 
3.4.1 DIAGNOSING A PROCESS 
3.4.1.1 Introduction 
Quality process improvement starts with a diagnostic journey where problems are 
identifi ed. Remedial activity will be taken and the process will be continuously 
monitored afterward. The common activities taken in the diagnostic journey are 
analyzing symptoms, formulating hypotheses, testing hypotheses, and identifying 
causes. Table 1 describes basic tools for the diagnostic journey. A description of them 
is given in Section 3.4.1.2 . 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

288 QUALITY PROCESS IMPROVEMENT 
3.4.1.2 Basic Tools for Diagnosing a Process 
Cause - and - Effect Diagram A cause - and - effect diagram relates potential causes 
of a problem to their effects. This is a tool that could be very useful in diagnosing 
a process. It focuses on the possible causes of a specifi c problem in a structured and 
systematic way. The following steps are suggested for constructing a cause - and - 
effect diagram: 
1. Defi ne the problem (effect). 
2. Write problem on the right side and draw an arrow from the left to the right 
side. 
3. Brainstorm the main categories of causes of problems and draw major branch 
arrows to the main arrow. 
4. For each major branch, detailed causal factors (subcauses) are drawn as 
subbranches. 
5. Write sub - subcauses branching off the subcauses. 
6. Ensure all the items that may be causing the problem are indicated in the 
diagram. 
Figure 1 shows a cause - and - effect diagram which is used to identify causes to yield 
a problem in a biopharmaceutical manufacturing process. Possible main causes and 
subcauses are identifi ed. Once the causes are identifi ed, other tools are employed 
to determine the contribution of various causes to the effect. Actions are taken to 
eliminate or minimize the impact of these causes. 
Pareto Chart The Pareto principle suggests a problem (effect) can be attributed 
to relatively few causes. In quantitative terms, 80% of the problems come from 20% 
of the causes (machines, raw materials, operators, etc.); therefore effort aimed at the 
right 20% can solve 80% of the problems. A Pareto chart includes three basic elements: 
(1) the causes to the total effect, ranked by the magnitude of the contribution; 
(2) the frequency of each cause; and (3) the cumulative - percent - of - total effect of 
TABLE 1 Basic Quality Process Improvement Tools during Process Diagnosis 
Common Activities to 
Diagnose Cause 
Basic Tools for Quality Process Improvement 
Cause  Effect 
Diagram 
Pareto Chart 
Histogram 
Scatter Diagram 
Normal 
Probability Plot 
Flow Diagrams 
Data Collection 
Box Plot 
Stratifi cation 
Analyzing symptoms        
Formulating hypotheses     
Testing hypotheses       
Identifying cause(s)      
Note : (  ) major; ( ) minor. 
0 0 
0 0 0 0 0 
0 0 0 
0 0 0 0 
0

DIAGNOSING A PROCESS 289 
the ranked causes. Figure 2 gives an example of a Pareto chart which exhibits errors 
found in a pharmacy store chain in one month. 
Histogram A histogram is a graphic summary of variation in a set of data. Data 
are clustered into categories and the values of individual clusters are plotted to give 
a series of bars. For illustration, Table 2 presents 40 observations on the shelf life of 
a certain drug and their frequency distribution. Figure 3 gives a histogram for the 
drug shelf life data. 
Scatter Diagram A scatter diagram is a basic tool to identify the potential relationship 
between two variables. Scatter diagrams are similar to line graphs in that 
they use horizontal and vertical axes to plot data points. However, they have a very 
specifi c purpose. Scatter diagrams show how much one variable is affected by 
another. The relationship between two variables is called their correlation. The 
FIGURE 1 Cause - and - effect diagram. 
Agitation pH Coolant 
flow 
Concentration 
Substrate 
Flow rate 
Feed 
Temperature 
Aeration
Oxygen Water 
temperature 
Yield 
FIGURE 2 A Pareto chart showing pharmacy errors. 
Count 
Percent 
Pharmacy error
Count 
29.8 12.4 6.3 2.1 1.2 
Cum % 48.1 78.0 90.4 96.7 
2452 
98.8 100.0 
1520 632 320 108 62 
Percent 48.1 
Miss 
ed 
drug 
allerg 
ies 
W 
rong 
patient 
Mixing 
up 
prescriptions 
Incorrect 
label 
Incorrect 
dosing 
Misread 
pres 
cription 
5000 
4000 
3000 
2000 
1000
0 
100 
80 
60 
40 
20 
0

290 QUALITY PROCESS IMPROVEMENT 
closer the data points come when plotted to making a straight line, the higher the 
correlation between the two variables. If the data points make a straight line going 
from the origin out to high x and y values, then the variables are said to have a 
positive correlation. If the line goes from a high value on the y axis to a high value 
on the x axis, the variables have a negative correlation. Figure 4 gives a few examples 
of scatter diagrams. 
Normal Probability Plot The normal probability plot is a graphical technique for 
assessing whether or not a data set is approximately normally distributed. The data 
are plotted against a theoretical normal distribution in such a way that the points 
form an approximate straight line. Departures from this straight line indicate departures 
from normality. The normal probability plot is important for quality process 
improvement since many other tools require the normality assumption. A normal 
TABLE 2 Drug Shelf Life (days) 
102.2 104.1 103.5 104.5 103.2 103.7 103.0 102.6 
103.4 101.6 103.1 103.3 103.8 103.1 104.7 103.7 
102.5 104.3 103.4 103.6 102.9 103.3 103.9 103.1 
103.3 103.1 103.7 104.4 103.2 104.1 101.9 103.4 
104.7 103.8 103.2 102.6 103.9 103.0 104.2 103.5 
Range Midpoint Frequency Cumutative % 
101.5 . x < 102.0 101.75 2 5.00 
102.0 . x < 102.5 102.25 2 10.00 
102.5 . x < 103.0 102.75 5 22.50 
103.0 . x < 103.5 103.25 15 60.00 
103.5 . x < 104.0 103.75 8 80.00 
104.0 . x < 104.5 104.25 6 95.00 
104.5 . x < 105.0 104.75 2 100.00 
FIGURE 3 Histogram of drug shelf life. 
0
2
4
6
8 
10 
12 
14 
16 
101.75 102.25 102.75 103.25 103.75 104.25 104.75 
Shelf life 
Frequenc 
. 00% 
20.00% 
40.00% 
60.00% 
80.00% 
100.00% 
120.00% 
Frequency 
Cumulative %

DIAGNOSING A PROCESS 291 
probability plot of the drug shelf life in Table 2 is given in Figure 5 . As seen from 
the plot, the observations follow a straight line and are contained in the 95% confi - 
dence interval. It can thus be said that the shelf life of this drug follows a normal 
distribution. 
Other Tools 
Box Plot This plot is useful when analyzing the pattern of the data. It displays 
several important features of data such as central tendency, variability, departure 
from symmetry, and presence of outliers. 
Flow Diagrams A process fl ow diagram can be used to study and understand 
the process. 
Data Collection Data are essential for making a proper evaluation of the current 
process. Tools for data collection include checklists and data sheets. 
FIGURE 4 Scatter diagrams. 
X 
Y 
No correlation 
X 
Y 
Negative correlation 
X 
Positive correlation 
Y

292 QUALITY PROCESS IMPROVEMENT 
Stratifi cation This technique is used to separate data into groups based on categories 
or characteristics. It is the basis for the application of other tools or it 
can be used with other data analysis tools such as scatter diagrams. 
3.4.2 STABILIZING AND IMPROVING A PROCESS 
3.4.2.1 Introduction 
Basic Concepts of a Control Chart The control chart is one of the main tools for 
quality process improvement. It is used to assess the nature of variation in a process 
and to facilitate the forecasting and management of a process. Values of the quality 
characteristic are plotted against the sample number or time, as shown in Figure 6 . 
The centerline represents the process average. The upper and lower control limits 
(UCL and LCL) are usually chosen as three standard deviations (SDs) above and 
below the centerline so they can be used to detect  out - of - control  situations without 
causing mamy false alarms. An out - of - control situation is usually signaled by a 
plotted point falling outside the control limits or a cluster of plotted points forming 
an abnormal pattern. 
FIGURE 5 Normal probability plot of drug shelf life with 95% confi dence interval. 
Shelf life 
Percent 
106.0 105.5 105.0 104.5 104.0 103.5 103.0 102.5 102.0 101.5 101.0 
99 
95 
90 
80 
70 
60 
50 
40 
30 
20 
10
5
1 
95% confidence interval 
FIGURE 6 Normal curve - based control chart. 
Upper control limit (UCL) 
Center line 
Lower control limit (LCL) 
Sample number 
X 
68.26% 
95.46% 
99.73% 
3. 2. 1. X +1. +2. +3.

Plotted points on a control chart are usually based on data collected from samples 
in a process. After a suffi cient number of samples are collected and the data are 
plotted on a control chart, the stability of the process can be evaluated. A stable 
process is  in control  while an out - of - control process is unstable. Depending on 
the type of quality characteristic, control charts can be divided into two groups: 
variable control charts and attribute control charts. Variable control charts are used 
to monitor quality characteristic that are continuously varying in nature; attribute 
control charts are used to monitor those quality characteristics that are not numerically 
measurable. The determination of the centerline and control limits are described 
in Sections 3.4.2.2 and 3.4.2.3 with respect to different types of control charts. 
Applications of Control Charts Control charts serve to direct management attention 
toward special causes of variation in a process when they appear. In evaluating 
control charts, the following symptoms could indicate a process that is out - 
of - control: 
 Outlier One or more point(s) that fell outside the control limits. 
 Run A series of plotted points above or below the centerline. 
 Trend A continual rise or fall of plotted points. 
 Cyclicity A pattern that repeats itself over time. 
The following steps are usually followed in a control chart  s development and 
application: 
 Determine a  base period  for initial control chart development. 
 Collect sample data from the base period. 
 Calculate the parameters for the control chart, that is, centerline and control 
limits. 
 Plot collected sample points on the chart with the centerline and control 
limits. 
 Determine whether the chart parameters can be used to monitor the process; 
revise the parameters if necessary. 
 Collect ongoing samples and continue monitoring the process using the 
developed control chart. 
 Conduct periodic audits on the parameters of the control chart. 
Variable control charts are widely applied in many manufacturing and nonmanufacturing 
settings. They can be used to monitor, for example, the inside diameter of 
an aircraft bearing, the moisture content of a drug tablet, the net weight of a pharmaceutical 
product, the processing time of phone inquiries, and the satisfaction level 
of customers. The latter two are examples of nonmanufacturing applications. 
Attribute control charts are less used compared to variable control charts. When 
it is not possible or practical to measure the quality characteristic of a product, 
attribute control charts are often applied. Examples of their application include 
monitoring the fraction of nonconforming of a certain sensor production, the number 
of defective diodes in an electronic assembly, the number of imperfections in textile 
STABILIZING AND IMPROVING A PROCESS 293

294 QUALITY PROCESS IMPROVEMENT 
production, the fraction of defective batches in a biomedical manufacturing production, 
and the number of errors found in a pharmacy store. 
In most applications, the choice between a variable control chart and an attribute 
control chart is clear - cut. In some cases, the choice will not be obvious. For instance, 
if the quality characteristic is the softness of an item, such as the case of pillow 
production, then either an actual measurement or a classifi cation of softness can be 
used. Quality managers and engineers will have to consider several factors in the 
choice of a control chart, including cost, effort, sensitivity, and sample size. Variable 
control charts usually provide more information to analysts but cost more to implement 
and use. Attribute control charts are less sensitive and expensive but usually 
requires large samples to reach certain statistical signifi cance. 
3.4.2.2 Control Charts for Attributes 
Control charts based on attribute data include the p chart, np chart, c chart, and u 
chart. The former two are applied when fraction nonconforming or number of nonconforming 
is a concern, and the latter two are used to deal with the nonconformities. 
Most pharmaceutical manufacturing industries employ one or more of these 
charts. 
p Control Chart A p chart can be used to monitor the fraction nonconforming of 
a process. Fraction nonconforming is defi ned as the ratio of the number of nonconforming 
items in a population to the total number of items in that population. In 
pharmaceutical manufacturing, an item will be classifi ed as nonconforming if it fails 
to conform to standards on one or more attributes, for example, fi ll volumes of vials, 
moisture content, hardness, and solubility. 
Let us suppose a random sample of n items is selected and examined from a 
process running with a stable nonconforming rate p and D units of nonconforming 
items are found; then D is a random variable following a binomial distribution 
with parameters n and p . If the true fraction nonconforming, p , is known, then the 
parameters of the p chart are 
UCL 
Centerline 
LCL
= + 
. 
=
= . 
. 
p 
p p 
n 
p
p 
p p 
n 
3 
1 
3 
1
( ) 
( ) 
(1) 
In practice, the fraction nonconforming, p , is unknown most of the time and is thus 
needed to be estimated from the sample data. An estimated p i can be calculated for 
the i th sample collected and an average p. value can be obtained as an arithmetic 
average of those individual p i found from the m samples: 
p 
D 
mn 
p 
m 
i
m 
i i
m 
i = = = = . . 1 1 
(2) 

The p. can then be used in place of p in Equation (1) in the application. It should be 
noted that the p. value needs to be assessed periodically to assure its representativeness 
of the average process fraction nonconforming. 
np Control Chart An np chart is used to monitor the number of nonconforming 
items produced in a process. Very similar to the p chart, the parameters of an np 
chart are 
UCL 
Centerline 
LCL
= + . 
=
= . . 
np np p 
np 
np np p 
3 1 
3 1
( ) 
( ) 
(3) 
As in the p chart, if the actual p value is not available, p. can be used in the 
calculation. 
c Control Chart A c chart can be used to monitor the number of nonconformities 
(defects) per inspection unit. An inspection unit can be a single unit of product, a 
batch of multiple products, or a certain measured volume (weight) of product. Many 
pharmaceutical manufacturing processes are lot based where raw material or semiproduct 
passes from one process to the next. For example, an inappropriately coated 
tablet in a coating process can be considered as a nonconformity (defect) where an 
inspection unit might be defi ned as 1 kg of the tablet. 
Suppose an inspection unit of a certain product is selected and examined from a 
process running with a stable nonconformity rate c per inspection unit and X nonconformities 
are found. Then X is a random variable following a Poisson distribution 
with parameter c . If the true nonconformity level c is known, then the parameters 
of the c chart are 
UCL 
Centerline 
LCL
= + 
=
= .
c c 
c
c c 
3
3 
(4) 
If the actual nonconformity level c is unknown, it can be estimated by using average 
c values obtained from m inspection units collected in a base period: 
c 
C 
m
i
m 
i = = . 1 
(5) 
The c. can then be used in place of c in Equation (4) in the application. Since it is 
possible to obtain a negative LCL using Equation (4) , a value of zero should be 
used in that case. 
u Control Chart A u chart is used to monitor the rate of nonconformities. The 
rate of nonconformities ( u ) is the number of nonconformities ( x ) in an inspection 
unit divided by the number of physical units ( n ) inspected (e.g., 100 ft of pipe, 100 
items in a batch). Similar to the c chart, the parameters of a u chart are 
STABILIZING AND IMPROVING A PROCESS 295

296 QUALITY PROCESS IMPROVEMENT 
UCL 
Centerline 
LCL
= + 
=
= . 
u 
u
n 
u
u 
u
n 
3
3 
(6) 
If the actual u value is not available, can be used in Equation (6) . 
Example 1 A medical device manufacturer is concerned about the nonconforming 
(defective) and the nonconformity (defect) produced in its recently set - up production 
line. Twenty batches of this medical device were randomly selected from the production 
line. Each batch contained 100 units. Each unit is inspected and is classifi ed as 
either conforming or nonconforming.  During the inspection, the number of nonconformities 
(defects) was also counted. The data collected are shown in Table 3 . 
3.4.2.3 Control Charts for Variables 
Control charts based on variable sample data include the x. chart and the s chart. 
When dealing with a numerically measurable quality characteristic, the x. chart is 
usually employed to monitor the process average and the s chart is used to monitor 
the process variability. When there is only one observation in each sample, the individual 
measurement chart ( I chart) and moving range chart (MR chart) are used to 
monitor the process average and variability. It should be noted that due to the poor 
TABLE 3 Nonconforming and Nonconformity Counts of 20 Batches of Medical Device 
Batch number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Nonconformings 3 2 4 2 5 2 1 2 0 5 2 4 1 3 6 0 1 2 3 2 
Nonconformities 9 7 13 8 6 8 10 10 7 10 12 9 11 15 8 12 11 8 7 15 
FIGURE 7 p Chart for medical device manufacturing example. 
Sample no. 
Fraction nonconforming 
19 17 15 13 11 9 7 5 3 1 
0.08 
0.06 
0.04 
0.02 
0.00 
_
P=0.025 
UCL=0.07184 
LCL=0 
Based on the data in Table 3 , the average fraction nonconforming, p. , can be 
obtained as 2.5%; the average nonconformity per batch, c. , is 9.8; and the average 
nonconformity per unit, , is 0.098. The resulting control charts are shown in Figures 
7  10 . These charts indicate that the process is in control and thus the parameters 
established here can be used to monitor future productions. 
u 
u

FIGURE 8 np Chart for medical device manufacturing example. 
Sample no. 
No. of nonconformities 
19 17 15 13 11 9 7 5 3 1 
8
6
4
2
0 
__ 
np =2.5 
UCL=7.184 
LCL=0 
FIGURE 9 c Chart for medical device manufacturing example. 
Sample no. 
No. of nonconformities 
19 17 15 13 11 9 7 5 3 1 
20 
15 
10
5
0 
_
C=9.8 
UCL=19.19 
LCL=0.41 
FIGURE 10 u Chart for medical device manufacturing example. 
Sample no. 
Nonconformity rate 
19 17 15 13 11 9 7 5 3 1 
0.20 
0.15 
0.10 
0.05 
0.00 
_
U=0.098 
UCL=0.1919 
LCL=0.0041 
sample size, the I and MR charts are less sensitive in detecting if the process is out 
of control than the x. and s charts. 
x. Control Chart An x. chart is used to monitor the process average. It is usually 
used in pharmaceutical manufacturing where multiple units are collected in each 
sample (e.g., a sample of multiple tablets formed by dry powders or wet granules.) 
Due to contamination risk and cost of sampling (including product loss due to 
STABILIZING AND IMPROVING A PROCESS 297

298 QUALITY PROCESS IMPROVEMENT 
sample volumes and incurred labor cost of laboratory analysis), the sample size is 
usually kept small. 
Sample means x. are plotted on the x. chart. Assume that random samples of n 
items are collected and examined from a stable process with a process mean . and 
standard deviation . . Then x. can be considered as a random variable following a 
normal distribution with mean . x. , and standard deviation . x. , where 
. . . 
. 
x x n 
= = and 
(7) 
If the true process mean . and standard deviation . are known, then the parameters 
of the x. chart are 
UCL 
Centerline 
LCL
= + = + 
= = 
= . = . 
. . . 
. 
. . 
. . . 
. 
x x 
x
x x 
n
n 
3 3 
3 3 
(8) 
Since . and . are not usually known, estimators of them can be obtained from the 
sample means ( x. ) and sample standard deviations ( s ) of the m samples collected in 
the base period: 
Estimator of 
Estimator of 
.
.
= = 
= 
. . 
= 
= 
= 
. 
. 
x 
x 
m
s m 
n n 
s 
c 
i
m 
i 
i
n 
i 
1 
1 
4 4 1 4 3 ( ) 
(9) 
Using the estimators, the parameters of the x. chart are now 
UCL 
Centerline 
LCL
= + = + 
=
= . = . 
x 
s c
n 
x A s 
x
x s c
n 
x A s 
3
3 
4 
3 
4 
3 
(10) 
The common values of constants c 4 and A 3 are tabulated in Table 4 for sample sizes 
from 2 to 10. Like other control charts, the values of x and s. should be periodically 
verifi ed to assure that they can be used to derive good estimators for the process 
average and process standard deviation. 
s Control Chart An s chart is used to monitor the process variability. Since it is 
equally important to ascertain that the variability and the mean of a process are in 
control, an s chart is usually used in conjunction with the x. chart. Sample standard 
deviations are plotted on the s chart. Consider s as a random variable with mean . s 
and standard deviation . s . Then the parameters of the s chart can be stated as

UCL 
Centerline 
LCL
= + 
=
= . 
. . 
.
. . 
s s 
s
s s 
3
3 
(11) 
In practice, the parameters of the s chart can be estimated using s. as 
UCL 
Centerline 
LCL
= + . = 
=
= . . = 
s 
s 
c 
c Bs 
s
s 
s 
c 
c Bs 
3 1 
3 1 
4 
4
2 
4 
4 
4
2 
3 
(12) 
If the LCL calculation results in a negative value, use zero as the LCL . 
TABLE 4 Values of Constants in Variable Control Chart 
Parameters 
n A 3 c 4 B 3 B 4 d 2 d 3 
2 2.659 0.798 0 3.267 1.128 0.853 
3 1.954 0.886 0 2.568 1.693 0.888 
4 1.628 0.921 0 2.266 2.059 0.880 
5 1.427 0.940 0 2.089 2.326 0.864 
6 1.287 0.952 0.030 1.970 2.534 0.848 
7 1.182 0.959 0.118 1.882 2.704 0.833 
8 1.099 0.965 0.185 1.815 2.847 0.820 
9 1.032 0.969 0.239 1.761 2.970 0.808 
10 0.975 0.973 0.284 1.716 3.078 0.797 
Example 2 In a Pet Tabs (pet vitamin tablets) production, the pharmaceutical 
manufacturer is using milling and micronizing machines to pulverize raw materials 
into fi ne particles. These fi nished particles are combined and processed further in 
mixing machines. The mixed ingredients are then pressed into tablets, dried, and 
sealed in packages. A normally distributed quality characteristic, moisture content, 
is monitored. Samples of n = 4 tablets are taken from the manufacturing process 
every hour. The data after 25 samples have been collected are shown in Table 5 . 
From these data, it is found that x = 10 254 . and s. = 0.926. Using Equations (10) 
and (12) , the parameters of the x. and s charts are found as: 
x. Chart s Chart 
UCL 11.761 2.098 
Centerline 10.254 0.926 
LCL 8.747 0 
The control charts are shown in Figure 11 . The x. and s charts show that the process 
is in control and thus the parameters established here can be used to monitor future 
productions. 
STABILIZING AND IMPROVING A PROCESS 299

300 QUALITY PROCESS IMPROVEMENT 
TABLE 5 Moisture Content (%) of 25 Samples of Pet Tabs 
Sample Number 
Observations 
x. s 1 2 3 4 
1 7.84 11.01 10.14 9.41 9.600 1.343 
2 10.51 9.1 9.52 10.83 9.990 0.814 
3 9.74 10.39 9.62 11.16 10.228 0.708 
4 10.71 11.41 10.71 8.63 10.365 1.203 
5 9.93 10.95 8.99 10.73 10.150 0.889 
6 9.94 10.27 9.35 9.42 9.745 0.438 
7 12.11 9.72 8.89 9.75 10.118 1.387 
8 9.61 8.93 11.12 8.75 9.603 1.077 
9 9.17 10.87 9.97 10.79 10.200 0.798 
10 11.41 10.39 8.83 12.19 10.705 1.451 
11 8.43 9.48 10.56 10.2 9.668 0.939 
12 9.92 10.13 9.66 8.21 9.480 0.868 
13 8.39 9.94 10.4 8.69 9.355 0.967 
14 10.42 10.27 10.94 10.91 10.635 0.341 
15 10.98 12.57 11.14 8.97 10.915 1.481 
16 9.73 10.05 12.82 12.43 11.258 1.592 
17 11.36 8.91 10.08 10.55 10.225 1.024 
18 9.42 11.12 9.01 10.52 10.018 0.973 
19 10.15 10.08 10.12 9.88 10.058 0.122 
20 11.73 11.1 10.75 9.94 10.880 0.746 
21 11.52 9.11 9.88 11 10.378 1.087 
22 11.29 10.43 11.6 11.74 11.265 0.588 
23 9.39 12.96 11.42 10.28 11.013 1.541 
24 10.26 9.59 9.33 9.26 9.610 0.456 
25 11.25 10.65 11.06 10.63 10.898 0.307 
FIGURE 11 x. and s charts for Pet Tab manufacturing example. 
Sample no. 
Sample mean 
25 23 21 19 17 15 13 11 9 7 5 3 1 
12 
11 
10
9 
__
X=10.254 
UCL=11.761 
LCL=8.747 
Sample no. 
Sample SD 25 23 21 19 17 15 13 11 9 7 5 3 1 
2.0 
1.5 
1.0 
0.5 
0.0 
_S
=0.926 
UCL=2.098 
LCL=0

Individuals Control Charts In some chemical and biopharmaceutical manufacturing 
processes involving lengthy and expensive procedures, it is not feasible to form 
a sample of size greater than one because only one product or one batch is available 
each time. When the sample size used for statistical process monitoring is limited 
to one, individual control charts, I and MR charts, are needed. 
The I chart is serving the same function as the x. chart except that now x is the value 
of the individual measurement. Assuming that x follows a normal distribution with 
mean . and standard deviation . , the theoretical parameters of the I chart are 
UCL 
Centerline 
LCL
= + 
=
= . 
. . 
.
. .
3
3 
(13) 
The process average . can be estimated by x. , which is 
.. = . = . x 
x 
m
i
m 
i 1 
(14) 
Since only individual measurements are available, moving ranges need to be calculated 
for the estimation of process standard deviation . . A k - point moving range, 
MR k , can be calculated as 
MR max( , . . . , min , . . . , k i i k i i k x x x x = . + + ) ( ) (15) 
For m individual measurements, there are m . k MR k available, and the process 
standard deviation . can be estimated as 
.. = = 
. =
. . MR MR k i
m k 
ki 
d 
m k 
d 2 
1 
2 
(16) 
The estimated process mean and standard deviation can be used to calculate the 
practical parameters for the I chart in Equation (13) . The constant d 2 value is determined 
by k and can be found by using k as n in Table 3 . Common k values can range 
from 2 to 5. 
The MR chart is used to monitor process variability. Considering MR k as a 
random variable with a mean of .MRk and a standard deviation of .MRk, the theoretical 
parameters of the MR chart can then be stated as 
UCL 
Centerline 
LCL 
MR MR 
MR 
MR MR 
= + 
=
= . 
. . 
.
. . 
k k 
k
k k 
3
3 
(17) 
Since .MRk and .MRk are not usually available, they can be estimated as 
. . . . MR MR MR and MR k k k k 
d
d 
= =3
2 
(18) 
STABILIZING AND IMPROVING A PROCESS 301

302 QUALITY PROCESS IMPROVEMENT 
The constant value of d 3 can also be found in Table 3 . If a negative LCL was 
obtained, use zero. 
3.4.2.4 Special Control Charts 
The control charts discussed earlier are very useful in the diagnostic aspects of 
quality process improvement. They can be used to stabilize a process by identifying 
out - of - control situations. After the process is stabilized and brought in control, 
further improvement of the process can be achieved by using some special control 
charts such as the cumulative sum (CUSUM) control chart and the exponentially 
weighted moving average (EWMA) control chart. These control charts can be used 
when  small shifts  in a process are of interest. 
CUSUM Control Chart A CUSUM chart provides an effi cient way of detecting 
small shifts in the mean of a process ( < 1/2 . ). For larger shifts ( > 1/2 . ), the x. chart 
is usually used. The CUSUM chart incorporates information contained in a sequence 
of sample points. It keeps track of the cumulative sum of the deviations between 
each sample point (a sample mean) and a target value. Unlike the x. chart, 
which often bases its out - of - control decision on just the most recently collected 
sample, the CUSUM calculated for a sample point carries the  history  prior to 
that sample. For example, a sequence of sample points above the centerline can 
trigger an out - of - control signal although all of them stayed well below the UCLs of 
the x. chart. 
There are two forms of the CUSUM chart, the tabular form and the V - mask form. 
Due to its practicality, the tabular form is more preferred in industrial settings. The 
tabular CUSUM accumulates deviations from a target value (or a known process 
mean . 0 ). Deviations above that target value are cumulated as a one - sided upper 
CUSUM ( C + ) and deviations below the target value are cumulated as one - sided 
lower CUSUM ( C . ): 
C x k C 
C k x C 
i i x i 
i x i i 
+ 
. 
+ 
. 
. 
. 
= . + + 
= . . + 
max[0, 
max , 
( ) ] 
[ ( ) ] 
. . 
. .
0 1 
0 1 0 
(19) 
where C C 0 0 0 + . = = . 
The parameter k is called the allowance and is usually determined as the magnitude 
of the shift to be detected in terms of . x. . If either Ci
+ or Ci
. exceeds a decision 
interval h , the process is considered out of control. In other words, the value of h is 
considered a UCL and . h is considered an LCL. Its centerline is always at zero. A 
reasonable value for h is fi ve times the process standard deviation . . 
EWMA Control Chart An EWMA control chart plots weighted moving average 
values for variables data. A weighting factor is chosen by the user to determine how 
older data points affect the mean value compared to more recent ones. Because the 
EWMA chart uses information from all samples, it is a good alternative to the 
CUSUM chart in detecting smaller process shifts. 
The EWMA for sample i ( z i ) is plotted on the chart and is defi ned as z i = . x. i + 
(1 . . ) z i . 1 , where z 0 = . 0 . The constant . defi nes the weight assigned to the current 

sample (0 < . . 1) and 1 . . is the weight assigned to earlier samples. Parameters 
of the EWMA are 
UCL 
Centerline 
LCL
= + 
. 
. . 
=
= . 
. 
. . 
. . 
. 
. 
. 
.
. . 
. 
. 
0 
2 
0
0 
2 
1 1 
2 
1 1 
L
L 
x 
i 
x 
[ ( ) ] 
[ ( .) ] 2i 
(20) 
where L is a design parameter that defi nes the width of the control limits. The choice 
of L = 3 and 0.05 < . . 0.25 is reasonable. The control limits will become wider when 
the sample number i is getting larger and fi nally reach constant values as 
UCL 
Centerline 
LCL
= + 
. 
=
= . 
. 
. . 
. 
. 
.
. . 
. 
. 
0
0
0 
2
2 
L
L 
x
x 
(21) 
Example 3 The data in Example 2 are now analyzed by CUSUM and EWMA 
charts. Table 6 shows calculated CUSUM and EWMA values. The value of h in 
CUSUM is chosen as 5 times the standard deviation of x. ( . . .x = 0 5027) and the value 
of k is chosen as 0.5. The Ci
+ and Ci
. are calculated using a target value . 0 = 10. 
The CUSUM chart is shown in Figure 12 . The value of . in EWMA is chosen as 0.2 
and L is chosen as 3. The UCL and LCL for individual samples are shown in Table 
6 and the EWMA chart is shown in Figure 13 . Although the x. and s charts in Figure 
6 indicate that the process is in control, both CUSUM and EWMA gave out - of - 
control signals at sample point 22. A small process shift has occurred after sample 
21. 
IMPROVING PERFORMANCE OF A PROCESS 303 
3.4.3 IMPROVING PERFORMANCE OF A PROCESS 
3.4.3.1 Introduction 
Basic Concepts After a process is diagnosed, corrected, and brought into statistical 
control, the next question is  How can the performance of a process be improved?  
To answer this question, quality managers and engineers need fi rst measure the 
present process performance. This measurement can be achieved through a process 
capability study which gauges the ability of a process to produce products according 
to the specifi cations. A process can achieve a state of statistical control but still exhibit 
a poor capability due to the variability in the process. It will be necessary to reduce 
variability to improve the process capability. Designed experiments based on statistical 
principles can offer helps toward reduction of variability and optimization of the 
process. Employing designed experiments, intentional changes can be made in various 
places in the process; results gathered from these experiments can lead to further 
process improvement and bring it to the next level. This section presents commonly 

304 QUALITY PROCESS IMPROVEMENT 
TABLE 6 CUSUM and EWMA Values for Pet Tabs Example 
Sample Number x. 
CUSUM EWMA 
Ci
+ Ci
. z i UCL LCL 
1 9.600 0.000 0.149 9.920 10.302 9.698 
2 9.990 0.000 0.000 9.934 10.386 9.614 
3 10.228 0.000 0.000 9.993 10.432 9.568 
4 10.365 0.114 0.000 10.067 10.458 9.542 
5 10.150 0.012 0.000 10.084 10.475 9.525 
6 9.745 0.000 0.004 10.016 10.485 9.515 
7 10.118 0.000 0.000 10.036 10.491 9.509 
8 9.603 0.000 0.146 9.950 10.495 9.505 
9 10.200 0.000 0.000 10.000 10.498 9.502 
10 10.705 0.454 0.000 10.141 10.500 9.500 
11 9.668 0.000 0.081 10.046 10.501 9.499 
12 9.480 0.000 0.350 9.933 10.501 9.499 
13 9.355 0.000 0.744 9.817 10.502 9.498 
14 10.635 0.384 0.000 9.981 10.502 9.498 
15 10.915 1.047 0.000 10.168 10.502 9.498 
16 11.258 2.054 0.000 10.386 10.502 9.498 
17 10.225 2.027 0.000 10.354 10.502 9.498 
18 10.018 1.794 0.000 10.286 10.502 9.498 
19 10.058 1.600 0.000 10.241 10.502 9.498 
20 10.880 2.229 0.000 10.368 10.502 9.498 
21 10.378 2.355 0.000 10.370 10.503 9.497 
22 11.265 3.369 0.000 10.549 10.503 9.497 
23 11.013 4.130 0.000 10.642 10.503 9.497 
24 9.610 3.489 0.139 10.435 10.503 9.497 
25 10.898 4.135 0.000 10.528 10.503 9.497 
h = 2.513 . = 0.2 
k = 0.5 L = 3 
FIGURE 12 CUSUM chart for Pet Tabs manufacturing example. 
Sample no. 
Cumulative sum 
25 23 21 19 17 15 13 11 9 7 5 3 1 
5
4
3
2
1
0 
-1 
-2 
0
UCL=2.513 
LCL=-2.513

FIGURE 13 EWMA chart for Pet Tabs manufacturing example. 
Sample no. 
EWMA 
25 23 21 19 17 15 13 11 9 7 5 3 1 
10.75 
10.50 
10.25 
10.00 
9.75 
9.50 
UCL=10.503 
LCL=9.497 
Target = 10 
used methods in process capability studies. Design - of - experiment techniques can be 
found elsewhere in this handbook and in many other textbooks. 
Specifi cation Limits, Control Limits, and Natural Tolerance Limits To conduct 
a process capability study, it is important to distinguish the specifi cation limits of a 
product, the control limits of the process producing the product, and the natural 
tolerance limits (NTLs) of the product. In general, specifi cation limits are given by 
customers or prescribed by in - house design engineers before production. A product 
that failed to meet the specifi cations is a nonconforming product. Control limits are 
usually determined by samples collected from a process during a base period. A 
sample point that fell outside the control limits will trigger an out - of - control state; 
however, a product produced in the out - of - control state is not necessarily a nonconforming 
product. It should also be noted that a sample point plotted in a control 
chart usually represents a statistic of the sample such as the sample mean. In other 
words, a single product that fell outside of the control limits will neither cause the 
process to be out of control nor become nonconforming. The variability of products 
produced can usually be described by its natural tolerance limits. It is commonly 
acceptable that the  3 standard deviations from the process mean be used as the 
natural tolerance limits. 
Example 4 Following Example 2 , the specifi cation limits are specifi ed as 10.00  
2.00, where: 
Nominal or target value ( . 0 ) = 10.00 
Upper specifi cation limit (USL) = 10.00 + 2.00 = 12.00 
Lower specifi cation limit (LSL) = 10.00 . 2.00 = 8.00 
The control limits for the x. chart are: 
Center line ( x ) = 10.254 
Upper control limit (UCL) = 11.761 
Lower control limit (LCL) = 8.747 
IMPROVING PERFORMANCE OF A PROCESS 305

306 QUALITY PROCESS IMPROVEMENT 
3.4.3.2 Process Capability and Improvement Studies 
Process Capability Indices Process capability indices provide a quantitative measure 
to assess the ability of a process to produce products that meet the specifi cations. A 
commonly used process capability index, denoted as C p , can be calculated as 
Cp = 
. USL LSL 
6. 
(22) 
where USL is the upper specifi cation limit, LSL is the lower specifi cation limit, and 
. is the process standard deviation. Since . is not usually known, it can be estimated 
by .. = s c / 4 . A C p = 1 means that the process is just capable. If the process is centered 
at its nominal value, it will produce 2,700 nonconforming products out of one million 
(PPM). The target value C p is usually set at 1.33 for an existing process and 1.50 for 
a new process. 
It should be noted that the C p value could not indicate the proper process capability 
if the process is not centered since C p does not account for where the process 
mean is with respect to the specifi cations. To alleviate this issue, another process 
capability index, C pk , is used: 
C C C pk pu pl = min( , ) 
Using the x  3. 
natural tolerance limits, they can be obtained as: 
Process mean ( x ) = 10.254 
Upper natural tolerance limit (UNTL) = 13.270 
Lower natural tolerance limit (LNTL) = 7.238 
The relationships among the three sets of limits are illustrated in Figure 14 . As can 
be seen from this fi gure, the current process is not centered at its nominal value and 
its specifi cation limits are tighter than its natural tolerance limits. Due to this, a 
portion of manufactured products ( . 5.4%) will not be able to conform to the 
specifi cations. 
FIGURE 14 Specifi cation limits, control limits, and natural tolerance limits for Pet Tabs 
manufacturing example. 
LSL m0 USL 
LNTL LCL x UCL UNTL

where 
C C pu pl = 
. 
= 
. USL 
and 
LSL 
3 
. 
. 
. 
. 3 
(23) 
The . value can be estimated by x and the . value can be estimated as discussed 
earlier. In general, a process is considered  centered  at the nominal value of the 
specifi cations when C p = C pk and  off centered  when C p < C pk . The relationships 
between C p and C pk are further illustrated in Figure 15 where the process mean has 
shifted from . 0 to . 0 + 2 . to . 0 + 4 . . As noted from the fi gure, C p remains the same 
regardless of the shift but C pk is signifi cantly reduced. 
FIGURE 15 Relationships between C p and C pk . 
0 2 4 6 8 10 12 14 16 18 20 
0 2 4 6 8 10 12 14 16 18 20 22 
0 2 4 6 8 10 12 14 16 18 20 22 24 
LSL m0 
s = 2 
USL
Cp = 1.667 
Cpk = 1.667 
Cp = 1.667 
Cpk = 1.0 
Cp = 1.667 
Cpk = 0.333 
IMPROVING PERFORMANCE OF A PROCESS 307 
If one - sided specifi cations are used, one - sided process capability can also be 
defi ned by Equation (23) where C pu is for upper specifi cation and C pl for lower 
specifi cation. 
Interpretation and Improvement of Process Capability Evaluation and interpretation 
of process capability represent an important step in process quality 

308 QUALITY PROCESS IMPROVEMENT 
improvement. A process must have its source of instability eliminated before it can 
be improved. Results obtained from process capability studies can help determine 
whether the process is stable and meeting its specifi cations. It should be noted that 
a valid process capability study is based on the normality assumption of the process. 
The normality assumption will need to be checked before proceeding to the next 
step. 
Conclusions regarding whether the process is centered at the target and is meeting 
the specifi cations can be drawn from the process capability study. When C p = C pk , 
the process is centered. When C p has a value of 1.0 or greater, the process is capable 
of producing products meeting specifi cations; otherwise, it is not capable. 
Example 5 Following Example 2 , C p and C pk are calculated as 
Cp = 
. 
= 
. 
. 
= USL LSL 
6. 
12 8 
6 1 0054 
0 6633 
. 
. 
C C C pk pu pl = = = min( , min , ) (. . ) . 0 5790 0 7476 0 5790 
where 
Cpu = 
. 
= 
. 
. 
= USL . 
. 3 
12 10 254 
3 1 0054 
0 5790 
. 
. 
. 
Cpl = 
. 
= 
. 
. 
= 
. 
. 
LSL 
3 
10 254 8 
3 1 0054 
0 7476 
. 
. 
. 
Figure 16 shows the histogram of the data in relation to the specifi cations. The x. and 
s charts in Figure 11 show that the process is in statistical control. However, since 
C p < C pk , the process is not centered. With a C pk value of 0.579, it is expected to have 
53,711 nonconforming Pet Tabs manufactured out of one million parts in this production 
line. 
FIGURE 16 Process capability plot for Pet Tabs manufacturing example. 

BIBLIOGRAPHY 
Aft , L. S. ( 1997 ), Fundamentals of Industrial Quality Control , 3rd ed., CRC Press , Boca Raton, 
FL . 
DeVor , R. E. , Chang , T. H. , and Sutherland , J. W. ( 2006 ), Statistical Quality Design and Control , 
2nd ed., Prentice - Hall , Upper Saddle Brook, NJ . 
Gitlow , H. , Gitlow , S. , Oppenheim , A. , and Oppenheim , R. ( 1989 ), Tools and Methods for the 
Improvement of Quality , Irwin , Boston . 
Grant, E. L. , and Leavenworth, R. S. (1996), Statistical Quality Control , 7th ed., McGraw-Hill, 
New York . 
Ishikawa , K. ( 1982 ), Guide to Quality Control , 2nd ed., Asian Productivity Organization , 
Tokyo, Japan . 
Juran , J. M. , and Godfrey , A. B. ( 1998 ), Juran  s Quality Handbook , 5th ed., McGraw - Hill , New 
York . 
Ledolter , J. , and Burrill , C. W. ( 1998 ), Statistical Quality Control: Strategies and Tools for 
Continual Improvement , Wiley , New York . 
Montgomery , D. C. ( 2004 ), Design and Analysis of Experiments , 6th ed., Wiley , New York. 
Montgomery , D. C. ( 2001 ), Introduction to Statistical Quality Control , 4th ed., Wiley , New 
York . 
Ryan , T. P. ( 2000 ), Statistical Methods for Quality Improvement , 2nd ed., Wiley , New York. 
Smith , G. M. ( 2003 ), Statistical Process Control and Quality Improvement , 5th ed., Prentice - 
Hall , Upper Saddle Brook, NJ . 
Summers , D. C. S. ( 2006 ), Quality , 4th ed., Prentice - Hall , Upper Saddle Brook, NJ . 
Tague , N. R. ( 2005 ), Quality Toolbox , ASQ Quality Press , Milwaukee . 
Thompson , J. R. , and Koronacki , J. ( 2001 ), Statistical Process Control: The Deming Paradigm 
and Beyond , 2nd ed., Chapman & Hall , New York . 
To improve the process capability, the process needs to be centered fi rst. This 
usually involves adjusting the process settings. Cause - and - effect diagrams, Pareto 
charts, and other tools discussed earlier in the chapter can be employed to fi nd 
causes to the  off - centering  problems. After the process is brought back to its 
nominal (10), the total nonconforming Pet Tabs produced will be dropped to 
46,673 PPM. This is still far from the 2700 PPM for a  just capable  process ( C p = 1), 
not to mention reaching the goal of 63 PPM at C p = 1.33. 
To further improve the process capability, the variability needs to be reduced. 
This can be achieved by designed experiments. Design of experiment (DOE) is a 
systematic approach that allows engineers and managers to make intentional 
changes in some process settings and assess the effects of those changes. An experiment 
can be designed in this example by varying a few key process settings such as 
drying time, mixing time, and temperature. Through a series of experimentations, 
optimum settings are found for these process variables and the variability of the 
process is reduced by 50%. With this reduction in process variability, the process is 
now exhibiting a C p of 1.265 with 694 PPM. This example highlights the benefi ts of 
process improvement. The move from an off - centered state to a centered state 
resulted in a reduction of process fall - out by 13.1%. With designed experiments, the 
process variability was cut in half and the process fall - out was signifi cantly reduced 
by 98.5%. 
BIBLIOGRAPHY 309


PROCESS ANALYTICAL 
TECHNOLOGY ( PAT ) 
SECTION 4


CASE FOR PROCESS ANALYTICAL 
TECHNOLOGY: REGULATORY AND 
INDUSTRIAL PERSPECTIVES 
Robert P. Cogdill 
Duquesne University, Center for Pharmaceutical Technology, Pittsburgh, Pennsylvania 
Contents 
4.1.1 Introduction 
4.1.2 Basis for Process Analytical Technology 
4.1.2.1 Process Analytical Chemistry 
4.1.2.2 Quality Management 
4.1.2.3 Lean Manufacturing 
4.1.3 Historical Factors Limiting Implementation of PAT 
4.1.3.1 Real and Perceived Technological Barriers 
4.1.3.2 Lack of Economic Incentive 
4.1.3.3 Regulatory Disincentives 
4.1.4 FDA Twenty - First - Century cGMPs Initiative 
4.1.4.1 Conception of the Initiative 
4.1.4.2 Risk - Based Orientation 
4.1.4.3 Quality Systems Approach 
4.1.4.4 Science - Based Policies 
4.1.4.5 International Collaboration 
4.1.5 PAT Evolution in Pharmaceutical Manufacturing 
4.1.5.1 Process Understanding 
4.1.5.2 PAT Principles and Tools 
4.1.5.3 Strategy for Implementation 
4.1.6 PAT Implementation Process 
4.1.6.1 Preparation 
4.1.6.2 Assessment 
4.1.6.3 Analyze 
4.1.6.4 Control 
4.1.6.5 Release Philosophy 
4.1.6.6 Optimization 
4.1 
313 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

314 REGULATORY AND INDUSTRIAL PERSPECTIVES 
4.1.7 Perspectives on the Impact of PAT 
References 
4.1.1 INTRODUCTION 
The implementation of process analytical technology (PAT) is occurring in what is 
perhaps the most exciting period of change in pharmaceutical manufacturing of the 
past three decades. A host of technological, regulatory, and market forces have 
converged during the last fi ve years, yielding new opportunities for innovation in 
the development and operation of pharmaceutical production processes. A major 
driving force for change is the Food and Drug Administration (FDA) initiative to 
implement a modern, risk - based framework for regulation and oversight of pharmaceutical 
manufacturing [1] . The objectives of this section are to outline the historical 
background of process analytics, to provide an overview of PAT in the pharmaceutical 
industry and the business drivers for change, to summarize the FDA  s new initiative 
and the PAT guidance [2] , and to present a basic plan for PAT implementation. 
While the focus of this chapter is PAT, it should be kept in mind that PAT is an 
important part of the much broader and risk - based paradigm introduced by the 
twenty - fi rst - century current good manufacturing practices (cGMPs) initiative. 
4.1.2 BASIS FOR PROCESS ANALYTICAL TECHNOLOGY 
Despite the fact that the FDA  s PAT framework (and guidance) began to take form 
just ahead of the creation of the twenty - fi rst - century cGMPs initiative in 2001, it is 
well known that several of the core concepts were pioneered decades ago by other 
manufacturing industries such as fi ne chemicals, semiconductors, petroleum, and 
consumer products. The main concepts that differentiate PAT from the traditional 
industrial pharmacy skill set (including pharmaceutical and materials science, chemistry, 
and engineering) are process analytical chemistry (PAC) and advanced manufacturing 
science (Figure 1 ). 
For the purpose of this discussion, the term manufacturing science is meant to 
describe the science and technology related to modern innovations in the design 
and management of manufacturing processes. Since it is neither practical nor necessary 
to cover all aspects of modern pharmaceutical manufacturing science in detail, 
the following sections are intended to introduce two specifi c topics which are popular 
in the current industrial vernacular but are not covered in detail in the pharmaceutical 
literature: quality management systems and  lean  manufacturing. 
4.1.2.1 Process Analytical Chemistry 
Process analytical chemistry generally describes the science and technology associated 
with displacement of laboratory - based measurements with sensors and instrumentation 
positioned closer to the site of operation. Although industrial process 
analyzers have been in use for more than 60 years [3] , the modern period of PAC 
essentially began with the formation of the Center for Process Analytical Chemistry 
(CPAC) in 1984 [4] . As described by Callis, Illman, and Kowalski [5] , the goal of 

BASIS FOR PROCESS ANALYTICAL TECHNOLOGY 315 
PAC is to  supply quantitative and qualitative information about a chemical process  
for monitoring, control, and optimization: they went on to defi ne fi ve  eras  of PAC: 
(1) off line, (2) at line, (3) online (4) inline, and (5) noninvasive, which describe the 
evolution of sensor technologies. In addition, they discussed the importance of issues 
beyond chemical sensing, such as sampling, extraction of information from data 
(chemometrics), integration with process controls, as well as the sociological aspects 
of PAC deployment (e.g., gaining the trust of plant operators). 
The industrial PAC movement has been bolstered by two decades of advances 
in materials science, electronics, and chemometrics. Since the inception of CPAC, 
the pace of innovation in sensors, instrumentation, and analytics has quickened 
dramatically. The development of more robust, sensitive photodetector materials, 
microelectromechanical systems (MEMSs), and fi ber optics and the perpetual 
advancement of computing power (as predicted by Moore  s law) have both increased 
the performance and reduced the cost of PAC. As a result, PAC is now a critical 
part of routine operations within the realm of industrial chemistry. Many general 
reviews on the subject of PAC (and PAT) have been published [6  10] . A series of 
literature reviews on the subject of PAC have been published regularly in Analytical 
Chemistry . 
The fi rst review [11] listed manuscripts published between 1987 and 1992, covering 
seven specifi c topics (general PAC, chromatography, optical spectroscopy, fi ber 
optics, mass spectrometry, chemometrics, and fl ow injection analysis), along with a 
section on needs for the future of PAC; in all, the fi rst review included 507 references. 
Subsequent reviews were published in 1995 [12] , 1999 [13] , 2001 [14] , 2003 
[15] , and 2005 [16] . The review series is an essential resource for scientists seeking 
information on specifi c PAC methods; in total, 2650 references covering more than 
16 topics were catalogued by the authors. 
Currently there are three major consortia involving university, government, 
and industrial partners  CPAC, the Measurement & Control Engineering Center 
(MCEC), and the Control Theory and Applications Centre (CTAC)  along with an 
annual conference, the International Forum on Process Analytical Chemistry 
(IFPAC), and numerous online resources that are devoted to issues related to 
process analytics [16] . In parallel with the FDA  s initiative, the term process 
FIGURE 1 Multidisciplinary components of PAT in pharmaceutical manufacturing. 

316 REGULATORY AND INDUSTRIAL PERSPECTIVES 
analytical chemistry is gradually being replaced in the industrial vernacular by 
process analytical technology . This refl ects the expansion of the fi eld as the importance 
of physical characterization, risk analysis, and manufacturing science is 
recognized. 
4.1.2.2 Quality Management 
Many of the quality improvement goals for implementation of PAT in the pharmaceutical 
industry have been achieved by companies in other industries, such as 
automobile production and consumer electronics, as a direct result of adopting principles 
of quality management. The lineage of modern quality management can be 
traced to the work of Walter Shewhart, a statistician for Bell Laboratories in the 
mid - 1920s [17] . His observation that statistical analysis of the dimensions of industrial 
products over time could be used to control the quality of production laid the 
foundation for modern control charts. Shewhart is considered to be the father of 
statistical process control (SPC); his work provides the fi rst evidence of the transition 
from product quality (by inspection) to the concept of quality processes [18, 19] . 
Shewhart  s methodologies were adopted and expanded by W. Edwards Deming 
[20] and Joseph M. Juran [21] , who are credited with the birth of the  total quality  
(TQC) approach in Japan following World War II. Successors to the total quality 
movement include management by objectives (MBO) (1960  s), Crosby  s zero - 
defects (ZD) movement (1970s), the American incarnation of total quality management 
(TQM) (1970s  1980s), quality circles (1970s), quality function deployment 
(QFD) (1980s), the International Organization for Standardization (ISO) 9000 
series (1987), and the Malcolm Baldridge National Quality Award (1987  present). 
The most recent major quality management methodology, Six Sigma (6 . ) [22, 23] , 
pioneered by Motorola, has become immensely popular because of the litany of 
corporate CEOs (e.g., Thomas Galvin, Jack Welch) who have openly credited their 
internal 6 . initiatives for dramatic improvements in bottom - line performance. All 
of these quality movements [24] , however, as well as PAT, are related to the principles 
of Shewhart, Deming, Juran, Crosby, Taguchi [25, 26] , and others, in that they 
are based on systematic methods for understanding the sources of variability in 
processes and minimizing their impact on product quality. 
The so - called DMAIC (defi ne, measure, analyze, improve, and control) methodology 
is a common framework used by improvement teams in many industries to 
apply the concepts of quality management to systematically identify, prioritize, 
and eliminate the root cause of quality problems. A variant of DMAIC, known as 
DMADV (defi ne, measure, analyze, design, and verify), is sometimes used when a 
process or operation requires complete redesign to bring about the desired quality 
improvement and is a central concept of the DFSS (design for six sigma) movement. 
The origins of DMAIC, DMADV, DFSS, and other various quality management 
cycles can be traced to the  Shewhart cycle  of (1) plan, (2) do, (3) study, and (4) 
act [24] . 
Arguably, the most important aspects of quality management for PAT are the 
concepts of quantitative process performance characterization using process capability 
indices as universal descriptors, which form the basis of the  measure  and 
 analyze  portions of the DMAIC model. Process capability indices consider simultaneously 
both process variability and process specifi cations to determine whether 

BASIS FOR PROCESS ANALYTICAL TECHNOLOGY 317 
the process is  capable  [27] . A process is said to be capable if the quality measurements 
for nearly all samples are within the specifi cation limits. A common version 
of the process capability index, Cpk , is calculated according to 
Cpk = 
. . ... 
... 
min 
USL 
, 
LSL 
3 
. 
. 
. 
. 3 
where . and . are the mean and standard deviation and USL and LSL are the upper 
and lower specifi cation limits, respectively, for a product quality measurement. 
Process capability indices are useful for process improvement studies because they 
transform diverse measures of quality (e.g., weight, concentration, rate) into dimensionless 
units, thereby allowing investigators to pinpoint major sources of variation 
in a process (operations which have the lowest Cpk scores) when many measurement 
systems and quality attributes are involved. 
The process capability index, Cpk , is related to the so - called  process sigma  such 
that a 6 . process corresponds to a Cpk of exactly 2.00, or 2.0 defective parts per 
billion (PPB), assuming .N (0, . ) quality variance distribution (can alternative calculation 
for process sigma estimates 3.4 defective parts per million for a 6 . process). 
Examples of the correspondence between Cpk , process sigma, and defect rate for 
.N (0, . ) distributions are shown in Figure 2 . The process capability (based on 
observed yield) of pharmaceutical manufacturers has been cited by some benchmark 
studies to be roughly 0.7 (2.1 . ) [28] . 
While industrial benchmarks clearly indicate that pharmaceutical manufacturers 
have many opportunities to improve quality control, direct comparison with other 
industries may be somewhat misleading. As opposed to such industries as semiconductor 
manufacturing, where defective parts are often readily apparent at some 
FIGURE 2 Graphical illustration of the correspondence between the defects per million 
opportunity (DPMO) process capability (C pk ) and process sigma (assuming normally distributed 
quality variation). 

318 REGULATORY AND INDUSTRIAL PERSPECTIVES 
point in the value chain (i.e., the device built from the part will fail), drug products 
suffer from a high degree of ambiguity in their quality specifi cations. 
For example, fi nished - product release specifi cations such as content uniformity 
are rarely correlated to clinical evidence; rather, they are set according to compendial 
test standards. Furthermore, the functional relationship between in - process 
material characteristics and fi nished - product quality is seldom known at a high level; 
hence, the assigned in - process specifi cations for some operations may over - or 
underestimate the true level of process capability. As the level of process understanding 
in the pharmaceutical industry increases, development of science - and 
evidence - based in - process and release specifi cations will improve the reliability of 
C pk as a tool for process characterization. 
For further information, the NIST/SEMATECH Handbook of Engineering Statistics 
, which is freely available online [23] , and the American Society for Quality 
( www.ASQ.org ), are excellent sources for background information and technical 
details related to quality management. 
4.1.2.3 Lean Manufacturing 
In contrast to quality management systems, which have clear parallels with PAT (i.e., 
reduction of quality variation), the links between PAT and lean manufacturing are 
less direct. In fact, while quality management systems are concerned with process 
analysis of quality variation, lean fl ow path management is concerned with process 
analysis of production time variation. Furthermore, the core concepts of lean manufacturing, 
however, provide the technology platform which the pharmaceutical 
industry will use to derive gains in production effi ciency from the adoption of PAT. 
Without considering the impact of PAT on production effi ciency [i.e., the return on 
investment (ROI) from implementing PAT], industry would have very little impetus 
to voluntarily embrace PAT. The following paragraphs are intended to provide a 
brief introduction to lean manufacturing; later portions of this chapter will discuss 
the business drivers for implementation of PAT. 
Lean manufacturing, or  lean,  is often misunderstood (not unlike TQM or 6 . ); 
for some people, lean business initiatives conjure  slash - and - burn  management 
tactics to reduce workforce levels or shut down low - productivity operations. In fact, 
lean manufacturing has been characterized as  an amalgam of methodologies 
including industrial engineering, just - in - time (JIT) (Osadas  s) 5 - S  s, TQC, continuous 
quality improvement (CQI), Visual Control, Total Productive Maintenance 
(TPM), Quality Circles, and Kaizen  [24] . 
The origins of lean manufacturing are often ascribed to the creation of the Toyota 
Production System (TPS) by the Toyota Motor Corporation. However, the history 
of lean manufacturing can be traced back to industrial developments which occurred 
more than 150 years before TPS. The foundation for modern manufacturing was 
laid by Eli Whitney in 1798; while Whitney is best known for his invention of the 
cotton gin, it is his invention of interchangeable parts and uniform production which 
revolutionized mass production ( www.EliWhitney.org ). 
Nearly a century later, Frederick W. Taylor introduced the concepts of time study 
and standardized work, coining the term scientifi c management . It was not until 1908, 
with Henry Ford  s introduction of the Model T, that the value of lean manufacturing 
was recognized worldwide. Henry Ford is considered by some to be the fi rst practi

BASIS FOR PROCESS ANALYTICAL TECHNOLOGY 319 
tioner of JIT manufacturing; furthermore, his manufacturing system has been 
described as the inspiration for TPS [29] . More recently Ford Motor Company has 
developed a modernized version of Henry Ford  s original system, the Ford Production 
System [24] , which borrows heavily from TPS. 
As a discipline of manufacturing science, lean manufacturing is a technical 
philosophy focused on the reduction of seven types of waste, or  muda,  in manufacturing: 
overproduction, waiting, transport, inappropriate processing, unnecessary 
inventory, excess motion, and defects. The transformation of a process to lean operation 
is accomplished using many tools and strategies. Arguably, the most important 
mechanism for change is to replace traditional  make to forecast  or  push  production 
scheduling with  pull  strategies, such as  kanban  cards. The principles of lean 
have been applied with success in manufacturing and service industries, as well as 
governmental entities. Not unlike quality management, there are literally hundreds 
of books describing the various tools and techniques used to apply lean methodologies. 
The Society of Manufacturing Engineers ( www.SME.org ) maintains publications, 
conferences, and a technical community devoted to production management 
and is a good fi rst source for more information on lean manufacturing. 
Compared with other industries, pharmaceutical manufacturers have been relatively 
late to adopt lean manufacturing; consequently, pharmaceutical cycle times 
are extremely long when compared with other industries [30, 31] . By comparing the 
ratio of total cost of goods sold (COGS) to inventory value for the top 22 publicly 
traded branded, generic, and biotech pharmaceutical companies to the reported 
fi gures for other process industries, a rough indication can be gained of how much 
less effectively pharmaceutical manufacturers manage their supply chains (Figure 
3 ). Furthermore, it would not be diffi cult for most industrial pharmaceutical scientists 
to fi nd common examples of each of the  seven wastes  in a typical pharmaceutical 
manufacturing facility. 
Admittedly, there are some constraints intrinsic to the industry which may ultimately 
prevent pharmaceutical manufacturers from achieving  world - class  supply 
chain and manufacturing performance. Furthermore, application of lean and quality 
management tools to pharmaceutical manufacturing is proving to be a unique challenge. 
A recent survey of 1500 pharmaceutical manufacturing professionals indicated 
that, while more than half of the companies surveyed have implemented lean, 
6 . , or operational excellence, less than half of those programs have yielded satisfactory 
results [32] . 
While these data seem to suggest that lean manufacturing is not suited to pharmaceutical 
manufacturing, it is important to consider that most lean methodologies 
(e.g., TPS) were developed for high - volume production of uniform products. 
Although many  blockbuster  drugs are produced in dedicated facilities or in plants 
specializing in only a few products, it is quite common for pharmaceutical manufacturers 
to produce many products in a single plant, having a high proportion of 
shared equipment. Traditional lean methods, such as kanban cards, are diffi cult to 
manage in a complex,  high - mix  production environment. In order to solve these 
limitations, innovative software algorithms for  fl ow path management  [33] have 
been developed to simulate, design, and optimize pharmaceutical production processes 
according to lean manufacturing principles. 
Furthermore, the effectiveness of lean manufacturing is limited by variability in 
the cycle time (C/T) for individual unit operations as well as by the fi nite risk of 

320 REGULATORY AND INDUSTRIAL PERSPECTIVES 
batch failure during production; this is true regardless of the complexity of the fl ow 
path or of the degree to which equipment is shared. Pharmaceutical manufacturers 
cope with such risks by building up long production queues to accumulate work in 
process (WIP) ahead of unit operations. While this helps to improve capacity utilization 
and overall equipment effectiveness (OEE), it decreases effi ciency by consuming 
working capital and increasing the intensity of overhead operations (required 
to fi nance, transport, and warehouse WIP). In order to gainfully implement lean, 
pharmaceutical manufacturers must fi rst minimize C/T variation and risks to product 
quality. 
Finally, it is well known that a signifi cant portion of the typical production C/T 
reported by industry is consumed by the delay between completion of a unit operation, 
sampling, analysis, reporting, and in - process or fi nished - product release. In 
some scenarios, PAT will enable manufacturers to release fi nished products to the 
market immediately, with no delay for manual, offl ine testing; this is the so - called 
real - time release (RTR) benefi t of PAT. Without PAT and RTR, the effectiveness 
of lean strategies in reducing C/T will be limited by the maximum rate of product 
inspection and release. Thus, it is critical for pharmaceutical manufacturers to deploy 
PAT and lean in parallel if real gains in process performance are to be realized. The 
lean  PAT concept is quite similar to lean  6 . , or  fusion management  [24] . 
FIGURE 3 Ratio of total COGS to reported inventory value. The ratio of COGS to inventories 
is a rough indicator of supply chain velocity. A large ratio implies that inventories are 
small relative to COGS and are turned over frequently. Toyota Motors, for example, which 
is well known for effective supply chain management, has a much higher ratio of COGS to 
inventories than General Motors. 
Budweiser 
Pepsi 
Microsoft 
Tyson 
Toyota 
Kelloggs 
Kraft foods 
Groupe Danone 
DOW 
FMC 
Coca Cola 
Unilever 
BASF 
Proctor & Gamble 
HJ Heinz 
ConAgra 
Celgene 
Genzyme 
Amgen 
Biogen IDEC 
Genentech 
General Motors 
Gilead 
Watson Labs 
Barr Laboratories 
TEVA 
Alpharma 
Mylan 
Forest labs 
Johnson & Johnson 
Merck 
Bristol Myers Squibb 
Astra Zeneca 
Novartis 
Sanofi Aventis 
GSK 
Eli Lilly 
Pfizer 
Wyeth 
2.00 
0.00 
4.00 
6.00 
(COGS/Inventory) ratio 
8.00 
10.00 
12.00 
14.00

4.1.3 HISTORICAL FACTORS LIMITING IMPLEMENTATION OF PAT 
Despite the evidence of fi scal and competitive benefi ts enjoyed by the various 
industries which have embraced process analytics, pharmaceutical companies have 
been notoriously restrained in their efforts to deploy PAT. Indeed, the pharmaceutical 
industry has slipped so far behind peer industries that a well - known Wall Street 
Journal article from 2003 [34] characterized the manufacturing prowess of drug 
makers as lagging  far behind potato - chip and laundry - soap makers.  While the 
declaration was shocking to many, it was, nonetheless, an accurate assessment. 
Before indicting the industry for gross negligence, however, it is important to consider 
the various factors which have acted over time to create the current state of 
affairs. 
Over the years, dozens of excuses have been provided for the industry  s lack of 
manufacturing innovation; many of the reasons are well known and have been 
published elsewhere [35] . For the sake of simplicity, the factors limiting the adoption 
of PAT can be distilled into three categories: real and perceived technological barriers, 
lack of economic incentive, and regulatory disincentives. 
4.1.3.1 Real and Perceived Technological Barriers 
Despite the fact that near infrared spectroscopy (NIR) has been used industrially 
for decades [36] , there has been hesitance to accept and trust  new  process analytical 
measurement technologies as equivalent or superior to traditional methods. For 
example, when a discrepancy between online NIR and laboratory analyses is 
observed, it is rare that the destructive reference methods are ever targeted as the 
source of error, despite the fact that NIR is often the more precise method. The 
hesitance to trust more advanced, multivariate tools (which are perhaps less directly 
understood) has certainly been a detriment to progress in deploying PAT. 
Similar concerns persist with regard to chemometrics (multivariate data analysis), 
information technology (IT), and advanced controls. One reason for such behavior 
may be the practice of calibrating and validating PAT sensors by correlating their 
signals to traditional, laboratory - based reference methods and characterizing performance 
in terms of prediction error [37  39] . It is a truism of statistics that, no 
matter how sensitive or accurate the PAT sensor may be in detecting quality variation, 
the performance of the reference method will always limit the level of perceived 
accuracy. A much more accurate depiction of the performance of PAT sensors 
compared to reference techniques would be to compare analytical fi gures of merit, 
such as signal - to - noise ratio (S/N) or analytical sensitivity, which explicitly account 
for measurement precision [40, 41] . 
Even though the perceptions of PAT instrumentation have begun to improve, 
companies continue to worry that the intensity of product quality sampling afforded 
by PAT sensors will result in negative consequences, such as increased inspection 
and investigations. In other words, many companies continue to  fear what they will 
fi nd  if they begin to analyze their operations more closely. Prior to the introduction 
of rapid, nondestructive quality monitoring tools, there were few alternatives for 
effi cient quality assurance except to rely on batch release criteria, such as the well - 
known U.S. Pharmacopeia (USP) . 905 . procedure, which were based on extremely 
limited sampling (i.e., assay 10 individual dosage units from a 30 - unit sample of a 
production - scale batch). 
HISTORICAL FACTORS LIMITING IMPLEMENTATION OF PAT 321

322 REGULATORY AND INDUSTRIAL PERSPECTIVES 
Despite the fact that the operating characteristic (OC) curve of the USP . 905 . 
test guarantees a signifi cant portion of each batch will have poor quality before 
batch rejection is probable [42, 43] , companies have become comfortable with their 
odds. Process analytical monitoring tools such as NIR spectroscopy, which are 
capable of high - speed sampling in line, online, or at line, have been perceived as an 
additional burden on the rate of successful batch release. 
By forgoing real - time, pervasive quality monitoring, however, companies incur 
signifi cant opportunity costs in at least three ways. First, without continuous monitoring 
there are few feasible opportunities for implementing RTR; time delays 
related to offl ine release testing are one of the most signifi cant factors limiting 
supply chain velocity in pharmaceutical manufacturing. Second, while there is some 
potential for  discovering  a greater number of batches which do not meet release 
criteria, statistical simulations suggest that potentially fewer batches will be rejected 
when larger sample sizes are considered. In other words, when the impact of measurement 
imprecision and the true distribution of quality characteristics are considered, 
traditional release testing methods pose fi nite risks of failing passable batches 
(which otherwise should have passed) because the limited sample does not adequately 
represent the characteristics of the population (Figure 4 ). Finally, and 
perhaps most importantly, traditional sampling techniques are an effective barrier 
to continuous improvement; based on fundamentals of statistical theory, it can be 
shown that samples of at least hundreds of individuals are required to detect incremental 
changes in process capability (Figure 5 ). Hence, even if a company were to 
investigate potential process improvements, only process capability changes of 
improbable magnitude would be recognized with statistical confi dence. 
FIGURE 4 Comparison of operational characteristic (OC) curves for the USP . 905 . ( a ) 
and PAT - based ( b ) release strategies generated by Monte Carlo simulation. The USP OC 
curve ( a ) is based on the assumption of 2% RSD measurement precision; the PAT OC curve 
( b ) assumes NIR measurement of 800 tablets with 0.9% measurement precision; both curves 
were estimated using the same simulated populations of one million tablets having varying 
levels of quality uniformity. Each curve consists of four regions: the regions above and below 
the sigmoid curve correspond to proportions of batches accurately passed or rejected based 
on the release criteria. Along the sigmoid curve are regions related to the rates of false batch 
failure (lower side of curve) and false batch acceptance (upper side of curve). The jagged 
nature of the curves is related to the limitations imposed by fi nite iterations. The slope of the 
curves demonstrates the superior specifi city (or  tunability  ) of release tests optimized for 
PAT systems. 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10
0 
Batches (%) 
98 96 94 92 90 88 
Within-batch true coverage (%) 
False 
fail lots
False pass 
lots 
(a) (b) 
98 96 94 92 90 88 
Within-batch true coverage (%)

4.1.3.2 Lack of Economic Incentive 
A common refrain within the industry has been that there simply is not suffi cient 
fi nancial return from investment in process analytics or manufacturing technology 
upgrades to justify spending. In some respects, this is a valid argument. Historically, 
many of the industries which have justifi ed signifi cant investment in process analytics 
utilized continuous manufacturing; it is far more diffi cult to effi ciently control continuous 
processes (relative batch production systems) without real - time process analytics 
[35] . Hence, while the pharmaceutical industry has been able to choose, many 
other manufacturers have been forced to integrate PAT into their operations. 
Since pharmaceutical investment in PAT continues to be an option rather than 
a priority for most companies, arguments justifying PAT spending are forced to 
compete with other spending initiatives for capital. During each planning cycle, 
company managers must decide whether to allocate additional capital toward 
diverse opportunities, such as greater research and development (R & D), improvements 
in manufacturing capabilities, or additional forces in sales and marketing [i.e., 
selling, general and administrative (SG & A)]. For any particular project to be funded, 
expected returns must not only exceed the company  s cost of capital [i.e., weighted 
average cost of capital (WACC)], winning projects may be required to exceed the 
company  s expected return on invested capital (ROIC) or at least provide expected 
returns in excess of other investment alternatives. A recent academic case study of 
the potential fi nancial returns on investment (ROI) in PAT and lean manufacturing 
in the pharmaceutical industry show, however, that many pharmaceutical manufacturers 
could ultimately benefi t tremendously by improving manufacturing performance 
[44] . 
FIGURE 5 Relationship between sampling rate and effective resolution of process capability 
assessment. The curve is based on the width of the confi dence intervals for estimation of 
mean and variance. The relationship shown does not consider the effect of reference measurement 
precision, which would further reduce the ability to discern changes in process 
capability. 
Detectable change in process capability (95% confidence) 
as a function of sampling rate 
Detectable change in Cpk (%) 
Samples assayed (N) 
10 100 200 300 400 500 600 700 800 900 1000 
1
2
3
4 5 
10 
20 
30 
50 
100 
USP <905>, 30 Samples 
HISTORICAL FACTORS LIMITING IMPLEMENTATION OF PAT 323

324 REGULATORY AND INDUSTRIAL PERSPECTIVES 
Unfortunately, proponents of PAT are only just beginning to develop the methods 
to quantify all of the potential opportunities for ROI. Furthermore, it is important 
to consider the relative level of risk posed by investment in PAT (as opposed to 
other alternatives). Unlike investments in sales or marketing, there remains 
considerable uncertainty in the industry regarding the likelihood of achieving ROI 
projections or the prospect of PAT investment creating new problems. For these 
reasons, management teams have typically found it easier to justify spending in 
R & D and marketing instead of PAT or manufacturing reforms. 
Besides concerns over the likelihood and magnitude of returns on PAT investments, 
it is often cited that manufacturing and optimizing the cost of production 
have simply not been a priority in the industry; manufacturing has often been 
viewed as a cost rather than a value - generating component. The distribution of 
corporate expenditures has been provided as evidence in support of this theory 
(Figure 6 ). Based on corporate annual income statements from 2005, the average 
expenditure on R & D and SG & A among the top - 10 branded pharmaceutical companies 
(by market capitalization, November 7, 2006) was nearly double their reported 
cost of goods sold. Another take on this theory is that institutional and individual 
investors (who own the pharmaceutical companies and supply the capital for their 
operation) and the boards of directors elected by them look favorably on the expansion 
of R & D and marketing investment while taking a more myopic view on the 
importance of manufacturing. It has sometimes been said that Wall Street rewards 
FIGURE 6 Distribution of the components of revenue (FY2005 annual data) for branded 
( a ), generic ( b ), and biotech ( c ) drug manufacturers. Companies are arranged according to 
market capitalization (as of November 2006). 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 
Net profit 
Tax, interest, other 
Research & development 
Net profit 
Tax, interest, other 
Research & development 
Cost of goods sold 
Cost of goods sold 
Selling, general & administrative 
Selling, general & administrative 
JNJ 
AMGN DNA GILD CELG GENZ BIIB 
PFE GSK NVS SNY 
Company (ticker symbol) 
Company (ticker symbol) 
MRK AZN WYE LLY BMK 
(a) 
% of revenues 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 
Net profit 
Tax, interest, other 
Net profit 
15% 
Other Exp. 
12%
R&D 
15% 
Branded 
Pharma 
COGS 
25% 
SG&A 
33% 
Net profit 
16% 
Other Exp. 
10%
R&D 
9% 
Generics 
COGS 
40%
SG&A 
25% 
Net profit 
19% 
Other Exp. 
14% 
R&D 
23% 
Biotech 
COGS 
16% 
SG&A 
28% 
R&d 
Cost of goods sold 
Selling, general & administrative 
TEVA FRX BRL 
Company (ticker symbol) 
MYL WPI ALO 
(b) 
% of revenues 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 
(c) 
% of revenues

(pharmaceutical companies) for innovation in discovery and replication in manufacturing 
[45] . It is not completely coincidence, for example, that Merck  s appointment 
of its president of manufacturing, Richard T. Clark, to chief executive in May 
2005, which, according to fi nancial journalists,  disappointed investors  who apparently 
would have preferred someone with a  research and development background 
 [46] , marked the beginning of a nearly 25% loss in market capitalization 
over the next six months. 
While the various reasons discussed for the pharmaceutical industry  s tepid 
approach to PAT and manufacturing reform are plausible, they are likely secondary 
to the real and perceived risks posed by the regulatory uncertainty surrounding 
innovation in manufacturing. For example, it is well known that many companies 
were beginning to use PAT tools long before the FDA  s initiative, which suggests 
that the economic benefi ts of process analytics have been recognized internally for 
some time. In response to the fear that their use of new technologies would spur 
additional investigations by the FDA, however, some of these companies operated 
in a  Don  t use, or don  t tell  manner with regard to PAT [45] . 
4.1.3.3 Regulatory Disincentives 
The real and perceived fear of regulatory noncompliance has arguably been one of 
the most important factors explaining the industry  s reluctance to pursue manufacturing 
innovation [1, 2] . While the fi rst 25 years of pharmaceutical GMP have been 
effective in ensuring the safety of prescription drug products for consumers, it has 
been achieved at the expense of innovation and fl exibility. Without the ability to 
adjust processes to account for changes in materials, operating conditions, or the 
level of process understanding, process analytics are of nearly no value since there 
is no capacity to act on new information (besides material/batch rejection). 
Furthermore, companies who dared to make changes or implement new technologies, 
whether conventional process improvements, new unit operations, or 
process analytics, were met with extensive supplemental documentation, FDA 
inspection, and the fi nite risk of production delays. Ultimately, the potential for 
regulatory action stifl ed the industry  s desire to pursue technologies which might 
have seemed extraordinary, such as real - time analytics or chemometrics. Finally, 
without the benefi ts conferred by the PAT guidance and risk - based cGMPs initiative, 
industry rarely had incentive to formally analyze the risk of established processes 
out of fear that what they might discover would be used against them in 
regulatory or legal actions. 
4.1.4 FDA TWENTY - FIRST - CENTURY c GMP s INITIATIVE 
The observation that the state of cGMP at the beginning of the twenty - fi rst - century 
was stifl ing innovation in pharmaceutical manufacturing did not go unnoticed by 
the FDA, which also saw opportunity in remodeling the regulatory framework. 
Since many changes, even minor operational modifi cations, required prior approval 
from the agency prior to implementation, regulators were swamped with thousands 
of supplements every year. Resources were stretched between processing of supplements, 
review and approval of new facilities, processes and documentation, and 
inspection; all the while, the FDA was being squeezed by external constraints on 
FDA TWENTY-FIRST-CENTURY cGMPs INITIATIVE 325

326 REGULATORY AND INDUSTRIAL PERSPECTIVES 
budget growth (Figure 7 ). As of 2001, FDA regulators were so burdened that they 
were unable to meet statutory biennial GMP inspections. Finally, the load of supplements, 
reviews, and inspections were acting as a signifi cant drag on the advancement 
to market of new pharmaceutical therapies. 
4.1.4.1 Conception of the Initiative 
The agency began a public dialogue on the state of pharmaceutical manufacturing 
and FDA regulation during discussions with the Advisory Committee for Pharmaceutical 
Science (ACPS) in July 2001, followed by further discussion within the FDA 
Science Board meetings in November 2001 and April 2002 [47] . A signifi cant focus 
of the discussions was the impact of the regulatory framework on innovation, quality, 
and effi ciency as well as opportunities for change. A new, risk - based paradigm which 
rewards innovative producers through opportunities for  regulatory relief  began to 
take shape, displacing the notion of regulatory compliance as a force for innovation. 
The new paradigm offered advantages to the FDA, as well, in that the level of inspection 
resources could be prioritized and allocated according to risk, thereby easing 
FIGURE 7 Trends in FDA workload and staffi ng resources. ( Adapted from L. X. Yu, Implementation 
of quality - by - design: Question - based review, Drug Information Association (DIA) 
42nd Annual Meeting, Philadelphia, PA, 2006 .) 
1000 
800 
600 
400 
200
0 
2001 2002 2003 2004 2005 
ANDAs 
Employees 
4000 
3500 
3000 
2500 
2000 
2001 2002 2003 2004 
Supplements

the strain on FDA resources. These changes signaled an evolution of what seemed 
to be an adversarial FDA  industry relationship toward greater cooperation. 
While the pharmaceutical incarnation of the term PAT was formally introduced 
during these meetings [48] , a signifi cant portion of the concepts which defi ne the 
core of PAT in pharmaceutical science were presented by industrial and academic 
scientists, many of whom had been building support for and working on these issues 
within their organizations for years. Industrial and academic presentations included 
topics such as total quality management [49] , new technologies for pharmaceutical 
manufacturing [50] , and QbD [51] , among others. 
In August 2002, the agency announced the Pharmaceutical cGMPs for the 21st 
Century initiative (or  the initiative  ), which began a two - year effort undertaken 
by a number of multidisciplinary working groups within the FDA, as well as the 
cGMP steering committee, to assess the current regulatory structure and defi ne the 
agency  s new vision for risk - based regulation of manufacturing and product quality. 
The new initiative, which was intended to modernize the FDA  s regulation of 
pharmaceutical quality for human, veterinary, and select human biological products, 
sought to reform the pharmaceutical as well as the chemistry, manufacturing, and 
controls (CMC) programs, with the following specifi c objectives: 
 Encourage the early adoption of new technological advances by the pharmaceutical 
industry. 
 Facilitate industry application of modern quality management techniques, 
including implementation of quality systems approaches, to all aspects of pharmaceutical 
production and quality assurance. 
 Encourage implementation of risk - based approaches that focus both industry 
and agency attention on critical areas. 
 Ensure that regulatory review, compliance, and inspection policies are based 
on state - of - the - art pharmaceutical science. 
 Enhance the consistency and coordination of the FDA  s drug quality regulatory 
programs, in part, by further integrating enhanced quality systems approaches 
into the agency  s business processes and regulatory policies concerning review 
and inspection activities. 
The result of the working groups  assessment enabled the development of the 
new framework embodied by the fi nalized twenty - fi rst - century cGMPs as well as 
the associated components, such as the PAT guidance. Throughout the assessment 
and development, and continuing during the  implementation phase  of the initiative, 
the following set of guiding principles has been maintained: 
 Risk - based orientation 
 Science - based policies and standards 
 Integrated quality systems orientation 
 International cooperation 
 Strong public health protection 
The fi nal report on the results and future plans for the initiative were released in 
September 2004. The report effi ciently describes the motives, origins, development 
FDA TWENTY-FIRST-CENTURY cGMPs INITIATIVE 327

328 REGULATORY AND INDUSTRIAL PERSPECTIVES 
process, and mechanisms for implementing and evaluating the initiative and can be 
found posted on the Center for Drug Evaluation and Research (CDER) Offi ce of 
Pharmaceutical Science (OPS) website ( http://www.fda.gov/cder/OPS/ ). 
Since it would be impractical to accurately describe all of the important aspects 
of the report within this space, the following sections are intended to detail some 
of the concepts and guiding principles of the initiative which are particularly important 
for understanding PAT. The organization of this summary is intended to effi - 
ciently describe selected concepts of the agency  s twenty - fi rst - century cGMPs and 
is not intended to mirror the structure or totality of the associated FDA documentation. 
All who are actively engaged in pharmaceutical manufacturing or are interested 
in PAT are encouraged to read the fi nal report [1] , which should be considered 
a primary source for direction. 
4.1.4.2 Risk - Based Orientation 
The FDA  s adoption of a risk - based orientation for regulation is the most important 
aspect of the twenty - fi rst - century cGMPs. It is a common misconception that the 
agency  s initiative describes a new set of practices for the industry. In fact, while the 
FDA is committed to encouraging innovation in the industry, the twenty - fi rst - 
century cGMPs initiative is entirely focused on changing the agency  s regulatory 
framework so that quality and innovation are rewarded with reduced oversight. 
Now that the agency has entered the implementation phase of the initiative, many 
of the previous regulatory disincentives have been eliminated. In other words, pharmaceutical 
companies are currently free to voluntarily choose whether or not to 
pursue innovative changes in their development, operation, and quality assurance 
of manufacturing processes such as PAT. 
Risk - Based Prioritization of c GMP Inspections The mechanism by which the 
FDA will encourage the industry to join in implementing the new methods is provided 
by the risk - based algorithm for prioritizing cGMP inspections. Incidentally, 
risk - based site selection is the same mechanism which will allow the agency to 
optimally allocate its limited oversight resources to achieve the greatest public 
health impact. Operational effi ciency is a major component of the FDA  s plans for 
the future. The key to the risk - based site selection program is the agency  s risk - 
ranking model, which has been deployed as a pilot program since the beginning of 
its 2005 fi scal year. 
The model is based on a hierarchical risk - ranking and risk - fi ltering method 
whereby a site risk potential (SRP) is estimated as a function of the weighted 
potentials for each of three top - level components of site risk  product, facility, and 
process (Figure 8 ). The risk potential for each of the three top - level components 
is calculated as a function of selected risk factors which are relevant to the component 
(specifi c to the site). A set of subcategories are defi ned for each top - level 
component; each subcategory is comprised of individual risk factors. The initial 
model weights (the actual risk scores at the lowest level) were optimized using 
a combination of empirical evidence and expert judgment. Examples of potential 
risk factors for each top - level component (and associated subcategories) were provided 
in a report which describes the fi rst iteration of pilot risk - ranking model in 
detail [52] . 

The results from the fi rst iteration of the risk - ranking model demonstrated the 
capability of the model to spread SRP scores for the purpose of fi ltering. Future 
iterations of the risk - ranking model will be generated by correlating predicted site 
risk potentials with data gathered by traditional oversight activities (e.g., cGMP 
compliance inspections) and adjusting the risk factor weights to maximize the effectiveness 
of SRP prediction (similar to multivariate linear regression). The selection 
of risk factors included in the fi rst iteration of the model was based on the availability 
of data. Some proposals for future iterations of the model include incorporating 
factors such as systems for continuous assessment of process capability as 
indicators of the site  s level of process understanding and control. Certainly, as the 
model is updated to capture the benefi ts of new best practices in manufacturing, 
such as PAT, the risk ranking will begin to provide effective incentive for producers 
to pursue innovation. 
4.1.4.3 Quality Systems Approach 
According to the FDA staff manual guide [53] , a quality system is a  set of formal 
and informal business practices and processes that focus on customer needs, 
leadership vision, employee involvement, continual improvement, informed decision 
making based on real - time data and mutually benefi cial relationships with 
external business partners to achieve organizational outcomes.  Based on this 
description, PAT should be considered to be an important tool for supporting a 
quality management system. As stated earlier, one of the FDA  s objectives in undertaking 
the initiative was to integrate quality systems and risk management approaches 
into its existing programs with the goal of encouraging industry to adopt modern 
and innovative manufacturing technologies, including industrial deployment of 
quality management systems such as those described earlier in this chapter (e.g., 
ISO 9000). 
In September 2006, the FDA released  Guidance for Industry: Quality Systems 
Approach to Pharmaceutical cGMP Regulations  [54] . The guidance is intended to 
 help manufacturers implementing modern quality systems and risk management 
approaches to meet the requirements of the Agency  s cGMP regulations,  in particular, 
Parts 210 and 211. In developing the guidance, the Quality System Guidance 
FIGURE 8 Schematic of FDA  s pilot risk - ranking model for calculation of site risk 
potential. 
CD1 CD2 CP1 CP2 CF1 CF2 
Top-level 
components 
Categories of 
risk factors 
Risk factors 
(quantitative or 
qualitative 
variables) 
Site risk potential 
Product Process Facility 
FDA TWENTY-FIRST-CENTURY cGMPs INITIATIVE 329

330 REGULATORY AND INDUSTRIAL PERSPECTIVES 
Development (QS) working group  mapped  the relationship between cGMP 
regulations and various quality system models both internal and external to the 
FDA. Their result is a comprehensive model which allows producers seeking to 
implement their own quality management systems to quickly identify those aspects 
of quality systems which are, and are not, correlated with cGMP. 
The QS guidance begins by defi ning critical concepts of modern quality systems, 
including quality, QbD and product development, quality risk management, corrective 
and preventative action (CAPA), change control, the  quality unit,  and the 
six - system inspection model. The discussion of the quality unit describes its relationship 
with the concepts of quality control (QC) and quality assurance (QA) and the 
relationship between the quality unit and the other units within the pharmaceutical 
manufacturing organization. The six - system inspection model is described as a 
blueprint for how compliance inspections will be organized under the new quality 
systems approach and should be considered a template for internal verifi cation of 
compliance within pharmaceutical organizations adopting quality management 
systems (Figure 9 ). 
The majority of the QS guidance is devoted to describing the essential components 
of modern quality systems, including four major factors which must be 
addressed: management responsibilities, resources, manufacturing operations, and 
evaluation activities. Each factor is described in detail, including aspects which 
overlap with cGMP regulations (for each factor there is a table listing the related 
regulatory citations). In particular, the manufacturing section describes aspects of 
quality systems (and related cGMPs) which are closely related to PAT, including 
raw materials analysis, operations monitoring, and procedures for addressing nonconformities. 
Finally, the guidance includes many important references and related 
guidance documents which should be considered by companies seeking to implement 
a quality management system. 
FIGURE 9 FDA  s six - system inspection model. 

4.1.4.4 Science - Based Policies 
Continuous improvement, which the agency describes as an  essential element in a 
modern quality system,  is aimed toward improving effi ciency by  optimizing a 
process and eliminating wasted efforts in production  [1] . One of the unintended 
consequences of the regulatory system (prior to the new initiative) had been the 
suppression of nearly all opportunities for continuous improvement in manufacturing 
once a pharmaceutical product has been approved for market. Changes to formulations 
and processes needed to be justifi ed regarding their impact on product 
quality, often requiring time - consuming postapproval supplements. Producers in 
most other modern industries (many of whom deal with public safety risks on par 
with or exceeding those managed by the pharmaceutical industry) make it a practice 
to continuously fi ne tune and adjust their operations to maximize quality and effi - 
ciency. Pharmaceutical manufacturers, on the other hand, have largely been constrained 
to treat demonstrated processes as if they were set in stone. 
While there is some logic to limiting the scope and pace at which changes can be 
made to processes, there is obvious fallacy in the idea that the fi rst approved con- 
fi guration for a drug manufacturing operation will be optimal, especially considering 
the enormous fi nancial and ethical pressures on process development teams to 
quickly bring new drug therapies to market. This realization spurred the agency to 
begin the process of developing science - based policies and standards to facilitate 
innovation , which currently includes three new updated guidance documents: 
 Sterile Drug Products Produced by Aseptic Processing  cGMP  [55] , the PAT 
guidance, and the draft guidance on comparability protocols. Each guidance document 
encourages voluntary adoption of new technologies in pharmaceutical manufacturing 
by defi ning modern, science - based regulatory mechanisms which enable 
producers to implement strategic improvements with opportunities for more effi - 
cient regulatory compliance. 
Comparability Protocols In fact, pharmaceutical manufacturers have always had 
the option to explore changes to their production processes. The difference between 
the old regulatory paradigm and the twenty - fi rst - century cGMPs initiative is that 
producers who seek to improve the quality and effi ciency of their processes will be 
able to implement changes much more quickly while spending signifi cantly fewer 
resources to maintain compliance. The key to achieving these benefi ts is demonstrating 
that there is suffi cient understanding of the process and changes to be made and 
that implementation of the improvements poses very little risk to consumers. 
A new mechanism for implementing process changes, which refl ects the inclination 
for science - based policies, is detailed in the FDA  s draft guidance  Comparability 
Protocols  Chemistry, Manufacturing, and Controls (CMC) Information  . A comparability 
protocol (CP) is a well-defi ned, detailed, written plan for assessing the 
effect of specifi c CMC changes in the identity, strength, quality, purity, and potency 
of a specifi c drug product as these factors relate to the safety and effectiveness of 
the product  [56] . Submission of a CP by a producer is optional and may be used to 
facilitate changes in a manufacturing process, analytical procedures, manufacturing 
equipment or facilities, or container closure systems or for implementation of PAT. 
The benefi t for producers submitting a CP is that, upon approval of a CP,  the 
FDA can designate, where appropriate, a reduced reporting category for future 
FDA TWENTY-FIRST-CENTURY cGMPs INITIATIVE 331

332 REGULATORY AND INDUSTRIAL PERSPECTIVES 
reporting of CMC changes covered by the approved CP  . For example, changes that 
otherwise would require submission, review, and acceptance of a postapproval supplement 
(PAS) might be designated as annual report (AR) changes if they were provided 
for in an approved CP. The CP is one of the mechanisms by which the FDA intends 
to reduce the number of supplements requiring review. Additionally, the CP was 
designed to facilitate free fl ow of communication with the agency, thereby reducing 
the risk that process changes will lead to unexpected regulatory shutdown or delay. 
Process Validation In agreement with the pursuit of science - based policies, the 
FDA has begun to revise the 1987  Guideline of General Principles of Process Validation 
 and in March 2004 released a revision of the compliance policy guide (CPG) 
(Section 490.100)  Process Validation Requirements for Drug Products and Active 
Pharmaceutical Ingredients Subject to Pre - Market Approval  [52] . The current revisions 
are designed to support continuous improvement and replace the notion of 
 three - batch  validation. The CPG describes the concept that, after having identi- 
fi ed and established control of all critical sources of variability, conformance batches 
are prepared to demonstrate that under normal conditions and operating parameters 
the process results in the production of acceptable product. However, the CPG 
does not describe how many conformance batches are required; rather, the manufacturer 
is expected to provide  sound rationale  for the procedure they choose to 
follow in demonstrating validation. 
The ambiguity in the revised (CPG) regulations may seem to signify that manufacturers 
would need to undertake even more extensive validation exercises when 
in fact the CPG contains language providing a pathway for batch release to market 
distribution concurrent with the manufacture of initial conformance batches or with 
a single conformance batch [57] : 
Advanced pharmaceutical science and engineering principles and manufacturing 
control technologies can provide a high level of process understanding and control 
capability. Use of these advanced principles and control technologies can provide a 
high assurance of quality by continuously monitoring, evaluating, and adjusting every 
batch using validated in - process measurements, tests, controls, and process endpoints. 
For manufacturing processes developed and controlled in such a manner, it may not 
be necessary for a fi rm to manufacture multiple conformance batches prior to initial 
distribution. 
Interpretation of the CPG suggests that implementation of PAT can be an important 
consideration for streamlining process validation. Finally, a quotable interpretation 
of the new science - based paradigm suggests that (instead of validating the process) 
producers should  control the process, and validate the controls.  Beyond revision 
of the CPG, FDA is expected in the near future to release draft guidance on process 
validation, which will be closely aligned with concepts associated with PAT, QbD, 
and the rest of the 21 st century cGMPs. 
4.1.4.5 International Collaboration 
Recognizing the current realities of the global marketplace, the FDA has made 
coordination with international regulatory partners a priority of the twenty - fi rst - 
century cGMPs initiative. By increasing its collaboration with international health 
and regulatory partners, the FDA has been able to leverage its resources through 

increased sharing of information and harmonization of activities. The International 
Conference on Harmonization of the Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) ( www.ich.org ) has been the dominant mechanism 
for international cooperation among pharmaceutical regulatory authorities 
in Europe, Japan, and the United States. 
A consensus vision statement was drafted at the July 2003 ICH meeting with 
regard to the objective of the ICH in harmonizing the efforts of regulatory bodies 
to establish quality systems approaches in their operations:  Develop a harmonized 
pharmaceutical quality system applicable across the life cycle of the product emphasizing 
an integrated approach to quality risk management and science.  
Three consensus guidelines defi ne the core of the ICH  s involvement in harmonization 
of pharmaceutical quality systems  Q8: Pharmaceutical Development, Q9: 
Quality Risk Management, and Q10: Pharmaceutical Quality Systems (in addition, 
each of the guidance documents cites critical areas of overlap with Q6A: Specifi cations: 
Test Procedures and Acceptance Criteria for New Drug Substances and New 
Drug Products: Chemical Substances). 
Q 8: Pharmaceutical Development According to the ICH Q8 guideline [58] , 
the aim of pharmaceutical development is to  design a quality product and the 
manufacturing process to deliver the product in a reproducible manner.  While 
QbD is not specifi cally mentioned in the guideline, the intent of the ICH Q8 expert 
working group (EWG) was to describe a system that would provide incentive for 
manufacturers to incorporate aspects of QbD and continuous improvement throughout 
the product life cycle. In achieving this goal, the guideline they produced 
describes the suggested contents for Section 3.2.P.2 of a regulatory submission in 
the ICH M4 common technical document (CTD) [59] and the FDA electronic 
common technical document (eCTD) [60] . 
The pharmaceutical development and quality overall summary (QOS) sections 
of the CTD (Figure 10 ) provide pharmaceutical scientists with dedicated channels 
to present regulators with the relevant knowledge and process understanding gathered 
during the development of a new product (which can be updated to support 
new knowledge gained over the life cycle of the product following approval). The 
knowledge communicated within these sections are important considerations for 
justifi cation of a lower site risk potential (i.e., SRP, with regard to risk - based inspection) 
and for facilitation of effi cient, question - based review (QbR) [61] . Question - 
based review is another mechanism by which the agency intends to streamline the 
regulatory process as well as reward producers for adopting best practices in quality 
management. 
In addition to facilitating risk - based oversight, the content of the pharmaceutical 
development and QOS sections of the CTD are critical to enabling continuous 
improvement and fl exible operation. The information and knowledge communicated 
within these sections provide scientifi c understanding to support the establishment 
of a manufacturing design space, in - process and release specifi cations, and 
manufacturing controls. 
As described within the Q8 guideline, a design space is the  multidimensional 
combination and interaction of input variables and process parameters that have 
been demonstrated to provide assurance of quality.  So long as process control is 
maintained within the bounds of the design space, operating parameters can be 
adjusted to improve product quality or manufacturing effi ciency. Based on the 
FDA TWENTY-FIRST-CENTURY cGMPs INITIATIVE 333

334 REGULATORY AND INDUSTRIAL PERSPECTIVES 
current defi nition, operation outside of the established design space would initiate 
a regulatory postapproval change process. Thus, complete and accurate communication 
of the knowledge supporting a company  s design space is vital for a company 
to maximize productivity while maintaining regulatory compliance. Furthermore, 
with the new communication pathways in place, companies have incentive to pursue 
manufacturing studies beyond marketing approval to expand their design space or 
to update specifi cations and controls. In addition to the product under review, if 
appropriate, experiences gained from the development (and manufacture) of similar 
drug products may be included. 
Q 9: Quality Risk Management The second working group (ICH Q9 EWG) is 
trying to better defi ne the principles by which risk management will be integrated 
into decisions by regulators and industry regarding quality, including cGMP compliance. 
In November 2005, the Q9 EWG released the  Step 4  version of the Q9 
guideline which defi nes the two primary principles of quality risk management, 
provides a model for the quality risk management process (Figure 11 ), and describes 
the terminology and tools for risk assessment and management. In addition, the 
document includes a concise reference list for more detailed information on risk 
management methods, such as failure mode effect and criticality analysis (FMECA), 
which are important tools for prioritized implementation of PAT. While it is not 
intended to be a  how to  manual for risk management, the Q9 guideline is a valu- 
FIGURE 10 Schematic illustration of the ICH M4 common technical document (CTD); 
the contents of the Quality Overall Summary (2.3) and Quality (3) modules are most relative 
to PAT. 
Module 2 
Module 1 
Regional 
Administrative 
Information 
1 
1.1 Submission 
Module 3 Module 4 Module 5 
Not part of the CTD
CTD 
CTD Table of Contents 
2.1 
CTD Introduction 
2.2 
Quality 
Oveall 
Summary 
2.3 
Quality 
3 
Nonclinical 
Overview 
2.4 
Nonclinical 
Study Reports 
4 
Clinical 
Overview 
2.5 
Nonclinical Written 
and Tabulated 
Summaries 
2.6 
Clinical 
Summary 
2.7 
Clinical 
Study Reports 
5

able information source for companies seeking to incorporate quality risk management 
into their operations [62] . 
Q 10: Pharmaceutical Quality Systems While the Step 2 document for the third 
tripartite guideline, Q10: Pharmaceutical Quality Systems, has not yet been released, 
the fi nal concept paper has been available since 2005 [63] . Similar to the manner by 
which the FDA  s quality systems approach guidance mapped the relationship 
between cGMPs and other industrial quality management systems, the Q10 guideline 
is anticipated to serve as a bridge between the approaches to quality systems 
taken by the different regional regulations, thereby helping to achieve global harmonization 
of quality systems. The guideline is expected to strengthen and complement 
issues covered in Q6A, Q8, and Q9 and will provide a foundation for a 
pharmaceutical quality system based on elements from the ISO 9001 and 9004 
standards. The guideline is also expected to develop harmonized defi nitions for 
issues critical to PAT, including continuous improvement activities, data - gathering 
methods, and the approach to measurement system validation. 
4.1.5 PAT EVOLUTION IN PHARMACEUTICAL MANUFACTURING 
Though it may be tempting to characterize PAT as a revolutionary change in pharmaceutical 
manufacturing, history will likely show that the beginning of the twenty - 
fi rst - century cGMPs initiative and the development of the PAT guidance mark the 
FIGURE 11 Schematic of quality risk management process described within ICH Q9. 
Initiate 
Quality Risk Management Process 
Risk Assessment 
Risk Identification 
Risk Analysis 
Risk Acceptance 
Risk Evaluation 
Risk Control 
Risk Reduction 
Output / Result of the 
Quality Risk Management Process 
Risk Review
Review Events 
unacceptable 
Risk Management tools 
Risk Communication 
PAT EVOLUTION IN PHARMACEUTICAL MANUFACTURING 335

336 REGULATORY AND INDUSTRIAL PERSPECTIVES 
beginning of a period of rapid evolution in pharmaceutical manufacturing which 
will extend far into the future. Even though the twenty - fi rst - century cGMPs initiative 
is more extensive (with regard to changing the relationship between the FDA 
and the pharmaceutical industry), interest in the PAT guidance and the opportunities 
it presents for the industry were initially much greater. More recently, perhaps 
in parallel with some changes in leadership in the agency, there has been a palpable 
shift of emphasis toward QbD, which was barely mentioned in many of the twenty - 
fi rst - century cGMPs documents. It is important to keep in mind that, just as most 
industries have seen a parade of  new  quality systems initiatives over the years 
since Shewhart  s fi rst methods were published, the principles upon which PAT and 
QbD are built, such as robust process design, quality monitoring, and effective controls, 
will persist regardless of the name of the initiative. Furthermore, as with PAT, 
QbD is not a new concept. Indeed, Dr. Genichi Taguchi, who has been credited by 
some as the father of QbD, began applying QbD in pharmaceutical manufacturing 
while working as a statistical consultant for Morinaga Pharmaceuticals Company of 
Japan from 1947  1949 [25] . 
The PAT guidance is unique when compared with typical FDA guidance documents 
in that it is not instructive or limiting per se; rather, the guidance describes 
the principles and tools upon which the PAT framework is built, with the goal of 
 highlighting opportunities and developing regulatory processes that encourage 
innovation.  The FDA  s goal in developing the PAT guidance was to eliminate the 
specter of regulatory uncertainty which has been identifi ed as a major factor limiting 
innovation in pharmaceutical manufacturing. The guidance works with existing 
regulations and was designed to be consistent with the agency  s twenty - fi rst - century 
cGMPs initiative. Furthermore, the guidance emphasizes that the decision on the 
part of manufacturers to work with the agency to implement PAT is voluntary. Since 
the guidance is not prescriptive in nature, it neither describes  how to do PAT  nor 
identifi es any particular practice or technology as  approved for PAT.  
4.1.5.1 Process Understanding 
The agency considers PAT to be a  system for designing, analyzing, and controlling 
manufacturing through timely measurements of critical quality and performance 
attributes of raw and in - process materials and processes, with the goal of ensuring 
fi nal product quality.  Based on this defi nition, it would be practical to consider PAT 
to be an expansion of PAC; PAT builds on the measurement and control aspects of 
PAC by incorporating additional emphasis on QbD and process understanding. 
According to the PAT guidance, a process is generally considered well understood 
when: 
1. All critical sources of variability are identifi ed and explained. 
2. Variability is managed by the process. 
3. Product quality attributes can be accurately and reliably predicted over the 
design space established for materials used, process parameters, manufacturing, 
environmental, and other conditions. 
Furthermore, according to the guidance, the ability to predict  refl ects a high degree 
of process understanding.  

Possession of a predictive model (for product quality attributes) alone does 
not necessarily constitute process understanding, however. A relatively common 
example would be prediction of material or product performance characteristics 
using multivariate measurements, such as prediction of tablet dissolution rate using 
NIR spectroscopy. Multiple researchers have demonstrated that (in some cases) it 
is possible to predict drug release from tablets in vitro using nondestructive NIR 
spectra by generating a calibration model for dissolution rate. Without demonstrating 
at least mechanistic understanding of the physicochemical feature (correlated 
to dissolution rate) being detected by NIR, the calibration model would constitute 
nothing more than pattern recognition (Figure 12 ) [64] . While such a calibration 
may be useful, without greater insight as to the basis for correlation, it would not 
likely be a useful demonstration of process understanding. 
Design Space and Quality by Design The concept of a multidimensional space of 
acceptable operating conditions, or design space, is perhaps one of the most important 
aspects of the twenty - fi rst - century cGMPs which facilitates continuous improvement. 
In a PAT - enabled environment, the process design space must provide 
evidence of QbD [65] and should be the mathematical medium by which process 
understanding and real - time control decisions are communicated (Figure 13 ). 
The current ICH Q8 defi nition of design space, unfortunately, offers little guidance 
with regard to the aspects of a process design space which are required for 
implementation. As a result, a variety of interpretations of what constitutes a suitable 
process design space have recently surfaced among industry participants. One 
of the most popular misconceptions is that an effective design space for a process 
or unit operation can be determined by the common trajectory of PAT measurements 
(i.e.,  process signature  ) related to product batches known to have acceptable 
quality (i.e.,  golden path  ). While such data are useful for monitoring, they 
are nothing more than a modern version of  3 - batch  process validation. Golden 
paths or process trajectories are not suffi cient for control since 1) the path itself is 
not necessarily predictive and 2) such controls would imply that a process is limited 
by its historical path in the space of process parameters. Originally, the term process 
signature was defi ned as a multivariate process measurement, that is, NIR spectrum, 
which contained features useful for describing the impact of the process on the 
chemical and physical aspects of the processed material [38] . 
FIGURE 12 Illustration of aspects of method understanding which must be in place to 
justify product performance measurements using indirect and/or nondestructive analyses. 
PAT EVOLUTION IN PHARMACEUTICAL MANUFACTURING 337

338 REGULATORY AND INDUSTRIAL PERSPECTIVES 
While it is perhaps too early to posit a conclusive standard for pharmaceutical 
process design space development, the following minimum criteria should be 
achieved for a process design space to be suitable for process control: 
 The process design space should be expressed in the form of a mathematical 
model which quantitatively links process capability , quality of input materials, 
and process operating parameters. 
 Relevant critical - to - quality product attributes should be considered by the 
design space model (e.g., content uniformity, bioavailability, stability). 
 Borrowing from a famous quote by Albert Einstein, the (design space) model 
should be as complex as necessary (for accurate prediction), but no less. 
 Product attributes that are superfl uous or are not known to be critical to quality 
should not be considered by the design space model (there should not be a 
penalty for monitoring such parameters, however). 
 In the same way that in vitro  in vivo correlation (IVIVC) is required to be 
granted a biowaiver for implementation of postapproval changes, the ability of 
the design space model to predict the quality of fi nished goods must be validated 
prior to implementation. 
 If the accuracy of the design space model cannot be established a priori with 
statistical signifi cance within portions of the parameter hyperspace, operation 
in such regimes should initiate supplementary quality assurance (inspection) 
activities until the design space model can be updated and revalidated. 
 If unacceptable product quality is observed during operation within a region 
of the design space expected to yield acceptable quality, the design space should 
be considered unsuitable for process control (due to drift or the appearance of 
new factors in the parameter space) until the missing factor(s) can be identifi ed 
and incorporated into the model and the model is revalidated. 
If such a model - based process design space includes a suffi cient portion of the 
factors affecting product quality variance, the process control space can be projected 
to defi ne the bounds of normal operation. Based on this defi nition, the control 
FIGURE 13 Interrelation between design space, PAT, and process control in a manufacturing 
system based on quality - by - design. ( Source : R. C. Lyon, Process monitoring of pilot - scale 
pharmaceutical blends by near - infrared chemical imaging and spectroscopy, Eastern Analytical 
Symposium (EAS), Somerset, NJ, 2006 .)

model algorithm for each operation in the manufacturing process would be generated 
from a subset of the control space spanned by the material qualities and processing 
parameters which impact that operation. Each unit operation control model 
seeks to adjust process parameters in a timely manner in response to changes in 
raw material (feedforward) or fi nished - product (feedback) quality. In other words, 
control the process and validate the controls. 
The mathematical linkage of the design space, process, and control models 
enables continuous optimization of product quality by seeking the optimal point 
within the control space. As the level of process understanding increases or as 
processing conditions evolve, factors might be added or removed from the design 
space and the process and control models updated. Furthermore, by considering 
other factors such as yield, effi ciency, or C/T as a function of the variables spanned 
by the process design space, the process might be co - optimized for quality and 
profi tability. 
It is likely that many pharmaceutical manufacturing operations are not understood 
in a way that product quality variance can be fully described in functional 
form (e.g., transfer functions); attaining such a level of manufacturing knowledge 
should be a goal for the industry. Using functional representations of process understanding 
as the basis set for a process design space, rather than historical performance, 
offers many operational advantages: 
 Effi cient Process Development While the current defi nition of design space 
does not preclude the incorporation of knowledge from other products and 
processes, model - based knowledge representation offers a more robust framework 
for incorporation of external or a priori information. Even though the 
level of quality expected by a particular combination of input and process 
parameters from another product is not likely to transfer to a new product or 
process (in absolute terms), the functional relationships which predict quality 
may be quite similar. Furthermore, model - based design space development 
enables direct incorporation of fi rst principles and mechanistic knowledge, 
which might signifi cantly reduce the complexity of experimental designs 
required for process development since signifi cant terms may be identifi ed in 
silico. 
 Quality by Design The incorporation of functional relationships between 
inputs, parameters, and product quality (or effi ciency), which inherently imply 
magnitude and directionality, enables the use of a process design space as a 
tool for multiobjective process optimization. Furthermore, the model - based 
representation of knowledge is compatible with concepts of risk management, 
enabling more fl exible operation since the risk associated with extrapolation 
could be predicted. 
 Control System Development Model - based design space development offers 
an ideal segue between process and control development. Quite literally, 
a model - based design space would provide the template for development 
of feedforward process control models. Moreover, development of a process 
design space using a model - based framework would facilitate control 
system validation and identifi cation of science - based, in - process, and release 
specifi cations. 
PAT EVOLUTION IN PHARMACEUTICAL MANUFACTURING 339

340 REGULATORY AND INDUSTRIAL PERSPECTIVES 
 Scaling and Technology Transfer Within the current system for process development, 
it is common to use designed experiments (i.e., DOE) where some 
input variables are product specifi c (e.g., excipient  grade  ) or process parameters 
are device dependent (e.g., chopper speed, damper angle). In a model - 
based paradigm, however, a process design space would ideally be generated 
using product - and device - independent units which have more basic physical 
meaning (e.g., modulus, viscosity, energy, or work). Designing and describing 
production processes in fundamental terms or, perhaps, standardized dimensionless 
units would facilitate scaling and transfer of design space and process 
control models to similar manufacturing processes that are based on the same 
physical operating principles. 
Academic research is currently underway to further develop the model - based 
design space concept. Working within the limits of the current system, though, producers 
who are able to demonstrate process understanding or are willing to invest 
in a PAT system to facilitate their development of process understanding can use 
the tools and provisions of the framework to pursue innovation and continuous 
improvement with more effi cient regulatory oversight (i.e., the ability to make 
changes without supplemental review). The PAT framework is described as consisting 
of two components: (1) a set of scientifi c principles and tools supporting innovation 
and (2) a strategy for regulatory implementation that will accommodate 
innovation. The following paragraphs will describe selected aspects of both components 
in detail. 
4.1.5.2 PAT Principles and Tools 
Central to the PAT framework is the acceptance that certain physical and mechanical 
attributes of pharmaceutical ingredients are not necessarily well understood and 
that even processes which have achieved signifi cant process understanding are 
subject to a fi nite level of stochastic variation. Thus, the core of the PAT guidance 
is allocated to describing the principles and tools, such as process analyzers and risk 
analysis, which producers can employ to augment process understanding and mitigate 
latent risks to product quality. 
PAT Tools The guidance describes four categories of PAT tools: 
 Multivariate tools for design, data acquisition, and analysis 
 Process analyzers 
 Process control tools 
 Continuous improvement and knowledge management tools 
Since each of the four categories draws upon methods and technology which are 
already established in other fi elds such as PAC, the discussion of each category 
within the guidance is focused on aspects which are unique or signifi cant to pharmaceutical 
manufacturing, such as process signature [2] . Furthermore, in keeping 
with the spirit of the framework as a catalyst for innovation, the agency made an 
effort to avoid mention of any particular tool or technology in the fi nal version of 

the PAT guidance. The PAT tools section of the guidance does, however, include 
cross - references to relevant portions of current regulations which should be considered 
by a manufacturer developing a PAT strategy or system. 
Standards for Pharmaceutical Applications of PAT During the early stages of 
developing the PAT framework, the agency was aware that the lack of international 
standards was a signifi cant impediment to regulatory coordination and implementation 
of PAT in the global pharmaceutical industry. In 2003, the FDA  s PAT team 
worked with ASTM International to form Technical Committee E55 on Pharmaceutical 
Application of Process Analytical Technology. The E55 committee addresses 
issues related to process control, design, and performance as well as quality acceptance/
assurance tests for the pharmaceutical manufacturing industry. Stakeholders 
in the committee include manufacturers of pharmaceuticals and pharmaceutical 
equipment, federal agencies, design professionals, professional societies, trade associations, 
fi nancial organizations, and academia ( www.ASTM.org ). 
As of mid - 2006, there were three subcommittees of E55: PAT system management, 
PAT system implementation and practice, and PAT terminology. The PAT 
team has been represented on E55 committees with a goal to ensure that standards 
developed are aligned with the PAT guidance and acceptable to the FDA. To date, 
one active standard has been published, while 16 additional standards have been 
proposed. The ASTM International provides another venue for international cooperation 
(consistent with the twenty - fi rst - century cGMPs initiative); the defi nitions 
of PAT (in the FDA guidance and ASTM E55) as well as other concepts are being 
incorporated into the ICH Q8 guidance. 
Real - Time Release ( RTR ) The PAT guidance defi nes RTR as  the ability to 
evaluate and ensure the acceptable quality of in - process and/or fi nal product based 
on process data.  Whereas fi nished products are typically released for marketing 
only after sampling, inspection (i.e., laboratory - based QC testing), and review, 
implementation of an RTR system enables release of fi nished products concurrent 
with the completion of manufacturing operations. Practically speaking, RTR is one 
of the most signifi cant, tangible benefi ts for producers who implement PAT, because 
it can facilitate dramatic reductions in process C/T. 
Real - time release is considered by the guidance to be comparable to alternative 
analytical procedures for fi nal product release and is defi ned within the guidance as 
an extension of parametric release. The defi ning characteristic of RTR is that it 
considers simultaneously the degree to which material attributes and process parameters 
are measured and controlled during manufacturing. It was not intended that 
RTR be implemented by simply installing a rapid measurement system at the end 
of a manufacturing process; such uses for PAT tools would be tantamount to inspection 
and would do nothing to improve quality management. 
The guidance does suggest, however, that it may be feasible to implement RTR 
without fi nished - product quality monitoring by using  the combined process measurements 
and other test data gathered during the manufacturing process.  Similar 
language is found in the USP general notices, where it is suggested that data derived 
from  [validation studies and] in - process controls may provide greater assurance 
that a batch meets a particular monograph requirement than analytical data derived 
from an examination of fi nished units drawn from that batch.  It would not be 
PAT EVOLUTION IN PHARMACEUTICAL MANUFACTURING 341

342 REGULATORY AND INDUSTRIAL PERSPECTIVES 
diffi cult to create a system more capable of detecting quality variation than current 
methods based on inspection. Recent statistical analyses [42] have demonstrated 
that, for determining batch quality, the traditional USP . 905 . method of content 
uniformity testing may indeed have little more statistical power than a coin toss 
until more than 5% of the product exceeds specifi cation limits (corresponds to 
within - batch C pk of approximately 0.65, only slightly worse than has been observed 
in a recent industry benchmarking study [28] ). 
On the other hand, deployment of an RTR system without fi nished - product 
monitoring would require the manufacturer to demonstrate a very high level of 
process understanding based on, for example, their development of a comprehensive 
design space and/or a well - validated process model. Even though it may be 
feasible to implement RTR without end - of - process monitoring, a well - designed PAT 
system will typically include some form of fi nal product quality monitoring as a 
means for mitigating latent risk and creating strategic redundancy in process controls 
and as an additional tool to bolster process understanding. 
4.1.5.3 Strategy for Implementation 
One of the FDA  s goals for the PAT guidance is to  tailor the Agency  s usual regulatory 
scrutiny to meet the needs of PAT - based innovations that (1) improve the 
scientifi c basis for establishing regulatory specifi cations, (2) promote continuous 
improvement, and (3) improve manufacturing while maintaining or improving the 
current level of product quality.  Recognizing that the achievement of this goal 
requires a unique interface between regulators and manufacturers seeking to implement 
PAT, a strategy for implementation based on the integrated systems approach 
was developed. An objective of the strategy for implementation is to facilitate clear, 
effective, and meaningful communication between the agency and industry, for 
example, in the form of meetings or informal communication. 
In practice, the strategy breaks with traditional industry  FDA modes of communication; 
whenever PAT is concerned, it is anticipated that regulators will communicate 
directly with the pharmaceutical scientists and engineers involved with 
development and operation of the PAT system rather than indirectly via a department 
of regulatory affairs. The components of the agency  s regulatory strategy 
include: 
 A PAT team approach for CMC review and cGMP inspections 
 Joint training and certifi cation of PAT review, inspection, and compliance 
staff 
 Scientifi c and technical support for the PAT review, inspection, and compliance 
staff 
 Recommendations provided within the PAT guidance 
PAT Team Approach FDA  s assembly of the PAT team was one of the most signifi 
cant incentives for the industry to pursue manufacturing innovation as described 
in the twenty - fi rst - century cGMPs initiative and the PAT guidance. The PAT team 
was put in place to ensure that industrial PAT applications were handled with expediency 
and accuracy by scientists familiar with the most up - to - date PAT methods. 

At one point the PAT team included more than 20 scientists, including investigators, 
compliance offi cers, reviewers, training coordinators, and a policy development 
team. More recently the agency has begun steps to  sunset  the PAT team, the duties 
of which will ultimately be handled by FDA staff trained in PAT systems. A comprehensive 
scientifi c training program was developed for the PAT team with guidance 
from the ACPS PAT subcommittee. Initial training began in January 2006, with 
plans for further training to be provided by faculty at Duquesne and Delaware 
Universities [47] . 
Research Data Provision In developing the PAT guidance, the FDA recognized 
that, even with the guidance in place, manufacturers seeking to evaluate the suitability 
or potential value of new technologies for process control may be hesitant, 
fi guring that such data will be subject to cGMP inspection, thereby increasing their 
liability with respect to regulatory actions. To allay these fears, the agency included 
a statement which applies to investigational deployment of new technologies [2] : 
Data collected using an experimental tool should be considered research data. If 
research is conducted in a production facility, it should be under the facility  s own 
quality system. . . . FDA does not intend to inspect research data collected on an existing 
product for the purpose of evaluating the suitability of an experimental process 
analyzer or other PAT tool. FDA  s routine inspection of a fi rm  s manufacturing process 
that incorporates a PAT tool for research purposes will be based on current regulatory 
standards (e.g., test results from currently approved or acceptable regulatory methods). 
Any FDA decision to inspect research data would be based on exceptional situations 
similar to those outlined in Compliance Policy Guide Sec. 130.300. Those data used to 
support validation or regulatory submissions will be subject to inspection in the usual 
manner. 
4.1.6 PAT IMPLEMENTATION PROCESS 
The PAT guidance identifi es three possible plans for companies seeking to implement 
PAT: 
 PAT can be implemented under the facility  s own quality system; cGMP inspections 
by the PAT team or PAT - certifi ed investigator can precede or follow PAT 
implementation. 
 A changes being effected (CBE), CBE in 30 days (CBE - 30), or prior approval 
(PAS) supplement can be submitted to the agency prior to implementation, 
and, if necessary, an inspection can be performed by a PAT team or PAT - 
certifi ed investigator before implementation. 
 A comparability protocol (CP) can be submitted to the agency outlining PAT 
research, validation, and implementation strategies and time lines. Following 
approval of this comparability protocol by the agency, one or a combination of 
the above regulatory pathways can be adopted for implementation. 
Refl ecting its nonprescriptive nature, the three implementation plans are essentially 
the only  how to  portions of the PAT guidance. This leaves industrial (and academic) 
scientists and engineers with the burden of determining how best to proceed 
PAT IMPLEMENTATION PROCESS 343

344 REGULATORY AND INDUSTRIAL PERSPECTIVES 
in the deployment of a PAT system. Despite the fact that some pioneering companies 
have been incorporating aspects of PAT in their operations since long before 
the start of the FDA  s twenty - fi rst - century cGMPs initiative, there continues to be 
signifi cant diversity in their approaches to implementation. While perhaps the ambiguity 
(in how best to proceed) has slowed the uptake of PAT to some degree, in the 
long run, the latitude is preferable since the optimal path of implementation will 
likely be unique for most facilities. 
With regard to drug manufacturers  implementation of PAT, a list of 10 questions 
has been presented which provides an initial checklist for companies seeking 
approval of their plans [10, 66] : 
1. Is this a PAT system? 
2. Does it have aspects of design, measurement, and manufacturing control? 
3. Are PAT principles and tools used? 
4. Which tools specifi cally are used for manufacturing control? 
5. How are continuous improvement and knowledge management 
performed? 
6. What risk - based approach has the company taken  assessment, prevention, 
and management? 
7. How are the PAT systems integrated? 
8. What kind of RTR is being proposed or used? 
9. What regulatory process is being considered? 
a. Can the companies  quality systems manage the PAT change? 
b. Are the submission proposals appropriate and justifi ed? 
10. What are the critical aspects that will be evaluated during site visits/ 
inspections? 
Drawing from aspects of the DMAIC model, as well as the risk - based orientation 
and quality systems approach espoused by the FDA  s twenty - fi rst - century cGMPs 
initiative, the Duquesne University Center for Pharmaceutical Technology (DCPT) 
has proposed a six - phase, iterative cycle for process improvement based on PAT 
(Figure 14 ). While there are certainly many acceptable variants of this strategy, some 
of which have begun to appear in conferences and the industrial literature, any successful 
PAT deployment, large or small, will most likely include some combination 
of these elements. In addition, each project phase will necessarily include one or 
more modules of training. Finally, while the project phases are presented as being 
discrete, most of the phases will overlap to some degree. In particular, consideration 
of the objectives for control, release strategies, and plans for continuous improvement 
should begin, along with management buy - in, early in the cycle. 
4.1.6.1 Preparation 
The preparation phase is arguably the most critical step in the path toward PAT 
implementation. Process analytical technology projects are inherently multidisciplinary, 
requiring acceptance and buy - in from corporate divisions which sometimes 

FIGURE 14 PAT implementation cycle with examples of associated activities for each 
phase. 
operate with rather divergent goals and procedures. Most importantly, those who 
are seeking to initiate a PAT project will need to obtain management buy - in at a 
level high enough in the corporate structure to ensure suffi cient resources will be 
available and that the company will be committed to positive change. During the 
preparation phase, a PAT team having a diverse background and critical skills 
should be assembled, and formal planning of the project should begin, including 
selection of the product and process to address. Ideally, dialogue with the FDA PAT 
team should begin early in the preparation phase. 
4.1.6.2 Assessment 
The PAT guidance clearly states that industrial implementations should be risk 
based. Soon after the PAT team and objective have been identifi ed, the project 
should commence with a formal risk assessment. The risk assessment should be 
focused on identifying and characterizing the failure modes which present risks to 
product quality; the outcome of the risk assessment will provide a means prioritizing 
the allocation of PAT resources and a baseline for review of the effect of PAT in 
mitigating risks to quality. 
4.1.6.3 Analyze 
The  analyze  phase of the project consists of the activities which are typically 
associated with PAC, including identifi cation and assessment of potential sensor 
technologies, method development, qualifi cation, and validation. In addition, 
designed experiments (DOE) or data - mining exercises may be performed to 
PAT IMPLEMENTATION PROCESS 345

346 REGULATORY AND INDUSTRIAL PERSPECTIVES 
generate process understanding or to support PAT goals. Plans for the IT infrastructure, 
sampling protocols, and development of controls should also be considered. 
4.1.6.4 Control 
The implementation of controls begins as each new analytical method or technology 
is deployed. Controls may be as simple as automated termination of a unit operation 
upon reaching an endpoint. With greater process understanding, more complex 
controls can be deployed, including feedback (e.g., control of punch force during 
tablet compaction, control of temperature or airfl ow during fl uid bed processing) 
or feedforward controls (e.g., adjustment of process parameters based on incoming 
raw - material quality). The development and implementation of controls should also 
consider operating procedures for adverse situation management and should initiate 
a reassessment of risk to determine the suitability of controls. 
4.1.6.5 Release Philosophy 
For PAT projects including implementation of RTR or some modifi cation of a preexisting 
release mechanism for an approved process, additional method development 
and validation procedures will be required. The real - time release decision will 
typically be determined by a process model, which can be a mathematical equation 
or algorithm within the control system; furthermore, the IT system must accurately 
convey the release decision and supporting data to downstream operations (i.e., 
warehouse, logistics), upstream operations (i.e., production scheduling, accounting), 
or the facility information repository. The interwoven IT and scientifi c components 
require an integrated systems approach to development, validation, deployment, 
and operation. Finally, implementation of PAT systems enables redefi nition of 
product quality acceptance criteria for release; the task of identifying robust release 
criteria suitable for large sample sizes, for example, continues to merit examination 
[43] . 
4.1.6.6 Optimization 
The optimization phase of the project provides an opportunity to assess the performance 
of the PAT system relative to the goals of the project as well as the level of 
latent risk in the system. Ideally, with the PAT s2ystem in place, the level of process 
understanding will be improving as more data are collected for every batch. The 
added insight into the operation may yield new opportunities for improving quality 
or effi ciency or for solving similar problems with another product. The key to success 
in the optimization stage is realizing that it is only the beginning of continuous 
improvement. 
4.1.7 PERSPECTIVES ON THE IMPACT OF PAT 
PAT and the twenty - fi rst - century cGMPs initiative have clearly made an impact 
within the pharmaceutical and associated industries. Signifi cant sums of capital 
are now fl owing in new directions to meet the challenges and opportunities pre

sented by the changes. Some people within the industry, however, question 
whether there will be much of a long - term impact, citing the litany of new eras 
in the industry (and their careers) that turned out to be more of the same. With 
just a bit of observation, though, it is not hard to see that it really is different 
this time. 
The modern pharmaceutical manufacturing industry fi nds itself in a diffi cult situation 
that perhaps few anticipated just 10 or 15 years ago. The rate of new blockbuster 
drug approvals has continued to wane, while new drug therapies become 
inexorably more expensive to discover and develop. Despite the fact that the market 
for drug sales has never been larger, drug company profi t margins are shrinking 
while consumers, feeling that pharmaceutical company profi ts are unjust, have 
reached new lows in their opinion of the industry. A recent survey by the Kaiser 
Family Foundation placed pharmaceutical companies just above oil and tobacco 
companies, and right below health management organizations (HMOs), in terms of 
public opinion [67] . Entities of signifi cant magnitude in both the public and private 
sector are increasingly applying pressure to capture an even greater portion of the 
industry  s compensation. Indeed, there is no shortage of industrial and fi nancial 
publications which have chronicled the pharmaceutical industry  s troubles [34, 45, 
68, 69] . 
The pharmaceutical industry is fortunate, perhaps, to follow (rather than lead) 
most other major industries in adopting truly automated controls, process analytics, 
quality management, and lean manufacturing. The performance of pharmaceutical 
companies relative to the benchmarks for world - class manufacturers provides a 
roadmap for improvement. If the pharmaceutical industry, as a whole, were able to 
at least approach the benchmarks for world - class manufacturing performance (by 
implementing PAT), the savings returned to consumers and shareholders would be 
immense (Figure 15 ). Finally, the returns on investment in PAT are not limited to 
major producers. Estimates based on recent benchmarks suggest that, by successfully 
transforming operations through the deployment of PAT and lean, a typical 
small or mid - sized pharmaceutical manufacturer could improve operating margins 
by up to 600 basis points [44] . 
Forces which are out of the industry  s control are providing more reasons 
than ever before to seek effi ciency in pharmaceutical manufacturing, and the 
FDA is doing its part to clear the way. While the pharmaceutical industry has 
likely been unjustly cast as a culprit behind America  s fi scal crisis in health care, the 
industry has ample opportunity to change for the benefi t of patients as well as 
investors. 
ACKNOWLEDGMENTS 
The author would like to thank the following reviewers for their input, which was 
essential to the quality of this manuscript: James K. Drennen, III, Ph.D., Director, 
Duquesne University Center for Pharmaceutical Technology, Senior Consultant, 
Strategic Process Control Technologies; Robbe C. Lyon, Ph.D., Deputy Director, 
Division of Product Quality Research FDA/CDER; D. Christopher Watts, Ph.D., 
Team Leader, Standards & Technology, FDA/CDER/OPS; and Tom Knight, Founder 
& Chief Strategy Offi cer, Invistics Corp. 
ACKNOWLEDGMENTS 347

348 REGULATORY AND INDUSTRIAL PERSPECTIVES 
FIGURE 15 Potential fi nancial returns from deployment of PAT and lean. The curves are 
calculated based on the aggregate COGS and inventories reported in the 2005 annual reports 
of the top 16 branded and generic pharmaceutical manufacturers (according to market capitalization). 
It is important to keep in mind that working capital savings are a one - time - only 
benefi t, while cost of quality and inventory fi nancing and overhead savings represent on - going 
returns on investment. Furthermore, while the curves may overestimate savings because of 
innacuracies in benchmark data or the limits on the opportunities for PAT implementation, 
they do not account for numerous other potential pathways for returns from PAT such as 
capacity increase, labor productivity enhancement, reduction of QC expense, or decreased 
time to market. 
Cost of Quality Saving ($ Billions) 
10
9
8
7
6
5
4
3
2
1
0
0.5 0.6 0.7 0.8 0.9 1 
Process Capability (Cpk) 
2 4 6 8 10 12 14 
Total Inventory Turn Rate (Turns/Year) 
35 
30 
25 
20 
15 
10
5
0 
Supply Chain Optimization Savings ($ Billions) 
Working Capital Savings 
Financing & Overhead Savings

REFERENCES 
1. U.S. Department of Health and Human Services ( 2004 ), Pharmaceutical CGMPs for 
the 21st century  A risk - based approach, Final report, Food and Drug Administration, 
Rockville, MD. 
2. U.S. Department of Health and Human Services ( 2004 ), Guidance for industry: PAT  A 
framework for innovative pharmaceutical development, manufacturing, and quality 
assurance, Food and Drug Administration, Rockville, MD. 
3. Clevett , K. J. ( 1986 ), Process Analyzer Technology , Wiley , New York . 
4. Illman , D. L. ( 1986 ), CPAC: An industry  university cooperative research center for 
process analytical chemistry , TrAC Trends Anal. Chem. , 5 , 164 . 
5. Callis , J. B. , Illman , D. L. , and Kowalski , B. R. ( 1987 ), Process analytical chemistry , Anal. 
Chem. , 59 , 624A . 
6. Balboni , M. L. ( 2003 ), Process analytical technology: concepts and principles, Pharm. 
Technol . 
7. Koch , M. V. ( 2006 ), Optimizing the impact of developments in micro - instrumentation on 
process analytical technology: a consortium approach , Anal. Bioanal. Chem. , 384 , 1049 . 
8. K u ppers , S. , and Haider , M. ( 2003 ), Process analytical chemistry  future trends in industry 
, Anal. Bioanal. Chem. , 376 , 313 . 
9. K u ppers , S. , and Haider , M. ( 2006 ), Process analytical chemistry , Anal. Bioanal. Chem. , 
384 , 1034 . 
10. Hinz , D. C. ( 2006 ), Process analytical technologies in the pharmaceutical industry: the 
FDA  s PAT initiative , Anal. Bioanal. Chem. , 384 , 1036 . 
11. Beebe , K. R. , et al ., ( 1993 ), Process analytical chemistry , Anal. Chem. , 65 , 199R . 
12. Blaser , W. W. , et al., (1995), Process analytical chemistry , Anal. Chem. , 67 , 47R . 
13. Workman , J. J. , et al ., ( 1999 ), Process analytical chemistry , Anal. Chem. , 71 , 121R . 
14. Workman , J. J. , et al ., ( 2001 ), Process analytical chemistry , Anal. Chem. , 73 , 2705 . 
15. Workman , J. J. , Koch , M. V. , and Veltkamp , D. J. ( 2003 ), Process analytical chemistry , Anal. 
Chem. , 75 , 2859 . 
16. Workman , J. J. , Koch , M. V. , and Veltkamp , D. J. ( 2005 ), Process analytical chemistry , Anal. 
Chem. , 77 , 3789 . 
17. Gluckman , P. , Roome , D. R. , Deming , W. E. , and Delavigne , K. ( 1993 ), Everyday Heroes 
of the Quality Movement: From Taylor to Deming, the Journey to Higher Productivity , 
2nd ed., Dorset house , New York . 
18. Shewhart , W. A. ( 1980 ), Economic Control of Quality of Manufactured Product , ASQC 
Quality Press , Milwaukee, WI . 
19. Shewhart , W. A. ( 1986 ), in Deming W. E. ed., Statistical Method from the Viewpoint of 
Quality Control , Dover , New York . 
20. Scherkenbach , W. W. ( 1991 ), The Deming Route to Quality and Productivity: Road Maps 
and Roadblocks , ASQC Quality Press , Milwaukee, WI . 
21. Juran , J. M. ( 2003 ), Architect of Quality: The Autobiography of Dr. Joseph M. Juran , 
McGraw - Hill , New York . 
22. Bhote , K. R. ( 2002 ), What is Six Sigma? The Ultimate Six Sigma . Vol 1. New York : 
AMACOM ; 9  14 . 
23. Galvin , R.W. ( 2002 ), Forward . The Ultimate Six Sigma . Vol 1. New York : AMACOM ; 
xxi  xxii . 
24. Marash , S. A. , Berman , P. , and Flynn , M. ( 2004 ), Fusion Management: Harnessing the 
Power of Six Sigma, Lean, ISO 9001:2000, Malcom Baldridge, TQM and Other Quality 
Breakthroughs of the Past Century , QSU Pub., Fairfax, VA . 
REFERENCES 349

350 REGULATORY AND INDUSTRIAL PERSPECTIVES 
25. Ealey , L.A. ( 1988 ), Quality by design. Taguchi Methods and U.S. industry . Dearborn, MI : 
ASI Press . 
26. Taguchi , G. , Chowdhury , S. , and Wu , Y. ( 2005 ), Taguchi  s quality engineering handbook . 
Hoboken, NJ : John Wiley & Sons . 
27. e - Handbook of Statistical Methods. NIST/SEMATECH . Available at: http://www.itl.nist. 
gov/div898/handbook/ . 
28. Macher , J. , and Nickerson , J. ( 2006 ), Pharmaceutical manufacturing research project: Final 
benchmarking report, Georgetown University, McDonough School of Business and 
Washington University Olin School of Business, Washington DC. 
29. Levinson, W. A. (2002), Henry Ford  s Lean Vision , Productivity Press , New York . 
30. Leiper , K. ( 2006 ), paper presented at the The Heidelberg PAT Conference, Heidelberg, 
Germany. 
31. Lewis , N. A. ( 2006 ), A tracking tool for lean solid - dose manufacturing , Pharm. Technol. 
30 , 94  108 . 
32. Roumeliotis , G. ( 2006 ), Lean proves mean in drug manufacturing , available: in - 
PharmaTechnologist.com . 
33. Gerecke , G. , and Knight , T. , Improving performance and reducing cycle time using fl ow 
path management: A case study , Pharm. Eng. 21 . 
34. Abboud , L. , and Hensley , S. ( 2003 ), Factory shift: New prescription for drug makers: 
Update the plants, Wall Street J. , Sept. 3, p. 1. 
35. Cooley , R. E. , and Egan , J. C. ( 2004 ), The impact of process analytical technology (PAT) 
on pharmaceutical manufacturing , Am. Pharm. Rev. , 7 , 62  68 . 
36. Cogdill, R. P. (2006), in Brittain, H. G. , Ed., Spectroscopy of Pharmaceutical Solids , Taylor 
& Francis Group , New York , pp. 313  412 . 
37. Cogdill , R. P. , et al ., ( 2005 ), Process analytical technology case study, Part II: Development 
and validation of quantitative for tablet API content and hardness , AAPS Pharm. Sci. 
Tech. , 6 , Article 38. 
38. Cogdill , R. P. , et al ., ( 2005 ), Process analytical technology case study, Part I: Feasibility 
studies for quantitative NIR method development , AAPS Pharm. Sci. Tech. , 6 , Article 
37. 
39. Cogdill , R. P. , Anderson , C. A. , and Drennen , J. K. ( 2005 ), Process analytical technology 
case study, Part III: Calibration monitoring and transfer , AAPS Pharm. Sci. Tech. , 6 , 
Article 39. 
40. Lorber , A. ( 1986 ), Error propagation and fi gures of merit for quantifi cation by solving 
matrix equations , Anal. Chem. , 58 , 1167 . 
41. Braga , J. W. B. , and Poppi , R. J. ( 2004 ), Figures of merit for the determination of the 
polymorphic purity of carbamazepine by infrared spectroscopy and multivariate calibration 
, J. Pharm. Sci. , 93 , 2124 . 
42. Lunney , P. , and Drennen , J. K. I. ( 2005 ), A prevention based strategy for quality control 
using PAT , NIR News , 16 , 7 . 
43. Sandell , D. , Diener , M. , Vukovinsky , K. , Hofer , J. , and Pazdan , J. ( 2006 ), Development of 
a content uniformity test suitable for large sample sizes , Drug. Info. J. , 40 , 337 . 
44. Cogdill , R. P. , Knight , T. P. , Anderson , C. A. , and Drennen , J. K. ( 2007 ), The fi nancial 
returns on investments in process analytical technologies and lean manufacturing: Benchmarks 
and case study , J. Pharm. Innov. , 2(12) , 38  50 . 
45. du Pre Gauntt , J. ( 2005 ), Quality manufacturing: A blockbuster opportunity for pharmaceuticals, 
Economist Intelligence Unit. 
46. Steyer , R. ( 2005 ), Merck names clark CEO, available: TheStreet.com , accessed May 5, 
2005. 

47. Watts , D. C. ( 2006 ), PAT  An FDA paper presented at the The Heidelberg PAT Conference, 
Heidelberg, Germany. 
48. Hussain , A. S. ( 2001 ), Emerging science issues in pharmaceutical manufacturing: Process 
analytical technologies , paper presented at the Science Board Presentations to FDA, 
Rockville, MD. 
49. Chisholm , R. S. ( 2001 ), TQMS, statistically based in-process control with real time quality 
assurance, the AstraZeneca total quality management strategy , paper presented at the 
Science Board Presentations to FDA, Rockville, MD. 
50. Raju , G. K. ( 2001 ), Pharmaceutical manufacturing: New technology opportunities , paper 
presented at the Science Board Presentations to FDA, Rockville, MD. 
51. Scherzer , R. H. ( 2002 ), Quality by design: A challange to the pharma industry , paper 
presented at the Science Board Presentations to FDA, Rockville, MD. 
52. U.S. Department of Health and Human Services (2004), Risk-based method for prioritizing 
cGMP inspections of pharmaceutical manufacturing sites  A pilot risk ranking 
model, Food and Drug Administration, Rockville, MD. 
53. U.S. Department of Health and Human Services ( 2006 ), SMG 2020  FDA quality 
system framework for internal activities, Food and Drug Administration, Rockville, 
MD. 
54. U.S. Department of Health and Human Services ( 2006 ), Guidance for industry: Quality 
systems approach to pharmaceutical cGMP regulations, Food and Drug Administration, 
Rockville, MD. 
55. U.S. Department of Health and Human Services ( 2004 ), Guidance for industry: Sterile 
drug products produced by aseptic processing  Current good manufacturing practice, 
Food and Drug Administration, Rockville, MD. 
56. U.S. Department of Health and Human Services ( 2003 ), Guidance for industry: Comparability 
protocols  Chemistry, manufacturing, and controls information, draft guidance, 
Food and Drug Administration, Rockville, MD. 
57. U.S. Food and Drug Administration (FDA) ( 2004 , Mar.), Sec. 490.100 Process validation 
requirements for drug products and active Pharmaceutical ingredients subject to pre - 
market approval (CPG 7132c.08), FDA, Rockville, MD. 
58. International Conference on Harmonization (ICH) ( 2004 ), Q8: Pharmaceutical development, 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH, Geneva. 
59. International Conference on Harmonization (ICH) ( 2004 ), M4: Organisation of the 
common technical document for the registration of pharmaceuticals for human use, 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH, Geneva. 
60. U.S. Department of Health and Human Services ( 2006 ), Guidance for industry: Providing 
regulatory submissions in electronic format  Human pharmaceutical product applications 
and related submissions using the eCTD specifi cations, Food and Drug Administration, 
Rockville, MD. 
61. Yu , L. X. ( 2006 ), Implementation of quality - by - design: Question - based review , paper 
presented at the Drug Information Association 42nd Annual Meeting, Philadelphia, 
PA. 
62. International Conference on Harmonization (ICH) ( 2005 ), Q9: Quality risk management, 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH, Geneva. 
63. International Conference on Harmonization (ICH) ( 2005 ), Q10: Pharmaceutical quality 
systems, fi nal concept paper, International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use, ICH, Geneva. 
REFERENCES 351

352 REGULATORY AND INDUSTRIAL PERSPECTIVES 
64. Hussain , A. S. ( 2006 ), Quality by design and bioequivalence/bioavailability assessment , 
paper presented at the The Heidelberg PAT Conference 2006, Heidelberg, Germany. 
65. Lyon , R. C. , and Hammond , S. ( 2006 ), Process monitoring of pilot - scale pharmaceutical 
blends by near - infrared chemical imaging and spectroscopy , paper presented at the 
Eastern Analytical Symposium, Somerset, NJ. 
66. D  Sa , A. ( 2005 ), Process analytical technology (PAT): regulatory process, review and 
inspection , paper presented at the 19th International Forum on Process Analytical Technology
IFPAC 2005, Arlington, VA. 
67. Views on prescription drugs and the pharmaceutical industry, The Kaiser Family Foundation, 
2005 . 
68. Arlington , S. , Barnett , S. , Hughes , S. , Palo , J. , and Shu , E. ( 2002 ), Pharma 2010: The threshold 
of innovation, IBM Business Consulting Services, Somers, NY. 
69. Arlington , S. , et al ., ( 2005 ), The metamorphosis of manufacturing, IBM Business Consulting 
Services, Somers, NY. 

353 
4.2 
PROCESS ANALYTICAL TECHNOLOGY 
Michel Ulmschneider and Yves Roggo 
F. Hoffmann-La Roche Ltd, Basel, Switzerland 
Contents 
4.2.1 Basic Concepts and Impact 
4.2.1.1 Defi nition 
4.2.1.2 What Motivated PAT? 
4.2.1.3 Root - Cause Analysis and Process Control 
4.2.1.4 When to Introduce PAT 
4.2.1.5 PAT Enhances Process Understanding 
4.2.1.6 Changing Current Practice Using PAT 
4.2.1.7 Promoting Physical Pharmacy and Pharmaceutical Sciences 
4.2.1.8 Data Mining 
4.2.1.9 Data Warehousing 
4.2.1.10 Data - Mining Methods for Pharmaceutical Processes 
4.2.1.11 Data - Mining Practice 
4.2.1.12 Comments about Data Mining 
4.2.1.13 PAT Methods 
4.2.1.14 Conclusion 
4.2.2 Vibrational Spectroscopy 
4.2.2.1 Introduction 
4.2.2.2 IR Spectroscopy Theory 
4.2.2.3 Mechanical Model of IR Vibration 
4.2.2.4 Quantum Mechanical Model 
4.2.2.5 Anharmonicity 
4.2.2.6 Structure Elucidation Using MIRS 
4.2.2.7 Extending Use of MIRS 
4.2.2.8 Raman Spectroscopy 
4.2.2.9 Introducing NIRS 
4.2.2.10 Benefi ts of NIRS 
4.2.2.11 Introducing MIR/NIR Chemical Imaging 
4.2.2.12 Design of MIR Instruments 
4.2.2.13 Conclusion 
Pharmaceutical Manufacturing Handbook: Regulations and Quality, edited by Shayne Cox Gad 
Copyright  2008 John Wiley & Sons, Inc.

354 PROCESS ANALYTICAL TECHNOLOGY 
4.2.3 Chemometrics 
4.2.3.1 Introduction 
4.2.3.2 From Univariate to Multivariate Regression 
4.2.3.3 Sample Quality and Data Error 
4.2.3.4 Mathematical Preprocessing of Spectroscopic Data 
4.2.3.5 Preprocessing NIR Data 
4.2.3.6 Mathematical Pretreatment and Transformation 
4.2.3.7 Principal - Component Analysis 
4.2.3.8 PCA Practice for NIRS 
4.2.3.9 Pattern Recognition 
4.2.3.10 SIMCA Classifi cation 
4.2.3.11 Regression 
4.2.3.12 Multiple Linear Regression 
4.2.3.13 PCR and PLS Regression 
4.2.3.14 Regression Practice in NIRS 
4.2.3.15 Some Pitfalls 
4.2.3.16 Example Analytical Applications of NIRS 
4.2.3.17 Conclusion 
Bibliography 
4.2.1 BASIC CONCEPTS AND IMPACT 
4.2.1.1 Defi nition 
Process analytical technology (PAT) is one of the objectives contained in the Initiative 
for Pharmaceutical cGMPs for the 21st Century published by the Food and Drug 
Administration (FDA). In a few words and according to the FDA  s guideline, PAT 
can be defi ned as a system for designing, analyzing, and controlling pharmaceutical 
manufacturing through the measurement of critical quality and performance parameters. 
The measurements performed on raw and in - process materials or process 
parameters are intended to enhance fi nal product quality. 
Process analytical technology encourages technological innovation, specifi cally 
the adoption of new analytical techniques by the pharmaceutical industry designed 
to improve the understanding and control of manufacturing processes. Both the 
FDA and industry experts expect benefi ts over conventional manufacturing practices: 
higher fi nal product quality, increased production effi ciency, decreased operating 
costs, better process capacity, and fewer rejects. Correspondingly, fundamental 
changes are also expected within the regulatory framework. The future of pharmaceutical 
production will require innovative technological approaches and more 
science - based processes. PAT will boost collaboration between research and development 
(R & D) and manufacturing departments inside companies and increase 
overall effi ciency. Approvals and inspections will increasingly focus on scientifi c and 
engineering principles. As a result, regulators will set higher expectations for new 
products from the outset. 
4.2.1.2 What Motivated PAT ? 
Preliminary discussions of PAT concepts between the FDA and certain pharmaceutical 
companies already active in this fi eld date back to the late 1990s. In September 

BASIC CONCEPTS AND IMPACT 355 
2004 the FDA released a document for the industry entitled  PAT Guidance for 
Industry: A Framework for Innovative Pharmaceutical Development , Manufacturing, 
and Quality Assurance.  PAT is clearly anchored in FDA corporate culture. 
Pharmaceutical companies are facing growing demands for increased productivity 
and reduced manufacturing costs. They also have to meet the evolving need for 
higher quality standards and higher drug expectations. At the same time the quest 
for new active substances remains a signifi cant issue. Reducing the attrition rate 
among selected candidates will bring more new medicines onto the market. In terms 
of drug marketing, the goal is to improve formulations so as to offer patients innovative 
and more effi cient solutions, and thus achieve commercial success or breakthrough. 
By prioritizing science - based design and introducing novel or improved 
process techniques, backed by the generation of increased critical data throughout 
a drug  s life cycle, the aim of the emerging PAT strategy is to direct the drug industry 
toward these essential goals. 
Because they have been used for many years, a variety of existing experimental 
methods and manufacturing processes are considered well established. They are 
trusted to generate few errors and make only modest contributions to process variation. 
Due to their longevity, they continue to be widely used in recent drug developments. 
Improvements in existing technologies are always possible and are constantly 
being made. However, this makes it diffi cult to consider or identify potential technological 
alternatives without critical review or a voluntary management decision 
to replace well - established techniques. The FDA noticed that nearly all recent drug 
developments lacked the possibility of enhancing and extending process capabilities 
toward newer or alternative technologies. More specifi cally, the FDA wanted to 
encourage drug manufacturers to achieve more innovation and improve risk management 
when releasing new medicines on the market. 
4.2.1.3 Root - Cause Analysis and Process Control 
When a quality problem arises in present - day production, it is increasingly diffi cult 
to identify the root cause. Thorough understanding of process and product performance 
often comes up against knowledge barriers, whether due to the escalating 
documentation burden, lack of time, or loss of expertise. The goal of PAT is to 
enhance process control and understanding so that procedures can be performed 
differently and more effi ciently. The PAT initiative facilitates and encourages the 
introduction of innovative approaches. It makes it possible to consider shifting from 
validation to continuous verifi cation. The next step is effective real - time release with 
continuous processing as an alternative to the conventional batch - after - batch production 
scheme. 
4.2.1.4 When to Introduce PAT 
Building quality into a pharmaceutical product has to be considered from the very 
beginning of the product  s life. Essential preconditions are the equal involvement 
of  and seamless communication between  R & D and manufacturing. One purpose 
of PAT is to provide a motivating framework to bring quality into a product from 
the outset. It is thus essential for it to be involved in the R & D phase. If product 
quality requirements are understood and implemented from the beginning, 

356 PROCESS ANALYTICAL TECHNOLOGY 
root - cause analysis of quality or process failure after scale - up to commercial manufacturing 
will be much easier. This is why PAT could play an even more important 
role in the design and analysis of manufacturing processes, enabling performance 
control to be based on timely measurement of well - described critical processing 
data. 
Data processing needs should also be considered in the context of overall process 
analysis strategy to meet emerging requirements for the speed and volume of data 
collection. Real - time analysis supported by knowledge management requires collecting 
and gathering all production batch information, for example, by data warehousing. 
Thus, a PAT data management strategy based on online process analysis 
or data mining can be set up long before generating large sets of measurement data. 
Historical data analysis should aim to cover method development, method validation, 
and ongoing performance monitoring, as well as routine results for a given 
manufacturing process. 
4.2.1.5 PAT Enhances Process Understanding 
Process analytical technology can greatly enhance process understanding. In fact, 
introducing PAT can act as a key driver to better process knowledge. The expected 
steps in implementing the PAT approach are the collection of online, in - line, and 
at - line data (Figure 1 ) on critical attributes, extraction of information, and analysis 
of process status data, ending with closure of the loop by dynamic process control. 
Innovating during development, applying cutting - edge techniques, and process 
modeling whenever possible, all contribute to a more fundamental exploration of 
the science behind the process. It is important to realize that PAT is not only the 
straightforward introduction of additional analytical techniques into a process but 
also the development of methods to predict future behavior according to given settings 
of the critical parameters. That means being able to predict fi nal product 
quality. For example, while implementing the process, it is important to explore all 
sources of component variation as well as their effect on the fi nished product in 
order to select which quality parameters (i.e., attributes) have to be measured for 
optimal and realistic process control. 
Science, engineering, and control technologies can provide a very high level of 
process understanding and control capability. A process is well understood when all 
FIGURE 1 In - line, online, and at - line process measurements. 
Spectrometer Spectrometer Spectrometer 
Reactor 
Inline Online Atline
Sampling 
Process flow

BASIC CONCEPTS AND IMPACT 357 
critical sources of variability are identifi ed and explained. The process should be 
robust enough to manage this variability. It is also expected that critical quality 
attributes can be accurately and reliably predicted in an adequate design space 
when other unexpected variables are encountered (e.g., change of raw material 
supplier). 
4.2.1.6 Changing Current Practice Using PAT 
An approach integrating R & D and manufacturing will enhance process understanding 
and make acceptable risk management possible. By establishing transferable 
process models, it will be possible to develop and implement adequate measurement 
technologies that match process needs rather than vice versa. More effi cient and 
cost - effective technology transfers will facilitate process knowledge, continuous 
process verifi cation, and compliance, thereby enhancing fi nal product quality. Better 
process understanding makes it possible to operate by continuous process verifi cation 
instead of three - batch validation. Measurement technique selection and integration 
occur very early. Accumulated pertinent knowledge is readily available 
through data - mining techniques to confi rm or control processing. A series of dynamic 
closed control/compliance loops at the process steps identifi ed as critical will increase 
confi dence in fi nal product quality. In addition knowledge accumulated over time 
will provide a basis for immediate and rapid intervention in the event of deviation 
or failure. 
A typical illustration of a PAT approach to quality improvement is the use of 
near - infrared spectroscopy (NIRS) to qualify excipients and active principles just 
before they enter the production process, for example, in dispensing. As discussed 
in the next part, near - infrared (NIR) spectra are informative about product structure 
and overall quality. Because with substances such as excipients the quality 
range was investigated at some time in the past and fi xed into a calibration, NIR 
measurement can provide simultaneous nondestructive confi rmation of the predominant 
physical and chemical parameters. This is an effective method of reducing 
uncertainties about possible causes of failure or poor quality during production. 
Each time a given excipient fails its quality requirements at the moment of use, 
immediate action can be taken. Control is possible before the risk of failure is 
increased. Such an approach is complementary to container - wise identifi cation of 
materials on delivery to a warehouse. 
4.2.1.7 Promoting Physical Pharmacy and Pharmaceutical Sciences 
Process analytical technology supposes a more science - based approach to pharmaceutical 
processes. As a matter of fact, it underlines the observed weakness in formal 
knowledge of the physical phenomena behind pharmaceutical processes. The physics 
is less well understood than the chemistry. Conventional physics has moved increasingly 
into the fi eld of activity of engineers and technologists. Formal approaches are 
lacking. As a consequence, much highly valuable knowledge of physical phenomena 
is dispersed across various disciplines. Expertise in physics is often purely technological 
rather than being formalized and integrated into a specifi c discipline. 
Just as the boundaries of physics and chemistry once merged to create 
physical chemistry, there is an opportunity now for assembling complementary 

358 PROCESS ANALYTICAL TECHNOLOGY 
scientifi c knowledge from various disciplines. It is a major challenge to improve 
understanding through in - depth investigation of the physical phenomena behind 
pharmaceutical processes. This objective motivates the enforcement of physical 
pharmacy to improve process understanding through a grounding in theoretical 
physics. 
One major issue is the science and technology of solid particles and powders: 
characterization, size and shape analysis, processing understanding, and so forth. 
Others include particle formation and fl uid  particle separation, mixture stability, 
and understanding and simulating the dynamics of powder mixtures. For example, 
the compaction state of powders and mixtures may change rapidly depending on 
storage time and conditions. Time to use is not always under control and unexpected 
changes may occur. Stirring a mixture of two free - fl owing powders of different size 
may result in segregation rather than improved mixture quality. The fl ow properties 
of powders depend not only on intrinsic characteristics of the different materials, 
such as particle size distribution, particle shape, and surface properties, but also on 
external conditions, such as humidity or compaction status. Further areas of interest 
include liquid drops, emulsions and colloids, bubbles, and polymers, as well as 
surface properties, surface analysis, interfacial and electrostatic phenomena, surface 
reactivity, wet chemistry properties, and solubility. 
4.2.1.8 Data Mining 
Complex processes generate large volumes of data over time. As ever - increasing 
volumes are collected and stored, the gap between buried information and usable 
accessible knowledge can quickly expand if care is not taken. Data mining extracts 
new knowledge out of accumulated observations and thus provides a basis for decision 
making and action. How to turn understanding of buried knowledge to best 
use? How to extract operational feedback from preexisting, but latent, dormant 
empirical knowledge? Such questions precede any data - mining project. 
As a multidisciplinary technique, data mining sits at the interface between statistics, 
mathematics, and computer science. It is a collection of methods for detecting 
regularities and patterns and for extracting knowledge from massive databases 
using conventional and advanced analytical tools. Another approach to data mining 
is to view it as the multivariate modeling of a real environment on the basis of 
multidimensional and accumulated historical data. Thus, data mining is similar to 
explorative data analysis. It is driven by the data itself. However, it must be considered 
as different from conventional statistics due to the huge volume of processed 
data, far above the megabyte scale. Beyond this critical database dimension, most 
conventional statistical packages exceed their operational limit. Data mining can 
also be performed without the help of professional statisticians. It runs according 
to semiautomatic procedures, which makes it widely attractive and more likely to 
be used in an industrial environment. 
Such situations are characteristic of pharmaceutical processes which accumulate 
a variety of historical data without consideration of pertinence. Accumulation is 
systematic and exhaustive. However, cross - links between data sources or types may 
not be established, leading to irrelevant and undetected redundancies. Reliability 
of the collected data is not clearly established over time and variations may not be 
detected. 

BASIC CONCEPTS AND IMPACT 359 
4.2.1.9 Data Warehousing 
The 1990s saw the development of data warehouses. An ideal data warehouse is a 
collection of historical data varying with time, organized by topic, aggregated in a 
unique database, and stored in a way that facilitates decision making (Figure 2 ). 
Three main functions are required to manage data warehouses. First, the data must 
be collected or else accessed by an alternative method, for example, as preexisting 
databases or fi les. Second, the data warehouse requires management and control 
tools. Only then can the third function operate, namely data analysis for the purpose 
of decision making and new knowledge. Dedicated information management tools 
mediate all external, operational, and historical data to the warehouse. Decisional 
information management components are used to extract and visualize the data 
warehouse information. Online analysis processing (OLAP) consists of the real - 
time analysis and visualization of the historical data. Data mining involves the 
extraction of rules and models constructed from the collected data. 
Online analysis processing mainly comprises the interactive exploration of multidimensional 
data sets, or data cubes, which are manipulated by operations from 
matrix algebra, for example, slice - and - dice, roll - up, and drill - down. Computing performance 
is related to data warehouse size and also data quality, for example, 
missing data, unsharpness, and redundancy. The multidimensionality issue is critical 
for extracting pertinent information and selecting the results to be stored and 
visualized. 
The data - mining tools now incorporated in much commercial software are a set 
of techniques and algorithms for exploring large databases in order to extract 
semantic links pertinent to event explanation and new knowledge acquisition. The 
more general goal of data mining is to extract rules and models for understanding 
connections and assisting decision making. There are numerous fi elds of application: 
risk analysis, manufacturing trends, raw material management, maintenance, process 
validation, development, quality control, and so forth. The idea behind data mining 
consists in introducing or proposing rules associated with likelihood coeffi cients 
established from a large set of existing (i.e., historical) data. The techniques used 
FIGURE 2 Schematic structure of a data warehouse. 
Data 
warehouse 
External data sources Internal data sources Operational data sources 
Data-mining 
modeling of rules 
prediction 
OLAP 
Data analysis 
visualization 
Transformation or 
pretreatments

360 PROCESS ANALYTICAL TECHNOLOGY 
are drawn from the fi elds of artifi cial intelligence and numerical and statistical data 
analysis, for example, functional modeling, learning machines, neuronal networks, 
Bayesian networks, support vector machines, modeling of associations, and explanatory 
rules, classifi cations, and segmentations. Their computing complexity derives 
from the dramatic up scaling from database to data warehouse level (from megabase 
to petabase, i.e., 10 6 . 10 15 ). 
4.2.1.10 Data - Mining Methods for Pharmaceutical Processes 
The data warehouse is a central repository of data accumulated over time from 
various origins: quality control, quality assurance, production, development, and the 
like. The accumulated data represent a potential gold mine, conferring competitive 
advantage by facilitating understanding of pharmaceutical process and optimizing 
it in the light of buried empirical knowledge. 
Data mining is used to extract previously unexploited data and knowledge. Its 
potential for acquiring knowledge and generating explanatory rules can overcome 
the loss of data or underused accumulated data. There are two ways of proceeding. 
The fi rst is proactive or directed, for example, hypothesis testing. Particular groupings 
or features are suspected, and verifi cation or confi rmation of identity is sought. 
The second is reactive or undirected, consisting of simple data exploration. Groupings 
are unknown, properties undetected or latent, and patterns unidentifi ed. Alternative 
terms for these approaches are supervised and unsupervised learning, 
respectively. Top - down and bottom - up approaches complement one another. For 
example, the confi rmatory tools of supervised learning can be used to verify and 
certify the quality of the discoveries obtained using the exploratory approach. 
What can be obtained using data - mining tools? Here is a short list of achievable 
goals: 
 Data characterization to extract or determine descriptors or indicators, for 
example, by generalizing, summarizing, or grouping 
 Establishment of associative and explanatory rules 
 Classifi cation (supervised learning) of items or objects in classes according to 
a given probability 
 Clustering of data items (unsupervised learning) in classes, after establishing 
class limits inductively from existing data sets 
 Detection of similarities in time series 
 Pattern recognition 
Data from external and internal sources is integrated, aggregated, or associated in 
time series. Data items may contain errors or the data may be missing, unsharp, 
redundant, or contradictory. A language with operators and variables is required to 
establish models. Validity levels also have to be defi ned using suitable optimization 
and validation criteria. In addition, a search method is required to extract the data 
from the data warehouse and prepare it for analysis. 
Data mining can, therefore, be considered as a three - step operation. Prior to any 
analysis, the collected data is preprocessed to integrate the warehouse, and some 
verifi cation is performed to maintain the data level: for example, integration, 

BASIC CONCEPTS AND IMPACT 361 
aggregation, or grouping of data from different internal and external sources. The 
data is then selected and data mining performed applying the appropriate algorithms 
or models. Results are visualized and interpreted for experts in the fi eld. 
4.2.1.11 Data - Mining Practice 
Data mining is part of an action process known as a business intelligence chain 
(Figure 3 ). Data mining is a fl exible solution to the recurrent problem of how to 
derive knowledge from data. The source for data mining is the existence of a large 
but buried data set. The corresponding data analysis is an intellectual method that 
applies only if integrated into the current operational process. Hypothesis testing, 
knowledge acquisition, and the generation of explanatory rules are directed by 
active collaboration between different process actors. Data mining is teamwork that 
requires expertise in various areas, such as information technology (IT), database 
management, and data analysis. However, the methods are available in commercial 
packages and may not require the expertise of traditional statisticians. It is the 
computer which is responsible for discovering patterns or identifying rules or features. 
In summary, data mining is a logical loop involving the following steps: 
 Business understanding 
 Precise setting of the data - mining project, for example: 
Defi nition of realistic objectives 
Field of treated data 
Inventory of available or usable data 
 Data preparation 
Extraction from internal or external sources 
Verifi cation and correction 
Pretreatment 
 Warehouse construction 
 Modeling, for example: 
Description and visualization 
Affi nity grouping 
Rules of association, explanatory rules 
Clustering 
FIGURE 3 Place of data mining in the decision chain. 
Data Information Knowledge Decision Action 
Business intelligence chain 
Data mining 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 

362 PROCESS ANALYTICAL TECHNOLOGY 
Classifi cation 
Estimation 
Prediction 
 Evaluation and comparison of models 
 Documentation and presentation of results 
 Deployment for action 
 Back to business understanding. 
4.2.1.12 Comments about Data Mining 
Data mining provides an explanatory analysis from a confi rmatory analysis. It is 
tempting to extract maximal value from available resources such as any kind of 
accumulated data. But maximal effi ciency requires critical insight into the expertise 
actually buried in data collections or warehouses. The goal of data exploration is to 
access the buried data to acquire the knowledge that will make explanation, prediction, 
or estimation possible. That is why data mining requires team effort from data 
specialists, users, information technologists, and specialists in the relevant fi eld (in 
this case, pharmaceutical process). It also requires senior management support 
throughout the organization. Mining is a matter of good practice according to established 
rules but also a challenge for innovative mathematical techniques. Not all 
patterns or rules found by data mining are interesting, although the results should 
remain logical and actionable by experts in the relevant fi eld. Because the 
algorithms involved tend to be complex and the data volume is huge, software 
implementation together with the level of information technology are major 
considerations. 
Data mining is driven by the accumulated data but always directed at solving a 
process, business, or research problem. The results are designed to make it easier to 
reach a diagnosis or make a decision. They are only likely to be useful in context: 
that is, they are not simply numbers and graphics but an aid to insight for experts 
in the relevant fi eld. Also, no single mining technique is equally applicable. A range 
of different methods or algorithms should be considered, as no one particular technique 
will work equally well or outperform all other techniques on all problems. 
Nor will the value of an analytical technique exceed that of the data upon which it 
is based. 
4.2.1.13 PAT Methods 
Almost any existing analytical method can serve the objectives of PAT. Many online 
applications already exist. With newer techniques, like NIR imaging or matrix - 
assisted laser desorption/ionization time - of - fl ight (MALDI - TOF) mass spectrometry, 
there are technological problems about performing online or inline analytics. 
Implementing a given analytical technique close to or during process does not 
always provide better process understanding. Attributes which are not informative 
should not be measured at all and are not worth the burden of complex process 
implementation. 
Use of the various techniques listed in Table 1 depends on process requirements. 
The validity of a given technique or analytical application is challenged by every 
0 
0 
0 

TABLE 1 Analytical Methods for PAT 
Method Description Online Application Chemical Identifi cation 
Pharmaceutical Application 
Examples 
Infrared, 
near - infrared, 
and 
Raman spectroscopy 
Vibrational spectroscopy 
(discussed in this chapter) 
. 
. 
Reaction monitoring 
Polymorphism 
Content determination 
Process monitoring (drying, 
granulation, blending) 
Hyperspectral imaging 
Vibrational spectroscopy 
coupled with a spatial 
analysis (cf. chemical 
imaging chapter) 
. 
Chemical compound distributions 
Counterfeit detection 
UV  Vis spectroscopy Photoelectron spectroscopy 
. 
. 
Color measurement 
Dissolution testing 
Cleaning validation (ppm - level 
detection) 
Terahertz spectroscopy Far - infrared spectroscopy; 
3D imaging 
. 
Polymorphism 
Coating integrity and thickness 
API distribution possible 
Laser - induced breakdown 
spectroscopy 
Plasma generated by a laser 
pulse and detection of the 
emitted light (destruction 
of sample) 
. 
Drug development 
Process troubleshooting 
Laser diffraction Interaction of a laser beam 
with particles and 
detection of the scattered 
light 
. 
Particle size determination 
Effusivity Combines thermal 
conductivity, density, and 
heat capacity 
. 
Mixing, 
blending, 
granulation 
monitoring 
Acoustic methods 
Active or passive 
. 
Solid, 
semisolid, 
and high viscose 
sample 
High shear granulation 
monitoring Crystallization 
monitoring 
363

364 PROCESS ANALYTICAL TECHNOLOGY 
technological advance or new analytical technique. Innovation continuously drives 
optimization of overall process performance. 
4.2.1.14 Conclusion 
Process Analytical Technology can be viewed as a constellation placing greater or 
less emphasis on a given activity depending on the current problem or situation 
(Figure 4 ). There is no written rule or straightforward path to progress through PAT. 
Experience and expertise are necessary, together with a good knowledge of the 
pharmaceutical environment. Once a pharmaceutical company has decided 
to implement PAT, continuous management support for the development and 
maintenance of PAT - related activities is critical. It is a strategic and necessary step 
for the future success of PAT to encourage, stimulate, and initiate scientifi c collaboration 
and interaction as well as the relevant education and training. Better understanding 
and control of chemical and pharmaceutical processes are greatly needed, 
as well as the development of advanced measurement tools and data analysis 
methods. 
A summary of PAT benefi ts follows: 
 Immediate action if quality is not met 
 Better process control and understanding 
 Less uncontrolled variation and less production waste 
 Better and more stable products 
 Data collection and improved historical knowledge 
Process analytical technology continuously improves product quality, extends the 
acquired knowledge base for new projects, and shortens time to market. 
FIGURE 4 PAT constellation (DoE, design of experiments). 
DoE 
Risk 
analysis 
Analytical 
methods 
PAT 
Chemometrics 
Data 
mining 
Physical 
pharmacy 
Pharmaceutical 
sciences 
Sensor 
technology 
Pharmaceutical 
technology

4.2.2 VIBRATIONAL SPECTROSCOPY 
4.2.2.1 Introduction 
Modern infrared (IR) spectroscopy is a versatile tool applied to the qualitative and 
quantitative determination of molecular species of all types. Its applications fall into 
three categories based on the spectral regions considered. Mid - IR (MIR) is by 
far the most widely used, with absorption, refl ection, and emission spectra being 
employed for both qualitative and quantitative analysis. The NIR region is particularly 
used for routine quantitative determinations in complex samples, which is of 
interest in agriculture, food and feed, and, more recently, pharmaceutical industries. 
Determinations are usually based on diffuse refl ectance measurements of untreated 
solid or liquid samples or, in some cases, on transmittance studies. Far - IR (FIR) 
is used primarily for absorption measurements of inorganic and metal - organic 
samples. 
Within the electromagnetic spectrum (Figure 5 ), the IR region ranges from 12,800 
to 10 cm . 1 or from 0.78 to 1000 . m. The IR domain is conveniently subdivided into 
NIR, MIR, and FIR, respectively, with the following limits: 
Near 0.78  2.5 4000  12,800 
Mid 2.5  50 200  4000 
Far 50  500 20  200 
Methods and applications differ with the IR subregion considered. Academia and 
analytical chemists commonly consider MIR as the default region of interest. 
Current MIR instruments are completely different from traditional grating spectrophotometer 
technology. The generalization of Fourier transform (FT)  based spectrometers 
in the early 1980s lowered instrument prices and increased the number 
and types of MIR applications, in particular thanks to the use of interferometers in 
improving signal - to - noise ratios and detection limits. IR applications were originally 
limited to qualitative organic analysis. Almost from the outset, absorption MIR 
became a well - established application for structure elucidation. Organic chemists 
were trained in the visual and direct interpretation of MIR spectra. Nowadays mid - 
IR spectroscopy (MIRS) tends to be more viewed as a useful tool for the quantitative 
analysis of complex samples by absorption and emission spectrometry, which 
may require calibration and data pretreatment. 
Near - IR measurements can be performed similarly to those using dedicated 
ultraviolet (UV) or visible spectrophotometers. Historically, the most important 
FIGURE 5 Limits and designation of the spectroscopic domains. 
cm-1 3.3 20 200 4 000 12 500 25 000 10 5 
Far Middle Near 
Microwaves IR VIS UV 
mm 3 000 500 50 2.5 0.8 0.4 0.1 
VIBRATIONAL SPECTROSCOPY 365

366 PROCESS ANALYTICAL TECHNOLOGY 
application was quantitative analysis in the food and feed industries. Only more 
recently have the chemical and pharmaceutical industries shown increasing interest 
in the NIR range. The major reason for the delay is in the type of information 
delivered. All observed bands result from overtones or combinations of overtones 
originating in the fundamental MIR region of the spectrum. Because the measurement 
method is nondestructive, samples are measured with little or no specifi c 
preparation. NIR spectra contain chemical and physical information on the sample. 
Direct interpretation is limited, if not impossible, meaning that multivariate data 
processing is routinely required to extract the relevant information. This led most 
analytical chemists to ignore the potential of NIR. Until the early 1990s, NIR spectrophotometers 
tended to be the dispersive type based on diffraction gratings. Subsequent 
technological advance has brought FT and diode array instruments. Filter 
instruments remain used for ultrarapid measurement of material composition in the 
food and feed industries. 
Being at the edge of the IR region, FIR is believed to have less industrial potential. 
This is partly due to unresolved experimental and technological diffi culties. FIR 
may provide relevant information, but at the cost of disproportionate effort. Routine 
use in the pharmaceutical environment is not anticipated in the near future, and for 
this reason we shall not discuss FIR further. 
The most recent developments in IR/NIR technology include imaging large sample 
surfaces, nondestructive analysis of solids by attenuated total refl ectance (ATR), and 
photoacoustic measurement. Instrument performance continues to increase, with particular 
respect to reliability and modularity. Spectrometer downsizing, speed of measurement, 
and mobility no longer represent critical challenges. However, what has 
really expanded the scope of MIR applications, and use of the full NIR region, has 
been the constant increase in computing power. The fi eld of application of IR spectroscopy 
is moving toward the quantitative analysis of complex samples in various 
measurement modes. These types of samples are characteristic of the pharmaceutical 
industry. Noninvasive spectral sampling using light probes is at last making in situ 
analytics attractive, for example, for performing online real - time measurements. 
Infrared microscopy was introduced in the early 1980s. Two microscopes, an 
ordinary optical microscope and an FT IR instrument with refl ection optics, were 
combined. The optical microscope is used to visually locate the spot of interest. The 
spot is then irradiated with the IR or NIR beam. There are numerous applications 
for noninvasive measurement, including of contaminants, particles, imperfections, 
and for fi ber identifi cation. Chemical imaging systems (CIS) are a refi nement of the 
technique. Spectra are collected from adjacent areas (pixels) on a larger surface. In 
practice, an imaging breakthrough became possible after moving away from pixel - 
after - pixel scanning. CIS fl exibility and speed of acquisition improved with the 
introduction of new detectors, for example, focal plane array (FPA) detectors. Multiple 
IR/NIR spectra (up to many thousand) are scanned in a single step on the 
sample surface. With image analysis algorithms and fast computers, current NIR/IR 
imaging techniques hold fresh promise for resolving quality problems. 
4.2.2.2 IR Spectroscopy Theory 
In a typical IR absorption spectrum of an organic substance (Figure 6 ), the ordinate 
is transmittance and the abscissa is the wavenumber. A linear wavenumber scale is 

preferred because of the linear relationship between wavenumber and energy and 
frequency. The frequency of an absorbed radiation is the molecular vibrational frequency 
actually responsible for the observed absorption. 
Infrared absorption, emission, or refl ection for molecular species can be explained 
by assuming transitions from one rotational or vibrational energy state to another. 
IR radiation is not energetic enough to produce electronic transitions similar to 
those resulting from UV, visible (Vis), or X - ray radiation. Absorption of IR radiation 
is limited to molecular species with small energy differences between various 
vibrational and rotational states. In order to absorb IR radiation, a molecule must 
undergo a net change in dipole moment as a consequence of its vibrational or rotational 
motion. Under these circumstances an alternating electrical fi eld interacts 
with the molecule and causes changes in the amplitude of one of its motions. The 
dipole moment is determined by the magnitude of the charge difference and the 
distance between the two charge centers. In addition, regular fl uctuation in dipole 
moment occurs, and a fi eld is established which interacts with the electrical fi eld 
associated with the incident radiation. If the radiation frequency exactly matches a 
natural vibrational frequency of the molecule, a transfer of energy takes place that 
changes the amplitude of molecular vibrations and absorption of radiation results. 
Similarly, the rotation of asymmetric molecules around their centers of mass results 
in periodic dipole fl uctuations which interact with radiation. Homonuclear species 
are not concerned and such compounds cannot absorb in the IR. 
The amount of energy required to cause a change in energy level is approximately 
equivalent to radiation of 100 cm . 1 or less. The relative positions of atoms in a molecule 
fl uctuate continuously, and multiple types of vibrations and rotations about 
the bonds in the molecule are possible. Exact analysis of all movements becomes 
FIGURE 6 Typical example of an infrared absorption spectrum. 
55 
60 
65 
70 
75 
80 
85 
90 
95 
%T 
500 1000 1500 2000 2500 3000 3500 
Wavelength ( cm1) 
VIBRATIONAL SPECTROSCOPY 367

368 PROCESS ANALYTICAL TECHNOLOGY 
impossible for molecules comprising several atoms. Not only do larger molecules 
have more vibrating possibilities, but intercenter interactions occur that must be 
taken into account. Vibrations may be of the stretching and bending variety. Stretching 
vibration involves a continuous change in interatomic distance along the axis of 
the bond between the atoms. Bending vibration is characterized by a change in the 
angle between two bonds and comes in four types: scissoring, rocking, wagging, and 
twisting. All vibration types may be possible in a molecule containing more than 
two atoms. In addition, vibration interaction or coupling may occur if the vibrations 
involve bonds to a single central atom with a change in the characteristic of the 
vibrations concerned. 
4.2.2.3 Mechanical Model of IR Vibration 
Infrared spectra result from light absorption by organic molecules. The easiest way 
to describe vibrational spectroscopy from a theoretical perspective is to consider 
the isolated vibrations of a mechanical model called the harmonic oscillator. Atomic 
stretching vibration behavior can be approximated by a mechanical model consisting 
of two masses, m 1 and m 2 , connected by an ideal spring. Displacement of one 
such mass along the spring axis results in harmonic motion. Many fundamental frequencies 
may be calculated by assuming that band energies arise from the vibration 
of the ideal diatomic harmonic oscillator (Figure 7 ), obeying Hooke  s law, that is, 
. . = 1
2 
k
u 
where . is the vibrational frequency, k the classical force constant, and 
u mm m m = + ( ) 1 2 1 2 , the reduced mass of the two atoms. 
The model provides a good description of true diatomic molecules and is not far 
from the average value of two atoms stretching within a polyatomic molecule. The 
corresponding potential - energy curve is the typical parabola illustrated in Figure 8 . 
This approximation gives the average vibration frequency of the bond. For example, 
the reduced masses for C  H, O  H, and N  H are 0.85, 0.89, and 0.87. These 
fi gures are similar, so the frequencies would be quite similar too. However, the 
electron - withdrawing and - donating properties of neighbors within molecules act 
FIGURE 7 Ideal diatomic harmonic oscillator. 
x 
x2 
0
requilibrium 
r 
x 
m1 m2 
x 1 
2 1

on the observed band strength, length, and frequency. An average value is of little 
use in structural determinations and these differences cause a real spectrum to 
develop. The force constant k is a measure of the stiffness of the chemical bond and 
is the equivalent of the force constant of the spring in the harmonic model. The k 
values vary widely and cause energy differences which can both be calculated and 
utilized in spectral interpretation. It has been possible to evaluate some force constants 
for various types of chemical bonds by IR spectroscopy. Generally, k has been 
found to range between 3 . 10 2 N/m and 8 . 10 2 N/m for most single bonds (average: 
5 . 10 2 N/m). Double and triple bonds are found to have k values two and three 
times this average, respectively. In practice, these average experimental values can 
be used to estimate the wavenumbers of fundamental absorption peaks, that is, 
peaks of the transition from the ground state to the fi rst excited state, for a variety 
of bond types. 
Classical mechanics does not apply to the atomic scale and does not take the 
quantized nature of molecular vibration energies into account. Thus, in contrast to 
ordinary mechanics where vibrators can assume any potential energy, quantum 
mechanical vibrators can only take on certain discrete energies. Transitions in vibrational 
energy levels can be brought about by radiation absorption, provided the 
energy of the radiation exactly matches the difference in energy levels between the 
vibrational quantum states and provided also that the vibration causes a fl uctuation 
in dipole. 
4.2.2.4 Quantum Mechanical Model 
Unlike the classical spring model for molecular vibrations, there are not an infi nite 
number of energy levels. Instead of a continuum of energies, there are discrete 
energy levels described by quantum theory. The time - independent Schr o dinger 
equation is solved using the vibrational Hamiltonian for a diatomic molecule. Values 
for the ground state ( . = 0) and succeeding excited states can be calculated by 
solving the equation (Figure 8 ). Absorption of a photon of the correct energy can 
cause the molecule to change between vibrational energy levels. At room temperature 
only the ground state has a signifi cant population, and so transitions due to 
absorption at these temperatures occur from the ground state. Transitions between 
ground state to energy level 1 give the fundamental absorption if this leads to a 
FIGURE 8 Energy diagram of the ideal diatomic oscillator. 
Potential energy 
V=0 
V=1 
V=2 
V=3 
Interatomic distance
Energy 
level 
VIBRATIONAL SPECTROSCOPY 369

370 PROCESS ANALYTICAL TECHNOLOGY 
change in molecular dipole moment. Transitions between ground state and energy 
level 2 or above give overtones. Transitions between multiple states can occur and 
give rise to combination bands. 
A simplifi ed version of the energy levels may be written for the energy levels of 
a diatomic molecule: 
E 
h k
u . . 
. 
. = + ( ) = 1
2 2 
0, 1, 2, . . . 
in which Hooke  s law terms can be seen. Rewritten using the quantum term 
hV h k u =( ) 2. , the equation reduces to 
E hV . . . = + ( ) = 1
2 
0, 1, 2, . . . 
In the case of polyatomic molecules, the energy levels become quite numerous. 
Ideally, one can treat such a molecule as a series of diatomic, independent, harmonic 
oscillators and the above equation can be generalized: 
E hV 
i
N 
i i . . . . . . . 1 2 
1 
3 6 
1 
1
2 
0 , , , . . . , , , . . . , 1, 2, 3, . . . 3 23 ( )= + ( ) = 
=
. 
. 
Any transition of an energy state from 0 to 1 in any one of the vibrational states 
( . 1 , . 2 , . 3 , . ) is fundamental and allowed by selection rules. Where the transition 
is from the ground state to . i = 2, 3, and so on and all others are zero, it is known 
as the fi rst overtone, the second overtone, and so on. Transitions from the ground 
state to a state for which . i = 1 and . j = 1 simultaneously are combinations. Other 
combinations, such as . i = 1, . j = 1, . k = 1, or . i = 2, . j = 1, and so forth are also 
possible. Typically, NIR spectra will contain these overtones and combinations 
derived from the fundamental vibrations which appear in the MIR. Overtones and 
combinations are not allowed, but appear as weak bands due to anharmonicity or 
Fermi resonance. As a rule, overtones occur at one - half and one - third of the fundamental 
absorption wavelength or 2 and 3 times the frequency. The majority of 
overtone peaks arise from the R  H stretching and bending modes because the 
dipole moment is high: O  H, C  H, S  H, and N  H are strong NIR absorbers 
and form most NIR bands. Since most absorption is repeated in the NIR range, this 
region is likely to be used to identify a molecule, as with MIR. As a consequence, 
IR bands are traditionally used to identify functional groups which have characteristic 
frequencies. NIR spectra are more overlapping, and, although bands can be 
identifi ed, they cannot be placed in relation to the rest of the molecule. NIR spectra 
are, therefore, mainly used to confi rm the identity of a material, as for true 
identifi cation. 
As given from the quantum mechanics equations, the energy for transition from 
energy levels 1 to 2 or 2 to 3 should be identical to that for transition from 0 to 1. 
Furthermore, quantum theory states that the only transitions that can take place 
are those for which, according to vibrational quantum theory, the vibrational 
quantum number changes by unity. This is the so - called selection rule. 

So far we have illustrated the classic and quantum mechanical treatment of the 
harmonic oscillator. The potential energy of a vibrator changes periodically as 
the distance between the masses fl uctuates. In terms of qualitative considerations, 
however, this description of molecular vibration appears imperfect. For example, as 
two atoms approach one another, Coulombic repulsion between the two nuclei adds 
to the bond force; thus, potential energy can be expected to increase more rapidly 
than predicted by harmonic approximation. At the other extreme of oscillation, a 
decrease in restoring force, and thus potential energy, occurs as interatomic distance 
approaches that at which the bonds dissociate. 
In theory, the wave equations of quantum mechanics can be used to derive near - 
correct potential - energy curves for molecular vibrations. Unfortunately, the mathematical 
complexity of these equations precludes quantitative application to all but 
the very simplest of systems. Qualitatively, the curves must take the anharmonic 
form. Such curves depart from harmonic behav