Pharmaceutical Process Validation.pdf

Previous edition: Pharmaceutical Process Validation: Second Edition, Revised and Ex-panded (I. R. Berry, R. A. Nash, eds.), 1993.

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DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive EditorJames SwarbrickPharmaceuTech, Inc

Pinehurst, North Carolina

Advisory Board

Larry L. Augsburger David E. NicholsUniversity of Maryland Purdue University

Baltimore, Maryland West Lafayette, Indiana

Douwe D. Breimer Stephen G. SchulmanGorlaeus Laboratories University of Florida

Leiden, The Netherlands Gamesville, Florida

Trevor M Jones Jerome P. SkellyThe Association of the Alexandria, Virginia

British Pharmaceutical IndustryLondon, United Kingdom

Hans E. Junginger Felix TheeuwesLeiden/Amsterdam Center Alza Corporation

for Drug Research Palo Alto, CaliforniaLeiden, The Netherlands

Vincent H. L. Lee Geoffrey T TuckerUniversity of Southern California University of Sheffield

Los Angeles, California Royal Hallamshire HospitalSheffield, United Kingdom

Peter G. WellingInstitut de Recherche Jouvemal

Fresnes, France


DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

1. Pharmacokmetics, Milo Gibaldi and Donald Perrier2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Sidney H. Willig, Murray M. Tuckerman, and WilliamS. Hitchings IV

3. Microencapsulation, edited by J. R Nixon4. Drug Metabolism. Chemical and Biochemical Aspects, Bernard Testa

and Peter Jenner5. New Drugs: Discovery and Development, edited by Alan A. Rubin6. Sustained and Controlled Release Drug Delivery Systems, edited by

Joseph R. Robinson7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher

T. Rhodes8. Prescription Drugs in Short Supply Case Histories, Michael A.

Schwartz9. Activated Charcoal' Antidotal and Other Medical Uses, David O.

Cooney10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner

and Bernard Testa11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by

James W, Munson12. Techniques of Solubilization of Drugs, edited by Samuel H Yalkow-

sky13. Orphan Drugs, edited by Fred E. Karch14. Novel Drug Delivery Systems: Fundamentals, Developmental Con-

cepts, Biomedical Assessments, Yie W. Chien15. Pharmacokmetics: Second Edition, Revised and Expanded, Milo

Gibaldi and Donald Perrier16 Good Manufacturing Practices for Pharmaceuticals' A Plan for Total

Quality Control, Second Edition, Revised and Expanded, Sidney HWillig, Murray M Tuckerman, and William S. Hitchings IV

17 Formulation of Veterinary Dosage Forms, edited by Jack Blodinger18 Dermatological Formulations. Percutaneous Absorption, Brian W

Barry19. The Clinical Research Process in the Pharmaceutical Industry, edited

by Gary M. Matoren20. Microencapsulation and Related Drug Processes, Patrick B. Deasy21. Drugs and Nutrients The Interactive Effects, edited by Daphne A.

Roe and T. Colin Campbell22. Biotechnology of Industrial Antibiotics, Enck J. Vandamme


23 Pharmaceutical Process Validation, edited by Bernard T Loftus andRobert A Nash

24 Anticancer and Interferon Agents Synthesis and Properties, edited byRaphael M Ottenbrtte and George B Butler

25 Pharmaceutical Statistics Practical and Clinical Applications, SanfordBolton

26 Drug Dynamics for Analytical, Clinical, and Biological Chemists,Benjamin J Gudzmowicz, Burrows T Younkm, Jr, and Michael JGudzmowicz

27 Modern Analysis of Antibiotics, edited by Adjoran Aszalos28 Solubility and Related Properties, Kenneth C James29 Controlled Drug Delivery Fundamentals and Applications, Second

Edition, Revised and Expanded, edited by Joseph R Robinson andVincent H Lee

30 New Drug Approval Process Clinical and Regulatory Management,edited by Richard A Guarino

31 Transdermal Controlled Systemic Medications, edited by Yie W Chien32 Drug Delivery Devices Fundamentals and Applications, edited by

Praveen Tyle33 Pharmacokinetics Regulatory Industrial Academic Perspectives,

edited by Peter G Welling and Francis L S Tse34 Clinical Drug Trials and Tribulations, edited by Alien E Cato35 Transdermal Drug Delivery Developmental Issues and Research Ini-

tiatives, edited by Jonathan Hadgraft and Richard H Guy36 Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,

edited by James W McGmity37 Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-

Sellassie38 Good Laboratory Practice Regulations, edited by Alien F Hirsch39 Nasal Systemic Drug Delivery, Yie W Chien, Kenneth S E Su, and

Shyi-Feu Chang40 Modern Pharmaceutics Second Edition, Revised and Expanded,

edited by Gilbert S Banker and Chnstopher T Rhodes41 Specialized Drug Delivery Systems Manufacturing and Production

Technology, edited by Praveen Tyle42 Topical Drug Delivery Formulations, edited by David W Osborne and

Anton H Amann43 Drug Stability Principles and Practices, Jens T Carstensen44 Pharmaceutical Statistics Practical and Clinical Applications, Second

Edition, Revised and Expanded, Sanford Bolton45 Biodegradable Polymers as Drug Delivery Systems, edited by Mark

Chasm and Robert Langer46 Preclmical Drug Disposition A Laboratory Handbook, Francis L S

Tse and James J Jaffe47 HPLC in the Pharmaceutical Industry, edited by Godwin W Fong and

Stanley K Lam48 Pharmaceutical Bioequivalence, edited by Peter G Welling, Francis L

S Tse, and Shrikant V Dinghe


49. Pharmaceutical Dissolution Testing, Umesh V. Sana/car50. Novel Drug Delivery Systems: Second Edition, Revised and

Expanded, Yie W. Chien51. Managing the Clinical Drug Development Process, David M. Coc-

chetto and Ronald V. Nardi52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control, Third Edition, edited by Sidney H. Willig and JamesR. Stoker

53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B.Sloan

54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J.Mickey

55. Radiopharmaceuticals: Chemistry and Pharmacology, edited byAdrian D. Nunn

56. New Drug Approval Process: Second Edition, Revised and Expanded,edited by Richard A. Guarino

57. Pharmaceutical Process Validation: Second Edition, Revised and Ex-panded, edited by Ira R. Berry and Robert A. Nash

58. Ophthalmic Drug Delivery Systems, edited byAshim K. Mitra59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A.

Walters and Jonathan Hadgraft60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck61. Pharmaceutical Particulate Carriers1 Therapeutic Applications, edited

by Alain Rolland62. Drug Permeation Enhancement: Theory and Applications, edited by

Dean S. Hsieh63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A.

Halls65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie66. Colloidal Drug Delivery Systems, edited byJorg Kreuter67 Pharmacokinetics: Regulatory Industrial Academic Perspectives,

Second Edition, edited by Peter G. Welling and Francis L. S. Tse68. Drug Stability: Principles and Practices, Second Edition, Revised and

Expanded, Jens T. Carstensen69. Good Laboratory Practice Regulations: Second Edition, Revised and

Expanded, edited by Sandy Weinberg70. Physical Characterization of Pharmaceutical Solids, edited by Harry

G. Bnttain71. Pharmaceutical Powder Compaction Technology, edited by Goran Al-

derborn and Christer Nystrom72. Modern Pharmaceutics. Third Edition, Revised and Expanded, edited

by Gilbert S. Banker and Christopher J Rhodes73. Microencapsulation. Methods and Industrial Applications, edited by

Simon Benita74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone75. Clinical Research in Pharmaceutical Development, edited by Barry

Bleidt and Michael Montagne


76 The Drug Development Process Increasing Efficiency and Cost Ef-fectiveness, edited by Peter G Welling, Louis Lasagna, and UmeshV Banakar

77 Microparticulate Systems for the Delivery of Proteins and Vaccines,edited by Smadar Cohen and Howard Bernstein

78 Good Manufacturing Practices for Pharmaceuticals A Plan for TotalQuality Control, Fourth Edition, Revised and Expanded, Sidney HWillig and James R Stoker

79 Aqueous Polymeric Coatings for Pharmaceutical Dosage FormsSecond Edition, Revised and Expanded, edited by James WMcGmity

80 Pharmaceutical Statistics Practical and Clinical Applications, ThirdEdition, Sanford Bolton

81 Handbook of Pharmaceutical Granulation Technology edited by DilipM Pankh

82 Biotechnology of Antibiotics Second Edition, Revised and Expanded,edited by William R Strohl

83 Mechanisms of Transdermal Drug Delivery, edited by Russell O Pottsand Richard H Guy

84 Pharmaceutical Enzymes edited by Albert Lauwers and SimonScharpe

85 Development of Biopharmaceutical Parenteral Dosage Forms, editedby John A Bontempo

86 Pharmaceutical Project Management, edited by Tony Kennedy87 Drug Products for Clinical Trials An International Guide to Formula-

tion Production Quality Control, edited by Donald C Monkhouseand Christopher T Rhodes

88 Development and Formulation of Veterinary Dosage Forms SecondEdition, Revised and Expanded, edited by Gregory E Hardee and JDesmond Baggot

89 Receptor-Based Drug Design, edited by Paul Leff90 Automation and Validation of Information in Pharmaceutical Pro-

cessing, edited by Joseph F deSpautz91 Dermal Absorption and Toxicity Assessment, edited by Michael S

Roberts and Kenneth A Walters92 Pharmaceutical Experimental Design, Gareth A Lewis, Didier

Mathieu, and Roger Phan-Tan-Luu93 Preparing for FDA Pre-Approval Inspections, edited by Martin D

Hynes III94 Pharmaceutical Excipients Characterization by IR, Raman, and NMR

Spectroscopy, David E Bugay and W Paul Fmdlay95 Polymorphism in Pharmaceutical Solids, edited by Harry G Brittam96 Freeze-Drymg/Lyophihzation of Pharmaceutical and Biological Prod-

ucts, edited by Louis Rey and Joan C May97 Percutaneous Absorption Drugs-Cosmetics-Mechanisms-Metho-

dology, Third Edition, Revised and Expanded, edited by Robert LBronaugh and Howard I Maibach


98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Ap-proaches, and Development, edited by Edith Mathiowitz, Donald E.Chtckering III, and Claus-Michael Lehr

99. Protein Formulation and Delivery, edited by Eugene J. McNally100. New Drug Approval Process: Third Edition, The Global Challenge,

edited by Richard A. Guarino101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid102 Transport Processes in Pharmaceutical Systems, edited by Gordon L

Amidon, Ping I. Lee, and Elizabeth M. Topp103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A.

Kotkoskie104 The Clinical Audit in Pharmaceutical Development, edited by Michael

R. Hamrell105. Pharmaceutical Emulsions and Suspensions, edited by Francoise

Nielloud and Gilberte Marti-Mestres106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B.

Dressman and Hans Lennernas107. Drug Stability: Principles and Practices, Third Edition, Revised and

Expanded, edited by Jens T. Carstensen and C. T. Rhodes108. Containment in the Pharmaceutical Industry, edited by James P.

Wood109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total

Quality Control from Manufacturer to Consumer, Fifth Edition, Revisedand Expanded, Sidney H Willig

110. Advanced Pharmaceutical Solids, Jens T Carstensen111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second

Edition, Revised and Expanded, Kevin L. Williams112 Pharmaceutical Process Engineering, Anthony J. Hickey and David

Ganderton113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and Ra-

chel F. Tyndale114. Handbook of Drug Screening, edited by Ramaknshna Seethala and

Prabhavathi B. Fernandas115. Drug Targeting Technology: Physical Chemical Biological Methods,

edited by Hans Schreier116. Drug-Drug Interactions, edited by A. David Rodngues117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian

and Anthony J. Streeter118. Pharmaceutical Process Scale-Up, edited by Michael Levin119. Dermatological and Transdermal Formulations, edited by Kenneth A.

Walters120. Clinical Drug Trials and Tribulations: Second Edition, Revised and

Expanded, edited by Alien Cato, Lynda Sutton, and Alien Cato III121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edi-

ted by Gilbert S. Banker and Chnstopher T. Rhodes122. Surfactants and Polymers in Drug Delivery, Martin Malmsten123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,

edited by Richard H. Guy and Jonathan Hadgraft


124. Good Laboratory Practice Regulations: Second Edition, Revised andExpanded, edited by Sandy Weinberg

125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Pack-age Integrity Testing. Third Edition, Revised and Expanded, MichaelJ. Akers, Daniel S. Larnmore, and Dana Morion Guazzo

126. Modified-Release Drug Delivery Technology, edited by Michael J.Rathbone, Jonathan Hadgraft, and Michael S. Roberts

127. Simulation for Designing Clinical Trials' A Pharmacokinetic-Pharma-codynamic Modeling Perspective, edited by Hui C Kimko and Ste-phen B Duffull

128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharma-ceutics, edited by Remhard H. H. Neubert and Hans-Hermann Rut-tinger

129. Pharmaceutical Process Validation: An International Third Edition, Re-vised and Expanded, edited by Robert A Nash and Alfred H. Wachter

130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Ex-panded, edited byAshim K. Mitra

131 Pharmaceutical Gene Delivery Systems, edited by Alam Rolland andSean M. Sullivan

ADDITIONAL VOLUMES IN PREPARATION

Biomarkers in Clinical Drug Development, edited by John C Bloomand Robert A. Dean

Pharmaceutical Inhalation Aerosol Technology: Second Edition, Re-vised and Expanded, edited by Anthony J Mickey

Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellas-sie and Charles Martin

Pharmaceutical Compliance, edited by Carmen Medina


Dedicated to Theodore E. Byers, formerly of the U.S. Food and DrugAdministration, and Heinz Sucker, Professor at the University of Berne,

Switzerland, for their pioneering contributions with respect tothe pharmaceutical process validation concept. We also acknowledge

the past contributions of Bernard T. Loftus and Ira R. Berry toward thesuccess of Pharmaceutical Process Validation.


Preface

The third edition of Pharmaceutical Process Validation represents a new ap-proach to the topic in several important respects.

Many of us in the field had made the assumption that pharmaceuticalprocess validation was an American invention, based on the pioneering work ofTheodore E. Byers and Bernard T. Loftus, both formerly with the U.S. Food &Drug Administration. The truth is that many of our fundamental concepts ofpharmaceutical process validation came to us from Validation of Manufactur-ing Processes, Fourth European Seminar on Quality Control, September 25,1980, Geneva, Switzerland, and Validation in Practice, edited by H. Sucker,Wissenschaftliche Verlagsegesellschaft, GmbH, Stuttgard, Germany, 1983.

There are new chapters in this edition that will add to the books impact.They include Validation for Medical Devices by Nishihata, Validation ofBiotechnology Processes by Sofer, Transdermal Process Validation by Neal,Integrated Packaging Validation by Frederick, Statistical Methods for Uni-formity and Dissolution Testing by Bergum and Utter, Change Control andSUPAC by Waterland and Kowtna, Validation in Contract Manufacturingby Parikh, and Harmonization, GMPs, and Validation by Wachter.

I am pleased to have Dr. Alfred Wachter join me as coeditor of this edi-tion. He was formerly head of Pharmaceutical Product Development for theCIBA Pharmaceutical Company in Basel, Switzerland, and also spent a numberof years on assignment in Asia for CIBA. Fred brings a very strong internationalperspective to the subject matter.

Robert A. Nash


Contents

PrefaceContributorsIntroduction

1. Regulatory Basis for Process ValidationJohn M. Dietrick and Bernard T. Loftus

2. Prospective Process ValidationAllen Y. Chao, F. St. John Forbes, Reginald F. Johnson,and Paul Von Doehren

3. Retrospective ValidationChester J. Trubinski

4. Sterilization ValidationMichael J. Akers and Neil R. Anderson

5. Validation of Solid Dosage FormsJeffrey S. Rudolph and Robert J. Sepelyak

6. Validation for Medical DevicesToshiaki Nishihata

7. Validation of Biotechnology ProcessesGail Sofer

8. Transdermal Process ValidationCharlie Neal, Jr.

9. Validation of LyophilizationEdward H. Trappler


10. Validation of Inhalation AerosolsChristopher J. Sciarra and John J. Sciarra

11. Process Validation of Pharmaceutical IngredientsRobert A. Nash

12. Qualification of Water and Air Handling SystemsKunio Kawamura

13. Equipment and Facility QualificationThomas L. Peither

14. Validation and Verification of Cleaning ProcessesWilliam E. Hall

15. Validation of Analytical Methods and ProcessesLudwig Huber

16. Computer System Validation:Controlling the Manufacturing ProcessTony de Claire

17. Integrated Packaging ValidationMervyn J. Frederick

18. Analysis of Retrospective Production Data UsingQuality Control ChartsPeter H. Cheng and John E. Dutt

19. Statistical Methods for Uniformity and Dissolution TestingJames S. Bergum and Merlin L. Utter

20. Change Control and SUPACNellie Helen Waterland and Christopher C. Kowtna

21. Process Validation and Quality AssuranceCarl B. Rifino

22. Validation in Contract ManufacturingDilip M. Parikh

23. Terminology of Nonaseptic Process ValidationKenneth G. Chapman

24. Harmonization, GMPs, and ValidationAlfred H. Wachter


Contributors

Michael J. Akers Baxter Pharmaceutical Solutions, Bloomington, Indiana,U.S.A.

Neil R. Anderson Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

James S. Bergum Bristol-Myers Squibb Company, New Brunswick, New Jer-sey, U.S.A.

Kenneth G. Chapman Drumbeat Dimensions, Inc., Mystic, Connecticut,U.S.A.

Allen Y. Chao Watson Labs, Carona, California, U.S.A.

Peter H. Cheng New York State Research Foundation for Mental Hygiene,New York, New York, U.S.A.

Tony de Claire APDC Consulting, West Sussex, England

John M. Dietrick Center for Drug Evaluation and Research, U.S. Food andDrug Administration, Rockville, Maryland, U.S.A.

John E. Dutt EM Industries, Inc., Hawthorne, New York, U.S.A.

Mervyn J. Frederick NV OrganonAkzo Nobel, Oss, The Netherlands

William E. Hall Hall & Pharmaceutical Associates, Inc., Kure Beach, NorthCarolina, U.S.A.

Ludwig Huber Agilent Technologies GmbH, Waldbronn, Germany


F. St. John Forbes Wyeth Labs, Pearl River, New York, U.S.A.

*Reginald F. Johnson Searle & Co., Inc., Skokie, Illinois, U.S.A.

Kunio Kawamura Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan

Christopher C. Kowtna DuPont Pharmaceuticals Co., Wilmington, Dela-ware, U.S.A.

*Bernard T. Loftus Bureau of Drugs, U.S. Food and Drug Administration,Washington, D.C., U.S.A.

Robert A. Nash Stevens Institute of Technology, Hoboken, New Jersey,U.S.A.

Charlie Neal, Jr. Diosynth-RTP, Research Triangle Park, North Carolina,U.S.A.

Toshiaki Nishihata Santen Pharmaceutical Co., Ltd., Osaka, Japan

Dilip M. Parikh APACE PHARMA Inc., Westminster, Maryland, U.S.A.

Thomas L. Peither PECONPeither Consulting, Schopfheim, Germany

Carl B. Rifino AstraZeneca Pharmaceuticals LP, Newark, Delaware, U.S.A.

Jeffrey S. Rudolph Pharmaceutical Consultant, St. Augustine, Florida, U.S.A.

Christopher J. Sciarra Sciarra Laboratories Inc., Hicksville, New York, U.S.A.

John J. Sciarra Sciarra Laboratories Inc., Hicksville, New York, U.S.A.

Robert J. Sepelyak AstraZeneca Pharmaceuticals LP, Wilmington, Delaware,U.S.A.

Gail Sofer BioReliance, Rockville, Maryland, U.S.A.

Edward H. Trappler Lyophilization Technology, Inc., Warwick, Pennsylva-nia, U.S.A.

*Retired


Chester J. Trubinski Church & Dwight Co., Inc., Princeton, New Jersey,U.S.A.

Merlin L. Utter Wyeth Pharmaceuticals, Pearl River, New York, U.S.A.

Paul Von Doehren Searle & Co., Inc., Skokie, Illinois, U.S.A.

Alfred H. Wachter Wachter Pharma Projects, Therwil, Switzerland

Nellie Helen Waterland DuPont Pharmaceuticals Co., Wilmington, Dela-ware, U.S.A.


Introduction

Robert A. NashStevens Institute of Technology, Hoboken, New Jersey, U.S.A.

I. FDA GUIDELINES

The U.S. Food and Drug Administration (FDA) has proposed guidelines withthe following definition for process validation [1]:

Process validation is establishing documented evidence which provides ahigh degree of assurance that a specific process (such as the manufactureof pharmaceutical dosage forms) will consistently produce a product meet-ing its predetermined specifications and quality characteristics.

According to the FDA, assurance of product quality is derived from care-ful and systemic attention to a number of important factors, including: selectionof quality components and materials, adequate product and process design, and(statistical) control of the process through in-process and end-product testing.

Thus, it is through careful design (qualification) and validation of both theprocess and its control systems that a high degree of confidence can be estab-lished that all individual manufactured units of a given batch or succession ofbatches that meet specifications will be acceptable.

According to the FDAs Current Good Manufacturing Practices (CGMPs)21CFR 211.110 a:

Control procedures shall be established to monitor output and to validateperformance of the manufacturing processes that may be responsible forcausing variability in the characteristics of in-process material and the drugproduct. Such control procedures shall include, but are not limited to thefollowing, where appropriate [2]:1. Tablet or capsule weight variation2. Disintegration time


3. Adequacy of mixing to assure uniformity and homogeneity4. Dissolution time and rate5. Clarity, completeness, or pH of solutions

The first four items listed above are directly related to the manufactureand validation of solid dosage forms. Items 1 and 3 are normally associatedwith variability in the manufacturing process, while items 2 and 4 are usuallyinfluenced by the selection of the ingredients in the product formulation. Withrespect to content uniformity and unit potency control (item 3), adequacy ofmixing to assure uniformity and homogeneity is considered a high-priority con-cern.

Conventional quality control procedures for finished product testing en-compass three basic steps:

1. Establishment of specifications and performance characteristics2. Selection of appropriate methodology, equipment, and instrumenta-

tion to ensure that testing of the product meets specifications3. Testing of the final product, using validated analytical and testing

methods to ensure that finished product meets specifications.

With the emergence of the pharmaceutical process validation concept, the fol-lowing four additional steps have been added:

4. Qualification of the processing facility and its equipment5. Qualification and validation of the manufacturing process through ap-

propriate means6. Auditing, monitoring, sampling, or challenging the key steps in the

process for conformance to in-process and final product specifications7. Revalidation when there is a significant change in either the product

or its manufacturing process [3].

II. TOTAL APPROACH TO PHARMACEUTICALPROCESS VALIDATION

It has been said that there is no specific basis for requiring a separate set ofprocess validation guidelines, since the essentials of process validation are em-bodied within the purpose and scope of the present CGMP regulations [2]. Withthis in mind, the entire CGMP document, from subpart B through subpart K,may be viewed as being a set of principles applicable to the overall process ofmanufacturing, i.e., medical devices (21 CFRPart 820) as well as drug prod-ucts, and thus may be subjected, subpart by subpart, to the application of theprinciples of qualification, validation, verification and control, in addition tochange control and revalidation, where applicable. Although not a specific re-


quirement of current regulations, such a comprehensive approach with respectto each subpart of the CGMP document has been adopted by many drug firms.

A checklist of qualification and control documentation with respect toCGMPs is provided in Table 1. A number of these topics are discussed sepa-rately in other chapters of this book.

III. WHY ENFORCE PROCESS VALIDATION?

The FDA, under the authority of existing CGMP regulations, guidelines [1], anddirectives [3], considers process validation necessary because it makes goodengineering sense. The basic concept, according to Mead [5], has long been

Table 1 Checklist of Qualification and Control Documentation

Qualification andSubpart Section of CGMPs control documentation

A General provisionsB Organization and personnel Responsibilities of the quality con-

trol unitC Buildings and facilities Plant and facility installation and

qualificationMaintenance and sanitationMicrobial and pest control

D Equipment Installation and qualification ofequipment and cleaning methods

E Control of components, containers Incoming component testing proce-and closures dures

F Production and process controls Process control systems, reprocess-ing control of microbial contami-nation

G Packaging and labeling controls Depyrogenation, sterile packaging,filling and closing, expire dating

H Holding and distribution Warehousing and distribution pro-cedures

I Laboratory controls Analytical methods, testing for re-lease component testing and sta-bility testing

J Records and reports Computer systems and informationsystems

K Return and salvaged drug products Batch reprocessing

Sterilization procedures, Air and water quality are covered in appropriate subparts of Table 1.


applied in other industries, often without formal recognition that such a conceptwas being used. For example, the terms reliability engineering and qualificationhave been used in the past by the automotive and aerospace industries to repre-sent the process validation concept.

The application of process validation should result in fewer product re-calls and troubleshooting assignments in manufacturing operations and moretechnically and economically sound products and their manufacturing processes.In the old days R & D gurus would literally hand down the go sometimesoverformulated product and accompanying obtuse manufacturing procedure,usually with little or no justification or rationale provided. Today, under FDAsPreapproval Inspection (PAI) program [4] such actions are no longer accept-able. The watchword is to provide scientifically sound justifications (includingqualification and validation documentation) for everything that comes out of thepharmaceutical R & D function.

IV. WHAT IS PROCESS VALIDATION?

Unfortunately, there is still much confusion as to what process validation isand what constitutes process validation documentation. At the beginning of thisintroduction several different definitions for process validation were provided,which were taken from FDA guidelines and the CGMPs. Chapman calls processvalidation simply organized, documented common sense [6]. Others have saidthat it is more than three good manufactured batches and should represent alifetime commitment as long as the product is in production, which is prettymuch analogous to the retrospective process validation concept.

The big problem is that we use the term validation generically to coverthe entire spectrum of CGMP concerns, most of which are essentially people,equipment, component, facility, methods, and procedural qualification. The spe-cific term process validation should be reserved for the final stage(s) of theproduct/process development sequence. The essential or key steps or stages ofa successfully completed product/process development program are presentedin Table 2 [7].

The end of the sequence that has been assigned to process validation isderived from the fact that the specific exercise of process validation shouldnever be designed to fail. Failure in carrying out the process validation assign-ment is often the result of incomplete or faulty understanding of the processscapability, in other words, what the process can and cannot do under a givenset of operational circumstances. In a well-designed, well-run overall validationprogram, most of the budget dollars should be spent on equipment, component,facility, methods qualification, and process demonstration, formerly called pro-cess qualification. In such a program, the formalized final process validation


Table 2 The Key Stages in the Product/ProcessDevelopment Sequence

Development stage Pilot scale-up phase

Product design 1 batch sizeProduct characterizationProduct selection (go formula)Process designProduct optimization 10 batch sizeProcess characterizationProcess optimizationProcess demonstration 100 batch sizeProcess validation programProduct/process certification

With the exception of solution products, the bulk of the work is nor-mally carried out at 10 batch size, which is usually the first scale-upbatches in production-type equipment.

sequence provides only the necessary process validation documentation requiredby the regulatory authoritiesin other words, the Good Housekeeping Seal ofApproval, which shows that the manufacturing process is in a state of control.

Such a strategy is consistent with the U.S. FDAs preapproval inspectionprogram [4], wherein the applicant firm under either a New Drug Application(NDA) or an Abbreviated New Drug Application (ANDA) submission mustshow the necessary CGMP information and qualification data (including appro-priate development reports), together with the formal protocol for the forthcom-ing full-scale, formal process validation runs required prior to product launch.

Again, the term validation has both a specific meaning and a general one,depending on whether the word process is used. Determine during the courseof your reading whether the entire concept is discussed in connection with thetopici.e., design, characterization, optimization, qualification, validation, and/or revalidationor whether the author has concentrated on the specifics of thevalidation of a given product and/or its manufacturing process. In this way thetext will take on greater meaning and clarity.

V. PILOT SCALE-UP AND PROCESS VALIDATION

The following operations are normally carried out by the development functionprior to the preparation of the first pilot-production batch. The developmentactivities are listed as follows:


1. Formulation design, selection, and optimization2. Preparation of the first pilot-laboratory batch3. Conduct initial accelerated stability testing4. If the formulation is deemed stable, preparation of additional pilot-

laboratory batches of the drug product for expanded nonclinical and/or clinical use.

The pilot program is defined as the scale-up operations conducted subse-quent to the product and its process leaving the development laboratory andprior to its acceptance by the full scale manufacturing unit. For the pilot programto be successful, elements of process validation must be included and completedduring the developmental or pilot laboratory phase of the work.

Thus, product and process scale-up should proceed in graduated steps withelements of process validation (such as qualifications) incorporated at each stageof the piloting program [9,10].

A. Laboratory BatchThe first step in the scale-up process is the selection of a suitable preliminaryformula for more critical study and testing based on certain agreed-upon initialdesign criteria, requirements, and/or specifications. The work is performed inthe development laboratory. The formula selected is designated as the (1 )laboratory batch. The size of the (1 ) laboratory batch is usually 310 kg of asolid or semisolid, 310 liters of a liquid, or 3000 to 10,000 units of a tablet orcapsule.

B. Laboratory Pilot BatchAfter the (1 ) laboratory batch is determined to be both physically and chemi-cally stable based on accelerated, elevated temperature testing (e.g., 1 month at45C or 3 months at 40C or 40C/80% RH), the next step in the scale-upprocess is the preparation of the (10 ) laboratory pilot batch. The (10 )laboratory pilot batch represents the first replicated scale-up of the designatedformula. The size of the laboratory pilot batch is usually 30100 kg, 30100liters, or 30,000 to 100,000 units.

It is usually prepared in small pilot equipment within a designated CGMP-approved area of the development laboratory. The number and actual size of thelaboratory pilot batches may vary in response to one or more of the followingfactors:

1. Equipment availability2. Active pharmaceutical ingredient (API)


3. Cost of raw materials4. Inventory requirements for clinical and nonclinical studies

Process demonstration or process capability studies are usually started in thisimportant second stage of the pilot program. Such capability studies consist ofprocess ranging, process characterization, and process optimization as a prereq-uisite to the more formal validation program that follows later in the pilotingsequence.

C. Pilot ProductionThe pilot-production phase may be carried out either as a shared responsibilitybetween the development laboratories and its appropriate manufacturing coun-terpart or as a process demonstration by a separate, designated pilot-plant orprocess-development function. The two organization piloting options are pre-sented separately in Figure 1. The creation of a separate pilot-plant or process-development unit has been favored in recent years because it is ideally suited tocarry out process scale-up and/or validation assignments in a timely manner. Onthe other hand, the joint pilot-operation option provides direct communicationbetween the development laboratory and pharmaceutical production.

Figure 1 Main piloting options. (Top) Separate pilot plant functionsengineeringconcept. (Bottom) Joint pilot operation.


The object of the pilot-production batch is to scale the product and processby another order of magnitude (100 ) to, for example, 3001,000 kg, 3001,000 liters, or 300,0001,000,000 dosage form units (tablets or capsules) insize. For most drug products this represents a full production batch in standardproduction equipment. If required, pharmaceutical production is capable of scal-ing the product/process to even larger batch sizes should the product requireexpanded production output. If the batch size changes significantly, additionalvalidation studies would be required. The term product/process is used, sinceone cant describe a product with discussing its process of manufacture and,conversely, one cant talk about a process without describing the product beingmanufactured.

Usually large production batch scale-up is undertaken only after productintroduction. Again, the actual size of the pilot-production (100 ) batch mayvary due to equipment and raw material availability. The need for additionalpilot-production batches ultimately depends on the successful completion of afirst pilot batch and its process validation program. Usually three successfullycompleted pilot-production batches are required for validation purposes.

In summary, process capability studies start in the development labora-tories and/or during product and process development, and continue in well-defined stages until the process is validated in the pilot plant and/or pharmaceu-tical production.

An approximate timetable for new product development and its pilotscale-up program is suggested in Table 3.

VI. PROCESS VALIDATION: ORDER OF PRIORITY

Because of resource limitation, it is not always possible to validate an entirecompanys product line at once. With the obvious exception that a companysmost profitable products should be given a higher priority, it is advisable todraw up a list of product categories to be validated.

The following order of importance or priority with respect to validation issuggested:

A. Sterile Products and Their Processes

1. Large-volume parenterals (LVPs)2. Small-volume parenterals (SVPs)3. Ophthalmics, other sterile products, and medical devices


Table 3 Approximate Timetable for New Product Development and PilotScale-Up Trials

CalendarEvent months

Formula selection and development 24Assay methods development and formula optimization 24Stability in standard packaging 3-month readout (1 size) 34Pilot-laboratory batches (10 size) 13Preparation and release of clinical supplies (10 size) and

establishment of process demonstration 14Additional stability testing in approved packaging 34

68-month readout (1 size)3-month readout (10 size)

Validation protocols and pilot batch request 13Pilot-production batches (100 size) 13Additional stability testing in approved packaging 34

912-month readout (1 size)68-month readout (10 size)3-month readout (100 size)

Interim approved technical product development report withapproximately 12 months stability (1 size) 13

Totals 1836

B. Nonsterile Products and Their Processes1. Low-dose/high-potency tablets and capsules/transdermal delivery sys-

tems (TDDs)2. Drugs with stability problems3. Other tablets and capsules4. Oral liquids, topicals, and diagnostic aids

VII. WHO DOES PROCESS VALIDATION?

Process validation is done by individuals with the necessary training and experi-ence to carry out the assignment.

The specifics of how a dedicated group, team, or committee is organizedto conduct process validation assignments is beyond the scope of this introduc-tory chapter. The responsibilities that must be carried out and the organizationalstructures best equipped to handle each assignment are outlined in Table 4. The


Table 4 Specific Responsibilities of Each Organizational Structure within the Scopeof Process Validation

Engineering Install, qualify, and certify plant, facilities, equipment, and sup-port system.

Development Design and optimize manufacturing process within design limits,specifications, and/or requirementsin other words, the estab-lishment of process capability information.

Manufacturing Operate and maintain plant, facilities, equipment, support sys-tems, and the specific manufacturing process within its designlimits, specifications, and/or requirements.

Quality assurance Establish approvable validation protocols and conduct processvalidation by monitoring, sampling, testing, challenging, and/or auditing the specific manufacturing process for compliancewith design limits, specifications, and/or requirements.

Source: Ref. 8.

best approach in carrying out the process validation assignment is to establish aChemistry, Manufacturing and Control (CMC) Coordination Committee at thespecific manufacturing plant site [10]. Representation on such an important lo-gistical committee should come from the following technical operations:

Formulation development (usually a laboratory function) Process development (usually a pilot plant function) Pharmaceutical manufacturing (including packaging operations) Engineering (including automation and computer system responsibili-

ties) Quality assurance Analytical methods development and/or Quality Control API Operations (representation from internal operations or contract

manufacturer) Regulatory Affairs (technical operations representative) IT (information technology) operations

The chairperson or secretary of such an important site CMC Coordination Com-mittee should include the manager of process validation operations. Typicalmeeting agendas may include the following subjects in the following recom-mended order of priority:

Specific CGMP issues for discussion and action to be taken Qualification and validation issues with respect to a new product/pro-

cess


Technology transfer issues within or between plant sites. Pre-approval inspection (PAI) issues of a forthcoming product/process Change control and scale-up, post approval changes (SUPAC) with

respect to current approved product/process [11].

VIII. PROCESS DESIGN AND CHARACTERIZATION

Process capability is defined as the studies used to determine the critical processparameters or operating variables that influence process output and the range ofnumerical data for critical process parameters that result in acceptable processoutput. If the capability of a process is properly delineated, the process shouldconsistently stay within the defined limits of its critical process parameters andproduct characteristics [12].

Process demonstration formerly called process qualification, representsthe actual studies or trials conducted to show that all systems, subsystems, orunit operations of a manufacturing process perform as intended; that all criticalprocess parameters operate within their assigned control limits; and that suchstudies and trials, which form the basis of process capability design and testing,are verifiable and certifiable through appropriate documentation.

The manufacturing process is briefly defined as the ways and means usedto convert raw materials into a finished product. The ways and means alsoinclude people, equipment, facilities, and support systems required to operatethe process in a planned and effectively managed way. All the latter functionsmust be qualified individually. The master plan or protocol for process capabil-ity design and testing is presented in Table 5.

A simple flow chart should be provided to show the logistical sequenceof unit operations during product/process manufacture. A typical flow chart usedin the manufacture of a tablet dosage form by the wet granulation method ispresented in Figure 2.

IX. STREAMLINING VALIDATION OPERATIONS

The best approach to avoiding needless and expensive technical delays is towork in parallel. The key elements at this important stage of the overall processare the API, analytical test methods, and the drug product (pharmaceutical dos-age form). An integrated and parallel way of getting these three vitally importantfunctions to work together is depicted in Figure 3.

Figure 3 shows that the use of a single analytical methods testing functionis an important technical bridge between the API and the drug product develop-ment functions as the latter two move through the various stages of develop-


Table 5 Master Plan or Protocol for Process Capability Design and Testing

Objective Process capability design and testingTypes of process Batch, intermittent, continuousTypical processes Chemical, pharmaceutical, biochemicalProcess definition Flow diagram, in-process, finished productDefinition of process output Potency, yield, physical parametersDefinition of test methods Instrumentation, procedures, precision, and

accuracyProcess analysis Process variables, matrix design, factorial design

analysisPilot batch trials Define sampling and testing, stable, extended runsPilot batch replication Different days, different materials, different equip-

mentProcess redefinition Reclassification of process variablesProcess capability evaluation Stability and variability of process output, eco-

nomic limitsFinal report Recommended SOP, specifications, and process

limits

Figure 2 Process flow diagram for the manufacture of a tablet dosage form by wetgranulation method. The arrows show the transfer of material into and out of each of thevarious unit operations. The information in parentheses indicates additions of material tospecific unit operations. A list of useful pharmaceutical unit operations is presented inTable 6.


Table 6 A List of Useful Pharmaceutical Unit Operations According to Categories

Heat transfer processes: Cooking, cooling, evaporating, freezing, heating, irradiating,sterilizing, freeze-drying

Change in state: Crystallizing, dispersing, dissolving, immersing, freeze-drying, neutral-izing

Change in size: Agglomerating, blending, coating, compacting, crushing, crystallizing,densifying, emulsifying, extruding, flaking, flocculating, grinding, homogenizing,milling, mixing, pelletizing, pressing, pulverizing, precipitating, sieving

Moisture transfer processes: Dehydrating, desiccating, evaporating, fluidizing, humidify-ing, freeze-drying, washing, wetting

Separation processes: Centrifuging, clarifying, deareating, degassing, deodorizing, dia-lyzing, exhausting, extracting, filtering, ion exchanging, pressing, sieving, sorting,washing

Transfer processes: Conveying, filling, inspecting, pumping, sampling, storing, trans-porting, weighing

Source: Ref. 13.

ment, clinical study, process development, and process validation and into pro-duction. Working individually with separate analytical testing functions andwith little or no appropriate communication among these three vital functions isa prescription for expensive delays. It is important to remember that the conceptillustrated in Figure 3 can still be followed even when the API is sourced fromoutside the plant site or company. In this particular situation there will probablybe two separate analytical methods development functions: one for the APImanufacturer and one for the drug product manufacturer [14].

X. STATISTICAL PROCESS CONTROL ANDPROCESS VALIDATION

Statistical process control (SPC), also called statistical quality control and pro-cess validation (PV), represents two sides of the same coin. SPC comprises thevarious mathematical tools (histogram, scatter diagram run chart, and controlchart) used to monitor a manufacturing process and to keep it within in-processand final product specification limits. Lord Kelvin once said, When you canmeasure what you are speaking about, and express it in numbers, then you knowsomething about it. Such a thought provides the necessary link between thetwo concepts. Thus, SPC represents the tools to be used, while PV representsthe procedural environment in which those tools are used.


Figure 3 Working in parallel. (Courtesy of Austin Chemical Co., Inc.)

There are three ways of establishing quality products and their manufac-turing processes:

1. In-process and final product testing, which normally depends on sam-pling size (the larger the better). In some instances, nothing short ofexcessive sampling can ensure reaching the desired goal, i.e., sterilitytesting.

2. Establishment of tighter (so called in-house) control limits that holdthe product and the manufacturing process to a more demanding stan-


dard will often reduce the need for more extensive sampling require-ments.

3. The modern approach, based on Japanese quality engineering [15], isthe pursuit of zero defects by applying tighter control over processvariability (meeting a so-called 6 sigma standard). Most pharmaceuti-cal products and their manufacturing processes in the United Statestoday, with the exception of sterile processes are designed to meet a4 sigma limit (which would permit as many as eight defects per 1000units). The new approach is to center the process (in which the grandaverage is roughly equal to 100% of label potency or the target valueof a given specification) and to reduce the process variability or noisearound the mean or to achieve minimum variability by holding bothto the new standard, batch after batch. In so doing, a 6 sigma limitmay be possible (which is equivalent to not more than three to fourdefects per 1 million units), also called zero defects. The goal of 6sigma, zero defects is easier to achieve for liquid than for solidpharmaceutical dosage forms [16].

Process characterization represents the methods used to determine thecritical unit operations or processing steps and their process variables, that usu-ally affect the quality and consistency of the product outcomes or product attri-butes. Process ranging represents studies that are used to identify critical processor test parameters and their respective control limits, which normally affect thequality and consistency of the product outcomes of their attributes. The follow-ing process characterization techniques may be used to designate critical unitoperations in a given manufacturing process.

A. Constraint AnalysisOne procedure that makes subsystem evaluations and performance qualificationtrials manageable is the application of constraint analysis. Boundary limits ofany technology and restrictions as to what constitutes acceptable output fromunit operations or process steps should in most situations constrain the numberof process variables and product attributes that require analysis. The applicationof the constraint analysis principle should also limit and restrict the operationalrange of each process variable and/or specification limit of each product attri-bute. Information about constraining process variables usually comes from thefollowing sources:

Previous successful experience with related products/processes Technical and engineering support functions and outside suppliers Published literatures concerning the specific technology under investi-

gation


A practical guide to constraint analysis comes to us from the applicationof the Pareto Principle (named after an Italian sociologist) and is also knownas the 8020 rule, which simply states that about 80% of the process output isgoverned by about 20% of the input variables and that our primary job is tofind those key variables that drive the process.

The FDA in their proposed amendments to the CGMPs [17] have desig-nated that the following unit operations are considered critical and thereforetheir processing variables must be controlled and not disregarded:

Cleaning Weighing/measuring Mixing/blending Compression/encapsulation Filling/packaging/labeling

B. Fractional Factorial DesignAn experimental design is a series of statistically sufficient qualification trialsthat are planned in a specific arrangement and include all processing variablesthat can possibly affect the expected outcome of the process under investigation.In the case of a full factorial design, n equals the number of factors or processvariables, each at two levels, i.e., the upper (+) and lower () control limits.Such a design is known as a 2n factorial. Using a large number of processvariables (say, 9) we could, for example, have to run 29, or 512, qualificationtrials in order to complete the full factorial design.

The fractional factorial is designed to reduce the number of qualificationtrials to a more reasonable number, say, 10, while holding the number of ran-domly assigned processing variables to a reasonable number as well, say, 9. Thetechnique was developed as a nonparametric test for process evaluation by Boxand Hunter [18] and reviewed by Hendrix [19]. Ten is a reasonable number oftrials in terms of resource and time commitments and should be considered anupper limit in a practical testing program. This particular design as presented inTable 7 does not include interaction effects.

XI. OPTIMIZATION TECHNIQUES

Optimization techniques are used to find either the best possible quantitativeformula for a product or the best possible set of experimental conditions (inputvalues) needed to run the process. Optimization techniques may be employed inthe laboratory stage to develop the most stable, least sensitive formula, or in thequalification and validation stages of scale-up in order to develop the most sta-


Table 7 Fractional Factorial Design (9 Variables in 10 Experiments)

Trial no. X1 X2 X3 X4 X5 X6 X7 X8 X9

1 2 + 3 + +4 + + + 5 + + + + 6 + + + + +7 + + + + + +8 + + + + + + + 9 + + + + + + + +

10 + + + + + + + + +

Worst-case conditions: Trial 1 (lower control limit). Trial 10 (upper control limit). X variablesrandomly assigned. Best values to use are RSD of data set for each trial. When adding up the databy columns, + and are now numerical values and the sum is divided by 5 (number of +s or s).If the variable is not significant, the sum will approach zero.

ble, least variable, robust process within its proven acceptable range(s) of opera-tion, Chapmans so-called proven acceptable range (PAR) principle [20].

Optimization techniques may be classified as parametric statistical meth-ods and nonparametric search methods. Parametric statistical methods, usuallyemployed for optimization, are full factorial designs, half factorial designs, sim-plex designs, and Lagrangian multiple regression analysis [21]. Parametricmethods are best suited for formula optimization in the early stages of productdevelopment. Constraint analysis, described previously, is used to simplify thetesting protocol and the analysis of experimental results.

The steps involved in the parametric optimization procedure for pharma-ceutical systems have been fully described by Schwartz [22]. Optimization tech-niques consist of the following essential operations:

1. Selection of a suitable experimental design2. Selection of variables (independent Xs and dependent Ys) to be tested3. Performance of a set of statistically designed experiments (e.g., 23 or

32 factorials)4. Measurement of responses (dependent variables)5. Development of a predictor, polynomial equation based on statistical

and regression analysis of the generated experimental data6. Development of a set of optimized requirements for the formula based

on mathematical and graphical analysis of the data generated


XII. WHAT ARE THE PROCESS VALIDATION OPTIONS?

The guidelines on general principles of process validation [1] mention threeoptions: (1) prospective process validation (also called premarket validation),(2) retrospective process validation, and (3) revalidation. In actuality there arefour possible options.

A. Prospective Process ValidationIn prospective process validation, an experimental plan called the validationprotocol is executed (following completion of the qualification trials) before theprocess is put into commercial use. Most validation efforts require some degreeof prospective experimentation to generate validation support data. This particu-lar type of process validation is normally carried out in connection with theintroduction of new drug products and their manufacturing processes. The for-malized process validation program should never be undertaken unless and untilthe following operations and procedures have been completed satisfactorily:

1. The facilities and equipment in which the process validation is tobe conducted meet CGMP requirements (completion of installationqualification)

2. The operators and supervising personnel who will be running thevalidation batch(es) have an understanding of the process and its re-quirements

3. The design, selection, and optimization of the formula have beencompleted

4. The qualification trials using (10 size) pilot-laboratory batches havebeen completed, in which the critical processing steps and processvariables have been identified, and the provisional operational controllimits for each critical test parameter have been provided

5. Detailed technical information on the product and the manufacturingprocess have been provided, including documented evidence of prod-uct stability

6. Finally, at least one qualification trial of a pilot-production (100 size)batch has been made and shows, upon scale-up, that there were nosignificant deviations from the expected performance of the process

The steps and sequence of events required to carry out a process validationassignment are outlined in Table 8. The objective of prospective validation is toprove or demonstrate that the process will work in accordance with a validationmaster plan or protocol prepared for pilot-product (100 size) trials.

In practice, usually two or three pilot-production (100 ) batches are pre-pared for validation purposes. The first batch to be included in the sequence


Table 8 Master Plan or Outline of a Process Validation Program

Objective Proving or demonstrating that the process worksType of validation Prospective, concurrent, retrospective, revalidationType of process Chemical, pharmaceutical, automation, cleaningDefinition of process Flow diagram, equipment/components, in-process, fin-

ished productDefinition of process output Potency, yield, physical parametersDefinition of test methods Method, instrumentation, calibration, traceability, preci-

sion, accuracyAnalysis of process Critical modules and variables defined by process capa-

bility design and testing programControl limits of critical vari- Defined by process capability design and testing pro-

ables gramPreparation of validation pro- Facilities, equipment, process, number of validation tri-

tocol als, sampling frequency, size, type, tests to perform,methods used, criteria for success

Organizing for validation Responsibility and authorityPlanning validation trials Timetable and PERT charting, material availability,

and disposalValidation trials Supervision, administration, documentationValidation finding Data summary, analysis, and conclusionsFinal report and recommenda- Process validated, further trials, more process design,

tions and testing

may be the already successfully concluded first pilot batch at 100 size, whichis usually prepared under the direction of the organizational function directlyresponsible for pilot scale-up activities. Later, replicate batch manufacture maybe performed by the pharmaceutical production function.

The strategy selected for process validation should be simple and straight-forward. The following factors are presented for the readers consideration:

1. The use of different lots of components should be included, i.e., APIsand major excipients.

2. Batches should be run in succession and on different days and shifts(the latter condition, if appropriate).

3. Batches should be manufactured in equipment and facilities desig-nated for eventual commercial production.

4. Critical process variables should be set within their operating rangesand should not exceed their upper and lower control limits duringprocess operation. Output responses should be well within finishedproduct specifications.


5. Failure to meet the requirements of the validation protocol with re-spect to process inputs and output control should be subjected to re-qualification following a thorough analysis of process data and formalreview by the CMC Coordination Committee.

B. Retrospective ValidationThe retrospective validation option is chosen for established products whosemanufacturing processes are considered stable and when on the basis of eco-nomic considerations alone and resource limitations, prospective validation pro-grams cannot be justified. Prior to undertaking retrospective validation, whereinthe numerical in-process and/or end-product test data of historic productionbatches are subjected to statistical analysis, the equipment, facilities and subsys-tems used in connection with the manufacturing process must be qualified inconformance with CGMP requirements. The basis for retrospective validationis stated in 21CFR 211.110(b): Valid in-process specifications for such charac-teristics shall be consistent with drug product final specifications and shall bederived from previous acceptable process average and process variability esti-mates where possible and determined by the application of suitable statisticalprocedures where appropriate.

The concept of using accumulated final product as well as in-process nu-merical test data and batch records to provide documented evidence of product/process validation was originally advanced by Meyers [26] and Simms [27] ofEli Lilly and Company in 1980. The concept is also recognized in the FDAsGuidelines on General Principles of Process Validation [1].

Using either data-based computer systems [28,29] or manual methods,retrospective validation may be conducted in the following manner:

1. Gather the numerical data from the completed batch record and in-clude assay values, end-product test results, and in-process data.

2. Organize these data in a chronological sequence according to batchmanufacturing data, using a spreadsheet format.

3. Include data from at least the last 2030 manufactured batches foranalysis. If the number of batches is less than 20, then include allmanufactured batches and commit to obtain the required number foranalysis.

4. Trim the data by eliminating test results from noncritical processingsteps and delete all gratuitous numerical information.

5. Subject the resultant data to statistical analysis and evaluation.6. Draw conclusions as to the state of control of the manufacturing pro-

cess based on the analysis of retrospective validation data.7. Issue a report of your findings (documented evidence).


One or more of the following output values (measured responses), whichhave been shown to be critical in terms of the specific manufacturing processbeing evaluated, are usually selected for statistical analysis.

1. Solid Dosage Forms1. Individual assay results from content uniformity testing2. Individual tablet hardness values3. Individual tablet thickness values4. Tablet or capsule weight variation5. Individual tablet or capsule dissolution time (usually at t50%) or disinte-

gration time6. Individual tablet or capsule moisture content

2. Semisolid and Liquid Dosage Forms1. pH value (aqueous system)2. Viscosity3. Density4. Color or clarity values5. Average particle size or distribution6. Unit weight variation and/or potency values

The statistical methods that may be employed to analyze numerical outputdata from the manufacturing process are listed as follows:

1 Basic statistics (mean, standard deviation, and tolerance limits) [21]2. Analysis of variance (ANOVA and related techniques) [21]3. Regression analysis [22]4. Cumulative sum analysis (CUSUM) [23]5. Cumulative difference analysis [23]6. Control charting (averages and range) [24,25]Control charting, with the exception of basic statistical analysis, is proba-

bly the most useful statistical technique to analyze retrospective and concurrentprocess data. Control charting forms the basis of modern statistical process con-trol.

C. Concurrent ValidationIn-process monitoring of critical processing steps and end-product testing ofcurrent production can provide documented evidence to show that the manufac-turing process is in a state of control. Such validation documentation can beprovided from the test parameter and data sources disclosed in the section onretrospective validation.


Test parameter Data source

Average unit potency End-product testingContent uniformity End-product testingDissolution time End-product testingWeight variation End-product testingPowder-blend uniformity In-process testingMoisture content In-process testingParticle or granule size distribution In-process testingWeight variation In-process testingTablet hardness In-process testingpH value In-process testingColor or clarity In-process testingViscosity or density In-process testing

Not all of the in-process tests enumerated above are required to demon-strate that the process is in a state of control. Selections of test parametersshould be made on the basis of the critical processing variables to be evaluated.

D. RevalidationConditions requiring revalidation study and documentation are listed as follows:

1. Change in a critical component (usually refers to raw materials)2. Change or replacement in a critical piece of modular (capital) equip-

ment3. Change in a facility and/or plant (usually location or site)4. Significant (usually order of magnitude) increase or decrease in batch

size5. Sequential batches that fail to meet product and process specifications

In some situations performance requalification studies may be requiredprior to undertaking specific revalidation assignments.

The FDA process validation guidelines [1] refer to a quality assurancesystem in place that requires revalidation whenever there are changes in packag-ing (assumed to be the primary container-closure system), formulation, equip-ment or processes (meaning not clear) which could impact on product effective-ness or product characteristics and whenever there are changes in productcharacteristics.

Approved packaging is normally selected after completing package perfor-mance qualification testing as well as product compatibility and stability studies.Since in most cases (exceptions: transdermal delivery systems, diagnostic tests,and medical devices) packaging is not intimately involved in the manufacturingprocess of the product itself, it differs from other factors, such as raw materials.


The reader should realize that there is no one way to establish proof orevidence of process validation (i.e., a product and process in control). If themanufacturer is certain that its products and processes are under statistical con-trol and in compliance with CGMP regulations, it should be a relatively simplematter to establish documented evidence of process validation through the useof prospective, concurrent, or retrospective pilot and/or product quality informa-tion and data. The choice of procedures and methods to be used to establishvalidation documentation is left with the manufacturer.

This introduction was written to aid scientists and technicians in the phar-maceutical and allied industries in the selection of procedures and approachesthat may be employed to achieve a successful outcome with respect to productperformance and process validation. The authors of the following chapters ex-plore the same topics from their own perspectives and experience. It is hopedthat the reader will gain much from the diversity and richness of these variedapproaches.

REFERENCES

1. Guidelines on General Principles of Process Validation, Division of Manufacturingand Product Quality, CDER, FDA, Rockville, Maryland (May 1987).

2. Current Good Manufacturing Practices in Manufacture, Processing, Packing andHolding of Human and Veterinary Drugs, Federal Register 43(190), 45085 and45086, September 1978.

3. Good Manufacturing Practices for Pharmaceuticals, Willig, S. H. and Stoker, J.R., Marcel Dekker, New York (1997).

4. Commentary, Pre-approval Inspections/Investigations, FDA, J. Parent. Sci. & Tech.45:5663 (1991).

5. Mead, W. J., Process validation in cosmetic manufacture, Drug Cosmet. Ind., (Sep-tember 1981).

6. Chapman, K. G., A history of validation in the United States, Part I, Pharm. Tech.,(November 1991).

7. Nash, R. A., The essentials of pharmaceutical validation in Pharmaceutical DosageForms: Tablets, Vol. 3, 2nd ed., Lieberman, H. A., Lachman, L. and Schwartz, J.B., eds., Marcel Dekker, New York (1990).

8. Nash, R. A., Product formulation, CHEMTECH, (April 1976).9. Pharmaceutical Process Validation, Berry, I. R. and Nash, R. A., eds., Marcel

Dekker, New York (1993).10. Nash, R. A., Making the Paper Match the Work, Pharmaceutical Formulation &

Quality (Oct/Nov 2000).11. Guidance for Industry, Scale-Up & Postapproval Changes, CDER, FDA (Nov

1995).12. Bala, G., An integrated approach to process validation, Pharm. Eng. 14(3) (1994).13. Farkas, D. F., Unit operations optimization operations, CHEMTECH, July 1977.


14. Nash, R. A., Streamlining Process Validation, Amer. Pharm. Outsourcing May2001.

15. Ishikawa, K., What is Total Quality Control? The Japanese Way, Prentice-Hall,Englewood Cliffs, NJ (1985).

16. Nash, R. A., Practicality of Achieving Six Sigma or Zero-Defects in PharmaceuticalSystems, Pharmaceutical Formulation & Quality, Oct./Nov. 2001.

17. CGMP: Amendment of Certain Requirements, FDA Federal Register, May 3,1996.

18. Box, G. E. and Hunter, J. S., Statistics for Experimenters, John Wiley, N.Y. (1978).19. Hendrix, C. D., What every technologist should know about experimental design,

CHEMTECH (March 1979).20. Chapman, K. G., The PAR approach to process validation, Pharm. Tech., Dec.

1984.21. Bolton, S., Pharmaceutical Statistics: Practical and Clinical Applications, 3rd ed.,

Marcel Dekker, New York (1997).22. Schwartz, J. B., Optimization techniques in product formulation. J. Soc. Cosmet.

Chem. 32:287301 (1981).23. Butler, J. J., Statistical quality control, Chem. Eng. (Aug. 1983).24. Deming, S. N., Quality by Design, CHEMTECH, (Sept. 1988).25. Contino, AV., Improved plant performance with statistical process control, Chem.

Eng. (July 1987).26. Meyer, R. J., Validation of Products and Processes, PMA Seminar on Validation

of Solid Dosage Form Processes, Atlanta, GA, May 1980.27. Simms, L., Validation of Existing Products by Statistical Evaluation, Atlanta, GA,

May 1980.28. Agalloco, J. P., Practical considerations in retrospective validation, Pharm. Tech.

(June 1983).29. Kahan, J. S., Validating computer systems, MD&DI (March 1987).


1Regulatory Basis forProcess Validation

John M. DietrickU.S. Food and Drug Administration, Rockville, Maryland, U.S.A.

Bernard T. LoftusU.S. Food and Drug Administration, Washington, D.C., U.S.A.

I. INTRODUCTION

Bernard T. Loftus was director of drug manufacturing in the Food and DrugAdministration (FDA) in the 1970s, when the concept of process validation wasfirst applied to the pharmaceutical industry and became an important part ofcurrent good manufacturing practices (CGMPs). His comments on the develop-ment and implementation of these regulations and policies as presented in thefirst and second editions of this volume are summarized below [1].

II. WHAT IS PROCESS VALIDATION?

The term process validation is not defined in the Food, Drug, and Cosmetic Act(FD&C) Act or in FDAs CGMP regulations. Many definitions have been of-fered that in general express the same ideathat a process will do what itpurports to do, or that the process works and the proof is documented. A June1978 FDA compliance program on drug process inspections [2] contained thefollowing definition:

This chapter was written by John M. Dietrick in his private capacity. No official support or endorse-ment by the Food and Drug Administration is intended or should be inferred.


A validated manufacturing process is one which has been proved to do whatit purports or is represented to do. The proof of validation is obtainedthrough the collection and evaluation of data, preferably, beginning fromthe process development phase and continuing through the productionphase. Validation necessarily includes process qualification (the qualifica-tion of materials, equipment, systems, buildings, personnel), but it also in-cludes the control on the entire process for repeated batches or runs.

The first drafts of the May 1987 Guideline on General Principles of ProcessValidation [3] contained a similar definition, which has frequently been used inFDA speeches since 1978, and is still used today: A documented program whichprovides a high degree of assurance that a specific process will consistently pro-duce a product meeting its pre-determined specifications and quality attributes.

III. THE REGULATORY BASIS FORPROCESS VALIDATION

Once the concept of being able to predict process performance to meet userrequirements evolved, FDA regulatory officials established that there was a le-gal basis for requiring process validation. The ultimate legal authority is Section501(a)(2)(B) of the FD&C Act [4], which states that a drug is deemed to beadulterated if the methods used in, or the facilities or controls used for, itsmanufacture, processing, packing, or holding do not conform to or were notoperated or administrated in conformity with CGMP. Assurance must be giventhat the drug would meet the requirements of the act as to safety and wouldhave the identity and strength and meet the quality and purity characteristicsthat it purported or was represented to possess. That section of the act sets thepremise for process validation requirements for both finished pharmaceuticalsand active pharmaceutical ingredients, because active pharmaceutical ingredi-ents are also deemed to be drugs under the act.

The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and211, were promulgated to enforce the requirements of the act. Although theseregulations do not include a definition for process validation, the requirement isimplicit in the language of 21 CFR 211.100 [5], which states: There shall bewritten procedures for production and process control designed to assure thatthe drug products have the identity, strength, quality, and purity they purport orare represented to possess.

IV. THE REGULATORY HISTORY OFPROCESS VALIDATION

Although the emphasis on validation began in the late 1970s, the requirementhas been around since at least the 1963 CGMP regulations for finished pharma-ceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved


in 1962 with Section 501(a)(2)(B) as an amendment. Prior to then, CGMP andprocess validation were not required by law. The FDA had the burden of prov-ing that a drug was adulterated by collecting and analyzing samples. This wasa significant regulatory burden and restricted the value of factory inspections ofpharmaceutical manufacturers. It took injuries and deaths, mostly involvingcross-contamination problems, to convince Congress and the FDA that a revi-sion of the law was needed. The result was the KefauverHarris drug amend-ments, which provided the additional powerful regulatory tool that FDA re-quired to deem a drug product adulterated if the manufacturing process was notacceptable. The first CGMP regulations, based largely on the PharmaceuticalManufacturers Associations manufacturing control guidelines, were then pub-lished and became effective in 1963. This change allowed FDA to expect apreventative approach rather than a reactive approach to quality control. Section505(d)(3) is also important in the implementation of process validation require-ments because it gives the agency the authority to withhold approval of a newdrug application if the methods used in, and the facilities and controls usedfor, the manufacture, processing, and packing of such drug are inadequate topreserve its identity, strength, quality, and purity.

Another requirement of the same amendments was the requirement thatFDA must inspect every drug manufacturing establishment at least once every2 years [6]. At first, FDA did this with great diligence, but after the worstCGMP manufacturing situations had been dealt with and violations of the lawbecame less obvious, FDA eased up its pharmaceutical plant inspection activi-ties and turned its resources to more important problems.

The Drug Product Quality Assurance Program of the 1960s and 1970sinvolved first conducting a massive sampling and testing program of finishedbatches of particularly important drugs in terms of clinical significance anddollar volume, then taking legal action against violative batches and inspectingthe manufacturers until they were proven to be in compliance. This approachwas not entirely satisfactory because samples are not necessarily representativeof all batches. Finished product testing for sterility, for example, does not assurethat the lot is sterile. Several incidents refocused FDAs attention to processinspections. The investigation of complaints of clinical failures of several prod-ucts (including digoxin, digitoxin, prednisolone, and prednisone) by FDA foundsignificant content uniformity problems that were the result of poorly controlledmanufacturing processes. Also, two large-volume parenteral manufacturers ex-perienced complaints despite quality control programs and negative sterility test-ing. Although the cause of the microbiological contamination was never proven,FDA inspections did find deficiencies in the manufacturing process and it be-came evident that there was no real proof that the products were sterile.

What became evident in these cases was that FDA had not looked at theprocess itselfcertainly not the entire processin its regulatory activities; itwas quality control- rather than quality assurance-oriented. The compliance offi-


cials were not thinking in terms of process validation. One of the first entriesinto process validation was a 1974 paper presented by Ted Byers, entitled De-sign for Quality [7]. The term validation was not used, but the paper describedan increased attention to adequacy of processes for the production of pharma-ceuticals. Another paperby Bernard Loftus before the Parenteral Drug Associ-ation in 1978 entitled Validation and Stability [8]discussed the legal basisfor the requirement that processes be validated.

The May 1987 Guideline on General Principles of Process Validation [3]was written for the pharmaceutical, device, and veterinary medicine industries.It has been effective in standardizing the approach by the different parts of theagency and in communicating that approach to manufacturers in each industry.

V. UPDATE

As discussed in the preceding sections, process validation has been a legal re-quirement since at least 1963. Implementation of the requirement was a slowand deliberate process, beginning with the development and dissemination of anagency policy by Loftus, Byers, and others, and leading to the May 1987 guide-line. The guideline quickly became an important source of information to phar-maceutical manufacturers interested in establishing a process validation pro-gram. Many industry organizations and officials promoted the requirements aswell as the benefits of validation. Many publications, such as PharmaceuticalProcess Validation [1] and various pharmaceutical industry journal articles,cited and often expanded on the principals in the guideline. During the sameperiod, computer validationor validation of computer controlled processesalso became a widely discussed topic in both seminars and industry publications.

The regulatory implementation of the validation requirement was also adeliberate process by FDA. During the 1980s, FDA investigators often reportedprocesses that had not been validated or had been inadequately validated. Batchfailures were often associated with unvalidated manufacturing processes. TheFDA issued a number of regulatory letters to deficient manufacturers citing thelack of adequate process validation as a deviation from CGMP regulations(21CFR 211.100), which causes the drug product to be adulterated within themeaning of Section 501(a)(2)(B) of the federal FD&C Act. Process validationwas seldom the only deficiency listed in these regulatory letters. The failure ofsome manufacturers to respond to these early warnings resulted in FDA filingseveral injunction cases that included this charge in the early 1990s. Most ofthese cases resulted in consent decrees, and ultimately the adoption of satisfac-tory process validation programs by the subject manufacturers. One injunctioncase filed in 1992, however, was contested in court and led to a lengthy writtenorder and opinion by the U.S. District Court in February of 1993 [9]. The court


affirmed the requirement for process validation in the current good manufactur-ing regulations, and ordered the defendants to perform process validation studieson certain drug products, as well as equipment cleaning validation studies. Thiscase and the courts ruling were widely circulated in the pharmaceutical industryand became the subject of numerous FDA and industry seminars.

The court also criticized the CGMP regulations for their lack of specific-ity, along with their ambiguity and vagueness. Responding to this criticism,FDA drafted revisions to several parts of these regulations. The proposed revi-sions were published in the Federal Register on May 3, 1996 [10]. One of themain proposed changes was intended to emphasize and clarify the process vali-dation requirements. The proposal included a definition of process validation(the same definition used in the 1987 guideline), a specific requirement to vali-date manufacturing processes, and minimum requirements for performing anddocumenting a validation study. These were all implied but not specific in the1978 regulation. In proposing these changes, FDA stated that it was codifyingcurrent expectations and current industry practice and did not intend to add newvalidation requirements. Comments from all interested parties were requestedunder the agencys rule-making policies, and approximately 1500 commentswere received. Most of the responses to the changes regarding process validationsupported the agencys proposals, but there were many comments regarding thedefinitions and terminology proposed about which processes and steps in a pro-cess should or should not require validation, the number of batches required forprocess validation, maintenance of validation records, and the assignment ofresponsibility for final approval of a validation study and change control deci-sions. Because of other high-priority obligations, the agency has not yet com-pleted the evaluation of these responses and has not been able to publish thefinal rule. In addition to the official comments, the proposed changes promptednumerous industry and FDA seminars on the subject.

Process validation is not just an FDA or a U.S. requirement. Similar re-quirements are included in the World Health Organization (WHO), the Pharma-ceutical Inspection Co-operation Scheme (PIC/S), and the European Union (EU)requirements, along with those of Australia, Canada, Japan, and other interna-tional authorities.

Most pharmaceutical manufacturers now put substantial resources intoprocess validation for both regulatory and economic reasons, but despite contin-ued educational efforts by both the agency and the pharmaceutical industry,FDA inspections (both domestically and internationally) continue to find somefirms manufacturing drug products using unvalidated or inadequately validatedprocesses. Evidently there is still room for improvement, and continued discus-sion, education, and occasional regulatory action appears warranted.

The future of process validation is also of great interest, especially withthe worldwide expansion of pharmaceutical manufacturing and the desire for


harmonized international standards and requirements. Many manufacturers arealso working on strategies to reduce the cost of process validation and incorpo-rate validation consideration during product design and development. New tech-nologies under development for 100% analysis of drug products and other inno-vations in the pharmaceutical industry may also have a significant effect onprocess validation concepts and how they can be implemented and regulated.

REFERENCES

1. Loftus, B. T., Nash, R. A., ed. Pharmaceutical Process Validation. vol. 57. NewYork: Marcel Dekker (1993).

2. U.S. Food and Drug Administration. Compliance Program no. 7356.002.3. U.S. Food and Drug Administration. Guideline on General Principles of Process

Validation. Rockville, MD: FDA, 1987.4. Federal Food Drug and Cosmetic Act, Title 21 U.S. Code, Section 501 (a)(2)(B).5. Code of Federal Regulations, Title 21, Parts 210 & 211. Fed Reg 43, 1978.6. U.S. Code, Federal Food Drug and Cosmetic Act, Title 21, Section 510 (h).7. Byers, T. E. Design for quality, Manufacturing Controls Seminar, Proprietary Asso-

ciation, Cherry Hill, NJ, Oct. 11, 1974.8. Loftus, B. T. Validation and stability, meeting of Parenteral Drug Association,

1978.9. U.S. v. Barr Laboratories, Inc., et al., Civil Action No. 92-1744, U.S. District Court

for the District of New Jersey, 1973.10. Code of Federal Regulations, Title 21, Parts 21 & 211, Proposed Revisions, Fed

Reg (May 3, 1996).


2Prospective Process Validation

Allen Y. ChaoWatson Labs, Carona, California, U.S.A.

F. St. John ForbesWyeth Labs, Pearl River, New York, U.S.A.

Reginald F. Johnson and Paul Von DoehrenSearle & Co., Inc., Skokie, Illinois, U.S.A.

I. INTRODUCTION

Validation is an essential procedure that demonstrates that a manufacturing pro-cess operating under defined standard conditions is capable of consistently pro-ducing a product that meets the established product specifications. In itsproposed guidelines, the U.S. Food and Drug Administration (FDA) has offeredthe following definition for process validation [1].

Process validation is establishing documented evidence that provides ahigh degree of assurance that a specific process (s

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