Pharmaceutical Process Validation.pdf

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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 Editor

James Swarbrick

PharmaceuTech, Inc

Pinehurst, North Carolina

Advisory Board

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

Baltimore, Maryland West Lafayette, Indiana Douwe D. Breimer Stephen G. Schulman Gorlaeus Laboratories University of Florida Leiden, The Netherlands Gamesville, Florida

Trevor M Jones Jerome P. Skelly The Association of the Alexandria, Virginia British Pharmaceutical Industry

London, United Kingdom

Hans E. Junginger Felix Theeuwes Leiden/Amsterdam Center Alza Corporation

for Drug Research Palo Alto, California Leiden, The Netherlands

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

Los Angeles, California Royal Hallamshire Hospital Sheffield, United Kingdom Peter G. Welling

Institut de Recherche Jouvemal Fresnes, France

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DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs

1. Pharmacokmetics, Milo Gibaldi and Donald Perrier

2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William

S. Hitchings IV

3. Microencapsulation, edited by J. R Nixon

4. Drug Metabolism. Chemical and Biochemical Aspects, Bernard Testa

and Peter Jenner

5. New Drugs: Discovery and Development, edited by Alan A. Rubin

6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson

7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes

8. Prescription Drugs in Short Supply Case Histories, Michael A.

Schwartz

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

Cooney

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

and Bernard Testa

11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by

James W, Munson

12. Techniques of Solubilization of Drugs, edited by Samuel H

Yalkow-sky

13. Orphan Drugs, edited by Fred E. Karch

14. Novel Drug Delivery Systems: Fundamentals, Developmental Con-cepts, Biomedical Assessments, Yie W. Chien

15. Pharmacokmetics: Second Edition, Revised and Expanded, Milo

Gibaldi and Donald Perrier

16 Good Manufacturing Practices for Pharmaceuticals' A Plan for Total Quality Control, Second Edition, Revised and Expanded, Sidney H

Willig, Murray M Tuckerman, and William S. Hitchings IV

17 Formulation of Veterinary Dosage Forms, edited by Jack Blodinger 18 Dermatological Formulations. Percutaneous Absorption, Brian W

Barry

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

by Gary M. Matoren

20. Microencapsulation and Related Drug Processes, Patrick B. Deasy 21. Drugs and Nutrients The Interactive Effects, edited by Daphne A.

Roe and T. Colin Campbell

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

24 Anticancer and Interferon Agents Synthesis and Properties, edited by

Raphael M Ottenbrtte and George B Butler

25 Pharmaceutical Statistics Practical and Clinical Applications, Sanford

Bolton

26 Drug Dynamics for Analytical, Clinical, and Biological Chemists,

Benjamin J Gudzmowicz, Burrows T Younkm, Jr, and Michael J Gudzmowicz

27 Modern Analysis of Antibiotics, edited by Adjoran Aszalos 28 Solubility and Related Properties, Kenneth C James

29 Controlled Drug Delivery Fundamentals and Applications, Second Edition, Revised and Expanded, edited by Joseph R Robinson and Vincent H Lee

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

31 Transdermal Controlled Systemic Medications, edited by Yie W Chien 32 Drug Delivery Devices Fundamentals and Applications, edited by

Praveen Tyle

33 Pharmacokinetics Regulatory • Industrial • Academic Perspectives, edited by Peter G Welling and Francis L S Tse

34 Clinical Drug Trials and Tribulations, edited by Alien E Cato

35 Transdermal Drug Delivery Developmental Issues and Research Ini-tiatives, edited by Jonathan Hadgraft and Richard H Guy

36 Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,

edited by James W McGmity

37 Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie

38 Good Laboratory Practice Regulations, edited by Alien F Hirsch 39 Nasal Systemic Drug Delivery, Yie W Chien, Kenneth S E Su, and

Shyi-Feu Chang

40 Modern Pharmaceutics Second Edition, Revised and Expanded,

edited by Gilbert S Banker and Chnstopher T Rhodes

41 Specialized Drug Delivery Systems Manufacturing and Production Technology, edited by Praveen Tyle

42 Topical Drug Delivery Formulations, edited by David W Osborne and Anton H Amann

43 Drug Stability Principles and Practices, Jens T Carstensen

44 Pharmaceutical Statistics Practical and Clinical Applications, Second Edition, Revised and Expanded, Sanford Bolton

45 Biodegradable Polymers as Drug Delivery Systems, edited by Mark

Chasm and Robert Langer

46 Preclmical Drug Disposition A Laboratory Handbook, Francis L S

Tse and James J Jaffe

47 HPLC in the Pharmaceutical Industry, edited by Godwin W Fong and

Stanley K Lam

48 Pharmaceutical Bioequivalence, edited by Peter G Welling, Francis L

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49. Pharmaceutical Dissolution Testing, Umesh V. Sana/car

50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W. Chien

51. Managing the Clinical Drug Development Process, David M. Coc-chetto and Ronald V. Nardi

52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Third Edition, edited by Sidney H. Willig and James R. Stoker

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

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

55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn

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

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

58. Ophthalmic Drug Delivery Systems, edited byAshim K. Mitra

59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft

60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck 61. Pharmaceutical Particulate Carriers1 Therapeutic Applications, edited

by Alain Rolland

62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh

63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan

64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls

65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie 66. Colloidal Drug Delivery Systems, edited byJorg Kreuter

67 Pharmacokinetics: Regulatory • Industrial • Academic Perspectives, Second Edition, edited by Peter G. Welling and Francis L. S. Tse 68. Drug Stability: Principles and Practices, Second Edition, Revised and

Expanded, Jens T. Carstensen

69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg

70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Bnttain

71. Pharmaceutical Powder Compaction Technology, edited by Goran Al-derborn and Christer Nystrom

72. Modern Pharmaceutics. Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher J Rhodes

73. Microencapsulation. Methods and Industrial Applications, edited by

Simon Benita

74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone

75. Clinical Research in Pharmaceutical Development, edited by Barry

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

V Banakar

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

78 Good Manufacturing Practices for Pharmaceuticals A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H

Willig and James R Stoker

79 Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms Second Edition, Revised and Expanded, edited by James W McGmity

80 Pharmaceutical Statistics Practical and Clinical Applications, Third Edition, Sanford Bolton

81 Handbook of Pharmaceutical Granulation Technology edited by Dilip

M 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 Potts

and Richard H Guy

84 Pharmaceutical Enzymes edited by Albert Lauwers and Simon

Scharpe

85 Development of Biopharmaceutical Parenteral Dosage Forms, edited

by John A Bontempo

86 Pharmaceutical Project Management, edited by Tony Kennedy 87 Drug Products for Clinical Trials An International Guide to

Formula-tion • ProducFormula-tion • Quality Control, edited by Donald C Monkhouse

and Christopher T Rhodes

88 Development and Formulation of Veterinary Dosage Forms Second Edition, Revised and Expanded, edited by Gregory E Hardee and J

Desmond Baggot

89 Receptor-Based Drug Design, edited by Paul Leff

90 Automation and Validation of Information in Pharmaceutical Pro-cessing, edited by Joseph F deSpautz

91 Dermal Absorption and Toxicity Assessment, edited by Michael S Roberts and Kenneth A Walters

92 Pharmaceutical Experimental Design, Gareth A Lewis, Didier

Mathieu, and Roger Phan-Tan-Luu

93 Preparing for FDA Pre-Approval Inspections, edited by Martin D

Hynes III

94 Pharmaceutical Excipients Characterization by IR, Raman, and NMR Spectroscopy, David E Bugay and W Paul Fmdlay

95 Polymorphism in Pharmaceutical Solids, edited by Harry G Brittam 96 Freeze-Drymg/Lyophihzation of Pharmaceutical and Biological

Prod-ucts, edited by Louis Rey and Joan C May

97 Percutaneous Absorption Drugs-Cosmetics-Mechanisms-Metho-dology, Third Edition, Revised and Expanded, edited by Robert L

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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. McNally 100. New Drug Approval Process: Third Edition, The Global Challenge,

edited by Richard A. Guarino

101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid

102 Transport Processes in Pharmaceutical Systems, edited by Gordon L

Amidon, Ping I. Lee, and Elizabeth M. Topp

103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A.

Kotkoskie

104 The Clinical Audit in Pharmaceutical Development, edited by Michael

R. Hamrell

105. Pharmaceutical Emulsions and Suspensions, edited by Francoise

Nielloud and Gilberte Marti-Mestres

106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B.

Dressman and Hans Lennernas

107. Drug Stability: Principles and Practices, Third Edition, Revised and Expanded, edited by Jens T. Carstensen and C. T. Rhodes

108. Containment in the Pharmaceutical Industry, edited by James P.

Wood

109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded, Sidney H Willig

110. Advanced Pharmaceutical Solids, Jens T Carstensen

111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition, Revised and Expanded, Kevin L. Williams

112 Pharmaceutical Process Engineering, Anthony J. Hickey and David

Ganderton

113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and

Ra-chel F. Tyndale

114. Handbook of Drug Screening, edited by Ramaknshna Seethala and

Prabhavathi B. Fernandas

115. Drug Targeting Technology: Physical • Chemical • Biological Methods,

edited by Hans Schreier

116. Drug-Drug Interactions, edited by A. David Rodngues

117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian

and Anthony J. Streeter

118. Pharmaceutical Process Scale-Up, edited by Michael Levin

119. Dermatological and Transdermal Formulations, edited by Kenneth A.

Walters

120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded, edited by Alien Cato, Lynda Sutton, and Alien Cato III 121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded,

edi-ted by Gilbert S. Banker and Chnstopher T. Rhodes

122. Surfactants and Polymers in Drug Delivery, Martin Malmsten

123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,

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

125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Pack-age Integrity Testing. Third Edition, Revised and Expanded, Michael

J. 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 and

Sean M. Sullivan

ADDITIONAL VOLUMES IN PREPARATION

Biomarkers in Clinical Drug Development, edited by John C Bloom

and 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

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

Switzerland, for their pioneering contributions with respect to the pharmaceutical process validation concept. We also acknowledge the past contributions of Bernard T. Loftus and Ira R. Berry toward the

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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 pharmaceutical process validation was an American invention, based on the pioneering work of Theodore E. Byers and Bernard T. Loftus, both formerly with the U.S. Food & Drug Administration. The truth is that many of our fundamental concepts of pharmaceutical 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 book’s impact. They include “Validation for Medical Devices” by Nishihata, “Validation of Biotechnology 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 and SUPAC” by Waterland and Kowtna, “Validation in Contract Manufacturing” by 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 the CIBA Pharmaceutical Company in Basel, Switzerland, and also spent a number of years on assignment in Asia for CIBA. Fred brings a very strong international perspective to the subject matter.

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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 and Drug Administration, Rockville, Maryland, U.S.A.

John E. Dutt EM Industries, Inc., Hawthorne, New York, U.S.A. Mervyn J. Frederick NV Organon–Akzo Nobel, Oss, The Netherlands William E. Hall Hall & Pharmaceutical Associates, Inc., Kure Beach, North Carolina, U.S.A.

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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 PECON—Peither 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.

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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.

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Introduction

Robert A. Nash

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

I. FDA GUIDELINES

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

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of 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: selection of 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 the process 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 of batches that meet specifications will be acceptable.

According to the FDA’s Current Good Manufacturing Practices (CGMPs) 21CFR 211.110 a:

Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to the following, where appropriate [2]:

1. Tablet or capsule weight variation 2. Disintegration time

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3. Adequacy of mixing to assure uniformity and homogeneity 4. Dissolution time and rate

5. Clarity, completeness, or pH of solutions

The first four items listed above are directly related to the manufacture and validation of solid dosage forms. Items 1 and 3 are normally associated with variability in the manufacturing process, while items 2 and 4 are usually influenced by the selection of the ingredients in the product formulation. With respect to content uniformity and unit potency control (item 3), adequacy of mixing 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 characteristics 2. Selection of appropriate methodology, equipment, and

instrumenta-tion to ensure that testing of the product meets specificainstrumenta-tions 3. 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 equipment

5. Qualification and validation of the manufacturing process through ap-propriate means

6. Auditing, monitoring, sampling, or challenging the key steps in the process for conformance to in-process and final product specifications 7. Revalidation when there is a significant change in either the product

or its manufacturing process [3].

II. TOTAL APPROACH TO PHARMACEUTICAL PROCESS VALIDATION

It has been said that there is no specific basis for requiring a separate set of process validation guidelines, since the essentials of process validation are em-bodied within the purpose and scope of the present CGMP regulations [2]. With this 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 of manufacturing, i.e., medical devices (21 CFR–Part 820) as well as drug prod-ucts, and thus may be subjected, subpart by subpart, to the application of the principles of qualification, validation, verification and control, in addition to change control and revalidation, where applicable. Although not a specific

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re-quirement of current regulations, such a comprehensive approach with respect to each subpart of the CGMP document has been adopted by many drug firms. A checklist of qualification and control documentation with respect to CGMPs 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], and directives [3], considers process validation necessary because it makes good engineering sense. The basic concept, according to Mead [5], has long been

Table 1 Checklist of Qualification and Control Documentation

Qualification and

Subpart Section of CGMPs control documentation

A General provisions

B Organization and personnel Responsibilities of the quality con-trol unit

C Buildings and facilities Plant and facility installation and qualification

Maintenance and sanitation Microbial and pest control

D Equipment Installation and qualification of

equipment 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 information systems

K Return and salvaged drug products Batch reprocessing

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applied in other industries, often without formal recognition that such a concept was being used. For example, the terms reliability engineering and qualification have 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 more technically and economically sound products and their manufacturing processes. In the old days R & D “gurus” would literally hand down the “go” sometimes overformulated product and accompanying obtuse manufacturing procedure, usually with little or no justification or rationale provided. Today, under FDA’s

Preapproval Inspection (PAI) program [4] such actions are no longer

accept-able. The watchword is to provide scientifically sound justifications (including qualification and validation documentation) for everything that comes out of the pharmaceutical R & D function.

IV. WHAT IS PROCESS VALIDATION?

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

The big problem is that we use the term validation generically to cover the 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 the product/process development sequence. The essential or key steps or stages of a successfully completed product/process development program are presented inTable 2[7].

The end of the sequence that has been assigned to process validation is derived from the fact that the specific exercise of process validation should never be designed to fail. Failure in carrying out the process validation assign-ment is often the result of incomplete or faulty understanding of the process’s capability, in other words, what the process can and cannot do under a given set of operational circumstances. In a well-designed, well-run overall validation program, 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 propro-cess validation

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Table 2 The Key Stages in the Product/Process Development Sequence

Development stage Pilot scale-up phase

Product design 1× batch size

Product characterization Product selection (“go” formula) Process design

Product optimization 10× batch size Process characterization

Process optimization

Process demonstration 100× batch size Process validation program

Product/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-up batches in production-type equipment.

sequence provides only the necessary process validation documentation required by the regulatory authorities—in other words, the “Good Housekeeping Seal of Approval,” which shows that the manufacturing process is in a state of control. Such a strategy is consistent with the U.S. FDA’s preapproval inspection

program [4], wherein the applicant firm under either a New Drug Application

(NDA) or an Abbreviated New Drug Application (ANDA) submission must show 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 course of your reading whether the entire concept is discussed in connection with the topic—i.e., design, characterization, optimization, qualification, validation, and/ or revalidation—or whether the author has concentrated on the specifics of the validation of a given product and/or its manufacturing process. In this way the text will take on greater meaning and clarity.

V. PILOT SCALE-UP AND PROCESS VALIDATION

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

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1. Formulation design, selection, and optimization 2. Preparation of the first pilot-laboratory batch 3. Conduct initial accelerated stability testing

4. 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 and prior to its acceptance by the full scale manufacturing unit. For the pilot program to be successful, elements of process validation must be included and completed during the developmental or pilot laboratory phase of the work.

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

A. Laboratory Batch

The first step in the scale-up process is the selection of a suitable preliminary formula for more critical study and testing based on certain agreed-upon initial design criteria, requirements, and/or specifications. The work is performed in the development laboratory. The formula selected is designated as the (1× ) laboratory batch. The size of the (1× ) laboratory batch is usually 3–10 kg of a solid or semisolid, 3–10 liters of a liquid, or 3000 to 10,000 units of a tablet or capsule.

B. Laboratory Pilot Batch

After the (1× ) laboratory batch is determined to be both physically and chemi-cally stable based on accelerated, elevated temperature testing (e.g., 1 month at 45°C or 3 months at 40°C or 40°C/80% RH), the next step in the scale-up process is the preparation of the (10× ) laboratory pilot batch. The (10 × ) laboratory pilot batch represents the first replicated scale-up of the designated formula. The size of the laboratory pilot batch is usually 30–100 kg, 30–100 liters, 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 the laboratory pilot batches may vary in response to one or more of the following factors:

1. Equipment availability

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3. Cost of raw materials

4. Inventory requirements for clinical and nonclinical studies

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

C. Pilot Production

The pilot-production phase may be carried out either as a shared responsibility between the development laboratories and its appropriate manufacturing coun-terpart or as a process demonstration by a separate, designated pilot-plant or process-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 to carry out process scale-up and/or validation assignments in a timely manner. On the other hand, the joint pilot-operation option provides direct communication between the development laboratory and pharmaceutical production.

Figure 1 Main piloting options. (Top) Separate pilot plant functions—engineering concept. (Bottom) Joint pilot operation.

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The object of the pilot-production batch is to scale the product and process by another order of magnitude (100× ) to, for example, 300–1,000 kg, 300– 1,000 liters, or 300,000–1,000,000 dosage form units (tablets or capsules) in size. For most drug products this represents a full production batch in standard production equipment. If required, pharmaceutical production is capable of scal-ing the product/process to even larger batch sizes should the product require expanded production output. If the batch size changes significantly, additional validation studies would be required. The term product/process is used, since one can’t describe a product with discussing its process of manufacture and, conversely, one can’t talk about a process without describing the product being manufactured.

Usually large production batch scale-up is undertaken only after product introduction. Again, the actual size of the pilot-production (100× ) batch may vary due to equipment and raw material availability. The need for additional pilot-production batches ultimately depends on the successful completion of a first pilot batch and its process validation program. Usually three successfully completed 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 pilot scale-up program is suggested inTable 3.

VI. PROCESS VALIDATION: ORDER OF PRIORITY

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

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

A. Sterile Products and Their Processes 1. Large-volume parenterals (LVPs) 2. Small-volume parenterals (SVPs)

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

Calendar

Event months

Formula selection and development 2–4

Assay methods development and formula optimization 2–4 Stability in standard packaging 3-month readout (1× size) 3–4

Pilot-laboratory batches (10× size) 1–3

Preparation and release of clinical supplies (10× size) and

establishment of process demonstration 1–4

Additional stability testing in approved packaging 3–4 6–8-month readout (1× size)

3-month readout (10× size)

Validation protocols and pilot batch request 1–3

Pilot-production batches (100× size) 1–3

Additional stability testing in approved packaging 3–4 9–12-month readout (1× size)

6–8-month readout (10× size) 3-month readout (100× size)

Interim approved technical product development report with

approximately 12 months stability (1× size) 1–3 Totals 18–36

B. Nonsterile Products and Their Processes

1. Low-dose/high-potency tablets and capsules/transdermal delivery sys-tems (TDDs)

2. Drugs with stability problems 3. Other tablets and capsules

4. 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 organized to conduct process validation assignments is beyond the scope of this introduc-tory chapter. The responsibilities that must be carried out and the organizational structures best equipped to handle each assignment are outlined inTable 4. The

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Table 4 Specific Responsibilities of Each Organizational Structure within the Scope of 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 requirements—in 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 design limits, specifications, and/or requirements.

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

Source: Ref. 8.

best approach in carrying out the process validation assignment is to establish a Chemistry, Manufacturing and Control (CMC) Coordination Committee at the specific 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. Typical meeting 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

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• 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 process

parameters or operating variables that influence process output and the range of numerical data for critical process parameters that result in acceptable process output. If the capability of a process is properly delineated, the process should consistently stay within the defined limits of its critical process parameters and product characteristics [12].

Process demonstration formerly called process qualification, represents

the actual studies or trials conducted to show that all systems, subsystems, or unit operations of a manufacturing process perform as intended; that all critical process parameters operate within their assigned control limits; and that such studies 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 used to convert raw materials into a finished product. The ways and means also include people, equipment, facilities, and support systems required to operate the process in a planned and effectively managed way. All the latter functions must be qualified individually. The master plan or protocol for process capabil-ity design and testing is presented inTable 5.

A simple flow chart should be provided to show the logistical sequence of unit operations during product/process manufacture. A typical flow chart used in the manufacture of a tablet dosage form by the wet granulation method is presented inFigure 2.

IX. STREAMLINING VALIDATION OPERATIONS

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

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

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develop-Table 5 Master Plan or Protocol for Process Capability Design and Testing Objective Process capability design and testing Types of process Batch, intermittent, continuous Typical processes Chemical, pharmaceutical, biochemical Process definition Flow diagram, in-process, finished product Definition of process output Potency, yield, physical parameters Definition of test methods Instrumentation, procedures, precision, and

accuracy

Process analysis Process variables, matrix design, factorial design analysis

Pilot batch trials Define sampling and testing, stable, extended runs Pilot batch replication Different days, different materials, different

equip-ment

Process redefinition Reclassification of process variables

Process capability evaluation Stability and variability of process output, eco-nomic limits

Final report Recommended SOP, specifications, and process limits

Figure 2 Process flow diagram for the manufacture of a tablet dosage form by wet granulation method. The arrows show the transfer of material into and out of each of the various unit operations. The information in parentheses indicates additions of material to specific unit operations. A list of useful pharmaceutical unit operations is presented in Table 6.

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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-dryhumidify-ing, washhumidify-ing, 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 and with little or no appropriate communication among these three vital functions is a prescription for expensive delays. It is important to remember that the concept illustrated inFigure 3can still be followed even when the API is sourced from outside the plant site or company. In this particular situation there will probably be two separate analytical methods development functions: one for the API manufacturer and one for the drug product manufacturer [14].

X. STATISTICAL PROCESS CONTROL AND PROCESS VALIDATION

Statistical process control (SPC), also called statistical quality control and pro-cess validation (PV), represents two sides of the same coin. SPC comprises the

various mathematical tools (histogram, scatter diagram run chart, and control chart) used to monitor a manufacturing process and to keep it within in-process and final product specification limits. Lord Kelvin once said, “When you can measure what you are speaking about, and express it in numbers, then you know something about it.” Such a thought provides the necessary link between the two concepts. Thus, SPC represents the tools to be used, while PV represents the procedural environment in which those tools are used.

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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 of excessive sampling can ensure reaching the desired goal, i.e., sterility testing.

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

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

3. The modern approach, based on Japanese quality engineering [15], is the pursuit of “zero defects” by applying tighter control over process variability (meeting a so-called 6 sigma standard). Most pharmaceuti-cal products and their manufacturing processes in the United States today, with the exception of sterile processes are designed to meet a 4 sigma limit (which would permit as many as eight defects per 1000 units). The new approach is to center the process (in which the grand average is roughly equal to 100% of label potency or the target value of a given specification) and to reduce the process variability or noise around the mean or to achieve minimum variability by holding both to the new standard, batch after batch. In so doing, a 6 sigma limit may be possible (which is equivalent to not more than three to four defects per 1 million units), also called “zero defects.” The goal of 6 sigma, “zero defects” is easier to achieve for liquid than for solid pharmaceutical dosage forms [16].

Process characterization represents the methods used to determine the

critical 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 process or test parameters and their respective control limits, which normally affect the quality and consistency of the product outcomes of their attributes. The follow-ing process characterization techniques may be used to designate critical unit operations in a given manufacturing process.

A. Constraint Analysis

One procedure that makes subsystem evaluations and performance qualification trials manageable is the application of constraint analysis. Boundary limits of any technology and restrictions as to what constitutes acceptable output from unit operations or process steps should in most situations constrain the number of process variables and product attributes that require analysis. The application of the constraint analysis principle should also limit and restrict the operational range of each process variable and/or specification limit of each product attri-bute. Information about constraining process variables usually comes from the following sources:

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

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A practical guide to constraint analysis comes to us from the application of the Pareto Principle (named after an Italian sociologist) and is also known as the 80–20 rule, which simply states that about 80% of the process output is governed by about 20% of the input variables and that our primary job is to find 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 therefore their processing variables must be controlled and not disregarded:

• Cleaning

• Weighing/measuring • Mixing/blending

• Compression/encapsulation • Filling/packaging/labeling B. Fractional Factorial Design

An experimental design is a series of statistically sufficient qualification trials that are planned in a specific arrangement and include all processing variables that 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 process variables, 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 process variables (say, 9) we could, for example, have to run 29, or 512, qualification trials in order to complete the full factorial design.

The fractional factorial is designed to reduce the number of qualification trials 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. The technique was developed as a nonparametric test for process evaluation by Box and Hunter [18] and reviewed by Hendrix [19]. Ten is a reasonable number of trials in terms of resource and time commitments and should be considered an upper limit in a practical testing program. This particular design as presented in Table 7does not include interaction effects.

XI. OPTIMIZATION TECHNIQUES

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

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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 variables randomly assigned. Best values to use are RSD of data set for each trial. When adding up the data by 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, Chapman’s so-called proven acceptable range (PAR) principle [20].

Optimization techniques may be classified as parametric statistical meth-ods and nonparametric search methmeth-ods. Parametric statistical methmeth-ods, usually employed for optimization, are full factorial designs, half factorial designs, sim-plex designs, and Lagrangian multiple regression analysis [21]. Parametric methods are best suited for formula optimization in the early stages of product development. Constraint analysis, described previously, is used to simplify the testing 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 design

2. Selection of variables (independent Xs and dependent Ys) to be tested 3. Performance of a set of statistically designed experiments (e.g., 23or

32factorials)

4. Measurement of responses (dependent variables)

5. Development of a predictor, polynomial equation based on statistical and regression analysis of the generated experimental data

6. Development of a set of optimized requirements for the formula based on mathematical and graphical analysis of the data generated

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XII. WHAT ARE THE PROCESS VALIDATION OPTIONS?

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

A. Prospective Process Validation

In prospective process validation, an experimental plan called the validation

protocol is executed (following completion of the qualification trials) before the

process is put into commercial use. Most validation efforts require some degree of prospective experimentation to generate validation support data. This particu-lar type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The

for-malized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily:

1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements (completion of installation

qualification)

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

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

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

5. Detailed technical information on the product and the manufacturing process 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 no significant deviations from the expected performance of the process The steps and sequence of events required to carry out a process validation assignment are outlined inTable 8. The objective of prospective validation is to prove or demonstrate that the process will work in accordance with a validation master 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

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Table 8 Master Plan or Outline of a Process Validation Program

Objective Proving or demonstrating that the process works Type of validation Prospective, concurrent, retrospective, revalidation Type of process Chemical, pharmaceutical, automation, cleaning Definition of process Flow diagram, equipment/components, in-process,

fin-ished product

Definition of process output Potency, yield, physical parameters

Definition of test methods Method, instrumentation, calibration, traceability, preci-sion, accuracy

Analysis of process Critical modules and variables defined by process capa-bility design and testing program

Control limits of critical vari- Defined by process capability design and testing

pro-ables gram

Preparation 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 authority

Planning validation trials Timetable and PERT charting, material availability, and disposal

Validation trials Supervision, administration, documentation Validation finding Data summary, analysis, and conclusions

Final 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, which is usually prepared under the direction of the organizational function directly responsible for pilot scale-up activities. Later, replicate batch manufacture may be 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 reader’s consideration:

1. The use of different lots of components should be included, i.e., APIs and 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 ranges and should not exceed their upper and lower control limits during process operation. Output responses should be well within finished product specifications.

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5. Failure to meet the requirements of the validation protocol with spect to process inputs and output control should be subjected to

re-qualification following a thorough analysis of process data and formal

review by the CMC Coordination Committee.

B. Retrospective Validation

The retrospective validation option is chosen for established products whose manufacturing 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, wherein the numerical in-process and/or end-product test data of historic production batches are subjected to statistical analysis, the equipment, facilities and subsys-tems used in connection with the manufacturing process must be qualified in conformance with CGMP requirements. The basis for retrospective validation is stated in 21CFR 211.110(b): “Valid in-process specifications for such charac-teristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability esti-mates where possible and determined by the application of suitable statistical procedures 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] of Eli Lilly and Company in 1980. The concept is also recognized in the FDA’s

Guidelines 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 batch

manufacturing data, using a spreadsheet format.

3. Include data from at least the last 20–30 manufactured batches for analysis. If the number of batches is less than 20, then include all manufactured batches and commit to obtain the required number for analysis.

4. Trim the data by eliminating test results from noncritical processing steps 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).

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

1. Solid Dosage Forms

1. Individual assay results from content uniformity testing 2. Individual tablet hardness values

3. Individual tablet thickness values 4. Tablet or capsule weight variation

5. Individual tablet or capsule dissolution time (usually at t50%) or

disinte-gration time

6. Individual tablet or capsule moisture content 2. Semisolid and Liquid Dosage Forms

1. pH value (aqueous system) 2. Viscosity

3. Density

4. Color or clarity values

5. Average particle size or distribution 6. Unit weight variation and/or potency values

The statistical methods that may be employed to analyze numerical output data 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 concurrent process data. Control charting forms the basis of modern statistical process con-trol.

C. Concurrent Validation

In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufac-turing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation.

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Test parameter Data source Average unit potency End-product testing Content uniformity End-product testing

Dissolution time End-product testing

Weight variation End-product testing

Powder-blend uniformity In-process testing

Moisture content In-process testing

Particle or granule size distribution In-process testing

Weight variation In-process testing

Tablet hardness In-process testing

pH value In-process testing

Color or clarity In-process testing

Viscosity 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 parameters should be made on the basis of the critical processing variables to be evaluated. D. Revalidation

Conditions 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-ment

3. Change in a facility and/or plant (usually location or site)

4. Significant (usually order of magnitude) increase or decrease in batch size

5. Sequential batches that fail to meet product and process specifications In some situations performance requalification studies may be required prior to undertaking specific revalidation assignments.

The FDA process validation guidelines [1] refer to a quality assurance system 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 product characteristics.

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 manufacturing process of the product itself, it differs from other factors, such as raw materials.

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The reader should realize that there is no one way to establish proof or evidence of process validation (i.e., a product and process in control). If the manufacturer is certain that its products and processes are under statistical con-trol and in compliance with CGMP regulations, it should be a relatively simple matter to establish documented evidence of process validation through the use of prospective, concurrent, or retrospective pilot and/or product quality informa-tion and data. The choice of procedures and methods to be used to establish validation 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 approaches that may be employed to achieve a successful outcome with respect to product performance and process validation. The authors of the following chapters ex-plore the same topics from their own perspectives and experience. It is hoped that the reader will gain much from the diversity and richness of these varied approaches.

REFERENCES

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

2. Current Good Manufacturing Practices in Manufacture, Processing, Packing and Holding of Human and Veterinary Drugs, Federal Register 43(190), 45085 and 45086, 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. 45:56–63 (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 Dosage Forms: 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.

Pharmaceutical Process Validation.pdf

James Swarbrick

Preface

Contents

Contributors

Introduction