Good Manufacturing Practices for Pharmaceutical

A Plan far Total Quality Control Irani Manufacturer to Consomer

Fifth Edition, Revised and Expended

Sidney H. Wig
Temple University Philadelphia, Pennsylvania

n
MARCEL D E K K E R

MARCEL DEKKER, INC.

NEW YORK BASEL

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

The preceding edition of this book was published as Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, by Sidney H. Willig and James R. Stoker.

ISBN: 0-8247-0425-8

This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microlming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive Editor

James Swarbrick
PharmaceuTech, Inc. Pinehurst, North Carolina

Advisory Board
Larry L. Augsburger University of Maryland Baltimore, Maryland Douwe D. Breimer Gorlaeus Laboratories Leiden, The Netherlands Trevor M. Jones The Association of the British Pharmaceutical Industry London, United Kingdom Hans E. Junginger Leiden/Amsterdam Center for Drug Research Leiden, The Netherlands Vincent H. L. Lee University of Southern California Los Angeles, California David E. Nichols Purdue University West Lafayette, Indiana Stephen G. Schulman University of Florida Gainesville, Florida Jerome P. Skelly Alexandria, Virginia

Felix Theeuwes Alza Corporation Palo Alto, California

Geoffrey T. Tucker University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom

Peter G. Welling Institut de Recherche Jouveinal Fresnes, France

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

1. Pharmacokinetics, Milo Gibaldi and Donald Perrier 2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV 3. Microencapsulation, edited by J. R. Nixon 4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner 5. New Drugs: Discovery and Development, edited by Alan A. Rubin 6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson 7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes 8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz 9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney 10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and Bernard Testa 11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson 12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky 13. Orphan Drugs, edited by Fred E. Karch 14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts, Biomedical Assessments, Yie W. Chien 15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier 16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV 17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger 18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry 19. The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren 20. Microencapsulation and Related Drug Processes, Patrick B. Deasy 21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell 22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme 23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler 25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton 26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz 27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos 28. Solubility and Related Properties, Kenneth C. James 29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition, Revised and Expanded, edited by Joseph R. Robinson and Vincent H. Lee 30. New Drug Approval Process: Clinical and Regulatory Management, edited by Richard A. Guarino 31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien 32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle 33. Pharmacokinetics: Regulatory Industrial Academic Perspectives, edited by Peter G. Welling and Francis L. S. Tse 34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato 35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives, edited by Jonathan Hadgraft and Richard H. Guy 36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by James W. McGinity 37. Pharmaceutical Pelletization Technology, edited by Isaac GhebreSellassie 38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch 39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang 40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 41. Specialized Drug Delivery Systems: Manufacturing and Production Technology, edited by Praveen Tyle 42. Topical Drug Delivery Formulations, edited by David W. Osborne and Anton H. Amann 43. Drug Stability: Principles and Practices, Jens T. Carstensen 44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition, Revised and Expanded, Sanford Bolton 45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark Chasin and Robert Langer 46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tse and James J. Jaffe 47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and Stanley K. Lam 48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S. Tse, and Shrikant V. Dinghe 49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W. Chien 51. Managing the Clinical Drug Development Process, David M. Cocchetto and Ronald V. Nardi 52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Third Edition, edited by Sidney H. Willig and James R. Stoker 53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan 54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J. Hickey 55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn 56. New Drug Approval Process: Second Edition, Revised and Expanded, edited by Richard A. Guarino 57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded, edited by Ira R. Berry and Robert A. Nash 58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra 59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft 60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck 61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by Alain Rolland 62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh 63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan 64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls 65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie 66. Colloidal Drug Delivery Systems, edited by Jrg Kreuter 67. Pharmacokinetics: Regulatory Industrial Academic Perspectives, Second Edition, edited by Peter G. Welling and Francis L. S. Tse 68. Drug Stability: Principles and Practices, Second Edition, Revised and Expanded, Jens T. Carstensen 69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg 70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain 71. Pharmaceutical Powder Compaction Technology, edited by Gran Alderborn and Christer Nystrm 72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita 74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone 75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and Michael Montagne

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar 77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein 78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker 79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded, edited by James W. McGinity 80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition, Sanford Bolton 81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh 82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by William R. Strohl 83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and Richard H. Guy 84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharp 85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo 86. Pharmaceutical Project Management, edited by Tony Kennedy 87. Drug Products for Clinical Trials: An International Guide to Formulation Production Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes 88. Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded, edited by Gregory E. Hardee and J. Desmond Baggot 89. Receptor-Based Drug Design, edited by Paul Leff 90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F. deSpautz 91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and Kenneth A. Walters 92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and Roger Phan-Tan-Luu 93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III 94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay and W. Paul Findlay 95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain 96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by Louis Rey and Joan C. May 97. Percutaneous Absorption: DrugsCosmeticsMechanismsMethodology, Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development, edited by Edith Mathiowitz, Donald E. Chickering III, and Claus-Michael Lehr 99. Protein Formulation and Delivery, edited by Eugene J. McNally 100. New Drug Approval Process: Third Edition, The Global Challenge, edited by Richard A. Guarino 101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid 102. Transport Processes in Pharmaceutical Systems, edited by Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp 103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie 104. The Clinical Audit in Pharmaceutical Development, edited by Michael R. Hamrell 105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and Gilberte Marti-Mestres 106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B. Dressman and Hans Lennerns 107. Drug Stability: Principles and Practices, Third Edition, Revised and Expanded, edited by Jens T. Carstensen and C. T. Rhodes 108. Containment in the Pharmaceutical Industry, edited by James P. Wood 109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded, Sidney H. Willig 110. Advanced Pharmaceutical Solids, Jens T. Carstensen 111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition, Revised and Expanded, Kevin L. Williams 112. Pharmaceutical Process Engineering, Anthony J. Hickey and David Ganderton 113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and Rachel F. Tyndale 114. Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhavathi B. Fernandes 115. Drug Targeting Technology: Physical Chemical Biological Methods, edited by Hans Schreier 116. DrugDrug Interactions, edited by A. David Rodrigues 117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J. Streeter 118. Pharmaceutical Process Scale-Up, edited by Michael Levin 119. Dermatological and Transdermal Formulations, edited by Kenneth A. Walters 120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III 121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 122. Surfactants and Polymers in Drug Delivery, Martin Malmsten 123. Transdermal Drug Delivery: Second Edition, Revised and Expanded, edited by Richard H. Guy and Jonathan Hadgraft
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

124. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg 125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers, Daniel S. Larrimore, and Dana Morton Guazzo 126. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts 127. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharmacodynamic Modeling Perspective, edited by Hui C. Kimko and Stephen B. Duffull 128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics, edited by Reinhard H. H. Neubert and Hans-Hermann Rttinger 129. Pharmaceutical Process Validation: An International Third Edition, Revised and Expanded, edited by Robert A. Nash and Alfred H. Wachter 130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Expanded, edited by Ashim K. Mitra 131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean M. Sullivan

ADDITIONAL VOLUMES IN PREPARATION

Biomarkers in Clinical Drug Development, edited by John Bloom Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revised and Expanded, edited by Anthony J. Hickey Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and Charles Martin Pharmaceutical Compliance, edited by Carmen Medina

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

Preface

Partisan bickering in the Congress of the United States, with added hostility between the President and the legislature, has occasioned much news media attention in 1999. So, in the United States, as in Europe and Japan, there continues growing political appeal in pressing drug manufacturers for price concessions in response to the problem of funding national health care systems. This has added to consideration of the economy of drugs, biologicals, vaccines, and medical devices; a lesser tolerance for growth in research costs; and a greater demand for reduction in manufacturing outlay. Much healthy innovation in Current Good Manufacturing Practices (CGMPs) will occur, but at some risk. Media criticism of promotional expenses can be anticipated. Because this edition continues insights requisite to the multinational activities of most manufacturers today, we take note of scientic and legal factors to a greater extent than before. The text contains guidelines that address these factors and questions that the reader will want to analyze in detail and update. We urge our readers to be alert to millennial revisions, additions, and deletions to published standards on which they presently rely. For example, in USP24-NF19, there have been more than 3900 revisions. The audience for this book is broader than just those involved in the manufacture of pharmaceuticals. This is an invaluable resource for private and independent inspection personnel, local and state inspection agencies, and quality assurance organizations contracted by distributors, and reects the growing role of
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

pharmacists acting as employees, or independently, in some aspect of quality control. With these caveats in place, the efforts, responsibilities, and commitments of governmental authorities and private industry will continue to focus on maintaining CGMPs for pharmaceuticals.
A drug or device shall be deemed to be adulterated(a)(2)(b) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. (21 USC 351)

As experience with federal courts in the United States has indicated, the CGMP regulations are usually held to be substantive and have been used to support the strictest of sanctions by their breach. These regulations truly apply to all drugs, whether or not they are characterized as old drugs; new drugs; Abbreviated New Drug Application (ANDA) drugs; investigational drugs; or ingredients of drugs, devices, or cosmetics. Since the inception of these regulations, if the FDA can establish that the regulatee has not conformed to CGMPs in its procedures, the FDA can allege that the resultant products are adulterated, whether or not they are currently distributed nationally or abroad. Then it may invoke all of its remedies as feasible against the product itself, as well as against the parties responsible, whether corporate or individual, national or extranational. Current Good Manufacturing Practices have taken on new signicance in this era of multinational suppliers of pharmaceuticals. Cross-licensing, joint ventures, strategic alliances, mergers, acquisitions, and divestitures underscore the necessity of maintaining standards of manufacturing and quality control across the geographical boundary of suppliers and distributors. In this edition, we offer enhanced denition of these activities. Advances in the design of pharmaceuticals, to at once expand and make more specic their applicability to modern medical armamentaria, have added complexities to the entire production process, on through to packaging and storage. Added to this are the growing concerns of adulteration and misbranding, given the potency of many new products. As if sheer medical and scientic progress were not enough to spur greater concern over CGMPs, new regulatory stress and the impact of legislation have enhanced the responsibilities of manufacturers and other suppliers. New regulatory enforcement, carrying stiff penalties, has been established. Where other regulated materials have cast a particular light on quality control needs of the distributor by court decisions or legislative or administrative action, they have been noted in this edition.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

Hand in hand with this are new enforcement alternatives via the statutory scheme, which threaten imposition of criminal sanctions on wrongdoers. To this end, there has been increased enlistment and training of government regulatory investigators. The fth edition of Good Manufacturing Practices for Pharmaceuticals both expands on and compresses the considerable material used in composing prior editions. As such, and because of their number, it becomes more difcult to identify contributors. Sufce it to say that the excellent advice of prior coauthors such as Drs. Murray M. Tuckerman, William S. Hitchings IV, and James R. Stoker has been enriched by years of cumulative experience and regulatory interaction. This edition also reects the cooperation of many private, industrial, and governmental employees on all levels and, where possible, citations have been offered for reference. Among those I would especially note and thank for their courtesy, comments, and assistance are James Ruger, Ph.D., J.D.; Kenneth C.H. Willig, Ph.D, J.D.; and Randi Cane. Sidney H. Willig

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

Contents

Preface Introduction 1. Status and Applicability of U.S. Regulations: Current Good Manufacturing Practices in Manufacturing, Processing, Packaging, and Holdings of Drugs 2. Finished Pharmaceuticals: General Provisions (Subpart A) 3. Organization and Personnel (Subpart B) 4. Buildings and Facilities (Subpart C) 5. Equipment (Subpart D) 6. Control of Components and Drug Product Containers and Closures (Subpart E) 7. Production and Process Controls (Subpart F) 8. Packaging and Labeling Controls (Subpart G) 9. Holding and Distribution (Subpart H)
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10. Laboratory Controls (Subpart I) 11. Records and Reports (Subpart J) 12. Returned and Salvaged Drug Products (Subpart K) 13. Repacking and Relabeling 14. Bulk Pharmaceutical Chemicals 15. The Pharmacist and Total Quality Control 16. Recalls and CGMPs: Enforcement Alternatives in the United States 17. Controlled Substances Safeguards (21 CFR 1300, et seq.) 18. The Inspection Procedure for Compliance in the United States: The Regulatee Is Inspected; The Rationale for Inspection (21 USC 373, 374) 19. FDA Pre-Approval Inspections/Investigations; The Road from SUPAC to the Food and Drug Modernization Act 20. Who Is the Manufacturer? Some Additional Considerations for the Multinational 21. Other GMPs 22. Other Approaches to Quality 23. Import and Export of Pharmaceuticals and Other Products Subject to CGMPs 24. Enhancement of Global Product Distribution Appendix A Food and Drug Modernization Act of 1997in Pertinent Part Appendix B Components/Repackagers Appendix C Hearing Procedures When FDA Proposes the Imposition of Civil Money Penalties Appendix D Section 601.12 Changes Currently Considered Important by CBER Appendix E USP24NF19 Information; Monographs; Tests; Assays

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

Introduction

Since the fourth edition of this book appeared, there have been major changes in the governmental agencies, such as the FDA in the United States, as well as in the manufacturing industry, where much realignment has taken place. These changes, along with the uctuation in the economics of global markets on which the industry depends, have created new methods of self-governance. The introduction of the Pre-Approval Inspection procedure linked product registration approval to Current Good Manufacturing Practice (CGMP) compliance. Delays in approvals have an adverse impact on the public as well as on pharmaceutical manufacturers, and media notice has pressured the FDA. The increased autonomy of FDA district ofces has sometimes created less than consistent interpretation and application of the regulations. This has been exacerbated by the FDAs aggressive use of extensive inspections (especially in the United States) and its issuance of large numbers of 483s, warning letters, and consent decrees. Some effort to improve internally has been made by compliance policy guides made available to each district ofce. Some companies have left themselves vulnerable by their inadequate attention to compliance. As many of our readers are aware, the FDA explains its policy on regulatory issues related to its statutory and regulatory authority in various ways. Using materials that have recently become available, we have tried to reect these positions for your information. One such method consists of the series of compliance policy guides provided to eld inspection and compliance staffs, regarding FDA
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

standards and procedures for determining compliance with Current Good Manufacturing Practice regulations. In this edition, we have sought to integrate and identify the pertinent guides wherever applicable in the text, rather than simply rely on our chapters dealing with inspection, which afford a broader vision of inspection for the regulatees preparation. It is our hope that using this additional method will reinforce the regulatees attention to both substance and procedure involved in FDA and equivalent national and international inspections. There has been increased emphasis on the application of CGMPs to the manufacturer of bulk pharmaceutical chemicals, and a separate chapter has been included on this subject. There has been some impact, mainly positive, from the International Conference on Harmonization, representing Europe, Japan, and the United States. Agreed-upon standards now exist for analytical method validation and for stability and impurities in new products. General agreement on product/production change requirements and on GMPs would be particularly valuable since the industry is now global. However, owing to difculties in obtaining agreement among the parties, progress is unlikely. A chapter has been included to highlight key issues and differences among GMPs of Europe, Canada, and the World Health Organization (WHO). As with previous editions, we have tried to provide some practicality to the application and understanding of the regulations. Several FDA guides and guidelines have been issued or updated in recent years, but the CGMP regulations have undergone only isolated changes, and they are now in need of an overhaul. It is hoped that this might be a collaborative project involving both the FDA and the industry, especially on a global scale. The FDA publishes guidelines and proposed regulatory changes in the Federal Register, thereby providing opportunities for comment. However, interactive involvement to discuss issues would help to prevent later confrontation without detracting from the FDAs responsibilities. At one time, compliance with an FDA guideline, while not mandatory, was considered compliance with the relevant section of the CGMP regulations. However, FDA lawyers have since stated that it is inappropriate to have interpretive documents that are binding only on one party (the FDA). Consequently, adherence to a guideline is no longer an assurance of CGMP compliance. (See Chapter 1 infra.) This constitutes a fundamental difference from other GMPs, in which following the entire GMP document as a guideline constitutes compliance, even while alternative approaches remain acceptable. The increasing use of inspection guides by the FDA to provide interpretion of the regulations bypasses the review process, since these are considered to be internal documents. It is a worthwhile and necessary addition to the framework of each manufacturing company to establish a written CGMP compliance program for each facility, along with a reasonable calendar for review and update. That is, of
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.

course, only one portion of the job. Unless that responsibility is undertaken to be implemented in a timely and conscientious manner, product failures attributable to errors in the established process will result in enforcement activity and remedial litigation. Therefore, the condential conduct of internal investigation and audit must be accompanied by a willingness to report circumstances that denote insufcient care and even misconduct. And the organization must respect the need to address problems promptly and fully, whether or not enforcement by authorities is imminent or threatened. Many of these procedures must utilize the effort and initiative of the organizations managers, executives, and professionals. In my long-term pharmaceutical experience, whether or not consultants are used, the role of company counsel in explaining self-evaluative privileges along with attorneyclient and workproduct protection is essential. Depending on the spectrum of company activity, compliance programs must embrace a variety of sales, distribution, antitrust, labor, employment, and environmental issues. More than ever, many of our contributors have emphasized that the global nature of the pharmaceutical industry and its collateral and supportive industries has created the need for geographical distribution of manufacturing facilities, accommodation to a diversity of regulatory and statutory governance, and adaptation to disparate human resources. In this new environment, cultural differences must be appreciated. The multinational manufacturer whose major roots lie outside the United States may not comprehend the strong reliance in the United States on litigation as a means of resolving matters that range from employment discontent to regulatory enforcement and even commercial disputes. Our European and Asian colleagues, who are accustomed to resolving conicts via nonjudicial processes or within legal systems that operate quite differently from ours, can nd the U.S. style of interplay somewhat bewildering. Similarly, the multinational manufacturer whose major base is in the United States may often be frustrated by difculties in attempting redress from suppliers and vendors who are sheltered by unique legal insulation in their country of origin. Often, despite the use of scientic, regulatory, and legal consultants conversant with special geographic areas, one nds that attitudes, traditions, and legal resources of the extranational area intransigent to the types of remediation found in the United States. Acquisitions, mergers, and downsizing in recent years have been consistent in the industry. For the United Statesbased manufacturer, not only has this resulted in a diminution of manufacturing facilities and transference of operations abroad, but it has also led to a revolution in the innovation of labor-soaring equipment. Beyond the care required for the introduction of such equipment, reductions in the workforce are a fertile source of employment litigation and enforcement initiatives.
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There is a great need in most major producing nations, such as the United States, to be aware of federal, state, and even local plant closing laws, and the assembled antidiscrimination statutes that may be invoked. Overworked and dissatised employees are a potential source of internal strife, and, along with released employees, provide regional and even national agencies with complaints that encourage investigative follow-up. In some national forums, particular emphasis is placed on sexual harassment and the multinational must be sensitive to specic litigatory concerns in the province of operation. My fundamental advice is for a current good manufacturing system that comprises those who do and those who independently audit the doing. Systems that become so employee-depleted that these functions cannot remain separate and independent are under an obvious handicap. GMPs, although important, represent only one element in maintaining and improving quality. If product quality is dened as meeting or exceeding customer needs and expectations, then mere compliance with GMPs does not provide assurance of meeting these requirements. GMP compliance is essentially a bureaucratic exercise, but one designed to improve quality, consistency, product safety, and efcacy. Other approaches are being used to drive the progress of quality with respect to customer satisfaction and the resulting business success. A new chapter has been included in this edition to describe two of these approaches: the Malcolm Baldrige National Quality Award and ISO 9000. The health care industry will continue to be regulated with a quality of judgment and reason that is exhibited in the main. We hope and anticipate that in the future the parties involved will be working cooperatively for the mutual benet of allthe customers, the industry, and the public.

Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.