Good Manufacturing Practices for Pharmaceuticalthe-eye.eu/public/Books/BioMed/Good...

Good Manufacturing Practicesfor Pharmaceutical

A Plan far Total Quality ControlIrani Manufacturer to Consomer

Fifth Edition, Revised and Expended

Sidney H. WigTemple University

Philadelphia, Pennsylvania

M A R C E L

MARCEL DEKKER, INC. NEW YORK • BASELnD E K K E R

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

The preceding edition of this book was published as Good ManufacturingPractices 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

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DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive Editor

James SwarbrickPharmaceuTech, Inc.

Pinehurst, North Carolina

Advisory Board

Larry L. AugsburgerUniversity of Maryland

Baltimore, Maryland

David E. NicholsPurdue UniversityWest Lafayette, Indiana

Douwe D. BreimerGorlaeus Laboratories

Leiden, The Netherlands

Stephen G. SchulmanUniversity of FloridaGainesville, Florida

Trevor M. JonesThe Association of the

British Pharmaceutical IndustryLondon, United Kingdom

Jerome P. SkellyAlexandria, Virginia

Hans E. JungingerLeiden/Amsterdam Center

for Drug ResearchLeiden, The Netherlands

Felix TheeuwesAlza CorporationPalo Alto, California

Vincent H. L. LeeUniversity of Southern California

Los Angeles, California

Geoffrey T. TuckerUniversity of SheffieldRoyal Hallamshire HospitalSheffield, United Kingdom

Peter G. WellingInstitut de Recherche Jouveinal

Fresnes, France


DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

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

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

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

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

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

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

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

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

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

James W. Munson12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky13. Orphan Drugs, edited by Fred E. Karch14. Novel Drug Delivery Systems: Fundamentals, Developmental Con-

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

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

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

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

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

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

Roe and T. Colin Campbell22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and

Robert A. Nash


24. Anticancer and Interferon Agents: Synthesis and Properties, edited byRaphael M. Ottenbrite and George B. Butler

25. Pharmaceutical Statistics: Practical and Clinical Applications, SanfordBolton

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 Aszalos28. Solubility and Related Properties, Kenneth C. James29. Controlled Drug Delivery: Fundamentals and Applications, Second

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

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

31. Transdermal Controlled Systemic Medications, edited by Yie W.Chien

32. Drug Delivery Devices: Fundamentals and Applications, edited byPraveen 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. Cato35. Transdermal Drug Delivery: Developmental Issues and Research Ini-

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

edited by James W. McGinity37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-

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

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

edited by Gilbert S. Banker and Christopher T. Rhodes41. Specialized Drug Delivery Systems: Manufacturing and Production

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

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

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

Chasin and Robert Langer46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S.

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

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

S. Tse, and Shrikant V. Dinghe49. Pharmaceutical Dissolution Testing, Umesh V. Banakar

50. Novel Drug Delivery Systems: Second Edition, Revised andExpanded, 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 TotalQuality Control, Third Edition, edited by Sidney H. Willig and JamesR. Stoker

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

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

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

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

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

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

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

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

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

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

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

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

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

G. Brittain71. Pharmaceutical Powder Compaction Technology, edited by Göran Al-

derborn and Christer Nyström72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited

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

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

Bleidt and Michael Montagne

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

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

78. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Fourth Edition, Revised and Expanded, Sidney 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, ThirdEdition, Sanford Bolton

81. Handbook of Pharmaceutical Granulation Technology, edited by DilipM. 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. Pottsand Richard H. Guy

84. Pharmaceutical Enzymes, edited by Albert Lauwers and SimonScharpé

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

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

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

88. Development and Formulation of Veterinary Dosage Forms: SecondEdition, Revised and Expanded, edited by Gregory E. Hardee and J.Desmond Baggot

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

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

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

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

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

Spectroscopy, David E. Bugay and W. Paul Findlay95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Prod-

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

dology, Third Edition, Revised and Expanded, edited by Robert L.Bronaugh and Howard I. Maibach

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

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

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

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

Kotkoskie104. The Clinical Audit in Pharmaceutical Development, edited by Michael

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

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

B. Dressman and Hans Lennernäs107. Drug Stability: Principles and Practices, Third Edition, Revised and

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

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

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

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

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

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

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

Prabhavathi B. Fernandes115. Drug Targeting Technology: Physical • Chemical • Biological Methods,

edited by Hans Schreier116. Drug–Drug Interactions, edited by A. David Rodrigues117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian

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

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

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

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

edited by Richard H. Guy and Jonathan Hadgraft

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

125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Pack-age Integrity Testing: Third Edition, Revised and Expanded, MichaelJ. Akers, Daniel S. 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-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 Reinhard H. H. Neubert and Hans-Hermann Rüt-tinger

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 andExpanded, edited by Ashim K. Mitra

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

ADDITIONAL VOLUMES IN PREPARATION

Biomarkers in Clinical Drug Development, edited by John Bloom

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

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

Pharmaceutical Compliance, edited by Carmen Medina

Preface

Partisan bickering in the Congress of the United States, with added hostility be-tween the President and the legislature, has occasioned much news media atten-tion in 1999. So, in the United States, as in Europe and Japan, there continuesgrowing political appeal in pressing drug manufacturers for price concessions inresponse to the problem of funding national health care systems. This has addedto consideration of the economy of drugs, biologicals, vaccines, and medicaldevices; a lesser tolerance for growth in research costs; and a greater demandfor reduction in manufacturing outlay. Much healthy innovation in Current GoodManufacturing Practices (CGMPs) will occur, but at some risk. Media criticismof promotional expenses can be anticipated.

Because this edition continues insights requisite to the multinational activi-ties of most manufacturers today, we take note of scientific and legal factors toa greater extent than before. The text contains guidelines that address these factorsand questions that the reader will want to analyze in detail and update. We urgeour readers to be alert to millennial revisions, additions, and deletions to pub-lished 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 manu-facture of pharmaceuticals. This is an invaluable resource for private and indepen-dent inspection personnel, local and state inspection agencies, and quality assur-ance organizations contracted by distributors, and reflects the growing role of

pharmacists acting as employees, or independently, in some aspect of qualitycontrol.

With these caveats in place, the efforts, responsibilities, and commitmentsof governmental authorities and private industry will continue to focus on main-taining CGMPs for pharmaceuticals.

A drug or device shall be deemed to be adulterated—(a)(2)(b) if it is a drugand 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 oradministered in conformity with current good manufacturing practice to as-sure that such drug meets the requirements of this Act as to safety and hasthe 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 CGMPregulations are usually held to be substantive and have been used to support thestrictest of sanctions by their breach. These regulations truly apply to all drugs,whether or not they are characterized as old drugs; new drugs; Abbreviated NewDrug Application (ANDA) drugs; investigational drugs; or ingredients of drugs,devices, or cosmetics. Since the inception of these regulations, if the FDA canestablish that the regulatee has not conformed to CGMPs in its procedures, theFDA can allege that the resultant products are adulterated, whether or not theyare currently distributed nationally or abroad. Then it may invoke all of its reme-dies as feasible against the product itself, as well as against the parties responsi-ble, whether corporate or individual, national or extranational.

Current Good Manufacturing Practices have taken on new significance inthis era of multinational suppliers of pharmaceuticals. Cross-licensing, joint ven-tures, strategic alliances, mergers, acquisitions, and divestitures underscore thenecessity of maintaining standards of manufacturing and quality control acrossthe geographical boundary of suppliers and distributors. In this edition, we offerenhanced definition of these activities.

Advances in the design of pharmaceuticals, to at once expand and makemore specific their applicability to modern medical armamentaria, have addedcomplexities to the entire production process, on through to packaging and stor-age. Added to this are the growing concerns of adulteration and misbranding,given the potency of many new products.

As if sheer medical and scientific progress were not enough to spur greaterconcern over CGMPs, new regulatory stress and the impact of legislation haveenhanced the responsibilities of manufacturers and other suppliers. New regula-tory enforcement, carrying stiff penalties, has been established.

Where other regulated materials have cast a particular light on quality con-trol needs of the distributor by court decisions or legislative or administrativeaction, they have been noted in this edition.

Hand in hand with this are new enforcement alternatives via the statutoryscheme, which threaten imposition of criminal sanctions on wrongdoers. To thisend, there has been increased enlistment and training of government regulatoryinvestigators.

The fifth edition of Good Manufacturing Practices for Pharmaceuticalsboth expands on and compresses the considerable material used in composingprior editions. As such, and because of their number, it becomes more difficultto identify contributors. Suffice it to say that the excellent advice of prior coau-thors such as Drs. Murray M. Tuckerman, William S. Hitchings IV, and JamesR. Stoker has been enriched by years of cumulative experience and regulatoryinteraction. This edition also reflects the cooperation of many private, industrial,and governmental employees on all levels and, where possible, citations havebeen offered for reference. Among those I would especially note and thank fortheir courtesy, comments, and assistance are James Ruger, Ph.D., J.D.; KennethC.H. Willig, Ph.D, J.D.; and Randi Cane.

Sidney H. Willig

Contents

PrefaceIntroduction

1. Status and Applicability of U.S. Regulations: Current GoodManufacturing 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 andClosures (Subpart E)

7. Production and Process Controls (Subpart F)

8. Packaging and Labeling Controls (Subpart G)

9. Holding and Distribution (Subpart H)

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 fromSUPAC to the Food and Drug Modernization Act

20. Who Is the Manufacturer? Some Additional Considerations forthe Multinational

21. Other GMPs

22. Other Approaches to Quality

23. Import and Export of Pharmaceuticals and Other ProductsSubject to CGMPs

24. Enhancement of Global Product DistributionAppendix A Food and Drug Modernization Act of 1997—in

Pertinent PartAppendix B Components/RepackagersAppendix C Hearing Procedures When FDA Proposes the Imposition

of Civil Money PenaltiesAppendix D Section 601.12 Changes Currently Considered

‘‘Important’’ by CBERAppendix E USP24–NF19 Information; Monographs; Tests; Assays

Introduction

Since the fourth edition of this book appeared, there have been major changesin the governmental agencies, such as the FDA in the United States, as well asin the manufacturing industry, where much realignment has taken place. Thesechanges, along with the fluctuation in the economics of global markets on whichthe industry depends, have created new methods of self-governance.

The introduction of the Pre-Approval Inspection procedure linked productregistration approval to Current Good Manufacturing Practice (CGMP) compli-ance. Delays in approvals have an adverse impact on the public as well as onpharmaceutical manufacturers, and media notice has pressured the FDA.

The increased autonomy of FDA district offices has sometimes created lessthan consistent interpretation and application of the regulations. This has beenexacerbated by the FDA’s aggressive use of extensive inspections (especially inthe United States) and its issuance of large numbers of 483s, warning letters, andconsent decrees. Some effort to improve internally has been made by compliancepolicy guides made available to each district office. Some companies have leftthemselves vulnerable by their inadequate attention to compliance.

As many of our readers are aware, the FDA explains its policy on regulatoryissues related to its statutory and regulatory authority in various ways. Usingmaterials that have recently become available, we have tried to reflect these posi-tions for your information. One such method consists of the series of compliancepolicy guides provided to field inspection and compliance staffs, regarding FDA

standards and procedures for determining compliance with Current Good Manu-facturing Practice regulations. In this edition, we have sought to integrate andidentify the pertinent guides wherever applicable in the text, rather than simplyrely on our chapters dealing with inspection, which afford a broader vision ofinspection for the regulatee’s preparation. It is our hope that using this additionalmethod will reinforce the regulatee’s attention to both substance and procedureinvolved in FDA and equivalent national and international inspections.

There has been increased emphasis on the application of CGMPs to themanufacturer of bulk pharmaceutical chemicals, and a separate chapter has beenincluded on this subject.

There has been some impact, mainly positive, from the International Con-ference on Harmonization, representing Europe, Japan, and the United States.Agreed-upon standards now exist for analytical method validation and for stabil-ity and impurities in new products. General agreement on product/productionchange requirements and on GMPs would be particularly valuable since the in-dustry is now global. However, owing to difficulties in obtaining agreementamong the parties, progress is unlikely. A chapter has been included to highlightkey issues and differences among GMPs of Europe, Canada, and the WorldHealth Organization (WHO).

As with previous editions, we have tried to provide some practicality tothe application and understanding of the regulations. Several FDA guides andguidelines have been issued or updated in recent years, but the CGMP regulationshave 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 andthe industry, especially on a global scale. The FDA publishes guidelines andproposed regulatory changes in the Federal Register, thereby providing opportu-nities for comment. However, interactive involvement to discuss issues wouldhelp to prevent later confrontation without detracting from the FDA’s responsibil-ities. 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 interpre-tive documents that are binding only on one party (the FDA). Consequently,adherence to a guideline is no longer an assurance of CGMP compliance. (SeeChapter 1 infra.) This constitutes a fundamental difference from other GMPs, inwhich 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 interpretionof the regulations bypasses the review process, since these are considered to beinternal documents.

It is a worthwhile and necessary addition to the framework of each manu-facturing company to establish a written CGMP compliance program for eachfacility, along with a reasonable calendar for review and update. That is, of

course, only one portion of the job. Unless that responsibility is undertaken tobe implemented in a timely and conscientious manner, product failures attribut-able to errors in the established process will result in enforcement activity andremedial litigation. Therefore, the confidential conduct of internal investigationand audit must be accompanied by a willingness to report circumstances thatdenote insufficient care and even misconduct. And the organization must respectthe need to address problems promptly and fully, whether or not enforcement byauthorities is imminent or threatened.

Many of these procedures must utilize the effort and initiative of the organi-zation’s managers, executives, and professionals. In my long-term pharmaceuti-cal experience, whether or not consultants are used, the role of company counselin explaining self-evaluative privileges along with attorney–client and work-product protection is essential.

Depending on the spectrum of company activity, compliance programsmust embrace a variety of sales, distribution, antitrust, labor, employment, andenvironmental issues.

More than ever, many of our contributors have emphasized that the globalnature of the pharmaceutical industry and its collateral and supportive industrieshas created the need for geographical distribution of manufacturing facilities,accommodation to a diversity of regulatory and statutory governance, and adapta-tion to disparate human resources. In this new environment, cultural differencesmust be appreciated. The multinational manufacturer whose major roots lie out-side the United States may not comprehend the strong reliance in the UnitedStates on litigation as a means of resolving matters that range from employmentdiscontent to regulatory enforcement and even commercial disputes. Our Euro-pean and Asian colleagues, who are accustomed to resolving conflicts via nonju-dicial processes or within legal systems that operate quite differently from ours,can find the U.S. style of interplay somewhat bewildering.

Similarly, the multinational manufacturer whose major base is in the UnitedStates may often be frustrated by difficulties in attempting redress from suppliersand vendors who are sheltered by unique legal insulation in their country oforigin. Often, despite the use of scientific, regulatory, and legal consultants con-versant with special geographic areas, one finds that attitudes, traditions, andlegal resources of the extranational area intransigent to the types of remediationfound in the United States.

Acquisitions, mergers, and downsizing in recent years have been consistentin the industry. For the United States–based manufacturer, not only has this re-sulted in a diminution of manufacturing facilities and transference of operationsabroad, but it has also led to a revolution in the innovation of labor-soaring equip-ment. Beyond the care required for the introduction of such equipment, reductionsin the workforce are a fertile source of employment litigation and enforcementinitiatives.

There is a great need in most major producing nations, such as the UnitedStates, to be aware of federal, state, and even local plant closing laws, and theassembled antidiscrimination statutes that may be invoked. Overworked and dis-satisfied employees are a potential source of internal strife, and, along with re-leased employees, provide regional and even national agencies with complaintsthat encourage investigative follow-up. In some national forums, particular em-phasis is placed on sexual harassment and the multinational must be sensitive tospecific litigatory concerns in the province of operation.

My fundamental advice is for a current good manufacturing system thatcomprises those who ‘‘do’’ and those who independently audit the ‘‘doing.’’Systems that become so employee-depleted that these functions cannot remainseparate and independent are under an obvious handicap.

GMPs, although important, represent only one element in maintaining andimproving quality. If product quality is defined as meeting or exceeding customerneeds and expectations, then mere compliance with GMPs does not provide assur-ance of meeting these requirements. GMP compliance is essentially a bureau-cratic exercise, but one designed to improve quality, consistency, product safety,and efficacy. Other approaches are being used to drive the progress of qualitywith respect to customer satisfaction and the resulting business success. A newchapter 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 ofjudgment and reason that is exhibited in the main. We hope and anticipate thatin the future the parties involved will be working cooperatively for the mutualbenefit of all—the customers, the industry, and the public.

1

Status and Applicabilityof U.S. RegulationsCurrent Good Manufacturing Practicesin Manufacturing, Processing, Packaging,and Holding of Drugs

This chapter addresses FDA and some other federal regulations that have beenpromulgated for statutory effectuation and implementation in the main. The majorstatute underlying such regulations is the Federal Food, Drug and Cosmetic Actas amended, which may be found in the U.S. Code at 21 USC 321 through 392.

The regulations discussed in the main are found at Title 21 of the Code ofFederal Regulations. The latter is composed of nine volumes. The parts in thesevolumes are arranged in the following order: Parts 1–99, 100–169, 170–199,200–299 (containing the bulk of the CGMPs), 300–499 (containing the bulk ofthe IND, NDA, and ANDA materials), 500–599, 600–799, 800–1299, and 1300–end. This last volume addresses matters subject to Drug Enforcement Administra-tion (DEA), the Department of Justice (DOJ), and the Office of National DrugControl Policy.

The text also addresses guidelines, recommendations, and agreements thatfor the most part are governmental in derivation. A new addition to the Appendixherein provides the official definitions for such and at the same time providesclues as to the reliance manufacturers may attach to a guideline, a recommenda-tion, or even formal agreements and memoranda of understanding or other similarwritten documents executed by the FDA (21 CFR 10.90 et seq.).

Similarly, the FDA has carefully defined the term Advisory Opinion at 21CRF 10.85 and—of special importance in the context of Chapter 18 following


dealing with inspective concerns of both ‘‘inspecteds’’ and ‘‘inspectors’’—astatement made or advice by an FDA employee is not an advisory opinion unlessissued in writing under that part. Where the assurance or advice is given orally,it is regarded as an informal communication that represents the personal bestjudgment of that employee, not the FDA, and does not obligate the agency orcommit it to the views expressed.

Current Good Manufacturing Practices (CGMP) regulations (21 CFR 210–226) are promulgated by the Commissioner of the Federal Food and Drug Admin-istration (FDA) under Section 701(a) of the Federal Food, Drug and CosmeticAct [21 USC 371(a)] in furtherance of the requirement of Section 501(a)(2)(B)of the Act [21 USC 351(a)(2)(B)], which specifies that a drug is deemed adulter-ated ‘‘if the methods used in, or the facilities or the controls used for, its manufac-ture, processing, packing or holding do not conform to or are not operated oradministered in conformity with current good manufacturing practice.’’ The pur-pose of Section 501(a)(2)(B) is to assure that such drug meets the requirementsof the act as to safety and has the identity and strength and meets the qualityand purity characteristics which it purports or is represented to possess. The FDAis of course committed to various programs and systems designed to assure thequality of all drug products by careful monitoring of drug manufacturer’s compli-ance with CGMP regulations. In order to identify their regulatees, Section 510(b)and (c) of the FFDC Act requires the registration of all producers of drugs anddevices. Congressional language that accompanied this amendment stated it was‘‘necessary to provide for the registration and inspection of all establishments inwhich drugs were manufactured, prepared, propagated, compounded or pro-cessed’’ since these products were likely to enter interstate commerce. Section510(h) requires that each registrant be inspected for compliance every two years.

The FDA includes as registrants manufacturers whose final products arehomeopathic drugs and requires that such products must be manufactured in con-formance with CGMPs but some requirements of 21 CFR 211 are consideredby them to be inapplicable. We have included FDA Compliance Guides as topreparation for, and marketing of, homeopathic drugs, below.

The approval process for drug marketing applications (original and abbrevi-ated new drug applications and Antibiotic Forms 5 and 6) includes a review ofthe manufacturer’s compliance with the CGMPs.

In recent years the FDA has assumed additional roles for assurance to vend-ees through programs like the Government-Wide Quality Assurance Programsfor drug purchase contracts by the Department of Defense and Veterans Affairsand the MAC program (Maximum Allowable Cost) program that became seminalto the manufacture of generics.

Decisions regarding compliance with CGMP regulations are based on in-spection of the facilities, sample analysis, and compliance history of the firm.


These data are summarized in profiles that represent several years of history ofthe firms.

CGMP deficiencies supporting regulatory action by the FDA also supportdecisions regarding nonapproval of NDA Supplements, as well as the purchasingcontracts and candidacy for MAC, so some FDA expanded action is likely. There-fore, issuance of a ‘‘warning’’ letter or other regulatory action based on discoveryof CGMP deficiencies must be accompanied by disapproval of any pending NDA,ANDA, or Supplement, or any government contract produced under the samedeficiencies.

The Federal Food, Drug and Cosmetic Act applies to drugs introduced intointerstate commerce in the United States, including drugs exported to or importedfrom other countries. Manufacturers in other countries who export to the UnitedStates are inspected either by the FDA or under reciprocal inspection agreementsas part of the New Drug Application (NDA) approval process and antibiotic drugcertification. Currently, such agreements exist between the United States andSweden, Switzerland, and Canada. Individual drug products are subjected to ex-tensive examination, including laboratory testing, before being allowed into theUnited States.

The FDA has the authority to deny entry to any drug, if there is a questionregarding its safety, identity, strength, quality, or purity. This authority is exer-cised unless factory inspection is permitted or inspection information is availableconcerning nondomestic firms, in lieu of conducting foreign inspections. Al-though this authority is exercised more rarely and tempered by Chapter 8 of theAct, the FDA also has the authority to deny exit to questionable drugs. (See alsoChapters 23 and 24 in this volume.)

The plan proposed by the authors is not designed as a minimum or as aregulatory compliance program, but as a viable approach that seeks to ensure thequality of pharmaceutical preparations. It has a sound economic base in that atevery step of its preparation the question was asked: ‘‘If this is not done, asidefrom susceptibility to legal actions, what are the probable economic conse-quences?’’ If the consequences are potentially more costly than the use of theindicated control, the control is recommended. Built into the system are suchfactors as quality control, security, personnel evaluation, and the inevitable docu-mentation trail of paper to show what was done, who did it and when, and whosaw and attested to the doing.

The problem is approached from the perspective of a consultant who hasa free hand to suggest procedures. Recommendations are presented primarily aschecklists covering aspects of quality control. Some areas of concern are indi-cated without recommendations as specific control procedures.

The Food and Drug Administration strives to ensure that the regulated in-dustries comply with a total quality control concept through its factory inspection


programs and through participation in voluntary CGMP compliance seminars andworkshops sponsored jointly with the industries or with educational institutions.The fact that a total quality control approach is necessary to prevent a drug prod-uct from being deemed adulterated under Section 501(a)(2)(B) and violative ofSection 301(b) of the Food, Drug and Cosmetic Act is indicated by 21 CFR 211,Current Good Manufacturing Practice for Finished Pharmaceuticals. Nowhere ingovernment documents or official compendia, however, is there a comprehensivecollection of specific measures to realize this concept. The concept of a totalquality control system is neither limited in scope to the analytical methods ofassay, control charts, product inspections made during the manufacturing pro-cesses and prior to finished dosage form distribution, nor to the statistical tech-niques utilized in these discrete operations. The concept includes all control mea-sures contributing to the completed market dosage form. The PharmaceuticalManufacturers Association in its ‘‘General Principles of Total Control of Qualityin the Drug Industry’’ consistently has stated that ‘‘Total control of quality as itapplies to the drug industry is the organized effort within an entire establishmentto design, produce, maintain and assure the specific quality in each unit or drugdistributed. Total control of quality is a plant-wide activity and represents theaggregate responsibility of all segments of a company.’’

In the following chapters an attempt is made to provide specific guidelinesand concepts that can serve as checks for critical operations within the entireorganization in order that a total quality control system can be achieved. Eachrequirement that is loosely generalized in Good Manufacturing Practice regula-tions will be enlarged and made more specific in order to include measures thatthe authors believe are necessary for good control.

§210.1 STATUS OF CURRENT GOOD MANUFACTURINGPRACTICE REGULATIONS

(a) The regulations set forth in this part and in Parts 211 through 229 ofthis chapter contain the minimum current good manufacturing practice formethods to be used in, and the facilities or controls to be used for, the manu-facture, processing, packing, or holding of a drug to assure that such drugmeets the requirements of the act as to safety, and has the identity andstrength and meets the quality and purity characteristics that it purports oris represented to possess.(b) The failure to comply with any regulation set forth in this part and inParts 211 through 229 of this chapter in the manufacture, processing, packingor holding of a drug shall render such drug to be adulterated under section501(a)(2)(B) of the act and such drug, as well as the person who is responsi-ble for the failure to comply, shall be subject to regulatory action.


§210.2 APPLICABILITY OF CURRENT GOODMANUFACTURING PRACTICE REGULATIONS

(a) The regulations in this part and in Parts 211 through 229 of this chapteras they may pertain to a drug and in Parts 600 through 680 of this chapteras they may pertain to a biological product for human use, shall be consideredto supplement, not supersede, each other, unless the regulations explicitlyprovide otherwise. In the event that it is impossible to comply with all appli-cable regulations in these parts, the regulations specifically applicable to thedrug in question shall supersede the more general.(b) If a person engages in only some operations subject to the regulationsin this part and in Parts 211 through 226 and Parts 600 through 680 of thischapter, and not in others, that person need only comply with those regula-tions applicable to the operations in which he or she is engaged. (See also21 CFR 207.)

§210.3 DEFINITIONS

(a) The definitions and interpretations contained in section 201 of the actshall be applicable to such terms when used in this part and in Parts 211through 226 of this chapter.(b) The following definitions of terms apply to this part and to Parts 211through 226 of this chapter.

(1) ‘‘Act’’ means the Federal Food, Drug, and Cosmetic Act, asamended (21 USC 321, et seq.).

As described in the Federal Register, this general introduction to what isprojected as a series of Good Manufacturing Practice (GMP) regulations for allhuman drug products, as well as specific products or specific processes, is ‘‘in-tended to be general enough to be suitable for essentially all drug products, flexi-ble enough to allow the use of sound judgment and permit innovation, and explicitenough to provide a clear understanding of what is required.’’ The concept placesa large burden on the manufacturer of pharmaceuticals. Adherence to the explicitregulations is a required minimum, but it is not adequate to ensure that a manufac-turer is in compliance. In addition, the manufacture of a pharmaceutical must beby current methods with current controls, thus setting as a requirement that whichis current or generally accepted in the drug industry as appropriate equipment,methodology, controls, and records. Even being ‘‘average’’ in all respects, com-pared with the industry, does not ensure that a manufacturer is in compliance,because the standard is not only that practices be ‘‘current’’ but that they alsobe ‘‘good.’’ Thus, if a new practice is introduced anywhere in the industry thatis better than what is current, then all manufacturers may seem obligated to adoptthe better practice.


Therefore, it can be seen that being in compliance with GMP is not a staticsituation, but requires the manufacturer to be aware not only of what is currentin the industry but also to be aware of innovations that may be good. It wouldseem also that a legitimate inquiry for evaluation of compliance is the measurestaken by a manufacturer to obtain knowledge, on a continuing basis, of both whatis current and may be good and to provide a method for incorporating the neces-sary changes into the already established system of manufacture and control.

The FDA currently makes available in electronic format various analyticdata from its centers. Those who do analytic work for manufacturers should becertain they are optimizing their knowledge of such accessible data by inquiryof the FDA, their own association resources, and that of the Association of Foodand Drug Officials of the United States. Sometimes these additional resourcesare also noted at FDA Science Forums on the Regulatory Sciences, and abstractsmay be available. For example, information routinely maintained within the Divi-sion of Pesticides and Industrial Chemicals can be retrieved. These data are acces-sible via the Prime Connection electronic bulletin board of the Center for FoodSafety and Applied Nutrition (CFSAN), accessible via an 800 number to anyonewith a computer and modem, and CFSAN’s VAX computer anonymous file trans-fer protocol (FTP) site, accessible via the Internet.

There is a current menu as to other sources of information from and aboutthe FDA that will aid regulatees at the end of this chapter.

USP Reference Standards are highly characterized specimens of drug sub-stances, major impurities, degradation products, and performance calibrators foruse in testing drugs and nutritional supplements. They are used to perform officialmethods of analysis in pharmaceutical testing. The manufacturer may use otherthan the official method of analysis, but on FDA inspection and challenge, thesubstance used and the product manufactured must meet the official specificationscontained in the USP-NF following the official method of analysis. USP MaterialSafety Data Sheets are available to purchasers of standards. USP also tests anddistributes other authenticated substances not currently included in the USP-NFthat are still in sufficient demand; FCC Reference Standards specified in the latestedition of the Food Chemicals Codex; and highly purified samples of chemicals,including drugs of abuse. Readers who seek information as to specific USP Refer-ence Standards, whether or not current, can call 1-800-227-8772 in the UnitedStates or 1-301-881-0666 for outside the U.S. and Canada.

It goes without saying that constant update acquisition of official and unof-ficial compendia is necessary for timely attention to the CGMPs as well. Thelaw requires that products meet the requirements of the United States Pharmaco-peia (USP)/National Formulary for the monographs applicable to their productsas labeled. Since these are not static, good reasoning, good science, and goodpractical issues arise. (See Appendix E below.) For example, where the manufac-turer has prepared the product in accord with the pertinent USP monograph and


that monograph undergoes a significant change five years later as to its methodol-ogy of analytic controls, what is a reasonable approach for the manufacturer?First, the manufacturer should implement the new controls promptly. As to prod-uct samples held in reserve, they are examples of product legally placed intoInterstate Commerce under analytic controls then in effect, and any obligationto retest them might not be reasonable. The exception might rest on the natureand importance of the change to such a product and on whether the manufacturermight have knowledge that the former method would find the product out ofcontrol in the marketplace at this date. In such an instance the safety and effective-ness of the product would weigh upon any decision. I am advised by Lee T.Grady, Ph.D., that in preparing USP24-NF19 there have been 3900-plus revi-sions. See a listing below.

Some troublesome questions that might arise are: When is a piece of ma-chinery no longer in compliance? For example, now that encapsulators are avail-able that can fill to a relative standard deviation of not more than 6%, is the useof old equipment that has a relative standard deviation of about 8% a violation perse? What about the use of fully automated tablet presses with a relative standarddeviation for tablet weights of about one-half that of the conventional presses?Should molded tablets with their very high (approximately 10%) relative standarddeviation for weight be permitted, when small, compressed tablets can be pro-duced with a relative standard deviation of about 4%?

It would seem that the answers to these questions are a matter of judgment,depending on the drug involved, official or NDA monographs, and other factors.The judgment will be that of the manufacturer, whose label claims must be com-pletely truthful, but the foundation for continuing dialogue between the FDA andindustry, if not controversy, has been laid.

The Congress intended that the phrase itself (current good manufacturingpractice) have a unique meaning. . . . The agency determines what constitutes‘‘current good manufacturing practice’’ based upon its experience with themanufacture of drugs through inspectional and compliance activities. . . .Although the practices must be ‘‘current’’ in the industry, they need not bewidely prevalent. Congress did not require that a majority or any other per-centage of manufacturers already be following the . . . practice . . . that . . .had been shown to be both feasible and valuable in assuring drug quality.[Federal Register]

The FDA also holds that, although it does not manufacture drugs, it hasthe unique ability to determine Current Good Manufacturing Practices for drugs,since it alone has access to the facilities and records of every manufacturer ofpharmaceuticals in the United States. Given the fact that many processes andcontrols are considered by individual manufacturers to be trade secrets, competi-tors, through the various associations of manufacturers or independent third par-


ties, such as the compendial authorities, are not likely to discover what nonpublicpractices are current.

Even if current practices were available, the FDA holds that it has specialtechnical and scientific expertise to determine which of the current practicesare also good. This expertise is inherent in reviews of production and controltechniques in New Drug Applications and Abbreviated New Drug Applications(ANDAs), supplemental applications, antibiotic certification forms, biological es-tablishment and product licenses, new animal drug applications, and proposedand final compendial standards. Additional experience is based on establishmentinspection reports filed by FDA investigators and the monitoring of drug recalls.

A current, although not necessarily predominant, practice is considered‘‘good’’ if:

1. It is feasible for manufacturers to implement.2. It contributes to ensuring the safety, quality, or purity of the drug

product.3. The value of the contributions or added assurance exceeds the cost in

money or other burdens of implementing or continuing the practice.

Also, note that in addition to proceeding against the drug, regulatory actionmay be taken against the person who is responsible for the failure to comply.Responsibility for failure to comply would seem extensible vertically from man-agement, which did not supply adequate supervision or directions, through qualitycontrol and individual production people, who did not follow directions, andhorizontally to supplies of raw materials, whose products did not meet purportedspecifications, as well as to contract laboratories. Since criminal penalties (finesand/or prison sentences) are possible, these regulations impose a standard ofresponsibility to have knowledge, to train subordinates, and to continually checkto ensure compliance with directives.

The legal standard for responsibility for all those engaged in drug manufac-ture is high. People entering this field of endeavor should be aware of the specialburden of complete accountability. Violation of the Federal Food, Drug and Cos-metic Act is handled under unique legal doctrine that does not require proof ofcriminal intent as a prerequisite for criminal culpability. In order to provide maxi-mum protection of the public health, Congress purposely neither required thatactual harm from contamination of a drug product has to be proven for a chargethat the product is adulterated nor that each article in the batch be adulteratedbefore the entire amount is subject to condemnation or other action. The law isaimed not only at removal of the adulterated article from commerce, but for thesame offense, and simultaneously, may seek punishment of a person. Note the‘‘person’’ is defined in Section 201(e) of the act to include corporations andpartnerships, as well as individuals. Landmark judicial decisions are (1) United


States v. Dotterweich, 320 U.S. 277 (1943) and (2) United States v. Park, 421U.S. 658 (1975).

Almost all civil and criminal actions initiated by the FDA are derived fromviolations of statutory definitions of misbranding and adulteration. This fact ismagnified by both the expanded areas of definition and prohibitions created bythe New Drug Amendments and the prevalent judicial policy of liberal construc-tion of the statute with its prime objective of consumer protection.

Currently, the adulteration statute, aside from the regulations on Good Man-ufacturing Practices, holds that the presence of a foreign substance, even of dis-tinct and contrary appearance from the product itself, could cause it to be adulter-ated. Previously, distinct substances, such as nails or pieces of a container notcommingled in such a manner as to masquerade as a part of the food itself, wouldnot have been considered an ingredient in support of a charge of adulteration.However, the courts have not been entirely consistent as to this interpretation,and no doubt the subject regulations will be used to strengthen the FDA positionof greater inclusion.

In 1952, a landmark decision in the 8th Circuit stated that a defendant mightenjoy a certain latitude where a ‘‘mere possibility’’ of contamination existed,subject to proof that factory conditions ‘‘would with reasonable possibility resultin contamination’’ (Berger v. The United States, 200 F.2d 818). Obviously then,today’s Good Manufacturing Practice regulations are viewed as the means forthe FDA to present to the court this ‘‘reasonable possibility’’ based on breachof said regulations. To increase the chances of success for enforcement, evidencefrom examination of samples will frequently be offered to show that the possibil-ity is realized.

(2) ‘‘Batch’’ means a specific quantity of a drug or other material that isintended to have uniform character and quality, within specified limits, andis produced according to a single manufacturing order during the same cycleof manufacture.(3) ‘‘Component’’ means any ingredient intended for use in the manufactureof a drug product, including those that may not appear in such drug product.(4) ‘‘Drug product’’ means a finished dosage form, for example, tablet, cap-sule, solution, etc., that contains an active drug ingredient generally, but notnecessarily, in association with inactive ingredients. The term also includesa finished dosage form that does not contain an active ingredient but is in-tended to be used as a placebo.(5) ‘‘Fiber’’ means any particulate contaminant with a length at least threetimes greater than its width.(6) ‘‘Non-fiber-releasing filter’’ means any filter, which after any appropriatepretreatment such as washing or flushing, will not release fibers into the com-ponent or drug product that is being filtered. All filters composed of asbestosare deemed to be fiber-releasing filters.(7) ‘‘Active ingredient’’ means any component that is intended to furnish


pharmacological activity or other direct effect in the diagnosis, cure, mitiga-tion, treatment, or prevention of disease or to affect the structure of any func-tion of the body of man or other animals. The term includes those compo-nents that may undergo chemical change in the manufacture of the drugproduct in a modified form intended to furnish the specified activity or effect.(8) ‘‘Inactive ingredient’’ means any component other than an ‘‘active ingre-dient.’’(9) ‘‘In-process material’’ means any material fabricated, compounded,blended, or derived by chemical reaction that is produced for, and used in,the preparation of the drug product.(10) ‘‘Lot’’ means a batch, or a specific identified portion of a batch, havinguniform character and quality within specified limits; or, in the case of adrug product produced by continuous process, it is a specific identifiedamount produced in a unit of time or quantity in a manner that assures itshaving uniform character and quality within specified limits.(11) ‘‘Lot number, control number, or batch number’’ means any distinctivecombination of letters, numbers or symbols, or any combination of them,from which the complete history of the manufacture, processing, packing,holding and distribution of a batch or lot of drug product or other materialcan be determined.(12) ‘‘Manufacture, processing, packing, or holding of a drug product’’ in-cludes packaging and labeling operations, testing and quality control of drugproducts.(13) ‘‘Medicated feed’’ means any ‘‘complete feed,’’ ‘‘feed supplement,’’or ‘‘feed concentrate’’ as defined in § 558.3 of this chapter and is a feed thatcontains one or more drugs as defined in section 201 (g) of the act. Medicatedfeeds are subject to Part 225 of this chapter.(14) ‘‘Medicated premix’’ means a substance that meets the definition in§ 558.3 of this chapter for a ‘‘feed premix,’’ except that it contains one ormore drugs as defined in section 201 (g) of the act and is intended for manu-facturing use in the production of a medicated feed. Medicated premixes aresubject to Part 226 of this chapter.(15) ‘‘Quality control unit’’ means any person or organizational element des-ignated by the firm to be responsible for the duties relating to quality control.(16) ‘‘Strength’’ means:

(i) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or

(ii) The potency, that is, the therapeutic activity of the drug productas indicated by appropriate laboratory tests or by adequately developed andcontrolled clinical data (expressed, for example, in terms of units by refer-ence to a standard).(17) ‘‘Theoretical yield’’ means the quantity that would be produced at anyappropriate phase of manufacture, processing, or packing of a particular drugproduct, based upon the quantity of components to be used, in the absenceof any loss or error in actual production.(18) ‘‘Actual yield’’ means the quantity that is actually produced at any ap-


propriate phase of manufacture, processing, or packing of a particular drugproduct.(19) ‘‘Percentage of theoretical yield’’ means the ratio of the actual yield(at any appropriate phase of manufacture, processing, or packing of a particu-lar drug product) to the theoretical yield (at the same phase), stated as apercentage.(20) ‘‘Acceptance criteria’’ means the product specifications and accep-tance/rejection criteria, such as acceptable quality level and unacceptablequality level, with an associated sampling plan, that are necessary for makinga decision to accept or reject a lot or batch (or any other convenient subgroupsof manufactured units).(21) ‘‘Representative sample’’ means a sample that consists of a number ofunits that are drawn based on rational criteria such as random sampling andintended to assure that the sample accurately portrays the material being sam-pled.

The role of the United States Pharmacopeia is of course not limited to the UnitedStates. This was true even prior to the time it became incorporated within theFederal Food, Drug and Cosmetic Act, for its ultimate importance in dealing withsuch portions of that law that recite prohibited acts. There are other pharmacopeiawith substantial recognition in the global and local manufacture and distributionof pharmaceuticals, but the U.S. Pharmacopeia is a major reference in this regard.

For that reason, and for the fact that in 1999 the USP announced a majorstructural reorganization for improved focus responsive to the ‘‘ongoing transfor-mation of health care science and technology,’’ it is perhaps helpful to brieflyreview its historic and present important role in the manufacture, labeling, andstandard setting vital to pharmaceutical manufacture.

Established in 1820 ‘‘to ensure that consumers receive medicines of thehighest possible quality, strength and purity in the United States,’’ it was destinedto reflect medical and pharmaceutical advances from the major European labora-tories and academia from the first. At present the USP provides standards formore than 3,400 drugs and dosage forms for medicines and dietary supplements.

While it has taken on additional duties in the areas of reporting and preven-tion programs regarding product problems and medication errors, the interest ofour readers is better expressed within their traditional roles in standard setting.

These can be summarized (and are currently handled by a newly formeddivision following the 1999 reorganization) as follows:

Standards—General Policies, Requirements, Nomenclature and Labeling,Veterinary Drugs, Excipients/Pharmaceutical Waters, Biologics and Biotechnol-ogy, Dietary Supplements, and Pharmaceuticals, which also includes the Refer-ence Standards Laboratory and the Research and Development Laboratory.

Located nearby the FDA in Rockville, MD 20852, they can be reached at301-998-6821, www.usp.org.


Under Uniform State Food and Drug Laws, the Federal Food, Drug andCosmetic Act, and the recent Food and Drug Administration Modernization Act,USP-NF standards are legally enforceable.

These standards are published in the USP-NF and legally recognized. Andonce the Food and Drug Administration approves a new drug product, the USPestablishes public standards for same that become similarly enforceable. It is hardto imagine that a manufacturer would not have copies of the current USP24/NF19 compendium available to the staff. All proposed revisions to USP-NF stan-dards are published for review and comment in a USP publication, PharmacopeiaForum. The USP-NF is, of course, also available on CD-Rom.

In this text we are advising you to check carefully information we haveprovided through the cooperation of USP staff members concerning the titles ofall test standards that the USP has added, revised, or deleted for the latest edition.For manufacturers and others, the USP publishes a catalog that contains someprior standards and monographs that are still required from time to time. TheUSP Reference Standards Catalog contains official lot numbers and pricing infor-mation for more than 1,250 established USP Reference Standards used in officialUSP-NF testing methods for prescription and non-prescription drugs, drugs ofabuse, and excipients (see Appendix E below).

Supplemental information available to the reader:FDA’s Electronic Bulletin Board—Available free by computer modem access(dial 1-800-222-0185). Provides the latest information from the FDA, including:

• FDA Medical Bulletin• FDA Enforcement Report• FDA Consumer features• Summaries of FDA Federal Register documents• News releases, talk papers, backgrounders• Speeches• FDA congressional testimony

Special Instructions: Set modem to 7 bits, even parity, full duplex, and 1 stopbit. To start, prompts and responses are:

• Login � bbs• Enter A Topic Code � Manual• Enter BBS Command � Help

For more information, write Parklawn Computer Center (BBS), 5600 FishersLane, Room 2B59, Rockville, MD 20857; or call (301) 443-7318.

FDA Consumer—The official magazine of the FDA. Ten issues a year,each containing in-depth feature articles written for the general public on FDA-related health issues. Also includes reports from FDA’s own investigators thatgo behind the scenes to show how the agency protects the public from unsafe


or worthless products. Subscriptions available for $15 per year from the Superin-tendent of Documents, Government Printing Office, Washington, DC 20402-9371.

FDA Medical Bulletin—Information about FDA-related issues and activi-ties of particular interest to health professionals. Sent to more than a milliondoctors and other health professionals approximately three times a year. Sendrequests to be placed on the mailing list to FDA Medical Bulletin, CirculationDept. (HFI-43), 5600 Fishers Lane, Rockville, MD 20857.

FDA Enforcement Report—Weekly update on actions taken in connectionwith agency regulatory activities, including seizures, injunctions, prosecutions,and dispositions. Recalls and medical device safety alerts voluntarily conductedby firms are also included. Subscriptions are available for $78 per year fromthe Superintendent of Documents, Government Printing Office, Washington, DC20402-9371.

Scientific and Technical Publications—Lists scientific and technical publi-cations written by the Center for Food Safety and Applied Nutrition. Issued annu-ally. Copies are available from the Office of Management, Center for Food Safetyand Applied Nutrition, FDA 200 C St., S.W., Washington, DC 20204.

FDA Veterinarian—Published bimonthly, this FDA publication coverscurrent issues concerning animal drugs, food additives, and devices. Subscrip-tions are available for $5 per year from the Superintendent of Documents, Gov-ernment Printing Office, Washington, DC 20402-9371.

Approved Drug Products with Therapeutic Equivalence Evaluations—Commonly called the ‘‘Orange Book,’’ the publication is available for $91 a yearfrom the Superintendent of Documents, Government Printing Office, Washing-ton, DC 20402-9371. A subscription includes periodic updates of the drug list-ings.

FDA’s Breast Implant Information Line—Provides up-to-date informationon breast implant studies and regulatory status. Call (1-800)532-4440; TTY(1-800)688-6167.

FDA’s Seafood Hotline—Provides information on seafood safety and regu-lations. Public affairs specialists are available to answer questions from noon to4 p.m. Eastern time, Monday through Friday. At other times callers can listento a recording on current seafood topics and leave messages to receive educationalmaterial or to report suspected seafood safety problems. Call (1-800)332-4010;(202)205-4314 in the Washington, DC, area.

AIDS Clinical Trial Information Service (ACTIS)—Provides informationabout AIDS and HIV-related trials currently under way throughout the UnitedStates. ACTIS is a joint project of the Centers for Disease Control and Prevention,the National Institutes of Allergy and Infectious Diseases, the National Libraryof Medicine, and FDA. Call (1-800)TRIALS-A between 9 a.m. and 7 p.m. East-ern time, Monday through Friday.


FDA’s CD-ROM—The FDA Office of Information Resource Managementhas created a CD-ROM containing FDA manuals and documents. This subscrip-tion service is updated quarterly and includes easy-to-use search software and auser’s guide. Documents currently available include:

Center for Drug Evaluation and Research, Current Good ManufacturingPractices, and New Drug Applications Guidelines

Center for Veterinary Medicine policy and proceduresChemistry ReviewCode of Federal Regulations (Title 21)Compliance Policy GuidesDrug Study/Health Fraud BulletinsFDA Import Alert Retrieval SystemFDA Phone BookFood, Drug and Cosmetic Act and Related LawsInvestigations Operations ManualMarket Names of FishMedical Products Quality ManualNew Regulations (Title 21)Preamble Medical Devices Reporting RegulationsRegulatory Procedures Manual, Chapter 5Regulatory Procedures Manual, Chapter 8Talk Papers/Press Releases

For more information on this service, call FDA’s Office of Information ResourcesManagement at (301)443-6770.

ADDITIONAL REFERENCES

Reinventing the Food and Drug Administration—Marie A. Urban: Food, Drug, Cosmeticand Medical Device Law Digest, Vol. 14, No. 2, 5/97.

The Generic Industry: An FDA Insiders View—Gerald F. Meyer: F.D.C.M.L. Digest Vol.7, No. 2. (May 1990).

Current Developments—FDA Reform. Vol. 14, No. 1 (Jan. 1997).

Following study of this chapter, it might be helpful, for staff review, todiscuss specific guides provided by the FDA to their field staff and others thatare pertinent as Regulatory Action Guidance.


Sec. 450.100 CGMP Enforcement Policy—OTC vs Rx Drugs(CPG 7132.10)

BACKGROUND:

Because of increased visibility and promotion of certain OTC preparations, there are peri-odic inquiries from district offices regarding whether or not the enforcement policy forCGMP regulations is the same for OTC drug products as it is for prescription (Rx) drugproducts.

Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act requires drugsto be manufactured in conformance with current good manufacturing practice. This sectiondoes not differentiate between OTC and Rx products and it was not intended by Congressto do so.

A prescription drug may be toxic or have other potential for harm, which requiresthat it be administered only under the supervision of a licensed practitioner (section503(b)(1) of the Act). For this reason, problems associated with its manufacture are gener-ally more likely to cause serious problems.

POLICY:

The CGMP regulations apply to all drug products, whether OTC or prescription.

REGULATORY GUIDANCE:

The selection of an enforcement action to be applied will be based on the seriousness ofthe deviation, including such factors as potential hazard to the consumer.

Issued: 4/1/82


2

Finished PharmaceuticalsGeneral Provisions (Subpart A)

§211.1 SCOPE

(a) The regulations in this part contain the minimum current goodmanufacturing practice for preparation of drug products for administrationto humans or animals.

(b) The current good manufacturing practice regulations in this chap-ter, as they pertain to drug products, and in Parts 600 through 680 of thischapter, as they pertain to biological products for human use, shall be consid-ered to supplement, not supersede, the regulations in this part unless the regu-lations explicitly provide otherwise. In the event it is impossible to complywith applicable regulations both in this part and in other parts of this chapteror in Parts 600 through 680 of this chapter, the regulation specifically appli-cable to the drug product in question shall supersede the regulation in thispart.

(c) Pending consideration of a proposed exemption, published in theFederal Register of September 29, 1978, the requirements in this part shallnot be enforced for OTC drug products if the products and all their ingredi-ents are ordinarily marketed and consumed as human foods, and which prod-ucts may also fall within the legal definition of drugs by virtue of their in-tended use. Therefore, until further notice, regulations under Part 110 of thischapter, and where applicable, Parts 113 to 129 of this chapter, shall be ap-plied in determining whether these OTC drug products that are also foods are


manufactured, processed, packed, or held under current good manufacturingpractice.

§211.2 DEFINITIONS

The definitions set forth in §210.3 of this chapter apply in this part.Briefly, this section states that the company’s adherence to the requirements

of the entire set of regulations determined whether its output will be judged asadulterated or violative. Adherence to the requirements initially necessitates ananalysis of all current operations within the company that affect the quality of thefinished marketed product. Such an analysis serves as a framework for structuringdecision and information flows between managers, operators, scientists, techni-cians, and other personnel who regulate product quality. An analysis of currentconditions also divides the flow of materials into discrete, sequential operationsfrom the receipt and sampling of raw materials to final accountability computa-tions during the market distribution, in order that critical procedures can be speci-fied and more closely examined.

The first step is to evaluate the chances of establishing and maintaining agood quality control program. The first list, therefore, is a description of theorganization.

1. Name of company2. Address3. Telephone4. Number of years in business5. How is the company controlled?

Independent Subsidiarya. Parent companyb. Address

6. OwnershipCorporation PartnershipPrivate Other

7. Field of operationDomestic Foreign

8. Type of operationManufacturer RepackerPacker Other

9. Extent of OperationsPlant locations No. of buildings No. of employees

10. Current approvalsDA registration VA contractDefense personnel Other


11. Membership in trade associations (show professional interest)Pharmaceutical Manufacturers Associations (i.e., PhRMA)The Proprietary AssociationNational Pharmaceutical CouncilParenteral Drug AssociationDrug and Allied Products GuildOther

12. Attendance at pharmaceutical meetings related to manufacturing andquality assurance operations.Person Position Meetings attended/DateDissemination of proceedings to managers and supervisory per-sonnel.Lecturer Subject Personnel in Attendance Date

13. To whom does it sell (approximate percentage of sales)?Wholesaler Hospital Physician VADirect pharmacy Defense personnel Other

14. How large is the sales force?15. What consultant services are used (including outside laboratories)?

Consultant:Training:Position when not consulting:Responsibility:Time per month:

16. In order for quality control to function properly, key executives mustbe appropriately educated, trained, and experienced. They should beapproachable and sensitized by training or experience to quality con-trol problems.Title Name Education Training ExperiencePresidentVice-PresidentSales ManagerMedical DirectorPlant ManagerEngineering ManagerProduction ManagerQuality Control DirectorLaboratory Head

17. Define the functional organization structure, including in detail allfunctions that contribute to acceptance or rejection decision for aproduct or its components.Who has the authority to:


a. reject defective materialb. approve rework of salvageable materialc. dispose of nonsalvageable material

It is important that quality control and production be kept sepa-rate and equal, usually by having the quality control manager andproduction manager report to the same executive, the plant manager.

It is prudent to permit personnel within both functions the au-thority to temporarily sequester material considered to be defectiveor potentially deficient while an appropriate investigation is made.The quality control function alone should have ultimate responsibil-ity for removing a product at any stage in its processing into or fromquarantine or into rejection status. Information from production andother sources should be utilized in arriving at a decision, but author-ity must be centralized and separated from the production func-tion.

18. Product Information: In order to initiate quality control procedures,the dimensions of operations should be estimated. This requires thefollowing information for the entire product line of the firm.Type and Quantity Quantity PackagedProduct Name Manufactured Own label Other labelTabletsTablets, coatedTablets, multilayerTablets, enteric coatedTablets, repeat dosageTablets, sustained releaseCapsulesCapsules, sustained releaseLiquids, externalLiquids, oralLiquids, oral, sustained releaseOphthalmic solutionsParenteral, sterile fillParenteral, sterilizedSyringe, prefilledSuppositoriesGranules, oralPowdersAerosolsAerosols, metered doseSterile dressings


How are the products promoted? (Obtain samples and packageinserts.) Professional journal Lay journal Internet

Newspaper Other

The same procedures should be followed in assessing the operations of alloutside contractors who contribute to the production of the finished pharmaceu-tical.

Attention should be focused on the critical concepts of a quality controlsystem. The production cycle for each drug must be controlled so that optimumquality levels can be attained for each manufacturing sequence. The efforts ofall personnel making product integrity decisions during processing must be coor-dinated and standardized to attain these desired levels. The materials and accom-panying information flow through production must demonstrate that control, en-gineering, and production management have determined potential sources of errorand have introduced control procedures to minimize the possibility.

A model of material and information flows for operations should showcomplete quality control surveillance of all operations involved with drug produc-tion, adequate information exchange to monitor and control this surveillance, andrecords that document all activity. The flow chart in Figure 1 depicts one modelfor an analysis of current operations that incorporates these considerations. More

Figure 1 Information and material flow with quality control surveillance.


specific documentation and information requirements necessary to achieve con-trol will be suggested in relevant CGMP chapters.

CGMP

Much of the foregoing pages of this chapter applies similarly to ‘‘FINISHEDHOMEOPATHIC DRUGS’’ and to this purpose we make some special recom-mendations below.

The recent increase in popularity of Homeopathic Drugs presents opportu-nities for smaller manufacturers, exporters, and importers.

Those of us with long memories remember many popular homeopathicremedies that were sold in pharmacies in the first third of the 20th century. Afavorite brand with enumerated remedies from 1 through the nineties was Hum-phreys Homeopathic Remedies. But homeopathy as a competitive branch of med-icine had been vanquished by aliopathy, and persons licensed as homeopathicphysicians were ‘‘grandfathered’’ into medical doctor licenses in all states.

In fact, in the great legislation that established the new drug approval proce-dure for the first time within the FFDC Act, President Roosevelt chose a NewYork Senator who was a former homeopathic physician to carry the ball in Con-gress, Dr. Royal S. Copeland.

Thus, although in the study of pharmacy we had all to study botany andpharmacognosy, which formed the background for homeopathic drug develop-ment, emphasis was placed on studies involving the aliopathic armamentariumand its consistency of standards based on current scientific methodology.

When as a professor at a pharmacy college or law school, I reached 201(9)of the FFDC Act, I would always invite students to visit the local homeopathichospital and examine the Homeopathic Pharmacopeia. Of course, that in all myexperience remained an assignment unmet.

The reader should recall that Section 201(g)(1) of the Act defines the term‘‘drug’’ to mean articles recognized in the official United States Pharmacopeia(USP), the official Homeopathic Pharmacopeia of the United States (HPUS), orofficial National Formulary (NF) or any supplement to them; and articles in-tended for use in the diagnosis, cure, mitigation, treatment, or the prevention ofthe disease in man or other animals; articles (other than food) intended to affectthe structure or any function of the body of man or other animals; and articlesintended for use as a component of any articles specified in the above. Whetheror not they are official homeopathic remedies, those products offered for the cure,mitigation, prevention, or treatment of disease conditions are regarded as drugswithin the meaning of Section 201(g)(1) of the Act. And as drugs they are patentlysubject to the CGMP’s with some reservations I have noted. Homeopathic drugsgenerally must meet the standards for strength, quality, and purity set forth in


the Homeopathic Pharmacopeia. Section 501(b) of the Act (21 U.S.C. 351) pro-vides in relevant part:

Whenever a drug is recognized in both the United States Pharmacopeia andthe Homeopathic Pharmacopeia of the United States it shall be subject tothe requirements of the United States Pharmacopeia unless it is labeled andoffered for sale as a homeopathic drug, in which case it shall be subject tothe provisions of the Homeopathic Pharmacopeia of the United States andnot to those of the United States Pharmacopeia.

Supplemental Information Regarding Homeopathic Drugs for those readers inter-ested in import, export, interstate commerce in such products. The FDA compli-ance policy guide has provided this information in main part:

CONDITIONS UNDER WHICH HOMEOPATHIC DRUGS MAYBE MARKETED (CPG 7132.15)

BACKGROUND:

The term ‘‘homeopathy’’ is derived from the Greek words homeo (similar) andpathos (suffering or disease). The first basic principles of homeopathy were for-mulated by Samuel Hahnemann in the late 1700s. The practice of homeopathyis based on the belief that disease symptoms can be cured by small doses ofsubstances that produce similar symptoms in healthy people.

The Federal Food, Drug and Cosmetic Act (the Act) recognizes as officialthe drugs and standards in the Homeopathic Pharmacopeia of the United Statesand its supplements [Sections 201 (g) (1) and 501 (b), respectively]. Until re-cently, homeopathic drugs have been marketed on a limited scale by a few manu-facturers who have been in business for many years and have predominantlyserved the needs of a limited number of licensed practitioners. In conjunctionwith this, homeopathic drug products historically have borne little or no labelingfor the consumer.

Today the homeopathic drug market has grown to become a multimilliondollar industry in the United States, with a significant increase shown in theimportation and domestic marketing of homeopathic drug products. Those prod-ucts that are offered for treatment of serious disease conditions must be dispensedunder the care of a licensed practitioner. Other products offered for use in self-limiting conditions recognizable by consumers may be marketed OTC.

This document provides guidance on the regulation of OTC and prescrip-tion homeopathic drugs and delineates those conditions under which homeopathicdrugs may ordinarily be marketed in the U.S. Agency compliance personnelshould particularly consider whether a homeopathic drug is being offered for use(or promoted) significantly beyond recognized or customary practice of homeopa-


thy. If so, priorities and procedures concerning the agency’s policy on healthfraud would apply. (See CPG 7150.10 ‘‘Health Fraud-Factors’’ in ConsideringRegulatory Action’’ 6/5/87.)

DEFINITIONS:

The following terms are used in this document and are defined as follows:

1. Homeopathy: The practice of testing the syndromes and conditions thatconstitute disease with remedies that have produced similar syndromesand conditions in healthy subjects.

2. Homeopathic Drug: Any drug labeled as being homeopathic that islisted in the Homeopathic Pharmacopeia of the United States (HPUS),an addendum to it, or its supplements. The potencies of homeopathicdrugs are specified in terms of dilution, i.e., 1� (1/10 dilution), 2�(1/100 dilution), etc. Homeopathic drug products must contain diluentscommonly used in homeopathic pharmaceutics. Drug products con-taining homeopathic ingredients in combination with non-homeopathicactive ingredients are not homeopathic drug products.

3. Homeotherapeutics: Involves therapy that utilizes drugs that are se-lected and administered in accordance with the tenets of homeopathy.

4. Homeopathic Pharmacopeia of the United States (HPUS): A compila-ti

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