-
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
This book is printed on acid-free paper.
HeadquartersMarcel Dekker, Inc.270 Madison Avenue, New York, NY
10016tel: 212-696-9000; fax: 212-685-4540
Eastern Hemisphere DistributionMarcel Dekker AGHutgasse 4,
Postfach 812, CH-4001 Basel, Switzerlandtel: 41-61-261-8482; fax:
41-61-261-8896
World Wide Webhttp:/ /www.dekker.com
The publisher offers discounts on this book when ordered in bulk
quantities. Formore information, write to Special
Sales/Professional Marketing at the headquar-ters 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 orby any means, electronic or mechanical, including
photocopying, microfilming,and recording, or by any information
storage and retrieval system, without per-mission 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.
www.dekker.com
-
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
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 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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
§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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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-
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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-
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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:
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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.
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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-
Copyright 2001 by Marcel Dekker, Inc. All Rights Reserved.
-
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