Good Pharmaceutical Manufacturing Practice: Rationale and Compliance

483 Pages·2004·11.93 MB·English

by  John Sharp

Good Pharmaceutical
Manufacturing Practice
Rationale and Compliance
© 2005 by John Sharp
Good Pharmaceutical
Manufacturing Practice
Rationale and Compliance
John Sharp
CRC PR ESS
Boca Raton London New York Washington, D.C.
© 2005 by John Sharp
PH1994_book.fm Page iv Friday, September 10, 2004 12:03 PM
Library of Congress Cataloging-in-Publication Data
Sharp, John, 1930–
Good pharmaceutical manufacturing practice : rationale and compliance / by John Sharp.
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-1994-3 (alk. paper)
1. Drugs—Standards—United States. 2. Drugs—Standards—European Union Countries.
3. Pharmaceutical industry—United States—Quality control. 4. Pharmaceutical industry—
European Union Countries—Quality control. 5. Drugs—Law and legislation—United States.
6. Drugs—Law and legislation—European Union Countries. I. Title.
RS189.S524 2004
362.17’82’0973—dc22
2004050322
This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted
with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been
made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the
validity of all materials or for the consequences of their use.
Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or
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identification and explanation, without intent to infringe.
Visit the CRC Press Web site at www.crcpress.com
© 2005 by John Sharp
No claim to original U.S. Government works
International Standard Book Number 0-8493-1994-3
Library of Congress Card Number 2004050322
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper
© 2005 by John Sharp
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PREFACE
Worldwide, there are more than 20 different official regulatory statements, national
and international, on Good Manufacturing Practice (GMP) for pharmaceutical (or
“drug” or “medicinal”) products. These regulatory statements may be termed
“regulations,” “guides,” or “guidelines,” and of the 20 or so of them, 2 stand out
as being the most influential and most frequently referenced: The United States
Current Good Manufacturing Practice Regulations (cGMPs) and the European
Commission’s “Good Manufacturing Practices for Medicinal Products for Human
and Veterinary Use” (the EC GMP guide). The full titles of these documents are
as follows:
1. Code of Federal Regulations 21 CFR, Part 210: Current Good Manufacturing
Practice in Manufacturing, Processing, Packing or Holding of Drugs; Gen-
eral. CFR, and Part 211: Current Good Manufacturing Practice for Finished
Pharmaceuticals. Revised April 1, 2002 (may be viewed on FDA website,
www.fda.gov).
For the purposes of this book, and for convenience, 21 CFR Part 210 and
Part 211 will be referred to as the US cGMPs.
2. “The rules governing medicinal products in the European Union, Volume
4, Good Manufacturing Practices, Medicinal Products for Human and Vet-
erinary Use” (European Commission, Directorate General — Industry, Phar-
maceuticals and Cosmetics), 1998 Edition. Updated September 27, 2002.
Published in Luxembourg by the Office for Official Publications of the
European Communities (may be viewed at http://pharmacos.eudra.org/F2/
eudralex/vol-4/pdfs-en/). The English version of this text is also published
in full as part of the U.K. Medicines Control Agency’s (MCA) “Rules and
Guidance for Pharmaceutical Manufacturer’s and Distributors 2002,” London,
The Stationery Office, 2002, ISBN 011 322559 8.
The object of this book is to present the major substance of these two
publications in a way that will permit a comparative consideration of the reasoning
behind each of the main requirements and to offer suggestions for their practical
implementation.
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There is another set of related guidelines, which are given in full in the above
MCA publication. These are the Guidelines on Good Distribution Practice (GDP)
of Medicinal Products for Human Use. These guidelines were issued in support
of the European Directive 2001/83/EC, which introduced the requirement for
wholesale dealers to obtain a formal authorization to engage in such activities.
The relevant paragraph (77/1) in that directive reads:
Member States shall take all appropriate measures to ensure that the
wholesale distribution of medicinal products is subject to the possession
of an authorisation to engage in activity as a wholesaler in medicinal
products, stating the place for which it is valid.
Although these regulatory texts are freely available in the public domain and
no formal permission is required to quote from them, I would like to express my
personal thanks to both the US FDA and the European Commission for making
them so readily available. While every attempt has been made in this book to
offer advice and guidance that will assist manufacturers in regulatory compliance,
it would be foolhardy to claim that it will ensure survival of all levels of regulatory
scrutiny. Further, while substantial portions of both the US cGMPs and the EC
GMP Guide are quoted here, the full texts are not presented. To ensure compliance,
reference must be made to the full original texts.
Note: Although the correct current title of the interstate partnership that exists
in Europe is the European Union (EU), readers of this book will notice references
to the titles of earlier manifestations of this assembly, notably the European
Economic Community (EEC) and the European Community (EC, also used to
signify the European Commission). This is because these earlier titles are still in
use, both in common European parlance, and in the titles of various European
directives and guidelines. The policy adopted for the purposes of this book is to
use for the title of a document the one by which it is most commonly known.
John Sharp
September 2004
© 2005 by John Sharp
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THE AUTHOR
John Sharp, BSc, CChem, FRSC, Hon. MRPharmS, CBiol, MiBiol, FIQA,
worked nearly 20 years in the pharmaceutical industry — in the practice and
management of the chemical analysis, QA/QC, production, and distribution of
most major categories of medicinal products and of the bulk production of a
number of active substances. He joined the U.K. Medicines Inspectorate in 1971
and was promoted to principal inspector in 1972. In addition to his inspection
duties, he compiled and edited the 1977 and 1983 editions of the U.K. Guide to
Good Pharmaceutical Manufacturing Practice or “The Orange Guide,” which later
formed the basis for the EC/EU GMP Guidelines. Since leaving the Inspectorate
in 1985, he has held appointments with the Association of the British Pharma-
ceutical Industry (as project manager) and has returned briefly to the Industry
(as technical director of Waverley Pharmaceutical). Since 1987, Sharp has run his
own consultancy business. He is the author of more than 70 published papers,
books, booklets, and manuals on many aspects of pharmaceutical technology,
QA/QC, etc. (including three entire modules in the Manchester University
Advanced Pharmaceutical Training series and four modules for the ABPI NVQ
Operator Training series). He has presented papers at technical, professional, and
academic seminars and symposia in Britain, Continental Europe, Canada, the U.S.,
Africa, and Asia. He is a member of the Editorial Board of the European Journal
of Parenteral and Pharmaceutical Sciences, and a referee for the U.S. Parenteral
Drug Association’s Journal of Pharmaceutical Science and Technology.
Sharp is an honors science graduate of London University, a fellow of the
Royal Society of Chemistry (and for many years a member of the RSC’s panel of
assessors for qualified persons), an honorary member of the Royal Pharmaceutical
Society (for services to Pharmacy in the field of GMP), a member of the Institute
of Biology, a fellow of the Institute of Quality Assurance, an honorary life member
of the Parenteral Society, and an honorary life member of the Pharmaceutical BFS
Operators Association. In 1996 he received the U.S. PDA’s Korczynski Award for
international contributions to the pharmaceutical sciences. In 2003 he received
the U.K. Parenteral Society’s George Sykes Memorial Award for his paper on
sterile products manufacture. He is a member of the Middlesex County Cricket
Club and the Harlequin Football Club.
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TABLE OF CONTENTS
Chapter 1 Introduction: Status and Applicability of US Regulations/
EU Guidelines — General Quality Issues................................1
Chapter 2 Personnel, Organization, and Training................................19
Chapter 3 Premises/Buildings and Facilities.........................................59
Chapter 4 Contamination and Contamination Control....................... 85
Chapter 5 Equipment...............................................................................99
Chapter 6 Materials Control..................................................................113
Chapter 7 Production and Process Controls.......................................149
Chapter 8 Packaging and Labeling Control.........................................171
Chapter 9 Holding and Distribution.....................................................191
Chapter 10 Laboratory Controls.............................................................211
Chapter 11 Records and Reports............................................................253
Chapter 12 Returned and Salvaged Drug Products...............................325
Chapter 13 Sterile Products Manufacture — Basic Principles.............329
Chapter 14 GMP and Quality Assurance in Sterile Products
Manufacture .........................................................................371
Chapter 15 Validation — General Principles.........................................405
Chapter 16 Validation — Applications...................................................439
Chapter 17 Self-Inspection and Quality Audit.......................................469
Chapter 18 US cGMPs and EC GMP Guide — Concluding
Comparison .........................................................................485
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1
INTRODUCTION:
STATUS AND APPLICABILITY
OF US REGULATIONS/
EU GUIDELINES — GENERAL
QUALITY ISSUES
The main objective of this book is to consider and compare the principle
requirements of Good Manufacturing Practice (GMP), most notably in:
(cid:1) The US Current Good Manufacturing Practice for Finished Pharmaceu-
ticals regulations (the “US cGMPs”)
(cid:1) The Guide to Good Manufacturing Practice for Medicinal Products of
the European Union (the “EC GMP Guide”)
This book will also discuss the rationale behind these requirements and will
propose ways and means of complying with them.
The approach generally adopted for this book, after the following consid-
eration of the status and applicability of these two major regulatory statements
on GMP, is to base each chapter on one of the subparts of the US cGMPs
(Organization and Personnel, Buildings, Equipment, etc.), which are quoted
(often in a somewhat abridged version) and then followed by the (also often
abridged) corresponding sections of the EC GMP Guide. These quotes are
then followed by a comparative discussion, which enlarges on the regulatory
requirements and proposes steps toward implementation and then compliance.
The reader should note that, although the quotes are verbatim, they may not
represent the full original regulatory texts, which should be consulted when-
ever necessary.
1
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2 (cid:1) Good Pharmaceutical Manufacturing Practice: Rationale and Compliance
STATUS AND APPLICABILITY
US cGMPs
Part 210 — Current Good Manufacturing Practice in Manufacturing,
Processing, Packaging, and Holding of Drugs:
Sec. 210.1 Status of current good manufacturing practice regulations.
(a) The regulations set forth in this part and in parts 211 through 226 of this
chapter contain the minimum current good manufacturing practice for
methods to be used in, and the facilities or controls to be used for, the
manufacture, processing, packing, or holding of a drug to assure that such
drug meets the requirements of the act as to safety, and has the identity
and strength and meets the quality and purity characteristics that it purports
or is represented to possess.
(b) The failure to comply with any regulation set forth in this part and in parts
211 through 226 of this chapter in the manufacture, processing, packing,
or holding of a drug shall render such drug to be adulterated under section
501(a)(2)(B) of the act and such drug, as well as the person who is
responsible for the failure to comply, shall be subject to regulatory action.
Sec. 210.2 Applicability of current good manufacturing practice regulations.
(a) The regulations in this part and in parts 211 through 226 of this chapter
as they may pertain to a drug and in parts 600 through 680 of this chapter
as they may pertain to a biological product for human use, shall be
considered to supplement, not supersede, each other, unless the regulations
explicitly provide otherwise. In the event that it is impossible to comply
with all applicable regulations in these parts, the regulations specifically
applicable to the drug in question shall supersede the more general.
(b) If a person engages in only some operations subject to the regulations in
this part and in parts 211 through 226 and parts 600 through 680 of this
chapter, and not in others, that person need only comply with those
regulations applicable to the operations in which he or she is engaged.
EC GMP Guide — Foreword
The Pharmaceutical Industry of the European Community maintains high stan-
dards of Quality Assurance in the development, manufacture and control of
medicinal products. A system of Marketing Authorisations ensures that all
medicinal products are assessed by a Competent Authority to ensure compliance
with contemporary requirements of safety, quality and efficacy. A system of
Manufacturing Authorisations ensures that all products authorised on the Euro-
pean market are manufactured only by authorised manufacturers, whose activ-
ities are regularly inspected by the Competent Authorities. Manufacturing
Authorisations are required by all pharmaceutical manufacturers in the Euro-
pean Community whether the products are sold within or outside of the
Community.
Two directives laying down principles and guidelines of good manufacturing
practice (GMP) for medicinal products were adopted by the Commission in
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Introduction: Status and Applicability of US Regulations/EU Guidelines (cid:1) 3
1991, the first for medicinal products for human use (Directive 91/356/EEC),
the second one for veterinary use (Directive 91/412/EEC). Detailed guidelines
in accordance with those principles are published in the Guide to Good
Manufacturing Practice which will be used in assessing applications for man-
ufacturing authorisations and as a basis for inspection of manufacturers of
medicinal products.
The principles of GMP and the detailed guidelines are applicable to all oper-
ations which require the authorisation referred to in Article 16 of Directive
75/319/EEC and in Article 24 of Directive 81/851/EEC as modified. They are
also relevant for all other large-scale pharmaceutical manufacturing processes,
such as that (sic) undertaken in hospitals, and for the preparation of products
for use in clinical trials.
All Member States and the Industry itself are agreed that the GMP requirements
applicable to the manufacture of veterinary medicinal products are the same
as those applicable to the manufacture of medicinal products for human use.
Certain detailed adjustments to the GMP guidelines are set out in two annexes
specific to veterinary medicinal products and to immunological veterinary
medicinal products.
The Guide is presented in chapters, each headed by a principle. Chapter 1 on
Quality Management outlines the fundamental concept of Quality Assurance
as applied to the manufacture of medicinal products. Thereafter each chapter
has a principle outlining the Quality Assurance objectives of that chapter and
a text which provides sufficient detail for manufacturers to be made aware of
the essential matters to be considered when implementing the principle.
In addition to the general matters of Good Manufacturing Practice outlined in
the 9 chapters of this guide, a series of annexes providing detail about specific
areas of activity is included. For some manufacturing processes, different
annexes will apply simultaneously (e.g., annex on sterile preparations and on
radio pharmaceuticals and/or on biological medicinal products).
A glossary of some terms used in the Guide has been incorporated after the
annexes.
The first edition of the Guide was published in 1989, including an annex on
the manufacture of sterile medicinal products.
The second edition was published in January 1992 … [it] … also included 12
additional annexes.
The basic requirements in the main guide have not been modified. 14 annexes
on the manufacture of medicinal products have been included in this third
edition.…
The Guide is not intended to cover security aspects for the personnel engaged
in manufacture. This may be particularly important in the manufacture of certain
medicinal products such as highly active, biological and radioactive medicinal
products, but they are governed by other provisions of Community or national
law.
© 2005 by John Sharp