Pharmaceutical Dosage Forms: Parenteral Medications, Third Edition (Vol 3): Volume 3: Regulations, Validation and the Future (Pharmaceutical Science)

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Pharmaceutical Dosage Forms: Parenteral Medications Third Edition

Volume 3: Regulations, Validation and the Future This three-volume set of Pharmaceutical Dosage Forms: Parenteral Medications is an authoritative, comprehensive reference work on the formulation and manufacture of parenteral dosage forms, effectively balancing theoretical considerations with the practical aspects of their development. As such, it is recommended for scientists and engineers in the pharmaceutical industry and academia, and will also serve as an excellent reference and training tool for regulatory scientists and quality assurance professionals.

Sandeep Nema Ph.D. is Executive Director, Pharmaceutical R&D, BioTherapeutics Pharmaceutical Sciences at Pfizer in St. Louis. Since graduating in 1992 with his doctorate, Dr. Nema has been involved with the development of small molecule and protein drugs via parenteral delivery, first at Mallinckrodt Medical and then at Pfizer (Searle, Pharmacia), and has led the formulation of four launched products. He is active in the American Association of Pharmaceutical Scientists (AAPS) and the Parenteral Drug Association (PDA), where he has chaired several meetings and focus groups. Dr. Nema holds an adjunct faculty appointment at the University of Tennessee.

First published in 1984 (as two volumes) and then last revised in 1993 (when it grew to three volumes), this latest revision will address the plethora of changes in the science and considerable advances in the technology associated with these products and routes of administration. The third edition of this book maintains the features that made the last edition so popular but comprises several brand new chapters, revisions to all other chapters, as well as high quality illustrations. Volume three presents: • An in-depth discussion of regulatory requirements, quality assurance, risk assessment and mitigation, and extractables/leachables. • Specific chapters on parenteral administrations devices, injection site pain assessment, and parenteral product specifications and stability testing. • Forward-thinking discussions on the future of parenteral product manufacturing, and siRNA delivery systems. • New chapters covering recent developments in the areas of visual inspection, quality by design (QbD), process analytical technology (PAT) and rapid microbiological methods (RMM), and validation of drug product manufacturing process.

John D. Ludwig Ph.D. is Vice President, Business Strategy, Operations, and Clinical Supply Planning, BioTherapeutics Pharmaceutical Sciences at Pfizer, and Site Director for the company’s St. Louis Laboratories. Dr. Ludwig received a B.S. degree in Pharmacy and Ph.D. degree in Pharmaceutics from the University of Tennessee, Memphis and has held numerous research and development positions at Burroughs Wellcome Co, Searle, Inc., Pharmacia, Inc., and Pfizer. He is active in the American Association of Pharmaceutical Scientists (AAPS) and the Parenteral Drug Association (PDA) Training and Research Institute, where he has contributed to developing professional training courses and has regularly served as an instructor.

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Nema Ludwig

Pharmaceutical Dosage Forms: Parenteral Medications

About the editors

Third Edition Volume 3: Regulations, Validation and the Future

About the book

Volume

Pharmaceutical Dosage Forms: Parenteral Medications Third Edition Volume 3: Regulations, Validation and the Future

Edited by Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK 52 Vanderbilt Avenue, New York, NY 10017, USA

www.informahealthcare.com

Sandeep Nema John D. Ludwig

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Pharmaceutical Dosage Forms

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Pharmaceutical Dosage Forms Parenteral Medications Third Edition Volume 3 Regulations, Validation and the Future Edited by Sandeep Nema Pfizer, Inc. Chesterfield, Missouri, U.S.A. John D. Ludwig Pfizer, Inc. Chesterfield, Missouri, U.S.A.

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First published in 1984 by Marcel Dekker, Inc., New York, New York. This edition published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK. Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th Floor, New York, NY 10017, USA. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37–41 Mortimer Street, London W1T 3JH, UK. Registered in England and Wales number 1072954. #2010 Informa Healthcare, except as otherwise indicated No claim to original U.S. Government works Reprinted material is quoted with permission. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, unless with the prior written permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK, or the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (http://www. copyright.com/ or telephone 978-750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. This book contains information from reputable sources and although reasonable efforts have been made to publish accurate information, the publisher makes no warranties (either express or implied) as to the accuracy or fitness for a particular purpose of the information or advice contained herein. The publisher wishes to make it clear that any views or opinions expressed in this book by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the publisher. Any information or guidance contained in this book is intended for use solely by medical professionals strictly as a supplement to the medical professional’s own judgement, knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures, or diagnoses should be independently verified. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as appropriately to advise and treat patients. Save for death or personal injury caused by the publisher’s negligence and to the fullest extent otherwise permitted by law, neither the publisher nor any person engaged or employed by the publisher shall be responsible or liable for any loss, injury or damage caused to any person or property arising in any way from the use of this book. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data available on application ISBN-13: 9781420086478 ISBN-13: 9781420086539 (three-volume set) Orders may be sent to: Informa Healthcare, Sheepen Place, Colchester, Essex CO3 3LP, UK Telephone: +44 (0)20 7017 5540 Email: [email protected] Website: http://informahealthcarebooks.com/ For corporate sales please contact: [email protected] For foreign rights please contact: [email protected] For reprint permissions please contact: [email protected] Typeset by MPS Limited, A Macmillan Company Printed and bound in India

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We dedicate this work to those who have inspired us. To my parents Walter and Ruth Ludwig and my wife Sue Ludwig To my parents Hari and Pratibha Nema and my wife Tina Busch-Nema

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Foreword

I was a faculty member at the University of Tennessee and a colleague of Dr. Kenneth Avis when he conceived, organized, and edited (along with H.A. Lieberman and L. Lachman) the first edition of this book series that was published in 1984. It was so well received by the pharmaceutical science community that an expanded three-volume second edition was published in 1992. Dr. Avis did not survive long enough to oversee a third edition, and it was questionable whether a third edition would ever be published until two of his graduate students, Drs. Nema and Ludwig, took it upon themselves to carry on Dr. Avis’ tradition. Their oversight of this third edition is work that their mentor would be highly pleased and proud of. From 29 chapters in the second edition to 43 chapters in this new edition, this three-volume series comprehensively covers both the traditional subjects in parenteral science and technology as well as new and expanded subjects. For example, separate chapter topics in this edition not found in previous editions include solubility and solubilization, depot delivery systems, biophysical and biochemical characterization of peptides and proteins, containerclosure integrity testing, water systems, endotoxin testing, focused chapters on different sterilization methods, risk assessment in aseptic processing, visual inspection, advances in injection devices, RNAi delivery, regulatory considerations for excipients, techniques to evaluate pain on injection, product specifications, extractables and leachables, process analytical technology, and quality by design. The editors have done an outstanding job of convincing so many top experts in their fields to author these 43 chapters. The excellent reputations of the authors and editors of this book will guarantee superb content of each chapter. There is no other book in the world that covers the breadth and depth of parenteral science and technology better than this one. In my opinion, the editors have achieved their primary objectives—publishing a book that contains current and emerging sterile product development and manufacturing information, and maintaining the high standard of quality that readers would expect. Michael J. Akers Baxter BioPharma Solutions Bloomington, Indiana, U.S.A.

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Preface

Pharmaceutical Dosage Forms: Parenteral Medications was originally published in 1984 and immediately accepted as a definitive reference in academic institutions and the pharmaceutical industry. The second edition was published in 1993. The ensuing years have produced incredible technological advancement. Classic small-molecule drugs are now complemented by complex molecules such as monoclonal antibodies, antibody fragments, aptamers, antisense, RNAi therapeutics, and DNA vaccines. There have been significant innovations in delivery devices, analytical techniques, in-silico modeling, and manufacturing and control technologies. In addition, the global regulatory environment has shifted toward greater emphasis on science-based risk assessment as evidenced by the evolving cGMPs, quality by design (QbD), process analytical technology (PAT), continuous processing, real time release, and other initiatives. The rapidly changing landscape in the parenteral field was the primary reason we undertook the challenging task of updating the three volumes. Our objectives were to (i) revise the text with current and emerging sterile product development and manufacturing science and (ii) maintain the high standard of quality the readers expect. The third edition not only reflects enhanced content in all the chapters, but also more than half of the chapters are new underscoring the rapidly advancing technology. We have divided the volumes into logical subunits—volume 1 addresses formulation and packaging aspects; volume 2, facility design, sterilization and processing; and volume 3, regulations, validation and future directions. The authors invited to contribute chapters are established leaders with proven track records in their specialty areas. Hence, the textbook is authoritative and contains much of the collective experience gained in the (bio)pharmaceutical industry over the last two decades. We are deeply grateful to all the authors who made this work possible. Volume 1 begins with a historical perspective of injectable drug therapy and common routes of administration. Formulation of small molecules and large molecules is presented in depth, including ophthalmic dosage forms. Parenteral packaging options are discussed relative to glass and plastic containers, as well as elastomeric closures. A definitive chapter is provided on container closure integrity. Volume 2 presents chapters on facility design, cleanroom operations, and control of the environment. A chapter discussing pharmaceutical water systems is included. Key quality attributes of sterile dosage forms are discussed, including particulate matter, endotoxin, and sterility testing. The most widely used sterilization techniques as well as processing technologies are presented. Volume 2 concludes with an in-depth chapter on lyophilization. Volume 3 focuses on regulatory requirements, risk-based process design, specifications, QbD, and extractables/leachables. In addition, we have included chapters on parenteral administration devices, siRNA delivery systems, injection site pain assessment, and control, PAT, and rapid microbiology test methods. Volume 3 concludes with a forward-looking chapter discussing the future of parenteral product manufacturing. These three volumes differ from other textbooks in that they provide a learned review on developing parenteral dosage forms for both small molecules and biologics. Practical guidance is provided, in addition to theoretical aspects, for how to bring a drug candidate forward from discovery, through preclinical and clinical development, manufacturing, validation, and eventual registration. The editors wish to thank Judy Clarkston and Lynn O’Toole-Bird (Pfizer, Inc.) for their invaluable assistance and organizational support during this project, and Sherri Niziolek and Bianca Turnbull (Informa Healthcare) for patiently leading us through the publishing process.

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PREFACE

We also acknowledge the assistance of Pfizer, Inc. colleagues Lin Chen and Min Huang for reviewing several of the chapters. We would like to express special gratitude to the late Kenneth E. Avis (University of Tennessee College of Pharmacy) for his dedication to teaching and sharing practical knowledge in the area of parenteral medications to so many students over the years, including us. Finally, we acknowledge the contributions of Dr Avis, Leon Lachman, and Herbert A. Lieberman who edited the earlier editions of this book series. Sandeep Nema John D. Ludwig

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Contents

Foreword Michael J. Akers Preface ix Contributors xiii

vii

1. cGMP regulations of parenteral drugs Terry E. Munson

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2. Risk assessment and mitigation in aseptic processing James Agalloco and James Akers

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3. Development challenges and validation of fill and finish processes for biotherapeutics 25 Karoline Bechtold-Peters 4. Visual inspection 52 Maria Toler and Sandeep Nema 5. Advances in parenteral injection devices and aids Donna L. French and James J. Collins

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6. siRNA targeting using injectable nano-based delivery systems Lan Feng and Russell J. Mumper

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7. Excipients for parenteral dosage forms: regulatory considerations and controls Sandeep Nema and Ronald J. Brendel 8. Techniques to evaluate damage and pain on injection Gayle A. Brazeau, Jessica Klapa, and Pramod Gupta 9. Parenteral product specifications and stability Michael Bergren

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148

10.

The management of extractables and leachables in pharmaceutical products Edward J. Smith and Diane M. Paskiet

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Process analytical technology and rapid microbiological methods Geert Verdonk and Tony Cundell

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Quality assurance Michael Gorman

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109

222

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CONTENTS

13. Application of Quality by Design in CMC development 246 Roger Nosal, Thomas Garcia, Vince McCurdy, Amit Banerjee, Carol F. Kirchhoff, and Satish K. Singh 14. Future of parenteral manufacturing 269 James Agalloco, James Akers, and Russell Madsen Index

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Contributors

Agalloco & Associates, Belle Mead, New Jersey, U.S.A.

James Agalloco James Akers

Akers Kennedy & Associates, Kansas City, Missouri, U.S.A.

Amit Banerjee

BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri, U.S.A.

Karoline Bechtold-Peters Process Science Department/Pharma Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany JHP Pharmaceuticals LLC, Rochester, Michigan, U.S.A.

Michael Bergren

Gayle A. Brazeau Department of Pharmacy Practice and Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, New York, U.S.A. Covidien, Hazelwood, Missouri, U.S.A.

Ronald J. Brendel

Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

James J. Collins Tony Cundell

Schering-Plough Research Institute, Union, New Jersey, U.S.A.

Lan Feng UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A. Genentech, Inc., South San Francisco, California, U.S.A.

Donna L. French

Thomas Garcia PharmaTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Groton, Connecticut, U.S.A. Michael Gorman St. Louis Laboratories, Pfizer, Inc., Chesterfield, Missouri, U.S.A. Pramod Gupta

Bausch & Lomb, Rochester, New York, U.S.A.

Carol F. Kirchhoff U.S.A.

BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri,

Jessica Klapa Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, U.S.A. Russell Madsen

The Williamsburg Group, LLC, Gaithersburg, Maryland, U.S.A.

Vince McCurdy PharmaTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Groton, Connecticut, U.S.A.

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CONTRIBUTORS

Russell J. Mumper UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A. PAREXEL Consulting, PAREXEL International, LLC, Waltham, Massachusetts,

Terry E. Munson U.S.A. Sandeep Nema U.S.A.

BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri,

Roger Nosal PharmaTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Groton, Connecticut, U.S.A. Diane M. Paskiet

West Pharmaceutical Services, Inc., Lionville, Pennsylvania, U.S.A.

Satish K. Singh BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri, U.S.A. Edward J. Smith Maria Toler

Packaging Science Resources, King of Prussia, Pennsylvania, U.S.A.

BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri, U.S.A.

Geert Verdonk Schering-Plough Pharmaceuticals, Oss, The Netherlands

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cGMP regulations of parenteral drugs Terry E. Munson

INTRODUCTION This chapter presents an overview of the current Good Manufacturing Practice (cGMP) regulations for parenteral drugs. Since most of the major world regulatory authorities follow either the U.S. or the European Union (EU) model for their GMP regulations, this chapter will focus only on these two regulations. U.S. REGULATIONS Food, Drug, and Cosmetic Act In the United States, the law that is violated when a parenteral drug product is not manufactured according to cGMPs is the Food, Drug, and Cosmetic Act (Act). Failure to follow GMPs is covered under Section 501, Adulterated Drugs and Devices section of the Act. Section 501(a)(2)(B) states: A drug or device shall be deemed to be adulterated— . . . if it is a drug and the methods used in, or the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to posses. . . .

This is the section of the law that requires manufacturers to produce drug in conformity with GMP practices. Adverse observations from manufacturing site inspections typically fall under this section of the Act. Two other sections of the action that should be noted, although they do not directly apply to the GMP regulations, are as follows: Section 501(b): “A drug or device shall be deemed to be adulterated— . . . If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength, quality, or purity falls below, the standards set forth in such compendium.” Section 501(c): “A drug or device shall be deemed to be adulterated— . . . If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity or quality falls below, that which it purports or is represented to posses.” Sections 501(b) and (c) citations result from the analysis of drug samples picked up either during inspections or at end-user sites in one of the Food and Drug Administration (FDA) laboratories. To fail the requirements in 501(b), the product must be tested exactly by the methods in the compendial monograph. One key element of this section is that the product only needs to be represented in the compendia to fall under the jurisdiction of this section, irrespective of whether or not it purports to be United States Pharmacopeia (USP)/National Formulary (NF). For example, Sodium Chloride Injection USP, Bacteriostatic Sodium Chloride Injection, and allergenic extract diluent (0.9% sodium chloride in water) are all represented in the compendia and thus subject to 501(b) of the Act. Section 501(c) is used for drugs not meeting the requirements that are in the drug application or in-house specifications. This could also apply to specifications that are in addition to the requirements in a compendial monograph. cGMP Regulations To implement the provisions of the Federal Food, Drug, and Cosmetic Act, Congress delegated to the FDA, through the Secretary of Health, Education, and Welfare, broad authority to promulgate regulations for the efficient enforcement of the Act under Section 701(a). The

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exceptions to this authority are those provisions of the Act that are cited in Section 701(e). These include several drug provisions relating to certain types of adulteration and misbranding. Regulations issued under Section 701(e) require an opportunity for a public hearing under formal rule-making procedures, referred to as an evidentiary public hearing. Regulations promulgated under Section 701(a) on the contrary are subject only to notice and comment or informal rulemaking under the provisions of the Administrative Procedures Act (1). To implement Section 501(a)(2)(B) of the Act, the FDA issued regulations, in accordance with Section 701(a) of the Act, defining what it considered “current good manufacturing practice.” The latest revisions of the cGMP regulations for human and veterinary drugs were published in the Federal Register of September 29, 1978, and became effective on March 28, 1979 (2). Because these regulations provide legal standards for controlling the quality of drugs, they should be of interest to all health professionals. They can also provide an insight into standard operating procedures that may serve those who are called upon to set up a quality control program on the handling and administration of parenterals in health care facilities. Unlike other regulations, regulatory controls are based primarily on inspections of establishments manufacturing, processing, packing, or holding human and veterinary drugs. The cGMP regulations are contained in Title 21 Code of Federal Regulations parts 210 and 211. Part 210—Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General Part 210 gives the status of the cGMP regulations. It indicates that failure to follow the regulations in parts 211 through 226 would render drug adulterated under Section 501(a)(2)(B) of the act. It also states that the person who is responsible for the failure to comply shall be subject to regulatory action. In the United States, typically the president or chief executive officer of the company is held responsible. In some cases the top manager of quality has also been cited in regulatory actions. Paragraph 210.2 describes the applicability of cGMP regulations. It states that parts 210 through 226 pertain to drugs, parts 600 through 680 pertain to biological products, and part 1271 pertains to human cell, tissue, or cellular or tissue-based products subject to Section 505 of the act or Section 351 of the Public Health Service Act, shall be considered to supplement, not supersede, each other, unless the regulation explicitly provide otherwise. This means that the cGMP regulation in parts 210 and 211 also apply to biological products and biotechnology products. It also states that investigational drugs used in phase 1, 2 or 3 clinical studies must comply with the regulations in part 211. The FDA has further clarified that all cGMP provisions except labeling and process validation requirements are to be applied to clinical products. The last section of part 210 lists definitions for some of the terms used in part 211. On September 8, 2008, the FDA published a revision to the non-fiber-releasing filter definition in part 210.3 (3). The reference to asbestos filters as fiber-releasing filters was deleted. Part 211—Current Good Manufacturing Practice for Finished Pharmaceuticals Subpart A: general provisions, including scope and definitions. This subpart is a repeat of the sections in 210.1 and 210.3. There is a statement that cGMPs in part 211 do not apply to Over-The-Counter (OTC) drug products that are ordinarily marketed and consumed as human foods. This is the case for vitamins and herbal products. Subpart B: organization and personnel. 1. 2. 3. 4.

Responsibilities and authority of a quality control unit are to be spelled out in writing. Personnel qualification for assigned functions and training in CGMP shall be conducted on a continuing basis. Only authorized personnel shall enter those areas of the buildings and facilities designated as limited-access areas. Consultants advising on CGMP shall be qualified, and records shall be maintained on their employment and qualifications.

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cGMP REGULATIONS OF PARENTERAL DRUGS

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Subpart C: buildings and facilities. 1. 2.

3. 4.

Buildings—their size, construction, and operational areas—are to be designed so that they are suited to the types of products produced or held therein to prevent contamination or mix-ups. Special operations require more detailed criteria as to the adequacy of the building and facilities. Thus, the requirements for aseptic processing must include floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable. Temperature and humidity controls. An air supply filtered through high-efficiency particulate filters under positive pressure, regardless of whether the flow is laminar or nonlaminar. A system of monitoring environmental conditions. A system for cleaning and disinfecting the room and equipment to produce aseptic conditions. Equipment for adequatea control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriatea for the manufacture, processing, packing, or holding of a drug product. Sanitation shall be assured by requiring written procedures for cleaning and assigning responsibility of seeing that they are followed. Rodenticides, insecticides, or fumigating agents shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Sanitation procedures shall apply to work performed by contractors.

Subpart D: equipment. 1. 2.

Adequacy of equipment design, size, and location should be validated. Equipment cleaning and maintenance record keeping is essential.

Subpart E: control of components and drug product containers and closures. 1. 2. 3. 4.

Take appropriate measures to establish suitable specifications, and assure conformance with the specifications by proper records.a Retest components, drug product containers, and closures as necessary due to conditions or passage of time that might adversely affect them. Assure that drug product containers and closures are not reactive, additive, or absorptive, so as to alter the strength, quality, or purity of the drug beyond the applicable specifications. Enforce standards and specifications to ensure that such hazards as pyrogens are eliminated from containers and closures for parenterals.

Subpart F: production and process controls. 1. 2.

a

Provide written procedures and change control with approval by the quality control unit. Validate each process to demonstrate that it will consistently do what it purports to do.

Such words as adequate and appropriate are used frequently in this and other sections of the CGMP. This puts the burden on the manufacturer of showing through data and performance records that the selections are “adequate” and “appropriate.” Such flexibility is viewed by industry as a desirable attribute in the cGMP.

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3. 4.

Control against microbiological contamination, including validation of the sterilization process. Reprocessing must be based on procedures that will ensure that reprocessed batches will conform to all established standards, specifications, and product characteristics.

Subpart G: packaging and labeling control. 1. 2. 3. 4.

Provide written procedures and documentation to assure that every stage, from the design, receipt, identification, storage, and handling of labeling and packaging to their application to the drug product, is adequately controlled. Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gangprinting sheets is adequately differentiated by size, shape, or color. Labeling reconciliation is waved for cut or roll labeling if a 100% examination for correct labeling is performed. All prescription drug products and most OTC drug products shall have expiration dates on their labeling on the basis of adequate stability studies. However, the commissioner proposed in a separate Federal Register document published at the same time as the cGMP final rule that certain OTC drug products be exempted from expiration dates. These included those OTC drug products used without dosage limitation provided that it could be shown that they are stable for at least three years. Drug products to be reconstituted at time of dispensing shall bear expiration information for both the reconstituted and unreconstituted products.

Subpart H: holding and distribution. 1. 2.

There shall be written procedures to describe the warehousing. Where necessary to produce product, there shall be appropriate environmental controls. There shall be written distribution procedures so that any recalls, if required, can be handled expeditiously.

Subpart I: laboratory controls. 1. 2. 3.

4. 5. 6. 7. 8.

Any specifications, standards, sampling plans, test procedures, or other laboratory controls, such as stability testing, are to be approved by the quality control unit. The laboratory controls required are specified. Testing and release procedures are specified for the usual drug products and exceptions in the case of short-lived radiopharmaceutical parenterals where batches may be released prior to completion of sterility and/or pyrogen testing. Appropriate laboratory testing is provided for, as necessary, of each batch of drug product required to be free of objectionable microorganisms. A written stability program on the basis of studies conducted in the same containerclosure system in which it will be marketed is required. Products purporting to be sterile and/or pyrogen-free must be batch tested prior to release. Reserve samples must have at least twice the quantity necessary for all tests except for sterility and pyrogen testing. Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained and controlled in a manner that assures their suitability for their intended use. If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin.

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Subpart J: records and reports. 1. 2. 3.

Documentation through written procedures and records is now required for practically all operations. The items to be reported in a laboratory assay report are spelled out for the first time in the cGMP. Complaints must be documented, and procedures must be followed in the investigation of complaints by quality control. The quality control unit is responsible for review of all production and control records.

Guidelines Guidelines are a tool used by the FDA to explain its interpretation of what is required to meet the regulations. Whenever the FDA perceives that the pharmaceutical industry does not understand the regulations or their intent, a group of in-house experts is assembled to generate the proposed guideline. Once the proposed document is submitted for public review and comment, it is finalized. Below is a list of guidelines that have been written and can be applied to parenteral drug products.

GMP Guidelines Guideline on General Principles of Process Validation, May, 1987, and November 2008 Draft Guideline on Sterile Drug Products Produced by Aseptic Processing, September, 2004 Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices, December, 1987 Guideline on the Preparation of Investigational New Drug Products, February, 1990 Guideline on Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processing, August 2008, Draft The most significant guideline for parenteral drug manufacture is the guideline for aseptic processing. The first aseptic guideline was issued in 1987. In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. It described the facilities, equipment, environmental conditions, and process validation requirements for products produced using aseptic processing. In addition, it described environmental monitoring and laboratory testing requirements. The only specific acceptance criteria given was nonviable particulate limits for clean rooms and adjacent areas and the acceptance criteria for the media fills used to validate the aseptic processes. Particulate limits are based on Federal Standard 209 (withdrawn). Media fill acceptance criteria was listed at 1 positive unit per 1000 units filled with media. This represents a contamination rate of 0.1%. A minimum of 3000 units was required to be able to detect the contamination rate with 95% confidence. In 2004, the FDA issued a revised guideline (4). The revision was necessary to incorporate improvement made by the pharmaceutical industry and new concepts being promoted by the FDA. During the development of the guideline, a great deal of effort was made to try to harmonize as much as possible with the EU requirements. In addition, the FDA assembled an expert panel made up of industry experts to assist in answering specific questions. This is the first time the industry has had any influence on guidelines during the development phase. Most of the recommendations made by the expert panel were adopted by the FDA.

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The most significant changes in the 2004 guideline are as follows: l l

l

l

l

l

l

Microbial limits were added to guideline. The nonviable and viable airborne particulate limits that are stated in the EU guide were adopted. The major exception is that settling plates are not required or expected by the FDA. The FDA also adopted the International Organization for Standardization (ISO) designations for clean room classification instead of the A to D designations used by the EU.

Clean area classification (0.5 mm particles/ft3)

ISO designation

100 1,000 10,000 100,000

5 6 7 8

>0.5 mm particles/m3

Microbiological active air action levels (cfu/m3)

Microbiological settling plates action levels (diam. 90 mm; cfu/4 hr)

3,520 35,200 352,000 3,520,000

1 7 10 100

1 3 5 50

Differential pressure is now expressed in pascals and as a range instead of a single value, that is, 10 to 15 Pa versus 0.05 in. of water. This range is the same as that in the EU. The requirement that the velocity in a unidirectional flow area should be 90  20 ft/min has been deleted. Instead each site must justify and validate that the velocities used are appropriate. Typically, airflow studies are used to demonstrate that at the measured velocity the airflow sweeps particles away from the product without generating turbulence. It also prevents extrinsic particulate matter from getting into the product. The FDA expects environmental monitoring data to be trended and analyzed for any trends that could indicate a potential risk to the products. A recommendation that the quality unit view all process simulations (media fill) was added. While this is a recommendation, it appears that the FDA investigators expect to see evidence that QA does observe and take notes on activities occurring during the process simulations. The FDA recommends that the media fill program address applicable issues such as - factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue); - representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments); - lyophilization, when applicable; - aseptic assembly of equipment (e.g., at start-up, during processing); - number of personnel and their activities; - representative number of aseptic additions (e.g., charging containers and closures as well as sterile ingredients) or transfers; - shift changes, breaks, and gown changes (when applicable); - type of aseptic equipment disconnections/connections; - aseptic sample collections; - line speed and configuration; - weight checks; - container closure systems (e.g., sizes, type, compatibility with equipment); and - specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance is mandated). This is the first time that the FDA has given such details concerning what should be covered by the process simulation procedure/protocols.

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The process simulation acceptance criteria was changed as follows: When filling fewer than 5000 units, no contaminated units should be detected. - One contaminated unit is considered cause for revalidation, following an investigation. When filling from 5000 to 10,000 units - One contaminated unit should result in an investigation, including consideration of a repeat media fill. - Two contaminated units are considered cause for revalidation, following investigation. When filling more than 10,000 units - One contaminated unit should result in an investigation. - Two contaminated units are considered cause for revalidation, following investigation.

It should be noted that it does not matter if 10,000 units or 150,000 units are filled, the acceptance criteria is the same. This is a significant change from the previous contamination rate concept where the more units filled with media, the more positive units allowed. Both the pharmaceutical industry and the FDA agreed that this approach was inappropriate. The goal of aseptic process is to produce a sterile product, that is, zero units contaminated. On the basis of industry input it was determined that the above criteria represented the current industry capabilities. Three new sections were added to the aseptic guideline to address the following: l

l

l

Aseptic processing isolators The main concerns raised were as follows: l Glove integrity. l Proper isolator design. l Pressure differentials—promotes the need for ISO 5 protection at opening in the isolator. l Isolators must be in classified rooms. ISO 8 is recommended. The isolator is prohibited from being in an unclassified room. l There is an extensive discussion of decontamination of isolators. For example, biological indicators must be used, if decontamination is used for product contact parts, a six-logarithm reduction must be proven and the frequency of decontamination must be justified and have supporting data. Blow/fill/seal technology Blow/fill/seal (BFS) machines must be designed to prevent extraneous contamination. The room environment can be ISO 8. Another major concern is container/closure integrity. The FDA requires that reliable and sensitive inspection processes must be established to make sure every unit is intact. Processing prior to filling and sealing operations Process simulations must cover all aseptic manipulations that occur to the product prior to the manufacturing process, including the holding times for sterile bulks.

Compliance Policy Guides Compliance policy guides (CPGs) were developed as a mechanism of disseminating the FDA policy to the district offices. CPGs were developed by centers or other headquarters units to explain how the FDA will enforce various aspects of the regulations or various situations that the field investigator may find. They are usually developed in response to questions on how to interpret a specific regulation or what is the agency policy concerning a specific subject. CPGs can be obtained through the National Technical Information Service or at http://www.fda.gov. One CPG that is particularly applicable to parenteral drugs is guide 7132a.13, “Parametric Release—Terminally Heat Sterilized Drug Products.” In this guide the FDA defines parametric release as “a sterility release procedure based upon effective control,

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monitoring, and documentation of a validated sterilization process cycle in lieu of release based upon end-product sterility testing.” The FDA will only accept parametric release for terminally heat sterilized parenteral drug products. Parametric release of drug products sterilized by filtration or ethylene oxide will not be allowed. For those products that are the subject of a new drug application, the manufacturer must submit a supplement and obtain approval prior to initiation of parametric release. Parametric release of drug products that do not require new drug applications cannot be used until the above requirements have been met. The firm should have the data to support parametric release at the manufacturing site. Firms planning on parametric release of non-New Drug Application (NDA) drug products should contact the local FDA district office prior to initiation so that the FDA can determine that they have met all the required criteria. There are four requirements listed in the guide that must be met before parametric release can be considered by the FDA. 1.

2. 3. 4.

The sterilization process cycle has been validated to achieve microbial bioburden reduction to 108 with a minimum safety factor of an additional six-logarithm reduction. All cycle parameters must be identified by the manufacturer as critical, for example, time, temperature, and pressure, or noncritical, for example, cooling time and heat-up time. Failure of one of the critical parameters must result in automatic rejection of the sterilizer load. Biological indicators can be used to evaluate cycle lethality where equipment malfunction prevents measurement of one critical cycle parameter. If more than one critical parameter is not met, the batch is considered nonsterile despite biological indicator sterility. Integrity for each container/closure system has been validated to prevent in-process and postprocess contamination over the product’s intended shelf life. Bioburden testing, covering total aerobic and spore counts, is conducted on each batch of presterilized drug product. Resistance of any spore-forming organism found must be compared to that of the organism used to validate the sterilization cycle. Chemical or biological indicators are included in each truck, tray, or pallet of each sterilizer load. Both chemical and biological indicators must be fully characterized and documented. Chemical indicators cannot be used to evaluate cycle lethality due to lack of time/temperature accuracy.

The FDA issued a draft guideline on the documentation that must be submitted in applications to support parametric release of human, biological, and veterinary drugs (4). The definition of parametric release has been revised to conform to the new focus of FDA. It is defined as “a sterility assurance release program where demonstrated control of the sterilization process enables a firm to use defined critical process controls, in lieu of the sterility test.” The release program should be based on the results of a risk assessment of the terminal sterilization cycle, demonstration of process understanding, and prior knowledge of the production and sterilization process. EU REGULATIONS EU Directives Directives in the EU are the same laws as in the United States. The directive that requires the EU member states to ensure that pharmaceutical manufacturers comply with GMP is in Chapter IV of Directive 75/319/EEC for human products and Chapter V of Directive 81/851/EEC for veterinary products. Another Directive, 92/25/EEC, requires all wholesale distributors to be authorized and comply with guidelines on Good Distribution Practice (GDP). The principles and guidelines of GMP are stated in two directives. Directive 91/356/EEC and 2003/94/2003 are for human medicinal products and 91/412/EEC is for veterinary products (5). It must be noted that while these are termed guidelines they should be treated the same as the GMP regulations in the United States. They are enforceable under the member state laws. GMP Regulations The GMP regulations are organized into nine general chapters.

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Chapter 1 Quality Management This chapter covers the requirements for quality assurance and quality control. The system of quality assurance appropriate for the manufacture of medicinal products should ensure that 1. 2. 3. 4. 5. 6. 7.

8. 9.

medicinal products are designed and developed in a way that takes account of the requirements of GMP and Good Laboratory Practice; production and control operations are clearly specified and GMP adopted; managerial responsibilities are clearly specified; arrangements are made for the manufacture, supply, and use of the correct starting and packaging materials; all necessary controls on intermediate products and any other in-process controls and validations are carried out; the finished product is correctly processed and checked, according to the defined procedures; medicinal products are not sold or supplied before a qualified person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control, and release of medicinal products; satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed, and subsequently handled so that quality is maintained throughout their shelf life; and there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system.

It should be noted that the legal responsibility for the quality of products rests with the qualified person. This is very different from the United States, where the CEO/president is ultimately held responsible for the quality of the products manufactured by the company. A qualified person must be noted in each Market Authorization Application. The basic requirements of quality control are that 1.

2. 3. 4. 5. 6.

7. 8.

adequate facilities, trained personnel, and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and, where appropriate, for monitoring environmental conditions for GMP purposes; samples of starting materials, packaging materials, intermediate products, bulk products, and finished products are taken by personnel and by methods approved by quality control; test methods are validated; records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting, and testing procedures were actually carried out. Any deviations are fully recorded and investigated; the finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper containers and correctly labeled; records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures; no batch of product is released for sale or supply prior to certification by a qualified person that it is in accordance with the requirements of the marketing authorization; and sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

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In addition to describing the function of the quality assurance and control, this chapter also describes the elements of the annual review of medicinal products. They are as follows: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

A review of raw materials used in the product, especially those from new sources A review of critical in-process controls and finished product results A review of all batches that failed to meet established specification(s) A review of all critical deviations or nonconformances and related investigations A review of all changes carried out to the processes or analytical methods A review of marketing authorization variations submitted/granted/refused, including those for third country dossiers A review of the results of the stability monitoring program A review of all quality-related returns, complaints and recalls, including export only medicinal products A review of adequacy of previous corrective actions For new marketing authorizations, a review of postmarketing commitments A list of validated procedures and their revalidation dates A list of qualified equipment and their requalification dates

Chapter 2 Personnel This chapter describes the duties of key personnel, including the qualified person. Since the qualified person is unique to the EU regulatory system, we will look at the duties of the qualified person. The duties are described in Article 51 of Directive 2001/83/EC and are summarized below. 1. 2. 3.

For medicinal products manufactured within the European Community, a qualified person must ensure that each batch has been produced and tested/checked in accordance with the directives and the marketing authorization. For medicinal products manufactured outside the European Community, a qualified person must ensure that each imported batch has undergone, in the importing country, the testing specified in paragraph 1 (b) of Article 51. A qualified person must certify in a register or equivalent document, as operations are carried out and before any release, that each production batch satisfies the provisions of Article 51.

As can be seen, the qualified person is responsible for ensuring the quality of all drug products introduced into the EU market. The person must obtain training and pass a test to become a qualified person. This training and test is to ensure that the person understands the requirements of the job. In some of the member states there are other basic requirements, such as the person must be a pharmacist or have a minimum number of years of experience. If the qualified person releases a product that lacks the required quality, they can be fined or sent to jail for exposing the public to a potential risk of injury.

Chapter 3 Premises and Equipment The basic requirement is that premises and equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. There is a very specific indication that separate facilities are required for highly sensitizing materials or biological preparations. In addition, certain antibiotics, certain hormones, certain cytotoxics, and highly active drugs should not be produced in the same facilities. The quality control laboratory should be separated from production areas, especially microbiology laboratories. U.S. regulations only mention penicillin as requiring separate facilities. Basically the requirements for the EU and the United States are essentially the same. The main difference is that the EU regulations give more detail as to what is expected.

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Chapter 4 Documentation This chapter describes the types of documents that are required. Documents required are as follows: l

l l l l l

l

Specifications for starting and packaging materials, intermediate and bulk products, and finished products Manufacturing formula and processing instructions Packaging instructions Batch processing records Batch packaging records Procedures l Receipt of materials l Sampling l Testing l Release and rejection Other documents l Validation protocol and reports l Equipment assembly and calibration l Maintenance, cleaning, and sanitation l Personnel training, clothing, and hygiene l Environmental monitoring l Pest control l Complaints l Recalls l Returns

As can be seen there is no difference between the type of procedures that are required by both the EU and the FDA. Again the most striking difference is that the EU guide gives more details. Chapter 5 Production The basic requirements are as follows: l l l

l

l

l l

l

l l l

Production operations must follow clearly defined procedure Production operations must prevent cross-contamination Production rooms and equipment should be identified with the product or material being processed All drug production processes and equipment should be validated and revalidated after significant changes to the equipment or process Starting materials must come from approved vendors and should be sampled and tested for compliance with applicable specifications Printed packaging materials should be controlled and issued by authorized personnel There should be physical separation between packaging operations so that mix-ups are prevented. In addition there should be procedure to inspect packaging area prior to use to ensure that all previous product and labels have been cleared from the area After packaging, all containers should be inspected to ensure that packaging is complete and contains all required information, especially lot identification and expiration date Rejected materials must be stored in separate restricted areas Reprocessing of rejected products should be a rare occurrence Returned product should be destroyed, but could be used in subsequent batches after testing by the quality control department

You will note that the above requirements are not that different from the U.S. GMP requirements.

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Chapter 6 Quality Control This chapter discusses the elements of Good Quality Control Laboratory Practice. Some of these elements are as follows: l

l l

l

Documentation—specifications, test procedures, sampling procedures, validation records, and out-of-specification/out-of-trend investigation procedures. Sampling—methods, sampling equipment, storage conditions, etc. Testing—method validation, analytical results review process, training of analysts, reagent preparation and documentation, glassware cleaning and use, and reference standard handling. Special attention is given to on-going stability testing programs. The program should be applied to both bulk active pharmaceutical ingredients and finished dosage forms. Protocols should be developed that describe all testing that is to be performed on products. All on-going stability testing should extend to the end of the shelf life of the product. The results of the stability testing should be made available to key personnel and the qualified person(s).

Chapter 7 Contract Manufacture and Analysis This chapter outlines the responsibilities of the company that hold the marketing authorization when they contract out the manufacturing and/or analysis of the product. It states that there should be a contract between the parties so that there is a clear understanding of the responsibilities of all the parties involved. The contract must clearly state how the qualified person releasing each batch will exercise their legal responsibilities. The U.S. regulations are silent concerning this topic. While the FDA encourages quality agreements that state who is responsible for which aspects of the GMP regulations and drug application commitments, there is no regulation that requires the agreement. Chapter 8 Complaints and Product Recall All complaints and other information concerning potentially defective products must be reviewed carefully according to written procedures. During review, if a product defect is discovered or suspected in a batch, consideration should be given to check other batches. There should be a periodic review of complaints for trends. There should be established written procedure to organize any recall activities. Recall operations should be capable of being initiated promptly and at any time. If recall is initiated, all regulatory authorities in all countries where the product was distributed must be notified. All recalled material must be properly identified and stored separately in a secure area. The effectiveness of the recall should be assessed during the recall. Chapter 9 Self-Inspection This chapter covers the requirements that manufacturers should conduct self-audits of their operations. Audits can be conducted by independent personnel within the company or by outside experts. All audits must be documented and corrective actions developed for any adverse observations during the audit. While the FDA does not have an equivalent section in their GMP regulations, they do consider it a duty of the quality organization to perform selfaudits. In addition to the above general chapters, there are 20 annexes that give more detailed requirements for specific product types or dosage forms. The annexes are as follows: Annex 1 Annex 2 Annex 3

Manufacture of sterile medicinal products (revision November 2008). The revised annex should be implemented by March 1, 2009, except for the provisions on capping of vials, which should be implemented by March 1, 2010. Manufacture of biological medicinal products for human use Manufacture of radiopharmaceuticals

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Annex 4 Annex Annex Annex Annex Annex Annex Annex Annex Annex Annex Annex Annex Annex Annex

5 6 7 8 9 10 11 12 13 14 15 16 17 18

Annex 19 Annex 20

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Manufacture of veterinary medicinal products other than immunological veterinary medicinal products Manufacture of immunological veterinary medicinal products Manufacture of medicinal gases Manufacture of herbal medicinal products Sampling of starting and packaging materials Manufacture of liquids, creams, and ointments Manufacture of pressurized metered dose aerosol preparations for inhalation Computerized systems Use of ionizing radiation in the manufacture of medicinal products Manufacture of investigational medicinal products Manufacture of products derived from human blood or human plasma Qualification and validation (July 2001) Certification by a qualified person and batch release (July 2001) Parametric release (July 2001) Good manufacturing practice for active pharmaceutical ingredients requirements for active substances used as starting materials from October 2005 covered under part II Reference and retention samples (December 2005) Quality risk management (February 2008)

Annex 1—Manufacturer of Sterile Medicinal Products Of the annexes, the one that has received the most attention is Annex 1 concerning the manufacture of sterile medicinal products. This annex gives very specific guidance as to what is required to produce sterile drug products. While the FDA guidelines, in general, do not give specific values, the FDA does require manufacturers to have documentation to justify that what they are doing is appropriate. In Annex 1, the EU gives very specific requirements and limits. The current version became official on March 1, 2009, except for the provision on capping of freeze-dried vials, which becomes official on March 1, 2010. Probably the most confusing requirement in the annex is the testing of nonviable airborne particulates in the “at-rest” and “in-operation” states. Limits are given for both states. These non-viable particulate limits are now closer to the limits in ISO14644 than in the previous version of annex 1. Except for grade A there is a different limit for the two states. Normally the at-rest state is only tested during commissioning of a new clean room or after significant changes are made to an existing clean room. But it appears that the EU investigators are requesting that at-rest testing be performed periodically on a routine basis. Currently, the FDA only considers the in-operation state for all of its recommendations. They are concerned with the condition of the environment when product is being exposed to it. The following table gives the particulate limits for the four clean room grades. Maximum permitted number of particles per m3 equal to or greater than the tabulated size At rest Grade A B C D

0.5 mm 3,520 3,520 352,000 3,520,000

In operation 5.0 mm 20 29 2,900 29,000

0.5 mm 3,520 352,000 3,520,000 Not defined

5.0 mm 20 2,900 29,000 Not defined

As can be seen, the other major difference between the EU and the FDA is the requirement to measure the particles at 5.0 mm. This has been a very controversial difference. The industry has argued that the 5 mm particles do not have to be measured. If you are going to market a product in the EU, you will have to monitor for both 0.5 and 5.0 mm particles.

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In addition, there is a requirement that after operations have been completed, the at-rest limits should be attained after a 15 to 20 minutes “clean-up” period. During the at-rest stage no activities or personnel are present. The annex also gives limits for microbiological monitoring of clean room, as shown in the following table. Recommended limits for microbial contamination

Grade A B C D

Air sample cfu/m3

Settle plates (diameter 90 mm) cfu/4 hr

Contact plates (diameter 55 mm) cfu/plate

107 cfu of Brevundimonas diminuta (ATCC 19146) per cm2 under worst-case process conditions expected during filtration of the drug product, and the ability to retain challenge microorganism (and hence ability to achieve a sterile product) is examined (4,7). Unfortunately, the bulk volumes required for these studies are substantial (several liters), even after usual scale-down to 47-mm diameter disks, which renders the study an expensive investigation, especially for highly concentrated formulations. Although complete filter validation package is only available at the time of process validation, it is recommended that at least a risk assessment or an abbreviated bacterial retention should be performed during clinical development for novel formulations, because filtration is the only sterilization step for the heat-unstable protein preparations. Coarser, foreign particles and large aggregates are removed during sterile filtration using a 0.2-mm filter. Consideration must be given to the desired removal of contaminants like bioburden and the undesirable removal of active substance or excipients by adsorption to the large surface of the filter membranes. The typical area of a 0.22-mm filter is >100 m2/g (8). Furthermore, the sterile filter must be compatible with the bulk protein solution under filtration conditions. For most protein formulations, this is uncritical given the aqueous nature, low-processing temperature between 0 and 308C, and a pH range between 5 and 8. However, during the process development stage, studies must be conducted to confirm the compatibility. Studies by Pitt (9) show that different filter materials bind protein weakly or very strongly depending on the polymer material. Pitt found that mixed cellulose ester and nylon have stronger affinity to proteins than poly(vinylidene fluoride), or PVDF, and polysulfone.

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Figure 4 Adsorption of surfactant (Tenside) from a monoclonal antibody containing formulated bulk (0.01% of polysorbate 80, pH 5.5) during filtration through three filter membranes, filter area 150 to 200 cm2.

Excipients can also bind to filters with varying avidity. Surfactants, for example, are preferentially distributed at surfaces because of their interfacial properties, their amounts can be reduced significantly if the formulation has low concentration of surfactant and the process involves multiple filtrations. In an unpublished study with antibody-containing bulk (0.01% polysorbate 80 and 5 mg/mL of an antibody), three sterile filters, composed of PVDF, polyether sulfone (PES), and cellulose acetate (CA), were examined (Fig. 4). The following order of loss of polysorbate 80 was observed: PVDF < CA