How to Validate a Pharmaceutical Process How to Validate a Pharmaceutical Process Steven A Ostrove, PhD President, Ostrove Associates, Inc., Elizabeth, NJ, United States AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright r 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods or professional practices, may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information or methods described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804148-2 Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library For Information on all Academic Press publications visit our website at http://www.elsevier.com/ Publisher: Mica Haley Acquisition Editor: Kristine Jones Editorial Project Manager: Tracy I Tufaga Production Project Manager: Anusha Sambamoorthy Designer: Mark Rogers Typeset by MPS Limited, Chennai, India DEDICATION This book is dedicated to my wife, Karen Without her love and support over my years in the industry, and on the road, this book would never have been possible AUTHOR BIOGRAPHY Steven A Ostrove, PhD Steven Ostrove, President of Ostrove Associates, Inc (OAI) provides validation and compliance consulting services to the Bio/Pharm industry In 1999, Dr Ostrove opened OAI in order to provide more personalized services to industry He brings over 35 years of industry experience to OAI OAI services include: start-up commissioning and validation; remediation for FDA warning letters and consent decrees OAI specializes in process validation, cleaning validation, and computer system qualifications Dr Ostrove has a PhD from Rutgers University in Biochemistry, a Masters in Biology from Adelphi University, and a Bachelors in Biology/Chemistry from SUNY Albany He started his career as a research biochemist at Merck; and, after three years of postdoctoral work (Mt Sinai School of Medicine and Columbia University— Harkness Eye Institute) in biochemistry, he moved to a technical service position at Pharmacia Biotech where he became the Manager of Computer Systems With this experience, he then joined a major engineering design company and started the corporate validationÀ regulatory department Moves to other major Architectural and Engineering firms resulted in his leading and reorganizing the ValidationÀRegulatory Affairs department for two additional firms Dr Ostrove has over 25 publications, including six book chapters, on a wide variety of topics, ranging from Affinity Chromatography to Process Validation Scale-Up He has been a course leader and organizer of training programs for ISPE and an invited lecturer by Pharma, PDA, and others He has served on the exam preparation committee for ISPE’s CPIP certification program and is currently a course director for three courses for the Center for Progressive xii Author Biography Innovative Education (CGMPs, QC Lab GMPs, and Process Validation) He has also served as an Adjunct Professor of Pharmaceutical Engineering at New Jersey Institute of Technology (Validation and Regulatory Affairs) and as an Adjunct Professor of Biology at Kean University (Biology) He recently completed service on an FDA advisory panel as the industry representative and received a service award for his tenure and contribution to the committee PREFACE There have been many books written about utility and equipment qualification as well as process validation All of these books and articles describe the technical inner workings of the various pieces of process equipment or systems These are helpful, but they not tell you how to move forward from there In performing a complete process validation program it is important to not only know what to or what not to but also to know why you are doing it Thus, the goal of this book is to lead you through the workings of a successful process validation program It includes those aspects of the surrounding operations that are necessary to complete the validation and attain full compliance to the Food and Drug Administration (FDA) Current Good Manufacturing Practices (CGMP) as found in the Code of Federal Regulations (CFR) Title 21 Parts 210 and 211 This book is about preparing for and performing an acceptable process validation (PV) program for either new or legacy products Notice, I again mention that it is a “program.” This is because process validation is more than just verifying that the process is reproducible and reliable There are many components, steps, and systems that are involved For example, the process equipment must be qualified, the automation system(s) must be validated and meet Part 11 requirements, and laboratory methods need to be validated, etc Another aspect that is critical to all compliance studies is maintaining data integrity As you can see, performing a compliant PV takes a lot of work and time It is important to show why things are done so that the operations are maintained within their control settings as well as their actual functioning By understanding the reasons for each step, understanding why things need to be recorded and how they need to be recorded, understanding the variables of the process and how they can be controlled (if at all), and the reasons why they are variable will allow you to comply with current FDA expectations and your own satisfaction that xiv Preface your product is safe and reproducible (ie, in control at all stages and if something was to go wrong you will be able to quickly mend the problem and get back into full compliance) This is not only good business but it is good manufacturing practice (GMP) Steven A Ostrove Ostrove Associates, Inc ACKNOWLEDGMENT I would like to thank Dr Ken Blashka for his thoughtful discussions and his very helpful review of this manuscript His comments and suggestions were extremely helpful in preparing the book ABOUT THE EXPERTISE IN THE PHARMACEUTICAL PROCESS TECHNOLOGY SERIES Numerous books and articles have been published on the subject of pharmaceutical process technology While most of them cover the subject matter in depth and include detailed descriptions of the processes and associated theories and practices of operations, there seems to be a significant lack of practical guides and “how to” publications The Expertise in the Pharmaceutical Process Technology series is designed to fill this void It comprises volumes on specific subjects with case studies and practical advice on how to overcome challenges that the practitioners in various fields of pharmaceutical technology are facing FORMAT • The series volumes will be published under the Elsevier Academic Press imprint in both paperback and electronic versions Electronic versions will be full color, while print books will be published in black and white SUBJECT MATTER • The series will be a collection of hands-on practical guides for practitioners with numerous case studies and step-by-step instructions for proper procedures and problem solving Each topic will start with a brief overview of the subject matter and include an exposé, as well as practical solutions of the most common problems along with a lot of common sense (proven scientific rather than empirical practices) • The series will try to avoid theoretical aspects of the subject matter and limit scientific/mathematical exposé (eg, modeling, finite elements computations, academic studies, review of publications, theoretical aspects of process physics or chemistry) unless absolutely vital for understanding or justification of practical approach as advocated by the volume author At best, it will combine both the practical (“how to”) and scientific (“why”) approach, based on ... Lab GMPs, and Process Validation) He has also served as an Adjunct Professor of Pharmaceutical Engineering at New Jersey Institute of Technology (Validation and Regulatory Affairs) and as an Adjunct... Installation qualification Performance qualification Commissioning Operational qualification Figure 1.1 Original approach VALIDATION 6 How to Validate a Pharmaceutical Process Commissioning Process. .. Elsevier Inc All rights reserved 16 How to Validate a Pharmaceutical Process a process validation is started (eg, The process Validation Guideline,2 Q7,3 Guide to Cleaning Validations,4 and many more—refer