FILTRATION HANDBOOK: LIQUIDS THEODORE H. MELZER MAIK W. JORNITZ PDA Bethesda, MD, USA DHI Publishing, LLC River Grove, IL, USA
10 9 8 7 6 5 4 3 2 1 ISBN: 1-930114-62-1 Copyright 2004 Theodore H. Melzer and Maik W. Jornitz All rights reserved. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system or transmitted in any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Typeset in the United Kingdom by Dolffin. Printed in the United States of America. Where a product trademark, registration mark, or other protected mark is made in the text, ownership of the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to any such marks in the book. While every effort has been made by the publisher and the author to ensure the accuracy of the information contained in this book, the organization accepts no responsibility for errors or omissions. The views expressed in this book are those of the editors and authors and may not represent those of either Davis Healthcare International or the PDA, its officers, or directors. PDA 3 Bethesda Metro Center Suite 1500 Bethesda, MD 20814 United States 301-986-0293 Davis Healthcare International Publishing, LLC 2636 West Street River Grove IL 60171 United States www.dhibooks..com
With love and respect we dedicate this work to those who inspire and support us. To Alta Dorette Jornitz, my wife and treasure Maik W. Jornitz To Xavier Magdalene Meltzer, with enduring love, wife and companion Theodore H. Melzer
CONTENTS Preface List of Abbreviations xi xiii Chapter 1: Regulations 1 Chapter 2: Purposes of Filtration 7 Chapter 3: Definitions and Terminology 13 Flow Rate 13 Throughput 13 Dirt-Holding Capacity 14 Porosity 14 Pore Size Ratings 15 Hydrophilic/Hydrophobic 15 Differential Pressure/Pressure Drop 16 Effective Filtration Area 17 Chapter 4: Filter Formation 19 Membrane Casting Machine 19 v
vi Contents Chapter 5: Depth Filters 23 Chapter 6: Membrane Filters 31 Chapter 7: Repetitive Filtration 37 Chapter 8: Filter Construction 41 Chapter 9: Materials of Construction 45 Filter Housings 47 Chapter 10: Steam Sterilization 49 Chapter 11: Mechanisms of Particle Removal 57 Direct Impaction 58 Adsorptive Sequestration 61 Factors Affecting the Retention of Particulates 65 Chapter 12: Extractables and Adsorptions 71 Chapter 13: Protein Adsorption 79 Chapter 14: Scale-Up 83 Chapter 15: Filter System Design 87 Flow and Differential Pressure 87 Series Arrangements 88 Parallel Arrangements 91 Chapter 16: Flow, Pressure, Filter Area 93 Chapter 17: ISO Requirements 97 Operational Procedure 97
Contents vii Chapter 18: Filter Handling 99 Handling of Filters 99 Chapter 19: Filtration Practice 103 Chapter 20: Validation 107 Bacterial Challenge Test 109 Chapter 21: Test Methods 113 Extractable Test 113 Chemical Compatibility Test 114 Other Tests 116 Particulate Matter 116 Ingredient Adsorption 117 Chapter 22: Troubleshooting 119 Steam Sterilization 119 Chemical Compatibility 124 Handling 126 Protection 131 References 133
ACKNOWLEDGEMENTS We wish to acknowledge our colleagues and friends within the biopharmaceutical industry, along with the filter manufacturers and regulatory agencies for their consideration and collegiality in sharing their experiences and findings over the years. Their technical wisdom included in this book will now become more widely available to the common good. We would like particularly to thank those individuals who supported our venture with appreciated encouragement and valued assistance. We especially thank Oscar W. Reif, Russel E. Madsen, Jr., A. Mark Trotter, Stephen Tingley, Jerold M. Martin and Dr. Richard V. Levy for their support and shared experiences. We recall our indebtedness to our predecessors, Prof. Dr. Karbachsch, Dr. David Pall, Dr. Karl H. Wallhaeusser, Dr. Timothy J. Leahy, Dr. Adrian Reti, and Peter R. Johnston for their pioneering work. Our most profound gratitude goes to Amy Davis, for her neverending assistance with editorial help, practical advice, and a sustaining spirit. ix
PREFACE The complexity of pharmaceutical filtrations, along with the large variety of filter types that are available and the many different purposes for which they may be employed, make necessary the careful training of those who would engage in filtration operations. Appropriate explanations of filter properties, of causes and effects in their management, and instructions in their manipulation gained from experience would be an ideal first step in such training. The regulatory authorities endorse training as being necessary for individuals working in filtration. Indeed there is an obligation, so stated by the Food and Drug Administration (FDA), to train those who are assigned such work. Presentations of lectures by those relatively expert in filtration techniques and knowledgeable in the underlying science are a common and useful way of training. Those being trained are equipped with lecture notes, hard copies of the slide presentations that illustrate the specific instructions or informational points being discussed. Of necessity, the slides messages are usually compressed in headline fashion, in order not to detract unduly from the lecturer s simultaneously spoken amplification. Note-taking by the course attendees is relied upon to supplement the usually brief illustrations. In concentrating upon unfamiliar concepts and novel teachings, the simultaneous taking of notes is seldom accomplished adequately. Rereading the illustrations and sparse notes after an interval of time will not serve as a meaningful review. The lecture training technique has the advantage of directing and focusing the lecturer s attention by questions from the audience. However, the constraints of time compel a quick assimilation of information by the attendees. The training, however purposeful and efficient, does not extend beyond the lecture period. A printed presentation of illustrations and textual elaborations, on the other hand, can repeatedly be re-examined for guidance, and as often as required. The purpose of this publication is to present an illustrated lecture series directed to the filtration of liquids. Following each slide will be the lecturer s amplification in printed form. Unlike an oral presentation, the headline-style limitations of the slides xi
xii Preface are compensated by the unlimited time available for the reader s comprehension of the ever-available text. No new material is presented, that the reader will miss while reflecting on what was last said. The advantage of asking questions is absent. However, the text is layered in its information. Simple core answers deliver the basic information considered essential to the training. However, where considered useful, the text is expanded to impart details to those whose background is sufficient to utilize them. The training, therefore, is tailored to the collective audience, whatever the level of technical sophistication. A list of further reading references are included at the end of the book. It is based primarily upon technical papers from peer-review journals. It reflects the scientific principles relevant to liquid filtrations as validated by experimental experiences. This effort emphasizes the resolve of the authors to present a handbook dedicated to the training of those engaged in the important field of pharmaceutical liquid filtrations. The authors would like to mention that they are currently working on further training handbooks, following a similar content and layout to this publication, but with different topics within filtration.