FILTRATION HANDBOOK: LIQUIDS
THEODORE H. MELZER MAIK W. JORNITZ
PDABethesda, MD, USA
DHI Publishing, LLCRiver Grove, IL, USA
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ISBN: 1-930114-62-1Copyright © 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 aretrieval 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 UnitedStates of America.
Where a product trademark, registration mark, or other protected mark is made in the text, ownership ofthe mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to anysuch marks in the book.
While every effort has been made by the publisher and the author to ensure the accuracy of theinformation contained in this book, the organization accepts no responsibility for errors or omissions. The viewsexpressed in this book are those of the editors and authors and may not represent those of either Davis HealthcareInternational or the PDA, its officers, or directors.
PDA3 Bethesda Metro CenterSuite 1500Bethesda, MD 20814United States301-986-0293
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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
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CONTENTS
Preface xi
List of Abbreviations 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
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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
Contentsvi
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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
Contents vii
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ix
ACKNOWLEDGEMENTS
We wish to acknowledge our colleagues and friends within the biopharmaceuticalindustry, along with the filter manufacturers and regulatory agencies for theirconsideration and collegiality in sharing their experiences and findings over the years.Their technical wisdom included in this book will now become more widely availableto the common good.
We would like particularly to thank those individuals who supported our venturewith appreciated encouragement and valued assistance. We especially thank Oscar W.Reif, Russel E. Madsen, Jr., A. Mark Trotter, Stephen Tingley, Jerold M. Martin andDr. Richard V. Levy for their support and shared experiences. We recall ourindebtedness 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 theirpioneering work. Our most profound gratitude goes to Amy Davis, for her never-ending assistance with editorial help, practical advice, and a sustaining spirit.
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PREFACE
The complexity of pharmaceutical filtrations, along with the large variety of filtertypes that are available and the many different purposes for which they may beemployed, make necessary the careful training of those who would engage in filtrationoperations. Appropriate explanations of filter properties, of causes and effects in theirmanagement, and instructions in their manipulation – gained from experience – wouldbe an ideal first step in such training. The regulatory authorities endorse training asbeing necessary for individuals working in filtration. Indeed there is an obligation, sostated by the Food and Drug Administration (FDA), to train those who are assignedsuch work.
Presentations of lectures by those relatively expert in filtration techniques andknowledgeable in the underlying science are a common and useful way of training.Those being trained are equipped with lecture notes, hard copies of the slidepresentations that illustrate the specific instructions or informational points beingdiscussed. Of necessity, the slides’ messages are usually compressed in headlinefashion, in order not to detract unduly from the lecturer’s simultaneously spokenamplification. Note-taking by the course attendees is relied upon to supplement theusually brief illustrations. In concentrating upon unfamiliar concepts and novelteachings, the simultaneous taking of notes is seldom accomplished adequately. Re-reading the illustrations and sparse notes after an interval of time will not serve as ameaningful review.
The lecture training technique has the advantage of directing and focusing thelecturer’s attention by questions from the audience. However, the constraints of timecompel a quick assimilation of information by the attendees. The training, howeverpurposeful and efficient, does not extend beyond the lecture period. A printedpresentation of illustrations and textual elaborations, on the other hand, can repeatedlybe re-examined for guidance, and as often as required.
The purpose of this publication is to present an illustrated lecture series directedto the filtration of liquids. Following each slide will be the ‘lecturer’s’ amplification inprinted form. Unlike an oral presentation, the headline-style limitations of the slides
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are compensated by the unlimited time available for the reader’s comprehension of theever-available text. No new material is presented, that the reader will miss whilereflecting 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 basicinformation considered essential to the training. However, where considered useful,the text is expanded to impart details to those whose background is sufficient to utilizethem. The training, therefore, is tailored to the collective audience, whatever the levelof technical sophistication.
A list of further reading references are included at the end of the book. It is basedprimarily upon technical papers from peer-review journals. It reflects the scientificprinciples relevant to liquid filtrations as validated by experimental experiences.
This effort emphasizes the resolve of the authors to present a handbook dedicatedto the training of those engaged in the important field of pharmaceutical liquidfiltrations.
The authors would like to mention that they are currently working on furthertraining handbooks, following a similar content and layout to this publication, but withdifferent topics within filtration.
Prefacexii
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