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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