FILTRATION HANDBOOK:

LIQUIDS

THEODORE H. MELZER
MAIK W. JORNITZ

PDA
Bethesda, MD, USA
DHI Publishing, LLC
River Grove, IL, USA

www.pda.org/bookstore
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 Davis Healthcare International Publishing, LLC

3 Bethesda Metro Center 2636 West Street
Suite 1500 River Grove
Bethesda, MD 20814 IL 60171
United States United States
301-986-0293 www.DHIBooks..com

www.pda.org/bookstore
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

www.pda.org/bookstore
www.pda.org/bookstore
 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

v
www.pda.org/bookstore
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

www.pda.org/bookstore
 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

www.pda.org/bookstore
www.pda.org/bookstore
 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 never-
ending assistance with editorial help, practical advice, and a sustaining spirit.

ix
www.pda.org/bookstore
www.pda.org/bookstore
 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. Re-
reading 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
www.pda.org/bookstore
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.

www.pda.org/bookstore