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PDA Technical Report No. 41: Virus filtration

Article  in  PDA journal of pharmaceutical science and technology / PDA · March 2005

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 Technical Report No. 41
Revised 2008
Virus Filtration

PDA Journal of
Pharmaceutical
Science and
Technology 2008

Supplement

Volume 62

No. S-4

www.pda.org/bookstore
Virus Filtration Task Force

Technical Report Authors

Kurt Brorson, U.S. Food and Drug Administration Mohammed Haque, Pall Corporation
Jennifer Campbell, Millipore Corporation Michael Morgan, Asahi Kasei, Planova Division
Jeffrey Carter, GE Healthcare
Terry Sato, Asahi Kasei, Planova Division
Sherri Dolan, Sartorius Stedim Biotech S.A.
Gail Sofer, SofeWare Associates
Mani Krishnan, Millipore Corporation
Scott Lute, U.S. Food and Drug Administration Srikanth Sundaram, Generamedix Inc.

Jerold Martin, Pall Corporation Klaus Tarrach, Sartorius Stedim Biotech S.A.

Technical Report Contributors

Amin Abujoub, Biogen Idec Inc. Leonard Pease, National Institute of Standards and
Hazel Aranha, GAEA Resources Inc. Technology, U.S. Dept. of Commerce

Damon Asher, Millipore Corporation Mahesh Prashad, Sartorius Stedim Biotech S.A.

Mark Bailey, Eli Lilly and Company Ted Meltzer, Capitola Consultants

Thierry Burnouf, Human Plasma Product Service Kathryn Remington, Cardinal Health
Cynthia Romero-Arroyo, Ortho Biologics Inc.
Qi Chen, Genentech, Inc.
Mike Rubino, Eli Lilly and Company
Mark Etzel, University of Wisconsin
Sakae Satoh, Asahi Kasei, Planova Division (retired)
Chris Dowd, Genentech, Inc.
Michael Shanks, Wellstat Biologics Corp
Charles Felice, Johnson & Johnson
Ailsa Shepherd, BioReliance Corporation
David Jen, Centocor, Inc.
Thomas Smith, GlaxoSmithKline
Paul Genest, Millipore Corporation
Michael Tarlov, National Institute of Standards and
Uwe E. Jocham, CSL Behring AG
Technology, U.S. Dept. of Commerce
Maik Jornitz, Sartorius Stedim Biotech S.A.
William Riordan, University of Wisconsin-Madison
Stanley Kidd, Pall Corporation Frank Van Engelenburg, Sanquin Blood Supply Found.
Marina Korneyeva, Talecris Biotherapeutics, Inc. Hannelore Willkommen, Regulatory Affairs &
Rich Levy, PDA Biological Safety Consulting
Carol Marcus-Sekura, BASI Peter Wojciechowski, Johnson and Johnson
Ichiro Moroe, Asahi Kasei, Planova Division Kaoru Yoshinari, Sepa-Sigma, Inc.

The content and views expressed in this technical report are thze result of a consensus achieved by the authoring
task force and are not necessarily views of the organizations they represent or the U.S. government.

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 Virus Filtration
Technical Report No. 41 (Revised 2008)
Supplement to the
PDA Journal of Pharmaceutical
Science and Technology
Vol 62, No. S-4
2008

© 2008 PDA

www.pda.org/bookstore
 Table of Contents

1.0 Introduction.....................................................2 6.0 VIRUS FILTER VALIDATION/

EVALUATION STUDIES........................................19
1.1 Purpose/Scope.................................................2
6.1 Filter Properties..............................................19
2.0 Glossary OF TERMS..........................................3 6.2 Test Virus.......................................................20
6.2.1 Virus Selection.........................................20
3.0 VIRUS-RETENTIVE FILTERS..................................7 6.2.2 Virus Stock Preparation and
3.1 Size Exclusion...................................................8 Maintenance............................................20
6.2.3 Virus Spike..............................................21
3.2 Other Retention Mechanisms...........................8
6.3 Scaled-Down Models.....................................23
3.3 Virus Retention Probability of
6.4 Operating Conditions for Validation,
Reduction Factor..............................................9 Revalidation and Number of Runs..................23
3.4 Virus Size/Retention Rating..............................9 6.5 Raw Materials and Equipment........................24
3.5 Protein Size/Sieving/Passage Rating...............10 6.5.1 Virus Filtration Devices and
Configurations.........................................24
4.0 VIRUS FILTER SELECTION AND 6.5.2 Integrity Testing During Development.......24
CHARACTERIZATION...........................................11 6.5.3 Membrane Lot Selection..........................25
4.1 Filter Construction..........................................11 6.5.4 Feedstream.............................................25
6.5.5 Filtration Conditions.................................25
4.2 Filter System Configurations..........................11
6.6 Virus Assays and Assay Validation................25
4.3 Particulates and Extractables.........................13
6.6.1 Assay Method Validation.........................26
4.4 Filter Compatibility.........................................14
6.7 Establishing Representative
4.5 Protein Recovery (Adsorption/ Worst-Case Process Conditions.....................27
Retention/Biocompatibility)............................15
7.0 INTEGRITY TESTING...........................................29
4.6 Thermal Stress Resistance.............................16
7.1 Manufacturer’s Checklist...............................30
4.7 Hydraulic Stress Resistance...........................16
7.2 Virus Retention Integrity Tests........................32
4.8 Toxicity Testing...............................................16 7.2.1 Dextran Retention....................................32
4.9 Viral/Phage Challenge Testing.........................17 7.2.2 Gold Particle Retention............................32
4.10 Cleaning/Sanitization/Sterilization...................17 7.2.3 Gas-Liquid Porosimetry............................33
7.2.4 Manual Bubble Point or Leak Testing.......33
5.0 PHYSICAL AND MECHANICAL 7.2.5 Manual Forward/Diffusive Flow...............33
CHARACTERIZATION...........................................18 7.2.6 Manual Pressure Hold/Decay...................35
5.1 Filtration Rate and Clogging (Throughput).........18 7.2.7 Automated Integrity Test Instruments for
5.2 Fluid/Piping.....................................................18 Gas Porosimetry-Based Test Methods.........36
7.2.8 Liquid and Liquid-Liquid Porosimetry.......36
5.3 Fluid/Filter......................................................18
7.3 Relationship between Integrity Tests and
5.4 Physical and Structural Limitations................18 Virus/Phage Retention....................................37
5.5 Miscellaneous................................................18 7.4 Failure Analysis/Troubleshooting....................37

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 Table of Contents

8.0 STERILIZATION....................................................38
8.1 Steam Sterilization.........................................38
8.2 Autoclave Sterilization....................................38
8.3 Sterilize-in-Place.............................................39
8.4 Irradiation Sterilization....................................39
8.5 Gas Sterilization..............................................39

9.0 APPENDICES.......................................................41
APPENDIX I: Virus Retention and Protein Passage
Nomenclature Classification..........41
APPENDIX II.a: Large Virus-Retentive Filter
Test Protocol.................................41
APPENDIX II.b: PR772 Preparation Procedures.....45
APPENDIX II.c: Procedure for Enumeration of
PR772 Bacteriophage...................48
APPENDIX III.a: Small Virus-Retentive Filter
Test Protocol.................................49
APPENDIX III.b: PP7 Preparation Procedures.........53
APPENDIX III.c: Procedure for the Enumeration of
PP7 Bacteriophage.......................56
APPENDIX IV: Filter Validation
Recommendations........................57

10.0 REFERENCES....................................................58

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 1.0  Introduction

1.1 Purpose/Scope
Biotechnological and biological therapeutic products are often manufactured using materials of
animal or human origin, including cultured primary or transformed cells, milk or other components
from transgenic animals, natural extracts and human or animal blood plasma. These products are
usually proteins that are manufactured by complex manufacturing processes. Although approved
recombinant biotherapeutics have an excellent safety record, the risk of contamination by known
or unknown pathogens exists, (1–6) and regulatory agencies worldwide require a demonstration of
viral safety prior to clinical use and/or marketing of biopharmaceuticals. (3, 7–10)

The risk of transmission of certain infectious pathogens cannot be completely mitigated by donor
screening, vaccination of patients, a single virus inactivation step, or virus testing of cell banks and
raw materials. It is desirable to introduce additional robust viral clearance steps in the biotherapeutic
purification processes to help reduce or eliminate viruses without compromising the molecular
integrity of the products. Virus-removal filters (often incorrectly termed “nanofilters”) are specifically
designed to remove viruses and other biomolecules from the product (protein) solution through a
size-exclusion mechanism.

Virus filtration is performed as part of a manufacturer’s overarching virus safety strategy. In this
context, virus filtration (size-based removal) is a complement to virus inactivation, both of which
contribute to virus clearance. (11–21) Implementation of virus clearance complements additional
measures, such as control over raw materials and testing of cell culture or plasma feedstock.
Collectively, these measures form the framework of a virus safety strategy.

This PDA Technical Report addresses virus-removal filters that retain viruses by a size-exclusion
mechanism. It explains how they work, recommends how to elect the best filter for various applica-
tions, and describes physical and biological/safety characterization of filters test methods, and valida-
tion of virus removal. This document should be considered as a guide; it is not intended to establish
any mandatory or implied standards.

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2 PDA Journal of Pharmaceutical Science and Technology Vol. 62 • No. S-4 • 2008
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