PDA TR40 Sterilizing Filtration of Gases

January/February 2005 Supplement Volume 58 No. S-1 Technical Report No. 40 Sterilizing Filtration of Gases PDA Journal of Pharmaceutical Science and Technology PDA TECHNICAL REPORT NO. 40 STERILIZING FILTRATION OF GASES December 4, 2004 PDA Sterile Gas Filtration Committee Frank Bing, Abbott Laboratories (Chair) Srikanth Sundaram, Ph.D., Schering-Plough Corporation (Co-Chair) Barry Bardo, Meissner Filtration Products, Inc. Thomas Britton, Millipore Corporation Robert Conway, Ph.D., Cuno Inc. Teresa M. Feeser, Ph.D., Eli Lilly & Co. Holly Haughney, Ph.D., Pall Corporation Ann Marie Jones, Fluor Corporation Maik W. Jornitz, Sartorius Corporation Stephen Langille, Ph.D., FDA Richard V. Levy, Ph.D., PAREXEL Consulting Russell E. Madsen, The Williamsburg Group, LLC Jerold Martin, Pall Corporation Leesa McBurnie, Meissner Filtration Products, Inc. Theodore H. Meltzer, Ph.D., Capitola Consulting Co. Didier Meyer, la Calhene, France Gregory M. Morris, Ph.D., Pfizer Inc David Ridealgh, Domnick Hunter Ltd. Hans G. Schroeder, Ph.D., International Consultants Assoc. Paul S. Stinavage, Ph.D., Pfizer Inc A. Mark Trotter, Sartorius Corporation Sterilizing Filtration of Gases Technical Report No. 40 Supplement Vol. 58, No. S-1 January/February 2005 © 2005 by PDA 1. INTRODUCTION/SCOPE STATEMENT ...................................................................................................................... 7 2. HISTORICAL BACKGROUND ....................................................................................................................................... 7 3. HOW GAS FILTERS WORK ........................................................................................................................................... 7 3.2 Retention of Smaller Particles .............................................................................................................................................. 7 3.2.2 Inertial Impaction ................................................................................................................................................................. 8 3.2.3 Gravitational Sedimentation ................................................................................................................................................. 9 3.2.4 Electrostatic Attraction ......................................................................................................................................................... 9 3.3 Net Retention Efficiency in Filtration of Dry Gases ............................................................................................................. 9 3.4 Factors that Affect the Retention Efficiency ....................................................................................................................... 10 4. FILTER SELECTION AND SYSTEM DESIGN CRITERIA ...................................................................................... 10 4.1 Retention Capability ........................................................................................................................................................... 10 4.2 Integrity Testing .................................................................................................................................................................. 11 4.3 Filtration Rate and Throughput .......................................................................................................................................... 11 4.4 Materials of Construction ................................................................................................................................................... 11 4.4.1 Hydrophobicity ................................................................................................................................................................... 11 4.4.2 Durability ........................................................................................................................................................................... 12 4.4.3 Toxicity ............................................................................................................................................................................... 12 4.4.4 Particle Shedding ................................................................................................................................................................ 12 4.4.5 Gas/Filter Compatibility ..................................................................................................................................................... 12 4.5 Water Blockage .................................................................................................................................................................. 13 4.6 Design Considerations for Condensation Control .............................................................................................................. 13 5. EXAMPLES OF SPECIFIC APPLICATIONS ............................................................................................................. 14 5.1 Product Contact Gases ........................................................................................................................................................ 14 5.2 Fermentor Inlet Air ............................................................................................................................................................. 14 5.3 Fermentor Off-Gas ............................................................................................................................................................. 14 5.4 Vent Filters on Compendial Water and Product Holding Tanks ......................................................................................... 15 5.5 Lyophilizer and Autoclave Vacuum Break ......................................................................................................................... 15 5.6 Gas Used for Drying and Transfer/Fill Line ....................................................................................................................... 15 5.7 Blow-Fill-Seal Equipment .................................................................................................................................................. 15 5.8 Environmental Air in Isolators ........................................................................................................................................... 16 6. STERILIZATION OF HYDROPHOBIC MEMBRANE FILTERS ............................................................................ 16 6.1 Sterilization in Steam Autoclave ......................................................................................................................................... 16 6.2 Steaming-in-Place (SIP) ..................................................................................................................................................... 16 6.3 Other Sterilization Methods ............................................................................................................................................... 17 7. VALIDATION OF FILTER RETENTION CAPABILITIES ....................................................................................... 17 7.1 Liquid Bacterial Retention Test .......................................................................................................................................... 17 7.1.1 Challenge Organism ........................................................................................................................................................... 18 7.1.2 Challenge Concentration and Effective Challenge Level ................................................................................................... 18 7.1.3 Pre-Challenge Integrity Test ............................................................................................................................................... 18 7.1.4 Challenge Test Method ....................................................................................................................................................... 18 7.1.5 Post-Challenge Integrity Test ............................................................................................................................................. 19 Table of Contents 7.1.6 Effluent Analysis ................................................................................................................................................................ 19 7.1.7 Interpretation of Results ..................................................................................................................................................... 19 7.2 Aerosol Bacterial Retention Test ........................................................................................................................................ 19 7.2.1 Aerosol Bacterial Challenge Organism .............................................................................................................................. 19 7.2.2 Preparation of the Challenge Suspension ........................................................................................................................... 19 7.2.3 Aerosol Bacterial Challenge Conditions ............................................................................................................................ 20 7.2.3.1 Challenge Size .................................................................................................................................................................... 20 7.2.3.2 Challenge Conditions ......................................................................................................................................................... 20 7.2.3.3 Challenge Concentration and Level .................................................................................................................................... 20 7.2.4 Challenge Test Methods ..................................................................................................................................................... 20 7.2.5 Interpretation of Results ..................................................................................................................................................... 22 7.3 Viral (Bacteriophage) Aerosol Challenge Tests .................................................................................................................. 22 7.3.1 Viral Challenge Organism .................................................................................................................................................. 22 7.3.2 Viral Aerosol Challenge Conditions ................................................................................................................................... 22 7.3.2.1 Challenge Size .................................................................................................................................................................... 22 7.3.2.2 Aggregation ........................................................................................................................................................................ 22 7.3.2.3 Challenge Conditions ......................................................................................................................................................... 23 7.3.2.4 Challenge Level/Infectivity ................................................................................................................................................ 23 7.3.3 Challenge Test Methods ..................................................................................................................................................... 23 7.3.4 Interpretation of Results ..................................................................................................................................................... 23 8. PHYSICAL INTEGRITY TESTING .............................................................................................................................. 23 8.1 Traditional Tests Using Wet Filters .................................................................................................................................... 24 8.1.1 Manual Bubble Point Tests ................................................................................................................................................. 24 8.1.2 Manual Diffusive/Forward Flow Test ................................................................................................................................. 25 8.1.2.1 Downstream Measurement Method .................................................................................................................................... 25 8.1.2.2 Upstream Measurement Method ........................................................................................................................................ 25 8.1.3 Manual Pressure Hold/Pressure Decay Test ....................................................................................................................... 27 8.2 Water Intrusion Integrity Test Approach ............................................................................................................................ 29 8.3 Aerosol Integrity Test ......................................................................................................................................................... 30 8.4 Automated Integrity Test Instruments ................................................................................................................................. 31 8.5 Considerations for Integrity Test Practices ......................................................................................................................... 31 8.6 Troubleshooting Integrity Test Failures .............................................................................................................................. 32 9. USER RESPONSIBILITIES FOR THE VALIDATION OF CRITICAL APPLICATIONS ..................................... 33 9.1 Bacterial or Viral Retention ................................................................................................................................................ 33 9.2 Integrity Testing .................................................................................................................................................................. 33 9.3 Compatibility and Service Life ........................................................................................................................................... 33 Appendix A: Theoretical Aspects of Retention Mechanisms in Air ............................................................................................ 35 Appendix B: Maintenance, Preparation, and Characterization of Brevundimonas diminuta Challenge Suspensions ......... 36 Appendix C: Filter Validation Recommendations ....................................................................................................................... 37 Appendix D: Theoretical Aspects of Integrity Testing ................................................................................................................. 38 REFERENCES................................................................................................................................................................................ 41 BIBLIOGRAPHY ........................................................................................................................................................................... 43 Vol. 58 , No. S-1, January/February 2005 7 1. INTRODUCTION/SCOPE STATEMENT Sterilizing filtration of a process gas stream is defined as the complete removal of all microbiological contaminants, excluding viruses. Under certain circumstances, other contaminants such as viruses and plasmids can also be removed by filtration. Thus, in the pharmaceutical in- dustry, particularly in the production of parenterals, there is a wide range of processes for which sterilizing filtra- tion of air or other process gases is appropriate and ap- plicable. Early and careful screening of potential filter types and configurations can result in fewer technical and regula- tory problems, fewer delays, more efficient processing and greater sterility assurance. Although other types of filters can be employed in the control of particulate mat- ter and removal of liquid droplets by coalescence, the focus of this technical report is limited to hydrophobic membrane filter elements. The objective is to assist the reader in the selection, qualification, and validation of a filter that is appropriate for the application on hand. While most gas applications use hydrophobic filters, this does not preclude the use of hydrophilic filters in dry gas sys- tems. For further information on the use of hydrophilic filters, refer to PDA Technical Report No. 26. This report is intended to complement PDA Techni- cal Report No. 26: Sterilizing Filtration of Liquids, and like other PDA Technical Reports it should be consid- ered an educational guide rather than a mandatory or implied standard. 2. HISTORICAL BACKGROUND Filtration of air and other gases has always been used in a wide range of applications within the pharmaceutical and biotechnology industry. The first generation of gas filtration used depth filters, such as cotton wads or glass fiber, ranging in scale from small plugs within tubes or bottles to large packed towers. Typically, such depth fil- ters were used in conjunction with elevated temperatures to prevent condensation of moisture within the filter medium. The second generation of gas filters consists of depth cartridges of borosilicate or polypropylene composition. These cartridges are available in configurations that are easier to use, and they provide improved operator han- dling and safety. They also have more consistent reten- tion characteristics as a consequence of improved non- woven media (fleece) technologies and more appropri- ate methods of construction. The retention capability of such cartridges can typically be verified by oil droplet aerosol challenges such as the DOP (dioctyl phthalate) test (discussed later in Sections 8.3). Nevertheless, the depth media of these second-generation cartridges con- tinues to present some limitations, particularly with re- gard to the potential for bacterial breakthrough. This led to the development of hydrophobic membrane filter ele- ments. Compared to the earlier depth media, hydrophobic mem- brane materials have the advantage that they are inher- ently more resistant to water blockage. While some of the early membranes had to be rendered hydrophobic by silicone coating or similar surface treatment, membranes made of inherently hydrophobic polymers have been available for over two decades. The most common poly- mers used for the production of hydrophobic membranes are polytetrafluoroethylene (PTFE), polyvinylidene flu- oride (PVDF), polypropylene (PP), and polyethylene (PE). Hydrophobic membranes can be produced in more defined ranges of retention ratings than depth media, and their retention capability is considerably less dependent on operational parameters such as moisture content or differential pressure imposed during their use. Filter ele- ments are available in various user-friendly configura- tions, including tubular, stacked disk, and pleated car- tridges. One additional advantage over depth media is that the retention capability of hydrophobic membrane filters can be correlated to physical non-destructive in- tegrity tests, as discussed later in this report. 3. HOW GAS FILTERS WORK 3.1 Size Exclusion In gas filtration,