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    NE25. Sterilizing Liquid Filtration TR26

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    ghostllh
    filter validation

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    NE25. Sterilizing Liquid Filtration TR26

    Uploaded by

    ghostllh
    580 views32 pages
    filter validation

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    filter validation

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    580 views32 pages

    NE25. Sterilizing Liquid Filtration TR26

    Uploaded by

    ghostllh
    filter validation

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 32
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    The key takeaways are that sterilizing filtration is important for drug manufacturing but the FDA does not think demonstrating lack of holes in a filter membrane guarantees retention of microorganisms. PDA Technical Report #26 provides guidance on sterilizing filtration.

    The FDA does not think demonstrating lack of holes in a filter membrane automatically implies retention of microorganisms. They also think microbial retentivity should be tested with the actual drug product since it may alter microorganism size or filterability.

    The purpose of PDA Technical Report #26 is to generate an educational monograph on sterilizing filtration technology for industry guidance. It is not intended as a standard or regulatory document.

    Life Sciences

    PDA Technical Report No. 26 Sterilizing Filtration of Liquids


    PDA New England Chapter June 13, 2007 Jerry Martin Sr. Vice President, Scientific Affairs Pall Life Sciences Co-author, PDA TR26 Member, PDA Sterilizing Filtration Task Force
    Filtration. Separation. Solution. SM

    Presentation Overview
    US FDA Issues PDA Tech Report Scope Task Force Members Contents Overview Key New Recommendations

    Pall Corporation 2007

    FDA Statement
    The agency does not agree that the demonstration of the lack of holes* in the membrane, by any selected membrane integrity test, automatically implies the retention of the microorganisms which may be present in the drug product.
    Peter Cooney, Ph.D., FDA CDER, PDA/FDA Forum, 7/95

    * (defects)
    Pall Corporation 2007

    FDA Published Statements on Filter Validation


    FDA Human Drug CGMP Notes, Dec., 1995 Since there is a possibility that the drug product may cause reduction in the size of the micro-organism, it is best to test the microbial retentivity of the filter with the microbial challenge in the actual drug product.

    Pall Corporation 2007

    FDA Published Statements on Filter Validation


    FDA CDER Perspective on Isolator Technology, ISPE Barrier Technology Conference, Dec, 1995 Recently, several instances have come to the Agencys attention, when passage of a drug product through a 0.2 m rated filter was not sufficient to remove contaminating microorganisms.

    Pall Corporation 2007

    FDA Published Statements on Filter Validation


    FDA CDER Perspective on Isolator Technology, ISPE Barrier Technology Conference, Dec, 1995 Issues to be considered are. How long will the filling line be operated? Does the subject drug product support growth? Does the drug product alter filter retentivity? Does the drug product alter the size of microorganisms or other physical trait, such as deformability, that could affect filterability?
    Pall Corporation 2007

    PDA Technical Report #26 Scope Statement


    Purpose: Generate an educational monograph on sterilizing filtration technology
    Not intended as a standard or regulatory document

    Include manufacturers, users and FDA Solicit PDA member and FDA review of drafts Publish Technical Report for industry guidance

    Pall Corporation 2007

    PDA TR26 Task Force


    Drug Manufacturers
    Pharmacia & Upjohn Abbott Laboratories Eli Lilly Glaxo Wellcome Merck

    Filter Manufacturers
    Pall (J. Martin) Millipore Sartorius W. L Gore & Assoc. Filterite (now part of Pall) Meissner

    Filtration Consultants
    J. Wilson (ex. Abbott) T. Meltzer H. Schroeder
    Pall Corporation 2007

    FDA Representative
    P. Stinavage, CDER
    (now at Pfizer and Chair of 2007 revision task force)

    Table of Contents
    1. Introduction 2. Pharmaceutical Filtration - History 3. How Filters Work 4. Filter Selection and Characterization 5. Physical and Mechanical Characteristics 6. Sterile Filter Validation / Bacterial Retention 7. Integrity Testing 8. Sterilization 9. Appendices and Bibliography
    Pall Corporation 2007

    Contents
    1. Introduction 2. Pharmaceutical Filtration
    Historical highlights

    3. How Filters Work


    Size exclusion Other retention mechanisms Bioburden retention probability Pore size rating

    Pall Corporation 2007

    Contents
    4. Filter Characterization and Selection
    Types, Configurations, Particle Shedding Extractables, Chemical Compatibility, Adsorption Thermal and Hydraulic Stress Resistance Toxicity Testing, Bacterial Challenge, Physical Integrity Testing

    5. Physical and Mechanical Characteristics


    Filtration Rate and Clogging (Throughput) Fluid Interactions, Physical and Structural Limitations

    Pall Corporation 2007

    Contents
    6. Sterile Filter Validation / Bacterial Retention
    Factors and Considerations for Retention Studies, Challenge Organism Selection and Culture, Challenge Concentration, Level, Aggregation, Viability Test Methods, Procedures and Protocols Nonbactericidal Processes and Fluids, Surrogates Bacteristatic/Bactericidal/Nondispersive Fluids Reduced Exposure Time, Modify Process/Formulation Indigenous Bioburden

    Pall Corporation 2007

    Contents
    6. Sterile Filter Validation / Bacterial Retention (cont.)
    Filter Medium versus Device Pressure Differential and Flow Rate Duration Downstream Sampling, Assay Membrane Selection Results Interpretation Product Bioburden Filter Configuration Change

    Pall Corporation 2007

    Contents
    7. Integrity Testing
    Integrity Testing Theory Integrity Test Results and Microbial Retention Product-Wetted vs.Water-Wetted Integrity Testing Upstream Testing, Automated Instruments When to Integrity Test Failure Analysis/Trouble Shooting

    8. Filter Sterilization
    Autoclave, Steam in Place Irradiation, Gas
    Pall Corporation 2007

    Contents
    Appendices
    A. B. C. D. Pore Size Estimation Toxicity and Filter Extractable Testing Filter Validation Recommendations Nondestructive Physical Integrity Test Methods

    E. Statistical Adjustment

    Bibliography

    Pall Corporation 2007

    Sterilizing Filter Validation Summary Concepts


    Select and Characterize Filter to Meet Process Conditions Adsorption Compatibility Extractables Microbial Retention Validation Relate Physical Test Parameters (Integrity Tests)

    Pall Corporation 2007

    FDA Guidelines on Aseptic Processing (1987)


    A sterilizing grade filter is one which, when challenged with the microorganism Pseudomonas diminuta at a minimum concentration of 107/cm2 of filter surface, will produce a sterile effluent

    Forget about it!


    Peter Cooney, Ph.D., FDA CDER PDA Annual Meeting, Washington, DC, Nov. 98
    Pall Corporation 2007

    PDA Filtration Committee Discussion Points


    A sterilizing grade filter is one that sterilizes the drug product.
    Peter Cooney, Ph.D., FDA CDER

    Filter claims for sterilizing grade will continue to be of value to drug manufacturers for selection and product-specific retention validation.
    PDA Filtration Committee
    Pall Corporation 2007

    PDA TR26 Summary

    Sterilization Validation
    Product sterilization may not be achieved with integral sterilizing grade filter cartridges
    Filter manufacturers integrity test limit and lot sample challenge predict Brevundimonas diminuta retention under standard test conditions (e.g. ASTM F838-83, now F838-05)

    Sterilization of drug product should be validated


    Confirm that drug product, process conditions and bioburden do not affect the process filters ability to produce sterile effluent
    Pall Corporation 2007

    PDA TR26 Summary

    Sterilization Validation
    PDA Technical Report # 26: The goal of conducting bacterial retention validation studies is to generate data demonstrating that the filtration process will consistently remove high levels of a standard bacterium, or relevant bioburden isolate, suspended within product (or surrogate fluid), under actual process conditions
    Pall Corporation 2007

    PDA TR26 Summary

    Sterilization Validation
    Every product need not be tested Products can be grouped into families Family extremes can be bracketed Worst case product models can be selected Scientific rationale must be documented

    Pall Corporation 2007

    PDA TR26 Summary

    Sterilization Validation
    Validate filtration sterilization process under worst case conditions for:
    Product - drug product formulation Process - drug filtration process Bioburden - drug and filling environment Membrane - physical QC specifications

    Pall Corporation 2007

    PDA TR26 Summary

    Relating Integrity Test Values


    Validation studies should establish the relationship between the chosen integrity test method and bacterial retention and serve as a basis for establishing appropriate parameters for the pre- and post- use integrity testing of production filters.
    Pall Corporation 2007

    Integrity Test Correlation


    Bubble Point
    Not consistent with filter area
    High area cartridges may have different BP than discs cut from identical pore distribution membrane

    Filter mfr certifies cartridge membrane BP > min. production membrane BP (prodn BP test) User confirms certified cartridge membrane BP > min. validated disc membrane BP (prodn BP test)
    Confirms membrane in cartridge is at least as tight as worst case validated membrane

    User tests assembly BP to > min. allowable limit for cartridge/assembly BP


    Confirms cartridge is free of leaks or perforations = integral.
    Pall Corporation 2007

    Integrity Test Correlation


    Forward Flow (a.k.a. Diffusion)
    Flow too low to measure on small discs
    Cant scale up disc flow to cartridge flow accurately

    Filter mfr certifies cartridge membrane BP > min. production membrane BP (prodn BP test) User confirms certified cartridge membrane BP > min. validated disc membrane BP (prodn BP test)
    Confirms membrane in cartridge is at least as tight as worst case validated membrane

    User tests assembly FF to < max. allowable limit for cartridge/assembly FF


    Confirms cartridge is free of leaks or perforations = integral.

    Pall Corporation 2007

    Summary Recommendations PDA TR#26


    Parametric approach for validation of sterilizing filtration process
    Worst case product/fluid or surrogate model Worst case process conditions Worst case bioburden model or isolate Worst case membrane discs based on manufacturers specification

    Relate production filter membrane/cartridge integrity to validated membrane disc retention and integrity specification
    Pall Corporation 2007

    PDA TR 26 Revision 2007


    24 Member Task Force
    Biotech, pharmaceutical, contract manufacturing, filter manufacturing and consultants

    Updated for current best practices Expanded sections New sections, e.g.
    Redundant filtration Re-sterilization of filters Integrity testing multi-cartridge systems Disposable filtration systems
    Pall Corporation 2007

    Process Risk Assessment Factors


    Higher Risk
    Higher levels, Diminutive organisms Higher Higher Growth promoting Ambient and higher Longer
    Pall Corporation 2007

    Factor
    Bioburden Differential pressure Flow rate Product Temperatures Time

    Lower Risk
    Lower levels Large organisms Lower Lower Bactericidal or preserved Refrigerated Shorter

    Integrity Test Failure Decision Tree


    Integrity Test Falure Analysis Decision Tree

    System Setup Checks


    Check that the test setup is assembled and functions properly. Check that the test equipment has been properly calibrated. Check that there are no leaks in the test system Check that the correct filter has been installed. Check that the temperature has remained within specified range during testing.

    Test Parameter Checks


    Check that the appropriate integrity test has been selected. Check that the correct test parameters are being used. Check that the correct wetting fluid and wetting procedure are being used.

    Rewet the filter & repeat integrity test

    Pall Corporation 2007

    Step 1

    Integrity Test Failure Decision Tree


    Pass/Fail

    Fail

    Increase flush volume/ time Increase differential pressure Apply back pressure

    Pass/Fail
    Fail

    Record Pass result. Filter is integral


    Pall Corporation 2007

    Step 2

    Filter Wetting (Stage I)

    Integrity Test Failure Decision Tree


    Fail
    Filter Wetting (Stage II)
    Pass

    Pass

    Flush filter with a low surface tension reference wetting liquid to enhance wetting per manufacturers instructions Repeat integrity test using appropriate test parameters and limits for low surface tension reference wetting liquid

    Record Pass result. Filter is integral

    Pass

    Pass/Fail
    Fail
    Record Fail result. The filter fails the test

    Pall Corporation 2007

    Step 3

    PDA TR 26 Revision 2007


    Select Review Phase (to 8/15) PDA Member Review Phase (to 9/15)
    Available to PDA members on website

    Publication (~Nov/Dec, 2007)


    Suppl. to PDA J. Paren. Sci. & Techol.

    Pall Corporation 2007

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