Академический Документы
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Presented by
Laura Okhio-Seaman
Sartorius Corporation
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Sterilizing Grade Filters
The definition of a sterilizing grade filter is one that will produce a sterile
effluent after being challenged by microorganisms at a challenge level of
greater than or equal to 1x107/cm2 of effective filtration area.
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Filter Qualification Tests
Physical Tests Compendial Tests (USP,EP)
Flow rates, differential Particle release
pressure, throughput Oxidizable substances
Sterilizability (SIP, Auto) Biosafety
Integrity tests (bubble point,
diffusive flow) Endotoxin
Other Tests
Biological Tests Non-volatile residue
Viability Quantitative and qualitative
Bacterial challenge test extractables analyses in
Bioburden studies water and ethanol
Leachables testing
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Validation of Sterilizing Grade Filters
4
Filter Qualification Tests
Viability
5
Filter Qualification Tests
6
Viability Test
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Viability Test Examples
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Filter Qualification Tests
Bacterial Challenge
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Bacterial Challenge Test
Filter Qualification by Supplier
Challenge Document
Stand. Cond.
Bacteria/Water Suspension
Challenge Document
Process Cond.
Bacteria/Product Suspension
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Bacterial Challenge Test
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Bacterial Challenge Test
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Bacterial Challenge Test
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Bacterial Challenge Test
Microscopic investigation
Criteria: single cells, motile cells
0.3 -
0.4 m
0.6-1.0 m
worst-case
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Bacterial Challenge Test
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Bacterial Challenge Test
Example:
Minimum Bubble Point Value: 46 psi
Release criteria of filter vendor: 50 psi
Low BP Range: 46 50.6 psi
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Filter Medium vs. Device
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Recovery Membrane Selection
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Pressure Differential and Flow Rate
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Manual BCT Set-up
pressure gauge
venting valve venting valve
valves
test filter
capsules
analytical
disc filters
peristaltic pump
syringe /
sample collection
20 test solution /
Brevundimonas diminuta
suspension
BCT Set-up for Small Scale Pleated Filters
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Big Bertha rig
Sartorius AG
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Possible BCT Strategies
Determine & Document viability of B. diminuta
in Product under Process Conditions
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
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BCT Strategies Method 1 (Direct Inoculation)
Determine & Document viability of B. diminuta
in Product under Process Conditions
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BCT Strategies Method 1 (Direct Inoculation)
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BCT Method 2 (Process Modification)
Determine & Document viability of B. diminuta
in Product under Process Conditions
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
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BCT Strategies Method 2 (Process Modification)
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BCT Strategies Method 3 (Time Period Challenge)
Determine & Document viability of B. diminuta
in Product under Process Conditions
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
28
BCT Strategies Method 3 (Time Period Challenge)
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
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BCT Strategies Method 5 (Preconditioning)
Determine & Document viability of B. diminuta
in Product under Process Conditions
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
31
BCT Strategies Method 5 (Preconditioning)
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BCT Strategies Method 6 (Bioburden Isolate)
Determine & Document viability of B. diminuta
in Product under Process Conditions
NOT VIABLE
Use product for time period that the Precondition filter with Product
challenge organism is viable followed by Microbial Challenge
33
BCT Strategies Method 6 (Bioburden Isolate)
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Filter Qualification Tests
Filter Integrity
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Integrity Test Correlation
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Integrity Test Correlation
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Bacterial Challenge Test
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Product Wet Integrity Testing
Bubble Point
Filter membrane is wetted with the product. Pressure is applied on the upstream
side of the filter. The pressure at which a stream of air bubbles is detected
downstream of the filter is known as the Minimum Bubble Point of the filter.
BP TEST
Pressure increase
45.000 PSI
OUTLET TUBING
POWER
CORD
SARTOCHECK 3 45.000 psi
N.I.S.T. TRACEABLE
REFERENCE
GAUGE BLIND END CAP
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Product Specific Integrity Test Bubble Point
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Product Wet Integrity Testing
Diffusive Flow
Depends mainly on the solubility of the test gas in the wetting fluid in addition
to temperature and test pressure. The filter membrane pores are wetted with
fluid and a gas pressure less than the BP is applied. Due to differential pressure,
gas diffuses through the fluid in the pores and is quantified as downstream flow
in mL/min.
BP TEST
Pressure increase
45.000 PSI GRADUATED
BURETTE
OUTLET TUBING
POWER
CORD
SARTOCHECK 3 45.000 psi
N.I.S.T. TRACEABLE
REFERENCE
GAUGE BLIND END CAP
NOTE: B E A K E R A N D I N V E R T E D
BURETTE MAY BE SUBSTITUTED
WITH A N.I.S.T. TRACEABLE MASS
FLOWMETER OR ROTAMETER.
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Product Specific Integrity Test Diffusive Flow
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Integrity Test Failure
TR #26 includes a Trouble Shooting Guide
in case of Integrity Test Failures:
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Guidance
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FDA Guidance on Aseptic Processing CGMP
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FDA
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FDA
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EC Guide to GMP of Sterile Medicinal Products
EC cGMP Guidance,
Revision of Annex 1.
Describes sterilization by
filtration, integrity test
needs, some validation
topics.
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ISO: AP of Health Care Products Filtration
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PDA
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Conclusion
Viability Testing
Bacterial Challenge Testing
Chemical Compatibility
Analysis of Extractables
Regulatory Product Integrity Testing
Requirement
Plant and Process Surveys
Filter Systems and Integrity Tester
Validation Validation
Process Related Validation Studies
Industry
Requirement
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Validation of Sterilizing Grade Filters
END
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