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BioPharmaceutical DivisionDiscover the More in Millipore.™
Operator Certification CourseIntegrity Testing Methodology
Hydrophobic filterIntegrity Testing
BioPharmaceutical DivisionDiscover the More in Millipore.™
Integrity testing overview
äParticle basedn Microorganismn Aerosols
äLiquid property based n Alcoholsn Water +\GUR&RUU
BioPharmaceutical DivisionDiscover the More in Millipore.™
Microorganism - Destructive Testn Aerosol microorganisms or liquid bacterial challengen Phage (T1, T3, phiX)n Bacteria (B. diminuta)
Aerosol Based - Non-destructive Testn "Smoke“: D.O.P.(Di-Octyl Phthalate), Glycerol, Corn oil (Dispersed Oil Particulate) etcn Methylene Blue, Sodium Flamen Issues
l Particle Distribution must be uniforml Must have correlation of particles vs microorganismsl High equipment costl Difficult to perform in-situ (particle counter downstream of filter)
Particle Based Integrity Testing
BioPharmaceutical DivisionDiscover the More in Millipore.™
Alcohol testTraditional Testing Principles
ä Typical wetting liquids are Isopropyl Alcohol (I.P.A. or Propanol-2), Methanol, Tert-butyl Alcohol, or a mixture of one of these and water
ä Uses same principles as a hydrophilic test
Diffusion & Bubble point
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BioPharmaceutical DivisionDiscover the More in Millipore.™
ä Changing solvent changes wetting & contact angleä Check alcohol concentration & quality
Alcohol testSolvent Effects on Bubble Point
BioPharmaceutical DivisionDiscover the More in Millipore.™
Alcohol testAdvantages
äNo special equipment requiredäFollows similar procedures to hydrophilic
membranes. Operator training time is reducedäTraditionaläReduced temperature influenceäWidely acceptedäWell understoodäCorrelated to bacterial challengeäCan be performed easily & quickly
BioPharmaceutical DivisionDiscover the More in Millipore.™
Alcohol testIssues
ä Alcohol / Water mixtures are often used due to:l costl flammabilityl high diffusionl possibility of evaporation
ä Secure areas and equipment neededä Can be difficult to perform in-situ
ä Some concerns with residual test solution remaining in filter holder / pipework after testing
ä Residual solution should be removed before filter sterilization
BioPharmaceutical DivisionDiscover the More in Millipore.™
Alternatives to Alcohol Integrity Testing
Needed primarily due to:n Issues with alcohol contamination of processes
l residuesn Risks inherent with the use of solvents
Water-Based Integrity Tests have been developed to overcome these issues
n Ease of use
BioPharmaceutical DivisionDiscover the More in Millipore.™
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testWater-Based Integrity Test Basis
äHydrophobic polymers repel water
äWater Intrusion PressureThe minimum pressure necessary to force water into the largest pores of a hydrophobic membrane.
IP = - 4kVCos(T)d
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WaterGasd
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testResistance to water intrusion
•Force water under pressure onto
the surface of the filter.
•Applied pressure is < integral
filter intrusion pressure
•The water pressure is maintained
but not increased.
•Pleated structures compact
under pressure
• If integral, the upstream pressure
will not drop below a preset
value.
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testResistance to water intrusion
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testResistance to water intrusion
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testResistance to water intrusion
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BioPharmaceutical DivisionDiscover the More in Millipore.™
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BioPharmaceutical DivisionDiscover the More in Millipore.™
HydroCorr test
n Applicable for all types of hydrophobic testable membranes
n Correlated to bacterial Challenge
n To be conducted on a perfectly dry membrane
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testPerforming Water-Based Tests
ManuallyUse a flow meter to measure actual upstream water displacement
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AutomaticallyUse a pressure transducer to measure upstream gas pressure loss
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Flowmeter 0.2 ml/min
BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testAutomated water based testing
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BioPharmaceutical DivisionDiscover the More in Millipore.™
Water testWater-Based Test Considerations
äMust have a leak-free systemäFilters must be dry and cleanäTemperature changes should be minimizedäReference testing is importantäMust have a complete validation packageäValues must be comprehensively correlated to
microorganism challenge