Operator Certification Course Integrity Testing …

1 BioPharmaceutical DivisionDiscover the More in millipore . Operator Certification CourseI ntegrity Testing MethodologyHydrophobic filterIntegrity TestingBioPharmaceutical DivisionDiscover the More in millipore . Integrity Testing overview Particle basednMicroorganismnAerosols Liquid property based nAlcoholsnWater+\GUR&RUUBioPharmaceutica l DivisionDiscover the More in millipore . Microorganism - Destructive TestnAerosol microorganisms or liquid bacterial challengenPhage (T1, T3, phiX)nBacteria (B. diminuta)Aerosol Based - Non-destructive Testn"Smoke : (Di-Octyl Phthalate), Glycerol, Corn oil (Dispersed Oil Particulate)etcnMethylene Blue, Sodium FlamenIssueslParticle Distribution must be uniformlMust have correlation of particles vs microorganismslHigh equipment costlDifficult to perform in-situ (particle counter downstream of filter)Particle Based Integrity TestingBioPharmaceutical DivisionDiscover the More in millipore . Alcohol testTraditional Testing Principles Typical wetting liquids are Isopropyl Alcohol ( or Propanol-2), Methanol, Tert-butyl Alcohol, or a mixture of one of these and water Uses same principles as a hydrophilic testDiffusion & Bubble pointFRPSUHVVHGDLU*DV)ORZ3 UHVVXUH%3 GLIIXVLRQEXON IORZBioPharmaceutical DivisionDiscover the More in millipore .

2 Changing solvent changes wetting & contact angle Check alcohol concentration & qualityAlcohol testSolvent Effects on Bubble PointBioPharmaceutical DivisionDiscover the More in millipore . Alcohol testAdvantages No special equipment required Follows similar procedures to hydrophilic membranes. Operator training time is reduced Traditional Reduced temperature influence Widely accepted Well understood Correlated to bacterial challenge Can be performed easily & quicklyBioPharmaceutical DivisionDiscover the More in millipore . Alcohol testI ssues Alcohol / Water mixtures are often used due to:lcostlflammabilitylhigh diffusionlpossibility of evaporation Secure areas and equipment needed Can be difficult to perform in-situ Some concerns with residual test solution remaining in filter holder / pipework after Testing Residual solution should be removed before filter sterilizationBioPharmaceutical DivisionDiscover the More in millipore . Alternatives to Alcohol Integrity TestingNeeded primarily due to:nIssues with alcohol contamination of processeslresiduesnRisks inherent with the use of solventsWater-Based Integrity Tests have been developed to overcome these issuesnEase of useBioPharmaceutical DivisionDiscover the More in millipore .

3 $GYDQWDJHV RI +\GUR&RUU 7 HVWn+\GUR&RUU WHVW RQO\ LQYROYHV ZDWHUwQR GRZQVWUHDP RSHUDWLRQwPLQLPDO ZDWHU IORZwGRHV QRW FRPSURPLVH VWHULOLW\n(DV\ WR DXWRPDWHn7 HVW FDQ EH SHUIRUPHG wLQ OLQHwDIWHU 6,3 wEHIRUH DQG DIWHU O\RSKLOL]DWLRQ7 HVW SUHVVXUH3 UHVVXUH GURS GXH WR ZDWHU GRZQZDUG PRYHPHQW'RZQVWUHDP DWPRVSKHULF SUHVVXUH:DWHU &:DWHU & +LJK SUHVVXUH GURS GXH WR ZDWHU LQWUXVLRQ'DPDJHG PHPEUDQH SRUWLRQ3 RUH VL]H ! PBioPharmaceutical DivisionDiscover the More in millipore . Water testWater-Based I ntegrity Test Basis Hydrophobic polymers repel water Water Intrusion PressureThe minimum pressure necessary to force water into the largest pores of a = - 4kVCos(T)dP1P2 WaterGasdVTIBioPharmaceutical 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.)

4 Pleated structures compact under pressure If integral, the upstream pressure will not drop below a preset atmP atmFXW DivisionDiscover the More in millipore . Water testResistance to water intrusionP atmP YLHZ01020 Time minBioPharmaceutical DivisionDiscover the More in millipore . Water testResistance to water intrusionP atmP YLHZ01020 Time minBioPharmaceutical DivisionDiscover the More in millipore . Water testResistance to water DivisionDiscover the More in millipore . +\GUR&RUU 7 HVWn+\GUR&RUU WHVW UHTXLUHVw)LOOLQJ RI WKH ILOWHU ZLWK :),nVWRUHG LQ D SUHVVXUH YHVVHOnGLUHFW VXSSO\ OLQHw(YDOXDWLRQ RI WKH DLU XSVWUHDP YROXPHw0 HDVXUHPHQW RI WKH SUHVVXUH GURSw&RQYHUVLRQ LQ +\GUR&RUU UDWH PO PLQ n+\GURFRUU D3 [ 9 3W [ W$LU 1 ,QWHJULW\ 7 HVWHU:),BioPharmaceutical DivisionDiscover the More in millipore . HydroCorr testnApplicable for all types of hydrophobic testable membranesnCorrelated to bacterial ChallengenTo be conducted on a perfectly dry membrane*DV)ORZPO PLQ7 LPH PLQXWHV BioPharmaceutical DivisionDiscover the More in millipore .]]

5 W ater testPerforming Water-Based TestsManuallyUse a flow meter to measure actual upstream water a pressure transducer to measure upstream gas pressure loss 0 bar Flowmeter ml/min BioPharmaceutical DivisionDiscover the More in millipore . W ater testAutomated water based Testing ,QVWUXPHQW GHWHUPLQHV YROXPH 9 9 FKDQJH E\ PHDVXULQJ WKH FRUUHVSRQGLQJ SUHVVXUH GURS 3 3 7KH JDV YROXPH LV DQ LVRODWHG V\VWHP WKHUH LV QR JDV H[FKDQJH GLIIXVLRQ LV QHJOLJLEOH 7KH WHPSHUDWXUH LV FRQVWDQW7KH LGHDO JDV ODZ ZULWWHQ IRU WKH V\VWHP LV 3 9 3 9 Q 5 7+\GUR&RUUPO PLQ 9 9 W 9 3 3 3 W 9 ' 3 W 3 $EVROXWH 3 3 9 9 QQ$V SOHDWV FRPSUHVV ZDWHU OHYHO GURSV 8 SVWUHDP DLU YROXPH LQFUHDVHV3 ULQFLSOH EDVHG RQ SUHVVXUH GHFD\ PRQLWRULQJ RQ WKH XSVWUHDP VLGH RI WKH ILOWHUBioPharmaceutical DivisionDiscover the More in millipore . Water testWater-Based Test Considerations Must have a leak-free system Filters must be dry and clean Temperature changes should be minimized Reference Testing is important Must have a complete validation package Values must be comprehensively correlated to microorganism challeng]