过滤芯完整性测试资料方案

密理博中国有限公司生物制药工艺部Content讲座目录Whywedointegritytestforsterilefilter?为什么要对除菌滤器进行完整性测试？MethodforIT?完整性测试的方法有哪些？Whybubblepointcouldreplacebacterialretentiontest?为什么可以用起泡点的方法代替细菌挑战试验？WhenshouldwedoIT?什么时候进行完整性检测？Bubblepointtheory.起泡点测试原理是什么？Diffusiontesttheory.扩散流测试原理是什么？Automaticintegritytester自动完整性测试仪Whatisfilterintegrity?什么是滤膜完整性?Integralmembrane完整滤膜Contaminant比膜孔大的污染物Non-integralmembrane非完整滤膜Contaminant比膜孔大的污染物Contaminantindownstream下游污染Nocontaminantindownstream下游没有污染物WhyIntegrityTest?为什么做完整性测试?CommonSense通常理解Filtrationisoftenthemostcriticalstepinanoperation过滤通常是操作的关键步骤Confirmationofmanufacturersspecifications确认制造规格Detectingleaksduetoo-rings,gaskets,seals检测O形环,垫圈,密封垫的泄漏Assuringthecorrectporesizefilter确认正确的过滤孔经Assuringintegritybeforesterilization确认灭菌前完整性Assuringintegrityaftersteamingorautoclaving确认蒸汽和消毒锅灭菌后完整性BusinessPractice商业惯例GovernmentGuidelines&Regulations法规要求Partofcorporatestandardoperatingprocedure公司标准操作规程Auditingrequirement审计需要Regulationsaboutintegritytest法规中对完整性测试的规定•FDAGuideline指南(2003)–Whateverfilterorcombinationoffiltersisused,validationshouldincludemicrobiologicalchallengestosimulateworst-caseproductionconditions…”对于由一个或多个滤器组成的过滤系统，对它的验证都应该包括在最差条件下进行的微生物挑战试验。•Revisionofannex1toECGuidetoGMPforsterilemedicinalproducts(1997)•欧盟对于无菌药品GMP指南的附件一(1997版)–“Theintegrityofthesterilizedfiltershouldbeverifiedbeforeuseandshouldbeconfirmedimmediatelyafterusebyanappropriatemethodsuchasabubblepoint,diffusivefloworpressureholdtest”–除菌过滤膜应该在使用前及使用后立即采取合适的方法确认其完整性,可以采用泡点,扩散流或压力保持的方法.•FDAGuidelineonSterileDrugProductsProducedbyAsepticProcessing(1987)•FDA对于无菌操作生产的无菌药品的要求(1987版)–“Normally,integritytestingofthefilterisperformedafterthefilterunitisassembledandsterilizedpriortouse.”–完整性测试通常在过滤器安装,灭菌后使用前进行•PDATechnicalReport#26•PDA技术报告26版–“ItgenerallyisregardedasacGMPrequirementthatfiltersorfiltersystemsroutinelybeintegritytestedbothpriortoandafteruse.”–现行的GMP要求过滤器及过滤系统在使用前及使用后均需要进行完整性测试Regulationsaboutintegritytest法规中对完整性测试的规定Where&WhenDoWeIntegrityTest?何时和何地做完整性测试?•WHENTODOIT?•什么时候做?•Beforesterilization•灭菌前•Beforeuse•使用前•Afteruse•使用后DETECTSWHAT?检查什么?Faultyhousings•外壳的问题•Out-of-theboxfailures包装以外的问题•Sterilizationinducedfailures•灭菌的影响•Stressinducedfailures•压力的影响Type分类Testname测试名称Tester测试实施者Destructive破坏性Bacterialretentiontest细菌挑战测试Manufacturerandcustomerdovalidation制造商以及客户进行验证时进行Non-destructive非破坏性Bubblepoint,diffusiontest起泡点测试，扩散测试Manufacturerreleaseandcustomeronsite制造商出厂时及使用者现场进行金标准•WhatAreTheIntegrityTestingChoices?•完整性测试的选择?Regulatory&qualityorganizationsneeddatafrombothtoassurereliableandpredictablefilterperformance法规和质量管理需要数据确保可靠和预知过滤器性能Destructivevs.Non-destructiveTesting破坏性和非破坏性测试Theremustbeacorrelationbetweenadestructiveandanon-destructiveintegritytest破坏性和非破坏性测试两者必须有关联Regulatoryrequirement法规需要FDAAsepticGuidelinesFDA无菌指南Validationjustificationfortheuseofatest测试应用的验证理由IntegrityTestingCorrelations完整性测试关联Bubblepointcanhaveadirectcorrelation起泡点有直接的关联Diffusion&othertestscanhaveango-nogocorrelation扩散和其它测试有”通过,不通过”关连#ofSamplesRetentiveNon-Retentive2468101214161820222426SpecificationWhatNon-DestructiveIntegrityTestsareAvailable?何种非破坏性测试合适?Capillarybasedtests基于毛细管测试BubblePoint起泡点HydroCorr挤水法(水侵入法)Corrtest水压法Diffusivebasedtests基于扩散测试Diffusion扩散ForwardFlow前向流Pressurehold/decay压力保持/衰减P1P2AirWaterdsqf•Bubblepointisthepressureatwhichgasdisplacesliquidfromthelargestsetoffilterporesandflowsrapidlythroughthefilter•起泡点是气体从湿润的最大膜孔挤出液体快速流出时的压力•Bubblepointindicatesthemagnitudeoftheforcesholdingliquidinthefilterstructure•起泡点显示过滤结构内保持液体的力的大小•Theoldestnon-destructiveintegritytest•最传统的非破坏性测试BubblePointIntroduction起泡点介绍Bubblepointtest泡点测试Integral完整膜Non-Integral非完整膜Fullywetting完全润湿的膜Pressurelessthanbubblepoint上游压力小于泡点值Nomassgasfluidobserved没有大量气流出现Pressurelessthanbubblepoint上游压力小于泡点值massgasfluidobserved破损出现的大孔保持力低,导致低于泡点即被吹干出现气流LargestPoreBubblePointTestApplicability起泡点测试适用性Usefulforqualifiedmanualtestingoffilterslessthanapproximately2000cm^2(~2sq.ft.)手动测试通常适用于过滤器面积小于2000平方厘米Usefulforautomaticintegritytestersforfilterswithgasflowratesofupto100ml/minorlimitoftheautomatictestersqualifications自动完整性测试仪适用于气体流速超过100毫升/分钟或自动测试仪的限定BubblePointEquation起泡点等式Thebubblepointisexpressedas:泡点可表达为4.k.γ.cosBP=-----------------dwhere这里k=shapecorrectionfactor形状校正因子=surfacetension表面张力=contactangle接触角d=porediameter孔径P1P2AirWaterdEffectonbubblepointtest泡点的影响因素Dependsoncapillaryforces;依赖毛细管力membranematerial,surfacetension,contactangle,effectivediameter,膜材料,表面张力,接触角,有效孔径起泡点说明(包括SOP)应当包括filtertype过滤器类型wettingliquid湿润液体Temperature温度minimumpressure最小压力Contactangle接触角的影响Solid/liquidinteraction固/液相互作用Changingthewettingfluidchangesthebubblepoint改变湿润液体会改变起泡点Appliestodifferentwettingfluid不同的湿润液体differentsurfacechemistries不同的表面化学性pre-usevs.post-usecomparison使用前和使用后比较Mustknowtheeffectsofthechanges,performflushingorconductproductbubblepointqualification必须知道变化的影响,进行冲洗或用产品泡点确认•Twosterilizinggradefilterswithidenticalbacterialretentionclaimsandperformancehavethefollowingminimumbubblepointspecifications:•两种无菌过滤膜用同一细菌截留有下列最小的起泡点规格:–Du