过滤技术及应用.ppt

过滤技术原理及应用,质保处2009.05,主要内容,过滤知识及原理过滤器的使用及维护完整性测试自动完整性测试仪,IntroductiontoFiltration过滤基本知识,主要内容,ImportantdifferencesinthetypesoffiltersusedinBioprocesses.生物制药中使用的不同类型过滤器及其特性Whyweusemembranefiltersforcriticalapplication关键应用中为什么使用膜过滤器,主要内容续,Howtorecognizefiltrationproblemsandperformbasictroubleshooting怎样理解过滤中的问题和解决简单故障,什么是过滤？,HowdoFiltersWork?过滤机理,SizeExclusion大小排除Particlesaretoolargetopassthroughthe“pore”基于大小来分离Examplesaretermedentrapment,sieving,surfacecapture例如拦截,筛分,表面捕获Adsorption吸附Particlessticktothefilterbychemical/electricalattraction颗粒由于化学/电荷作用粘附在滤器上,RetentionMechanisms影响过滤的因素,Mechanismscanbeaffectedby:截流机制可以被以下因素影响：Fluidcharacteristics流体特性Operatingconditions操作条件Particletype颗粒类型Filtertype过滤膜类型,影响过滤的因素(流体特性),Viscosity粘度Chemical/Ioniccontent化学/离子成分CommentsSlowflowallowsmorecontact较慢流速有较多接触Mixing/Contacttimecanbecritical混合/接触时间有较大影响Onlyaffectadsorptiveretention只影响吸附截留-NOTsizeexclusion不影响大小排除,影响过滤的因素(操作条件),Particlespeed/velocity颗粒速度Appliedpressure过滤压力Comments建议Slowflowisgood选择低流速betterretentionatslowerflow越低的流速,越好的截留Matrixmovementisbad结构移动是不利的particlesandfiberscanbereleasedfromdepthfilters颗粒和纤维能从深层过滤器析出Velocity/DifferentialPressurecanhaveamajoreffectonadsorptiveretention-Littletonoeffectonsizeexclusion速度/压差对吸附截留有重要影响,对大小排除影响相当小,影响过滤的因素(颗粒类型),Deformable(soft)可变形颗粒Non-deformable(hard)不可变形颗粒Comments建议Underpressuresoftparticlescanintrudeintothefilterstructurecausingmoreeffectivefilterblinding在压力下软性颗粒会进入过滤膜内并导致更多的过滤堵塞例如:凝胶Hardparticlesformopencakes硬颗粒形成一层饼例如:沙子,影响过滤的因素(滤膜的影响),Porerating孔径Structure结构Rigidormovable刚性或可移动CommentsSterilizingfiltercommonrating(legaldefinition)除菌过滤-公共孔径(法规定义)Prefiltershavenominalratings-eachmanufacturerhastheirownstandardsandmethods预过滤-额定孔径,每一个制造商有自己的定义和方法,0.22umDuraporeSurface(3,000 x),0.22umDuraporeCross-section(600 x),FilterMaterialsHydrophilic过滤材质亲水性,“WaterLoving”亲水Wetspontaneously(orwithlittleeffort)withwaterCellulosicmaterials(i.e.Regeneratedcellulose,mixedcelluloseester,etc.)纤维素材料Polycarbonatewithadditives(i.e.PVPP),Modifiedpolysulfone,Nylon,Modifiedpolyvinylidenefluoride(PVDF)聚碳化合物Applications应用Filtrationandsterilefiltrationofaqueousoraqueous/organicsolutions水或水/有机溶液混合的过滤和除菌过滤,FilterMaterialsHydrophobic过滤材质疏水性,“Waterhating”疏水Notspontaneouslywetwithwater.Watercanremainorbe“tricked”toenterfilter水被截流或巧妙进入膜PTFE-Polytetrafluoroethylene,PVDF-PolyvinylidenefluoridePolypropylene,Polysulfone,PolycarbonateApplications应用Solvent,acid,base,andchemicalfiltration溶剂,酸,碱和化学品过滤Tank/Equipmentvents,processgas,fermentationinlet/exhaustfilters罐/设备呼吸器,工艺用气,发酵进气/排气过滤,过滤器分类,深层过滤器表面过滤器特性膜过滤器,WhatdoDepthFilterslooklike?深层过滤器,Fibrous(canshedfibers)纤维(有纤维脱落)Difficulttogiveanaccurateporesizerating不能给出一个确切的空径Thick(3-30mm)30高压灭菌60min126CKVGL囊式除菌滤芯：3高压灭菌60min126C;不能在线灭菌Millidisk除菌滤器：5SIP60min135C;5高压灭菌60min126C。Aervent空气/有机溶剂除菌滤器：150（100正向/50反向）SIP30min145C;Express聚醚砜除菌过滤器：25次正向（或22次正向，3次反向）30min135C;一定要预先阅读说明书-实际工艺使用次数需要确认,GasFilterChangeoutCriteria气体过滤器更换标准,PreventativeMaintenance预防性维护Oxidation氧化Integrityfailure完整性失败Filterblockage过滤膜堵塞Toomanysterilizationcycles太多灭菌次数Filterchangeoutcanvary;1weekto1year过滤器更换时间范围很广(从1周到1年)Needdocumentation需要文本支持Increasedscrutiny应不断进行检查,FiltrationSummary总结,Therearetwomajorretentionmechanismsinliquids在流体过滤中有两类过滤机理Adsorption,SizeExclusion吸附,大小排除Threetypesoffiltersarecommonlyusedinbiopharmaceuticalfiltration三类过滤器普遍使用在生物制药Depth,Surface,Membrane深层,表面,膜过滤Filtermaterialsaresuppliedaseither过滤介质以下列形式提供Disc,StackedDisc,PleatedCartridge圆盘,层叠式,柱式Filtersblockbyeither过滤堵塞可以是Gradual,TotalorCake逐渐堵塞,完全堵塞Filtrationproblemscanbesolved过滤问题可以被解决Monitoringandoptimizingarekeytechniques监测和优化是关键技术,IntegrityTestingTheory完整性测试理论,内容目录,为什么要对除菌滤器进行完整性测试？完整性测试的方法有哪些？为什么可以用起泡点的方法代替细菌挑战试验？什么时候进行完整性检测？起泡点测试原理是什么？扩散流测试原理是什么？自动完整性测试仪,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,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,法规中对完整性测试的规定,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#26PDA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,Where&WhenDoWeIntegrityTest?何时和何地做完整性测试?,WHENTODOIT?Detectwhat?什么时候做?检查什么？Beforesterilizationfaultyhousings?灭菌前外壳的问题Beforeuseout-of-theboxfailures使用前包装以外的问题Afterusesterilizationinducedfailures使用后灭菌的影响stressinducedfailures压力的影响,WhatAreTheIntegrityTestingChoices?完整性测试方法的选择?,金标准,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FDAAsepticGuidelinesFDA无菌指南Validationjustificationfortheuseofatest测试应用的验证理由,IntegrityTestingCorrelations完整性测试关联,WhatNon-DestructiveIntegrityTestsareAvailable?何种非破坏性测试合适?,BubblePointIntroduction起泡点介绍,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,泡点测试,BubblePointTestApplicability起泡点测试适用性,BubblePointEquation起泡点等式,泡点的影响因素,接触角的影响,ExamplesoftheEffectofContactAngleandSurfaceTensiononBubblePointValues接触角和表面张力对起泡点值的影响实例,DiffusionTestingIntroduction扩散流测试介绍,Gasdissolvesinliquidheldintheporesofafullywettedmembranefilter.气体溶解在完全湿润的滤器膜孔内的液体中Apressuredifferentialwillgiveadifferentgasconcentrationacrossthefilter.膜压差造成跨膜气体浓度差Resultsingasflowthroughtheliquiddissolvedinthefilterpores.结果使膜孔溶解的气体流出,扩散流测试,DiffusionTestingEquation扩散测试方程,AReasonforDiffusionTesting什么情况下采用扩散测试,DiffusionTestApplicability扩散测试适用性,FactorsAffectingDiffusionTests扩散测试的影响因素,ExampleofChangedDiffusionalFlow举例,ExampleofChangedDiffusionalFlow举例,ExampleofChangedDiffusionalFlow举例,“DiffusionTesting”Summary扩散测试总结,疏水滤膜采用有机溶剂进行完整性测试的问题,HydroCorrTestingHydrocorr测试,HydroCorrTestResistancetowaterintrusion水浸入法测试,HydroCorrTestResults测试结果,HydroCorrTestConsiderations测试的注意点,Musthavealeak-freesystem必须在一密闭系统内进行Filtersmustbedryandclean过滤芯必须干燥且干净ItisrelativelyeasytoHydrocorrtest“veryhydrophobic”membranessuchasPTFE对于疏水性很强的滤芯,例PTFE材质的膜,水浸入法是相当容易Successfullytesting“lesshydrophobic”membranessuchasPVDFrequiresidealconditionsthatcanbedifficulttoachieveinactualbiopharmaceuticalprocesses在实际的生物制药工艺中,测试一些疏水性不强的滤膜,例PVDF膜是比较困难的Temperaturechangesshouldbeminimized尽量减少温度的变化Referencetestingisimportant相关的参考比较重要Musthaveacompletevalidationpackage必须有一完整的验证文本Valuesmustbecomprehensivelycorrelatedtomicroorganismchallenge数据必须与细菌挑战相关,完整性测试失败处理措施,润湿建议,Summary总结,BubblepointandDiffusion(or“Forwardflow”)areBOTHvalidintegritytestsasperregulatoryagencies.起泡点,扩散流（或前向流）和HydroCorr是法规认可的完整性测试方法Thechoiceofanintegritytestdependsonthetestingequipment,thefiltermanufacturer,thecompanysphilosophyandthetestingenvironment完整性测试的选择倚赖测试装置，过滤器制造商，公司体系和测试环境Bubblepointprovidesadirectcorrelationtobacterialretention,thecriticalperformancecharacteristic起泡点提供与细菌截留的直接关联，重要的性能特性Diffusiontestingprovidesasensitivewaytodetermineintegrityforlargerareafilters扩散测试提供一个敏感方法来测试大面积过滤器,AutomatedIntegrityTesters自动完整性测试仪,WhyDoPeopleUseAutomaticTesters为何用户会选用自动测试仪,PostSIPIntegrityTestingSIP后的完整性测试,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#26PDA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,AutomatedIntegrityTesting自动完整性测试,A.Duringintegritytestinggasmoleculesleavethesystemduetodiffusionorbulkflow在完整性测试中,气体流失的原因是扩散及穿孔后的流失B.Fewergasmoleculesupstreamresultsinlowerpressure.上游气体分子越少压力越低C.Allelsebeingconstant,thechangeinpressurecanbeusedtodeterminethegasflowrate在其它参数保持稳定的状况下,压力的改变可以确定气体的流速,PV=nRTWhere其中:P=pressur