過濾技術(shù)原理及應(yīng)用質(zhì)保處2016.04主要內(nèi)容過濾知識及原理過濾器的使用及維護(hù)完整性測試自動完整性測試儀IntroductiontoFiltration

過濾基本知識主要內(nèi)容ImportantdifferencesinthetypesoffiltersusedinBioprocesses.–生物制藥中使用的不同類型過濾器及其特性Whyweusemembranefiltersforcriticalapplication–關(guān)鍵應(yīng)用中為什么使用膜過濾器主要內(nèi)容—續(xù)Howtorecognizefiltrationproblemsandperformbasictroubleshooting–怎樣理解過濾中的問題和解決簡單故障什么是過濾？HowdoFiltersWork?

過濾機(jī)理SizeExclusion大小排除Particlesaretoolargetopassthroughthe“pore”基于大小來分離Examplesaretermedentrapment,sieving,surfacecapture例如攔截,篩分,表面捕獲Adsorption吸附Particlessticktothefilterbychemical/electricalattraction顆粒由于化學(xué)/電荷作用粘附在濾器上RetentionMechanisms

影響過濾的因素Mechanismscanbeaffectedby:截流機(jī)制可以被以下因素影響：Fluidcharacteristics流體特性O(shè)peratingconditions操作條件Particletype顆粒類型Filtertype過濾膜類型影響過濾的因素(流體特性)Viscosity粘度Chemical/Ioniccontent化學(xué)/離子成分CommentsSlowflowallowsmorecontact較慢流速有較多接觸Mixing/Contacttimecanbecritical混合/接觸時間有較大影響Onlyaffectadsorptiveretention只影響吸附截留-NOTsizeexclusion不影響大小排除影響過濾的因素(操作條件)Particlespeed/velocity顆粒速度Appliedpressure過濾壓力Comments建議Slowflowisgood選擇低流速betterretentionatslowerflow越低的流速,越好的截留Matrixmovementisbad結(jié)構(gòu)移動是不利的particlesandfiberscanbereleasedfromdepthfilters顆粒和纖維能從深層過濾器析出Velocity/DifferentialPressurecanhaveamajoreffectonadsorptiveretention-Littletonoeffectonsizeexclusion速度/壓差對吸附截留有重要影響,對大小排除影響相當(dāng)小影響過濾的因素(顆粒類型)Deformable(soft)可變形顆粒Non-deformable(hard)不可變形顆粒Comments建議Underpressuresoftparticlescanintrudeintothefilterstructurecausingmoreeffectivefilterblinding在壓力下軟性顆粒會進(jìn)入過濾膜內(nèi)并導(dǎo)致更多的過濾堵塞例如:凝膠Hardparticlesformopencakes硬顆粒形成一層餅例如:沙子影響過濾的因素(濾膜的影響)Porerating孔徑Structure結(jié)構(gòu)Rigidormovable剛性或可移動CommentsSterilizingfilter–commonrating(legaldefinition)除菌過濾-公共孔徑(法規(guī)定義)Prefiltershavenominalratings-eachmanufacturerhastheirownstandardsandmethods預(yù)過濾---額定孔徑,每一個制造商有自己的定義和方法0.22umDuraporeSurface(3,000x)0.22umDuraporeCross-section(600x)FilterMaterials–Hydrophilic

過濾材質(zhì)—親水性“WaterLoving”親水Wetspontaneously(orwithlittleeffort)withwaterCellulosicmaterials(i.e.Regeneratedcellulose,mixedcelluloseester,etc.)纖維素材料Polycarbonatewithadditives(i.e.PVPP),Modifiedpolysulfone,Nylon,Modifiedpolyvinylidenefluoride(PVDF)聚碳化合物Applications應(yīng)用Filtrationandsterilefiltrationofaqueousoraqueous/organicsolutions水或水/有機(jī)溶液混合的過濾和除菌過濾

FilterMaterialsHydrophobic

過濾材質(zhì)—疏水性

“Waterhating”疏水Notspontaneouslywetwithwater.Watercanremainorbe“tricked”toenterfilter水被截流或巧妙進(jìn)入膜PTFE-Polytetrafluoroethylene,PVDF-PolyvinylidenefluoridePolypropylene,Polysulfone,PolycarbonateApplications應(yīng)用Solvent,acid,base,andchemicalfiltration溶劑,酸,堿和化學(xué)品過濾Tank/Equipmentvents,processgas,fermentationinlet/exhaustfilters罐/設(shè)備呼吸器,工藝用氣,發(fā)酵進(jìn)氣/排氣過濾

過濾器分類

深層過濾器表面過濾器特性膜過濾器

WhatdoDepthFilterslooklike?深層過濾器

Fibrous(canshedfibers)纖維(有纖維脫落)Difficulttogiveanaccurateporesizerating不能給出一個確切的空徑Thick(3-30mm)&oftenadsorptive厚度(3-30毫米),通常有吸附Giveapercentage(i.e.30-70%)particlereduction只能給出顆粒減少的比例Havethegreatestcapacity較大的承污能力Examples-Microfiberglass,String-wound,padfilters例如-玻璃纖維,線繞式,壓板式

WhatdoSurfaceFilterslooklike?表面過濾器

Fiberslockedtogetherbyheatormembranecoating纖維用熱粘合或膜涂布Givenanominalratingorratedbythefilteritprotects可以給出公稱空徑Thin(1mmorless)&SlightlyAdsorptive較薄(小于1毫米),較小吸附Giveapercentage(90-99.9%)particlereduction給出顆粒減少的比例(90-99.9%)Examples-Celluloseestercoatedcelluloseorpolyesterweb例如-纖維素酯涂纖維或聚酯片

KeyMembraneFilterCharacteristics膜過濾器的特性

Strong,RigidNOTbrittle堅強(qiáng)，硬不易碎Tortuouspathway曲折的通道Notalltheretentionontop不是都截流在膜表面Veryhighinternalarea非常高的內(nèi)表面積65-75%porosity65%-75%開孔率KeyMembraneFilterCharacteristics膜過濾器的特性-續(xù)Sizeexclusion–particleretentiondoesnotchangewithfloworpressure大小排除－顆粒截流與流速和壓力無關(guān)Sterilizingfiltersmusthave>99.99999%removal無菌過濾器必須具有大于99.99999%截流Integritytestable(diffusion&/orbubblepoint)能做完整性測試HowareMembraneFiltersMade?

膜過濾是怎樣制造的？ProducedbyCasting鑄造膜Nylon,Cellulose(mixedester,regenerated),PVDF,Polysulfone尼龍,纖維素(混合酯,改良),聚偏二氟乙烯,聚砜ProducedbyStretching拉伸膜PTFE聚四氟乙烯WhatdoCastFilterslooklike?

鑄造方式制造的膜過濾器Mainlymadebycastingmembrane主要由鑄造方式制造Canbeeitherhydrophilicorhydrophobic可以是親水和疏水Ratedonthesizeofthesmallestparticleitretains孔徑是對最小的顆粒的截留Verythin(100-260um)非常?。?00-260微米）Adsorptiondependsonmaterials吸附與材料相關(guān)Examples例如Celluloseester纖維素酯Regeneratedcellulose改良纖維素Nylon尼龍Polysulfones聚砜PVDF聚偏二氟乙烯WhatdoStretchedfilterslooklike?

拉伸方式制造的膜過濾器Slotshapedpores狹窄的孔道Verythin非常薄Oftenbondedtoasupportmaterial常常與支撐結(jié)合Canhavehighproteinadsorption有較高的蛋白吸附Examples例如PTFE-"Teflon"聚四氟乙烯Naturallyhydrophobic天然疏水Mosthydrophobicpolymer過濾系統(tǒng)配置澄清(Millistak+orPolygard)預(yù)過濾(MilligardorPolysep-II)最終(Durapore0.22or0.45μm）深層表面膜過濾系統(tǒng)配置–孔徑逐漸減小的過濾系列–Clarifyingfilter-澄清過濾?深層過濾?在過濾系列開始是最大的過濾容量–Prefilter-預(yù)過濾?Prefilter-預(yù)過濾-表面過濾?中等截留，中等載量–Finalfilter-除菌過濾?除菌膜?最大的過濾截留率PerformanceofFiltrationSystems過濾系統(tǒng)性能TypesofParticlesinBiologicalFluids

生物流體中顆粒類型Non-deformabletypes不可變形顆粒Resinbeadsorfines樹脂粒Drugcrystals藥物晶體Carbonfines炭粒DiatomaceousEarth(D.E.)硅燥土Formporouspermeablecakes.在膜上形成可流通的餅Deformabletypes可變形顆粒Proteins蛋白Lipids脂 Sugarcomplexes糖復(fù)合物Canmovethroughthefilter,breakupandcompressintoimpermeablecakes.能穿過膜,破碎,壓縮CakeFormation

形成濾餅*Happenswithhardparticles發(fā)生在硬顆粒*Particlesbuilduponthesurfaceofthefilter顆粒堆積在過濾膜的表面TotalPoreBlocking

完全堵塞Happenswithdeformableparticles發(fā)生在可變形顆粒Particlescompletelyblockthe"pore“顆粒完全堵塞膜“孔”HappenswithlittleprefiltrationORparticlesslightlylargerthantheporesize發(fā)生在缺少預(yù)過濾或顆粒略大于孔徑的情況GradualPorePlugging

逐漸堵塞

Happenswithhardordeformableparticles發(fā)生在硬顆粒和可變形顆粒Particlesbuilduponthe"pore"throatoropening顆粒堆積在孔道或表面

Mostcommonwithbiologicals大多發(fā)生在生物化學(xué)顆粒HowdoBlockedFiltersReact?

過濾器堵塞的現(xiàn)象Gradualblockagemostcommon逐漸堵塞經(jīng)常發(fā)生"Everythingwasgoingalright,thenallofasuddenthefilterblocked”一切正常,然后突然過濾器堵塞了過濾器的堵塞現(xiàn)象流速下降可能低于要求的流速(如灌裝速度)壓力上升可能超過過濾系統(tǒng)承受的壓差過濾柱或管道/連接件顆粒可能穿過過濾器污染/堵塞下游過濾器過濾成本改變時間,產(chǎn)品和過濾器的成本系統(tǒng)停止或更換過濾器過濾器堵塞的原因本道工序濾膜的選擇，孔徑，面積操作條件（流速，溫度，壓力）上道工序濾膜的選擇產(chǎn)品本身的變化產(chǎn)品過濾前作壓力流速實驗怎樣最優(yōu)化過濾過程？使用低的起始壓差~1-2psidor~0.1bar監(jiān)測和調(diào)整壓差深層過濾:10-15PSID表面過濾和膜過濾:30PSID不超過制造商的規(guī)格確保過濾在合時壓力下進(jìn)行TypicalFilterConfigurations–1

典型過濾器配置-1圓盤過濾器13-293毫米直徑傳統(tǒng)的濾器可同時使用深層、表面濾膜通常用于小批量過濾成本低分量重安裝困難占地面積大TypicalFilterConfigurations–2

典型過濾器配置-2StackedDisk層疊式圓盤Membranebondedtobothsidesofasupportdisk膜結(jié)合在圓盤支撐的兩邊Supportdisksbondedtogether圓盤支撐結(jié)合在一起Allfiltersworkinparallel所有過濾器平行Lowhold-upvolume殘液低Easytouse&compact使用方便緊湊Eitherreplacementfilter(Millidisk)ordisposabledevice(Millipak)有可替換的和一次性使用的過濾器Non-metallic非金屬Non-flexingstructure不可變形構(gòu)造Lowresistancetobackpressure承受反壓低TypicalFilterConfigurations–3

典型過濾器配置-3PleatedCartridge折疊式Membraneheldbetweensupportingmaterial膜在支撐材料間Thermoplasticwelding熱熔2-5materialsofconstruction2-5種結(jié)構(gòu)材料Goodforward&reversepressureresistance

較高的正/反壓承受能力

Largesurfacearea大過濾面積Multiplysteamable多次蒸氣滅菌Varietyofsizes,surfaceareasando-ringconfigurations各種規(guī)格，表面積和Ｏ形圈結(jié)構(gòu)Canhaveprefilter/finalfilterinthesamecartridge能將予過濾和除菌過濾膜結(jié)合在同一過濾芯內(nèi)CartridgeInstallationTips

過濾器安裝知識濕潤O型圈，易于安裝檢查過濾外殼方向–inlet/outlet不要過緊，合適的套筒不需要太大的力量避免直接用手接觸過濾器使用前沖洗過濾器最大滅菌次數(shù)滅菌次數(shù)：–CVGL除菌濾芯：?30SIP30min@135°C;30高壓滅菌60min@126°C–KVGL囊式除菌濾芯：?3高壓滅菌60min@126°C;不能在線滅菌–Millidisk除菌濾器：?5SIP60min@135°C;5高壓滅菌60min@126°C。–Aervent空氣/有機(jī)溶劑除菌濾器：150（100正向/50反向）SIP30min@145°C;–Express聚醚砜除菌過濾器：?25次正向（或22次正向，3次反向）30min@135°C;一定要預(yù)先閱讀說明書-實際工藝使用次數(shù)需要確認(rèn)GasFilterChangeoutCriteria

氣體過濾器更換標(biāo)準(zhǔn)

PreventativeMaintenance

預(yù)防性維護(hù)Oxidation氧化Integrityfailure完整性失敗

Filterblockage過濾膜堵塞Toomanysterilizationcycles太多滅菌次數(shù)Filterchangeoutcanvary;1weekto1year過濾器更換時間范圍很廣(從1周到1年)Needdocumentation需要文本支持Increasedscrutiny應(yīng)不斷進(jìn)行檢查FiltrationSummary總結(jié)Therearetwomajorretentionmechanismsinliquids在流體過濾中有兩類過濾機(jī)理Adsorption,SizeExclusion吸附,大小排除Threetypesoffiltersarecommonlyusedinbiopharmaceuticalfiltration三類過濾器普遍使用在生物制藥Depth,Surface,Membrane深層,表面,膜過濾Filtermaterialsaresuppliedaseither過濾介質(zhì)以下列形式提供Disc,StackedDisc,PleatedCartridge圓盤,層疊式,柱式Filtersblockbyeither過濾堵塞可以是Gradual,TotalorCake逐漸堵塞,完全堵塞Filtrationproblemscanbesolved過濾問題可以被解決Monitoringandoptimizingarekeytechniques監(jiān)測和優(yōu)化是關(guān)鍵技術(shù)IntegrityTestingTheory完整性測試?yán)碚搩?nèi)容目錄為什么要對除菌濾器進(jìn)行完整性測試？完整性測試的方法有哪些？為什么可以用起泡點的方法代替細(xì)菌挑戰(zhàn)試驗？什么時候進(jìn)行完整性檢測？起泡點測試原理是什么？擴(kuò)散流測試原理是什么？自動完整性測試儀WhyIntegrityTest?

為什么做完整性測試?CommonSense通常理解Filtrationisoftenthemostcriticalstepinanoperation過濾通常是操作的關(guān)鍵步驟Confirmationofmanufacturersspecifications確認(rèn)制造規(guī)格Detectingleaksduetoo-rings,gaskets,seals檢測O形環(huán),墊圈,密封墊的泄漏Assuringthecorrectporesizefilter確認(rèn)正確的過濾孔經(jīng)Assuringintegritybeforesterilization確認(rèn)滅菌前完整性Assuringintegrityaftersteamingorautoclaving確認(rèn)蒸汽和消毒鍋滅菌后完整性BusinessPractice商業(yè)慣例GovernmentGuidelines&Regulations法規(guī)要求Partofcorporatestandardoperatingprocedure公司標(biāo)準(zhǔn)操作規(guī)程Auditingrequirement審計需要法規(guī)中對完整性測試的規(guī)定FDAGuideline指南(2003)–Whateverfilterorcombinationoffiltersisused,validationshouldincludemicrobiologicalchallengestosimulateworst-caseproductionconditions…”對于由一個或多個濾器組成的過濾系統(tǒng)，對它的驗證都應(yīng)該包括在最差條件下進(jìn)行的微生物挑戰(zhàn)試驗法規(guī)中對完整性測試的規(guī)定Revisionofannex1toECGuidetoGMPforsterilemedicinalproducts(1997)歐盟對于無菌藥品GMP指南的附件一(1997版)–“Theintegrityofthesterilizedfiltershouldbeverifiedbeforeuseandshouldbeconfirmedimmediatelyafterusebyanappropriatemethodsuchasabubblepoint,diffusivefloworpressureholdtest”–除菌過濾膜應(yīng)該在使用前及使用后立即采取合適的方法確認(rèn)其完整性,可以采用泡點,擴(kuò)散流或壓力保持的方法.FDAGuidelineonSterileDrugProductsProducedbyAsepticProcessing(1987)FDA對于無菌操作生產(chǎn)的無菌藥品的要求(1987版)–“Normally,integritytestingofthefilterisperformedafterthefilterunitisassembledandsterilizedpriortouse.”–完整性測試通常在過濾器安裝,滅菌后使用前進(jìn)行PDATechnicalReport#26PDA技術(shù)報告26版–“ItgenerallyisregardedasacGMPrequirementthatfiltersorfiltersystemsroutinelybeintegritytestedbothpriortoandafteruse.”–現(xiàn)行的GMP要求過濾器及過濾系統(tǒng)在使用前及使用后均需要進(jìn)行完整性測試Where&WhenDoWeIntegrityTest?

何時和何地做完整性測試?WHENTODOIT?Detectwhat?什么時候做?檢查什么？Beforesterilizationfaultyhousings?滅菌前外殼的問題Beforeuseout-of-theboxfailures使用前包裝以外的問題Afterusesterilizationinducedfailures使用后滅菌的影響

stressinducedfailures

壓力的影響WhatAreTheIntegrityTestingChoices?

完整性測試方法的選擇?金標(biāo)準(zhǔn)Regulatory&qualityorganizationsneeddatafrombothtoassurereliableandpredictablefilterperformance法規(guī)和質(zhì)量管理需要數(shù)據(jù)確?？煽亢皖A(yù)知過濾器性能Destructivevs.Non-destructiveTesting

破壞性和非破壞性測試Theremustbeacorrelationbetweenadestructiveandanon-destructiveintegritytest破壞性和非破壞性測試兩者必須有關(guān)聯(lián)

Regulatoryrequirement法規(guī)需要

FDAAsepticGuidelinesFDA無菌指南

Validationjustificationfortheuseofatest

測試應(yīng)用的驗證理由IntegrityTestingCorrelations完整性測試關(guān)聯(lián)WhatNon-DestructiveIntegrityTestsareAvailable?何種非破壞性測試合適?BubblePointIntroduction起泡點介紹Bubblepointisthepressureatwhichgasdisplacesliquidfromthelargestsetoffilterporesandflowsrapidlythroughthefilter起泡點是氣體從濕潤的最大膜孔擠出液體快速流出時的壓力Bubblepointindicatesthemagnitudeoftheforcesholdingliquidinthefilterstructure起泡點顯示過濾結(jié)構(gòu)內(nèi)保持液體的力的大小Theoldestnon-destructiveintegritytest最傳統(tǒng)的非破壞性測試泡點測試BubblePointTestApplicability起泡點測試適用性BubblePointEquation起泡點等式泡點的影響因素接觸角的影響ExamplesoftheEffectofContactAngleandSurfaceTensiononBubblePointValues接觸角和表面張力對起泡點值的影響實例DiffusionTestingIntroduction擴(kuò)散流測試介紹Gasdissolvesinliquidheldintheporesofafullywettedmembranefilter.氣體溶解在完全濕潤的濾器膜孔內(nèi)的液體中Apressuredifferentialwillgiveadifferentgasconcentrationacrossthefilter.膜壓差造成跨膜氣體濃度差Resultsingasflowthroughtheliquiddissolvedinthefilterpores.結(jié)果使膜孔溶解的氣體流出擴(kuò)散流測試DiffusionTestingEquation擴(kuò)散測試方程AReasonforDiffusionTesting什么情況下采用擴(kuò)散測試DiffusionTestApplicability擴(kuò)散測試適用性FactorsAffectingDiffusionTests擴(kuò)散測試的影響因素ExampleofChangedDiffusionalFlow舉例ExampleofChangedDiffusionalFlow舉例ExampleofChangedDiffusionalFlow舉例“DiffusionTesting”Summary擴(kuò)散測試總結(jié)疏水濾膜采用有機(jī)溶劑進(jìn)行完整性測試的問題HydroCorrTestingHydrocorr測試HydroCorrTestResistancetowaterintrusion水浸入法測試HydroCorrTestResults測試結(jié)果HydroCorrTestConsiderations測試的注意點Musthavealeak-freesystem必須在一密閉系統(tǒng)內(nèi)進(jìn)行Filtersmustbedryandclean過濾芯必須干燥且干凈ItisrelativelyeasytoHydrocorrtest“veryhydrophobic”membranessuchasPTFE對于疏水性很強(qiáng)的濾芯,例PTFE材質(zhì)的膜,水浸入法是相當(dāng)容易Successfullytesting“l(fā)esshydrophobic”membranessuchasPVDFrequiresidealconditionsthatcanbedifficulttoachieveinactualbiopharmaceuticalprocesses在實際的生物制藥工藝中,測試一些疏水性不強(qiáng)的濾膜,例PVDF膜是比較困難的Temperaturechangesshouldbeminimized盡量減少溫度的變化Referencetestingisimportant相關(guān)的參考比較重要Musthaveacompletevalidationpackage必須有一完整的驗證文本Valuesmustbecomprehensivelycorrelatedtomicroorganismchallenge數(shù)據(jù)必須與細(xì)菌挑戰(zhàn)相關(guān)完整性測試失敗處理措施潤濕建議Summary總結(jié)BubblepointandDiffusion(or“Forwardflow”)areBOTHvalidintegritytestsasperregulatoryagencies.起泡點,擴(kuò)散流（或前向流）和HydroCorr是法規(guī)認(rèn)可的完整性測試方法Thechoiceofanintegritytestdependsonthetestingequipment,thefiltermanufacturer,thecompany‘sphilosophyandthetestingenvironment完整性測試的選擇倚賴測試裝置，過濾器制造商，公司體系和測試環(huán)境Bubblepointprovidesadirectcorrelationtobacterialretention,thecriticalperformancecharacteristic起泡點提供與細(xì)菌截留的直接關(guān)聯(lián)，重要的性能特性Diffusiontestingprovidesasensitivewaytodetermineintegrityforlargerareafilters擴(kuò)散測試提供一個敏感方法來測試大面積過濾器AutomatedIntegrityTesters自動完整性測試儀WhyDoPeopleUseAutomaticTesters為何用戶會選用自動測試儀PostSIPIntegrityTestingSIP后的完整性測試Revisionofannex1toECGuidetoGMPforsterilemedicinalproducts(1997)歐盟對于無菌藥品GMP指南的附件一(1997版)–“Theintegrityofthesterilizedfiltershouldbeverifiedbeforeuseandshouldbeconfirmedimmediatelyafterusebyanappropriatemethodsuchasabubblepoint,diffusivefloworpressureholdtest”–除菌過濾膜應(yīng)該在使用前及使用后立即采取合適的方法確認(rèn)其完整性,可以采用泡點,擴(kuò)散流或壓力保持的方法.FDAGuidelineonSterileDrugProductsProducedbyAsepticProcessing(1987)FDA對于無菌操作生產(chǎn)的無菌藥品的要求(1987版)–“Normally,integritytestingofthefilterisperformedafterthefilterunitisassembledandsterilizedpriortouse.”–完整性測試通常在過濾器安裝,滅菌后使用前進(jìn)行PDATechnicalReport#26PDA技術(shù)報告26版–“ItgenerallyisregardedasacGMPrequirementthatfiltersorfi