歐盟對(duì)滅菌技術(shù)的要求

歐盟對(duì)滅菌技術(shù)的要求SterilisationTechnology–

EURegulatoryExperiencesthecompliancegroupStanO’NeillCPAPE2011年會(huì)Agenda內(nèi)容Background背景TypicalProcessdescription典型工藝的描述Virtualinspection–typicalissues我們來(lái)作一次虛擬的檢查–看常見(jiàn)的問(wèn)題Miscellaneous其它Background背景ExperienceinindustryinRegAffairsandQA(asQP)priortoIMB在進(jìn)愛(ài)爾蘭藥品管理局前，有制藥、法規(guī)與QA(QP)的經(jīng)驗(yàn)10YearsIMB,experienceinmosttechnologies,EMEAIWG,andtraining.愛(ài)爾蘭藥品管理局10年，有多種技術(shù)、EMEAIWG以及培訓(xùn)方面的經(jīng)驗(yàn)Nowa“virtualinspector”現(xiàn)在是“事實(shí)上的檢查員”Soletsdoa“virtualinspection”好，我們來(lái)做當(dāng)一回“檢查員”Butletstalkaboutthesolutions/strategies/positions;notjusttheproblems.我們先來(lái)討論戰(zhàn)略位置/策略/解決方案，而不只是討論問(wèn)題Typicalprocess典型工藝Rawmaterialsampling原料取樣Materialsdispensed物料配制Rawmaterialsmixed原料混合Bulkproductfiltered已過(guò)濾的藥液Productfilled已灌裝產(chǎn)品Bulkproductstored藥液儲(chǔ)存Unitssealed密封產(chǎn)品Unitsstoppered已加塞產(chǎn)品Unitsinspected已檢查品Q(chēng)ualitycontrol質(zhì)量控制Sealedunitsterminallysterilised密封產(chǎn)品最終滅菌Colourcodingsystem彩色編碼系統(tǒng)Processingsteps操作步驟Aseptic無(wú)菌操作TerminallySterilized最終滅菌Problem問(wèn)題Solution解決方案Ancillarysteps輔助步驟ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsRawmaterialsamplingIdentitytestingofeachcontainerofAPIandexcipientsValidatedNIRacceptableoneachcontainerwithMAidentitytestoncompositeClassificationandgarbingforsamplingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.MaterialsdispensedClassificationandgarbingfordispensingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.Sampling&identification加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助操作原料取樣對(duì)每個(gè)容器的原料藥與輔料進(jìn)行鑒別實(shí)驗(yàn)可用經(jīng)驗(yàn)證的近紅外，在生產(chǎn)現(xiàn)場(chǎng)對(duì)組份作每個(gè)容器的鑒別試驗(yàn)取樣區(qū)級(jí)別與著裝C級(jí)區(qū)(與配制活動(dòng)同級(jí))，不穿室外衣服物料稱(chēng)量配料區(qū)級(jí)別與著裝C級(jí)區(qū)(與配制活動(dòng)同級(jí))，不穿室外衣服原料鑒別ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsRawmaterialsmixedBulkproductfilteredWeepingsealbetweencleanandnon-cleansideofmixingshaftUnderstandingthesystem,ensuringweepingfluidisWFI.Pre-use,poststerilizationintegritytestThetestshouldbeperformed,asconfirmedbytheEMEA.Numeroustechnicalsolutionsarepossible.TandPnotindependentofcontrolsystemsConsiderintroductionofindependentmonitoringsystem.Ataminimum,apressuregaugeperiodicallychecked.SterilizationofequipmentusingSIPT&Pmonitoring原料混合過(guò)濾的半成品攪拌軸清潔和不清潔間的密封要淋洗搞清楚系統(tǒng)，保證用注射用水淋洗使用前，滅菌后，作完整性測(cè)試正如EMEA確認(rèn)的那樣，應(yīng)進(jìn)行測(cè)試，可采用多種技術(shù)方案溫度與壓力不獨(dú)立于控制系統(tǒng)考慮引入獨(dú)立的監(jiān)測(cè)系統(tǒng)，至少定期檢查壓力表使用在線(xiàn)滅菌的滅菌設(shè)備加工步驟無(wú)菌最終滅菌問(wèn)題解決方案輔助步驟攪拌密封清潔、過(guò)濾器、監(jiān)測(cè)系統(tǒng)BulkproductstoredHoldingtimeexceededOftenamis-undestandingthatthereisanabsolutelimit.Longertimescanbevalidated,(takingintoaccountMAfiling).ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsHoldingtime半成品儲(chǔ)存存放時(shí)間超標(biāo)經(jīng)常出現(xiàn)誤解，認(rèn)為限度是絕對(duì)的。時(shí)間長(zhǎng)一些可經(jīng)過(guò)驗(yàn)證(考慮上市場(chǎng)許可的要求)加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助步驟存放時(shí)間ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsProductfilledAutoclavevalidationforporousloadsUseofairdetectorsinautoclaves,useofHTM2010validationcriteria,useof5pulsestomeetequilibrationtimecriteriaAsepticprocessingSterilizationofancillarysuppliese.g.pens,paperWheresteamsterilizationnotpossible,considergammairradiationSterilizationofcomponentsbyethyleneoxide-"torturouspath"VentplasticbagswithatyvexstripOperatorbehaviourPractiseobservationofsetupandobservationofgarbinginanon-familiarenvironment(e.g.Board.Room)wheresuitablefacilitiesnotavailable.Tunnelvalidation,lackofobjectivecriteriaConsideruseofobjectivecriteriasuchasFHVentplasticbags產(chǎn)品灌裝多孔裝載蒸汽滅菌的驗(yàn)證在滅菌柜采用空氣探測(cè)器，采用HTM2010標(biāo)準(zhǔn)，用5個(gè)脈沖使平衡時(shí)間達(dá)到標(biāo)準(zhǔn)無(wú)菌工藝輔助材料，如筆，紙的滅菌在不可能蒸汽滅菌時(shí)，考慮射線(xiàn)輻照滅菌部件用環(huán)氧乙烷滅菌--“折磨人的路徑"塑料袋口用tyvex條操作人員的行為在無(wú)合適設(shè)備時(shí)，在不熟悉的環(huán)境(如會(huì)議室)中，安排調(diào)試和著裝，觀(guān)察人員的行為隧道滅菌器驗(yàn)證無(wú)客觀(guān)標(biāo)準(zhǔn)考慮使用客觀(guān)標(biāo)準(zhǔn)如FH加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助步驟紙筆滅菌及人員行為UnitsstopperedFreezedrying;pressurenotmonitoredduringsterilisationofchamberDesignindependentpressuremonitoringintosterilisationcycle.Freezedrying;nosystemtoassessforshelfcoolantleakage,potentiallyenteringunitsUsepressureholdtesttocheckshelfintegrity.Maynecessitatevapourpressurecalculationsforcoolant.2ndchoice-declarechembertobesanitisedratherthansterilised2ndchoice-checkcoolantlevelsinbetweenbatchesSterilisationofstoppersusingstopperprocessorConsideredtobeSIPratherthanautoclaving,solowersterilityassuranceDesigntakingaccountofsomeaspectsofautoclavesandautoclavevalidationcriteria.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepspressurenotmonitored已加塞瓶/單元凍干：凍干腔室/箱滅菌過(guò)程中沒(méi)監(jiān)測(cè)壓力在滅菌程序設(shè)計(jì)中,增加獨(dú)立的壓力監(jiān)測(cè)凍干：無(wú)系統(tǒng)來(lái)評(píng)估冷媒的泄露,有可能進(jìn)入瓶/單元中使用壓力保持試驗(yàn)對(duì)系統(tǒng)檢漏，有必要計(jì)算冷媒的蒸汽壓第2種辦法-聲明腔室是消毒處理的，不是滅菌的第2種辦法-在批與批之間檢查冷媒的水平用塞處理機(jī)滅菌膠塞考慮在線(xiàn)滅菌而不是高壓滅菌,由此降低了無(wú)菌保證水平設(shè)計(jì)中考慮蒸汽滅菌的相關(guān)因素及蒸汽滅菌程序驗(yàn)證的標(biāo)準(zhǔn)加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助步驟凍干Unitssealedcapping!wheretobegin!GradeAairsupply.Viablemonitoringofarea.Raisedstopperdetectionsystemmeasuring"thegap"FMEAforparametricreleaseincompleteorinaccurateFMEAspreparedonlybyexperts.Considerusingfreshpairofeyes.DoublecheckcrucialelementssuchastrainingUnitssteamsterilisedProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsCapping已密封單元軋蓋!在此開(kāi)始!A級(jí)送風(fēng)，測(cè)浮游菌。膠塞監(jiān)測(cè)系統(tǒng)，以檢查“縫隙、凸起及錯(cuò)位”FMEA對(duì)參數(shù)放行不完全或不準(zhǔn)確FMEA僅由專(zhuān)家編寫(xiě)，考慮用新的眼光來(lái)審視，重點(diǎn)審視培訓(xùn)這類(lèi)關(guān)鍵要素作蒸汽滅菌軋蓋加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助步驟UnitsinspectedValidationofautomatedinspectionsystemscomplicatedvshumansUnderstandlimitationsofhumaninspectione.g.90%detectabilitycutoffpointForsemi-automatedequipment,noluxreadingsinaccordancewithPh.EurDefendpositionbasedondifferenttypeofequipment,differentlightsource,noblack/whitebackground,inabilitytoplaceluxometerinameaningfullocationQualitycontrolSterilitytestmedianotinaccordancewithsuppliersinstructions(overcookedissue)Validateliquidloadsfor121degCfor15mins,orobtainconfirmationfromsupplierfrommediathatnotanissue.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsautomatedinspectionsystems檢查單元驗(yàn)證自動(dòng)檢測(cè)系統(tǒng)，比人工法復(fù)雜理解人工檢查的局限性，如90%的可檢出率對(duì)于半自動(dòng)設(shè)備，不需要符合歐洲藥典照度的要求根據(jù)不同設(shè)備設(shè)放置位置，不同光源，無(wú)黑/白色背景，不能在一個(gè)有意義的位置放照度計(jì)質(zhì)量控制無(wú)菌檢查培養(yǎng)基不按供應(yīng)商說(shuō)明處理(煮得過(guò)久的問(wèn)題)對(duì)121℃x15分鐘滅菌的液體裝載做驗(yàn)證，或從培養(yǎng)基供應(yīng)商確認(rèn)無(wú)問(wèn)題加工步驟無(wú)菌操作最終滅菌問(wèn)題解決方案輔助步驟自動(dòng)檢查系統(tǒng)Miscellaneous其它TransferbarforALULsystemsnotsterilisabl