歐盟對滅菌技術(shù)的要求

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

EURegulatoryExperiencesthecompliancegroupStanO’NeillCPAPE2011年會Agenda內(nèi)容Background背景TypicalProcessdescription典型工藝的描述Virtualinspection–typicalissues我們來作一次虛擬的檢查–看常見的問題Miscellaneous其它Background背景ExperienceinindustryinRegAffairsandQA(asQP)priortoIMB在進(jìn)愛爾蘭藥品管理局前，有制藥、法規(guī)與QA(QP)的經(jīng)驗10YearsIMB,experienceinmosttechnologies,EMEAIWG,andtraining.愛爾蘭藥品管理局10年，有多種技術(shù)、EMEAIWG以及培訓(xùn)方面的經(jīng)驗Nowa“virtualinspector”現(xiàn)在是“事實上的檢查員”Soletsdoa“virtualinspection”好，我們來做當(dāng)一回“檢查員”Butletstalkaboutthesolutions/strategies/positions;notjusttheproblems.我們先來討論戰(zhàn)略位置/策略/解決方案，而不只是討論問題Typicalprocess典型工藝Rawmaterialsampling原料取樣Materialsdispensed物料配制Rawmaterialsmixed原料混合Bulkproductfiltered已過濾的藥液Productfilled已灌裝產(chǎn)品Bulkproductstored藥液儲存Unitssealed密封產(chǎn)品Unitsstoppered已加塞產(chǎn)品Unitsinspected已檢查品Qualitycontrol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無菌操作TerminallySterilized最終滅菌Problem問題Solution解決方案Ancillarysteps輔助步驟ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsRawmaterialsamplingIdentitytestingofeachcontainerofAPIandexcipientsValidatedNIRacceptableoneachcontainerwithMAidentitytestoncompositeClassificationandgarbingforsamplingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.MaterialsdispensedClassificationandgarbingfordispensingareaGradeC(equivalentactivitytocompounding).Nooutdoorclothing.Sampling&identification加工步驟無菌操作最終滅菌問題解決方案輔助操作原料取樣對每個容器的原料藥與輔料進(jìn)行鑒別實驗可用經(jīng)驗證的近紅外，在生產(chǎn)現(xiàn)場對組份作每個容器的鑒別試驗取樣區(qū)級別與著裝C級區(qū)(與配制活動同級)，不穿室外衣服物料稱量配料區(qū)級別與著裝C級區(qū)(與配制活動同級)，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，作完整性測試正如EMEA確認(rèn)的那樣，應(yīng)進(jìn)行測試，可采用多種技術(shù)方案溫度與壓力不獨立于控制系統(tǒng)考慮引入獨立的監(jiān)測系統(tǒng)，至少定期檢查壓力表使用在線滅菌的滅菌設(shè)備加工步驟無菌最終滅菌問題解決方案輔助步驟攪拌密封清潔、過濾器、監(jiān)測系統(tǒng)BulkproductstoredHoldingtimeexceededOftenamis-undestandingthatthereisanabsolutelimit.Longertimescanbevalidated,(takingintoaccountMAfiling).ProcessingstepsAsepticTerminallySterilisedProblemSolutionAncillarystepsHoldingtime半成品儲存存放時間超標(biāo)經(jīng)常出現(xiàn)誤解，認(rèn)為限度是絕對的。時間長一些可經(jīng)過驗證(考慮上市場許可的要求)加工步驟無菌操作最終滅菌問題解決方案輔助步驟存放時間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證在滅菌柜采用空氣探測器，采用HTM2010標(biāo)準(zhǔn)，用5個脈沖使平衡時間達(dá)到標(biāo)準(zhǔn)無菌工藝輔助材料，如筆，紙的滅菌在不可能蒸汽滅菌時，考慮射線輻照滅菌部件用環(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合適設(shè)備時，在不熟悉的環(huán)境(如會議室)中，安排調(diào)試和著裝，觀察人員的行為隧道滅菌器驗證無客觀標(biāo)準(zhǔn)考慮使用客觀標(biāo)準(zhǔn)如FH加工步驟無菌操作最終滅菌問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/箱滅菌過程中沒監(jiān)測壓力在滅菌程序設(shè)計中,增加獨立的壓力監(jiān)測凍干：無系統(tǒng)來評估冷媒的泄露,有可能進(jìn)入瓶/單元中使用壓力保持試驗對系統(tǒng)檢漏，有必要計算冷媒的蒸汽壓第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)滅菌膠塞考慮在線滅菌而不是高壓滅菌,由此降低了無菌保證水平設(shè)計中考慮蒸汽滅菌的相關(guān)因素及蒸汽滅菌程序驗證的標(biāo)準(zhǔn)加工步驟無菌操作最終滅菌問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!在此開始!A級送風(fēng)，測浮游菌。膠塞監(jiān)測系統(tǒng)，以檢查“縫隙、凸起及錯位”FMEA對參數(shù)放行不完全或不準(zhǔn)確FMEA僅由專家編寫，考慮用新的眼光來審視，重點審視培訓(xùn)這類關(guān)鍵要素作蒸汽滅菌軋蓋加工步驟無菌操作最終滅菌問題解決方案輔助步驟UnitsinspectedValidationofautomatedinspectionsystemscomplicatedvshumansUnderstandlimitationsofhumaninspectione.g.90%detectabilitycutoffpointForsemi-automatedequipment,noluxreadingsinaccordancewithPh.EurDefendpositionbasedondifferenttypeofequipment,differentlightsource,noblack/whitebackground,inabilitytoplaceluxometerinameaningfullocationQualitycontrolSterilitytestmedianotinaccordancewithsuppliersinstructions(overcookedissue)Validateliquidloadsfor121degCfor15mins,orobtainconfirmationfromsupplierfrommediathatnotanissue.ProcessingstepsAsepticTerminallySterilizedProblemSolutionAncillarystepsautomatedinspectionsystems檢查單元驗證自動檢測系統(tǒng)，比人工法復(fù)雜理解人工檢查的局限性，如90%的可檢出率對于半自動設(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，無黑/白色背景，不能在一個有意義的位置放照度計質(zhì)量控制無菌檢查培養(yǎng)基不按供應(yīng)商說明處理(煮得過久的問題)對121℃x15分鐘滅菌的液體裝載做驗證，或從培養(yǎng)基供應(yīng)商確認(rèn)無問題加工步驟無菌操作最終滅菌問題解決方案輔助步驟自動檢查系統(tǒng)Miscellaneous其它TransferbarforALULsystemsnotsterilisabl