淺析GMP檢查發(fā)現(xiàn)的風(fēng)險(xiǎn)分級

1、HealthProductsandFoodBranchInspectorate食品與健康類產(chǎn)品檢查員Guide-0023指南-0023RiskClassificationofGMPObservations,2003editionGMP檢查發(fā)現(xiàn)的風(fēng)險(xiǎn)分級，2003版Supersedes:June1st,2000editionDateissued:April4th,2003Dateofimplementation:June1st,2003Cedocumentestaussidisponibleenfraaisn.?本文可提供法語版GuiadaTABLEOFCONTENTS目錄TOCo1-5hz1.

2、0PURPOSE目的42.0BACKGROUND背景43.0SCOPE范圍44.0DEFINITIONS定義:55.0GUIDE指南正文7Assignmentoftherisktoanobservation針對缺陷界定風(fēng)險(xiǎn)7Assignmentoftheinspectionrating檢查評定8Risk1observation:1類風(fēng)險(xiǎn)缺陷8Risk2observation:2類風(fēng)險(xiǎn)缺陷8Risk3observations:3類風(fēng)險(xiǎn)缺陷9Additionalguidanee補(bǔ)充9Appendix1附錄110Appendix2附錄213Appendix3附錄3211.0PURPOSE目的Tocl

3、assifytheobservationsnotedduringestablishmentinspectionsaccordingtotheirrisk.依據(jù)風(fēng)險(xiǎn)的程度對企業(yè)檢查中的發(fā)現(xiàn)進(jìn)行分級。ToensureuniformityamongtheinspectorsoftheHealthProductsandFoodBranchInspectorate(theInspectorate)intheattributionoftheratingfollowingestablishmentinspections.確保食品與健康產(chǎn)品檢查員(檢查員)在對企業(yè)進(jìn)行評估時(shí)采用統(tǒng)一的標(biāo)準(zhǔn)。Toinformth

4、eindustryofthesituationsthattheInspectorateconsidersunacceptableandthatwillgenerateaNonCompliant(NC)ratingfollowinganinspection.將各種不被檢察員接受進(jìn)而導(dǎo)致認(rèn)證失敗的情況明確告知企業(yè)。2.0BACKGROUND背景Duringanestablishmentinspection,deviationsfromFothoedandDrugRegulationsandthecurrenteditionoftheGoodManufacturingPractices(GMP)gu

5、idelinesarenotedbytheinspectorandthesedeviationsappearasobservationsintheinspectionexitnotice.Ajudgementbasedontheseobservationsisthenmadebytheinspectorandanoverallrecommendationforthecontinuationorissuanceoftheestablishmentlicence(ratingofCompliance)ornottocontinueorissuethelicence(ratingofNonCompl

6、iance)isgiven.AttributionofaNCratingmayhaveseriousconsequencesforacompany,rangingfromtheimplementationofimportantcorrectivemeasurestothetemporarysuspensionorterminationoftheEstablishmentLicence(EL).Therefore,thesesituationsofnon-conformityhavetobewelldefined,unambiguousanddirectlysupportedbytheappli

7、cableregulations.在工廠檢查時(shí)，凡違反食品藥品法和現(xiàn)行GMP的行為都將被檢察員記錄下來作為離開時(shí)檢查通告中的檢查缺陷?；谶@些缺陷，檢查人員將做出判斷并對是否應(yīng)該授予或延續(xù)企業(yè)許可證(合規(guī)評定)或不授予或取消企業(yè)許可證(不合規(guī)評定)給出綜合性意見。得到不合規(guī)評定有可能給企業(yè)帶來嚴(yán)重的后果，包括停業(yè)整頓或吊銷執(zhí)照。因此，所有不合規(guī)的界定應(yīng)有清晰明確的定義并有章可循。3.0SCOPE范圍ThedefinitionofadruginCanadacoversawidevarietyofproductsrangingfrompharmaceuticalsandbiologicstonat

8、uralhealthproductssuchashomeopathicsandherbalpreparations.ThisguidancedocumentcoversallsuchproductstowhichDivision2ofPartCoFfothoedandDrugRegulationsappliesandisbasedonthecurrenteditionoftheGMPGuidelines.ItisrecognisedthattheevaluationoftheconformitytotheGMPshouldbecommensuratewiththeriskinvolvedtak

9、ingintoaccountthenatureandextentofthedeviationinrelationwiththecategoryofproductsevaluated.Nonetheless,mostofthesituationsinvolvingfraud,misrepresentationorfalsificationofproductsordatawillgenerateaNCrating,irrespectiveofthecategoryofproductsinvolved.在加拿大，藥品定義廣泛，從生化藥物到自然的健康產(chǎn)品如順勢療法和草藥都屬于此范疇。本文依照現(xiàn)行GMP

10、制定，適用于所有食品藥品法C部第2章節(jié)所規(guī)定的產(chǎn)品。GMP合規(guī)評估和風(fēng)險(xiǎn)評估是同時(shí)進(jìn)行的，而風(fēng)險(xiǎn)評估需要根據(jù)缺陷的性質(zhì)與程度同時(shí)與評估產(chǎn)品的類別聯(lián)系起來，這些都已得到業(yè)界的認(rèn)同。但是，大多數(shù)導(dǎo)致認(rèn)證失敗的發(fā)現(xiàn)如產(chǎn)品或數(shù)據(jù)存在虛假，歪曲或蓄意偽造都沒有考慮產(chǎn)品的類別。Theappendicesattachedtothepresentdocumentdescribetheobservationsrelatedtoeachcategoryofrisk.Pleasenotethatthelistofobservationsineachappendixisnotexhaustiveandthataddi

11、tionalobservationsmaybeaddedwhereappropriate.本文附錄描述了檢查發(fā)現(xiàn)相應(yīng)的風(fēng)險(xiǎn)級別。請注意附錄中并未完全列舉所有的檢查發(fā)現(xiàn)，需要之處可以補(bǔ)充。ThenumberingsystemassignedtoeachsectionintheappendicesisareferencetotheapplicableregulationsinthecurrenteditionoftheGMPguidelines.附件各章節(jié)中的數(shù)字代表現(xiàn)行GMP法規(guī)中相關(guān)章節(jié)，以備參考。4.0DEFINITIONS定義:Thefollowingdefinitionsareprovi

12、dedtocomplementthosealreadyavailableundertheglossaryoftermsinthecurrenteditionoftheGMPGuidelinesorotherrelateddocumentsreferencedintheGMPGuidelines.以下定義是對現(xiàn)行GMP法規(guī)或其相關(guān)文件釋義部分的補(bǔ)充Observation缺陷:AdeviationordeficiencytoGMPnotedbyaninspectorduringtheinspectionofadrugestablishmentthatisconfirmedinwritingtoth

13、ecompanyintheexitnoticTeh.eobservationsareclassifiedas“Critica,l“M”ajora”nd“Othera”ndareassignedariskclassification,rangingfrom“1crfiotircal”to2for“majorto”3for“other”.藥品企業(yè)檢查過程中，所有被檢查人員寫入報(bào)告的偏差或不足。缺陷分為嚴(yán)重，主要和一般，分別用1（代表嚴(yán)重），2（代表主要），3（代表一般）表示其風(fēng)險(xiǎn)級別。Criticalobservation嚴(yán)重缺陷：Observationdescribingasituationth

14、atislikelytoresultinanon-compliantproductorasituationthatmayresultinanimmediateorlatenthealthriskandanyobservationthatinvolvesfraud,misrepresentationorfalsificationofproductsords嚴(yán)重缺陷包括可能導(dǎo)致產(chǎn)品不合格的缺陷，可能對健康造成立即的或延后的危害的缺陷以及涉及產(chǎn)品或數(shù)據(jù)存在虛假，歪曲或蓄意偽造的缺陷。AppendixIlistsobservationsthattheInspectorateconsiderscriti

15、calwhichwillbeassignedaRisk1.附錄1列出了檢察員認(rèn)為屬于1類風(fēng)險(xiǎn)的嚴(yán)重缺陷。Majorobservation主要缺陷：Observationthatmayresultintheproductionofadrugnotconsistentlymeetingitsmarketingauthorization.主要缺陷是指導(dǎo)致產(chǎn)品不能持續(xù)達(dá)到既定標(biāo)準(zhǔn)的缺陷。Appendix2listsobservationsthatareconsideredmajorandwhichwillbeassignedaRCkiiainRisk2observationsmaybeupgraded

16、toRisk1.Theyareindicatedwithanari)ow附錄2列出了檢察員認(rèn)為屬于2類風(fēng)險(xiǎn)的主要缺陷。一部分可以上升為1類風(fēng)險(xiǎn)的2類風(fēng)險(xiǎn)已用箭頭標(biāo)明。Otherobservation般缺陷：ObservationthatisneithercriticalnormajorbutisadeparturefromtheGMP.一般缺陷指不屬于嚴(yán)重或主要缺陷但偏離GMP要求的缺陷?！癘therobservationsarenotlistedassuch(Observationsthatareneithercriticalnormajorareconsideredas“otherandw

17、illbeassignedaRisk3)Appendix3listsRisk3observationsthatmaybeupgradedtoRisk2.般風(fēng)險(xiǎn)沒有像1，2類風(fēng)險(xiǎn)一樣被全部列舉出來(所有不屬于嚴(yán)重或主要的缺陷都?xì)w于一般缺陷，屬3類風(fēng)險(xiǎn)。)附錄3列舉了可以上升為2類風(fēng)險(xiǎn)的3類風(fēng)險(xiǎn)。Criticalproduc最高風(fēng)險(xiǎn)產(chǎn)品:Acriticalproductisoneforwhichanyofthefollowingcriteriamayapply:下列情況有任何一條成立，則該產(chǎn)品屬于最高風(fēng)險(xiǎn)產(chǎn)品。Inarrowtherapeuticwindo具有窄治療窗的藥物Ihightoxicit

18、y毒性藥物Isterileproduc無菌產(chǎn)品工biologicaldru生物藥品工complexmanufacturingproce生產(chǎn)工藝復(fù)雜的產(chǎn)品Processforwhichslightdeviationsinthecontrolofparanceteld5resultinanon-uniformproductoraproductnotmeetingitsspecifications.Asexample,powdermixingorgranulationforlowdosagesolidforms,longacting/delayedactionproducts,sterileprod

19、i工藝參數(shù)控制上一點(diǎn)小的偏差便能引發(fā)產(chǎn)品不均一或不合格的情況。如小劑量固體制劑中的混合與制粒，長效或緩釋藥品，無菌藥品。Note注意：OTClowdosagevitaminsandmineralspreparationsandCategory4products(aslistedinInterpretation2.3undersectionC.02.028)shouldnotbeconsideredascriticalproductsevenwhenthemanufacturingprocessesinvoIvedarecomplex.非處方低劑量藥物如維生素，微量元素類制劑以及4類產(chǎn)品(參見章

20、節(jié)下2.3的解釋)盡管制造工藝非常復(fù)雜但仍不被認(rèn)作為最高風(fēng)險(xiǎn)產(chǎn)品。Highriskproduc高風(fēng)險(xiǎn)產(chǎn)品:Anyproductthatmaytriggerahealthriskevenatlowlevels,followingcross-contamination.Thoseincludebutarenotlimitedtopenicillins,certaincytotoxicandbiologicalproducts.任何只需小劑量便能危害健康，引起交叉污染的產(chǎn)品，包括但不僅限于：盤尼西林，部分細(xì)胞毒素和生物制品。LowRiskproduct風(fēng)險(xiǎn)產(chǎn)品:ProductssuchasCateg

21、ory4product（aslistedinInterpretation2.3undersectionC.02.028）,naturalhealthproductsincludingvitaminsandmineralspreparationsthatarenotascheduledrugorasteriledrug,andcertaintopicalnonprescriptionveterinaryformulationsregistereoideugs”.4類產(chǎn)品（參見節(jié)下2.3的解釋），自然健康產(chǎn)品包括維生素，微量元素類非周期性，非無菌性制劑，還有部分注冊為“老藥”的非處方類獸藥。Acr

22、onymS縮寫:C:Complian合規(guī)CIP:Clean-ln-Placet線清潔COA:EL:CertificateofAnalys檢驗(yàn)報(bào)告EstablishmentLicen企業(yè)許可證GMP:HVAC:GoodManufacturingPractices品生產(chǎn)質(zhì)量管理規(guī)范Heat,Ventilation,AirConditionin空調(diào)系統(tǒng)IRS:InspectionReportingSyste檢查報(bào)告MRA:MutualRecognitionAgreeme互認(rèn)協(xié)議NC:Non-compliant不合規(guī)OTC:Over-The-Counter非處方藥PM:PackagingMateria

23、包材PW:PurifiedWater純化水QC:QualityControl質(zhì)量管理部門（QA+QC）RM:RawMaterial原料WFI:WaterForInjection注射用水5.0GUIDE指南正文Assignmentoftherisktoanobservation對缺陷界定風(fēng)險(xiǎn)Whereasitisrecognizedthatitisimpossibletoencompasseverysituationthatmaygeneratearisk,thefollowingprinciplesshouldbeconsidered:鑒于我們都認(rèn)識(shí)到不可能將所有可能導(dǎo)致危險(xiǎn)的情況都羅列出來，

24、因此在界定風(fēng)險(xiǎn)時(shí)請考慮以下準(zhǔn)則：-Theriskassignedwillbeinrelationtothenatureofthedeviationaswellasthenumberofoccurrences.風(fēng)險(xiǎn)的界定應(yīng)與缺陷的性質(zhì)與發(fā)生次數(shù)關(guān)聯(lián)起來。Generally,whenonlylowriskproductsareinvoIved,arisk1willnotbeassignedtoobservationsdescribedinAppendix1,exceptforextremesituationssuchasfraudorwidespreadcross-contamination,in

25、festationorunsanitaryconditions.般而言，當(dāng)涉及的產(chǎn)品為低風(fēng)險(xiǎn)產(chǎn)品時(shí)，附錄1中所描述的缺陷不應(yīng)被界定為1類風(fēng)險(xiǎn)，除非極端情況發(fā)生，如：虛假，大范圍交叉污染，感染或不衛(wèi)生情形。Wherearisk2observationisre-evaluatedasarisk1(risk2observationwithanarrtohwis),situationisimmediatelybroughttotheattentionofcothmepanysofficials,properexplanationwillbeprovidedtotheestablishmentandth

26、isexplanationshouldbecaptured“inIntshpeectorsComments”fieldofthe“InspecntioSummary”intheIRS.當(dāng)2類風(fēng)險(xiǎn)被重新評估為一類風(fēng)險(xiǎn)時(shí)(2類風(fēng)險(xiǎn)中標(biāo)有箭頭的缺陷)，應(yīng)立即告知企業(yè)的管理層并進(jìn)行合理的解釋，解釋內(nèi)容應(yīng)記錄在檢查報(bào)告總結(jié)部分的檢察員意見欄中。Assignmentoftheinspectionratin檢查評定Theoverallinspectionratingassignedisbasedontheriskinvolvedtakingintoaccountthenatureandextentofthe

27、deviationswiththecategoryofproductsevaluated.綜合評定基于存在的風(fēng)險(xiǎn)，缺陷的性質(zhì)與程度以及評估產(chǎn)品的類別。5.2.1Risk1observation類風(fēng)險(xiǎn)缺陷Generally,aNCratingisassignedwhenaRisk1observationisnotedduringaninspection.一般而言，出現(xiàn)1類風(fēng)險(xiǎn)缺陷，企業(yè)將被評定為不合規(guī)。Suchsituationisimmediatelybroughttotheattentionmanagementistobenotifiedinatimelymanner.這類情況應(yīng)被立即告知企

28、業(yè)管理層并及時(shí)報(bào)告給檢查機(jī)構(gòu)管理層Whereintheopinionoftheinspectortheresultingproductspresentasignificanthealthhazard,appropriateenforcementactionsmaybeinitiated.如果檢察員認(rèn)為相關(guān)產(chǎn)品存在對健康的嚴(yán)重威脅，將會(huì)對其啟動(dòng)適當(dāng)?shù)膹?qiáng)制手段。Risk2observation:2類風(fēng)險(xiǎn)缺陷Generally,aCratingisassignedwhenRisk2observationsarenotedduringaninspeHcotiowne.ver,aNCratingmayb

29、eassignedinthefollowingsituations:一般而言，出現(xiàn)2類風(fēng)險(xiǎn)缺陷，企業(yè)仍將被評定為合規(guī)，但在以下情況出現(xiàn)時(shí)，企業(yè)將被評定為不合規(guī)：-WhennumerousRisk2observationsarenotedduringaninspectionindicatingthatthecompanydoesnotcontrolitsprocessesandoperationssufficiently.當(dāng)2類風(fēng)險(xiǎn)缺陷顯示出企業(yè)在工藝和運(yùn)作方面沒能加以足夠的控制時(shí)。-RepetitionofmanyRisk2observationsnotedduringpreviousinsp

30、ectionsindicatingthatthecompanydidnot:當(dāng)許多前次檢查發(fā)現(xiàn)的2類風(fēng)險(xiǎn)缺陷重復(fù)出現(xiàn)，顯示出企業(yè)沒有能夠-implementthecorrectiveactionssubmittedfollowingthepreviousinspectionor按照遞交的計(jì)劃執(zhí)行前一次檢查缺陷的糾正工作或-didnotputinplaceadequatepreventiveactionsinatimelymannertoavoidrecurrenceofsuchdeviations.沒有及時(shí)采取足夠的預(yù)防措施來防止偏差的再次發(fā)生。523Risk3observations：3類風(fēng)

31、險(xiǎn)缺陷ACratingwillbeassignedinallsituationswhereonlyRisk3observationsarenoted.如果僅發(fā)現(xiàn)3類風(fēng)險(xiǎn)缺陷，企業(yè)將被評定為合規(guī)的。5.3Additionalguidance卜充WhenaNCratingisassigned,theinspectorwillissueadraftInspectionExitNoticeduringtheexitmeeting.Thedraftinspectionexitnoticewillbereviewedforqualityassurancepurposesbeforethefinalrepo

32、rtisissuedtoanestablishment.當(dāng)企業(yè)被評定為不合規(guī)時(shí)，檢查員將在檢查結(jié)束的總結(jié)會(huì)上遞交檢查通告草稿。在最終報(bào)告發(fā)至企業(yè)之前，草稿可以用于質(zhì)量保證目的的閱讀。Whenobservation(s)leadingtoaNCratingaremade,theInspectionExitNoticecouldbeissuedwithaCratingif,duringtheinspection:當(dāng)出現(xiàn)導(dǎo)致企業(yè)被評定為不合規(guī)的缺陷時(shí)，如果企業(yè)能夠在檢查其間完成下列工作，檢查通告仍會(huì)給出企業(yè)合規(guī)的結(jié)論：-theestablishmentimmediatelyimplementsall

33、necessaryactionstoresolvethecause(s)oftheobservation(s)leadingtotheNCratingand,企業(yè)立即采取必要措施根除導(dǎo)致缺陷發(fā)生的原因并且sufficientassurancecanbeprovidedtopreventarecurrence.-采取足夠的預(yù)防措施防止缺陷再度發(fā)生。Insuchinstances,theriskassignedtotheobservationwillremainthesame.這種情況下，原來對缺陷所作的風(fēng)險(xiǎn)評估等級仍保持不變。Ifthemanagementofthecompanywishesto

34、disputetheresultsoftheinspectionre“poDrt,istphueteresolutionandappea”lsmechanismdescribedintheGMPandELEnforcementPolicyPOL-0004shouldbefollowed.如果企業(yè)希望對檢查結(jié)果進(jìn)行申辯，GMP與企業(yè)強(qiáng)制認(rèn)證政策POL-0004中的“爭議解決與上訴”機(jī)制將被啟動(dòng)。Appendix1附錄1Risk1(Critical)Observations類風(fēng)險(xiǎn)(嚴(yán)重)缺陷廠房-Noairfiltrationsystemtoeliminateairbornecontaminant

35、sthatarelikelytobegeneratedduringfabricationorpackaging.-沒有空氣過濾系統(tǒng)以消除生產(chǎn)和包裝時(shí)可能產(chǎn)生的沉降污染。-Generalizedmalfunctioningoftheventilationsystem(s)withevidenceofwidespreadcrosscontamination.大范圍交叉污染的事實(shí)表明通風(fēng)系統(tǒng)存在故障。Inadequatesegregationofmanufacturingortestingareasfromothermanufacturinghairgehasforriskproducts.高風(fēng)險(xiǎn)產(chǎn)

36、品之間的生產(chǎn)區(qū)域或測試區(qū)域沒能有效地隔開。設(shè)備Equipmentusedforcomplexmanufacturingoperationsofcriticalproductsnotqualifiedandwithevidenceofmalfunctioning.用于最高風(fēng)險(xiǎn)產(chǎn)品復(fù)雜生產(chǎn)過程的設(shè)備不合規(guī)定同時(shí)也存在故障。人員IndividualinchargeofQualityControl(QC)orproductionforafabricatocrroitfical/highriskproductsdoesnotholdauniversitydegreeinasciencerelatedto

37、theworkbeingconadnucdteddoesnothavesufficientpracticalexperienceintheirresponsibilityarea.管理最高風(fēng)險(xiǎn)，高風(fēng)險(xiǎn)產(chǎn)品質(zhì)量管理或生產(chǎn)的人員沒有相關(guān)領(lǐng)域的大學(xué)文憑同時(shí)缺乏足夠的實(shí)踐經(jīng)驗(yàn)。衛(wèi)生-Evidenceofwidespreadaccumulationofresidues/extraneousmatterindicativeofinadequatecleaning.-清潔的不夠充分，存在大范圍殘留/異物積聚。-Evidenceofgrossinfestation.-明顯的蟲害或污染原料檢驗(yàn)Evidenceo

38、ffalsificationormisrepresentationofanalyticalresults.分析結(jié)果造假或歪曲Noevidenceoftesting(COA)availablefromthesupplier/syntheatnizdernotestingdonebytheCanadianfabricator.缺少供應(yīng)商的檢驗(yàn)報(bào)告同時(shí)企業(yè)也沒做相關(guān)的測試。生產(chǎn)控制-NowrittenMasterFormula.-沒有書面的主處方-MasterFormulaormanufacturingbatchdocumentshowinggrossdeviationsorsignificantc

39、alculationerrors.-主處方或生產(chǎn)批記錄存在明顯的偏差或嚴(yán)重的計(jì)算錯(cuò)誤。-Evidenceoffalsificationormisrepresentationofmanufacturingandpackagingorders.-生產(chǎn)和包裝訂單的造假或錯(cuò)誤質(zhì)控部門-NopersoninchargeofQCavailableonpremisesinCanada.-加拿大工廠內(nèi)沒有質(zhì)量管理負(fù)責(zé)人-QCdepartmentnotadistinctandindependentunit,lackingrealdecisionalpoweer,viwdiethncethatQCdecision

40、sareoftenoverruledbyproductiondepartmentormanagement.-質(zhì)量管理部門不是獨(dú)立的機(jī)構(gòu)，缺乏真正的決定權(quán)，有證據(jù)表明質(zhì)量管理部門的決定常被生產(chǎn)或管理層否定。成品檢驗(yàn)-Finishedproductnottestedforcompliancewithapplicablespecificationsbytheimporter/distributorbeforereleaseforsaleandnoevidenceisavailablethattheproductshavebeentestedbythefabricator.-銷售前，進(jìn)口商/分銷商沒有

41、按照合適的標(biāo)準(zhǔn)對成品進(jìn)行檢驗(yàn)同時(shí)沒有證據(jù)顯示生產(chǎn)商做過相關(guān)測試。-Evidenceoffalsificationormisrepresentationoftestingresults/forgeryofCOA.-檢驗(yàn)結(jié)果造假或歪曲/偽造檢驗(yàn)報(bào)告記錄-Evidenceoffalsificationormisrepresentationofrecords.-記錄造假或歪曲事實(shí)穩(wěn)定性-Nodataavailabletoestablishtheshelf-lifeofproducts.-缺少建立產(chǎn)品效期的數(shù)據(jù)-Evidenceoffalsificationormisrepresentationofst

42、abilitydata/forgeryofCOA.-穩(wěn)定性數(shù)據(jù)的造假或歪曲/偽造檢驗(yàn)報(bào)告無菌產(chǎn)品-CriticalsterilizationcyclesbasedonProbabilityofSurvivalnotvalidated.-關(guān)鍵滅菌過程沒有基于細(xì)菌存活率的進(jìn)行驗(yàn)證。-WaterforInjection(WFI)systemsnotvalidatedwithevidenceofproblemssuchasmicrobial/endotoxincountsnotwithinspecifications.-注射用水系統(tǒng)未作驗(yàn)證，存在微生物/內(nèi)毒素超標(biāo)的情況。-Nomediafillspe

43、rformedtodemonstratethevalidityofasepticfillingoperations.-無菌灌裝工藝未做培養(yǎng)基灌裝驗(yàn)證。-Noenvironmentalcontrols/Nomonitoringforviablemicroorganismsduringfillingforasepticallyfilledproducts.-無菌灌裝產(chǎn)品在灌裝期間缺少環(huán)境監(jiān)控/微生物監(jiān)控。-Asepticfillingoperationsmaintainedfollowingunsatisfactoryresultsobtainedformediafills.-培養(yǎng)基灌裝驗(yàn)證失敗后

44、仍繼續(xù)進(jìn)行無菌灌裝生產(chǎn)。-Batchesfailinginitialsterilitytestreleasedforsaleonthebasisofasecondtestwithoutproperinvestigation.-產(chǎn)品基于第二次無菌檢測結(jié)果放行，而對首次的菌檢失敗未作調(diào)查。Appendix2附錄2Risk2(Major)Observations2類風(fēng)險(xiǎn)(主要)缺陷廠房-Malfunctioningoftheventilationsystemthatcouldresultinpossiblelocalizedorocccarosisosn-alcontamination.-通風(fēng)系統(tǒng)的

45、故障導(dǎo)致固定的或間歇性的交叉污染。-Maintenance/periodicverificationsuchasairfilterreplacement,monitoringofpdreiffsesruernetialsnotperformed(T)-沒有做維護(hù)/周期性的性能確認(rèn)如：空氣過濾器的更換，檢測壓差。Accessorysupplies(steam,air,nitrogen,dustcollection,etc.)notqualified.輔助系統(tǒng)(蒸氣，空氣，氮?dú)?，灰塵收集)不符合要求HeatVentilationAirConditioning(HVAC)andpurifiedwat

46、er(PW)systemnotqualified.空調(diào)系統(tǒng)和純化水系統(tǒng)不符合要求Temperatureandhumiditynotcontrolledormonitoredwhennecess(ea.ryg.storagenotinaccordancewithlabellingrequirements).在需要監(jiān)控溫濕度的環(huán)節(jié)沒能監(jiān)控溫濕度(如未按溫濕度要求存放標(biāo)簽)Damages(holes,cracksorpeelingpaint)towalls/ceilingsimmediatelyadjacentorabovemanufacturingareasorequipmentwherethep

47、roductisexposed.與產(chǎn)品暴露區(qū)域直接相鄰或在其上方的墻面，天花板損壞(破洞，裂縫或油漆剝落)Un-cleanablesurfacescreatedbypipes,fixturesorductsdirectlyaboveproductsormanufacturingequipment.無法進(jìn)行表面清潔的管道經(jīng)過產(chǎn)品或生產(chǎn)設(shè)備的上方。Surfacesfinish(floors,wallsandceilings)thatdonotpermiteffectivecleaning.地板，墻體和天花板表面的外層涂料或覆蓋無法有效清潔。Unsealedporousfinishinmanufac

48、turingareaswithevidenceofcontamination(mildew,mould,powderfrompreviousproductions,etc(.T.)生產(chǎn)區(qū)域未封閉的孔狀表面內(nèi)在污染(霉菌，前批生產(chǎn)的藥粉等等)Insufficientmanufacturingspacethatcouldleadtomix(-uTp)s.生產(chǎn)區(qū)域空間太小易造成差錯(cuò)Physicalandelectronicquarantineaccessibletounauthorizedpersonnel/Physicalqauraerantinenotwellmarkedand/ornotres

49、pectedwhenus(eTd).未經(jīng)授權(quán)的人員可以通過機(jī)械和電子門禁/機(jī)械隔離的區(qū)域缺少標(biāo)示而且/或沒有按規(guī)程使用。Noseparatearea/Insufficientprecautionstopreventcontaminationorcross-contamdiunraintigonRMsampling.原料抽樣缺少獨(dú)立區(qū)域/沒有足夠的預(yù)防措施來防止污染或交叉污染。設(shè)備Equipmentdoesnotoperatewithinitsspecificatio(Tn)s.不在其額定范圍內(nèi)操作設(shè)備。Equipmentusedforcomplexmanufacturingoperations

50、notqua(lTif)ied.-用于復(fù)雜生產(chǎn)的設(shè)備不合要求。-CleaninPlace(CIP)equipmentnotvalidated.-在線清潔設(shè)備沒有驗(yàn)證。-Tanksformanufacturingofliquidsandointmentsnotequippedwithsanitaryclamps.-液體制劑或油膏劑的生產(chǎn)罐沒有采用清潔卡箍。Storedequipmentnotprotectedfromcontamina(iOn.設(shè)備存放時(shí)未作保護(hù)以防止污染。Inappropriateequipmentforproduction:surfacesporousandnon-clean

51、able/materialtoshedparticles(T)設(shè)備不適于生產(chǎn)：表面多孔無法清潔/材料自身易產(chǎn)生顆粒。Evidenceofcontaminationofproductsbyforeignmaterialssuchasgrease,oil,rustandfproamrticlestheequipmen(tT.)產(chǎn)品被設(shè)備上的物質(zhì)污染如油脂，銹跡和顆粒。Nocoversfortanks,hoppersorsimilarmanufacturingequipment.罐體，料斗或類似的生產(chǎn)設(shè)備沒有蓋子。No/inadequateprecautionstakenwhenequipments

52、uchasovenorautoclavecontaitnhsanmoreoneproduct(possibilityofcross-contaminationormix-u(pTs).同時(shí)存放有多個(gè)產(chǎn)品的生產(chǎn)設(shè)備如烘箱或滅菌柜沒有預(yù)防交叉污染或混淆的措施或措施不充分。Equipmentlocationdoesnotpreventcross-contaminationorpossiblemix-upsforoperationsperformedincommonare(aT.)共用區(qū)域內(nèi)設(shè)備的擺放位置不能防止交叉污染或混淆。PWsystemnotmaintainedoroperatedtoprov

53、idewaterofadequatequ(aTl)ity.純化水系統(tǒng)未很好地維護(hù)與操作，導(dǎo)致不能提供合格的水。Leakinggaskets.墊圈破漏Nocalibrationprogramforautomatic,mechanical,electronicormeasuringequipment/norecordsmaintained.自動(dòng)化設(shè)備，機(jī)械設(shè)備，電子設(shè)備或測量設(shè)備沒有校驗(yàn)計(jì)劃/沒有校驗(yàn)記錄。Noequipmentusagelogs.沒有設(shè)備使用記錄。人員IndividualinchargeofQCorProductionforafabricator,packager/labelle

54、rortesterdoehsolndotauniversitydegreeinasciencerelatedtotheworkbeingcondourctdeodesnothavesufficientpracticalexperienceintheirresponsibilityarea.-負(fù)責(zé)生產(chǎn)，包裝/貼簽或測試的質(zhì)量管理或生產(chǎn)人員沒有相關(guān)領(lǐng)域的大學(xué)文憑同時(shí)缺少足夠的實(shí)踐經(jīng)驗(yàn)。IndividualinchargeofQCforadistributor,importerorwholesalerisnotqualifiedbyacademictrainingandexperience.負(fù)責(zé)分銷

55、商，進(jìn)口商或批發(fā)商的質(zhì)量管理人員沒有達(dá)到應(yīng)有的教育與工作經(jīng)驗(yàn)要求。DelegationofresponsibilitiesforQCorProductiontoinsufficientlyqualifiedpersons.質(zhì)量管理與生產(chǎn)沒有足夠的合格人員以履行其職責(zé)。InsufficientpersonnelforQCorProductionoperationsresultinginahighprobabilityoferror.質(zhì)量管理與生產(chǎn)人手不足導(dǎo)致錯(cuò)誤率很高。-InsufficienttrainingforpersonnelinvolvedinproductionandQCresult

56、inginrelatedeGvMiaPtions.-生產(chǎn)與質(zhì)量管理人員培訓(xùn)不足導(dǎo)致了相應(yīng)的GMP偏差發(fā)生。清潔-Sanitationprogramnotinwritingbutpremisesinacceptablestateofcleanliness.廠房雖然潔凈但缺少書面的清潔計(jì)劃。NoStandardOperatingProcedure(SOP)formicrobial/environmentalmonitoring,nolaimctitiosnforareaswheresusceptiblenon-sterileproductsaremanufactured.沒有微生物/環(huán)境監(jiān)控的標(biāo)準(zhǔn)

57、操作流程，在易受污染的非無菌產(chǎn)品生產(chǎn)區(qū)域沒有設(shè)立監(jiān)控措施限。Cleaningprocedureforproductionequipmentnotvalidated(includinganalyticalmethods).生產(chǎn)設(shè)備清潔方法沒做驗(yàn)證(包括分析方法)Cleaningprocedureforproductionequipmentnotvalidatedwhennon-dedicatedequipumsedntisforhighriskproductst).在非專用設(shè)備用于高風(fēng)險(xiǎn)類產(chǎn)品生產(chǎn)的情況下，設(shè)備清潔方法沒做驗(yàn)證。Incompletehealthrequirements.不完整的健

58、康要求。原料檢驗(yàn)Reducetestingprograminplacewithoutadequatecertificationofthevendors/suppliers.在未對銷售商/供應(yīng)商進(jìn)行足夠資質(zhì)認(rèn)證的情況下減少測試項(xiàng)目。Waterusedintheformulationisnotofacceptablequality.配方用水質(zhì)量達(dá)不到要求。Noidentitytestperformedbythemanufacturerafterreceiptonitspremises/TestingforidentitynotdoneoneachcontainerforAPIsorafterman

59、ipulationorrepackagingbythirdparty.收料后沒做鑒別/未對每桶原料做鑒別/經(jīng)第三方處理或重包裝后未做鑒別。COAshowingincompletetesting.檢驗(yàn)報(bào)告上的測試不完全。Incompletespecifications.標(biāo)準(zhǔn)不全。SpecificationsnotapprovedbyQC.標(biāo)準(zhǔn)未被質(zhì)量管理部門批準(zhǔn)。Testmethodsnotvalidated.檢驗(yàn)方法沒有驗(yàn)證。UseofAPIaftertheretestdatewithoutproperretesting.過再驗(yàn)期的活性成分原料沒做再檢驗(yàn)而直接使用。UseofinactiveR

60、Maftertheexpirationdatewithoutproperretesting.未做檢驗(yàn)而使用過期的非主成分原料。Multiplelotscomprisingonereceptionnotconsideredasseparateforsampling,testingandrelease.將多批物料做為一次收料而未分開采樣，測試與放行。NoSOPforconditionsoftransportationandstorage.-沒有規(guī)定運(yùn)輸儲(chǔ)藏條件的SOP。-Certificationofbrokersorwholesalersallowedwithoutproperdocumenta