（質(zhì)量認(rèn)證）加拿大GMP檢查風(fēng)險分級

（質(zhì)量認(rèn)證）加拿大GMP檢查風(fēng)險分級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)險分級，2003版Supersedes:June1st,2000editionDateissued:April4th,2003Dateofimplementation:June1st,2003Cedocumentestaussidisponibleenfran?ais.本文可提供法語版TABLEOFCONTENTS目錄1.0PURPOSE目的32.0BACKGROUND背景33.0SCOPE范圍34.0DEFINITIONS定義:45.0GUIDE指南正文65.1Assignmentoftherisktoanobservation針對缺陷界定風(fēng)險65.2Assignmentoftheinspectionrating檢查評定75.2.1Risk1observation:1類風(fēng)險缺陷75.2.2Risk2observation:2類風(fēng)險缺陷75.2.3Risk3observations:3類風(fēng)險缺陷85.3Additionalguidance補充8Appendix1附錄19Appendix2附錄212Appendix3附錄3211.0PURPOSE目的Toclassifytheobservationsnotedduringestablishmentinspectionsaccordingtotheirrisk.依據(jù)風(fēng)險的程度對企業(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)行評估時采用統(tǒng)一的標(biāo)準(zhǔn)。ToinformtheindustryofthesituationsthattheInspectorateconsidersunacceptableandthatwillgenerateaNonCompliant(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,deviationsfromtheFoodandDrugRegulationsandthecurrenteditionoftheGoodManufacturingPractices(GMP)guidelinesarenotedbytheinspectorandthesedeviationsappearasobservationsintheinspectionexitnotice.Ajudgementbasedontheseobservationsisthenmadebytheinspectorandanoverallrecommendationforthecontinuationorissuanceoftheestablishmentlicence(ratingofCompliance)ornottocontinueorissuethelicence(ratingofNon-Compliance)isgiven.AttributionofaNCratingmayhaveseriousconsequencesforacompany,rangingfromtheimplementationofimportantcorrectivemeasurestothetemporarysuspensionorterminationoftheEstablishmentLicence(EL).Therefore,thesesituationsofnon-conformityhavetobewelldefined,unambiguousanddirectlysupportedbytheapplicableregulations.在工廠檢查時，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ThedefinitionofadruginCanadacoversawidevarietyofproductsrangingfrompharmaceuticalsandbiologicstonaturalhealthproductssuchashomeopathicsandherbalpreparations.ThisguidancedocumentcoversallsuchproductstowhichDivision2ofPartCoftheFoodandDrugRegulationsappliesandisbasedonthecurrenteditionoftheGMPGuidelines.ItisrecognisedthattheevaluationoftheconformitytotheGMPshouldbecommensuratewiththeriskinvolvedtakingintoaccountthenatureandextentofthedeviationinrelationwiththecategoryofproductsevaluated.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)險評估是同時進(jìn)行的，而風(fēng)險評估需要根據(jù)缺陷的性質(zhì)與程度同時與評估產(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.Pleasenotethatthelistofobservationsineachappendixisnotexhaustiveandthatadditionalobservationsmaybeaddedwhereappropriate.本文附錄描述了檢查發(fā)現(xiàn)相應(yīng)的風(fēng)險級別。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:ThefollowingdefinitionsareprovidedtocomplementthosealreadyavailableundertheglossaryoftermsinthecurrenteditionoftheGMPGuidelinesorotherrelateddocumentsreferencedintheGMPGuidelines.以下定義是對現(xiàn)行GMP法規(guī)或其相關(guān)文件釋義部分的補充Observation缺陷:AdeviationordeficiencytoGMPnotedbyaninspectorduringtheinspectionofadrugestablishmentthatisconfirmedinwritingtothecompanyintheexitnotice.Theobservationsareclassifiedas“Critical”,“Major”and“Other”andareassignedariskclassification,rangingfrom1for“critical”to2for“major”to3for“other”.藥品企業(yè)檢查過程中，所有被檢查人員寫入報告的偏差或不足。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)險級別。Criticalobservation嚴(yán)重缺陷:Observationdescribingasituationthatislikelytoresultinanon-compliantproductorasituationthatmayresultinanimmediateorlatenthealthriskandanyobservationthatinvolvesfraud,misrepresentationorfalsificationofproductsordata.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。AppendixIlistsobservationsthattheInspectorateconsiderscriticalwhichwillbeassignedaRisk1.附錄1列出了檢察員認(rèn)為屬于1類風(fēng)險的嚴(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。Appendix2listsobservationsthatareconsideredmajorandwhichwillbeassignedaRisk2CertainRisk2observationsmaybeupgradedtoRisk1.Theyareindicatedwithanarrow(↑).附錄2列出了檢察員認(rèn)為屬于2類風(fēng)險的主要缺陷。一部分可以上升為1類風(fēng)險的2類風(fēng)險已用箭頭標(biāo)明。Otherobservation一般缺陷: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ther”observationsarenotlistedassuch(Observationsthatareneithercriticalnormajorareconsideredas“other”andwillbeassignedaRisk3).Appendix3listsRisk3observationsthatmaybeupgradedtoRisk2.一般風(fēng)險沒有像1，2類風(fēng)險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。）附錄3列舉了可以上升為2類風(fēng)險的3類風(fēng)險。Criticalproduct最高風(fēng)險產(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)險產(chǎn)品。narrowtherapeuticwindow具有窄治療窗的藥物hightoxicity劇毒性藥物sterileproduct無菌產(chǎn)品biologicaldrug生物藥品complexmanufacturingprocess:生產(chǎn)工藝復(fù)雜的產(chǎn)品Processforwhichslightdeviationsinthecontrolofparameterscouldresultinanon-uniformproductoraproductnotmeetingitsspecifications.Asexample,powdermixingorgranulationforlowdosagesolidforms,longacting/delayedactionproducts,sterileproducts.工藝參數(shù)控制上一點小的偏差便能引發(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)shouldnotbeconsideredascriticalproductsevenwhenthemanufacturingprocessesinvolvedarecomplex.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C.02.028章節(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)險產(chǎn)品。Highriskproduct高風(fēng)險產(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低風(fēng)險產(chǎn)品:ProductssuchasCategory4product(aslistedinInterpretation2.3undersectionC.02.028),naturalhealthproductsincludingvitaminsandmineralspreparationsthatarenotascheduledrugorasteriledrug,andcertaintopicalnonprescriptionveterinaryformulationsregisteredas“olddrugs”.4類產(chǎn)品（參見C.02.028章節(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。Acronyms縮寫:Compliant合規(guī)CIP: Clean-In-Place在線清潔COA: CertificateofAnalysis檢驗報告EL: EstablishmentLicence企業(yè)許可證GMP: GoodManufacturingPractices藥品生產(chǎn)質(zhì)量管理規(guī)范HVAC: Heat,Ventilation,AirConditioning空調(diào)系統(tǒng)IRS: InspectionReportingSystem檢查報告MRA: MutualRecognitionAgreement互認(rèn)協(xié)議NC: Non-compliant不合規(guī)OTC: Over-The-Counter非處方藥PM: PackagingMaterial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GUIDE指南正文Assignmentoftherisktoanobservation針對缺陷界定風(fēng)險Whereasitisrecognizedthatitisimpossibletoencompasseverysituationthatmaygeneratearisk,thefollowingprinciplesshouldbeconsidered:鑒于我們都認(rèn)識到不可能將所有可能導(dǎo)致危險的情況都羅列出來，因此在界定風(fēng)險時請考慮以下準(zhǔn)則：Theriskassignedwillbeinrelationtothenatureofthedeviationaswellasthenumberofoccurrences.風(fēng)險的界定應(yīng)與缺陷的性質(zhì)與發(fā)生次數(shù)關(guān)聯(lián)起來。Generally,whenonlylowriskproductsareinvolved,arisk1willnotbeassignedtoobservationsdescribedinAppendix1,exceptforextremesituationssuchasfraudorwidespreadcross-contamination,infestationorunsanitaryconditions.一般而言，當(dāng)涉及的產(chǎn)品為低風(fēng)險產(chǎn)品時，附錄1中所描述的缺陷不應(yīng)被界定為1類風(fēng)險，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(risk2observationwithanarrow),thissituationisimmediatelybroughttotheattentionofthecompany’sofficials,properexplanationwillbeprovidedtotheestablishmentandthisexplanationshouldbecapturedinthe“Inspector’sComments”fieldofthe“InspectionSummary”intheIRS.當(dāng)2類風(fēng)險被重新評估為一類風(fēng)險時（2類風(fēng)險中標(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)記錄在檢查報告總結(jié)部分的檢察員意見欄中。5.2Assignmentoftheinspectionrating檢查評定Theoverallinspectionratingassignedisbasedontheriskinvolvedtakingintoaccountthenatureandextentofthedeviationswiththecategoryofproductsevaluated.綜合評定基于存在的風(fēng)險，缺陷的性質(zhì)與程度以及評估產(chǎn)品的類別。5.2.1Risk1observation:1類風(fēng)險缺陷Generally,aNCratingisassignedwhenaRisk1observationisnotedduringaninspection.一般而言，出現(xiàn)1類風(fēng)險缺陷，企業(yè)將被評定為不合規(guī)。Suchsituationisimmediatelybroughttotheattentionofthecompany’sofficials.TheInspectoratemanagementistobenotifiedinatimelymanner.這類情況應(yīng)被立即告知企業(yè)管理層并及時報告給檢查機(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，將會對其啟動適當(dāng)?shù)膹?qiáng)制手段。5.2.2Risk2observation:2類風(fēng)險缺陷Generally,aCratingisassignedwhenRisk2observationsarenotedduringaninspection.However,aNCratingmaybeassignedinthefollowingsituations:一般而言，出現(xiàn)2類風(fēng)險缺陷，企業(yè)仍將被評定為合規(guī)，但在以下情況出現(xiàn)時，企業(yè)將被評定為不合規(guī)：WhennumerousRisk2observationsarenotedduringaninspectionindicatingthatthecompanydoesnotcontrolitsprocessesandoperationssufficiently.當(dāng)2類風(fēng)險缺陷顯示出企業(yè)在工藝和運作方面沒能加以足夠的控制時。RepetitionofmanyRisk2observationsnotedduringpreviousinspectionsindicatingthatthecompanydidnot:當(dāng)許多前次檢查發(fā)現(xiàn)的2類風(fēng)險缺陷重復(fù)出現(xiàn)，顯示出企業(yè)沒有能夠implementthecorrectiveactionssubmittedfollowingthepreviousinspectionor按照遞交的計劃執(zhí)行前一次檢查缺陷的糾正工作或didnotputinplaceadequatepreventiveactionsinatimelymannertoavoidrecurrenceofsuchdeviations.沒有及時采取足夠的預(yù)防措施來防止偏差的再次發(fā)生。5.2.3Risk3observations:3類風(fēng)險缺陷ACratingwillbeassignedinallsituationswhereonlyRisk3observationsarenoted.如果僅發(fā)現(xiàn)3類風(fēng)險缺陷，企業(yè)將被評定為合規(guī)的。5.3Additionalguidance補充WhenaNCratingisassigned,theinspectorwillissueadraftInspectionExitNoticeduringtheexitmeeting.Thedraftinspectionexitnoticewillbereviewedforqualityassurancepurposesbeforethefinalreportisissuedtoanestablishment.當(dāng)企業(yè)被評定為不合規(guī)時，檢查員將在檢查結(jié)束的總結(jié)會上遞交檢查通告草稿。在最終報告發(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，如果企業(yè)能夠在檢查其間完成下列工作，檢查通告仍會給出企業(yè)合規(guī)的結(jié)論：theestablishmentimmediatelyimplementsallnecessaryactionstoresolvethecause(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)險評估等級仍保持不變。Ifthemanagementofthecompanywishestodisputetheresultsoftheinspectionreport,the“Disputeresolutionandappeals”mechanismdescribedintheGMPandELEnforcementPolicyPOL-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。Appendix1附錄1Risk1(Critical)Observations1類風(fēng)險（嚴(yán)重）缺陷PremisesC.02.004廠房Noairfiltrationsystemtoeliminateairbornecontaminantsthatarelikelytobegeneratedduringfabricationorpackaging.沒有空氣過濾系統(tǒng)以消除生產(chǎn)和包裝時可能產(chǎn)生的沉降污染。Generalizedmalfunctioningoftheventilationsystem(s)withevidenceofwidespreadcross-contamination.大范圍交叉污染的事實表明通風(fēng)系統(tǒng)存在故障。Inadequatesegregationofmanufacturingortestingareasfromothermanufacturingareasforhighriskproducts.高風(fēng)險產(chǎn)品之間的生產(chǎn)區(qū)域或測試區(qū)域沒能有效地隔開。EquipmentC.02.005設(shè)備Equipmentusedforcomplexmanufacturingoperationsofcriticalproductsnotqualifiedandwithevidenceofmalfunctioning.用于最高風(fēng)險產(chǎn)品復(fù)雜生產(chǎn)過程的設(shè)備不合規(guī)定同時也存在故障。PersonnelC.02.006人員IndividualinchargeofQualityControl(QC)orproductionforafabricatorofcritical/highriskproductsdoesnotholdauniversitydegreeinasciencerelatedtotheworkbeingconductedanddoesnothavesufficientpracticalexperienceintheirresponsibilityarea.管理最高風(fēng)險，高風(fēng)險產(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)文憑同時缺乏足夠的實踐經(jīng)驗。SanitationC.02.007C.02.008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RawMaterialTesting C.02.009 C.02.010原料檢驗Evidenceoffalsificationormisrepresentationofanalyticalresults.分析結(jié)果造假或歪曲Noevidenceoftesting(COA)availablefromthesupplier/synthetizerandnotestingdonebytheCanadianfabricator.缺少供應(yīng)商的檢驗報告同時企業(yè)也沒做相關(guān)的測試。ManufacturingControl C.02.011 C.02.012生產(chǎn)控制NowrittenMasterFormula.沒有書面的主處方MasterFormulaormanufacturingbatchdocumentshowinggrossdeviationsorsignificantcalculationerrors.主處方或生產(chǎn)批記錄存在明顯的偏差或嚴(yán)重的計算錯誤。Evidenceoffalsificationormisrepresentationofmanufacturingandpackagingorders.生產(chǎn)和包裝訂單的造假或錯誤QualityControlDepartment C.02.013 C.02.014 C.02.015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,lackingrealdecisionalpower,withevidencethatQCdecisionsareoftenoverruledbyproductiondepartmentormanagement.質(zhì)量管理部門不是獨立的機(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。FinishedProductsTesting C.02.018 C.02.019成品檢驗-Finishedproductnottestedforcompliancewithapplicablespecificationsbytheimporter/distributorbeforereleaseforsaleandnoevidenceisavailablethattheproductshavebeentestedbythefabricator.銷售前，進(jìn)口商/分銷商沒有按照合適的標(biāo)準(zhǔn)對成品進(jìn)行檢驗同時沒有證據(jù)顯示生產(chǎn)商做過相關(guān)測試。Evidenceoffalsificationormisrepresentationoftestingresults/forgeryofCOA.檢驗結(jié)果造假或歪曲/偽造檢驗報告Records C.02.020toC.02.024記錄Evidenceoffalsificationormisrepresentationofrecords.記錄造假或歪曲事實Stability C.02.027 C.02.028穩(wěn)定性Nodataavailabletoestablishtheshelf-lifeofproducts.缺少建立產(chǎn)品效期的數(shù)據(jù)Evidenceoffalsificationormisrepresentationofstabilitydata/forgeryofCOA.穩(wěn)定性數(shù)據(jù)的造假或歪曲/偽造檢驗報告SterileProducts C.02.029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)行驗證。WaterforInjection(WFI)systemsnotvalidatedwithevidenceofproblemssuchasmicrobial/endotoxincountsnotwithinspecifications.注射用水系統(tǒng)未作驗證，存在微生物/內(nèi)毒素超標(biāo)的情況。Nomediafillsperformedtodemonstratethevalidityofasepticfillingoperations.無菌灌裝工藝未做培養(yǎng)基灌裝驗證。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)基灌裝驗證失敗后仍繼續(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（主要）缺陷PremisesC.02.004廠房Malfunctioningoftheventilationsystemthatcouldresultinpossiblelocalizedoroccasionalcross-contamination.通風(fēng)系統(tǒng)的故障導(dǎo)致固定的或間歇性的交叉污染。Maintenance/periodicverificationsuchasairfilterreplacement,monitoringofpressuredifferentialsnotperformed.(↑)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，氮氣，灰塵收集）不符合要求HeatVentilationAirConditioning(HVAC)andpurifiedwater(PW)systemnotqualified.空調(diào)系統(tǒng)和純化水系統(tǒng)不符合要求Temperatureandhumiditynotcontrolledormonitoredwhennecessary(e.g.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/ceilingsimmediatelyadjacentorabovemanufacturingareasorequipmentwheretheproductisexposed.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。Unsealedporousfinishinmanufacturingareaswithevidenceofcontamination(mildew,mould,powderfrompreviousproductions,etc..)(↑)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-ups.(↑)生產(chǎn)區(qū)域空間太小易造成差錯Physicalandelectronicquarantineaccessibletounauthorizedpersonnel/Physicalquarantineareanotwellmarkedand/ornotrespectedwhenused.(↑)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-contaminationduringRMsampling.原料抽樣缺少獨立區(qū)域/沒有足夠的預(yù)防措施來防止污染或交叉污染。EquipmentC.02.005設(shè)備Equipmentdoesnotoperatewithinitsspecifications.(↑)不在其額定范圍內(nèi)操作設(shè)備。Equipmentusedforcomplexmanufacturingoperationsnotqualified.(↑)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)備沒有驗證。Tanksformanufacturingofliquidsandointmentsnotequippedwithsanitaryclamps.液體制劑或油膏劑的生產(chǎn)罐沒有采用清潔卡箍。Storedequipmentnotprotectedfromcontamination.(↑)設(shè)備存放時未作保護(hù)以防止污染。Inappropriateequipmentforproduction:surfacesporousandnon-cleanable/materialtoshedparticles.(↑)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,rustandparticlesfromtheequipment.(↑)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/inadequateprecautionstakenwhenequipmentsuchasovenorautoclavecontainsmorethanoneproduct(possibilityofcross-contaminationormix-ups).(↑)同時存放有多個產(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-upsforoperationsperformedincommonarea.(↑)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。PWsystemnotmaintainedoroperatedtoprovidewaterofadequatequality.(↑)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)備沒有校驗計劃/沒有校驗記錄。Noequipmentusagelogs.沒有設(shè)備使用記錄。PersonnelC.02.006人員IndividualinchargeofQCorProductionforafabricator,packager/labellerortesterdoesnotholdauniversitydegreeinasciencerelatedtotheworkbeingconductedordoesnothavesufficientpracticalexperienceintheirresponsibilityarea.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)文憑同時缺少足夠的實踐經(jīng)驗。IndividualinchargeofQCforadistributor,importerorwholesalerisnotqualifiedbyacademictrainingandexperience.負(fù)責(zé)分銷商，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)致錯誤率很高。InsufficienttrainingforpersonnelinvolvedinproductionandQCresultinginrelatedGMPdeviations.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。SanitationC.02.007 C.02.00↑清潔Sanitationprogramnotinwritingbutpremisesinacceptablestateofcleanliness.廠房雖然潔凈但缺少書面的清潔計劃。NoStandardOperatingProcedure(SOP)formicrobial/environmentalmonitoring,noactionlimitsforareaswheresusceptiblenon-sterileproductsaremanufactured.沒有微生物/環(huán)境監(jiān)控的標(biāo)準(zhǔn)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)備清潔方法沒做驗證（包括分析方法）Cleaningprocedureforproductionequipmentnotvalidatedwhennon-dedicatedequipmentisusedforhighriskproducts(↑).在非專用設(shè)備用于高風(fēng)險類產(chǎn)品生產(chǎn)的情況下，設(shè)備清潔方法沒做驗證。Incompletehealthrequirements.不完整的健康要求。RawMaterialTesting C.02.009 C.02.010原料檢驗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目。Waterusedintheformulationisnotofacceptablequality.配方用水質(zhì)量達(dá)不到要求。Noidentitytestperformedbythemanufacturerafterreceiptonit’spremises/TestingforidentitynotdoneoneachcontainerforAPIsoraftermanipulationorrepackagingbythirdparty.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.檢驗報告上的測試不完全。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.檢驗方法沒有驗證。UseofAPIaftertheretestdatewithoutproperretesting.過再驗期的活性成分原料沒做再檢驗而直接使用。UseofinactiveRMaftertheexpirationdatewithoutproperretesting.未做檢驗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)定運輸儲藏條件的SOP。Certificationofbrokersorwholesalersallowedwithoutproperdocumentation.對所許可的中間商或批發(fā)商缺少書面的的授權(quán)。ManufacturingControls C.02.011 C.02.012生產(chǎn)控制MasterFormulaeprepared/verifiedbyunqualifiedpersonnel.主處方由無資質(zhì)人員編寫/核對。Complexproductionprocessesnotvalidated.(↑)復(fù)雜生產(chǎn)工藝沒有驗證。Incompletevalidationstudies/reportsforcomplexmanufacturingprocess(lackofevaluation/approval).復(fù)雜生產(chǎn)工藝的驗證研究/報告不完整（缺少評估/批準(zhǔn)）Changeoverproceduresformanufacturingofmedicinal/non-medicinalproductsarenotvalidatedornotavailable.藥品/非藥品生產(chǎn)的改換規(guī)程沒有驗證/缺失。Unapproved/undocumentedmajorchangescomparedtoMasterProductionDocuments.(↑)生產(chǎn)工藝上的重大改變沒有經(jīng)過批準(zhǔn)/沒有書面記錄。DeviationsfrominstructionsduringproductionnotdocumentedandnotapprovedbyQC.對生產(chǎn)指令的偏差未做書面記錄同時未經(jīng)質(zhì)量管理部門認(rèn)可。Discrepanciesinyieldorreconciliationfollowingproductionnotinvestigated.對生產(chǎn)收率或物料平衡的差異未作調(diào)查。LineclearancebetweenproductionofdifferentproductsnotcoveredbySOPandnotdocumented.沒有不同產(chǎn)品之間清場的SOP同時沒有書面記錄。Noregularchecksformeasuringdevices/norecords.測量儀器沒有定期檢查/沒有記錄。Lackofproperidentificationofin-processmaterialsandproductionroomsresultinginahighprobabilityofmix-ups.生產(chǎn)區(qū)域和中間物料沒有適當(dāng)?shù)臉?biāo)識非常容易造成混淆。Inadequatelabelling/storageofrejectedmaterialsandproductsthatcouldgeneratemix-ups.報廢物料沒有標(biāo)識不清，儲藏空間不夠，易引起混淆。Uponreceipt,bulkandin-processdrugs,RMandPMnotheldinquarantineuntilreleasedbyQC.收料后，在由質(zhì)量管理部門放行之前，粗制品，中間體，原料和包材沒有放置到待檢區(qū)域。Productionpersonnelusingbulkandin-processdrugs,RMandPMwithoutpriorauthorizationbyQC.(↑)未經(jīng)質(zhì)量管理部門的授權(quán)，生產(chǎn)人員使用粗制品，中間體，原料和包材。Inadequate/inaccuratelabellingofbulk/in-processdrugs,RMandPM.粗制品，中間體，原料和包材標(biāo)識不清/不正確RMdispensingnotdonebyqualifiedpersons,accordingtoanSOP.沒有按照SOP，由有資質(zhì)的人員完成配料。MasterFormulaeincompleteorshowinginaccuraciesintheprocessingoperations.主處方不完整或在生產(chǎn)過程中顯示出不夠準(zhǔn)確。Changesinbatchsizenotprepared/verifiedbyqualifiedpersonnel.產(chǎn)品規(guī)格更換沒有由有資質(zhì)的人員完成/審核。Inaccurate/incompleteinformationinmanufacturing/packagingbatchdocuments.生產(chǎn)包裝批文件信息不準(zhǔn)確/不完整。Althoughdocumented,combinationofbatchesdonewithoutQCapproval/notcoveredbySOP.盡管有文件記錄，但未經(jīng)質(zhì)量管理部門批準(zhǔn)合并批號/沒有SOP涵蓋此內(nèi)容。Nowrittenproceduresforpackagingoperations.包裝操作沒有書面規(guī)程規(guī)定。Non-standardoccurrencesduringpackagingnotinvestigatedbyqualifiedpersonnel.有資質(zhì)的人員未對包裝過程中出現(xiàn)的非正常情況進(jìn)行調(diào)查。Inadequatecontrolofcodedandnon-codedprintedPM(includingstorage,dispensing,printing,disposal).編碼，未編碼打印的包裝材料（儲藏，發(fā)放，打印和銷毀）控制不嚴(yán)。Noorinadequateself-inspectionprogram/ProgramdoesnotaddressallapplicablesectionsofGMPs/Recordsincompleteornotmaintained.自檢計劃缺少或不完全/自檢計劃沒能涵蓋所應(yīng)涉及的GMP領(lǐng)域/自檢記錄不完整或沒有保存。ProductsimportedfromforeignsitesthatarenotlistedontheForeignSiteAnnexoftheEstablishmentLicence(↑)產(chǎn)品由海外工廠進(jìn)口，但海外工廠沒有在企業(yè)許可證附件-海外工廠中列出。Recall:召回：Absenceofrecallprocedurecombinedwithdistributionpracticesthatwouldnotpermitanadequaterecall(distributionrecordsunavailableornotkept).缺少召回程序同時發(fā)貨操作的方式導(dǎo)致不可能完全召回（發(fā)貨記錄缺失或未留記錄）Improperquarantineanddisposalpracticesthatwouldallowrecalled/rejectedunitstobereturnedforsale.隔離和銷毀操作不當(dāng)，可能導(dǎo)致召回產(chǎn)品，退貨重新被銷售。QualityControlDepartmentC.02.013 C.02.014 C.02.015質(zhì)量管理部門Inadequatefacilities,personnelandtestingequipment.設(shè)施，人員和測試儀器不足Noauthoritytoenterproductionareas.(↑)無權(quán)進(jìn)入生產(chǎn)區(qū)域NoSOPsapprovedandavailableforsampling,inspectionandtestingofmaterials.物料抽樣，檢查和測試的SOP未被批準(zhǔn)或無法獲得。ProductsmadeavailableforsalewithoutapprovalofQCdepartment.(↑)產(chǎn)品未經(jīng)質(zhì)量管理部門批準(zhǔn)便可以銷售。ProductsreleasedforsalebyQCwithoutproperverificationofmanufacturingandpackagingdocumentation.質(zhì)量管理部門未核對生產(chǎn)與包裝的文件，便批準(zhǔn)銷售產(chǎn)品。Deviationsandborderlineconformancesnotproperlyinvestigatedanddocumented,accordingtoaSOP.偏差和緊扣質(zhì)量底線的合格情況沒能按照SOP進(jìn)行完全的調(diào)查并做書面記錄。RM/PMusedinproductionwithoutpriorapprovalofQC.原料與包材未經(jīng)質(zhì)量管理部門批準(zhǔn)便已用于生產(chǎn)。Reprocessing/ReworkingdonewithoutpriorapprovalofQCdepartment.(↑)未經(jīng)質(zhì)量管理部門批準(zhǔn)而進(jìn)行再制/返工操作。Nosystemforcomplainthandlingandreturnedgoods.沒有投訴與退處理貨的系統(tǒng)。SOPscoveringoperationsthatcanaffectthequalityofaproductsuchastransportation,storage,etc.notapprovedbyQCdepartment/notimplemented.可能影響產(chǎn)品品質(zhì)的操作如運輸，存儲等等的SOP沒有經(jīng)質(zhì)量管理部門批準(zhǔn)/沒有被執(zhí)行。Absenceofchangecontrolsystem.缺少更改控制Fortestinglaboratories,(inhouseorcontract)thesystemsandcontrolsinplacefortheproperqualification,operation,calibrationandmaintenanceofequipment,standards,solutions,andrecordskeepingdonotassurethattheresultsandconclusionsgeneratedareaccurate,preciseandreliable.(↑)測試實驗室（內(nèi)部或外部）的現(xiàn)場管理與監(jiān)控體系（包括驗證，操作，校驗，設(shè)備維護(hù)，標(biāo)準(zhǔn)品，各種溶液，記錄保存）無法保障其出具數(shù)據(jù)的準(zhǔn)確，精密和可靠。PackagingMaterialTestingC.02.016C.02.017包材檢驗Reducetestingprograminplacewithoutadequatecertificationofvendors/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目。AbsenceoftestingofPM.缺少包材檢驗SpecificationsnotapprovedbyQC.質(zhì)量標(biāo)準(zhǔn)沒有被質(zhì)量管理部門批準(zhǔn)。Noidentitytestdonebythepackager/labellerafterreceiptonitspremises.包裝/貼簽人員領(lǐng)料后未做鑒別測試。Certificationofbrokersorwholesalersdonewithoutproperdocumentation.對中間商或批發(fā)商所做認(rèn)證沒有正確地書面歸檔。FinishedProductTestingC.02.01↑C.02.019成品檢驗Noncompliantproductsmadeavailableforsalewithoutproperjustification.(↑)沒有充分的解釋而銷售不合格品。Incomplete/inadequatespecifications.不完整/不正確的質(zhì)量標(biāo)準(zhǔn)FinishedproductspecificationsnotapprovedbyQC.成品標(biāo)準(zhǔn)未經(jīng)質(zhì)量管理部門批準(zhǔn)。Incompletetesting.測試不完全。NoidentitytestinguponreceiptinCanadafromnon-MRAcountryandnoperiodiccompleteconfirmatorytesting.從非互認(rèn)國家進(jìn)口到加拿大的產(chǎn)品未做鑒別試驗同時沒有周期性的全項檢驗。Testmethodsnotvalidated.分析方法沒有驗證。NoSOPforconditionsoftransportationandstorage.沒有SOP規(guī)定儲藏運輸?shù)臈l件。Useofuniqueidentifierprinciplesnotmeetingtheacceptableoptions.使用不被接受的特殊鑒別方法RecordsC.02.020toC.02.024記錄AbsenceofMasterProductionDocuments.缺少生產(chǎn)主記錄Unavailabilityofdocumentationfromsuppliersinatimelymanner.供應(yīng)商提供文件不及時。SamplesC.02.025C.02.026樣品Retainedsamplesnotkeptforfinishedproducts.成品未做留樣。Failuretosubmitretainedsampleswhenalternativesampleretentiongranted.沒有遞交留樣而擅自改變留樣計劃。StabilityC.02.027C.02.02↑穩(wěn)定性Insufficientnumberoflots/insufficientdatatoestablishshelf-life.用于建立效期的數(shù)據(jù)和樣品數(shù)量不夠。Noactiontakenwhendatashowsth