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1、2018年FDA483表中缺陷项（按六大系统分类）目录一 .生产系统2二 .质量系统36三.实验室控制系统109四 .设施和设备系统163五 .包装和贴签185六 .物料系统187七 .其它188一.生产系统1 .印度AlkemLaboratories20180411OBSERVATION13缺陷13Employeesengagedinthemanufactureandprocessingofadrugproductlackthetrainingandexperiencerequiredtoperformtheirassignedfunctions.从事药品生产和加工的员工缺乏履行其指定职责所
2、需的培训和经验。Specifically,yourfirmusesanelectronictrainingmanagementsystem,Nichelon5,todocumentthetrainingofyouremployees,whichwasaccessedon27March2018.Yoursystemdocumentsanemployeethatwasobservedusinganuncontrolled,non-validatedspreadsheettocalculate%RSD,didnotattendTrainingonGoodDocumentationPractice(G
3、DP)andGoodLaboratoryPractices(GLP)conductedbyyourfirmon17January2018.Accordingtoyourfirm,swrittenprocedure,CQA0031z“TrainingManagementSyStem，cGMPrefreshertrainingistobecompleted(b)(4);missedtrainingsaretobecompletedwithin(b)(4).具体来说，你公司使用了电子培训管理系统，Nichelon5,来记录你们员工的培训，2018-03-27进入了该系统。你们的系统记录了一位员工被发
4、现正使用未受控未验证的表格来计算RSD,缺席你公司2018-01-17的GDP培训和GLP培训。依据你公司的书面程序CQA0031“培训管理系统”，CGMP更新培训要XX完成，缺席者要在XX内完成。2 .印度SunPharmaceutical20180306OBSERVATloN2缺陷2Writtenproceduresforcleaningandmaintenancefailtoincludedescriptioninsufficientdetailofthemethodsofdisassemblingandreassemblingequipmentasnecessarytoassurepr
5、opercleaningandmaintenance.书面清洁和维护程序未包括对于设备必要时进行拆卸和重新组装以确保适当清洗维护的足够详细描述。Specifically,yourequipmentisnotinstalledandmaintainedaccordingtoawrittenproceduretoreducerisktoproductcontactsurfacesorprocessmaterials.具体来说，你们的设备未依书面程序安装和维护以减少产品接触表面或工艺物料的风险。D.On12Feburary2018,Iobservedbulkproduct(b)(4)tanksloc
6、atedinthematerialpreparealabeledas“Cleaned”.However,Iobservedtank#SH159havinga(b)(4)(b)(4)residueonthe(b)(4)gasket.Thistankisdedicatedtoinjectable(b)(4)production.Ialsoobservedtank#SH412tohaveatornanddegraded(b)(4)stylegasketinstalledatthe(b)(4).Thistankwaslastusedforbulk(b)(4)Injection.Thecleaningp
7、rocedure#PAR-215/05doesnotspeakdirectlytocleaningorreplacementofthe(bW4)gasket.2018-02-12,我查看了位于物料准备区域标示为已清洁的散装产品XX罐。我发现罐#SH159的XX垫圈上有XX/XX残留。该罐是注射剂XX生产专用设备。我还发现罐#SH412上XX处安装的XX型垫圈磨损降解。此罐上次用于散装XX注射剂。清洁程序#PAR-215/05未直接讲要清洁或更换XX垫圈。E.On14February2018,1observeddegradedanddiscolored(b)(4)gasketson(b)(4)s
8、toragetankthatsupplies(b)(4)totheproductionareainBlock(b)(4).Ialsoobserveddegradedanddiscoloredgasketsinbulk(b)(4)drugformulationequipment(productcontactsurface).Thereisnowrittenprocedurewithrespecttothisequipmentthatspecifiesserviceorreplacementofgaskets(ENG-020/11).2018-02-14,我发现给XX车间生产区域提供XX的XX贮罐
9、上的XX垫圈已降解变色。我还发现散装XX制剂设备(产品接触表面)上垫圈已降解变色。OBSERVATIoN 3l3Writtenproceduresarelackingwhichdescribeinsufficientdetailthesampling,testing,approvalandrejectionofdrugproductcontainersandclosures.书面程序缺乏对取样、检测、批准和拒收药品容器密闭器的详细描述。Specifically,thefirmswrittenprocedureTAR-139/105CIeaningandOperationofVial/Ampou
10、le(b)(4)Machines,EffectiveDate:11/112017mallowstheperformanceof2sequentialfailureswithoutinitiationofadeviationinvestigation.Theprocedurealsostates,repeatrejectionfromthe(b)(4)operationasfalserejectionFR1,FR2andFR3.具体来说，公司的书面程序PAR-139/10XX西林瓶/安甑设备清洁和操作生效日期2017-11-11,允许2次连续性能失败而不启动偏差调查。该程序还说，重复拒收XX操作
11、作为误拒FRLFR2和FR3。3.印度AlembicPharmaceuticals20180410OBSERVATIoN3缺陷3Therearenowrittenprocedureforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess.无书面的生产和工艺控制程序用以确保药品具备其理应具备的鉴别、剂量、质量和纯度。Specifically,the(b)(4)HoldT
12、imeStudiesthatyourfirmhasconductedfordrugproductsmarketedintheUSaredeficient.Thebatchsizesusedfortheestablishmentof(b)(4)HoldTimesdonotrepresentthecommercialbatchsizeofthedrugproducts.Todate,yourfirmhasconducted(b)(4)HoldTimeStudiesutilizingthisapproachforall(b)(4)representingapproximately(b)(4)drug
13、productsintendedfortheUSmarketasevidencedbythefollowingexamples:具体来说，你公司实施的美国市场XX药品XX存放时长研究有缺陷。用于建立XX存放时间的批量并不能代表该药品的商业批量。截至今日，你公司已实施了XX存放时长研究，将此方法用于代表近XX个美国药品的所有XX。证据如下：此处表格内容全被遮盖，所列表项目有药名、批量、工艺、用于XX存放时长研究的数量、所建立的存放时间。SinceMarch2016,approximately113investigationshavebeeninitiatedforeither(b)(4)orAs
14、sayfailureatthe(b)(4)stageforproductsmarketedintheUS.自2016年3月以来，美国销售的产品已因XX步骤XX或含量不合格启动约113例调查。4 .英国Dr.Reddys20170926OBSERVATlON2缺陷2Cleaningproceduresorcleanstatusisnotestablished.未建立清洁程序或清洁状态。Specifically,具体来说DuringthereviewoftheQualityRiskManagementPlanforArea(b)(4)Equipment161022MW17zdated08Aug20
15、17.Thecleaningproceduresarenotvalidatedforequipmentusedinproductionof(b)(4)API.Suchasthedisassemblingof(b)(4)ID#(b)OOl5priortocleaning.在对2017-08-08日的XX区的设备161/022/MW/17质量风险管理计划审核过程中发现用于XX原料药生产的设备的清洁程序未经验证。例如，设备XXID#(b)(4)0015清洁之前的拆卸操作。Duringthewalkthroughofthewarehouseonl2Sept2017,1observedinthe(b)(
16、4)equipmentstorageareawithseveralaccessories/potablemachine/dismantledmachinepartsusedinmanufacturingof(b)(4)APIthatwerenotidentifiedascleanordirty.Examplesoftheequipmentaccessoriesincludethefollowing,butnotlimitedtotheglass(b)(4)bottleszConicalflask,transferhoses,and(b)(4).Thelastuseoftheequipmentw
17、asdocumentedinbatchrecord(b)(4)on15Nov2015.Additionallytherearenocleaningholdtimesestablishedintheprocedures.2017-09-12在仓库里发现XX设备存贮区有几个用于XX原料药生产的辅助何移动设备/拆卸后的机器部件未标识为清洁或待清洁。此设备辅助件的例子包括但不仅限于玻璃XX瓶、锥形瓶、软管和XXo该设备的最后使用日期在批记录XX中记载为2015-ll-15o另外，在程序里也未设定清洁后保持时长。5 .马来西亚BioconSdnBhd20180312OBSERVATlON1缺陷1Proc
18、eduresdesignedtopreventmicrobiologicalcontaminationofdrugproductspurportingtobesterilearenotestablishedorfollowed.未建立和遵守设计用以防止无菌产品免受微生物污染的程序。Specifically,yourprocesssimulationstudies(mediafill)areinadequate.具体来说，你们的工艺模拟研究(培养基灌装)是不充分的。A.Duringmyreviewofthemediafillbatchrecords(MFBR)for(b)(4)drugprodu
19、cts(i.e.(b)(4),Ifoundthat(b)(4)stopperedvialsshowing(b)(4)sealdefectwererejectedandnotincubated.在我对XX药品(即XX)培养基灌装批记录(MFBR)的审核中,我发现XX加塞的瓶显示XX密封缺陷被拒，没有进行培养。Forexample,例如 (b)MRBR(b)(4April2016;846(b)sealrejects 2016年4月，846瓶因密封性被拒 (b)MRBR(b)(4)fMay2016;2,007(b)(4)sealrejects 2016年5月，2007瓶因密封性被拒 (b)(4)MR
20、BR(b)(4),May2016;1,310(b)(4)sealrejects 2016年5月，1310瓶因密封性被拒 (b)(4)MRBR(b)(4),January2016;504(b)(4)sealrejects 2016年1月，504瓶因密封性被拒 (b)MRBR(b)(4),January2016;139(b)(4)sealrejects 2016年1月，139瓶因密封性被拒AccordingtocontrolprocedureBMQASOP019uAsepticProcessSimulations(MediaFills)Section6.1.5statesUnitswithinte
21、gritydefects(example:crackedunits,brokenunits,containerwhicharenotsealed,vialswithout(b)(4)stoppers,etc.)shallnotbeconsideredaspartofincubationandshallbereconciledandrejectedaccordingly.Therefore,yourmediafillpracticesandproceduresareinsufficienttojustifyexcludingunitsinsuchcircumstances.Evenmore,wh
22、enthereferenceddrugproductsaremultidoseproducts.依据控制程序BMQASOPoI9无菌工艺模拟(培养基灌装)，第6.1.5部分说有完整性缺陷的单位(例如，裂瓶、破瓶、容器未密封、无XX塞的瓶等)均不应作为培养的一部分，应相应地进行数量衡算和拒收。因此，你们的培养基灌装作法和程序是有缺陷的，它未论证为何在此情形下要排除这些单位。当所指药品为多剂量药品时数量则更多。B.Thereisnoassurancethatyourprocesssimulationstudies(mediafills)performedinthe(b)FillingMachine
23、s(03-02(b)(4)aretrulyrepresentativeoftheconditionobservedand/orthatmightoccurduringroutineasepticfillingoperationsof(b)(4).Thisisevidencedinthat,althoughcorrectiveandinherentoperatorsinterventionsaresimulatedduringmediafills,thefrequencyandthedurationatwhichtheseinterventionsaresimulatedarenotestabl
24、ishedbasedonathoroughevaluationofthehistoricaland/orretrospectivedata.你们在XX灌装机(03-02XX)上进行的工艺模拟研究(培养基灌装)无法确保真实代表日常XX无菌灌装操作中可能发生和/或观察到的条件。证据如下，尽管在培养基灌装模拟了矫正的原有操作员干预情况，但这些所模拟的干预行为的频次和时长并非基于对历史性和/或回顾性数据的全面评I古而建立。a) YourQualityUnitestablishedtheacceptancecriteriaforintegrity,fillingvolumeandsealintegrit
25、yofthe(b)(4)basedonlyontheevaluationoftheGOODunitspost100%visualinspection.However,theapprovedre-qualificationReportBM/RQ/P/050-02,dated02/04/2018,doesnotincludeanevaluationoftherejected(b)(4)andtheclassificationofthedifferentdefectsfoundduringtheinitial100%visualinspection.Moreover,thereisnodocumen
26、tedevidencethatdemonstratetheinitialvisualinspectionwasperformed.Therefore,thereisnoassurancetheresultsobtainedduringthere-qualificationofthe(b)(4)FillingMachineareaccurate.你们质量部门仅是基于对好的单位100%目视检查评估建立了XX的完整性、灌装体积和密封完整性可接受标准。但是，2018-02-04所批准的重新确认报告BM/RQ/P/050-02并不包括对拒收XX的评估，以及对初始100%目视检查中发现的不同缺陷的分类。另
27、外，也没有书面证据证明执行了初始目视检查。因此无法确保在XX灌装机再验证中所获得的结果是准确的。b) Aspartoftherequalificationactivitiesofthe(b)(4)FillingMachine(03-02-(b)(4)for(b)(4)ml,vialformat),yourQualityUnitrequiresthevisualexaminationof(b)(4)vialsfordetectingthepresenceofintegritydefectsandcontaminantsinvialsfilledfrom(b)(4)%to(b)(4)%speedr
28、ange.However,the叩Prc)VedrequalificationReportBMPDPRQP041-01zDated01/25/2017,doesnotdescribethesamplingplanthatwasfollowedandhowwasestablishedthenumberofsamplescollectedinordertoensurethatrepresentativessampleweretakenforthevisualexamination.作为XX灌装机(03-02-XX,XX毫升西林瓶)再确认活动的一部分,你们质量部门要求对XX瓶进行目视检查,以发现XX
29、%至XX%速度范围内所灌装瓶的完整性缺陷和污染物。但是，2017-01-25批准的再确认报告BM/PDP/RQ/P/041-01并未描述所遵循的取样计划，也未描述为确保目视检查所取样品具有代表性是如何订立所取样品的数量。6.印度Dr.Reddys20180321OBSERVATlON5缺陷5Thereisnoassurancethattheequipmentusedintheproductionof(b)(4)and(b)(4)APIarealwaysmaintainedand/orkeptin/underproperconditionsformanufacturingoperationsan
30、dtopreventthecontaminationoftheproductshandledand/orprocessedintheequipment.Thefollowingconditionswereobservedon2018-03-05zduringthewalkthroughtheproductionareasin(b)(4)-Block(usedtoproduce(b)(4)and(b)(4)fortheUSmarket:未能确保XX和XX原料药生产所用设备总是维持在和/或保持在适当的生产操作条件下，防止设备中所处理和/或加工产品发生污染。2018-03-05在检查XX车间生产现场
31、(用于生产美国市场的XX和XX)时发现以下情况：A.Apieceof(b)(4)materialwasobservedinside(b)(4)#(b)(4)-12usedfor(b)(4)productionandtheequipmentwasissueda“cleaned“statusandvisuallyinspected.在XX生产所用XX设备内发现一片XX物料,该设备状态为已清洁”并经过了目视检杳。B.Apieceoffabricthreadwasobservedinside(b)(4)#(b)(4)-14usedfor(b)(4)production.Inaddition,the(b
32、)(4)wasobservedwithpresenceofholesandwasplacedinuseon2018-01-10,cleaned,andvisuallyinspectedon2018-02-17.Theareaaroundthegasketofthecoverwasobservedwith(b)(4)staincolor.XX生产所用XX设备内发现一段纤维绳。另外,XX设备于2018-01-10使用,2018-02-17清洁并经目视检查，但发现XX上面有洞。盖子垫圈周围发现有XX污渍颜色。C.PresenceofproductWasobservedinsidethefollowi
33、ngproductionequipmentalthoughtheequipmentwascleanedandvisuallyinspectedaftercleaning:在以下生产设备内看到有产品残留，虽然这些设备都是清洁过并且在清洁后经过目视检查：a. (b)(4)#(b)(4)-20and(b)(4)#(b)(4)-09/02locatedinCleanroom(b)-BIoCkBuilding#(b)(4)usedfor(b)(4)finishedAPIproduction.XX车间洁净区内XX原料药成品生产所用XX设备b. (b)(4)#(b)(4)-06/01usedfor(b)(4
34、)production.用于XX生产的XX设备c. (b)(4)ID#(b)(4)-03thatisusedfor(b)(4)production用于XX生产的XX设备d. (b)(4)#(b)(4)-01usedfor(b)(4)productionalthoughconsideredcleanedandverified,用于XX生产的XX设备,虽然认为是清洁过并确认过e. Onthe(b)(4)inside(b)(4)#(b)(4)-17/01usedfor(b)(4)production.用于XX生产的XX设备内的XX上f. Ontheshaftinside(b)(4)#(b)(4)-1
35、4/02usedfor(b)(4)production.用于XX生产的XX设备内的轴上7 .印度CiplaLimited20180420OBSERVATloN2缺陷2Writtenproceduresforproductionandprocesscontrolsarenotdesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess.生产和工艺控制书面程序设计无法确保药品具备其应有的鉴别、剂量、质量和纯度。Specifically
36、,therearenoestablishedrejectlimits,eitherbyindividualfailuremodesorcumulativetotals,per(b)(4)orbatch,formediafillprocesssimulations.Forexample,thefollowingtableshowsthenumberofrejectedunitsof(b)(4)fromvariousmediafillbatchesprocessedon(b)(4)(b)(4)Line(b)(4)coincidentalwiththesimulationofspecificproc
37、essinterventions.具体来说，对于培养基灌装工艺模拟按批次或按XX,既未建立单个失败模式的拒收限度，亦未建立累积总数拒收限度。例如，下表显示出XX产线上不同培养基灌装批中XX被拒单位的数量以及巧合的特定工艺干预模拟。MediaFill培养基灌装(b)(4)Intervention干预Approx.,#ofUnitsPotentiallyAffected可能受影响的单位数量约#of“other”(b)/Pinholerejects其它XX/针孔拒收数量(b)(4)rejectrateXX拒收率Batch(b)(4)Lot(b)AdjustmentofBatch(b)XX批调整(b)
38、(4)(b)-131.9%Batch(b)(4)Lot(b)MediaheldforBatch(b)(4)priortofilling批XX在灌装之前培养基存放(b)(b)-32.8%Lot(b)ShutoffoffillingroomAHUforBatch(功批号XX灌装间AHU关机(b)(4)(b)(4)-46.6%Lot(b)(b)(4)re-(b)(4)of(b)fillinglineXX灌装线的重新XX(b)(b)(4)-87.3%Lot(b)(4)(b)(4)re-(b)(4)of(b)(4)fillinglineXX灌装线的重新XX(b)(b)(4)50%Batch(b)(4)L
39、ot(b)PowerfailuresimulatedforNLT(b)(4)NLTXX模拟粉末失败(b)(b)(4)-75.3%Batch(b)(4)Lot(b)Changingof(b)(4)XX变更(b)(b)(4)-101.8%Batch(b)(4)Lot(b)(4)Noworst-case/unplannedinterventions没有最差情形/计划外干预(b)(4)(b)(4)-42.0%Lot(b)Fillingarea(b)(4)openedNLT灌装区XX开放NLT(b)(4)(b)(4)-104.5%Lot(b)Alignmentof(b)(4)与XX一致(b)(b)(4)
40、-107.0%Lot(b)(4)Changingof(b)(4)XX变更(b)(b)(4)344.4%Batch(b)(4)Lot(b)(b)(4)alignment与XX致(b)(4)(b)(4)-26.9%Lot(b)Rightside(b)(4)locknon-functional右侧XX锁定不动作(b)(b)(4)48.8%Lot(b)(4)(b)(4)adjustment(b)(4)re-(b)(4)XX调整XX重新XX(b)(b)(4)-116.4%Mediafillunitsthataredeemedtohavequality-relatecfailuressuchasttoth
41、er,(b)(4),andpinholerejectsarenotincubated.Thus,thelackofqualitydefectrejectlimitsformediafillstudiesdoesnotprovideadequatestudyacceptancecriteriatodemonstrateasepticprocessrobustness.被认为有质量相关失败，例如“其它”、XX和针孔拒收的培养基灌装单位未放置稳定性。因此，培养基灌装研究缺乏质量缺陷拒收限度导致无法提供足够的研究可接受标准以证明无菌工艺稳定性。8 .印度SuvenLifeSciencesLimited
42、20180424OBSERVATION2缺陷2Equipmentandutensilsarenotcleanedandmaintainedtopreventcontaminationthatwouldalterthesafety,identity,strength,qualityorpurityoftheIntermediatesandAPIsmanufactured.设备和工器具未清洁并保存以防止对所生产的中间体和API形成可能改变安全性、鉴别、剂量、质量或纯度的污染。Specifically,on05February2018and08February2018,duringtheinspec
43、tionofyour(b)(4)whichareusedinthemanufacturingprocessforvariedAPIsinProductionBlock-(b)(4)Area.Yourfirmfailedtoadequatelycleanandvisuallyinspectthefollowing(b)(4).具体来说，2018年2月5日和2018年2月8日，在对生产车间XX区域你们用于不同APl生产工艺的XX检查期间，你们公司未能充分清洁和目视检查XX：A. (b)(4)-3109isusedintheproductionof(b)(4)API/Intermediate;Iob
44、servedwhatappearstobediscolorationresembling(b)(4)insidethe(b)(4)-3109inareasthatcomeintodirectcontactwithdrugproduct.Thestatusofthisnon-dedicated(b)(4)wasidentifiedascleaned.(b)-3109用于XX原料药/中间体的生产：我发现在XX-3109内直接接触药品的区域有类似变色的地方。该非专用XX的状态标识为已清洁。B. (b)(4)-3139:!observedthegasketusedtoprotectthe(b)(4)a
45、ndthe(b)(4)of(b)(4)-3139waswrappedinTeflontapeandstartingtounravel.IobservedwhatappearedtobemissingpiecesoftheTeflontapeatthebottomofthe(b)(4).Inaddition,!observedwhatappearedtobeawhite,powderyresiduealongtheinsideofthe(b)(4).Thestatusofthisequipmentwasidentifiedascleanedandavisualinspectionwasdocum
46、entedintheEquipmentUseLogbook.(b)-3139:我发现用于保护XX-3139的XX和XX的垫圈用聚四氟乙烯带包裹，已经开始散开。我发现在XX底部有聚四氟乙烯带掉落的碎片。另外，我发现在XX内部有白色粉状残留。该设备的状态被标为已清洁，设备使用日志上有记录目视检查。C. (b)(4)-3137:1observedwhatappearstobe(b)(4)residueandblackresiduealongsidethesidesofthis(b)(4).Inaddition,Iobservedthe(b)(4)boltslocatedonthebottomofth
47、e(b)(4)thatcomesindirectcontactwithdrugproductstohavea(b)(4)discoloration.Iobservedaholeatthebottomofthe(b)(4)Indicatingthis(b)(4)isdamaged.TheEquipmentUseLogbookdocumentstheequipmentqualificationwerecompletedon29December2017andthestatusofthisnon-dedicatedequipmentwasidentifiedascleaned.(b)(4)-3137:
48、我发现在此XX的边沿有XX残留和黑色残留。另外，我发现位于XX底部的XX螺栓与药品有直接接触，已有XX变色。我发现在XX底部有一个孔洞，显示XX已受损。该设备使用日志记录了该设备确认是在2017年12月29日完成的，此非专用设备的状态标识为已清洁。OBSERVATlON3缺陷3ManufacturingBatchRecordsaredeficient.生产批记录有缺陷。Specifically,具体来说A. On13February2018zyourfirmfailedtodocumentin-processchecksduringthemanufacturingofthedurgproduct,(b)(4)Tablets,Batch#(b)(4)onForm,FCQO-F320,asoutlinedinStep(b)(4)oftheBatchManufacturingRecord.
