欧盟检查失败案例参考.docx

1、无锡积大欧盟检查失败检查方：意大利检查日期：2015-6-11产品：无菌冻干谷胱甘肽钠检查区域：一厂和3号生产车间不符合情况：检查发现28个缺陷，15个缺陷为重大缺陷。重大缺陷：多个生产步骤有关于无菌保证的偏差，产品有污染风险：a）取样间（念头14-15-16）：更衣间设计不适当，不能将污染风险降至最小；不同洁净级别之间的压差没有监测；更衣程序不符合洁净区的要求。b)生产区域（偏差19-20-21-24）：不同洁净级别相邻区域的压差不符合欧洲GMP指南要求的值，有些生产房间的清洁状况很差，处理不充分，B级区粒子计数（即冻干机和压盖间）位置不适合既定用途，原料药从混合机转移到铝听时不能排除原料药污染风险。c)验证（偏差7从a到j）：不同活动的验证方法没有根据GMP要求正确实施，验证报告不够详细（仓库温度分布研究、工具无菌状态保存时间、UV传递窗内物品放置时间、胶塞灭菌用温热灭菌柜的灭菌时过滤器最大数量验证、铝听灭菌用的干热灭菌验证、称重间的称量罩验证、取样间HVAC验证、预冻间级别验证、工艺模拟即将散装产品装入冻干机的最大灌装时间以及将原料药从混合机转移至铝听和压盖的最大时间验证报告。d）包装和标签（偏差5-10-11-13）：有些测试中发现没有对无菌谷胱甘肽钠冻干粉的容器密闭系统进行管理，不能保证产品的无菌状态；一个“错误”和未更新的标签用作标准来确认原料药的发运标签；在原料药仓库里，无菌原料药的铝听没有密封；铝盖没有批号标识无法追溯。e）化验室测试（偏差28）：发现一些IR仪器的偏差，特别是红外没有通过ID和密码的受控权限，不能禁止拷贝和重命名文件。f）人员行为（偏差2-7i(ii)18-19）：在检查期间，检查团对同一个问题从工人和管理人员得到的回答不一致，相互冲突；有时这些答案看起来是根据检查官的要求进行修正。文件展示不清楚，例如：有些平面图被替换了，有些文件与主题无关。最后，管理人员在现场检查过程中未能遵守更衣程序。Natureofnon-compliance:TheinspectionwasperformedbyGMPinspectorsinrelationtothemanufactureofsterileglutathionesodiumlyophilisedobjectofavariation.Theinspectionwasfocusedonsite1andproductionworkshopnumber3.Duringtheinspection28deficiencieswerefound,15ofwhichwereratedasmajordeficiencies.MajorDeficiencies:Inmanyproductionstepsdeviationswerefoundregardingthesterilityassuranceandariskofcontaminationoftheproduct:a)Samplingroom(deviations14-15-16):thechangingroomwasnotdesignedinasuitablewaytominimizetheriskofcontamination;thedifferentialpressurebetweentheareasmaintainedatdifferentcleanlinessgradewasnotmonitored;thegarmentsprocedurewasnotinaccordancetotheprincipleofclassifiedareas;b)Productionareas(deviations19-20-21-24):thepressuredifferentialbetweenadjacentareasatdifferentcleanlinessgradewasnotincompliancewiththeguidancevalueoftheEuropeangoodmanufacturingpractices;themaintenanceandcleaningconditionsofsomeproductionroomswerepoorandnotadequatelyhandled;theparticlecountersinBclassgrade(i.e.freeze-dryersandcappingroom)wereunsuitablelocatedfortheintendeduse;theAPItransferfromthemixertoaluminumtindidnotexcludeariskofAPIcontamination.c)Validation(deviation7fromletteratoj):thevalidationapproachfordifferentactivitieswasnotcorrectlyperformedaccordingtotheGMPrequirementsandvalidationreportswerenotdetailed(warehousetemperaturemapping;holdingtimeforsterilizationoftools;stay-timeinUV-passbox;maximumnumberoffilterssterlisation(20)validationforthemoistheatsterilizerusedfortherubberstoppersterilization;validationforthedryheatsteriliserusedforthealuminiumtinsterilisation;validationforLAFinweighingroom;validationfortheHVACofthesamplingroom;validationforfront-freezingroomclassification;validationreportfortheprocesssimulationnamelymaximumfillingtimeofloadingthebulkproductinfreeze-dryersandmaximumtimeoftransferringAPIfrommixertoaluminumtinsandcapping.d)Packagingandlabeling(deviations5-10-11-13):themanagementforthecontainerclosuresystemforsterileglutathionesodiumfreeze-driedwasfoundlackinginsometeststoguaranteethesterilityassuranceoftheproduct;a“wrong“andnot-updatedlabelwasusedasastandardtoverifytheshippinglabelsofAPI;intheAPIwarehouse,thealuminumtinsofsterileAPIwerenotsealed;thealuminumcapswerenotidentifiedwithabatchnumberloosingtraceability.e)Laboratorytesting(deviation28):somedeviationswerefoundfortheIRinstrument,inparticulartheIRsoftwarehadnotacontrolledaccessviaIDandpasswordanditwasnotforbiddentocopyandrenameafile.f)Personnelbehavior(deviations2-7i(ii)-18-19):duringtheinspection,theinspectorsteamreceivedinconsistentandconflictinganswersonthesametopicfrombothpersonnelandmanagement;sometimestheanswersseemedtobemodifiedaccordingtotheinspectorsrequests.Thedocumentationwasshowedinanambiguouswayastheexamples:somelayoutswerereplaced;somedocumentationwasunrelatedtothetopic.Finallymanagementdidnotcomplywiththeclothingprocedureduringtheinspectiontour.2、济南金达药化欧盟GMP检查失败检查时间：2015-6-26地址:山东省济南市章丘市龙泉路6121号检查官方：意大利不符合情况：共18个缺陷，其中1个关键，6个重大。关键缺陷是不正式未受控存贮区域里有原料和成品，仓库门被移走后，换了一块板用螺丝固定在墙上，然后检查期间要求公司给弄开了。在此区域存贮的物料管理并不在质量保证体系内，检查员调查发现有严重的数据造假风险。6个重大缺陷中的一个与类似问题有关，有一个被锁住的车库在检查官要求后才打开。余下其它5个重大缺陷均与质量保证体系以下方面相关：培训、清洁验证、HPLC分析数据完整性破坏、微生物实验室、关键中间体合同生产商确认。Natureofnon-compliance:Intotal18deficiencieswereidentifiedbytheinspectionteam,oneofthemwasclassifiedascriticalandsixasmajor.Thecriticalobservationwasrelatedtoanunofficialandnon-controlledstorageareacontainingmainlyrawmaterialsandfinishedproductswhichhadbeenmadeinaccessibletoinspectorsasthedoorhadbeenremovedandreplacedwithapanelfixedwithscrewstothewall,whichduringtheinspectiontheCompanywasrequestedtoremove.ThematerialstoredinthisareawastobemanagedoutsideoftheQualityAssurancesystemandtheinvestigationcarriedoutbytheinspectionteamconcludedtherewasaseriousriskofdatafalsification.Oneofthesixmajordeficiencieswasrelatedtoaverysimilarissue,asaccesstoalockedgaragewasgiventotheinspectionteamonlyhoursafterrequestingit.Inbothcasestheexplanationsprovidedwerenotsoundanddifferentversionsweregivenduringtheinspection.TheremainingfivemajordeficiencieswererelatedtospecificaspectsoftheQualityAssuranceSystemwithregardstotraining,cleaningvalidation,breachesofdataintegrityinthecontextofHPLCanalysis,microbiologicallaboratory,qualificationofcontractmanufacturerofakeyintermediateofNitrofurantoinproduction.3、印度PARABOLICDRUGSLIMITED欧盟检查失败检查方：意大利检查日期：2015-6-17检查地址：PDL-2,PlotNo.45,IndustrialArea,PhaseII,PanchkulaDistrict,Haryana,134113,India检查品种：DICLOXACILLINSODIUM原料药不符合情况：发现质量管理体系严重失控，在下列领域发现的关键和重大偏差表明所有EU-GMP要求的“原则”均存在缺陷（除了2.13和2.14外）：文件、样品和物料保存和控制不充分、伪造文件和数据、QC化验室数据完整性和数据安全、变更控制、偏差管理和风险管理。总共发现27个缺陷：3个关键：文件管理体系、做假、数据安全和完整性7个主要缺陷分布在QC、人员、文件记录和变更控制Natureofnon-compliance:Thequalitymanagementsystemwasfoundt