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Causal AnalysisReport/因果分析报告Event Description/事件描述The detergentresult ofGlatt Granulationtrain SampleNo.
37.2in cleaningperiodic revalidationfor Xelodawas out of acceptance criteria.希罗达周期性清洁再验证中,Glatt制粒干燥系统的清洁剂结果样品编号
37.2超出接受标准Discrepancy IDnumber/差异ID号码TW1079413Causal AnalysisTeam Participants/因果分析小组成员Function/职能Name/姓名QA LilyZhou/周玲洁QV LilyLi/李志珍Prod-SME ZhaoBin/赵斌Prod-SME XuFeng/徐锋Prod-SME AlexYu/郁昊MSAT-SME ChenJie/陈洁Documentation ofall information/data availablefrom theinitial Investigation/初步调查中获取的所有信息/数据的记录
1.RCA—Fishbone diagram/因果分析--------鱼骨图
1.1Material/物料方面•Possible cause1:Citric Acid可能原因1柠檬酸The supplierfor citric acid is not changed since last cleaning validation
2022.01自从上次清洁验证
2022.01至今,柠檬酸的供应商未发生过变更The quantityof citric acid wasweighed bytwo operatorsand formulationof citricacid solution wasperformed bytwo operators.Citric acidsolution waspumped into detergent storage container foruse.Operator checkedthe setpoint ofdosing pumpwas correct.During WIP process,operator wasalwaysbeside the detergent storagecontainer and confirmed allcitricacidsolutionwasused up.No remarkofabnormity was found onlogbook.柠檬酸由双人称量,柠檬酸溶液由双人配制使用前,柠檬酸溶液被吸入清洁剂储罐中待用员工检查计量泵的设定值正确在WIP期间,员工始终在清洁剂储罐旁边并确保所有柠檬酸溶液用尽查看相关日志,没有发现异常情况Outcome:No.结果不是可能原因•Possible cause2:CIP100可能原因2CIP100The supplierfor CIP100is not changed since last cleaning validation
2022.01自从上次清洁验证
2022.01至今,CIP100的供应商未发生过变更Two wholedrums of CIP100are usedfor WIP.CIP100is pumpedintodetergent storagecontainerforuse.Operator checkedthe setpoint ofdosing pumpwas correct.During WIP process,operator wasalwaysbeside thedetergentstoragecontainer andconfirmed allCIP100were usedup.No remarkofabnormity was found onlogbook.两整桶CIP100用于WIPCIP100被吸入清洁剂储罐中待用员工检查计量泵的设定值正确在WIP期间,员工始终在清洁剂储罐旁边并确保所有CIP100用尽查看相关日志,没有发现异常情况Outcome:No.结果不是可能原因•Possible cause3:Glove forcleaning可能原因3手套用于清洁The supplierfor rubber glove is notchangedsince last cleaning validation
2022.01自从上次清洁验证
2022.01至今,手套的供应商未发生过变更Rubber glove is singleused.70%Ethanol isonly used during gowningbefore enteringgranulation room.No70%ethanol is used duringmanual cleaning.乳胶手套为一次性使用只在进入制粒间前的更衣时使用过70%乙醇在手工清洁期间没有使用过70%乙醇According tocurrent samplingprocedure sop0105674v
2.0,the Sterileglove is used duringCV visualinspectionform
2022.
06.
12.Before
2022.
06.12,the rubber glove isused duringCV visual inspection.The Sterileglove andrubberglove is singleused,and no70%ethanol isused whenwearing glove.依据现行版取样程序sop0105674V
2.0,自起,清洁验证目检时使用无菌手套在前,清洁验证目检时使用乳胶手套无菌手套和乳胶手套均为一次性使用,戴手套时不使用70%乙醇Above all,interference of70%ethanol to thedetergentresult canbe excluded.综上,70%乙醇对清洁剂结果的干扰可以被排除Outcome:No.结果不是可能原因•Possible cause4:Glove forSampling可能原因4手套用于取样The supplierfor gloveisnotchangedsincelastcleaningvalidation
2022.
01.According tocurrentsampling proceduresop0105674v
2.0,the Sterilegloveisused duringvisual inspectionand TOCsamplingform
2022.
06.
12.Before
2022.
06.12,the rubbergloveisused duringvisual inspectionandTOC sampling.The Sterileglove andrubbergloveis singleused,and no70%ethanol isused whenwearingglove.自从上次清洁验证
2022.01至今,手套的供应商未发生过变更自起,依据现行版取样程序sop0105674V
2.0,在目检和TOC取样时使用无菌手套在2前,目检和TOC取样时使用乳胶手套无菌手套和乳胶手套均为一次性使用,戴手套时不使用70%乙醇Outcome:No.结果不是可能原因•Possible cause5:Low fibrewiper可能原因5低纤维抹布Low fibrewiper isusedduringmanual cleaningfor machineand parts.Visual inspectionbeforesampling metthe acceptance criteria.低纤维抹布用于设备和部件的手工清洁取样前的目检结果符合可接受标准Outcome:No.结果不是可能原因•Possible cause6:Drinking water可能原因6饮用水The qualitymonitoring parametershardness,chlorine andconductivity are all within acceptancecriteria duringclearance according to SRD-0101917uOperational LogSheet of SHiP PWsystem”.And,no abnormaltrend forthese parameterswasfound.根据SRD-0101917SHiP饮用水系统运行记录表”,清场期间的水质监测参数硬度、余氯和电导率均在可接受标准内且没有发现数据有不良趋势Outcome:No.结果不是可能原因•Possible cause7:Purified water可能原因7纯水The qualitymonitoring parametersozone andconductivity areall withinacceptance criteriaduringclearance according to printout ofSHiPPUW system.And,no abnormaltrend forthese parameters根据SHiP纯水系统的打印记录,清场期间的水质监测参数臭氧和电导率均在可接受范围内且没有发现数据有不良趋势Outcome:No.结果不是可能原因•Possible cause8:TX761sampling swab可能原因8TX761取样棉签Type ofsampling swabis Texwipe TX761,and itisusedin theanalytical methodvalidation andcleaningvalidation ofdetergent samplingactivities,and itisusedblank swabas blanksample.Abnormal resultis neverfound tillnow.取样棉签的型号是TexwipeTX761,在分析方法验证和清洁验证过程中所有的清洁剂取样中均使用该棉签进行取样,同时,进行使用空白棉签作为空白对照样品,至今未发现异常结果Outcome:No.结果不是可能原因
1.2Man/人员方面•Possible cause1:Qualification forOperator Cleaning可能原因1操作员工的清洁资质All operatorsparticipated in the clearanceare trainedof current SOP-0102731Cleaning procedure forGlatt granulationtrain inHP plant.They areall qualifiedfor manualcleaning withqualificationcertificate.所有参预清场的员工都被培训过现行版SOP・0102731“高致敏车间Glatt制粒干燥系统的清洁程序”他们均有手工清洁的资质认证证书Ou忙ome:No.结果不是可能原因•Possible cause2:Qualification forsampling staff可能原因2取样员工的资质Sampling personis trainedand qualified,and havetaken CVsamples foralmost3years.取样员工受过培训过,是有资质的,且已进行近3年的清洁验证取样Outcome:No.结果不是可能原因
1.3Measure/测量方面•Possible cause1:alarms duringWIP可能原因1WIP期间的报警Checking printoutof WIP process,it wasfound thatat10:
162022.
08.31,alarm452-1MTank loopwaterflow-actual valueminnoccurred in“WIP STOP55step.In“WIP STOP55step,washing forGlatt pausedandwater replenishingof drinking water tankwas in-process.It caused the alarm452-1that thevalueof water flow forreplenishing drinking water wastoo low.Before“WIP STOPstep,7steps fordrinkingwater washing/rinse4steps forVG and3steps forFBD hadcompleted and3steps fordrinking waterwashing/rinse1step forVG and2steps forFBD wasnot performed.And,steps fordrinking waterwashing/rinse wereafter CIP100washing.查看WIP程序的打印报告,发现在上午1016,452・1报警Tank loopwaterflow-actual valuevmin”发生在“生在暂停”步骤在骤在暂停”步骤,对Glatt的清洗暂停,饮用水储罐正在补水饮用水补水流量太小导致了452-1报警的发生在“警的发暂停”步骤前,7步饮用水清洗/淋洗4步VG,3步FBD已完成,剩余3步饮用水清洗/淋洗1步VG,2步FBD还未进行饮用水清洗步骤是在CIP100清洗步骤后进行的During stoppingperiod ofmachine,alarm138-366Product containerseal-leak occurred and causedthe upper sealof FBDdeflated.At thattime,drinking water might enterthe gapbetween upper seal andFBD bowl rim.The alarmwas causedby leakageof compressed air duct.The ductwas replacedandalarm wasremoved afterabout16min and the upper seal inflated.Some drinking watermightresiduein the space between the upper seal and FBD bowl rim.在设备住手期间,138-3报警Product containerseal-leak”发生并导致FBD上密封圈放气此时,饮用水可能进入上密封圈和FBD碗形腔体边缘的间隙中该报警是由于压缩空气管道漏气导致的报警发生16分钟后,管道被更换,报警消除,上密封圈重新充气一些饮用水可能残留在上密封圈和FBD碗壁间的空隙中Alarm138-3will occurwhen theseal pressureof FBDlower seal is min.Confirmed bysupplier,thisalarm willcause upper seal andlower sealdeflate together.Pls.see attachment-01for Explanation forthe principleof alarm138-3provided bythe supplier.Moreover,Simulation runand supportingtest wasperformed after thediscrepancy occurred:When intentionallystopping the compressed air supply tolowerseal,Alarm138-3occurred,and the upper seal wasfounddeflated atthe sametime.Whenintentionally stoppingthe compressed airsupplyto upper seal,Alarm139-3occurred,and the lowerseal wasalso founddeflated atthe sametime.138・3报警为FBD碗形腔体的下密封圈的压力v最小值时发生的报警经供应商确认,该报警会导致上密封圈和下密封圈同时泄气供应商对138-3报警原理的解释见附件・01此外,在该偏差发生后,进行了摹拟运行及支持性测试人为中断下密封圈的压缩空气供应,浮现报警138・3,同时观察到上密封圈也泄气了;人为中断上密封圈的压缩空气供应,浮现报警139-3,同时观察到下密封圈也泄气了When thealarms occurred,WIPprocesswas during drinkingwater washing/rinse afterCIP100washing.There mightbe someCIP100residue indrinkingwaterinthespace betweentheuppersealand FBDbowl rim.报警发生时,WIP程序处于CIP100清洗后的饮用水清洗/淋洗步骤中残留在上密封圈和FBD碗形腔体边缘之间的空隙中的饮用水中可能有CIP100残留The laststep of WIPprocessis drying.So,drinkingwaterin spacebetweentheupperseal and FBDbowl rim wasevaporated,but residueofCIP100was onupperseal and FBDbowl rim.WIP程序的最后一步为干燥所以,在上密封圈和FBD碗形腔体边缘之间的空隙中的饮用水蒸发了,但是CIP100可能残留在上密封圈和FBD碗形腔体边缘上Outcome:YES结果是可能的原因・Possible cause2:Visual inspectionbefore sampling可能原因2取样前的目检MSAT,QV andProd personhave performedvisualinspectionbefore sampling,andconfirmedtheequipment wasvisual cleanno residueand foreignobjects anddry.MSAT,QV和生产部员工在取样前进行了目检,并确认设备目视清洁无残留和异物并干燥Outcome:No.结果不是可能原因
1.4Machine/设备方面・Possible cause1:Glatt granulation and FBD system可能原因1Glatt制粒干燥系统The Glatt granulationandFBDsystemis withinrevalidation duedate.Maintenance isperformedaccording tomaintenance plan.Glatt制粒干燥系统在再验证有效期内维护行动按照维护计划进行Outcome:No.结果不是可能原因
1.5Environment/环境方面•Possible cause1:Temperature,humidity anddifferential pressure可能原因1温湿度及压差The temperature,humidity anddifferential pressureof granulationroom iswithinacceptancecriteriaduring clearanceaccording toprintoutofBMS system.根据BMS系统打印记录,在清场期间制粒间的温湿度和压差均在可接受标准内Outcome:No.结果不是可能原因
1.6Method/方法方面•Possible cause1:WIP recipe可能原因1WIP处方There isno changefor WIPrecipe sincelastcleaningvalidation
2022.
01.Checking printoutofWIPforthis clearance,WIPprocessis integrated.The stepsand parametersareallcorrect.从上次清洁验证
2022.01至今,WIP处方没有变更查看本次清场的WIP打印记录,WIP程序完整所有步骤和参数正确Outcome:No.结果不是可能原因•Possible cause2:Manual cleaning可能原因2手工清洁There isno changefor manualcleaning proceduresincelastcleaningvalidation
2022.
01.Manualcleaning forthe FBDbowl rimand uppersealisperformedaftercitricacidwashing andafter thewholeWIP recipeaccordingtocurrent SOP-0102731n CleaningprocedureforGlattgranulationtrain inHPplant”.All operatorparticipated inthe clearanceare qualifiedfor manualcleaning withqualifiedcertificate.The cleaningstatus isdouble checkedafter manualcleaning,and thereisnovisible powderandwater traceon FBDbowl rimand upperseal.从上次清洁验证
2022.01至今,手工清洁程序没有变更根据现行版SOP-0102731有高致敏车间Glatt制粒干燥系统的清洁程序”,FBD碗的边缘和上密封圈在柠檬酸清洗后和整个WIP程序后进行所有参预清场的员工均有手工清洁的资质认证证书在手工清洁后,清洁状态经双人复核,在FBD碗边缘和上密封圈没有发现可见粉尘和水迹Outcome:No.结果不是可能原因•Possible cause3:Sampling method可能原因3取样方法The samplingprocedure isaccordingtocurrentSOP-0105674,Sampling forCleaning Validation55,andtherecovery ofsampling methodwas validated.取样程序是依据现行版SOP-0105674,“清洁验证的取样”进行的,且取样方法的回收率已经过验证Outcome:No.结果不是可能原因
2.RCA—5Whys/因果分析——5Wh/s•1st-Why detergenttest resultof SamplingNo.
37.2wasoutofacceptancecriteria为什么样品
37.2的清洁剂测试结果超出接受标准?CIP100residue contaminatedthe FBDbowl rimand wascollected bysampling.CIP100残留污染了FBD碗形腔体的边缘,被取样采集到•2nd-Why CIP100residue contaminatedthe rim为什么CIP100残留污染了FBD碗形腔体的边缘?Drinking waterwith CIP100residue enteredthe gapbetween uppersealandrim whenupper sealdeflated;and remainedand couldnt be cleanedafter upperseal re-inflated.上密封圈泄气时,带有CIP100残留的饮用水进入上密封圈和FBD碗形腔体边缘的间隙中;上密封圈重新充气后留在间隙中,且无法被清洗干净•3rd-Why theCIP100residue inthe gapcouldntbecleaned为什么留在间隙中的CIP100残留无法被清洗干净?Alarm138-1occurred duetothecompressed air duct ofthelowersealwasleakage.Mechanics replacedthe duct,then bothseals werere-inflated.Cleaning watercouldnt rinsethe gapaftertheupperseal re-inflated.Mechanics fixedthe problemcausedthealarm,but noadditionalcleaning action was taken.由于下密封圈压缩空气管道漏气,发生了138-1报警机修更换了管道,上、下密封圈重新充气上密封圈重新充气后,清洁用水无法冲洗密封圈和碗沿之间的间隙机修解决了引起报警的问题,但没有做额外的清洁行动•4th-Why noadditional cleaningactionwastaken为什么没有做额外的清洁行动?Current alarm handling focuseson solvingthe problem,not requiresassessing potential risk to relevantprocess.目前的报警处理流程关注解决问题本身,不要求评估对相关流程的潜在风险•5th-Why currentalarmhandlingdoesnt assesspotentialrisk torelevantprocess为什么目前的报警处理流程不要求评估对相关流程的潜在风险?Improper/Inadequate handlingprocess forcritical GMP alarms关键GMP报警的处理流程不当/不足Conclusion/结论•Possible contaminationpathway basedon rootcause analysis/根本原因分析得出的可能的污染途径Alarm138-3occurredanduppersealof FBDbowl deflated—►Drinking waterwith CIP100enteredthe gapbetween sealandFBDbowlrim一Alarm138-3removed anduppersealreinflated一Drinkingwater withCIP100remained inthespacebetween uppersealandFBDbowlrim—Drinking waterwasevaporated afterdrying stepbut CIP100residue remainedon FBDbowlrim一Detergent testresult outofacceptancecriteria浮现报警138-3,FBD碗形腔体的上密封圈泄气一饮用水及CIP100进入上密封圈和腔体边缘的缝隙一报警138-3解除,上密封圈重新充气一饮用水及CIP100留在上密封圈和腔体边缘的空隙中一干燥过程中饮用水蒸发,但CIP100残留在腔体边缘上一清洁剂样品结果超出接受标准•Cause conclusion/原因结论Abnormal deflateand re-inflate ofuppersealduringdrinkingwaterwashing/rinse processdue tocompressedairduct leakage由于压缩空气管道漏气,上密封圈在饮用水清洗/淋洗过程中发生了不正常的泄气并重新充气•Improper/lnadequate handlingprocess forcritical GMPalarms关键GMP报警处理流程不当/不足Follow upaction/后续行动CAPA TW1097877has beeninitiated toreduce therisktomanufacturing process/cleaning processresultedfrom improper/inadequate alarmhandling byestablishing processon handling critical GMPalarms andupdatingrisk assessment documents.开启CAPA TW1097877通过建立关键GMP报警的处理流程及更新风险评估文件,来降低由于报警处理不当/不足而对生产流程/清洁流程造成影响的风险Planned actions/计划的行动A.To updateGlatt Granulationequipment riskassessmentdocumentFMEA-RMP-SH-2022-017to includetherisk ofcompressedairductleakage/更新Glatt制粒机设备风险评估文件FMEA-RMP-SH-2022-017,加入压缩空气管道漏气的风险As minimum,thecompressedair ductsin SHiPplant shouldbe replacedevery5years.In addition,duringannual overhaul,maintenance teamwill checkand assesswhether thecompressedairducts shouldbereplaced.SHiP车间的压缩空气管道至少每5年更换一次而且在年度大修时,机修团队会检查并评估压缩空气管道是否需要更换Responsible:Prod,Maintenance team/Chenxi Fu负责人生产部,机修团队/傅晨曦B.To updateE2E riskassessment documentsof XelodaTab/Cellcept Cap/Cellcept Tabto includethe risktomanufacturing process/cleaning processresulted fromimproper/inadequate alarmhandling/更新希罗达片剂/骁悉胶囊/骁悉片剂的E2E风险评估文件,加入由于报警处理不当/不足而对生产流程/清洁流程造成影响的风险Responsible:Prod,GMP supportteam/Tony Lu负责人生产部,GMP支持团队/陆舜尧C.To classifythe manufactureequipment alarms,and establishinstruction onhandlingcriticalGMPalarm/对创造设备报警进行分类,建立对关键GMP报警误处理的指导Responsible:Prod,Maintenance team/Chenxi Fu负责人生产部,机修团队/傅晨曦Reference/参考Attachment-01Explanationforthe principleof alarm138-3provided bysupplier附件-01:供应商对138-3报警原理的解释Completed By/Date填写人/日期。