偏差處理案例分析

1、CausalAnalysisReport/因果分析報(bào)告EventDescription/事件描述ThedetergentresultofGlattGranulationtrain(SampleNo.37.2)incleaningperiodicrevalidationforXelodawasoutofacceptancecriteria.希羅達(dá)周期性清潔再驗(yàn)證中，Glatt制粒干燥系統(tǒng)的清潔劑結(jié)果(樣品編號(hào)37.2)超出接受標(biāo)準(zhǔn)。DiscrepancyIDnumber/差異ID號(hào)碼TW1079413CausalAnalysisTeamParticipants/因果分析小組成員Function/

2、職能Name/姓名QALilyZhou/周玲潔QVLilyLi/李志珍Prod-SMEZhaoBin/趙斌Prod-SMEXuFeng/徐鋒Prod-SMEAlexYu/郁昊MSAT-SMEChenJie/陳潔Documentationofallinformation/dataavailablefromtheinitialInvestigation/初步調(diào)查中獲取的所有信息/數(shù)據(jù)的記錄1. RCAFishbonediagram/因果分析魚(yú)骨圖1.1 Material/物料方面：Possiblecause1:CitricAcid可能原因1：檸檬酸Thesupplierforcitricacidi

3、snotchangedsincelastcleaningvalidation(2013.01)自從上次清潔驗(yàn)證(2013.01)至今，檸檬酸的供應(yīng)商未發(fā)生過(guò)變更。Thequantityofcitricacidwasweighedbytwooperatorsandformulationofcitricacidsolutionwasperformedbytwooperators.Citricacidsolutionwaspumpedintodetergentstoragecontainerforuse.Operatorcheckedthesetpointofdosingpumpwascorrect

4、.DuringWIPprocess,operatorwasalwaysbesidethedetergentstoragecontainerandconfirmedallcitricacidsolutionwasusedup.Noremarkofabnormitywasfoundonlogbook.檸檬酸由雙人稱量，檸檬酸溶液由雙人配制。使用前，檸檬酸溶液被吸入清潔劑儲(chǔ)罐中待用。員工檢查計(jì)量泵的設(shè)定值正確。在WIP期間，員工始終在清潔劑儲(chǔ)罐旁邊并確保所有檸檬酸溶液用盡。查看相關(guān)日志，沒(méi)有發(fā)現(xiàn)異常情況。Outcome:No.結(jié)果：不是可能原因。Possiblecause2:CIP100可能原因2:

5、CIP100ThesupplierforCIP100isnotchangedsincelastcleaningvalidation(2013.01)自從上次清潔驗(yàn)證(2013.01)至今，CIP100的供應(yīng)商未發(fā)生過(guò)變更。TwowholedrumsofCIP100areusedforWIP.CIP100ispumpedintodetergentstoragecontainerforuse.Operatorcheckedthesetpointofdosingpumpwascorrect.DuringWIPprocess,operatorwasalwaysbesidethedetergentsto

6、ragecontainerandconfirmedallCIP100wereusedup.Noremarkofabnormitywasfoundonlogbook.兩整桶CIP100用于WIPoCIP100被吸入清潔劑儲(chǔ)罐中待用。員工檢查計(jì)量泵的設(shè)定值正確。在WIP期間，員工始終在清潔劑儲(chǔ)罐旁邊并確保所有CIP100用盡。查看相關(guān)日志，沒(méi)有發(fā)現(xiàn)異常情況。Outcome:No.結(jié)果：不是可能原因。Possiblecause3:Glove(forcleaning)可能原因3:手套(用于清潔)Thesupplierforrubbergloveisnotchangedsincelastcleaning

7、validation(2013.01)自從上次清潔驗(yàn)證(2013.01)至今，手套的供應(yīng)商未發(fā)生過(guò)變更。Rubbergloveissingleused.70%Ethanolisonlyusedduringgowningbeforeenteringgranulationroom.No70%ethanolisusedduringmanualcleaning.乳膠手套為一次性使用。只在進(jìn)入制粒間前的更衣時(shí)使用過(guò)70%乙醇。在手工清潔期間沒(méi)有使用過(guò)70%乙醇。Accordingtocurrentsamplingprocedure(sop0105674v2.0),theSterilegloveisuse

8、dduringCVvisualinspectionform2015.06.12.Before2015.06.12,therubbergloveisusedduringCVvisualinspection.TheSterilegloveandrubbergloveissingleused,andno70%ethanolisusedwhenwearingglove.依據(jù)現(xiàn)行版取樣程序(sop0105674v2.0),自2015.06.12起，清潔驗(yàn)證目檢時(shí)使用無(wú)菌手套。在2015.06.12前，清潔驗(yàn)證目檢時(shí)使用乳膠手套。無(wú)菌手套和乳膠手套均為一次性使用，戴手套時(shí)不使用70%乙醇。Aboveall

9、,interferenceof70%ethanoltothedetergentresultcanbeexcluded.綜上，70%乙醇對(duì)清潔劑結(jié)果的干擾可以被排除。Outcome:No.結(jié)果：不是可能原因。Possiblecause4:Glove(forSampling)可能原因4:手套(用于取樣)Thesupplierforgloveisnotchangedsincelastcleaningvalidation(2013.01).Accordingtocurrentsamplingprocedure(sop0105674v2.0),theSterilegloveisusedduringvis

10、ualinspectionandTOCsamplingform2015.06.12.Before2015.06.12,therubbergloveisusedduringvisualinspectionandTOCsampling.TheSterilegloveandrubbergloveissingleused,andno70%ethanolisusedwhenwearingglove.自從上次清潔驗(yàn)證(2013.01)至今，手套的供應(yīng)商未發(fā)生過(guò)變更。自2015.06.12起，依據(jù)現(xiàn)行版取樣程序(sop0105674v2.0),在目檢和TOC取樣時(shí)使用無(wú)菌手套。在2015.06.12前，目檢

11、和TOC取樣時(shí)使用乳膠手套。無(wú)菌手套和乳膠手套均為一次性使用，戴手套時(shí)不使用70%乙醇。Outcome:No.結(jié)果：不是可能原因。Possiblecause5:Lowfibrewiper可能原因5:低纖維抹布Lowfibrewiperisusedduringmanualcleaningformachineandparts.Visualinspectionbeforesamplingmettheacceptancecriteria.低纖維抹布用于設(shè)備和部件的手工清潔。取樣前的目檢結(jié)果符合可接受標(biāo)準(zhǔn)。Outcome:No.結(jié)果：不是可能原因。Possiblecause6:Drinkingwater

12、可能原因6:飲用水Thequalitymonitoringparameters(hardness,chlorineandconductivity)areallwithinacceptancecriteriaduringclearanceaccordingtoSRD-0101917aOperationalLogSheetofSHiPPWsystem”.And,noabnormaltrendfortheseparameterswasfound.根據(jù)SRD-0101917SHiP飲用水系統(tǒng)運(yùn)行記錄表”，清場(chǎng)期間的水質(zhì)監(jiān)測(cè)參數(shù)(硬度、余氯和電導(dǎo)率)均在可接受標(biāo)準(zhǔn)內(nèi)。且沒(méi)有發(fā)現(xiàn)數(shù)據(jù)有不良趨勢(shì)。Outco

13、me:No.結(jié)果：不是可能原因。Possiblecause7:Purifiedwater可能原因7:純水Thequalitymonitoringparameters(ozoneandconductivity)areallwithinacceptancecriteriaduringclearanceaccordingtoprintoutofSHiPPUWsystem.And,noabnormaltrendfortheseparameters根據(jù)SHiP純水系統(tǒng)的打印記錄，清場(chǎng)期間的水質(zhì)監(jiān)測(cè)參數(shù)(臭氧和電導(dǎo)率)均在可接受范圍內(nèi)。且沒(méi)有發(fā)現(xiàn)數(shù)據(jù)有不良趨勢(shì)。Outcome:No.結(jié)果：不是可能原因。P

14、ossiblecause8:TX761samplingswab可能原因8:TX761取樣棉簽TypeofsamplingswabisTexwipeTX761,anditisusedintheanalyticalmethodvalidationandcleaningvalidationofdetergentsamplingactivities,anditisusedblankswabasblanksample.Abnormalresultisneverfoundtillnow.取樣棉簽的型號(hào)是TexwipeTX761,在分析方法驗(yàn)證和清潔驗(yàn)證過(guò)程中所有的清潔劑取樣中均使用該棉簽進(jìn)行取樣，同時(shí)，進(jìn)

15、行使用空白棉簽作為空白對(duì)照樣品，至今未發(fā)現(xiàn)異常結(jié)果。Outcome:No.結(jié)果：不是可能原因。1.2 Man/人員方面Possiblecause1:QualificationforOperator(Cleaning)可能原因1：操作員工的清潔資質(zhì)AlloperatorsparticipatedintheclearancearetrainedofcurrentSOP-0102731CleaningprocedureforGlattgranulationtraininHPplant“Theyareallqualifiedformanualcleaningwithqualificationcerti

16、ficate.所有參與清場(chǎng)的員工都被培訓(xùn)過(guò)現(xiàn)行版SOP-0102731“高致敏車間Glatt制粒干燥系統(tǒng)的清潔程序”。他們均有手工清潔的資質(zhì)認(rèn)證證書(shū)。Outcome:No.結(jié)果：不是可能原因。Possiblecause2:Qualificationforsamplingstaff可能原因2:取樣員工的資質(zhì)Samplingpersonistrainedandqualified,andhavetakenCVsamplesforalmost3years.取樣員工受過(guò)培訓(xùn)過(guò)，是有資質(zhì)的，且已進(jìn)行近3年的清潔驗(yàn)證取樣。Outcome:No.結(jié)果：不是可能原因。1.3 Measure/測(cè)量方面Possib

17、lecause1:alarmsduringWIP可能原因1:WIP期間的報(bào)警shingCheckingprintoutofWIPprocess,itwasfoundthatat10:162015.08.31,alarm452-1Tankloopwaterflow-actualvalueminoccurredinWIPSTOPstep.InWIPSTOPstep,waforGlattpausedandwaterreplenishingofdrinkingwatertankwasin-process.Itcausedthealarm452-1thatthevalueofwaterflowforre

18、plenishingdrinkingwaterwastoolow.Before“WIPSTOPstep,7stepsfordrinkingwaterwashing/rinse(4stepsforVGand3stepsforFBD)hadcompletedand3stepsfordrinkingwaterwashing/rinse(1stepforVGand2stepsforFBD)wasnotperformed.And,stepsfordrinkingwaterwashing/rinsewereafterCIP100washing.查看WIP程序的打印報(bào)告，發(fā)現(xiàn)在2015.08.31上午10:

19、16,452-1報(bào)警Tankloopwaterflow-actualvaluemin”發(fā)生在“生在“暫停”步驟。在“驟。在暫?！辈襟E，對(duì)Glatt的清洗暫停，飲用水儲(chǔ)罐正在補(bǔ)水。飲用水補(bǔ)水流量太小導(dǎo)致了452-1報(bào)警的發(fā)生。在“警的發(fā)暫?！辈襟E前，7步飲用水清洗/淋洗（4步VG,3步FBD）已完成，剩余3步飲用水清洗/淋洗（1步VG,2步FBD）還未進(jìn)行。飲用水清洗步驟是在CIP100清洗步驟后進(jìn)行的。Duringstoppingperiodofmachine,alarm138-3Productcontainerseal-leakoccurredandcausedtheuppersealofF

20、BDdeflated.Atthattime,drinkingwatermightenterthegapbetweenuppersealandFBDbowlrim.Thealarmwascausedbyleakageofcompressedairduct.Theductwasreplacedandalarmwasremovedafterabout16minandtheuppersealinflated.SomedrinkingwatermightresidueinthespacebetweentheuppersealandFBDbowlrim.在設(shè)備停止期間，138-3報(bào)警Productcont

21、ainerseal-leak”發(fā)生并導(dǎo)致FBD上密封圈放氣。此時(shí)，飲用水可能進(jìn)入上密封圈和FBD碗形腔體邊緣的間隙中。該報(bào)警是由于壓縮空氣管道漏氣導(dǎo)致的。報(bào)警發(fā)生16分鐘后，管道被更換，報(bào)警消除，上密封圈重新充氣。一些飲用水可能殘留在上密封圈和FBD碗壁間的空隙中。Alarm138-3willoccurwhenthesealpressureofFBDlowersealismin.Confirmedbysupplier,thisalarmwillcauseuppersealandlowersealdeflatetogether.Pls.seeattachment-01forExplanation

22、fortheprincipleofalarm138-3providedbythesupplier.Moreover,Simulationrunandsupportingtestwasperformedafterthediscrepancyoccurred:Whenintentionallystoppingthecompressedairsupplytolowerseal,Alarm138-3occurred,andtheuppersealwasfounddeflatedatthesametime.Whenintentionallystoppingthecompressedairsupplyto

23、upperseal,Alarm139-3occurred,andthelowersealwasalsofounddeflatedatthesametime.138-3報(bào)警為FBD碗形腔體的下密封圈的壓力最小值時(shí)發(fā)生的報(bào)警。經(jīng)供應(yīng)商確認(rèn)，該報(bào)警會(huì)導(dǎo)致上密封圈和下密封圈同時(shí)泄氣。供應(yīng)商對(duì)138-3報(bào)警原理的解釋見(jiàn)附件-01o此外，在該偏差發(fā)生后，進(jìn)行了模擬運(yùn)行及支持性測(cè)試：人為中斷下密封圈的壓縮空氣供應(yīng)，出現(xiàn)報(bào)警138-3,同時(shí)觀察到上密封圈也泄氣了；人為中斷上密封圈的壓縮空氣供應(yīng)，出現(xiàn)報(bào)警139-3,同時(shí)觀察到下密封圈也泄氣了。Whenthealarmsoccurred,WIPprocesswa

24、sduringdrinkingwaterwashing/rinseafterCIP100washing.TheremightbesomeCIP100residueindrinkingwaterinthespacebetweentheuppersealandFBDbowlrim.報(bào)警發(fā)生時(shí)，WIP程序處于CIP100清洗后的飲用水清洗/淋洗步驟中。殘留在上密封圈和FBD碗形腔體邊緣之間的空隙中的飲用水中可能有CIP100殘留。ThelaststepofWIPprocessisdrying.So,drinkingwaterinspacebetweentheuppersealandFBDbowlri

25、mwasevaporated,butresidueofCIP100wasonuppersealandFBDbowlrim.WIP程序的最后一步為干燥。所以，在上密封圈和FBD碗形腔體邊緣之間的空隙中的飲用水蒸發(fā)了，但是CIP100可能殘留在上密封圈和FBD碗形腔體邊緣上。Outcome:YES結(jié)果：是可能的原因。Possiblecause2:Visualinspectionbeforesampling可能原因2:取樣前的目檢MSAT,QVandProdpersonhaveperformedvisualinspectionbeforesampling,andconfirmedtheequipme

26、ntwasvisualclean（noresidueandforeignobjects）anddry.MSAT,QV和生產(chǎn)部員工在取樣前進(jìn)行了目檢，并確認(rèn)設(shè)備目視清潔(無(wú)殘留和異物)并干燥。Outcome:No.結(jié)果：不是可能原因。1.4 Machine/設(shè)備方面Possiblecause1:GlattgranulationandFBDsystem可能原因1:Glatt制粒干燥系統(tǒng)TheGlattgranulationandFBDsystemiswithinrevalidationduedate.Maintenanceisperformedaccordingtomaintenanceplan.

27、Glatt制粒干燥系統(tǒng)在再驗(yàn)證有效期內(nèi)。維護(hù)行動(dòng)按照維護(hù)計(jì)劃進(jìn)行。Outcome:No.結(jié)果：不是可能原因。1.5 Environment/環(huán)境方面Possiblecause1:Temperature,humidityanddifferentialpressure可能原因1：溫濕度及壓差Thetemperature,humidityanddifferentialpressureofgranulationroomiswithinacceptancecriteriaduringclearanceaccordingtoprintoutofBMSsystem.根據(jù)BMS系統(tǒng)打印記錄，在清場(chǎng)期間制粒間的

28、溫濕度和壓差均在可接受標(biāo)準(zhǔn)內(nèi)。Outcome:No.結(jié)果：不是可能原因。1.6 Method/方法方面Possiblecause1:WIPrecipe可能原因1:WIP處方ThereisnochangeforWIPrecipesincelastcleaningvalidation(2013.01).CheckingprintoutofWIPforthisclearance,WIPprocessisintegrated.Thestepsandparametersareallcorrect.從上次清潔驗(yàn)證(2013.01)至今，WIP處方?jīng)]有變更。查看本次清場(chǎng)的WIP打印記錄，WIP程序完整。所有

29、步驟和參數(shù)正確。Outcome:No.結(jié)果：不是可能原因。Possiblecause2:Manualcleaning可能原因2:手工清潔Thereisnochangeformanualcleaningproceduresincelastcleaningvalidation(2013.01).ManualcleaningfortheFBDbowlrimanduppersealisperformedaftercitricacidwashingandafterthewholeWIPrecipeaccordingtocurrentSOP-0102731CleaningprocedureforGlatt

30、granulationtraininHPplant”.Alloperatorparticipatedintheclearancearequalifiedformanualcleaningwithqualifiedcertificate.Thecleaningstatusisdoublecheckedaftermanualcleaning,andthereisnovisiblepowderandwatertraceonFBDbowlrimandupperseal.從上次清潔驗(yàn)證（2013.01）至今，手工清潔程序沒(méi)有變更。根據(jù)現(xiàn)行版SOP-0102731有高致敏車間Glatt制粒干燥系統(tǒng)的清潔程

31、序”，F(xiàn)BD碗的邊緣和上密封圈在檸檬酸清洗后和整個(gè)WIP程序后進(jìn)行。所有參與清場(chǎng)的員工均有手工清潔的資質(zhì)認(rèn)證證書(shū)。在手工清潔后，清潔狀態(tài)經(jīng)雙人復(fù)核，在FBD碗邊緣和上密封圈沒(méi)有發(fā)現(xiàn)可見(jiàn)粉塵和水跡。Outcome:No.結(jié)果：不是可能原因。Possiblecause3:Samplingmethod可能原因3:取樣方法ThesamplingprocedureisaccordingtocurrentSOP-0105674,“SamplingforCleaningValidation”,andtherecoveryofsamplingmethodwasvalidated.取樣程序是依據(jù)現(xiàn)行版SOP-0

32、105674,“清潔驗(yàn)證的取樣”進(jìn)行的，且取樣方法的回收率已經(jīng)過(guò)驗(yàn)證。Outcome:No.結(jié)果：不是可能原因。2.RCA5Whys因果分析5Whys1 st-WhydetergenttestresultofSamplingNo.37.2wasoutofacceptancecriteria?為什么樣品37.2的清潔劑測(cè)試結(jié)果超出接受標(biāo)準(zhǔn)？CIP100residuecontaminatedtheFBDbowlrimandwascollectedbysampling.CIP100殘留污染了FBD碗形腔體的邊緣，被取樣收集到。2 nd-WhyCIP100residuecontaminatedther

33、im?為什么CIP100殘留污染了FBD碗形腔體的邊緣？DrinkingwaterwithCIP100residueenteredthegapbetweenuppersealandrimwhenuppersealdeflated;andremainedandcouldntbecleanedafteruppersealreinflated.上密封圈泄氣時(shí)，帶有CIP100殘留的飲用水進(jìn)入上密封圈和FBD碗形腔體邊緣的間隙中；上密封圈重新充氣后留在間隙中，且無(wú)法被清洗干凈。3rd-WhytheCIP100residueinthegapcouldntbecleaned?為什么留在間隙中的CIP100

34、殘留無(wú)法被清洗干凈？Alarm138-1occurredduetothecompressedairductofthelowersealwasleakage.Mechanicsreplacedtheduct,thenbothsealswerere-inflated.Cleaningwatercouldntrinsethegapaftertheuppersealre-inflated.Mechanicsfixedtheproblemcausedthealarm,butnoadditionalcleaningactionwastaken.由于下密封圈壓縮空氣管道漏氣，發(fā)生了138-1報(bào)警。機(jī)修更換了

35、管道，上、下密封圈重新充氣。上密封圈重新充氣后，清潔用水無(wú)法沖洗密封圈和碗沿之間的間隙。機(jī)修解決了引起報(bào)警的問(wèn)題，但沒(méi)有做額外的清潔行動(dòng)。4 th-Whynoadditionalcleaningactionwastaken?為什么沒(méi)有做額外的清潔行動(dòng)？Currentalarmhandlingfocusesonsolvingtheproblem,notrequiresassessingpotentialrisktorelevantprocess.目前的報(bào)警處理流程關(guān)注解決問(wèn)題本身，不要求評(píng)估對(duì)相關(guān)流程的潛在風(fēng)險(xiǎn)。5th-Whycurrentalarmhandlingdoesntassesspot

36、entialrisktorelevantprocess?為什么目前的報(bào)警處理流程不要求評(píng)估對(duì)相關(guān)流程的潛在風(fēng)險(xiǎn)？Improper/InadequatehandlingprocessforcriticalGMPalarms關(guān)鍵GMP報(bào)警的處理流程不當(dāng)/不足Conclusion/結(jié)論P(yáng)ossiblecontaminationpathwaybasedonrootcauseanalysis/根本原因分析得出的可能的污染途徑Alarm138-3occurredanduppersealofFBDbowldeflatedfDrinkingwaterwithCIP100enteredthegapbetween

37、sealandFBDbowlrimfAlarm138-3removedanduppersealreinflatedfDrinkingwaterwithCIP100remainedinthespacebetweenuppersealandFBDbowlrimfDrinkingwaterwasevaporatedafterdryingstepbutCIP100residueremainedonFBDbowlrim-Detergenttestresultoutofacceptancecriteria出現(xiàn)報(bào)警138-3,FBD碗形腔體的上密封圈泄氣飲用水及CIP100進(jìn)入上密封圈和腔體邊緣的縫隙-報(bào)警

38、138-3解除，上密封圈重新充氣-飲用水及CIP100留在上密封圈和腔體邊緣的空隙中-干燥過(guò)程中飲用水蒸發(fā)，但CIP100殘留在腔體邊緣上-清潔劑樣品結(jié)果超出接受標(biāo)準(zhǔn)Causeconclusion/原因結(jié)論Abnormaldeflateandre-inflateofuppersealduringdrinkingwaterwashing/rinseprocessduetocompressedairductleakage由于壓縮空氣管道漏氣，上密封圈在飲用水清洗/淋洗過(guò)程中發(fā)生了不正常的泄氣并重新充氣Improper/InadequatehandlingprocessforcriticalGMPalarms關(guān)鍵GMP報(bào)警處理流程不當(dāng)/不足Followupaction/后續(xù)行動(dòng)CAPATW1097877hasbeeninitiatedtoreducetherisktomanufacturingprocess/cleaningprocessres