QRADD模塊注射用頭孢呋辛鈉mg生產(chǎn)工藝風(fēng)險評估報(bào)告

華北制藥河北華民藥業(yè)有限責(zé)任公司NCPCHebeiHuaminPharmaceuticalCo.,Ltd.2D模塊注射用頭孢呋辛鈉750mg生產(chǎn)工藝風(fēng)險評估報(bào)告ProcessRiskAssessmentReportabouttheManufactureof750mgCefuroximeSodiumPowderforInjectioninModule2D報(bào)告編號AssessmentNo.QRA2D-2013001-00頁號PageNo.第4頁共42頁目的/Purpose該報(bào)告目的在于評估2D模塊注射用頭孢呋辛鈉750mg的生產(chǎn)工藝過程可能存在的風(fēng)險，以及應(yīng)采取的控制措施以最大限度地降低藥品生產(chǎn)過程中的污染、交叉污染以及混淆、差錯等風(fēng)險，確保能夠持續(xù)穩(wěn)定地生產(chǎn)符合質(zhì)量要求的產(chǎn)品。Thisreportistoassesstheprobablerisksduringthemanufactureprocessof750mgCefuroximeSodiumPowderforInjectioninModule2D,andalsothemeasuresweshalltaketomaximallyreduceriskscausedbycontamination,cross-contamination,mix-upanderrorinthemanufacturingprocess,aimingatsteadilyobtainingproductswhichcomplieswiththespecifications.范圍/Scope該風(fēng)險評估報(bào)告適用于2D模塊注射用頭孢呋辛鈉750mg（歐盟產(chǎn)品）的產(chǎn)品生產(chǎn)工藝。ThisRiskAssessmentreportapplystothemanufactureprocessof750mgCefuroximeSodiumPowderforInjection(forEUMarket)inModule2D.參考文件/ReferencesEudraLex，歐盟藥品準(zhǔn)則第4卷-人用及獸用藥品歐盟藥品質(zhì)量管理規(guī)范，附錄1：無菌產(chǎn)品生產(chǎn)。EudraLex,TheRulesGoverningMedicinalProductsintheEuropeanUnionVolume4,EuropeanUnionGuidelinestoGoodManufacturingPractice,MedicinalProductsforHumanandVeterinaryUse,Annex1ManufactureofSterileMedicinalProducts.Q/00-MG-013質(zhì)量風(fēng)險管理規(guī)程QualityRiskManagement系統(tǒng)描述/SystemDescription無菌頭孢呋辛鈉、玻璃瓶、膠塞和鋁塑蓋直接采購。這些物料經(jīng)過質(zhì)量控制部的取樣、測試后，由物料放行人批準(zhǔn)放行使用。ThesterileAPIcefuroximesodium,glassvials,rubberstoppersandAlu.flip-offcapsaredirectlypurchased.Allmaterialsaresampled,testedbyqualitycontrolandreleasedbyauthorizedpersonnelformanufacturinguse.印制的標(biāo)簽（卷）、單獨(dú)折疊的說明書、印制的紙盒和紙箱直接采購。在包裝過程中，將在瓶簽上打印批特有的信息。Thepre-printedrolllabels,individuallyfoldedpre-printedpackageinserts,pre-printedcartonsandpre-printedboxesforthepackagingarepurchased.Thelabelsareimprintedwithlotspecificinformationduringthepackagingoperation.無菌原料藥包裝在無菌、密封的鋁桶中。將無菌API桶連接到分裝機(jī)上專有的接口后，即可將無菌API提供給分裝機(jī)進(jìn)行分裝。ThesterileCefuroximesodiumisprovidedinsterile,sealedaluminumcontainers.TheCefuroximesodiumisprovidedtothefillinglinebyattachinganaluminumcanofthesterileCefuroximesodiumtothedesignatedfittingonthefillingmachine.呼吸袋裝免洗膠塞經(jīng)蒸汽滅菌后通過分裝機(jī)膠塞振料斗輸入到分裝機(jī)上。Theready-to-sterilizestoppersaresterilizedandthenintroducedtothefillingmachinebyastoppervibrationbowl.西林瓶通過傳送帶送到洗瓶機(jī)Thevialsaremovedintothevialwasherbyaconveyor.洗瓶機(jī)用于清洗西林瓶，共經(jīng)過六個步驟。后四個清洗步驟裝有噴針提升裝置，以能夠使噴針到達(dá)西林瓶的內(nèi)部和外部，并將過濾后的循環(huán)注射用水、過濾后的壓縮空氣或過濾后的新鮮注射用水集中有效地噴淋到所需清洗的部位。TheVialWasherisusedtowashglassvials.Sixwashingstepsshallbeundergone;thelastfourstepincorporatesneedle-liftingunitswheretheneedlesreachinsideandoutsidethevialsinordertodeliveraconcentratedsprayoffilteredrecycledWFI,filteredcompressedairorfreshfilteredWFI.清洗工藝結(jié)束后，還未全部干燥的西林瓶自動地經(jīng)過卸載區(qū)傳送至隧道烘箱。隧道烘箱通過干熱法對清洗過的西林瓶進(jìn)行滅菌及去熱原。西林瓶自動地進(jìn)入滅菌隧道后，將經(jīng)過如下三個工藝區(qū)：Attheendofthecycle,thepartiallydriedvialsaredeliveredindividuallytoanunloadingtrayforonwardtransfertothesterilizingtunnel.TheSterilizingTunnelisusedtosterilizeanddepyrogenatewashedvialsbyexposingthemtodryheat.Vialsareautomaticallyloadedintothetunnelbeforebeingpassedthrough3processingzones:預(yù)熱段Infeedzone加熱段Heatingzone冷卻段Coolingzone離開隧道烘箱后，西林瓶進(jìn)入到分裝機(jī)的進(jìn)瓶轉(zhuǎn)盤上傳送至分裝機(jī)。Finally,thevialsareconveyedtoaninfeedturntablethatwillfeedthevialsonwardtothefillingmachine.分裝機(jī)用于把藥粉分裝至西林瓶中。無菌藥粉由分裝機(jī)的振粉管供至粉箱中使用。計(jì)量孔將精確計(jì)量的藥粉裝入西林瓶中。隨后，已經(jīng)滅菌的膠塞壓入西林瓶，并確認(rèn)膠塞位置的正確性。已經(jīng)過滅菌的膠塞通過料斗進(jìn)入到壓膠塞振蕩器。TheVialFillingLineisusedtofillpowderpharmaceuticalproductintovials.Thesterilepowderissuppliedviathechutefromthealuminumcan.Thedosepistondeliversapreciseamountofproducttoeachvial.Vialsaresubsequentlystoppered.Sterilizedstoppersaresuppliedviaafeederintothestoppervibratingbowl.裝粉壓塞后，西林瓶通過輸送帶傳至壓蓋機(jī)進(jìn)行壓蓋密封。Filledstopperedvialsarethentransferredviaconveyortothecappingmachinewherethevialsaresealed.最后，中間產(chǎn)品通過目測檢查后進(jìn)行逐瓶貼標(biāo)，瓶簽經(jīng)貼標(biāo)機(jī)打印批號、效期信息后，人工裝盒貼盒封后裝箱，紙箱上貼上箱簽，封好箱后打包入庫，紙盒上產(chǎn)品批號等信息為包材自帶，無需生產(chǎn)過程中打印。ThevialsmovetothevisualinspectionandthengetlabelledwithbatchNo.andexpirydateprintedonitbythelabellingmachine,manuallypackedintheboxfurtherinthetransportcarton.Pastethecartonlabel,beforewarehousing.InformationlikebatchNo.ontheboxispre-printed,thereisnoneedtoprintthemduringproduction.風(fēng)險分析/RiskAnalysis由風(fēng)險評估小組（成員包括：賈翠玉、殷麗杰、李賽、黃潔）使用影響分析（FMEA）方法對注射用頭孢呋辛鈉750mg生產(chǎn)過程中的膠塞滅菌、分裝零部件清洗滅菌、小瓶洗滌滅菌、分裝、壓蓋、燈檢、包裝7個工序進(jìn)行風(fēng)險分析，詳見附表1。TheRiskAssessmentteam(teammember:JiaCuiyu,YinLijie,LiSai,HuangJie)shallperformtheRiskAssessmentonstoppersterilization,washingandsterilizationoffillingcomponents,vialwashinganddepyrogenation,filling,capping,visualinspectionandpackagingduringthemanufactureof750mgCefuroximeSodiumPowderforInjectionasperFMEA,seeAppendix1fordetails.結(jié)論/Conclusion2D模塊注射用頭孢呋辛鈉750mg的生產(chǎn)工藝中膠塞滅菌工序中對膠塞內(nèi)毒素不合格風(fēng)險無控制措施，需增加控制風(fēng)險措施方可保證能夠持續(xù)穩(wěn)定的生產(chǎn)符合質(zhì)量要求的產(chǎn)品。NoriskcontrolmeasuresaboutOOSonendotoxinofstoppershavebeentakeninthestoppersterilizationstepduringthemanufactureof750mgCefuroximeSodiumPowderforInjectioninModule2D,wehavetotakeriskcontrolmeasuresforsteadilyobtainingproductswhichcomplieswiththespecifications.總之，當(dāng)前發(fā)現(xiàn)的膠塞內(nèi)毒素不合格風(fēng)險不可接受，需要對2D模塊注射用頭孢呋辛鈉750mg的生產(chǎn)工藝進(jìn)行減小風(fēng)險的措施。其他工序風(fēng)險控制均可滿足要求。Inconclusion,theriskdetectedaboutOOSonendotoxinofstopperscannotbeaccepted,wehavetotakemeasurestoreducerisksinthemanufactureprocessof750mgCefuroximeSodiumPowderforInjectioninModule2D.Riskcontrolmeasureinotherstepscanmeetthespecifications.建議/Recommendations修訂《注射用無菌粉末用鹵化丁基橡膠塞檢驗(yàn)標(biāo)準(zhǔn)操作規(guī)程EP》C/00-TM-027，增加對每批膠塞來料內(nèi)毒素進(jìn)行檢驗(yàn)，同時修訂《注射用無菌粉末用鹵化丁基橡膠塞質(zhì)量標(biāo)準(zhǔn)（EP）》Q/00.6.164，增加來料膠塞內(nèi)毒素控制。ReviseC/00-TM-027TestMethodforHalogenatedbutylrubberstoppersforpowderforinjections(EP),inwhichweshalladdtheendotoxintestforeachbatchofstoppers,alsoreviseQ/00.6.164SpecificationofHalogenatedbutylrubberstoppersforpowderforinjections(EP),inwhichtheendotoxincontrolforeachbatchofstoppersshallbeadded.雖膠塞的無菌和水分風(fēng)險均可接受，但在在蒸汽滅菌柜PQ確認(rèn)（編號：PQP-101-2D-AUT-01-00）中未進(jìn)行計(jì)時準(zhǔn)確性和膠塞干燥工藝參數(shù)確認(rèn)，建議增加蒸汽滅菌柜PQ補(bǔ)充測試，增加計(jì)時準(zhǔn)確性和滅菌后膠塞水分測定，以確認(rèn)膠塞干燥工藝。Althoughtheresultsonsterilityandwaterofstoppersarecomplieswithspecifications,butthereisnotimingaccuracytestordryingparametersverificationforstoppersinthePQofAutoclave(PQP-101-2D-AUT-01-00),werecommendtocarryoutPQaddendumofAutoclave,inwhichweperformthetimingaccuracytestandthewatertestforsterilizedstopperstoverifydryingparametersforstoppers變更歷史/ChangeHistory版本號Version更新內(nèi)容Description00FirstIssue新建批準(zhǔn)/Approval職責(zé)Responsibility公司/職務(wù)Company/Title姓名Name簽名Signature日期Date起草Writtenby101WorkshopViceManager101車間副主任賈翠玉審核Reviewedby101WorkshopManager101車間主任邵壯審核ReviewedbyQualityManagementDirector

質(zhì)量管理部部長沈梅批準(zhǔn)ApprovedbyHeadofQuality

質(zhì)量負(fù)責(zé)人劉樹林華北制藥河北華民藥業(yè)有限責(zé)任公司NCPCHebeiHuaminPharmaceuticalCo.,Ltd.2D模塊750mg注射用頭孢呋辛鈉生產(chǎn)工藝風(fēng)險評估報(bào)告ProcessRiskAssessmentReportabouttheManufactureof750mgCefuroximeSodiumPowderforInjectioninModule2D報(bào)告編號AssessmentNo.QRA2D-2013001-00頁號PageNo.第43頁共42頁附錄Appendix1. 風(fēng)險評估表RiskAssessmentFormA膠塞滅菌工序StoppersterilizationNo.風(fēng)險RiskRORSRDORS[RO+RS+RD]風(fēng)險控制RiskControlREFRS[ORS+RE]接受Acceptable1滅菌后膠塞無菌不合格OOSonsterilityofsterilizedstoppers.1315對蒸汽滅菌柜進(jìn)行了DQ（編號：DQPM·227-00）IQ（編號：IQP-101-2D-AUT-01-00）OQ（編號：OQP-101-2D-AUT-01-00）PQ（編號：PQP-101-2D-AUT-01-00），確認(rèn)蒸汽滅菌柜能夠滿足工藝使用要求。CarryouttheDQ(DQPM·227-00),IQ(IQP-101-2D-AUT-01-00),OQ(OQP-101-2D-AUT-01-00)andPQ(PQP-101-2D-AUT-01-00)toverifythattheautoclavecanmeettherequirementsoftheprocess.在蒸汽滅菌柜PQ確認(rèn)（編號：PQP-101-2D-AUT-01-00）中，對滅菌負(fù)載和滅菌溫度（121℃）、滅菌時間（30min）進(jìn)行確認(rèn)，溫度分布、殺死率和生物指示劑挑戰(zhàn)均合格。InthePQofautoclave(PQP-101-2D-AUT-01-00),wehaveverifiedtheloads,sterilizationtemperature(121℃)andsterilizationtime(30min),inwhichtheresultsofheatdistribution,lethalityandbiologicalindicatorchallengetestsmettheacceptancecriteria.《蒸汽滅菌柜操作規(guī)程》2D/03-IU-020中規(guī)定了膠塞負(fù)載和滅菌溫度121℃、時間30分鐘，規(guī)定參數(shù)與設(shè)備PQ一致。Wespecifythestopperload,thesterilizationtemperature(121℃)andsterilizationtime(30min)in2D/03-IU-020OperationofAutoclave,whicharethesameparametersverifiedinPQ.當(dāng)膠塞滅菌過程中，滅菌溫度低于設(shè)定溫度，設(shè)備會自動報(bào)警并判定滅菌失敗，需重新滅菌。Whenthetemperatureislowerthanthesetvalueduringsterilization,theequipmentwillraiseanalarmanddeterminethefailureofthistimeofsterilization,anewsterilizationneedstobecarriedout.滅菌、除熱原驗(yàn)證規(guī)程Q/00-QV-010中規(guī)定每年對蒸汽滅菌柜進(jìn)行PQ再確認(rèn)。Re-qualificationofautoclaveshallbecarriedouteachyearasperQ/00-QV-010Sterilization&DepyrogenationValidation《蒸汽滅菌柜操作規(guī)程》2D/03-IU-020中規(guī)定每批滅菌結(jié)束均要檢查呼吸袋上的滅菌指示帶是否變色，確認(rèn)滅菌效果Itisspecifiedin2D/03-IU-020OperationofAutoclavethatoperatorsshallcheckwhetherthecolouroftheindicatorlineontheautoclavebaghaschangedtoensurethesterilizingeffect.膠塞滅菌記錄中記錄滅菌溫度和時間等參數(shù)，并有溫度時間等連續(xù)打印記錄，每批滅菌結(jié)束均審核簽字。TheparameterslikesterilizationtemperatureandtimearerecordedintheStopperSterilizationRecord,andtheequipmentprinterwillprintoutthecontinuousrecordaswell,thisrecordischeckedandsignedofeachbatch.-10-5Yes2膠塞水分不合格OOSonwaterofsterilizedstoppers0314對蒸汽滅菌柜進(jìn)行了DQ（編號：DQPM·227-00）IQ（編號：IQP-101-2D-AUT-01-00）OQ（編號：OQP-101-2D-AUT-01-00）PQ（編號：PQP-101-2D-AUT-01-00），確認(rèn)蒸汽滅菌柜能夠滿足工藝使用要求要求。CarryouttheDQ(DQPM·227-00),IQ(IQP-101-2D-AUT-01-00),OQ(OQP-101-2D-AUT-01-00)andPQ(PQP-101-2D-AUT-01-00)toverifythattheautoclavecanmeettherequirementsoftheprocess.《蒸汽滅菌柜操作規(guī)程》2D/03-IU-020中規(guī)定了真空干燥時間80分鐘和正脈沖10次，規(guī)定參數(shù)與設(shè)備PQ一致。Wespecifythedryingtime(80min)andpositivepulsetime(10times)in2D/03-IU-020OperationofAutoclave,whicharethesameparametersverifiedinPQ.《2D模塊中控操作規(guī)程》Q/03-OS-004規(guī)定對每批膠塞水分進(jìn)行檢驗(yàn)，標(biāo)準(zhǔn)≤0.3%。ItisspecifiedinQ/03-OS-004Module2DIn-ProcessControlthatwatershallbetestedofeachsterilizationbatchandthespecificationofwaterisnomorethan0.3%.膠塞滅菌記錄中記錄真空干燥時間和正脈沖次數(shù)等參數(shù)，并有壓力時間等連續(xù)打印記錄，每批滅菌結(jié)束均審核簽字。TheparameterslikevacuumdryingtimeandpositivepulsetimearerecordedintheStopperSterilizationRecord,theequipmentprinterwillprintoutthepressuretimediagramaswell,thisrecordischeckedandsignedofeachbatch.-10-6Yes3膠塞可見異物、外觀不合格OOSonvisibleparticleandappearanceofsterilizedstoppers0314《注射用無菌粉末用鹵化丁基橡膠塞檢驗(yàn)標(biāo)準(zhǔn)操作規(guī)程EP》C/00-TM-027規(guī)定對每批膠塞來料的潔凈度和可見異物、外觀進(jìn)行檢驗(yàn)，檢驗(yàn)結(jié)果滿足《注射用無菌粉末用鹵化丁基橡膠塞質(zhì)量標(biāo)準(zhǔn)（EP）》Q/00.6.164要求方放行使用。ItisspecifiedinC/00-TM-027TestMethodforHalogenatedbutylrubberstoppersforpowderforinjections(EP)thatweshalltestthecleanness,visibleparticleandappearanceofeachbatchofstoppers,thebatchwillbereleasedonlywhenthetestresultsmeetQ/00.6.164SpecificationofHalogenatedbutylrubberstoppersforpowderforinjections(EP)膠塞為呼吸袋裝，滅菌過程不會破壞包裝完整性，污染膠塞Stoppersarepackagedintheautoclavebag,whichmeanstheintegrityofbagwillnotbedestroyedtocausecontaminationaboutstoppersduringsterilization.-5-1Yes4膠塞內(nèi)毒素不合格OOSonendotoxinofstoppers0314無None0-4No

B.分裝零部件清洗、滅菌工序WashingandsterilizationoffillingcomponentsNo.風(fēng)險RiskRORSRDORS[RO+RS+RD]風(fēng)險控制RiskControlREFRS[ORS+RE]接受Acceptable1分裝零部件清洗不合格Non-conformationonwashingoffillingcomponents.1315氣流分裝機(jī)清洗驗(yàn)證R-CVP11101B-004確認(rèn)清洗方法滿足工藝要求。InR-CVP11101B-004AirflowFillingandStopperMachineCleaningRe-validationProtocolthecleaningmethodshavebeenverifiedtobeconformtotheprocessrequirements《分裝機(jī)清潔規(guī)程》2D/03-EC-002規(guī)定了分裝零部件的清洗方法，與清洗驗(yàn)證中清洗方法一致。Cleaningmethodsspecifiedin2D/03-EC-002CleaningofFillingMachinearethesamewhichhasbeenvalidatedintheCV.分裝零部件清洗記錄納入批生產(chǎn)記錄中審核FillingComponentsCleaningRecordswillbefiledandreviewedinBMR.-50Yes2分裝零部件無菌不合格OOSonsterilityoffillingcomponents.1315在蒸汽滅菌柜PQ確認(rèn)（編號：PQP-101-2D-AUT-01-00）中，對滅菌負(fù)載和滅菌溫度（121℃）、滅菌時間（20min）進(jìn)行確認(rèn)，溫度分布、殺死率和生物指示劑挑戰(zhàn)均合格。InthePQofautoclave(PQP-101-2D-AUT-01-00),wehaveverifiedtheloads,sterilizationtemperature(121℃)andsterilizationtime(20min),inwhichtheresultsofheatdistribution,lethalityandbiologicalindicatorchallengetestsmettheacceptancecriteria.《蒸汽滅菌柜操作規(guī)程》2D/03-IU-020中規(guī)定了滅菌分裝零部件負(fù)載和滅菌溫度121℃、時間20分鐘，規(guī)定參數(shù)與設(shè)備PQ一致。Wespecifythefillingcomponentsload,thesterilizationtemperature(121℃)andsterilizationtime(20min)in2D/03-IU-020OperationofAutoclave,whicharethesameparametersverifiedinPQ.蒸汽滅菌柜滅菌過程中，滅菌溫度低于設(shè)定溫度，設(shè)備會自動報(bào)警并判定滅菌失敗，需重新滅菌。Whenthetemperatureislowerthanthesetvalueduringsterilization,theequipmentwillraiseanalarmanddeterminethefailureofthistimeofsterilization,anewsterilizationneedstobecarriedout.《滅菌、除熱原驗(yàn)證規(guī)程》Q/00-QV-010中規(guī)定每年對蒸汽滅菌柜進(jìn)行PQ再確認(rèn)。Re-PQofautoclaveshallbecarriedouteachyearasperQ/00-QV-010Sterilization&DepyrogenationValidation《蒸汽滅菌柜操作規(guī)》2D/03-IU-020中規(guī)定每批滅菌結(jié)束均要檢查呼吸袋上的滅菌指示帶是否變色，確認(rèn)滅菌效果。Itisspecifiedin2D/03-IU-020OperationofAutoclavethatoperatorsshallcheckwhetherthecolouroftheindicatorlineontheautoclavebaghaschangedtoensurethesterilizingeffect.分裝零部件滅菌記錄中記錄滅菌溫度和時間等參數(shù)，并有溫度時間等連續(xù)打印記錄，每批滅菌結(jié)束均審核簽字。TheparameterslikesterilizationtemperatureandtimearerecordedintheFillingComponentsSterilizationRecord,andtheequipmentprinterwillprintoutthecontinuousrecordaswell,thisrecordischeckedandsignedofeachbatch.-10-5YesC、小瓶洗滌、滅菌工序VialwashinganddepyrogenationNo.風(fēng)險RiskRORSRDORS[RO+RS+RD]風(fēng)險控制RiskControlREFRS[ORS+RE]接受Acceptable1小瓶可見異物、不溶性微粒不合格OOSonvisibleparticleandinsolubleparticleofthevial1315洗瓶機(jī)VialWasher對洗瓶機(jī)進(jìn)行了DQ（編號：DQPM·055-00）IQ（編號：IQP-101-2D-WMC-01-00和IQP-101-2D-WMC-02-00）OQ（編號：OQP-101-2D-WMC-01-00和OQP-101-2D-WMC-02-00）PQ（編號：PQP-101-2D-WMC-01-00和PQP-101-2D-WMC-02-00），確認(rèn)洗瓶機(jī)能夠滿足工藝使用要求要求。CarryoutDQ(DQPM·055-00),IQ(IQP-101-2D-WMC-01-00,IQP-101-2D-WMC-02-00),OQ(OQP-101-2D-WMC-01-00,OQP-101-2D-WMC-02-00)andPQ(PQP-101-2D-WMC-01-00,PQP-101-2D-WMC-02-00)toverifythatthewashercanmeettherequirementsoftheprocess.洗瓶機(jī)PQ（編號：PQP-101-2D-WMC-01-00和PQP-101-2D-WMC-02-00）中對洗瓶參數(shù)新鮮注射用水壓力（2.0-3.0Bar）和循環(huán)注射用水壓力（2.5-3.0Bar）、噴淋水壓力（1.5-2.0Bar）、洗瓶速度（≤200瓶/分）確認(rèn)，確認(rèn)此參數(shù)下洗后小瓶可見異物和不溶性微粒合格。ItwasverifiedinthePQofWasher(PQP-101-2D-WMC-01-00,PQP-101-2D-WMC-02-00)thatunderthefreshWFIpressureof2.0-3.0Bar,recycledWFIpressureof2.5-3.0Bar,rinsingWFIpressureof1.5-2.0Barandthewashingspeedof≤200vials/min,thevisibleparticleandinsolubleparticlecanmeetthespecifications.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定洗瓶參數(shù)新鮮注射用水壓力（2.0-3.0Bar）和循環(huán)注射用水壓力（2.5-3.0Bar）、噴淋水壓力（1.5-2.0Bar）、洗瓶速度（≤200瓶/分），并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄。WespecifythefreshWFIpressureof2.0-3.0Bar,recycledWFIpressureof2.5-3.0Bar,rinsingWFIpressureof1.5-2.0Barandthewashingspeedof≤200vials/minintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.當(dāng)新鮮注射用水、循環(huán)注射用水、噴淋水壓力低于設(shè)定值，設(shè)備會自動報(bào)警停機(jī)。當(dāng)洗瓶機(jī)超聲波發(fā)生器出現(xiàn)故障時，設(shè)備會自動報(bào)警停機(jī)。WhenthepressureoffreshWFI,recycledWFIortherinsingWFIislowerthanthesetvalue,theequipmentwillraiseanalarmandstopautomatically.Whenthefaultofultrasonicgeneratoroccurs,theequipmentwillraiseanalarmandstopautomatically.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定每批生產(chǎn)前確認(rèn)噴針暢通方可生產(chǎn)。WespecifyintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX)thatbeforetheproduction,operatorsshallcheckandensurenosprayneedleisblocked.《洗瓶維護(hù)保養(yǎng)規(guī)程》2D/03-IU-041中規(guī)定每月對對超聲波頻率進(jìn)行鋁箔測試確認(rèn)。Itisspecifiedin2D/03-IU-041MaintenanceofVialWasherthataluminumfoiltestverificationtoultrasonicfrequencyshallbecarriedouteverymonth.《2D模塊中控操作規(guī)程》Q/03-OS-004規(guī)定每班對洗后小瓶外觀和可見異物進(jìn)行檢驗(yàn)。ItisspecifiedinQ/03-OS-004Module2DIn-ProcessControlthattheappearanceandvisibleparticleofwashedvialsshallbetestedineachshift.-10-5Yes隧道烘箱Tunnel對隧道烘箱進(jìn)行了DQ（編號：DQPM·073-00）IQ（編號：IQP-101-2D-TNS-01-00和IQP-101-2D-TNS-02-00）OQ（編號：OQP-101-2D-TNS-01-00和OQP-101-2D-TNS-02-00）PQ（編號：PQP-101-2D-TNS-01-00和PQP-101-2D-TNS-02-00），確認(rèn)隧道烘箱能夠滿足工藝使用要求。CarryoutDQ(DQPM·073-00),IQ(IQP-101-2D-TNS-01-00,IQP-101-2D-TNS-02-00),OQ(OQP-101-2D-TNS-01-00,OQP-101-2D-TNS-02-00)andPQ(PQP-101-2D-TNS-01-00,PQP-101-2D-TNS-02-00)toverifythatthetunnelcanmeettherequirementsoftheprocess.隧道烘箱OQ（編號：OQP-101-2D-TNS-01-00和OQP-101-2D-TNSC-02-00）中對隧道烘箱的A級環(huán)境潔凈度和高效過濾器完整性進(jìn)行了確認(rèn)。IntheOQoftunnel(OQP-101-2D-TNS-01-00,OQP-101-2D-TNS-02-00)thecleanlinessofgradeAinthetunnelandHEPAintegrityhavebeenverified.“再確認(rèn)/再驗(yàn)證規(guī)程”Q/00-QV-003規(guī)定每24個月進(jìn)行高效過濾器完整性確認(rèn)。HEPAintegrityverificationshallbecarriedoutevery24monthsasperQ/00-QV-003Re-Qualification&Re-Validation.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定隧道烘箱各段壓差，并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄。WespecifythedifferentialpressureofeachzoneintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.《2D模塊中控操作規(guī)程》Q/03-OS-004規(guī)定每班對滅菌后小瓶外觀和可見異物進(jìn)行檢驗(yàn)。ItisspecifiedinQ/03-OS-004Module2DIn-ProcessControlthattheappearanceandvisibleparticleofwashedvialsshallbetestedineachshift.2小瓶水分不合格OOSonwaterofthevial1315洗瓶機(jī)VialWasher洗瓶機(jī)PQ（編號：PQP-101-2D-WMC-01-00和PQP-101-2D-WMC-02-00）中對吹干壓縮空氣壓力（2.0-3.0Bar）確認(rèn)。Thedryingcompressedairpressureof2.0-3.0BarhasbeenverifiedinthePQofthewasher(PQP-101-2D-TNS-01-00,PQP-101-2D-TNS-02-00).注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定吹干壓縮空氣壓力（2.0-3.0Bar），并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄。Wespecifythedryingcompressedairpressureshallbe2.0-3.0BarintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.當(dāng)吹干用壓縮空氣壓力低于設(shè)定值時，設(shè)備會自動報(bào)警停機(jī)。Whenthedryingcompressedairpressureislowerthanthesetvalue,theequipmentwillraiseanalarmandstopautomatically.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定每批生產(chǎn)前確認(rèn)噴針暢通方可生產(chǎn)。WespecifyintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX)thatbeforetheproduction,operatorsshallcheckandensurenosprayneedleisblocked.-10-5Yes隧道烘箱Tunnel注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定隧道烘箱滅菌溫度和網(wǎng)帶電機(jī)頻率，并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄。WespecifythedepyrogenationtemperatureandbeltmotorfrequencyintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.隧道烘箱滅菌過程中當(dāng)干燥滅菌溫度低于設(shè)定值時，設(shè)備會報(bào)警停車。Whenthedepyrogenationtemperatureislowerthanthesetvalueduringdepyrogenation,theequipmentwillraiseanalarmandstopautomatically.《2D模塊中控操作規(guī)程》Q/03-OS-004規(guī)定每班對滅菌后小瓶水分進(jìn)行檢驗(yàn)。ItisspecifiedinQ/03-OS-004Module2DIn-ProcessControlthatthewaterofdepyrogenatedvialsshallbetestedineachshift.3小瓶無菌、內(nèi)毒素不合格OOSonsterilityandendotoxinofthevial1326對隧道烘箱進(jìn)行了DQ（編號：DQPM·073-00）IQ（編號：IQP-101-2D-TNS-01-00和IQP-101-2D-TNS-02-00）OQ（編號：OQP-101-2D-TNS-01-00和OQP-101-2D-TNS-02-00）PQ（編號：PQP-101-2D-TNS-01-00和PQP-101-2D-TNS-02-00），確認(rèn)隧道烘箱能夠滿足工藝使用要求要求。CarryoutDQ(DQPM·073-00),IQ(IQP-101-2D-TNS-01-00,IQP-101-2D-TNS-02-00),OQ(OQP-101-2D-TNS-01-00,OQP-101-2D-TNS-02-00)andPQ(PQP-101-2D-TNS-01-00,PQP-101-2D-TNS-02-00)toverifythatthetunnelcanmeettherequirementsoftheprocess.隧道烘箱PQ（編號：PQP-101-2D-TNS-01-00和PQP-101-2D-TNSC-02-00）中對小瓶的滅菌溫度（330-350℃），烘箱網(wǎng)帶電機(jī)頻率（2D1≤68%，2D2≤57%）進(jìn)行確認(rèn)，溫度分布、殺死率和內(nèi)毒素挑戰(zhàn)均合格。InthePQoftunnel(PQP-101-2D-TNS-01-00,PQP-101-2D-TNSC-02-00)weverifiedtheheatdistribution,lethalityandendotoxinchallengetestunderthetemperatureof330-350℃andthebeltmotorfrequency(2D1≤68%，2D2≤57%),andthetestresultsmetthespecifications.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定隧道烘箱滅菌溫度和網(wǎng)帶電機(jī)頻率，并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄。WespecifythedepyrogenationtemperatureandbeltmotorfrequencyintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.隧道烘箱滅菌過程中當(dāng)干燥滅菌溫度低于設(shè)定值時，設(shè)備會報(bào)警停車。Whenthedepyrogenationtemperatureislowerthanthesetvalueduringdepyrogenation,theequipmentwillraiseanalarmandstopautomatically.《滅菌、除熱原驗(yàn)證規(guī)程》Q/00-QV-010中規(guī)定每年對隧道烘箱進(jìn)行PQ再確認(rèn)。Re-PQofthetunnelshallbecarriedouteveryyearasperQ/00-QV-010Sterilization&DepyrogenationValidation.《洗瓶/隧道烘箱操作規(guī)程》2D/03-IU-001規(guī)定每月對隧道烘箱網(wǎng)帶速度和電機(jī)頻率對應(yīng)關(guān)系進(jìn)行確認(rèn)。Correspondingrelationbetweenbeltspeedandthemotorfrequencyshallbeverifiedeverymonthasper2D/03-IU-001OperationofVialWasher&SterilizingTunnel.隧道烘箱OQ（編號：OQP-101-2D-TNS-01-00和OQP-101-2D-TNS-02-00）中對隧道烘箱的A級環(huán)境潔凈度和高效過濾器完整性進(jìn)行了確認(rèn)。IntheOQoftunnel(OQP-101-2D-TNS-01-00,OQP-101-2D-TNS-02-00)thecleanlinessofgradeAinthetunnelandHEPAintegrityhavebeenverified.《再確認(rèn)/再驗(yàn)證規(guī)程》Q/00-QV-003規(guī)定每24個月進(jìn)行高效過濾器完整性確認(rèn)。HEPAintegrityverificationshallbecarriedoutevery24monthsasperQ/00-QV-003Re-Qualification&Re-Validation.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定隧道烘箱各段壓差，并規(guī)定操作工在生產(chǎn)前、生產(chǎn)過程中每小時、生產(chǎn)結(jié)束前檢查確認(rèn)并記錄，設(shè)備可連續(xù)打印滅菌溫度、時間曲線，滅菌結(jié)束后經(jīng)審核簽字。WespecifythedifferentialpressureofeachzoneintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),andtheoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.TheprinteronthetunnelprintsouttheTemperature-timediagram,whichwillbecheckedandsignedafterthedepyrogenationprocess.-10-4Yes4小瓶使用不正確Incorrectuseofvials1315注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中分裝指令規(guī)定批生產(chǎn)使用小瓶的物料代碼、批號和數(shù)量，分裝指令經(jīng)工藝員起草，車間主任審核，QA批準(zhǔn)。Theinformationlikematerialcode,batchNo.andquantityofvialstobeusedforproductioninthemanufacturingorderinBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX)shallbedraftedbyprocessengineer,checkedbytheworkshopmanagerandapprovedbyQA.《物料接收退回規(guī)程》2D/03-AO-001中規(guī)定輔助人員按照生產(chǎn)指令發(fā)放小瓶，且物料接收過程雙人復(fù)核。Itisspecifiedin2D/03-AO-001DistributionandReturnofPackagingMaterialinWorkshop101thatauxiliarypersonneldistributevialsaccordingtothemanufacturingorderandthematerialreceptionshallbedoublechecked.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中記錄批生產(chǎn)用小瓶批號、數(shù)量。BatchNo.andquantityofvialsarerecordedintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX).《清場規(guī)程》2D/03-PO-008中規(guī)定批生產(chǎn)前對上批物料清場確認(rèn)和生產(chǎn)后對上批物料清場。Itisspecifiedin2D/03-PO-008LineClearancethatlineclearanceofthelastbatchshallbecheckedbeforeproduction,andthelineclearanceshallbecarriedoutaftereverybatchofproduction.-50Yes

D.分裝工序FillingNo.風(fēng)險RiskRORSRDORS[RO+RS+RD]風(fēng)險控制RiskControlREFRS[ORS+RE]接受Acceptable1產(chǎn)品裝量不合格OOSonconformityofweight1315產(chǎn)品裝量設(shè)定方面Settingofuniformityofweightforproducts注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中分裝指令下發(fā)裝量控制標(biāo)準(zhǔn)裝量和裝量上下限，分裝指令經(jīng)工藝員起草，車間主任審核，QA批準(zhǔn)。ThestandarduniformityofweightandthecontrolledrangeofitinthemanufacturingorderintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX)aredraftedbyprocessengineer,checkedbyworkshopmanagerandapprovedbyQA.注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）規(guī)定生產(chǎn)前分裝人員根據(jù)分裝指令設(shè)定產(chǎn)品裝量，設(shè)定裝量后復(fù)核確認(rèn)，裝量設(shè)置內(nèi)容打印在分裝機(jī)自動稱量記錄中并審核。ItisspecifiedintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX)thatfillingoperatorsshallsetanddoublechecktheuniformityofweightfortheproducts,thesetforuniformityofweightwillbeprintedoutintheweighingrecordandchecked.-10-5Yes分裝機(jī)裝量控制方面Controloffillingmachineforuniformityofweight對分裝機(jī)進(jìn)行了DQ（編號：DQPM·091-00）IQ（編號：IQP-101-2D-FSM-01-00和IQP-101-2D-FSM-02-00）OQ（編號：OQP-101-2D-FSM-01-00和OQP-101-2D-FSM-02-00）PQ（編號：PQP-101-2D-FSM-01-00和PQP-101-2D-FSM-02-00），確認(rèn)分裝機(jī)能夠滿足工藝使用要求。CarryoutDQ(DQPM·091-00),IQ(IQP-101-2D-FSM-01-00,IQP-101-2D-FSM-02-00),OQ(OQP-101-2D-FSM-01-00,OQP-101-2D-FSM-02-00)andPQ(PQP-101-2D-FSM-01-00,PQP-101-2D-FSM-02-00)toverifythatthefillingmachinecanmeettherequirementsoftheprocess.分裝過程中設(shè)備會連續(xù)自動稱量，每兩分鐘抽查6只產(chǎn)品裝量，當(dāng)裝量超出警戒限時，設(shè)備會自動調(diào)整裝量，當(dāng)裝量超出糾偏限時，設(shè)備會報(bào)警停機(jī)，逐支稱量確認(rèn)合格后方生產(chǎn)。Fillingmachineautomaticallyandsuccessivelyweigh6semi-finishedproductsineach2minutesforuniformityofweight,outofalarmlimitwillleadthemachinetoautoadjustment,outofrejectlimitwillstopthefillingandadjustthechargingweight,fillingwillbecontinuedwhenthechargingweightofeachvialprovedtobewithinthelimit.在分裝機(jī)OQ（編號：OQP-101-2D-FSM-01-00和OQP-101-2D-FSM-02-00）中對稱量系統(tǒng)準(zhǔn)確性和裝量超標(biāo)自動報(bào)警剔除功能進(jìn)行確認(rèn)。TheweighingaccuracyandautoalarmingandrejectfunctionfortheOOSonchargingweightofthefillingmachinehavebeenverifiedintheOQoffilingmachine(OQP-101-2D-FSM-01-00,OQP-101-2D-FSM-02-00)《分裝操作規(guī)程》2D/03-IU-002規(guī)定每批生產(chǎn)前對分裝機(jī)稱量天平進(jìn)行校正，并記入批記錄審核。Itisspecifiedin2D/03-IU-002OperationofFillingMachinethatoperatorsshallcarryoutthedailycheckforthebalanceinthefillingmachinebeforeeachbatchofproductionandfiletheinformationintheBMRforreview.U/00-IC-004《電子天平檢定方法》中規(guī)定，每年對分裝機(jī)自動稱量天平進(jìn)行校驗(yàn)。CalibrationofbalanceinthefillingmachineshallbeperformedonceayearasperU/00-IC-004VerificationRegulationforElectronicBalance.分裝機(jī)PQ（編號：PQP-101-2D-FSM-01-00和PQP-101-2D-FSM-02-00）中確認(rèn)分裝卸粉壓力（0.01-3.00Bar）、內(nèi)清壓力(1.0-6.0Bar)、外清壓力(0-6.0Bar)、真空壓力（-0.08—0.10Bar）

符合工藝要求。Theblowoutpressure(0.01-3.00Bar),insidecleaningpressure(1.0-6.0Bar),outsidecleaningpressure(0-6.0Bar)andvacuumpressure(-0.08—0.10Bar)havebeenverifiedinthePQoffillingmachine(PQP-101-2D-FSM-01-00,PQP-101-2D-FSM-02-00).注射用頭孢呋辛鈉750mg批生產(chǎn)記錄（編號：M/033204-2DV和M/033204-2DX）中規(guī)定卸粉、清理、真空壓力的合格范圍，分裝生產(chǎn)開始前和生產(chǎn)結(jié)束后以及生產(chǎn)過程中每小時確認(rèn)各項(xiàng)壓力符合要求，并記錄。Theblowoutpressure,cleaningpressureandvacuumpressurehavebeenspecifiedintheBMRof750mgCefuroximeSodiumPowderforInjection(M/033204-2DV,M/033204-2DX),theoperatorsshallcheckandrecordtheseparametersbeforetheproduction,everyhourduringandattheendoftheproduction.當(dāng)卸粉或真空吸粉壓力超出規(guī)定范圍時，設(shè)備會自動報(bào)警停車。WhentheOOSforblowoutpressureorthevacuumpressureoccurs,theequipmentwillraiseanalarmandstop.《2D模塊中控操作規(guī)程》Q/03-OS-004規(guī)定每班對半成品進(jìn)行裝量差異檢查。ItisspecifiedinQ/03-OS-004Module2DIn-ProcessControlthattheuniformityofweightforsemi-finishedproductsshallbetestedineachshift.《燈檢操作規(guī)程》2D/03-IU-009規(guī)定，燈檢崗位人員每30分鐘抽查兩支產(chǎn)品