歐盟清潔驗證方案(帶風險分析)

Abcd上海勃林格殷格翰藥業(yè)有限公司BoehringerIngelheimShanghaiPharmaceuticalsCo.,Ltd.CleaningValidation清潔驗證方案ProtocolSystemName/設備名：氣霧劑生產(chǎn)線MDIProductionLineDocumentNo./文件號：CV-04-P.01Page/頁數(shù):頁附件21ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件21ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件21ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件21ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位ActiveIngredient(mg/swab)活性成分Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件22ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件22ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件22ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期附件22ANALYTICALRESULTS分析結果ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011ProductName: BatchNo.: Equipment:產(chǎn)品名稱批號 設備EquipmentPart設備部位Microbes(CFU/swab)微生物Pass合格Fail不合格1234567891011Signature________________________________ Date________________________簽名日期

附件23HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本：SamplingRecoveryTest取樣回收率試驗ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期：QualityAssurance:質(zhì)量保證部Page1of3Safety安全Wearpowder-freeglovesandgoggles.戴防護手套和安全眼鏡.Useafumecupboardwhileworkingwithorganicsolvents.使用有機溶媒時要用通風櫥.EquipmentandMaterials設備和物料Equipment設備Stainlesssteelsurfacemadeofthesamematerialastheequipmentconstructionmaterialwhichshouldbesampled.取相同材質(zhì)的不銹鋼板一塊Swabusedasthesampledlocationintheequipment:Name_____________棉簽：名稱_____________SuitableglassErlenmeyerflasks.容量瓶.Powder-freegloves防護手套Cleanpincers清潔鉗子Materials物料Extractingsolventforactivematerialsampling:用于活性成分萃取的溶液:Choosetheappropriatesolventtakingintoconsiderationthesolubilityofthecontaminantactiveingredient(s)init.Thetoxicityofthesolventshouldalsobeconsidered.FluvastatinSodiumselectsthewatertoextractactivematerial.選擇適當?shù)娜軇?，考慮其對活性成分的溶解性和毒性。這里選用水來作為萃取劑。75%alcoholforcleaningagentssampling.清潔劑用75％酒精溶液.Activeingredientoftheproducttobevalidatedforcleaning.產(chǎn)品中活性成分被清洗驗證Procedure程序Theaimofthistestistodeterminethereliabilityofthesamplingmethod,andtotakeintoaccountlossduetosamplinglimitation.此試驗的目的是決定取樣方法的可靠性,同時考慮由于取樣限制造成的損失.Thistestistobeperformedforthepredeterminedactiveingredientinaccordancewiththespecificprotocolfortheequipment.執(zhí)行預先確定的與設備草案相一致的活性成分的試驗.附件23HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本：SamplingRecoveryTest取樣回收率試驗ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期：QualityAssurance:質(zhì)量保證部Page2of3MethodforActiveIngredient活性成分取樣方法Usingtheappropriatesolvent(hereusingwater),prepareastocksolutioncalculatedtoyieldtheapproximateamountoftheactiveingredientascalculatedforthemaximalallowablecontaminationlevel(butnotmorethanx3ofthecalculatedvalue)per0.5ml.使用適當?shù)娜軇?這里選用水)配制原料溶液，濃度大約是最底定量限(但是不能超過限度的三倍)每0.5ml.2. Applyameasuredamountofthestocksolutiontothetestsurface(6x10x10cm)anddryitinanoven(37).配制已知濃度的溶液，均勻圖布于鋼板上(6x10x10cm)，烘干(37).3. Allowthesampletocoolatroomtemperature.允許樣品室溫冷卻.4. Wearglovesandtake6samplesfromthetestsurface;every10x10cmsurfacehasonesampleandtakeatleast2swabsamplesineverysurface(usingnewglovesandadifferentswabwettedwiththeextractingsolution).戴手套從擦拭表面6個10x10cm大小的區(qū)域分別取樣,每次用至少兩根棉簽擦拭(使用新的手套和蘸有萃取液的棉簽).5. TransfereachswabintoasuitablelabeledglassErlenmeyerflaskandprotectitfromexternalcontamination.Thesamplingmustbe.pleteasquicklyaspossibletopreventsolventevaporationandcontaminantredepositiononthesampledsurface.轉移棉簽到標記好的容量瓶中，避免外來污染.取樣必須盡快完成以免溶劑揮發(fā)和污染物沉積到樣品表面.6. SubmitthelabeledsealedglassErlenmeyerflasktotheanalyticallaboratoryimmediatelyalongwiththeblanksample(oneswabwettedwiththeextractingsolvent)andtheappropriateanalyticalrequestform.填寫分析申請單，遞交標記好的密封的樣品容量瓶和空白樣品（萃取劑潤濕的棉簽）到分析實驗室.7. Thesamplingrecoveryvalueistheratiobetweenthemeasuredvaluesandtheexpectedvalues.取樣回收率是標準值和期望值之比.AcceptanceCriteria認可標準Theoverallsamplingyieldvalueofswabsshouldbenotlessthan70%.全部棉簽取樣回收率不小于70%.Incaseswherelowresultsareobtainedinareproduciblemanner,thesamplesurfaceareamaybesampledagainusingasecondswabandtheresultsobtainedfrombothswabssummedup.如果小于70%，可以另外取一只棉簽在同一取樣面積重復以上操作，兩者之和大于70%。附件23HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本：SamplingRecoveryTest取樣回收率試驗ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期：QualityAssurance:質(zhì)量保證部Page3of3TestResult回收率實驗結果:Swabsamplingtestresults:不銹鋼板100(cm)2區(qū)域擦拭結果：Selectarea選擇區(qū)域Testactiveingredientamount測得樣品量（ug）Swabpercent回收率（％）Meanswabpercent平均回收率（％）RSD（％）75%alcohol75%酒精123456附件24

HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本.SwabChacterizationforCleaningValidation棉簽特性研究ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page1of3Safety安全Wearpowder-freeglovesandgoggles.戴防護手套和安全眼鏡.Useafumecupboardwhileworkingwithorganicsolvents.使用有機溶媒時要用通風櫥EquipmentandMaterials設備和物料Swabstobetested.測試用棉簽Analyticalinstrumentation.分析儀器Pincers.鑷子GlassErlenmeyerflasks.容量瓶.Purifiedwater.純化水.Solventtobeusedtosaturateswab.棉簽浸透液.Solventtobeusedtoextracttheswabaccordingtothespecificcleaningvalidationprotocol.棉簽萃取液Procedure程序Swababsorptioncapacity棉簽吸收能力1. Individuallyweigh10unuseddryswabs.分別稱量10個干燥的棉簽重量.2. Soakeachswabinthepurifiedwater.將棉簽浸到純化水中.3. Usingpincers,removetheswabfromthewater,holdituntildrippingstops,andplaceitimmediatelyonthebalancepan.用鑷子將棉簽取出，直到不再滴落溶液為止，立即將棉簽放到天平盤上.4. Individuallyweighthe10saturatedswabsandcalculatetheswabsolventabsorptioncapacity.分別稱量10個蘸有溶液的棉簽，計算棉簽的吸收能力.附件24

HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本.SwabChacterizationforCleaningValidation棉簽特性研究ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page2of3Swabinterference棉簽干擾PlaceonunuseddryswabinErlenmeyerflasks,whicheachcontainingoneofthefollowingsolvents.在錐形瓶中放入干燥的未使用的棉簽，每個錐形瓶含有一種下列溶劑Purifiedwater純化水Swabextractingsolventtobeusedintheanalyticaltestmethod分析時的棉簽萃取液2. Shakefor5minutes.振搖5分鐘.3. Testtheextractionsolventbytheanalyticalmethodstobeusedtodeterminetheactiveingredient,respectively,andcalculatetheswabinterferenceresponse,tobetakenintoaccountintheanalyticaldetermination.檢測活性成分的棉簽萃取液，計算棉簽干擾影響。Acceptancecriteria認可標準Theswabsuitabilityisbasedonthefollowingconsiderations:棉簽的適用性是建立在下列考慮之上:Nochangeinswabappearanceandcolor.棉簽的外觀和顏色沒有改變.Swabdurabilitywithoutsignsofdisintegration,fibersorsediments.棉簽經(jīng)久耐用，沒有纖維脫落及沉淀產(chǎn)生.Waterabsorptioncapacityisnotlessthanthevolumeofsolventorwaterneededtodissolvethecalculatedamountofresidualactiveingredient,respectively.水的吸收能力不能少于需要溶解活性物質(zhì)殘留的體積.附件24

HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本.SwabChacterizationforCleaningValidation棉簽特性研究ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page3of3Testresults:試驗結果：Purifiedwater純化水12345678910Dryswabweight干棉簽重（g）Wetswabweight濕棉簽重（g）Absorptionweight棉簽吸水量（g）

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HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本SwabSamplingforCleaningValidation清潔驗證棉簽取樣ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page1of4Safety安全Wearpowder-freeglovesandgoggles.戴防護手套和安全眼鏡。EquipmentandMaterials設備和原料Swab:Useapprovedswabs,suchasTexwipeorWhatmanpaper.棉簽:使用被核準的棉簽Solvent:Fortheactiveingredient,usethesolventprescribedinthespecificcleaningvalidationprotocol.溶劑：用清潔驗證草案中指定的溶劑對活性成分取樣。Samplingframe:Forflatsurfaces,usea10cmx10cmstainlesssteelframewithahandle.取樣結構：平坦表面10×10cm，不銹鋼結構Pincers.鑷子GlassErlenmeyerflasks.容量瓶Procedure程序 Note:Extremecareshouldbetakentopreventswabcontaminationduringhandling.注意:注意避免操作中棉簽被污染.Activeingredients活性成分1. Usingcleanpincerssoaktheswabinthesolventandholdituntildrippingstops.將棉簽浸到指定的溶液中，飽和后將溶液滴掉，直到不再滴落為止.2. Rubthesaturatedswabmanuallyoverthesamplesurfaceareadesignatedintheequipmentdiagramappearinginthespecificcleaningvalidationprotocol.Forflatsurfaces,usethestainlesssteelframe.Forsmallersurfacesandhard-to-reachlocations,rubthewholesurface.用手拿住棉簽，在事先劃好面積的設備表面用力均勻的擦拭，平坦表面擦拭不銹鋼結構，對于小的表面和不好擦拭的表面，要擦拭整個表面. SwabbingisperformedinacontrolledfashionbystrikingthesamplesurfaceareaasindicatedintheFigure12.1.擦拭方式參考下圖1.3.TransfertheswabintoalabeledglassErlenmeyerflaskandsealtheflask.將擦拭好的棉簽放到標記好的容量瓶中，蓋上蓋子附件25

HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本SwabSamplingforCleaningValidation清潔驗證棉簽取樣ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page2of44. Repeattheprocedureforeachlocationindicatedontheequipmentdiagramandrecordthesamplingonthesamplingformofthecleaningvalidationprotocol.對所有的取樣位置進行取樣，程序同上。5. Submitsamplesforanalysis.將樣品送到QC化驗AcceptanceCriteria認可標準SeeAttachment26.見附件26.Cleaningvalidationprotocolsamplingform清潔驗證草案取樣圖Figure1.SwabSampling棉簽取樣 附件25

HisunPharmaceuticalsCo.,Ltd.海正藥業(yè)EditionNo.:版本SwabSamplingforCleaningValidation清潔驗證棉簽取樣ValidationUnit:驗證小組Supersedes:替代Production:生產(chǎn)部門EffectiveDate:執(zhí)行日期QualityAssurance:質(zhì)量保證部Page3of4Cleaningvalidationtestresul