最新APIC原料药厂清洁验证指南(202205-中英文)

PAGE\*Arabic\*MERGEFORMAT61/NUMPAGES\*Arabic\*MERGEFORMAT61APIC原料药厂清洁验证指南〔202205中英文〕ACTIVEPHARMACEUTICALINGREDIENTSCOMMITTEE(APIC)GUIDANCEONASPECTSOFCLEANINGVALIDATIONINACTIVEPHARMACEUTICALINGREDIENTPLANTSAPIC原料药工厂中清洁验证指南May2022TableofContents1.0FOREWORD前言2.0OBJECTIVE目的3.0SCOPE范围4.0ACCEPTANCECRITERIA可接受4.1Introduction介绍4.2MethodsofCalculatingAcceptanceCriteria可接受标准的计算方法4.2.1.Acceptancecriteriausinghealth-baseddata使用基于健康数据的可接受标准4.2.2AcceptancecriteriabasedonTherapeuticDailyDose基于日治疗剂量的可接受标准4.2.3.AcceptancecriteriabasedonLD50基于半数致死量的可接受标准4.2.4GeneralLimitasacceptancecriteria作为可接受标准的通用限度4.2.5SwabLimits擦拭限度4.2.6RinseLimits淋洗限度4.2.7Rationalefortheuseofdifferentlimitsinpharmaceuticalandchemicalproduction在药品和化学生产中使用不同限度的合理性5.0LEVELSOFCLEANING清洁级别5.1Introduction介绍5.2CleaningLevels清洁级别5.3CleaningVerification/Validation清洁验收/验证6.0CONTROLOFCLEANINGPROCESS清洁过程的控制7.0BRACKETINGANDWORSTCASERATING分类法和最差情况分级法7.1Introduction介绍7.2BracketingProcedure分类法程序7.3CleaningProcedures清洁程序7.4WorstCaseRating最差情况分级8.0DETERMINATIONOFTHEAMOUNTOFRESIDUE残留量检测8.1Introduction介绍8.2ValidationRequirements验证要求8.3SamplingMethods取样方法8.4AnalyticalMethods分析方法9.0CLEANINGVALIDATIONPROTOCOL清洁验证9.1Background背景9.2Purpose目的9.3Scope范围9.4Responsibility职责9.5SamplingProcedure取样程序9.6Testingprocedure分析方法9.7Acceptancecriteria可接受标准9.8Deviations偏差9.9Revalidation再验证10.0VALIDATIONQUESTIONS验证问题11.0REFERENCES参考文献12.0GLOSSARY词汇13.0COPYRIGHTANDDISCLAIMER版本及声明1.0FOREWORD前言TheoriginalversionofthisguidancedocumenthasnowbeenupdatedbytheAPICCleaningValidationTaskForceonbehalfoftheActivePharmaceuticalIngredientCommittee(APIC)ofCEFIC.本指南文件的原版本现已由APIC清洁验证工作组代表CEFIC的APIC委员会进行了更新。TheTaskForcemembersare:-以下是工作组的成员AnnickBonneure,APIC,BelgiumTomBuggy,DSMSinochemPharmaceuticals,TheNetherlandsPaulClingan,MacFarlanSmith,UKAnkeGrootaert,JanssenPharmaceutica,BelgiumPeterMungenast,MerckKGaA,Germany.LuisaPaulo,HovioneFarmaCienciaSA,PortugalFilipQuintiens,Genzyme,BelgiumClaudeVandenbossche,AjinomotoOmnichem,BelgiumJosvanderVen,AspenOssB.V.,TheNetherlandsStefanWienken,BASF,Germany.Withsupportandreviewfrom:-以下为提供支持和进行审核的人员PietervanderHoeven,APIC,BelgiumAnthonyStorey,Pfizer,U.K.RainerFendt,BASF,Germany.Thesubjectofcleaningvalidationinactivepharmaceuticalingredientmanufacturingplantshascontinuedtoreceivealargeamountofattentionfromregulators,companiesandcustomersalike.原料药生产工厂的清洁验证一直是法规人员、公司和客户等关注的问题。TheintegrationofCleaningValidationwithinaneffectiveQualitySystemsupportedbyQualityRiskManagementProcessesshouldgiveassurancethatAPIManufacturingOperationsareperformedinsuchawaythatRiskstopatientsrelatedtocleaningvalidationareunderstood,assessedforimpactandaremitigatedasnecessary.原料药生产企业应将清洁验证与有效的质量体系相结合，由质量风险管理来支持，了解与清洁验证相关的患者风险，评估其影响，并在必要时降低风险。Itisimportantthattherequirementsforthefinishedmanufacturingcompaniesarenottransferredbackintheprocesstoactivepharmaceuticalingredientmanufacturerswithoutconsiderationforthedifferentprocessesthattakeplaceatthisstage.重要的是，不能将对制剂生产企业的要求直接用于原料药生产商，而不考虑在此阶段所用生产工艺的差异。Forexample,higherlimitsmaybeacceptableinchemicalproductioncomparedtopharmaceuticalproductionbecausethecarry-overriskismuchlowerfortechnicalandchemicalmanufacturingreasons例如，与制剂生产相比，化学生产可以接受较高的残留限度，因为技术原因，化学生产所带入后续产品的残留风险会低很多。ThedocumentreflectstheoutcomeofdiscussionsbetweenAPICmembercompaniesonhowcleaningvalidationrequirementscouldbefulfilledandimplementedaspartofroutineoperations.本文件反映了APIC成员公司之间关于如何满足清洁验证的要求及作为日常操作来实施的讨论结果。Inaddition,APICisaligningthisguidancewiththeISPERiskMaPPGuide[1]ISPEBaseline?PharmaceuticalEngineeringGuide,Volume7–Risk-BasedManufactureofPharmaceuticalProducts,InternationalSocietyforPharmaceuticalEngineering(ISPE),FirstEdition,September2022,.[1]thatfollowstheQualityRiskManagementProcessesasdescribedintheICHQ9GuidanceonQualityRiskManagement.另外，APIC将本指南与“ISPE基于风险的药品生产指南〞保持一致，遵守“ICHQ9质量风险管理〞中的“质量风险管理〞。ThecriteriaofAcceptableDailyExposure(ADE)isnowrecommendedtobeusedbycompaniestodecideifDedicatedFacilitiesarerequiredornotandtodefinetheMaximumAcceptableCarryOver(MACO)ofAPI’sinparticular,inMulti-PurposeEquipment.目前推荐公司使用“可接受日暴露水平〞标准来决定是否专用设施需要界定原料药“最大可接受残留MACO〞，特别是针对多用途设备。AnewchapterisintroducedtodefinefactorsthatshouldbeconsideredinControlsofTheCleaningProcesstomanagetheRisksrelatedtopotentialchemicalormicrobiologicalcontamination.放入了一个新章节，对“清洁工艺的控制〞中要考虑的因素进行了定义，以管理与潜在化学和微生物污染有关的风险。ThePDATechnicalReportNo.29–PointstoConsiderforCleaningValidation[2]ParenteralDrugAssociation(PDA)GuidanceforIndustry.TechnicalReportNo.29(Revised2022)PointstoConsiderforCleaningValidation,DestinA.LeBlanc,GretchenAllison,JenniferL.Carlson,KoshyGeorge,IgorGorsky,IrwinS.Hirsh,JamieOsborne,GregRandall,Pierre-MichelRiss,GeorgeVerghese,JennWalsh,VivienneYankah.[2]isalsorecommendedasavaluableguidancedocumentfromindustry.也推荐企业将“PDA第29号技术----清洁验证中应考虑的问题〞作为有用的指南文件进行参考。ThefollowingtopicsarediscussedinthePDAdocument:Cleaningprocess(CIP/COP):designandqualification以下问题在PDA文件中进行了讨论：清洁工艺〔CIP/COP〕：设计和确认—Typesofresidues,settingacceptancecriteria,samplingandanalyticalmethods—残留类型、设定可接受标准、取样和分析方法—Maintenanceofthevalidatedstate:criticalparametersmeasurements,processalarms,changecontrol,trending&monitoring,trainingandperiodicreview—维护验证状态：关键参数测量、工艺警示、变更控制、趋势&监控、培训和周期性评审—Documentation—文件2.0Objective目的Thisdocumenthasbeenpreparedtoassistcompaniesintheformulationofcleaningvalidationprogrammesandshouldnotbeconsideredasatechnicalstandardbutastartingpointforinternaldiscussions.Thedocumentincludesexamplesonhowmembercompanieshavedealtwithspecificareasandissuesthatarisewhenperformingcleaningvalidation.本文件的目的是帮助公司制订清洁验证程序，不能作为是一个技术标准，只应该作为内部讨论的出发点。本文包括了成员公司如何处理其特殊领域的例子，以及在实施清洁验证时提出的问题点。3.0Scope范围SixspecificareasareaddressedinthisGuidancedocument:本指南文件包括6个方面AcceptanceCriteria可接受标准LevelsofCleaning清洁水平Controlofthecleaningprocess清洁工艺的控制BracketingandWorstCaseRating分类法和最差情况分级Determinationoftheamountofresidue残留量的检测CleaningValidationProtocol清洁验证方案Finally,themostfrequentlyaskedquestionsareansweredtogivefurtherguidanceonspecificpointsrelatedtocleaningvalidation.最后是一些常见问题及答复，对一些与清洁验证有关的特殊情况给予指导。4.0AcceptanceCriteria可接受标准4.1.Introduction概述Companiesmustdemonstrateduringvalidationthatthecleaningprocedureroutinelyemployedforapieceofequipmentlimitspotentialcarryovertoanacceptablelevel.Thatlimitestablishedmustbecalculatedbasedonsoundscientificrational.公司在验证时要证明各设备日常所用的清洁程序能将带入下一产品的潜在残留限制在一个可以接受的水平。所建立的限度必须进行科学合理的计算。Thissectionprovidespracticalguidanceastohowthoseacceptancecriteriacanbecalculated.Itisimportantthatcompaniesevaluateallcasesindividually.Theremaybespecificinstanceswheretheproductmixintheequipmentrequiresfurtherconsideration.本局部提供实用的指南，指导如何计算这些可接受标准。公司对各案进行各案评估是非常重要的。有时还需要考虑产品从哪步开始混入设备中。TheacceptancecriteriapreferablyshouldbebasedontheAcceptableDailyExposure(ADE)calculationswheneverthisdataisavailable.TheAcceptableDailyExposuredefinesalimitatwhichapatientmaybeexposedeverydayforalifetimewithacceptablerisksrelatedtoadversehealtheffects.CalculationsofAcceptableDailyExposuresofAPI’sandintermediatesareusuallydonewithinvolvementofindustrialhygienistsandtoxicologists,whoreviewallavailabletoxicologyandclinicaldatatosetthelimits.Thejustificationofthecalculationshouldbedocumented.如果可以获得可接受日暴露〔ADE〕值，最好依据其计算可接受标准。可接受日暴露限度定义的是患者终身每天暴露于该浓度，但对健康的不良影响仍处于可接受风险水平。原料药和中间体的ADE一般由企业的卫生学家和毒理学家来制订，他们会审核各种可以获得的毒性和临床数据来设定限度。计算的合理性要进行记录。InmanycasesOccupationalExposureLimits(OEL)willbedefinedforAPI’s,IntermediatesandIndustrialChemicalsbyIndustrialHygienistsandtoxicologistsandtheOELdataisthenusedtodefinecontainmentmeasuressuchthatoperatorsareadequatelyprotectedwhileworkingwiththechemicals.在很多情况下，会由行业卫生学家和毒理学家对原料药、中间体和工业级化学品的职业暴露限度〔OEL〕值进行界定，这时应使用OEL数据来制订限制措施，例如，操作人员在操作化学物质时需要受到充分保护。TheOELdatacanalsobeusedtocalculatetheADEforcleaningofequipment.OEL数据也可以用于计算设备清洁的ADE值。Incertaincaseswhereavailabilityofpharmacologicalortoxicologicaldataislimited,forexampleforchemicals,rawmaterials,intermediatesorAPI’sinearlyphaseclinicaltrials,cleaninglimitsbasedonfractionofclinicaldoses,LD50orgeneralcleaninglimitsmaybecalculated.Inthesecases,carcinogenic,genotoxicandpotencyeffectofthesestructuresshouldbeevaluatedbytoxicologists.在特定情况下，如果药性或毒性数据有限，例如，化学物质、原料、中间体或处于早期临床试验的原料药，其清洁限度可以基于临床剂量、半数致死量或一般清洁限度来计算。在这种情形下，需要有毒理学家对其结构的致癌性、基因毒性和效价影响进行评估。Theacceptancecriteriaforequipmentcleaningshouldbebasedonvisuallycleanindryconditionsandananalyticallimit.设备清洁的可接受标准应依据枯燥状态下目视清洁及分析限度。Unlikeinpharmaceuticalproduction,whereresiduesonthesurfaceofequipmentmaybe100%carriedovertothenextproduct,inAPIproductionthecarry-overriskismuchlowerfortechnicalandchemicalmanufacturingreasons.Thereforeallthefollowingexamplesforcalculatingthelimitscanbeadaptedtothesuitablesituationbyusingdifferentfactors.Acompetentchemistwithdetailedknowledgeabouttheequipmentandthechemicalprocessesandthepropertiesofthechemicalsinvolvedsuchassolubilityshouldjustifythisfactorbyevaluatingthespecificsituation.在制剂生产中，设备外表残留会100%被带入下一产品，而在原料药生产中，由于技术和化学生产原因，带入风险要低很多。因此，以下限度计算举例可以采用不同平安因子后用于适当的情形。应有一名具备设备和化学工艺知识，知晓所涉及化学品特性，如溶解度的化学家对特定情形下应使用的平安系统进行评估。4.2.MethodsofCalculatingAcceptanceCriteria计算可接受标准的方法4.2.1Acceptancecriteriausinghealth-baseddata采用健康根底数据的可接受标准TheMaximumAllowableCarryover(MACO)shouldbebasedupontheAcceptableDailyExposure(ADE)whenthisdataisavailable.TheprincipleofMACOcalculationisthatyoucalculateyouracceptablecarry-overofyourpreviousproduct,basedupontheADE,intoyournextproduct.在可以获得可接受日暴露水平〔ADE〕值时，最大允许残留〔MACO〕应基于ADE计算。MACO计算的原那么是基于ADE值，计算你允许从你的上一个产品带入下一个产品中的残留量。Procedure程序CalculatetheADE(AcceptableDailyExposure)accordingtothefollowingequationandusetheresultforthecalculationoftheMACO.根据以下公式计算ADE值，将结果用于MACO值的计算：MACO=NOAEL×BWUFc×MF×PKFromtheADEnumber,aMACOcanbecalculatedaccordingto:根据以下公式从ADE值计算MACO值：MACO=ADEprevious×MBSnextTDDnextMACO=ADE上一产品×MBS下一产品TDD下一产品MACOMaximumAllowableCarryover:acceptabletransferredamountfromthepreviousproductintoyournextproduct(mg)允许最大残留：从上一产品带入下一产品的最大可接受量ADEAcceptableDailyExposure(mg/day)可接受日暴露水平NOAELNoObservedAdverseEffectLevel(mg/kg/day)未观察到副反响的水平BWIstheweightofanaverageadult(e.g.70kg)平均成人体重UFcCompositeUncertaintyFactor:combinationoffactorswhichreflectstheinter-individualvariability,interspeciesdifferences,sub-chronic-to-chronicextrapolation,LOEL-to-NOELextrapolation,databasecompleteness.组分不确定因子：反映单个变量之间、不同品种差异、亚急性折算为急性外推、LOEL折算为NOEL外推、数据完整性等补偿因素的综合系数MFModifyingFactor:afactortoaddressuncertaintiesnotcoveredbytheotherfactors修正因子：用于表达未被其它因子覆盖的不确定因素PKPharmacokineticAdjustments药动学调整TDDnextStandardTherapeuticDailyDoseforthenextproduct(mg/day)下一产品的标准治疗日服用剂量MBSnextMinimumbatchsizeforthenextproduct(s)(whereMACOcanendup)(mg)下一产品的最小批量〔MACO全部带入其中〕ThedraftEMA/CHMP/CVMP/SWP/19430/2022makesreferencetothePermittedDailyExposure(PDE).ThePDEusesthenoobservedeffectlevel(NOEL)insteadofthenoobservedadverseeffectlevel(NOAEL)usedintheADEcalculation.ThePDEmayalsobeusedasalternativetotheADEtocalculatetheMACO.EMA/CHMP/CVMP/SWP/19430/2022草案中引用了允许日暴露〔PDE〕值。PDE采用了无可见影响水平〔NOEL〕代替无可见不良反响水平〔NOAEL〕用于ADE的计算。PDE值也可以用于代替ADE值来计算MACO值。Insteadofcalculatingeachpotentialproductchangesituation,theworstcasescenariocanbechosen.ThenacasewithmostactiveAPI(lowestADE)ischosentoendupinthefollowingAPIwiththesmallestratioofbatchsizedividedwithTDD(MBS/TDDratio).可以选择最差情况方案来替代对每个可能的产品更换情况下的残留计算。这时，可以选择活性最强的原料药〔ADE最低〕作为上一产品，选择批量TDD比值〔MBS/TDD比值〕最小的原料药作为后续产品。IfOELdataisavailable,theADEcanbederivedfromtheOEL.如果可以获得OEL值，那么可以从OEL值计算ADE值。4.2.2.AcceptancecriteriabasedonTherapeuticDailyDose基于日治疗剂量的可接受标准WhenlimitedtoxicitydataisavailableandtheTherapeuticDailyDose(TDD)isknown,thiscalculationmaybeused.ItisusedforfinalproductchangeoverAPIProcess—AtoAPIProcess—B.如果可以获得有限毒性数据和日治疗剂量〔TDD〕值，可以采用本计算方式。它可以用在原料药生产工艺A更换到原料药生产工艺B。Procedure程序EstablishthelimitforMaximumAllowableCarryover(MACO)accordingtothefollowingequation.根据以下公式建立允许最大残留〔MACO〕值：MACO=TDDprevious×MBSnextSF×TDDnextMACO=TDD上一产品×MBS下一产品SF×TDD下一产品MACOMaximumAllowanceCarryover:acceptabletransferredamountfromthepreviousproductintoyournextproduct(mg)允许最大残留：从上一产品中可以接受转入下一产品的数量(mg)TDDpreviousStandardTherapeuticDailyDoseoftheinvestigatedproduct(inthesamedosagefromasTDDnext)(mg/day)所讨论的产品的日标准治疗剂量〔以下一产品TDD计的同样剂量〕(mg/day)TDDnextStandardTherapeuticDailyDoseforthenextproduct(mg/day)下一产品的日标准治疗剂量(mg/day)MBSnextMinimumbatchsizeforthenextproduct(s)(whereMACOcanendup(mg)下一产品的最小批量〔MACO会携入的产品〕(mg)SFSafetyfactor(normally1000isusedincalculationsbasedonTDD).平安系数〔一般基于TDD值采用1000来计算〕4.2.3.AcceptancecriteriabasedonLD50基于半致死量的可接受标准Incaseswherenootherdataisavailable(e.g.ADE,OEL,TDD,…)andonlyLD50dataisavailable(e.g.chemicals,intermediates,detergents,…),theMACOcanbebaseduponLD50data.如果没方法获得其它数据〔例如，ADE、OEL、TDD等值〕，只能获得半数致死量数据〔例如化学物质、中间体、清洁剂……〕，MACO可以基于半数致死量数据来计算。Procedure程序CalculatethesocalledNOELnumber(NoObservableEffectLevel)accordingtothefollowingequationandusetheresultfortheestablishmentofMACO(See[3]oepage53-forreference).根据以下公式，计算NOEL值〔无可见影响水平〕，用于建立MACO值〔参见第53页的【3】局部，供参考〕NOEL=LD50×BW2000FromtheNOELnumberaMACOcanbecalculatedaccordingto:从NOEL值，用以下公式计算MACO值：MACO=NOELprevious×MBSnextSFnext×TDDnextMACO=NOEL上一产品×MBS下一产品SF下一产品×TDD下一产品MACOMaximumAllowanceCarryover:acceptabletransferredamountfromthepreviousproductintoyournextproduct(mg)允许最大残留：从上一产品中可以接受转入下一产品的数量(mg)NOELpreviousNoObservedEffectLevel(mg/day)无可见影响水平(mg/day)LD50LethalDose50inmg/kganimal.Theidentificationoftheanimal(mouse,ratetc.)andthewayofentry(IV,oraletc.)isimportant(mg/kg)50%的动物致死量，单位mg/kg。动物种类〔大鼠、小鼠等〕和摄入途径〔注射、口服等〕也很重要(mg/kg)BWIstheweightofanaverageadult(e.g.70kg)(kg)成年人平均体重〔例如70kg〕(kg)20002000isanempiricalconstant经验常数TDDnextStandardTherapeuticDailyDoseforthenextproduct(mg/day)下一产品的日标准治疗剂量(mg/day)MBSnextMinimumbatchsizeforthenextproduct(s)(whereMACOcanendup)下一产品的最小批量〔MACO会携入的产品〕(mg)SFnextSafetyfactor平安系数Thesafetyfactor(SF)variesdependingontherouteofadministration(seebelow).Generallyafactorof200isemployedwhenmanufacturingAPIstobeadministeredinoraldosageforms.平安系数〔SF〕根据摄入途径不同而不同〔见下〕。一般系数200用于口服剂型原料药生产。Safetyfactors:平安系数Topicals10–100局部给药Oralproducts100–1000口服给药Parenterals1000–10000注射给药4.2.4GeneralLimitasacceptancecriteria可接受标准的一般限度IfMACOcalculationsresultinunacceptablyhighorirrelevantcarryoverfigures,ortoxicologicaldataforintermediatesarenotknown,theapproachofagenerallimitmaybesuitable.Companiesmaychoosetohavesuchanupperlimitasapolicy.Thegenerallimitisoftensetasanupperlimitforthemaximumconcentration(MAXCONC)ofacontaminatingsubstanceinasubsequentbatch.如果MACO计算结果太高，不能接受，或者与带入数字不相关，或中间体毒性数据未知，那么适用通用限度方法。公司可以选择例如一个最高限度作为原那么。通用限度一般设定为一种污染物质在后续批次中最大浓度上限〔MAXCONC〕。Procedure程序EstablishMACOppm,basedonagenerallimit,usingthefollowingequations.利用以下公式，基于一个通用限度建立MACO限度，ppm为单位。MACOppm=MAXCONCxMBSMACOppmMaximumAllowableCarryover:acceptabletransferredamountfromtheinvestigatedproduct(“previous〞).Calculatedfromgeneralppmlimit.允许最大残留：所讨论的产品〔上一产品〕被带入下一产品的可接受值，一般表达为ppm限度MAXCONCGenerallimitformaximumallowedconcentration(kg/kgorppm)of“previous〞substanceinthenextbatch.允许上一产品在下一产品中的最大浓度通用限度〔kg/kg或ppm〕MBSMinimumbatchsizeforthenextproduct(s)(whereMACOcanendup)下一产品的最小批量E.g.foragenerallimitof100ppm:MACO=0.01%oftheminimumbatchsize(MBS),andforagenerallimitof10ppm:MACO=0.001%oftheminimumbatchsize(MBS).例如，对于通用限度为100ppm：MACO=最小批量〔MBS〕的0.01%，对于通用限度为10ppm：MACO=最小批量〔MBS〕的0.001%。Remarks:TheICHimpuritydocument(Q3)indicatesthatupto0.1%ofanindividualunknownor0.5%totalunknownsmaybepresentintheproductbeingtested.注：ICH杂质文件〔Q3〕指出，在被测试的产品中，单个未知杂质可以达0.1%，总未知杂质可以到达0.5%。Ageneralupperlimitforthemaximumconcentrationofacontaminatingsubstanceinasubsequentbatch(MAXCONC)isoftensetto5-500ppm(100ppminAPIsisveryfrequent)ofthepreviousproductintothenextproductdependingonthenatureofproductsproducedfromtheindividualcompany(e.g.toxicity,pharmacologicalactivity…).根据各公司所生产产品的属性不同〔例如，毒性、药物活性等〕，从上一产品带入下一产品中的污染物质最大浓度通用上限通常设定为5-500ppm〔原料药中100ppm是很常见的〕。TheThresholdofToxicologicalConcern(TTC)conceptcouldbeappliedtointermediatesorAPI’swithnoclinical(e.g.earlydevelopment)ortoxicologicaldata.Thisconceptincludesthreecategoriesofproductswithlimitedornodata:毒性关注阈值〔TTC〕概念可以应用于没有临床〔例如早期研发阶段〕或毒性数据的中间体或原料药。这个概念将数据有限或没有数据的产品分为3个类别Productsthatarelikelytobecarcinogenic;可能致癌的产品Productsthatarelikelytobepotentorhighlytoxic;可能具有效价或高毒性的产品Productsthatarenotlikelytobecarcinogenic,potentorhighlytoxic.可能致癌、具有效价或高毒性的产品ThecorrespondingADE’srecommendedforthesethreecategoriesare1,10,100μg/day,respectively.对应此三类所推荐的ADE值分别为1、10和100μg/天。AnotherpossibilitytocalculateyourADEforintermediatesorAPI’s,withnoclinicalortoxicologicaldata(e.g.earlydevelopment),isbasedupontheexposuredurationofyournextproduct.ThevaluesoftheCHMPguidelineontheLimitsofGenotoxicImpurities(ref.EMEA/CHMP/SWP/431994/2022)canbeusedforyourADE.在没有临床或毒性数据〔例如研发早期〕时，计算中间体或API的ADE还有另一个方法，就是基于下一产品的暴露时长。可以将CHMP指南“基因毒性杂质〞〔参见EMEA/CHMP/SWP/431994/2022〕限度值可以用于ADE计算。Note-Ifyoudecidetoemploytheconceptoflevelsofcleaning(ref.section5),thendifferentsafetyfactors(ppmlimits)maybeusedfordifferentlevels.EspeciallyiftheproductcleanedoutiswithinthesamesyntheticchainandcoveredbythespecificationoftheAPI,muchhigher(qualified)levelsareacceptable.注：如果你决定采用清洁水平概念〔参见第5局部〕，那么对于不同水平可以采用不同的平安系数〔ppm限度〕。特别是如果被清洁的产品是在同一条合成链中，且其限度包括在原料药的质量标准中，那么残留水平较高〔确认过的〕时也是可以接受的。4.2.5SwabLimits擦拭限度Ifhomogeneousdistributionisassumedonallsurfaces,arecommendedvaluecanbesetforthecontentinaswab.Themaximumallowablecarryoverfromonebatchtoanothercanbeestablishedbasedone.g.ADE,NOELorTDD(seeabove).Ifthetotaldirectcontactsurfaceisknown,thetargetvalueforcontaminationpersquaremetercanbecalculatedaccordingequation4.2.5-I.Thiscanbeusedasbasicinformationforpreparationofamethodofanalysisanddetectionlimit.如果假定所有外表上残留的分布是均匀的，可以给擦拭样品设定一个推荐值。可以根据例如ADE值、NOEL或TDD〔见上〕设定一批到另一批的最大允许残留值。如果知道直接接触产品的总面积，那么可以根据公式计算单位面积上的污染目标值，该值可以在制订方法验证方案和检测限值时参考。Equation4.2.5-ITargetvalue[μg/dm2]=MACO[μg]Totalsurface[dm2]公式4.2.5-I目标值[μg/dm2]=MACO[μg]总外表积[dm2]Alsoothermethodswithdifferentswablimitsfordifferentsurfacesinapieceofequipmentand/orequipmenttraincanbeused.Iftheequipmentcanbedividedinseveralparts,differentswablimitsmaybetakenforthedifferentpartsbuildinguptheequipmenttrain.Iftheresultofonepartisexceedingthetargetvalue,thewholeequipmenttrainmaystillbewithintheMACOlimit.TheCarryOveristhencalculatedaccordingequation4.2.5-II(seebelow).也可以对同一设备和/或设备链不同的外表使用不同的擦拭限度。如果设备被分为几个局部，对可以针对设备链不同局部采用不同的擦拭限度。如果一个部件的结果超出了目标值，整个设备链的残留值仍可能是在MACO的限度以内。这时，可以按公式〔见下〕计算残留量。Duringequipmentqualificationandcleaningvalidationhardtocleanpartscanbedetermined.Ratherthandeclaringthehardtocleanpartastheworstcaseswablimitforthewholeequipmenttrain,itcouldbeseparatedanddealtwithasmentionedabove.Itshouldbenotedthatdifferenttypesofsurfaces(e.g.stainlesssteel,glasslined,Teflon)mayshowdifferentrecoveriesduringswabbing.Inthosecasesitmaybebeneficialtodividetheequipmenttraininseveralparts,andcombinetheresultsinatableormatrix.ThetotalcalculatedamountshouldbebelowtheMACO,andtheindividualswabresultsshouldnotexceedthemaximumexpectedresiduesestablishedduringcleaningvalidation/equipmentqualification.Recoverystudiesandmethodvalidationarenecessarywhenapplyingswabbingasamethodtodetermineresidues.在设备确认和清洁验证中，可以确定哪个部件是难以清洁的。其实可以采用上述的方法来将难以清洁的部件分开来，而不需要采用最难清洁的部件作为最差擦拭情况的限度用于整个设备链。要注意不同材质外表〔例如，不锈钢、搪玻璃、聚四氟乙烯〕可能有不同的擦拭回收率。在这种情况下，如果把设备链划分为几个局部，将结果在一份表或类别中合并可能会比拟好。合计数量应低于MACO值，单个擦拭结果不应超过在清洁验证/设备确认中所设立的最大高期望值。在使用擦拭方法测定残留量时，要进行回收率研究和方法验证。Equation公式CO[μg]=Σ(Ai[dm2]×mi[μg/dm2])COTrue(measured)totalquantityofsubstance(possiblecarryover)onthecleanedsurfaceincontactwiththeproduct,calculatedfromresultsofswabtests.采用擦拭检测结果计算出的与产品直接接触的已清洁外表实际总残留量AiAreaforthetestedpieceofequipment#i.所测试的i设备的面积miQuantityinμg/dm2,foreachswabperareaofswabbedsurface(normally1dm2)单位擦拭面积的残留数量4.2.5.1.SettingAcceptanceCriteriaforSwabLimits对擦拭限度设定可接受标准Foreachitemtested,thefollowingacceptancecriteria(AC)apply.以下可接受标准适用于各测试工程：AC1.Thecleaningresultofanindividualpartshouldnotexceedthemaximumexpectedresidue.单个设备清洁结果应不超过最大可接受残留量。AC2.ForthetotalequipmenttraintheMACOmustnotbeexceeded.总设备链的MACO不得超过。Indeterminingacceptancelimits,allpossiblecasesoffollowingproductsintherelevantequipmentshallbetakenintoaccou