PDA TR29清潔驗(yàn)證考慮要點(diǎn)

TechnicalReportNo.29(Revised2012)PointstoConsiderCleaningParadigmChangeinManufacturingOperationsSMPDATaskForceonTechnicalReportNo.29(Revised2012):toConsiderforCleaningAuthorsDestinA.LeBlanc,Cleaning(Chair)GretchenAllison,PfizerL.Carlson,GenentechGeorge,ConsultantIgorIrwinS.Hirsh,NordiskAS

JamieOsborne,Siegfried(USA),Inc.GregRandall,BaxterBiosciencePierre-MichelRiss,EliLillySTERISCorporationLtd.ThecontentandviewsexpressedinthisTechnicalReportaretheresultofaconsensusachievedbytheauthorizingTaskForceandarenotnecessarilyviewsoftheorganizationstheyrepresent.PointstoTechnicalReportNo.29(Revised2012)ISBN:978-0-939459-48-3?2012ParenteralDrugAssociation,Inc.Allrightsreserved.ParadigmChangeinManufacturingOperations(PCMOSM)launchedtheprojectrelatedtothePCMOprograminDecember2008tohelpimple-mentthescientificapplicationoftheICHQ8,Q9andQ10series.BoardofDirectorsap-thisprogramincooperationwiththeRegulatoryAffairsandQualityAdvisoryBoard,andBiotechnologyAdvisoryBoardandScienceAdvisoryBoardofAlthoughthereaoftoaddressthisconcept,thePCMOprogramfol-andthedrugproductthestrategicthemeofprocessrobustnesswith-intheofthemanufacturingoperations.ThisprojectfocusesonPharmaceuticalQualitySystemsasanenablerofQualityRiskManagementandManagement.UsingtheParenteralDrugAssociation’s(PDA)membershipexpertise,thegoaloftheParadigmChangeinManufacturingOperationsProjectistodrivetheestablishmentof‘bestpractice’docu-mentsand/ortrainingeventsinordertoassistpharmaceuticalmanufacturersofInvestigationalMedicinalProducts(IMPs)andcommercialproductsinimplementingtheICHguidelinesonPhar-maceuticalDevelopment(ICHQ8,Q11),QualityRiskManagement(ICHQ9)andPharmaceuticalQualitySystems(ICHQ10).PCMOfollowstheproductlifecycleconceptandhasthefollowingstrategicintent:EnableancontinualofproductsandsystemsIntegratescienceandtechnologyintomanufacturingpracticeEnhancemanufacturingprocessriskbaseddecisionmakingandmanage-mentcommunicationamongindustryandregulatoryauthoritiesTheProductLifeCyclePharmaceuticalDevelopmentTechnologyPharmaceuticalDevelopmentTechnologyTransferCommercialManufacturingProductDiscontinuationTableofContentsTableofContentsIntroduction 1Purpose/Scope 1Glossaryof3DefinitionofAcronyms 5CleaningProcessDesignandDevelopment 7CleaningProcessDesign 7CleaningProcessOverview 8Physical-chemicalAspects 9DesignConsiderations 10LocationofCleaning 10In-PlaceCleaning 10Clean-in-Place(CIP)Systems 10SolventRefluxCleaning 11PlaceboBatchesasaCleaningMethod 11Out-of-PlaceCleaning 11Clean-Out-of-PlaceSystems 12Automatedvs.ManualSystems 12ManualProcesses 12Semi-AutomatedProcesses 12AutomatedProcesses 13SoilEvaluationandCategorization 13SoilCategories 13SoilRemoval 13EquipmentConsiderations 14Dedicated–NondedicatedManufacturingEquipment NonproductContact–ProductContactSurfaces Low-RiskSites–High-RiskSites.15MaterialsofConstruction 15OperationalConsiderations 15CleaningAgentSelection 16ProductConsiderations 16ProductRiskConsiderations 17CleaningDevelopmentLaboratoryExperiments 17SoilSelection 17ParameterSelection 18ParameterInteractions 19MeasurementstoDetermineCleaningEffectiveness 19CleaningProcessScale-Up 193.5.1 SettingProcessControls 19Applyingthe“DesignSpace”Conceptto

CleaningProcesses 20StandardOperatingProcedures 21OperatorTrainingfortheCleaningProcess 21IntroductionofNewProductstoaValidatedCleaningSystem 22Qualification 23ProtocolElements 23KeyProtocolIssues 23NumberofRunsinaProtocol 24MockSoiling 24Worst-CaseProcessConditions 24DispositionofProductsandEquipmentduringValidation Grouping/FamilyApproach 25ProductGrouping 26EquipmentGrouping 26IntroductionofaNewProductorEquipmentintoaGroup “CleaningVerification”Documentation 27ResidueandLimits 29ConsiderationsforDevelopingLimits 29TheBasisforQuantitativeLimits 30AcceptableConcentrationofResidueinNextProduct ARLBasedonDrugActiveDose 30ARLBasedon31ADEDeterminationsBasedonISPE’sRisk-MaPP CalculationsBasedonLD50Data 32OtherARLDeterminations 33AcceptableCarryover 33SurfaceAreaLimit 34LimitinProtocolSamples 34LimitperSwab 34ConcentrationLimitinExtractedSwabSolvent 34ConcentrationLimitinRinseSamplingSolution 35ConsolidatedExpressions 35ExampleCalculations 36OtherConsiderations 36MultipleNextProducts 36NextProductinVerificationApproach DefaultLimits 37UseofDifferentSafetyFactors 38DifferentRoutesofAdministration 38DifferentDosesforAdultsandChildren 38HumanandVeterinaryProductsManufacturedonSameEquipment 38ResiduesofGenotoxicandOtherHighlyHazardousActiveIngredients LimitsBasedonAnalyticalDetectionLimits 39DegradationoftheActiveIngredient.39LimitsNotMeasureable 39LimitsforOrganicSolvents 39DedicatedEquipment 40DividingaLimitamongVariousPiecesofEquipment 40 LimitsforPreferentialTransfertoaPortionoftheNextProduct LimitsforBiotechnologyManufacture 40ProductswithMoreThanOneActiveIngredient BioburdenLimits 41EndotoxinLimits 42VisuallyCleanCriterion 42Sampling 43SamplingMethodSelection 43DirectSamplingMethods 43VisualInspection 43InstrumentalMethods 44RinseSampling 44ExtractionRinseSamplingforSmallParts SolventRefluxSampling 46SwabandWipeSampling 46PlaceboSampling 47SamplingforMicrobialandEndotoxinAnalysis 47AdditionalConsiderations 48SamplingRecoveryStudies 48GeneralConsiderations 48Swab/WipeRecovery 49RinseRecovery 50“Recovery”inVisualInspection 51RecoveryforBioburdenandEndotoxinSampling 51TrainingandQualificationofSamplers 51

KeyIssuesforTrainingforSwabSampling 52KeyIssuesforTrainingforRinseSampling TrainingforVisualInspection 52AnalyticalMethods 54PurposesoftheAnalyticalMethods 54PracticalConsiderationsinSelectingAnalyticalMethods Specificvs.NonspecificAnalyticalMethodsforValidationProtocols RegulatoryStatusofSpecificandNonspecificMethods MostCommonlyUsedAnalyticalTechniques56LiquidChromatography(LC) 56UltraViolet/VisibleSpectrophotometry(UV/Vis) OrganicCarbon(TOC) 57Conductivity 57OrganolepticEvaluation 58OtherUsefulAnalyticalTechniques 597.5.1 pH 59InfraRed(IR) 59LightMicroscopy 59Titrations 59GravimetricAnalysis 59EnzymeLinkedImmunosorbantAssay(ELISA) 60AtomicAbsorption(AA)andInductivelyCoupledPlasma(ICP) 60IonMobilitySpectrometry(IMS) 60MicrobialMethods 60Endotoxin 60Bioburden 60AnalyticalMethodValidation 61GeneralPrinciples 61CompendialMethods 62VisualInspection 63BioburdenMethods 63TransfertoanotherLaboratoryandUseofContractLaboratories 63MaintenanceofValidatedState 64CriticalParameterMeasurement 64ProcessAlarms 64ChangeControl 65RoutineMonitoring 66DataTrendingandReview 66EvaluationofCumulativeChanges 67Training 67PeriodicReview 67Documentation 69CleaningValidationMasterPlans 69ElementsofaComprehensivePlan 70HarmonizationofSiteCleaningValidationPrograms DocumentationforDesign/Development 71DocumentationforQualification 72DocumentationforValidationMaintenance 72OtherDocumentationConsiderations 73SpecialConsiderations 75CleaningAgents 757575OrganicSolvents 75CommodityAlkali 75CommodityAcids 75FormulatedDetergents 75FactorsinSelection 76BroadSpectrumEffectiveness 76SubstrateCompatibility 76StabilityandShelfLife 76Analyzability 76Disposal 76Safety 7676Rinsability 76Quality 76NonproductContactSurfaces 76ProcessAnalyticalTechnology 77TimelyMeasurements 77forCleaningProcessControl 77AdditionalConsiderationsforOnlineMeasurements CleanHoldConsiderations 78NewandUsedEquipment 80NewEquipment 80CleaningProcedureDevelopment 80Post-InstallationCleaning 81

GroupingImpact 81LimitCalculationImpact 81UsedEquipment 81MeasurementSystemsAnalysis(MSA)10.6.1MSAComponents AttributeR&R 82MinimizingVariations 82MSAandCleaningValidationStrategy 82CleaningforAPIManufacture 83DrugProducts 84DrugProductswithSystemicAvailability 84DrugProductswithNoorLimitedSystemicAvailability AdjustedCalculation 85ModificationBasedonFrequencyofApplication 85ModificationBasedonAmountAppliedperSurfaceArea AdditionalConsiderations 86AdditionalSafetyConsiderations 86AdditionalCleaningConsiderations 86AnimalDrugProducts 86PackagingComponentsandPackagingEquipment 86PrimaryPackagingComponents 86OralDosageFormsPrimaryPackagingComponents ParenteralDosageFormsPrimaryPackagingComponents PackagingEquipment 87PrimaryPackagingEquipment 87SecondaryPackagingEquipment.88andHoses 88Excipients 89DedicatedEquipment 89ReasonsforDedication 89CleaningValidationIssues 9011.0RegulatoryandGuidanceDocuments 9112.0References 9213.0SuggestedReadings 94FIGURESANDTABLESINDEX3.1-1 CPPandCQAConsiderationsthathavePotentialRiskImpacttoaCleaningProcess 3.1-2 TheCleaningSpectrum 83.2-1 CleaningProcessSteps(Examples) 96.1.2-1 ComparisonofGrabSamplingversusSeparateSamplingRinse 45

6.1.2-2 AdvantagesandLimitationsofRinseSampling 456.1.3-1 AdvantagesandLimitationsofSwab/WipeSampling 47Figure9.5-1 DocumentationforProcessFlow 74PAGEPAGE100/149Introduction引言Cleaningvalidationplaysanimportantroleinreducingthepossibilityofproductcontaminationfrompharmaceuticalmanufacturingequipment.Itdemonstratesthatthecleaningprocessadequatelyandconsistentlyremovesproductresidues,processresiduesandenvironmentalcontaminantsfromthemanufacturingequipment/system,sothatthisequipment/systemcanbesafelyusedforthemanufactureofspecifiedsubsequentproducts(whichmaybethesameoradifferentproduct).AsusedinthisReport,“product”maybeadrugproduct,activepharmaceuticalingredient,intermediate,oranothertypeofformulation.If“drugproduct”isintended,thatterminologywillbeutilized.Principlesandpracticesgiveninthisreportmayapplytoavarietyofmanufacturingsituations.Itisincumbentonthereadertodecidetheappropriatenessofthoseprinciplesandpracticestohis/herspecificsituation.持續(xù)充分除去生產(chǎn)設(shè)備上/系統(tǒng)中產(chǎn)品殘留、工藝殘留和環(huán)境污染，所以該設(shè)備/系統(tǒng)可以安全地生（相同或不同產(chǎn)品用于各種生產(chǎn)情況。讀者應(yīng)自行決定這些原則和規(guī)范是否適用他/她的具體情況。Thisreportbuildsonthe1998PDATechnicalReportNo.29,PointstoConsiderforCleaningValidation(1).Thisreportalsohasutilizedprinciplesandspecificwordingfromthe2010PDATechnicalReportNo.49,PointstoConsiderforBiotechnologyCleaningValidation(2).TheauthorsofthisrevisedTechnicalReport#29wouldliketothankthemembersoftheTaskForceswhowereresponsibleforthosetwoearlierdocumentsformakingourjobeasier.1998PDA29號(hào)“清潔驗(yàn)證要點(diǎn)”(1)2010PDA49(2)29號(hào)作者非常感謝這兩個(gè)較早版本的工作組成員，使我們的工作變得更容易。ThisrevisedTechnicalReportpresentsupdatedinformationthatisalignedwithlifecycleapproachestovalidationandtheInternationalConferenceonHarmonisation(ICH)guidelinesQ8(R2)-PharmaceuticalDevelopment,Q9-QualityRiskManagementandQ10-PharmaceuticalQualitySystem(3,4,5).Also,thisreportaimstoassistreaderswhowanttocreateorbenchmarkacleaningvalidationprogramfortheirequipmentandfacilities.本修訂版技術(shù)報(bào)告提出了更新的信息，即結(jié)合了生命周期的驗(yàn)證方法和國(guó)際協(xié)調(diào)會(huì)議（ICH）的指Q8(R2)-藥物開(kāi)發(fā)、Q9-Q10-制藥質(zhì)量體系(3,4,5)。此外，這份報(bào)告也有助于讀者建立或評(píng)估自己的設(shè)備、設(shè)施的清潔驗(yàn)證計(jì)劃。ThisTaskForcewascomposedofEuropeanandNorthAmericanprofessionalsfrompharmaceuticalmanufacturers,cleaningchemicalsuppliers,andconsultingcompanies.Thereporthasundergoneaglobal,technicalpeerreviewtoensureconcepts,terminology,andpracticespresentedarereflectiveofsoundscienceandcanbeusedglobally.該工作組是由歐盟和北美的制藥專(zhuān)家、清潔化學(xué)品供應(yīng)商和咨詢(xún)公司組成。該報(bào)告經(jīng)過(guò)了一個(gè)全球性的技術(shù)同行評(píng)審，確保概念、術(shù)語(yǔ)、規(guī)范科學(xué)、合理，可在全球范圍使用。Purpose/Scope目的/范圍ThisTechnicalReportcoversallfacetsofcleaningvalidationforpharmaceuticalmanufacturers,includingbothmanufacturersofAPIsanddrugproducts.Italsoappliestobiotechnologymanufacturing;however,thereadershouldconsultPDATechnicalReportNo.49,PointstoConsiderforBiotechnologyCleaningValidationformoredetailandspecificsforbiotechnologymanufacturing(2).Wehaveincludedalifecyclecleaningvalidationapproach,includingdesign/developmentofthecleaningprocess,processqualification(includingtheprotocolruns),andongoingvalidationmaintenance.Whilethedocumentdiscussesrisk-basedapproaches,itdoesnotprovidedetailsaboutrisk-basedmanufacturing.PDAhasformedaTaskForcetowriteaTechnicalReportonthattopic.PDA49(2)，獲得生物/工藝確認(rèn)（包括方案實(shí)施）和持續(xù)驗(yàn)證維護(hù)。盡管采用了基于風(fēng)險(xiǎn)的方法，本報(bào)告沒(méi)有詳細(xì)論述基于風(fēng)險(xiǎn)的生產(chǎn)。PDA已經(jīng)成立了撰寫(xiě)該主題技術(shù)報(bào)告的工作組。cannotemphasizeenoughhowimportantriskanalysesareintheselectionofandvalidationofcleaningprocessesandtheirvalidation.Thisincludesthetraditionalriskanalysisbasedoneffectsonproductqualityandonpatients.Italsoincludesbusinessriskconsiderations,suchasstepstakentominimizelostproductfromcontamination(evenifdetectionsystemsareinplacetopreventreleaseofthatcontaminatedproductforconsumeruse).低（即使有檢測(cè)系統(tǒng)防止受污染的產(chǎn)品被放行。ThesepracticesandtheassociatedguidanceinthisReportarebasedontechnicalconsiderationsandshouldbeapplicableinallregulatoryenvironments.However,theintentofthisTechnicalReportisnottoprovideadetailedplanorroadmapforapharmaceuticalmanufacturertoperformcleaningvalidation.Rather,asthetitlesuggests,itpresents“pointstoconsider”asonedesignsacleaningvalidationprogramforprocessequipmentbasedonanunderstandingofmanufacturingandcleaningprocesses.Incleaningvalidation,therearegenerallymultiplewaystoaccomplishthesamegoalofacompliant,scientificallysoundandpracticalcleaningvalidationprogram.Whereoptionsaregiven,therationalesforsuchoptionsarealsogenerallygiven.Examplesarenotmeanttobeprescriptiveorlimiting;theymerelyillustrateacertainpractice.ActualacceptablepracticesshouldnotbeconsideredlimitedbythediscussioninthisReport.Basedonanunderstandingoftheuniquenatureofanyindividualsituation,differentapproachesoradditionalissuesshouldalsobeconsidered.Soundsciencebasedonanunderstandingofthecleaningandmanufacturingprocessesmayleadtootherequallyacceptablepractices.TheForcethatdevelopedthisdocumenthopesthatthereportwillbeusedinthisspiritandwillnotbesolelyusedasachecklist.法不應(yīng)被本技術(shù)報(bào)告中討論所限制?；趯?duì)任何單個(gè)情況獨(dú)特性的理解，不同的方法或其他問(wèn)題也應(yīng)考慮。對(duì)于清潔和制造工藝的合理、科學(xué)理解可能會(huì)導(dǎo)致其他同樣可以接受的做法。制定本文件的工作組希望該報(bào)告的使用應(yīng)本著這一精神而不僅僅作為一個(gè)檢查清單使用。Thisreportshouldbeconsideredtobearesourcetohelpguidethedevelopmentorevaluationofacleaningvalidationprogram.Itisnotintendedtoestablishmandatorystandardsforcleaningvalidation.Itisintendedtobeasingle-sourceoverviewforpharmaceuticalmanufacturersthatcomplementsexistingregulatoryguidanceandotherdocumentsreferencedinthisdocument.ThereadershouldalsobeawarethataspecifictopicmaybediscussedinseveralsectionsofthisTechnicalReport.Therefore,amorecompleteperspectivemaybeobtainedbyconsideringallrelevantsectionsaboutacertaintopic.Furthermore,whilemanyapproachesarepresentedhere,specificapproachesutilizedforagivencleaningprocessshouldbeselectedbasedonagoodunderstandingofthatprocess,aswellastheappropriatenessoftheselectedpracticeforthatspecificsituation.ItisnotenoughtomerelysaythatthepracticeismentionedasanacceptableoneinPDATechnicalReportNo.29;eachfirmshouldbepreparedtodefendwhytheselectedapproachisavalidoneforitsoperations(1).PDA29號(hào)是作為一個(gè)可以接受的操作”是不夠的，每個(gè)企業(yè)應(yīng)該準(zhǔn)備回答為什么所選擇的方法是一個(gè)有效的方法(1)。Glossaryof術(shù)語(yǔ)集AcceptableDailydosethatisunlikelytocauseanadverseeffectifanindividualisexposed,byanyroute,atorbelowthisdoseeverydayforalifetime.可接受的日暴露量：指通過(guò)任何途徑，在等于或低于此劑量時(shí)一個(gè)人終身接觸都不可能造成不利影響的劑量。AcceptableDailyamountofasubstanceconsumedonadailybasisthatisconsideredatasafelevel.可接受的每日攝入量：每日攝入某種物質(zhì)被認(rèn)為是安全水平的劑量。AcceptanceCriteria：Numericallimits,ranges,orothersuitablemeasuresfortheacceptanceoftestresults.可接受標(biāo)準(zhǔn)：接受測(cè)試結(jié)果的數(shù)值限度，范圍，或其它合適的測(cè)量值。AcceptanceLimit：Themaximumamountofresidueallowedinaproduct,inananalyticalsample,orasanamountpersurfacearea.可接受限度：產(chǎn)品中允許的最大殘留量，以分析樣品中殘留含量或每表面積殘留數(shù)量表示。ActivePharmaceuticalIngredient(API)orDrugSubstance：Anysubstanceormixtureofsubstancesintendedtobeusedinthemanufactureofadrug(medicinal)productandwhenusedintheproductionofadrug,becomesanactiveingredientofthedrugproduct(alsocalled“drugsubstance”).藥用活性成分（API）或原料藥：用于制備制劑的任何物質(zhì)或混合物質(zhì)，如果用于生產(chǎn)藥品，該物質(zhì)或混合物就為制劑的一個(gè)活性成分（。Analyte：Substance(usuallyaresidue)forwhichananalysisisbeingperformed.分析物（：（通常是指殘留物。Blank：Analyticalsampletakentoestablishbackgroundvaluefortheanalyticalmeasurementwhichmaybesubtractedfromanexperimentalvaluetodeterminethe“true”value.空白對(duì)照：用于分析測(cè)量建立背景值的分析樣品，可將實(shí)驗(yàn)測(cè)試結(jié)果減去該背景值以確定“真”值。Campaign：Processingofmultiplelotsorbatchesofthesameproductseriallyinthesameequipment.階段性生產(chǎn)：多個(gè)批次的同一產(chǎn)品在同一設(shè)備連續(xù)加工。Changeover：Thestepstakenforswitchingmultiproductequipmentfromthemanufactureofoneproducttothemanufactureofadifferentproduct.切換生產(chǎn)：指在多品種生產(chǎn)設(shè)備上從一個(gè)產(chǎn)品的切換至另一產(chǎn)品的制造所采取的步驟。Clean：Havingproductresidues,processresidues,andenvironmentalcontaminantsremovedtoanacceptablelevel.清潔：將產(chǎn)品殘留、工藝殘留和環(huán)境污染物去除至可接受的水平。CleanHoldtimefromtheendofthecleaningprocessuntiltheequipmentisusedagain(whichmaybeproductmanufacture,autoclaving,orasteaminplace(SIP)cycle).清潔保持時(shí)間：指從清潔工藝結(jié)束至設(shè)備再次使用（也可以是產(chǎn)品生產(chǎn)、高壓滅菌或在線(xiàn)蒸汽滅菌（CleaningAgent：Thesolutionorsolventusedinthewashingstepofacleaningprocess.Examplesofcleaningagentsarewater,organicsolvent,commoditychemicaldilutedinwater,andformulateddetergentdilutedinwater.清潔劑：清潔工藝中用于清洗步驟的溶液或溶劑。清潔劑有水、有機(jī)溶劑、用水稀釋的日用化學(xué)品和用水稀釋的配方洗滌劑。Cleaningdocumentationthatassuresanyproductandprocess-relatedmaterialintroducedintoequipmentaspartofthemanufacturingprocessstreamisremovedandtheequipmentisadequatelystored.清潔規(guī)程：指保證隨生產(chǎn)引入到設(shè)備中的所有產(chǎn)品及工藝相關(guān)的物料被除去，設(shè)備被適當(dāng)?shù)卮娣诺奈募?。CleaningProcess：Aprocessthatisusedtoremoveanyproduct,process-relatedmaterialandenvironmentalcontaminantintroducedintoequipmentaspartofthemanufacturingstream.清潔工藝：指清除因生產(chǎn)而引入設(shè)備的任何產(chǎn)品、工藝相關(guān)的物料和環(huán)境污染物的過(guò)程。CleaningValidation：Documentedevidencewithahighdegreeofassurancethatacleaningprocesswillresultinproductsmeetingtheirpredeterminedqualityattributesthroughoutitslifecycle.清潔驗(yàn)證：指一個(gè)清潔工藝能夠確保產(chǎn)品在其生命周期內(nèi)滿(mǎn)足預(yù)定質(zhì)量屬性的有效證明文件。CleaningVerification：Aone-timesamplingandtestingtoensurethatspecifiedequipmenthasbeenproperlycleanedfollowingaspecificcleaningevent.清潔效果確認(rèn)：一次性取樣和測(cè)試以確保所指定的設(shè)備在清潔后已得到適當(dāng)清潔。oamiaonnudesededueoresideevlncenedqupentsuasornaanactudproduct.污染：指在已清潔的設(shè)備表面或生產(chǎn)的產(chǎn)品中不期望的殘留物或殘留水平。Coupon：Asmall,generallyflatportionofadefinedmaterialofconstruction(suchasstainlesssteelorPTFE)andofadefinedsurfacefinish,typicallyusedforlaboratorycleaningevaluationsand/orforlaboratorysamplingrecoverystudies材質(zhì)試樣：一塊小的、通常是平整的特定材質(zhì)（如不銹鋼或PTFE）樣品，經(jīng)過(guò)特定表面處理，主要用于實(shí)驗(yàn)室清潔評(píng)估和/或用于實(shí)驗(yàn)室取樣回收率研究。DedicatedEquipment：Equipmentusedexclusivelyforthemanufactureofonlyonedrugproduct,bulkdrugsubstance,orintermediate.專(zhuān)用設(shè)備：專(zhuān)門(mén)用于一種制劑、原料藥或中間體生產(chǎn)的設(shè)備。Degradation：Breakdown(usuallychemical)ofmaterialduringmanufacture(includingduringandafterthecleaningprocess).降解：在制造過(guò)程中（包括清潔過(guò)程及清潔后）物質(zhì)的分解（通常是化學(xué)的。DirtyHoldTime：Thetimefromtheendofproductmanufacturinguntilthebeginningofthecleaningprocess(alsocalled“soiledholdtime”).生產(chǎn)后保持時(shí)間：生產(chǎn)結(jié)束至清潔過(guò)程開(kāi)始的時(shí)間（DryEquipment：Novisiblewaterintheequipmentorlinewhenviewedunderappropriatelightingconditions.干燥的設(shè)備：在適當(dāng)照明條件下觀察設(shè)備或生產(chǎn)線(xiàn)無(wú)可見(jiàn)水分。EquipmentTrain：Thesequenceofequipmentthroughwhichaproductisproducedorprocessed.設(shè)備組：按照產(chǎn)品生產(chǎn)或加工流程排列的一組設(shè)備。FreeDrainedEquipment：Novisiblewaterpoolintheequipmentorlinewhenviewedunderappropriatelightingconditions(butmaycontainwaterdroplets).自排水設(shè)備：在適當(dāng)?shù)恼彰鳁l件下觀察設(shè)備或生產(chǎn)線(xiàn)無(wú)可見(jiàn)積水（但可能含有水滴。GroupingStrategy：Astrategyforestablishingsimilarcleaningprocesses,usuallybasedonsimilarproductsorsimilarequipment,andtovalidatethecleaningprocessbasedprimarilyonvalidationdataforarepresentativeofthegroup.分組策略：是指根據(jù)同類(lèi)產(chǎn)品或類(lèi)似設(shè)備建立類(lèi)似的清潔工藝的策略，主要根據(jù)代表性的產(chǎn)品/設(shè)備的驗(yàn)證數(shù)據(jù)來(lái)驗(yàn)證該清潔工藝。HighlyHazardousDrugActive：Adrugactivethatcancauseseriousadverseeffectsattypicaldoses.Thoseadverseeffectsaregenerallynotrelatedtothemaintherapeuticactivityofthedrug,andincludeseffectssuchascarcinogenicity,mutagenicity,genotoxicity,reproductivehazards,allergenicity,andcytotoxicity.高度危險(xiǎn)的藥物活性成分：指在常用劑量下可導(dǎo)致嚴(yán)重副作用的藥物活性成分。這些副作用通常與藥物治療的主要功能是不相關(guān)的，包括致癌性，致突變性，基因毒性，生殖危害，致敏性和細(xì)胞毒性。InvestigationalMedicinalpharmaceuticalformofanactivesubstanceorplacebobeingtestedorusedasareferenceinaclinicaltrial.臨床用藥品：活性物質(zhì)或安慰劑的藥物制劑，用于臨床試驗(yàn)的測(cè)試或?qū)φ?。LD50：Thedoseofamaterialwhichresultsin50%mortalityinananimaltest半數(shù)致死量：動(dòng)物實(shí)驗(yàn)中導(dǎo)致50%死亡的劑量。Limit：Avalueforaresidueabovewhichacleaningprocesswouldnotbeacceptable限度：指一殘留物水平，超過(guò)該數(shù)值，則該清潔工藝不符合要求。Marker：Componentofaproductoracleaningagentusedasananalytetoquantitatethetotalamountofproductorcleaningagentpresent.標(biāo)記物：一個(gè)產(chǎn)品或清潔劑的成分，作為分析物對(duì)產(chǎn)品或清潔劑總量進(jìn)行定量。Mocksoilwhichisusedinplaceofthemanufacturedproductduringacleaningvalidationprotocol(alsocalleda“surrogate”soil).模擬污物：清潔驗(yàn)證中用于替代所生產(chǎn)產(chǎn)品的污物（也叫“污物替代物MockSoiling：Aprocessofsoilingtheequipmentforacleaningvalidationprotocolinwhichsoilisappliedtotheequipmentsurfacestosimulatetheconditionofthesoilonthosesurfacesfollowingtypicalproductmanufacturing.模擬臟污：清潔驗(yàn)證方案中弄臟設(shè)備的過(guò)程，即將污物涂布至設(shè)備表面以模擬常規(guī)產(chǎn)品生產(chǎn)后設(shè)備表面上臟污狀況。NormalDose：Thetherapeuticdoseofaproductasgivenontheapprovedproductlabeling.正常劑量：指經(jīng)批準(zhǔn)在產(chǎn)品標(biāo)簽上列出的產(chǎn)品治療劑量。ProductChangeover：Proceduralstepstakenforswitchingfromthemanufacturingofoneproducttoanotherproduct.產(chǎn)品切換：從制造一種產(chǎn)品切換到另一種產(chǎn)品所采取的程序。RecoveryStudy：Alaboratorystudycombiningthesamplingmethodandanalyticalmethodtodeterminethequantitativerecoveryofaspecificresidueforadefinedsurface.回收率研究：結(jié)合取樣方法和分析方法確定特定表面上殘留物定量回收率的實(shí)驗(yàn)室研究。Residue：Chemicalormicrobiologicalmaterialremainingonequipmentsurfacesafteracleaningprocess.殘留物：清潔后殘留在設(shè)備表面的化學(xué)物或微生物。Soil：Thechemicalormicrobiologicalmaterialsleftonprocessequipmentaftercompletionofprocessmanufacturing,butbeforeinitiationofthecleaningprocess.污物：生產(chǎn)結(jié)束之后清潔開(kāi)始之前遺留在工藝設(shè)備上的化學(xué)或微生物物質(zhì)。Worst-CaseProcessCondition：Aconditionorsetofconditionsencompassingupperand/orlowerprocessinglimitsandcircumstances,withinstandardoperatingprocedures,whichposethegreatestchanceofproductorprocessfailurewhencomparedtoidealconditions(suchconditionsdonotnecessarilyinduceproductorprocessfailure).最差工藝條件：指在標(biāo)準(zhǔn)的操作程序中包含工藝限度和工藝條件上下限的一個(gè)或一組工藝條件。與理想條件比較產(chǎn)品或工藝會(huì)產(chǎn)生最大的失敗機(jī)會(huì)（這些條件不一定會(huì)引起產(chǎn)品或過(guò)程失效。CaseSoil：Asoilthatisthemostdifficulttocleanfromproductionequipmentbasedonknowledgegeneratedfromlaboratorystudies,scientificproperties,and/orproductionexperience.最差污物：指基于實(shí)驗(yàn)室研究、科學(xué)性質(zhì)和/或生產(chǎn)經(jīng)驗(yàn)等知識(shí)確定的最難從生產(chǎn)設(shè)備上清潔的污物。DefinitionofAcronyms首字母縮略詞AA:AtomicAbsorptionAA:原子吸收ADE:AcceptableDailyExposureADE:可接受的日暴露量ADI:AcceptableDailyIntakeADI:可接受的每日攝入量API:ActivePharmaceuticalIngredientAPI:藥物活性成分CAPA:CorrectiveandPreventiveActionsCAPA:糾正與預(yù)防措施CBER:CentersForBiologicalEvaluationandResearchCBER:生物評(píng)價(jià)與研究中心CDER:CentersforDrugEvaluationandResearchCDER:藥物評(píng)價(jià)與研究中心CFU:ColonyFormingUnitCFU:菌落形成單位CGMPs:CurrentGoodManufacturingPracticesCGMPs:現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范CIP:Clean-In-PlaceCIP:在線(xiàn)清潔COP:CleanOut-of-PlaceCOP:離線(xiàn)清潔CPP:CriticalProcessParametersCPP:關(guān)鍵工藝參數(shù)CQA:CriticalQualityAttributesCQA:關(guān)鍵質(zhì)量屬性CZE:CapillaryZoneElectrophoresisCZE:毛細(xì)管區(qū)帶電泳法

DOE:DesignofExperimentsDOE:實(shí)驗(yàn)設(shè)計(jì)ELISA:EnzymeLinkedImmunosorbantAssayELISA:酶聯(lián)免疫吸附