中英文-PDA TR03 干热灭菌验证

8IGLRMGEP�6ITSVX�2S�����6IZMWIH�����:EPMHEXMSR�SJ�(V]�,IEX�4VSGIWWIW�9WIH�JSV�(IT]VSKIREXMSR�ERH�7XIVMPM^EXMSR�8IGLRMGEP�6ITSVX�2S�����6IZMWIH�����:EPMHEXMSR�SJ�(V]�,IEX�4VSGIWWIW�9WIH�JSV�(IT]VSKIREXMSR�ERH�7XIVMPM^EXMSR�11.0Introduction简介ThistechnicalreportisanupdateofPDA'sTechnicalReportNo.3,ValidationofDryHeatProcessesusedforSterilizationandDepyrogenationwhichwasissuedin1981.Thetechnicalreportfocusesonthemicrobiologyandengineeringqualificationofdry-heatsterilizationanddepyrogenationprocessesandthegeneralapproachtosterilizationanddepyrogenationscienceinbatchandcontinuoussterilizers(ovensandtunnels).Thistechnicalreportisbasedonstandarddepyrogenationandsterilizationscience.这份技术报告是1981年发布的PDA第3号技术报告“用于灭菌和除热原的干热灭菌工艺验证”的更新。这份技术报告着重于干热灭菌和除热原工艺的微生物和设计确认，以及批次生产和连续性灭菌器（烘箱和隧道）中灭菌和除热原的通用方法。这份报告的依据是除热原和灭菌科学。TheprimaryobjectiveoftheTechnicalReportTeamwastodevelopascientifictechnicalreportondry-heatdepyrogenationandsterilizationprocessesthatprovidesrecommendationsforusebyindustryandregulators.Referencestoappropriateandcurrentscientificpublications,internationalregulatorydocuments,journalarticles,technicalpapersandbooksareusedwheremoredetailandsupportivedatacanbefound.技术报告团队的主要目的是开发有关干热除热原和灭菌工艺的科学技术报告，能够对用于工业生产和法规提供建议。采用了适宜并是当前的科学出版物、国际法规文件、期刊论文、技术报告以及书籍这些参考资料，其中有更详细和更具支持性的数据。TheTechnicalReportTeamiscomposedofdiverseinternationalteamofprofessionalstoensurethemethods,terminologyandpracticesofdry-heatdepyrogenationandsterilizationprocessesreflectsoundscienceandcanbeusedglobally.Thistechnicalreportwasdisseminatedindraftforpublicreviewandcommentpriortopublicationtoensureitssuitabilityasarecommendationofbestpracticestoindustry.技术报告团队由不同的国际团队专家组成以保证干热除热原和灭菌工艺的方法，术语以及实践能够反映全面的科学性并能够全球通用。这份技术报告在正式发表前以公众评论的形式传播，以保证其作为工业中最佳实践建议的合理性。1.1PurposeandScope目的和范围Thistechnicalreportprovidesinformationtothemanufacturersofpharmaceuticalproductsforvalidatingdry-heatdepyrogenationandsterilizationprocesses.Theconceptsandmethodspresentedwithinthistechnicalreportarenotintendedtobearegulatorystandard,butratheraspointstobeconsideredduringthevalidationofdry-heatprocesses.Othertechnicallyequivalentmethodsmayexistandmaybeusediftheycanbesupportedbysoundscientificmethods.这份技术报告提供了关于制药生产企业进行干热除热原和灭菌工艺验证的相关信息。该技术报告中提到的概念和方法不是一项法规标准，但是可作为干热工艺验证中的指导。其他等效的技2术方法也可能存在并被应用，如果这些其他方法有合理的科学方法做支持。Thistechnicalreportisintendedtogiveinformationaboutcurrentindustrypracticesandapproachestovalidatingdry-heatdepyrogenationandsterilizationprocesses.Inaddition,sectionswillcovervariousaspectsofdry-heatsterilizationusingbiologicalindicators.这份技术报告的目的是为目前工业实践以及干热除热原和灭菌工艺验证方法提供信息支持。此外，报告的一些章节覆盖了干热灭菌使用的生物指示剂的各方面。Thistechnicalreportisorganizedinachronologicalfashion,startingwithadiscussionofthegeneralconceptsofdepyrogenationandsterilizationsciencewhicharethefoundationuponwhichtobuildarobustprocess.Thisincludesuseofbiologicalindicatorsandendotoxinindicators.Alsoincludedarepointstoconsiderinequipmentdesign,equipmentverification,processdevelopmentandperformancequalificationfornewsystemsandthedevelopmentandvalidationofprocessesforexistingsystems.该技术报告是以时间顺序排列，以除热原和灭菌科学的通用概念开始，而这是建立稳固工艺的基础。其中包括了生物指示剂和内毒素指示剂的使用。也包括了新系统的设备设计、设备确证、工艺开发以及性能确认，还包括现有系统中工艺设计和验证中所需考虑的问题。Inthediscussionofprocessdevelopment,particularattentionhasbeengiventotheloadtype,loadingpatterns,andtemperatureprofilesfordepyrogenationandsterilizationinbothovensandtunnels.Thesectionsarefollowedbyabriefdiscussionofitemsforconsiderationduringroutineprocessingandongoingmaintenanceofthevalidatedprocess.工艺开发的讨论中，对于在烘箱和隧道中进行除热原和灭菌的负载种类、负载模式以及温度曲线都给予特殊的关注。在已验证工艺的日常操作和持续维护中所需考虑的内容在这一部分也做了简要讨论。Thebackgroundsectionsondepyrogenation/sterilizationscienceandendotoxin/biologicalindicatorsarenotcomprehensive—butprovideinformationspecifictodry-heatprocesses.Informationwithinthetechnicalreportisapplicabletobothforcedhotairdry-heatbatchprocesses(chambers)andtocontinuousprocesses(tunnels).Informationwithinthistechnicalreportdoesnotapplytodry-heatprocessesusedforthesterilizationofoilbasesandoilbasedproducts,fixedprocessingstreamsortothoseprocessesusinginfraredandmicrowaveheatingmedia.关于除热原/灭菌科学和内毒素/生物指示剂的背景部分并不全面——但是所提供的信息是针对干热工艺的。技术报告中的信息既适用于强制热空气干热批生产工艺（腔体），也适用于连续性工艺（隧道）。本技术报告中的信息不适用于油性基质及油性基质产品，固定工艺流程或者那些使用红外及微波加热介质的工艺中灭菌所用的干热工艺。CurrentFDA,ICH,andotherregulatorydefinitionsareusedexceptwhenmoreclarityisaddedbytheTechnicalReportTeam.Regulatoryguidelinesofferotherdefinitionsthatmaybeconsidered.Variationsintheuseofsometermsmaydifferfromcompanytocompanyand3somemaybesubjecttochangeinthefuture.However,thetermsusedinavalidationprogrammustbeclearlydefinedandwellunderstoodwithinthecompanyandclearlydefinedininternalStandardOperatingProcedures(SOPs),standards,andinregulatoryfilings.Forthepurposesofthistechnicalreport,thefollowingdefinitionsareused.使用的是当前FDA、ICH以及其他管理当局的名词定义，但技术报告团队添加上更清晰的内容这种情况除外。可以考虑法规指南提供的其他定义。一些术语在各公司之间的使用可能是不同的，而一些术语在未来可能会有变化。但是，验证程序中使用的术语必须清晰定义并且能够在公司内被清楚理解，在内部标准操作规程（SOP）、标准及管理文件中也应清楚定义。本技术报告出于这样的目的，使用如下定义。42.0GlossaryofTerms术语表BacterialEndotoxin细菌内毒素EndotoxinsarefeverproducingsubstancescommonlyfoundinthecellwallofcertainGramnegativebacteria.内毒素是存在于革兰氏阴性菌细胞壁中的致热物质。BacterialEndotoxinTest(BET)细菌内毒素试验（BET）AssayformeasuringactiveendotoxinbycombiningaliquidtestsamplewithLimulusamebocytelysate(LAL)reagentandmeasuringtheresultingproportionalreactionviavisual,turbidimetric,chromogenic,orothervalidatedmeansofdetection.一种测量活性内毒素的测定方法，将液态供试样品与鲎试剂（LAL）相混合，采用目视检查、浊度法、色谱法或者其他验证过的检测方法测定产生的成比例反应。BatchOven批处理式烘箱Aconvectionovenwithachamberorchamberswhereitemsaredry-heatsterilizedordepyrogenatedasasingleloadinadiscontinuousprocess.一个带有腔体的对流恒温烘箱或者腔体本身能够进行干热灭菌或者除热原，在不连续性工艺中可作为一个独立载体。Theoventypicallyusesoneormorefilterstoremoveairparticles.这种烘箱一般使用一个或多个过滤器来去除空气粒子。BiologicalIndicatorChallengeSystem(Bl)生物指示剂挑战系统（BI）Atestsystemcontainingviablemicroorganismsofapureandspecifiedstrainprovidingadefinedresistancetoaspecifiedsterilizationprocess(1).一种检测系统，包括纯的并且是特定菌株的生长微生物，对特定灭菌工艺具有特定的耐受性（1）。[Synonym:BIchallengesystem,microbialchallengesystem,andmicrobioilogicalchallengesystem.]【同义词：BI挑战系统，微生物挑战系统，和微生物学挑战系统。】BiologicalQualification生物确认Acomponentofperformancequalificationthatdemonstrates,byuseofbiologicalindicators,thattherequiredlethalityisachievedconsistentlythroughouttheload.性能确认的一个组成部分，用以证明，通过生物指示剂的使用，能够在负载的过程中持续达到所要求的致死率。Commissioning调试Awellplanned,documentedandmanagedengineeringapproachtothestart-upandtransferoffacilities,systemsandequipmenttotheend-userthatresultsinasafeandfunctionalenvironmentthatmeetsestablisheddesignanduserrequirementspecifications.CommissioningprecedesQualificationandincludesthreephases:5设施、系统以及设备开始并转移到终端使用者的一种有充分性、有文件并且是基于工程管理的方法，这样可获得安全的并具备相应功能的环境，满足已确定的设计要求和用户需求标准。试运行应先于确认，包括三个阶段：1.Inspection,testing,andregulation检查，测试以及调整2.Adjustmentandsettingofwork调试和工作设置3.Functionaltesting功能测试ContinuousConvectionTunnel连续式对流隧道AconvectionovenwithaconveyorbeltthattransportsarticlesthroughseveraltemperaturezonesthataresuppliedwithheatedforcedHEPAfilteredair.Thepre-heat/loadingzonewarmsarticlespriortotheheatzone,theheatzoneheatsarticlestosterilizationordepyrogenationtemperatureandthecoolzonecoolsarticlespriortoconveyanceoutoftheunit.带有传送带的对流烘箱，可传送物品通过几个温度区，这些温度区均供应热强制HEPA滤过空气。在加热区域前，预热/装载区对物品预热，加热段对物品加热达到灭菌或去热原的温度，在运输出去之前的冷却段对物品进行冷却。[Synonym:TunnelSterilizer]【同义词：隧道灭菌器】Convection对流Thetransferofheatbythecirculationormovementoftheheatedliquidorgas.通过加热液体或气体的循环或者移动传递热量。Depyrogenation除热原Thedestructionand/orremovalofbacterialendotoxins.Adepyrogenationprocessshoulddemonstrateatleast99.9%ora3-logendotoxinreduction.破坏和/或移除细菌内毒素。除热原工艺应该显示内毒素下降至少99.9%或者3个log值。D-ValueD值Thetimeinminutesrequiredforaone-logarithm,or90%,reductionofthepopulationofmicroorganismsusedasabiologicalindicatorunderspecifiedlethalconditions.Fordry-heatsterilization,theD-valueshouldalwaysbespecifiedwithareferencetemperature,DT.Forexample,abiologicalindicator(BI)challengesystemwithaD160℃=1.9minutes,requires1.9minutesat160℃toreducethepopulationbyonelogarithm(2).在指定致死条件下，用作生物指示剂的微生物的数量下降一个对数值或90%的所需时间，以分钟表示。对于干热灭菌，D值应该以参考温度DT来规定。例如，某一生物指示剂（BI）挑战系统，其D160℃=1.9分钟，即要求在160℃时在1.9分钟之内能够减少一个对数值的微生物数量（2）。6DwellTime保压时间Theperiodthatitemsaresubjectedtoagivenprocessingcondition.物品处于给定工艺条件的时间。[Synonym:ResidenceTime]【同义词：停留时间】EndotoxinIndicator(El)forDepyrogenation用于除热原的内毒素指示剂（El）Anarticlechallengedwithavialofendotoxin(oracarrierspikedwithendotoxin)designedforuseindepyrogenationstudies.Theendotoxin(apurifiedlipopolysaccaride)isvalidatedforuseinoronanendotoxinindicator.Thecarrierismadefromamaterialappropriatefortheintendeddepyrogenationprocessestowhichitwillbesubjected.Theendotoxinonacarrierisaddedataconcentrationsufficienttoallowrecoveryofaminimumof1000USPendotoxinunits/carrier.Theendotoxinindicatorwouldallowforaccurateindicationofatleasta3-logreductioninUSPendotoxinunitsduringdepyrogenationprocesschallenges(3,4).除热原研究中使用的挑战试验物品同时带有一小瓶内毒素（或者加样有内毒素的载体）。用在内毒素指示剂中的内毒素（一种纯化的脂多糖）是经过验证的。载体是由适用于预期除热原工艺的物料制成。在载体中加入一定浓度的内毒素，该浓度对于保证最低1000USP内毒素单位/载体的回收率是足够用的。除热原工艺挑战中，内毒素指示剂要求按照美国药典内毒素单位，至少减少3个对数值（3,4）。ExposurePhase暴露阶段Thephaseoftheprocessinwhichtheappropriateparametersaremaintainedwithindefinedrangesforthetime(exposuretimeordwellperiod)andtemperaturedeterminedtobenecessarytoachievethedesiredlethality.在定义的时间（暴露时间或者保压阶段）和温度范围内，该工艺阶段中要求保持适当的参数，对达到预期的的致死率是必要的。F-Value(LethalityFactor)F值（致死因子）Ameasurementofprocesseffectiveness.TrefzFisthecalculatedequivalentlethality(usingaspecifiedz-value)forasterilizationprocess,intermsofminutesatareferencetemperature(Tref),deliveredbyasterilizationprocesstoanitem.工艺效力的测量。TrefzF是某一灭菌工艺经计算而得的等效致死率（采用指点定的Z值），在在参考温度下（Tref）的分钟表示，通过灭菌工艺传递至物品。FHAtermusedwhenthespecificreferenceconditionsofTref=160°Candz=20°Careusedtocalculatetheequivalentlethality.Forexample,whenthez-valueoftheBIis20°CaprocesswithanF(T=160°C,z=20°C)orFHequalto8minutesisequivalent(intermsofdeliveredlethality)toasquarewaveprocessof8minutesat160°C.Asquarewaveprocessthatprovidedan7exposureof45.2minutesat145°CwouldalsoyieldanFHof8minutes.当采用指定参考条件Tref=160°C和z=20°C时，用于计算计算等效致死率采用的一个术语。例如，BI的z值是20℃，F(T=160℃，z=20℃)或者FH等于8分钟的工艺（以传递致死率表示），相当于在160℃条件下8分钟的方波工艺。在145℃条件下可提供45.2分钟暴露的方波工艺也能够得到8分钟的FH。F-ValueforDepyrogenation除热原的F值ThetermF-valuemayalsobeusedindryheatdepyrogenationprocessestocalculatethetimeinminutesequivalenttoalethalityorendotoxindestructioneffectdeliveredbydryheatat250°C.TheF-valuereferencetemperatureissetat250°Candthez-valueminimumissetat46.4°C(5).F值的概念也用于干热除热原工艺来计算在250℃条件下干热产生的致死率或是内毒素破坏效果的时间，以分钟表示。F值参考温度被设置为250摄氏度，Z值最小设置为46.4℃（5）。Heat热量Energythatistransferredasaresultofatemperaturedifferencebetweenanobjectanditssurroundings.作为物品和环境之间温度有差异的结果而发生传递的能量。HeatPenetration热穿透Heatpenetrationtestingisatemperaturemeasurementthatisusedtoevaluatetheamountofenergythathasbeentransferredtothematerialswithintheload.Formeasurementsofheatpenetration,theprobesshouldbeplacedintheloadwiththetipsofthesensorsincontactwiththeitemsbeingevaluated.热穿透试验是一种温度测试，用于评估已传给装载内物料能量的量。对于热穿透测试，探头应放置在装载物内，让传感器的尖端与待评价的物品相接触。Heat-upPhase升温阶段Thephaseofaprocessthatoccurspriortotheexposurephase.Processparametersaredevelopedforthisphaseinordertomeetapplicableuserrequirementsforloadconditioning(e.g.,pre-heating).工艺的这个阶段出现在暴露阶段之前。该阶段工艺参数的开发是为了满足装载条件下适宜的用户需求（比如，预热）。Lipopolysaccharide脂多糖AcomponentofthecellwallofGramnegativebacteria.革兰氏阴性菌细胞壁的一种组成成分。LoadZone装载区Areawithininthechamberwherematerialstobesterilizedordepyrogenatedmaybeplaced.腔体内的区域，在该区域内进行物品的灭菌或者除热原。MaximumLoad最大装载量8Themaximumquantityormassofitemspermittedinadepyrogenationorsterilizationload.除热原或者灭菌装载方式中物品的数量或质量的最大允许量。MinimumLoad最小装载量Theminimumquantityormassofitemspermittedinadepyrogenationorsterilizationload.除热原或者灭菌装载方式中物品的数量或质量的最小允许量。OperatingParameters运行参数Values(e.g.,time,temperature,air-flow)thatarecontrolledand/ormeasuredthatcollectivelydefineeachphaseofaprocess(e.g.,heat-up,exposure,cool-down).用来定义每一个工艺阶段（如加热、灭菌、冷却）且需要加以收集的控制和测试的参数（如时间、温度、气流）。CriticalParameters关键参数Valuesthatarecontrolledand/ormeasuredandarelinkedtosafetyandefficacyofaproductortheprocess.Failuretomeetacriticalparametershouldresultinrejectionoftheload.需要控制和/或测量且与产品的安全和功效相关的参数。关键参数不合格时，装载物不得放行。KeyParameters重要参数Valuesthatarecontrolledand/ormeasuredandareusedtoassuretheongoing"stateofcontrol"andconsistencyofruns.Failuretomeetakeyprocessparametershouldresultinaninvestigationwithadocumentedrationaleforthedispositionoftheload.需控制和/或测试以保证处于“受控状态”并且正常运行。重要工艺参数不合格时，需进行调查，并文件记录装载物处理的原因。OverkillDesignApproach过度杀灭设计方法Adesignapproachwhereminimalinformationisrequiredabouttheproductbioburden.AworstcasebioburdenassumptionisusedtodeterminethedeliveredlethalityneededtoachieveaProb-abilityofaNon-SterileUnit(PNSU)of10~6onorintheitemsbeingsterilized.Fordepyrogenation,theoverkilldesignapproachisa3-logreductionofanendotoxinindicatoramount.是一种需要最小量产品生物负荷信息的设计方法。最差生物负荷情况假设用于确定致死率需要达到在待灭菌的物品上面或里面的10~6菌可能含有1个非无菌单位（PNSU）。对于除热原，过度杀灭设计方法要将热原指示剂量降低3个对数单位。ParametricRelease参数放行Asterilityreleasesystembaseduponeffectivecontrol,monitoring,documentation,andbatchrecordsreviewofavalidatedsterilizationprocessinlieuofreleaseproceduresbasedonendproductsterilitytesting.一种基于对已验证无菌工艺进行有效控制、监控、文件化管理和批记录审核的无菌放行系统，而非基于成品无菌检验的放行程序。9PenetrationProbe热穿透探针Athermocoupleplacedincontactwiththeloaditemtomeasurethetemperatureoftheloaditem.放置在装载物品旁与其相接触的热电偶，测量装载物品的温度。PerformanceQualification(PQ)性能确认（PQ）Documentedverificationthattheequipmentandancillarysystems,asconnectedtogether,canperformeffectivelyandreproduciblybasedontheapprovedprocessmethodandspecifications(6).证明一个已连接好的设备及辅助系统能根据批准的工艺及技术要求有效并重现性运行且有文件和记录的相关活动（6）。PhysicalQualification物理确认Acomponentofperformancequalificationthatdemonstratesthatpre-determinedphysicalrequirementsincludingtemperaturedistributionandheatpenetrationareachievedconsistentlythroughouttheload.是性能确认的一个组成部分，证明包括温度分布和热穿透在内的预设的物理要求能够在整个装载过程中始终如一达到要求。ProbabilityofaNonsterileUnit(PNSU)非无菌单位可能性（PNSU）Thenumberthatexpressestheprobabilityofoccurrenceofanon-sterileunitafterexposuretoasterilizationprocess.Withinthepharmaceuticalindustry,adesignend-pointbetterthanorequaltotheprobabilityofonenon-sterileunitinamillionunitsisexpected,i.e.,PNSU≤10-6.用于表示在暴露于灭菌工艺之后非无菌单位出现的概率的数字。在制药工业中，期望设计的终点要达到好于或者等于一百万中出现一个非无菌单位的概率。即PNSU≤10-6。Product-specificDesignApproach产品特异性设计方法Asterilizationdesignapproachthatisbasedonthecharacteristicsofthebioburden(onorintheload)andtheheatsensitivityoftheproductthatdeliversthelethalityneededtoachieveaPNSU≤10~6onorintheitemstobesterilized.是一种基于生物负荷（装载上或内）的特性以及产品的热敏感度的无菌设计方法，传送的致死率需达到灭菌后物品上或物品内的PNSU≤10-6。ProcessQualification工艺确认Documentedverificationthatasystemiscapableofconsistentlyperformingorcontrollingtheactivitiesoftheprocessesitisrequiredtoperformorcontrol,accordingtowrittenandpreapprovedspecifications,whileoperatinginitsspecifiedoperatingenvironment.有文件证据证实系统能够持续性执行或者控制工艺活动，根据书面的或者批准的标准执行和控制，其中操作在指定操作环境下进行。Pyrogen热原Anysubstancecapableofelicitingafebrile(orfever)responseuponinjectionorinfection(as10inendotoxinreleasedinvivobyGram-negativebacteria(7).注射或者感染时任何能够诱发发热（发烧）反应的物质（比如革兰氏阴性菌内源性释放的内毒素）（7）。Requalification再确认Periodicconfirmationtodemonstratethatequipmentperformancehasnotchangedfromitsqualifiedstate.周期性确认，证明设备性能没有发生变化偏离其确认状态。Revalidation再验证Repeatingpartialorfullvalidationofaprocessafteraprocesschangeisimplemented.Re-validationischange-based,nottimebased.工艺发生变化后重复进行的部分或全部工艺的验证。再验证是以变化为基础而不是以时间为基础。ResistanceTemperatureDevice(RTD)电阻温度检测器（RTD）Sensorsthatexploitthepredictablechangeinelectricalresistanceofsomematerialswithchangingtemperature.利用某些材料的电阻可随温度变化出现可预测变化的传感器。RoutineOperationalProcess日常操作程序Parametersthatarespecifiedforongoingoperations.日常操作指定的参数。Theoperationalprocessistypicallycontrolledtoproduceadditionallethalityoverthequalifiedminimumparameters(i.e.,timeandtemperature)inordertoprovideincreasedsterilityassurance.操作过程通常是受控的，以产生超过已确认的最小参数（即时间和温度）的额外致死率，目的是提供更高程度的无菌保证。SterilizationProcess灭菌工艺Aprocessusedtorenderaproductfreeofviableorganismswithaspecifiedprobability.用于使产品中不存在规定概率微生物的工艺。SterilityAssuranceLevel(SAL)无菌保证水平（SAL）Probabilityofasingleviablemicroorganismoccurringonorinanitemaftersterilization.灭菌后出现在物品中或物品上的单个可见微生物的概率。Note:ThetermSALtakesaquantitativevalue,generally10~6.Whenapplyingthisquantitativevaluetoassuranceofsterility,anSALof10~6hasalowervaluebutprovidesagreaterassuranceofsterilitythananSALof10~3(8).注意：SAL这个术语代表了定量值，通常是10-6。当使用这个定量值来保证无菌时，10-6这个SAL值是一个下限值，但是与10-3这个值相比具有更高的保障程度（8）。SterilizationCycle灭菌循环11Asequenceofdefinedoperatingparameters(e.g.,timeandtemperature)requiredtorenderanitemsterile.所需的一系列定义好的运行参数（比如，时间和温度）使物品达到无菌状态。SurvivorCurve存活曲线Graphicalrepresentationoftheinactivationofapopulationofmicroorganismswithincreasingexposuretoamicrobicidalagentunderstatedconditions(9).在指定条件下随着对暴露于杀菌剂时间的延长微生物数量逐渐减少的图示（9）。Thermocouple热电偶Adeviceformeasuringtemperatureinwhichapairofwiresofdifferentmetalsarejoinedandthefreeendsofthewiresareconnectedtoaninstrument(suchasavoltmeter)thatmeasurestheelectricalpotentialdifferencecreatedatthejunctionofthetwometals.一个用于测量温度的装置，该装置上连接有一对不同金属的电线并且电线的自由端连接在仪器上（比如电压计），测量两个金属连接产生的电位差。TemperatureDistribution温度分布Temperaturemeasurementoftheheatingmedium(e.g.,forcedhotair)acrossthechamberloadzone.腔体装载区域内热介质（比如强迫性热空气）的温度测量。ThermometricStudy测温研究Theutilizationofindependenttemperaturemonitoringdevicestodetermineatemperatureprofilewithintheloadzoneandanalysisofthecollecteddata.利用独立的温度监控装置测量负载区域温度曲线并分析收集的数据。Validation验证Adocumentedprogramthatprovidesahighlevelofscientificassurancethatamanufacturingprocesswillreliablyproduceacceptableproduct.Theproofofvalidationisobtainedthroughrationalexperimentaldesignandtheevaluationofdata,preferablybeginningfromtheprocessdevelopmentphaseandcontinuingthroughthecommercialproductionphase(6).一个能够提供高水平科学保证生产工艺能可靠地生产出可接受的产品的有文件和记录证明的程序。验证的证据应通过验证的合理设计并对数据资料进行评估获得，这些数据资料最好始于工艺的开发阶段，直至商业化生产（6）。Verification确证Asystematicapproachtoverifythatmanufacturingsystems,actingsinglyorincombination,arefitforintendeduse,havebeenproperlyinstalled,andareoperatingcorrectly.Thisisanumbrellatermthatencompassesalltypesofapproachestoassuringequipmentisfitforuse.Approachesincludequalification,commissioningandqualification,verification,systemvalidation,orother(10).一种系统方法来确证独立活动或者联合活动的生产系统是符合其预期使用目的的，已经进行适12当的安装并操作正确。这是一个涵盖性术语，包括了保证设备符合其用途要求的多种方法。方法包括确认、调试和确认、确证、系统验证或其他（10）。WaterforBacterialEndotoxinTest(BET)细菌内毒素检验用水（BET）SterileWaterforInjectionorotherwaterthatshowsnoreactionwiththespecificbacterialendotoxintestreagentwithwhichitistobeused,atthelimitofsensitivityofsuchreagent(11).无菌注射用水或者其他水，在这类试剂灵敏度的限值下与指定的细菌内毒素检测试剂不发生反应（11）。WorstCaseLoad最差装载条件Theloadconfigurationthatisdeterminedtobemostdifficulttosterilizeordepyrogenate.Thisisafunctionoftheprocesscontrolstrategyandloaditemcharacteristics(e.g.,mass,configuration).经测定认为是最难灭菌或者除热原的装载组成方式。这是工艺控制策略和装载物品特性的一个功能（比如，质量，结构）。-value-值ThenumberofdegreesoftemperaturechangetochangetheD-valuebyafactorof10.Thezvalueallowsintegrationofthelethaleffectsofheatasthetemperaturechangesduringtheheatingandcoolingphasesofthedry-heatprocess.D值发生10个因子变化时温度的变化值。z值允许热量的致死效果进行整合，因为在干热工艺的加热阶段和冷却阶段温度会发生变化。133.0TheScienceOfDryHeatDepyrogenationAndSterilization干热除热原和灭菌的科学Dryheatprocessescanprovidesterilizationorbothdepyrogenationandsterilization.Thepurposeoftheprocesswilldictatethevalidationapproach.Thefollowingsectionprovidesinformationandsciencebehinddepyrogenationandsterilizationmethodsusedfordry-heatprocesses.干热过程能够实现灭菌或者除菌除热原。该过程的目的将决定验证方法。以下部分提供了用于干热过程的热原去除和灭菌方法背后的信息和科学。3.1Depyrogenation除热原Thereareanumberofdepyrogenationmethodsusedtoinactivateorremovebacterialendotoxins(12,13).Dry-heatdepyrogenationistheprimarymethodusedfortheinactivationofbacterialendotoxinsbythermaldestruction.Dry-heatdepyrogenationovensortunnelshavebeenusedforthedepyrogenationofheat-resistantmaterialslikeglassware,metalequipment,instruments,containers,andheatstablechemicals(7,12-15).ThedevelopmentanduseoftheLimulusamebocytelysate(LAL)assayhasalsoprovidedameansofassessingtheperformanceofdry-heatendotoxininactivationonaquantitativebasis(11,16,17).用于消除或灭活细菌内毒素热原的方法有很多（12,13）。干热除热原是用于细菌内毒素灭活的主要方法，方式为通过热破坏。干热除热原烘箱或隧道已用于耐热材料如玻璃器具、金属设备、工具、容器和热稳定的化学物质的除热原（7,12-15）。鲎试剂测定法（LAL）的发展和使用还提供了在定量的基础上评估干热灭活内毒素的一种手段（11,16,17）。Theselectedtemperatureandexposuretimeshouldbeappropriatelyvalidatedtodemonstratethatthedry-heatdepyro