湿热灭菌的介绍参数放行

BaxterConfidential*ParametricReleaseofMoistHeatSterilizedProductsatBaxter百特湿热灭菌产品的参数放行MikeSadowskiDirector,SterileManufacturingSupport无菌生产技术支持总监RoundLake,IllinoisUSABaxterConfidential*Introduction介绍ThispresentationwillbelimitedtoparametricreleaseasitrelatestoBaxtermoistheatsterilizationprocesses本次演讲仅限于百特湿热灭菌生产产品的参数放行BaxterConfidential*ParametricRelease-GeneralDefinition参数放行--基本定义Sterilereleaseofproductbasedontheachievementofvalidatedprocessparameters产品无菌放行应基于所有经过验证的工艺参数符合要求Baxter’sposition:Parametricreleaseisthe“naturalend”toaproperlyvalidatedprocess百特观点：参数放行是生产过程经过验证的“自然结果”Notdependentonresultsofsterilitytest不依靠无菌检查的结果BaxterConfidential*Baxter’sUSImplementationHistory百特在美国实施参数放行的历史FirstparametricreleasesubmissionintheUnitedStatesin1981.Delayinapprovalduetoconflictwithintheagency.1981年第一次在美国申请参数放行，由于管理机构(FDA)内部意见不统一而被推迟审批ApprovalgrantedforLVPs&SVPsinJanuary,1985,priortoissuanceofformalguidancetotheindustry.1985.1获得FDA批准对大小容量输液实行参数放行。此时FDA尚无正式工业 指南 验证指南下载验证指南下载验证指南下载星度指南下载审查指南PDF TheInitialSubmissionServedastheModelforFutureRequirements百特的首次申请所递交的材料被FDA视为将来要求的模式FDACompliancePolicyGuide7132a.13issuedin1987.1987年，FDA颁布了参数放行政策指南7132a.13BaxterConfidential*AllmoistheatsterilizedUSproductsproducedattheNorthCove,NC,Jayuya,PRandCleveland,MSfacilitiesarereleasedparametrically.在NorthCove,NC,Jayuya,PRandCleveland,MSfacilities工厂生产的湿热灭菌的美国产品才用参数放行。AllnewproductsintheUnitedStates,fortheabovefacilities,aresubmittedforparametricrelease.以上工厂生产的所有美国新产品将递交申请参数放行。Baxter’sUSImplementationHistory百特在美国实施参数放行的历史BaxterConfidential*CurrentBaxterParametricReleaseLocations目前百特实施参数放行的地区Australia澳大利亚Brazil巴西Canada*加拿大Chile智利China**中国Columbia哥伦比亚Germany德国*Manf.Locations:USandCanada*生产地址：美国和加拿大**InCombinationw/SterilityTest**与无菌检验结合实施Ireland以色列Mexico墨西哥Spain西班牙Singapore新加坡UnitedKingdom英国(Thetford)UnitedStates美国BaxterConfidential*SterilityTestvs.ParametricRelease无菌检验vs.参数放行BaxterConfidential*LimitationsofSterilityTest无菌检查的局限性Aninadequateprocessmonitor不充分的生产过程监测10to20productunitsperbatch每批仅抽取10-20个样品SuccessfultestsforsterilitytellsuslittleabouttheSterilityAssuranceLevel(SAL)ofunitsinthebatch样品检测合格不能完全代表同批其它产品的无菌水平(SAL)BaxterConfidential*StatisticallyLimited统计学局限DetectionSensitivity(n=20samples)检验灵敏度MicroorganismConcentration微生物污染ProbabilityofOneSterilityTestPositive无菌检查阳性概率1.01.00.10.880.010.180.0010.0210-61.9X10-5LimitationsofSterilityTest无菌检查的局限性BaxterConfidential*SterilityTestingisPronetoInaccurateResults无菌检查易获得不精确的结果FalsePositiveRateisHigh假阳性率高Complexityoftestsample检测样品复杂Numberofmanipulationsrequired需要多次处理Number/experienceof“Testers”检验人员的经验/人员差异Environmentalfactors环境因素Unnecessaryproductrejection不必要的产品报废LimitationsofSterilityTest无菌检查的局限性BaxterConfidential*SterilityTestisCostlytoPerform执行无菌检查耗费成本Multipleproductsamplesfromeachload每个灭菌柜次取样Testenvironmentvalidationmaintenance测试环境验证及保养Speciallytrainedpersonnel特殊 培训 焊锡培训资料ppt免费下载焊接培训教程 ppt 下载特设培训下载班长管理培训下载培训时间表下载 操作人员LaborCost人工成本Mediaandequipmentpreparation准备培养基和设备Highproductinventoriesrequired产品库存量大14DaySterilityTest“Hold”14天无菌检验‘等待’期ProductCost产品成本LimitationsofSterilityTest无菌检查的局限性BaxterConfidential*MoistHeatSterilizationProcess湿热灭菌工艺的特点Non-toxic无毒LessExpensive经济UniversallyRecognized普遍认可BroadSpectrumLethality广谱杀菌能力（molds霉菌，yeasts酵母，bacteria细菌/spores孢子，viruses病毒）Oldest,Safest,MostDependableProcess最古老，最安全，最可靠的工艺EasilyControlledandValidated易于控制和验证PreferredbyMostRegulatoryBodies被多数法规机构推荐使用WhytheMoistHeatSterilizationProcess?为什么采用湿热灭菌工艺？BaxterConfidential*“Natural”CandidateforParametricRelease参数放行是“自然”结果MinimalKeyParameters至少关键灭菌参数Temperature:115–125oC温度：105–135oCExposureTime:12-120minutes暴露时间：5–200minutesPressure:-SaturatedSteamPressure@121oC=30PSIA/15PSIG压力：121oC的饱和蒸汽压=30PSIA/15PSIGWhytheMoistHeatSterilizationProcess?为什么采用湿热灭菌工艺？BaxterConfidential*ParametricReleaseRequirements–US参数放行要求–美国FDACompliancePolicyGuide7132a.13,issuedin1987FDA法规7132a.13,1987年出版USPharmacopoeia31美国药典31版AAMITIR13:PrinciplesofIndustrialMoistHeatSterilizationAAMI技术指引：工业湿热灭菌原理ISO11134:Sterilizationofhealthcareproducts–Requirementsforvalidationandroutinecontrol–IndustrialmoistheatsterilizationISO11134:医疗产品的灭菌–验证及日常控制要求-工业湿热灭菌PDATechnicalReportNo.30(1999)PDA技术 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 No30(1999)BaxterConfidential*FDACompliancePolicyGuide7132a.13FDA政策法规指南7132a.13ParametricRelease:参数放行定义Asterilityreleaseprocedurebaseduponeffectivecontrolofavalidatedsterilizationprocesscycleinlieuofreleasebaseduponend-productsterilitytesting.Allparameterswithintheproceduremustbemetbeforethelotisreleased.参数放行：为一种替代对最终产品作无菌检查的无菌放行系统。它基于对一个经过验证的灭菌生产过程进行有效的控制。一批产品放行前，系统中 规定 关于下班后关闭电源的规定党章中关于入党时间的规定公务员考核规定下载规定办法文件下载宁波关于闷顶的规定 的所有参数必须符合规定。BaxterConfidential*FDACPG7132a.13RequirementsFDACPG7132a.13要求CycleValidation灭菌循环验证Container/ClosureIntegrityValidated容器或封口完整性验证Bio-burdenTesting微生物负载检测ChemicalorBiologicalindicatorsineachindividualSterilizerTruck(carrierorpallet).每一灭菌车(货架或托盘)放化学或生物指示剂BiologicalIndicator(BI)Documentation文件化管理生物指示剂BaxterConfidential*USPharmacopoeia31美国药典31版USP<1222>:TerminallySterilizedPharmaceuticalProduct—ParametricReleaseUSP<1222>：最终灭菌药品–参数放行Modeofsterilizationwellunderstood灭菌过程被充分理解Criticalphysicalprocessingparametersdefined定义关键过程物理参数Lethalityofthecyclevalidatedmicrobiologically验证灭菌循环的微生物致死性10-6SALrequired要求10-6SAL（无菌保证）FDAapprovalrequired得到FDA批准BaxterConfidential*AAMITIR13Wherereliableprocessmeasurementandcontrolcanbedocumentedfortheentiremanufacturingprocess,andcorrelatedwithsterilityassurance,terminallysterilizeditemscanbeconsideredforreleaseinaccordancewithdeliveredprocessparameters当可靠的过程测量和控制可以用来记录整个生产过程及与其相关的无菌保证，那么最终灭菌产品可以按生产过程参数进行放行。CompliancewithANSI/AAMI/ISO11134initsentiretyallowsforparametricrelease符合ANSI/AAMI/ISO11134的要求，可以允许执行参数放行。AAMI(AssociationfortheAdvancementofMedicalInstrumentation)BaxterConfidential*ISO11134Title:Sterilizationofhealthcareproducts—Requirementsforvalidationandroutinecontrol—Industrialmoistheatsterilization标题：医疗产品的灭菌–验证及日常控制要求-工业湿热灭菌Note:ISO11134hasbeenreplacedbyISO17665(fullyeffectiveendof2009)注意：ISO11134将被ISO17665（2009年底生效）(formedicaldevices)Generalconsiderations,includingpersonneltrainingandpackaging总要求，包括人员培训和包装Equipment设备Processdevelopment工艺开发Processvalidation过程验证Routinesterilization常规灭菌BaxterConfidential*ISO111348.5Releaseofsterilizedproducts灭菌产品的放行Processparametersmonitoredduringroutinesterilizationshallbewithinthevalidatedlimits日常生产过程中监控的生产参数应该在验证限度内。Asystemtodifferentiatebetweenprocessedandunprocesseditemsshallbeused应该建立区分加工过产品及未加工过产品的系统。Onlyauthorizedpersonsshallreleaseproductsaftersterilization只有授权人才可以放行灭菌后产品。A.8.5Releaseofsterilizedproducts灭菌产品的放行“…finishedproducttestingorbiologicalindicatortestingmightberequiredbysomeregulatoryauthorities.”“…某些国家法规可能要求最终产品测试或微生物指示剂测试。”BaxterConfidential*PDATechnicalReportNo.30(1999)PDA技术报告No30(1999)Appliesonlytoproductswith10-6SAL仅适用于10-6无菌保证的产品CriticalParametersmustbemettoachieverelease关键参数满足要求后，才能进行放行Demonstratethatentireloadexposedtosterilizationprocess证明整个装载都经过灭菌过程Proceduresinplacetodocumentqualification,processing,andreleaserequirements.有程序记录验证、生产过程和放行要求Note:ThisdocumentiscurrentlyunderrevisioninfinalreviewandexpectedtobeissuedinQ3,2009.注意：该文件正在做最终复核，预计2009年第三季度发布。BaxterConfidential*BaxterCompliance百特执行要求ProductDesignControl产品设计控制SterilizationEquipment灭菌设备SterilizationProcessValidation灭菌工艺验证PhysicalLethality(CombinationStudies)物理性细菌致死性（联合实验）MicrobiologicalLethality微生物致死性Container/ClosureIntegrity容器或封口完整性Sterile/Non-sterileSegregation灭菌/非灭菌的隔离RiskAssessment/FailureModeandEffectsAnalysis(FMEA)风险分析/失败模式及效应分析(FMEA)BaxterConfidential*ProductDesignControl产品设计控制Formalproductdesignandvalidationprocedures正式产品设计和验证过程BillofMaterials产品物流清单Incominginspectionandsamplingofrawmaterialsandcomponents原料和组件的进厂取样检验Evaluationofchangeprocedures变更流程的评估BaxterConfidential*SterilizationEquipment灭菌设备Equipmentconfigurationcontrol设备配置控制HardwareandSoftware硬件和软件Robustrecirculatingwatersystem设计可靠的水循环系统以防非无菌水进入灭菌后的系统Redundantinstrumentation多种检测仪器Routinecalibration常规校验Routinemaintenance常规维护保养IQ/OQvalidation安装/运行验证BaxterConfidential*Validatedandcontrolledsoftwareprograms软件程序需经验证并受控Controlsystemmonitorsandensuresdeliveryofcriticalparametersandcomparesresultswithredundantinstrumentation控制系统监测并确保关键参数的实现，并与多种检测结果比较SterilizationEquipment灭菌设备BaxterConfidential*SterilizationProcessValidation灭菌过程验证Combinationpenetration/distributionstudiestovalidateminimumandmaximumproductrequirementsaremet联合热穿透及热分布研究，以验证最小和最大产品符合规定Fractionalvalidationtoensuresufficientlethalityinsolutionandclosuresystem用分段验证确保对溶液和密封的包装系统有足够的杀灭能力Routinerequalificationofprocess工艺常规再验证Closureintegrityvalidated密封完整性验证Specifiedloadingpatterns特定装载方式验证BaxterConfidential*SterilityAssuranceLevel无菌保证水平Mostmedicaldevicesanddrug/pharmaceuticalproductsrequirea10-6SAL大多数医疗器械和药品/医药产品需要10-6无菌保证Therecannotbemorethanonenon-sterileunitinevery1,000,000processed每一百万产品中不能存在多于一个非无菌产品Moststerilizationprocessesfarexceedthisprobability湿热灭菌过程可以远高于这个可能性。BaxterConfidential*BioburdenTesting生物负荷检测Conductedoneachbatchofpre-sterilized(nonsterile)drugproduct每批产品应在灭菌前检测微生物负载Quantityandresistanceofsporeformingorganismsfoundmustbemonitoredandcomparedtothatoftheorganismusedtovalidatethecycle对新发现的孢子进行耐热研究并与验证所用的微生物比较BaxterConfidential*In-ProcessBioburdenTestingResults生产过程生物负荷测试结果Performedforover20yearssinceParametricReleaseapproved自从参数放行被批准后，执行了20年TotalCountsshowlowlevelsoforganisms总菌数显示了低水平的微生物Rarelydetectspores几乎没有监测到孢子SporeresistancesignificantlylessthanBIusedtovalidatetheprocess孢子的热抗性远低于用于过程验证的生物指示剂（BI）Duetohistoryofdemonstratedcontrol,FDAhasapprovedParametricReleaseforBaxterwithoutholdingforbio-burdenresults根据历史数据证实过程受控制，FDA批准百特的参数放行且无需等待生物负荷结果。BaxterConfidential*BIDocumentation生物指示剂文件管理EachMoistHeatBILot(In-House)每批湿热用的BI批号Organism’sname微生物名称Source来源D-valueD值Sporeconcentration孢子浓度Expirationdate有效期Storageconditions贮存条件BaxterConfidential*Container/ClosureIntegrity包装容器及封口的完整性RobustDesign产品设计Validatedtodemonstratemicrobialbarriereffectivenessforin-processandpost-processovertheproduct’sshelflife验证产品在生产过程中及生产后有效期内均可防止被污染Validationshouldincludephysicalormicrobialingresstests验证应包括物理或微生物侵入实验“WorstCase”heathistoryprocessing历史“最差”加热过程Mustutilizerepresentativeunitsfromtypicalproduction必须使用正常生产的产品BaxterConfidential*Sterile/Non-sterileSegregation灭菌/未灭菌产品隔离PhysicalBarriers物理隔断Loadreconciliation–counttoensurethequantityofproductenteringthesterilizerequalsthequantityexitingsterilizationarea装载平衡–数量计算以确保进入灭菌器的产品数量等于到达已灭菌区域产品数量Sterilizerproducttruckdesignpreventslossofaunit-sidescreensortraydesign产品灭菌车设计防止产品丢失–侧窗或者板设计Chemicalindicatorsoneveryproducttruck–demonstrateexposuretoasterilizationcycle化学指示剂放置在每个灭菌车–证明产品曾经暴露于灭菌循环BaxterConfidential*ChemicalorBiologicalIndicators(BI’s)化学或生物指示剂（BI）Mustbeincludedineachtruck,trayorpalletofeachsterilizerload每个灭菌循环内每载车必须放置化学或生物指示剂Timeand/ortemperatureresponsecharacteristicsandstabilityoftheindicatoraredocumented记录指示剂对时间及温度的反应特性和稳定性Minimumdegradationvaluesorcolorchange(e.g.autoclavetape)requiredforeachsterilizationcycleareestablished建立每个灭菌循环的最小降解值Chemicalindicatorscannotbeusedtoevaluatecyclemicrobiologicallethality化学指示剂不能用于评估灭菌循环的杀灭能力BI’saretypicallynotusedforroutinereleaseofmoistheatsterilizedpharmaceuticalproducts生物指示剂通常不用在湿热灭菌产品的日常放行Chemicalindicatorsareavisualaidusedtodemonstratethatproducthasbeenexposedtoasterilizationprocess化学指示剂只是帮助目视管理证明产品曾经暴露于灭菌循环BaxterConfidential*RiskAssessment/FMEA风险评估/FMEAPerformedforeachsterilizationprocesstoensureriskofundetectedfailuresiseliminated针对每个灭菌过程进行评估，确保未发现的失败已被消除。Evaluatesprobabilityofafailure,riskassociatedwiththatfailure,andthedetectabilityofthatfailure.评估失败的可能性、相关风险及失败的可检测性。BaxterConfidential*UpcomingDocuments即将被批准的文件USFDAGuidanceforIndustrySubmissionofDocumentationinApplicationsforParametricReleaseofHumanandVeterinaryDrugProductsTerminallySterilizedbyMoistHeatProcesses美国FDA指引-工业申请文件，用于申请最终湿热灭菌的人用药和兽用药参数放行PDAhasprovidedindustrycommentsFDA已经批准工业注释CompliancePolicyGuidealsoexpectedtobeupdated符合性指导政策也需要被更新PDATR30(ParametricRelease)参数放行DraftroutedforcommentsbyFDA07/08.FDA在2007年08月起草征询意见BeingledbyMikeSadowskiofBaxterSterilityAssurance.百特无菌保证部门Mike领导BaxterConfidential*UpdateonChinaParametricReleaseExperience中国在参数放行上的经验BaxterConfidential*Summary:总结BaxterisaglobalsterilizationleaderthathasbeensuccessfullyusingParametricReleaseformoistheatsterilizedsolutionproductsforover20years.百特是全球灭菌工艺的领先者，已经在湿热灭菌的输液产品上成功实施了超过20年的参数放行。