YH-MOS-SP-11A辐照灭菌过程控制规范

湖南佑华医疗用品有限公司辐照火菌过程控制规范Irradiationsterilizationprocesscontrolspecification版权所有，注意保密YH-MOS-QP-111RevA第1页共12页版本号VersionNo修改日期ModifiedDate修改内容描述DescriptionaboutmodifiedcontentA2020316首次发布InitialReleased制定：审核：批准：签名签名签名发放部门Distributiondepartment研发中心、质量法规、生产运营、物料管理R&D,Qualityregulation,Operationdepartment. Materialmanagementdepartment.湖南佑华医疗用品有限公司辐照火菌过程控制规范Irradiationsterilizationprocesscontrolspecification版权所有，注意保密YH-MOS-QP-111RevA第2页共12页1.0目的Purpose对辐照灭菌进行控制，保证文件的适用性和有效性。ControlofIrradiationsterilizationtoensurethesuitabilityandeffectivenessofthedocumentation2.0范围Scope适用于本公司辐照灭菌产品控制。Suitableforthecontrolofourcompany'sIrradiationsterilizationproducts.3.0职责Responsibility3.1研发中心：负责提供产品材料所能够承受的灭菌方式，且满足设定的灭菌条件。R&D:Responsibleforprovidingthesterilizationmethodthattheproductmaterialscanwithstandandmeetthesetsterilizationconditions.3.2生产运营：负责准备灭菌的产品。Operationdepartment:Responsibleforpreparingproductsforsterilization3.3质量法规：负责灭菌供商的审核，灭菌验证；灭菌前、后产品指标的检测，审核灭菌公司提供灭菌报告。Qualityregulations:responsiblefortheauditofsterilizationsuppliers,sterilizationverification;testingofproductindicatorsbeforeandaftersterilization,andinspectionofsterilizationreportsprovidedbythecompany3.4物料管理部：负责外包装后，产品放行前（灭菌前、后）的隔离，灭菌货物的运输、与灭菌公司的灭菌协议签订和沟通。Materialmanagement:Afterbeingresponsiblefortheouterpackaging,theproductisreleasedbeforetherelease（beforeandaftersterilization）,thetransportationofthesterilizedgoods,andthesterilizationagreementwiththesterilizationcompany.4.0程序Process定义definition4.1.1灭菌批：在同一灭菌柜内，同一灭菌条件下，满足同灭菌要求的一定量的产品。Sterilizationbatch:acertainamountofproductsthatmeetthesterilizationrequirementsunderthesamesterilizationconditionsinthesamesterilizer4.1.2SAL=SterilityAssuraneeLevel 无菌保证水平，表示已灭菌物品的微生物存活的概率。Asepticassurancelevel,indicatingtheprobabilityofmicrobialsurvivalofsterilizeditems.4.1.3生物负载：一件产品和（或）无菌屏障系统上存活的微生物的总数。Bioburden:Thetotalnumberofmicroorganismsaliveonaproductand/orsterilebarriersystem灭菌供商选择及评价 Sterilizationsupplierselectionandevaluation4.2.1对供货商的质量管理和生产能力评估（查看供商的资质、现场审核等方式） 。Qualitymanagement andproduction capacityassessmentforsuppliers（checksupplierqualifications,on-siteaudits,etc.）4.2.2对灭菌厂商评估的项目：ProjectforevaluationofsterilizationmanufacturersA） 确认灭菌设备是经过安装验证和运行验证。ConfirmthatthesterilizationequipmentisverifiedbyinstallationandverifiedbyoperationB） 确认灭菌操作员是经过专业培训并持有上岗证。ConfirmthatthesterilizationoperatorisprofessionallytrainedandholdsacertificateofemploymentC） 确认质量体系相关文件的建立。ConfirmtheestablishmentofrelevantdocumentsofthequalitysystemD） 灭菌过程是经过确认，并能够提供符合要求的报告。ThesterilizationprocessshouldbeconfirmedandcanprovideareportthatmeetstherequirementsE） 当更换灭菌公司或者出现无菌不合格情况时，需要重新进行灭菌验证。Whenthesterilizationcompanyisreplacedorthesterilityisunqualified,thesterilizationverificationneedstoberepeated.。灭菌确认流程Sterilizationconfirmationprocess灭菌确认常规灭菌控制灭菌有效性保持灭菌确认Sterilizationconfirmation产品定义Productdefinition产品定义时，包括对包装的确定。同时应对产品包装或产品在包装中的装载模式加以规定。如果为一个产品族建立灭菌剂量，需要定义产品族。Productdefinitionincludesthedeterminationofpackaging.Atthesametime,theproductpackagingortheloadingmodeoftheproductinthepackaging shallbespecified.Ifasterilizationdoseisestablishedforaproductfamily,theproductfamilyneedstobedefined过程定义Processdefinition建立最大可接受剂量 Establishamaximumacceptabledose可根据包装材料以及产品原材料供应商的一些实验数据确定或进行灭菌实验，考察产品的最大可接受剂量。Determineorcarryoutsterilizationexperimentsbasedonsomeexperimentaldataofpackagingmaterialsandproductrawmaterialsupplierstoexaminethemaximumacceptabledoseoftheproduct建立灭菌剂量Establishsterilizationdose按照ISO11137-1建立灭菌剂量，应从两种方法中选一种建立灭菌剂量的方法:EstablishasterilizationdoseinaccordancewithISO11137-1.Oneoftwomethodsshouldbeusedtoestablishasterilizationdose.获得并利用生物负载数量和 /或辐射抗力的信息建立灭菌剂量；Obtainanduseinformationonbioburdenquantityand/orradiationresistancetoestablishsterilizationdoses。选择并证实15kGy或25kGy的灭菌剂量；在证实15kGy或25kGy时，通过剂量实验提供证据证明所选择的灭菌剂量能够满足规定的无菌要求。Selectandconfirm15kGyor25kGysterilizationdose;whenconfirming15kGyor25kGy,provideevidencethroughdoseexperimentstoprovethattheselectedsterilizationdosecanmeetthespecifiedsterilityrequirements以多批次VDmax25为例：(其他情况请参照ISO11137-2)VDmax25证实方法的程序-适用于多个生产批次。Takemulti-batchVDmax25asanexample:(PleaserefertoISO11137-2inothercases)ProcedureforVDmax25verificationmethod-applicabletomultipleproductionbatches注：本方法仅适用于产品平均生物负载 <1000bNote:Thismethodisonlyapplicabletoproductswithanaveragebiologicalloadof <1000步骤1：产品样本的获得Step1:Obtainproductsamples从三个独立生产批次的产品中，每批至少获取 10个单元产品。Getatleast10unitproductsfromeachofthreeindependentproductionbatches步骤2:确定平均生物负载Step2:Determinetheaveragebioburden按照ISO11737-1确定产品的平均生物负载；确定批平均生物负载（每生产批产品的生物负载的算术平均值）与总平均生物负载（所有产品的生物负载算术平均值） ；DeterminetheaveragebioburdenoftheproductinaccordancewithISO11737-1;determinetheaveragebioburdenofthebatch(arithmeticaverageofthebioburdenperproductionbatch)

andthetotalaveragebioburden(thearithmeticaverageofthebioburdenofallproducts)a)如果一个或多个批平均 >2(总平均生物负载)，取最高批平均。Ifoneormorebatchesaverage>2x(totalaveragebioburden),takethehighestbatchaverageb）如果每一批的批平均v2x（总平均生物负载），取总平均值。Ifthebatchaverageofeachbatchis<2（totalaveragebioburden）,takethetotalaverage当SIP=1.0，如果表1中没有要查的平均生物负载，使用表中生物负载值最近的且大于计算的生物负载值。WhenSIP=1.0,ifthereisnoaveragebioburdentobecheckedinTable1,themostrecentbioburdenvalueinthetableisgreaterthanthecalculatedbioburdenvalue.当SIPv1.0，用SIP平均生物负载除以SIP得到完整产品的生物负载。如果表 1中没有计算的平均生物负载，使用表中最近的且大于计算生物负载值的列表生物负载值查找 SIP=1.0VDmax25值和相关的减少因子。WhenSIP<1.0,dividetheaveragebioburdenofSIPbySIPtogetthebioburdenofthecompleteproduct.IfthereisnocalculatedaveragebioburdeninTable1,usethemostrecentlistofbioburdenvaluesgreaterthanthecalculatedbioburdenvalueinthetabletofindtheSIP=1.0VDmax25valueandtherelatedreductionfactor步骤3:确定VDmax25Step3:DetermineVDmax25根据产品平均生物负载结合表 1，按照SIPVDmax25=(SIP=1.0VDmax25)+(SIPDoseReductionFactorxlogSIP)公式,计算SIPVDmax25。CalculateSIPVDmax25accordingtotheaveragebioburdenoftheproductinconjunctionwithTable1,andaccordingtotheformulaSIPVDmax25=(SIP=1.0VDmax25)+(SIPDoseReductionFactorxlogSIP)步骤4:完成验证剂量实验Step4:Completetheverificationdoseexperiment以VDmax25辐照10个单元产品，要求辐照剂量合格，应满足如下条件：Irradiate10unitproductswithVDmax25,therequiredradiationdoseisqualified,andthefollowingconditionsshouldbemet实施到单元产品上的最高剂量 <VDnax25*(1.0+10%)；Thehighestdoseappliedtotheunitproduct<VDmax25Thehighestdoseappliedtotheunitproduct<VDmax25*(1.0+10%)2）实施到单元产品上的最高剂量与最低剂量的算术平均值〉 90%ofVDmax25Thearithmeticmeanofthehighestandlowestdosesappliedtotheunitproductis>90%ofVDmax25按照ISO11737-2完成10个单元产品的无菌检测。Completethesterilitytestof10unitsaccordingtoISO11737-2步骤5:结果判定Step5:Resultsjudgment如果10个单元产品的无菌检测的阳性份数不多于 1.0个，则证实25kGy作为灭菌剂量，即日常辐照加工的最低吸收剂量要求为 25.0kGy;Ifthenumberofpositivetestsforaseptictestingof10unitproductsisnotmorethan1.0,then25kGyisconfirmedasthesterilizationdose,thatis,theminimumabsorbeddoserequiredfordailyirradiationprocessingis25.0kGy如果10个单元产品的无菌检测的阳性份数为 2.0个，则执行剂量验证实验；Ifthenumberofpositivetestsforthesterilitytestof10unitproductsis2.0,thenperformadoseverificationexperiment如果10个单元产品的无菌检测的阳性份数多于 2.0个，则验证无效。Ifthenumberofpositivetestsforsterilitytestof10unitproductsismorethan2.0,theverificationisinvalid.表1对于平均生物负载W1000CFU时VDmax25和剂量减少因子的值25ValuesforVDmaxanddosereductionfactoratanaveragebioburden w1000CFUAverageBioburdenSIP=1.0VDmax25(kGy)SIPDoseReductionFactor(kGy)AverageBioburdenSIP=1.0VDmax25(kGy)SIPDoseReductionFactor(kGy)0.100.0n/aa508.83.250.150.9n/aa558.93.230.201.4n/aa608.93.210.251.8n/aa659.03.200.302.2n/aa709.13.190.352.5n/aa759.13.170.402.7n/aa809.23.150.452.9n/aa859.13.110.503.1n/aa909.13.080.603.4n/aa959.13.050.703.6n/aa1009.03.010.803.8n/aa1109.02.96湖南佑华医疗用品有限公司辐照火菌过程控制规范Irradiationsterilizationprocesscontrolspecification版权所有，注意保密YH-MOS-QP-111RevA第7页共12页AverageBioburdenSIP=1.0VDmax25(kGy)SIPDoseReductionFactor(kGy)AverageBioburdenSIP=1.0VDmax25(kGy)SIPDoseReductionFactor(kGy)0.904.0n/aa1209.02.911.04.24.171308.92.861.54.84.051408.92.832.05.23.971508.92.792.55.53.911608.82.763.05.73.861708.82.723.55.93.821808.82.694.06.13.791908.72.674.56.23.762008.72.645.06.33.732208.72.605.56.53.712408.62.566.06.63.692608.62.526.56.73.672808.62.497.06.73.653008.62.467.56.83.643258.52.438.06.93.623508.52.408.57.03.613758.52.379.07.03.594008.42.349.57.13.584258.42.32107.13.574508.42.30117.23.554758.42.28127.33.535008.42.26137.43.515258.32.24147.53.505508.32.22157.63.485758.32.21167.63.476008.32.19177.73.466508.32.16187.83.457008.22.14197.83.437508.22.12207.93.428008.22.09228.03.408508.22.07248.13.399008.12.05268.13.379508.12.04288.23.3610008.12.02308.33.34NOTEifVDmax25=0.0kGy,productitemsarenot358.43.31irradiated.aNotapplicable;408.63.29intherangeofaverage458.73.27uiuuuiueii 0u.a,iiieeniiie piuuuci 厂一i.u丿 isusedandhencetheSIPDoseReductionFactorisnotgiven.确认灭菌工艺（灭菌供方完成）Confirmsterilizationprocess（completedbysterilizationsupplier）1） 设备安装确认（IQ）；2） 设备运行确认（OQ）；3） 产品合格性确认（PQ）the该部分最主要的是确定剂量场分布，从而确定灭菌工艺。theThemainthinginthispartistodeterminethedistributionofthedosefieldandthussterilizationprocess.? 在辐照容器中，呈网络分布的剂量计的分布图；Distributiondiagramofdosimetersdistributedinanetworkinanirradiationcontainer?最大、最小剂量；Maximumandminimumdoses?最大、最小剂量的位置；Locationofmaximumandminimumdoses?使用的辐照装置；Irradiationdevice?产品的装箱模式；Productpackingmode? 剂量场分布或源排列的编号。Numberofdosefielddistributionorsourcearrangement灭菌确认的审核和批准Reviewandapprovalofsterilizationconfirmation质量法规部将整个灭菌确认过程进行总结、形成灭菌确认报告，并与灭菌供方确定常规灭菌工艺参数。TheQualityLawDepartmentsummarizestheentiresterilizationconfirmationprocess,formsasterilizationconfirmationreport,anddeterminesthegeneralsterilizationprocessparameterswiththesterilizationsupplier.常规灭菌控制Routinesterilizationcontrol4.5.1灭菌供应商根据灭菌确认形成的灭菌工艺参数和装载方式等，进行灭菌。bySterilizeaccordingtosterilization processparametersandloadingmethodsconfirmedbysterilization湖南佑华医疗用品有限公司辐照火菌过程控制规范Irradiationsterilizationprocesscontrolspecification版权所有，注意保密YH-MOS-QP-111RevA第9页共12页4.5.2生产人员按照SOP进行日常灭菌装箱操作。 灭菌装箱方式如有变动， 由质量法规部人员进行评估对灭菌有效性的影响。DailysterilizationandpackingoperationsinaccordaneewithSOP .Ifthereisachangeinthesterilizationandpackingmethod,theimpactoftheevaluationbythequalityandregulationsdepartmentontheeffectivenessofsterilization4.5.3采购应与灭菌供方形成灭菌委托协议，在协议中明确灭菌要求和质量责任。Procurementshouldformasterilizationentrustmentagreementwiththesterilizationsupplier,specifyingthesterilizationrequirementsandqualityresponsibilityintheagreement4.5.4生产部负责整理灭菌产品清单，并填写《委外灭菌单》 ，将灭菌产品运送或快递至灭菌供方，灭菌供方根据灭菌协议进行灭菌。Theproductiondepartmentisresponsibleforsortingthelistofsterilizedproducts,andfillingoutthe “ExternalSterilizationOrder ”,transportingordeliveringthesterilizpcbductstothesterilizingsupplier,andthesterilizingsuppliersterilizesaccordingtothesterilizationprotocol.4.5.5灭菌供方完成灭菌过程和剂量检测后返回本公司，同时出具《辐照证明书》 。Thesterilizationsupplierreturnstothecompanyaftercompletingthesterilizationprocessanddosetesting,andissuesan"IrradiationCertificate"4.5.6质量法规部负责对灭菌后的产品进行检验。Thequalityregulationdepartmentisresponsibleforinspectingthesterilizedproducts.灭菌有效性的保持 Maintenanceofsterilizationeffectiveness通过生物负载监测、剂量审核及产品族的保持来确定灭菌剂量的持续有效，通过辐照条件的保持来确认辐照加工的持续有效。Determine thecontinuedeffectiveness ofsterilization dosesthroughbioburdenmonitoring,doseaudits,andmaintenanceofproductfamilies,andconfirmthecontinuedeffectivenessofirradiationprocessingbymaintainingirradiationconditions产品生物负载的监测 Productbioburdenmonitoring? 当产品的平均生物负载大于或等于 1.5时，生物负载检测的最大时间间隔为 3个月。Whentheaveragebioburdenoftheproductisgreaterthanorequalto1.5,themaximumtimeintervalforbioburdendetectionis3months? 当产品的平均生物负载小于 1.5时，并且按Whentheaveragebioburdenoftheproductislessthan1.5,使用方法2(见GB18280.2)建立灭菌剂量，或Usemethod2(seeGB18280.2)toestablishasterilizationdose选用25kGy为灭菌剂量，生物负载检测的最大时间间隔为 3个月。25kGyisselectedasthesterilizationdose,andthemaximumtimeintervalforbioburdendetectionis3months?当产品的平均生物负载小于1.5时，并且按a)使用方法1(见GB18280.2)建立灭菌剂量，或b)选用15kGy为灭菌剂量，生物负载检测的最大时间间隔为 1个月。Whentheaveragebioburdenoftheproductislessthan1.5,andaccordingtoa)usemethod1(seeGB18280.2)toestablishthesterilizationdose,orb)select15kGyasthesterilizationdose,themaximumtimeintervalforbioburdendetectionis1month.?如果产品批的时间间隔大于1个月，如适用，每个产品批应检测生物负载。Ifthebatchintervalisgreaterthan1month,eachproductbatchshouldbetestedforbioburden,ifapplicable? 如果生物负载实验的结果超过规定的限值， 则依据ISO11737-1的方法进行调查。如果调查的结果显示生物负载实验的结果是真实的，则采取措施并立即进行灭菌剂量审核。Iftheresultsofthebioburdenexperimentexceedthespecifiedlimits,investigateaccordingtothemethodofISO11737-1.Iftheresultsoftheinvestigationshowthattheresultsofthebioburdenexperimentarereal,take actionandimmediatelyperformasterilization dosereview灭菌剂量审核 Sterilizationdoseconfirmation建立灭菌剂量后，在产品连续生产阶段， 质量法规部应每3个月应组织抽取代表产品进行剂量审核，在连续生产一年后，如产品的生物负载监测和剂量审核连续有效， 剂量审核的频率减可少为半年一次， 但每年至少一次；在产品不连续生产阶段， 质量法规部负责在生产正式产品前应完成剂量审核。 剂量审核按照ISO11137-2要求需完成生物负载实验、 剂量实验及无菌实验。如剂量审核成功，则灭菌剂量持续有效。Afterthesterilizationdoseisestablished,inthecontinuousproductionphaseoftheproduct,theQualityandLawDepartmentshallorganizerepresentativeproductstobedosedevery3monthsforadoseaudit.Thefrequencyreductioncanbeaslowashalfayear,butatleastonceayear.Inthediscontinuousproductionstageoftheproduct,thequalityregulations departmentisresponsibleforcompletingthedoseauditbeforeproducingtheformalproduct.Thedoseauditshallcompletethebioburdentest,dosetestandsterilitytestinaccordaneewiththerequirementsofISO11137-2.Ifthedoseauditissuccessful,thesterilizationdosewillcontinuetobeeffective产品族的保持Productfamilyretention质量法规部每年应对产品族进行审查，以确保产品族和代表产品族的产品持续有效。生产过程中，应对生产条件、生产工艺发生改变的产品及新产品应进行初始污染检测，确保代表产品的持续有效。湖南佑华医疗用品有限公司辐照火菌过程控制规范Irradiationsterilizationprocesscontrolspecification版权所有，注意保密YH-MOS-QP-111RevA第11页共12页Thequalityregulationsdepartmentshallreviewtheproductfamilyeveryyeartoensurethattheproductfamilyandtheproductsrepresentingtheproductfamilyarecontinuouslyeffective.Duringtheproduction process,productsthathavechangedproductionconditionsandproductionprocessesandnewproductsshouldbetestedforinitialpollutiontoensurethecontinuedeffectivenessoftherepresentativeproduct464辐照条件的保持 Maintenanceofirradiationconditions灭菌供方的辐照条件发生变化时，质量法规部根据影响的结果进行剂量分布实验或再确认或更换辐照机构。Whentheirradiationconditionsofthesterilizationsupplierchange,thequalityregulationsdepartmentwillconductdosedistributionexperimentsorreconfirmorreplacetheirradiationmechanismaccordingtotheresultsoftheimpact.灭菌过程重新确认 Reconfirmationofsterilizationprocess在发生以下情况时，质量法规部需要评定影响并形成文件，需要时进行重新确认：Inthefollowingcases,thequalityregulationsdepartment needstoassesstheimpactanddocumentit,andreconfirmitifnecessary1） 辐照机构发生变化时，需进行辐照机构确认、辐照加工确认；Whentheirradiationmechanismchanges,itisnecessaryto confirmthe irradiationmechanismandtheirradiationprocessing.2） 当代表产品发生变化、剂量审核失败导致重新建立灭菌剂量时，需进行辐照剂量确认；Whentherepresentativeproductchangesa