YH-MOS-SP-11A輻照滅菌過程控制規(guī)范

湖南佑華醫(yī)療用品有限公司輻照火菌過程控制規(guī)范Irradiationsterilizationprocesscontrolspecification版權(quán)所有，注意保密YH-MOS-QP-111RevA第1頁共12頁版本號VersionNo修改日期ModifiedDate修改內(nèi)容描述DescriptionaboutmodifiedcontentA2020316首次發(fā)布InitialReleased制定：審核：批準：簽名簽名簽名發(fā)放部門Distributiondepartment研發(fā)中心、質(zhì)量法規(guī)、生產(chǎn)運營、物料管理R&D,Qualityregulation,Operationdepartment. Materialmanagementdepartment.湖南佑華醫(yī)療用品有限公司輻照火菌過程控制規(guī)范Irradiationsterilizationprocesscontrolspecification版權(quán)所有，注意保密YH-MOS-QP-111RevA第2頁共12頁1.0目的Purpose對輻照滅菌進行控制，保證文件的適用性和有效性。ControlofIrradiationsterilizationtoensurethesuitabilityandeffectivenessofthedocumentation2.0范圍Scope適用于本公司輻照滅菌產(chǎn)品控制。Suitableforthecontrolofourcompany'sIrradiationsterilizationproducts.3.0職責Responsibility3.1研發(fā)中心：負責提供產(chǎn)品材料所能夠承受的滅菌方式，且滿足設定的滅菌條件。R&D:Responsibleforprovidingthesterilizationmethodthattheproductmaterialscanwithstandandmeetthesetsterilizationconditions.3.2生產(chǎn)運營：負責準備滅菌的產(chǎn)品。Operationdepartment:Responsibleforpreparingproductsforsterilization3.3質(zhì)量法規(guī)：負責滅菌供商的審核，滅菌驗證；滅菌前、后產(chǎn)品指標的檢測，審核滅菌公司提供滅菌報告。Qualityregulations:responsiblefortheauditofsterilizationsuppliers,sterilizationverification;testingofproductindicatorsbeforeandaftersterilization,andinspectionofsterilizationreportsprovidedbythecompany3.4物料管理部：負責外包裝后，產(chǎn)品放行前（滅菌前、后）的隔離，滅菌貨物的運輸、與滅菌公司的滅菌協(xié)議簽訂和溝通。Materialmanagement:Afterbeingresponsiblefortheouterpackaging,theproductisreleasedbeforetherelease（beforeandaftersterilization）,thetransportationofthesterilizedgoods,andthesterilizationagreementwiththesterilizationcompany.4.0程序Process定義definition4.1.1滅菌批：在同一滅菌柜內(nèi)，同一滅菌條件下，滿足同滅菌要求的一定量的產(chǎn)品。Sterilizationbatch:acertainamountofproductsthatmeetthesterilizationrequirementsunderthesamesterilizationconditionsinthesamesterilizer4.1.2SAL=SterilityAssuraneeLevel 無菌保證水平，表示已滅菌物品的微生物存活的概率。Asepticassurancelevel,indicatingtheprobabilityofmicrobialsurvivalofsterilizeditems.4.1.3生物負載：一件產(chǎn)品和（或）無菌屏障系統(tǒng)上存活的微生物的總數(shù)。Bioburden:Thetotalnumberofmicroorganismsaliveonaproductand/orsterilebarriersystem滅菌供商選擇及評價 Sterilizationsupplierselectionandevaluation4.2.1對供貨商的質(zhì)量管理和生產(chǎn)能力評估（查看供商的資質(zhì)、現(xiàn)場審核等方式） 。Qualitymanagement andproduction capacityassessmentforsuppliers（checksupplierqualifications,on-siteaudits,etc.）4.2.2對滅菌廠商評估的項目：ProjectforevaluationofsterilizationmanufacturersA） 確認滅菌設備是經(jīng)過安裝驗證和運行驗證。ConfirmthatthesterilizationequipmentisverifiedbyinstallationandverifiedbyoperationB） 確認滅菌操作員是經(jīng)過專業(yè)培訓并持有上崗證。ConfirmthatthesterilizationoperatorisprofessionallytrainedandholdsacertificateofemploymentC） 確認質(zhì)量體系相關(guān)文件的建立。ConfirmtheestablishmentofrelevantdocumentsofthequalitysystemD） 滅菌過程是經(jīng)過確認，并能夠提供符合要求的報告。ThesterilizationprocessshouldbeconfirmedandcanprovideareportthatmeetstherequirementsE） 當更換滅菌公司或者出現(xiàn)無菌不合格情況時，需要重新進行滅菌驗證。Whenthesterilizationcompanyisreplacedorthesterilityisunqualified,thesterilizationverificationneedstoberepeated.。滅菌確認流程Sterilizationconfirmationprocess滅菌確認常規(guī)滅菌控制滅菌有效性保持滅菌確認Sterilizationconfirmation產(chǎn)品定義Productdefinition產(chǎn)品定義時，包括對包裝的確定。同時應對產(chǎn)品包裝或產(chǎn)品在包裝中的裝載模式加以規(guī)定。如果為一個產(chǎn)品族建立滅菌劑量，需要定義產(chǎn)品族。Productdefinitionincludesthedeterminationofpackaging.Atthesametime,theproductpackagingortheloadingmodeoftheproductinthepackaging shallbespecified.Ifasterilizationdoseisestablishedforaproductfamily,theproductfamilyneedstobedefined過程定義Processdefinition建立最大可接受劑量 Establishamaximumacceptabledose可根據(jù)包裝材料以及產(chǎn)品原材料供應商的一些實驗數(shù)據(jù)確定或進行滅菌實驗，考察產(chǎn)品的最大可接受劑量。Determineorcarryoutsterilizationexperimentsbasedonsomeexperimentaldataofpackagingmaterialsandproductrawmaterialsupplierstoexaminethemaximumacceptabledoseoftheproduct建立滅菌劑量Establishsterilizationdose按照ISO11137-1建立滅菌劑量，應從兩種方法中選一種建立滅菌劑量的方法:EstablishasterilizationdoseinaccordancewithISO11137-1.Oneoftwomethodsshouldbeusedtoestablishasterilizationdose.獲得并利用生物負載數(shù)量和 /或輻射抗力的信息建立滅菌劑量；Obtainanduseinformationonbioburdenquantityand/orradiationresistancetoestablishsterilizationdoses。選擇并證實15kGy或25kGy的滅菌劑量；在證實15kGy或25kGy時，通過劑量實驗提供證據(jù)證明所選擇的滅菌劑量能夠滿足規(guī)定的無菌要求。Selectandconfirm15kGyor25kGysterilizationdose;whenconfirming15kGyor25kGy,provideevidencethroughdoseexperimentstoprovethattheselectedsterilizationdosecanmeetthespecifiedsterilityrequirements以多批次VDmax25為例：(其他情況請參照ISO11137-2)VDmax25證實方法的程序-適用于多個生產(chǎn)批次。Takemulti-batchVDmax25asanexample:(PleaserefertoISO11137-2inothercases)ProcedureforVDmax25verificationmethod-applicabletomultipleproductionbatches注：本方法僅適用于產(chǎn)品平均生物負載 <1000bNote:Thismethodisonlyapplicabletoproductswithanaveragebiologicalloadof <1000步驟1：產(chǎn)品樣本的獲得Step1:Obtainproductsamples從三個獨立生產(chǎn)批次的產(chǎn)品中，每批至少獲取 10個單元產(chǎn)品。Getatleast10unitproductsfromeachofthreeindependentproductionbatches步驟2:確定平均生物負載Step2:Determinetheaveragebioburden按照ISO11737-1確定產(chǎn)品的平均生物負載；確定批平均生物負載（每生產(chǎn)批產(chǎn)品的生物負載的算術(shù)平均值）與總平均生物負載（所有產(chǎn)品的生物負載算術(shù)平均值） ；DeterminetheaveragebioburdenoftheproductinaccordancewithISO11737-1;determinetheaveragebioburdenofthebatch(arithmeticaverageofthebioburdenperproductionbatch)

andthetotalaveragebioburden(thearithmeticaverageofthebioburdenofallproducts)a)如果一個或多個批平均 >2(總平均生物負載)，取最高批平均。Ifoneormorebatchesaverage>2x(totalaveragebioburden),takethehighestbatchaverageb）如果每一批的批平均v2x（總平均生物負載），取總平均值。Ifthebatchaverageofeachbatchis<2（totalaveragebioburden）,takethetotalaverage當SIP=1.0，如果表1中沒有要查的平均生物負載，使用表中生物負載值最近的且大于計算的生物負載值。WhenSIP=1.0,ifthereisnoaveragebioburdentobecheckedinTable1,themostrecentbioburdenvalueinthetableisgreaterthanthecalculatedbioburdenvalue.當SIPv1.0，用SIP平均生物負載除以SIP得到完整產(chǎn)品的生物負載。如果表 1中沒有計算的平均生物負載，使用表中最近的且大于計算生物負載值的列表生物負載值查找 SIP=1.0VDmax25值和相關(guān)的減少因子。WhenSIP<1.0,dividetheaveragebioburdenofSIPbySIPtogetthebioburdenofthecompleteproduct.IfthereisnocalculatedaveragebioburdeninTable1,usethemostrecentlistofbioburdenvaluesgreaterthanthecalculatedbioburdenvalueinthetabletofindtheSIP=1.0VDmax25valueandtherelatedreductionfactor步驟3:確定VDmax25Step3:DetermineVDmax25根據(jù)產(chǎn)品平均生物負載結(jié)合表 1，按照SIPVDmax25=(SIP=1.0VDmax25)+(SIPDoseReductionFactorxlogSIP)公式,計算SIPVDmax25。CalculateSIPVDmax25accordingtotheaveragebioburdenoftheproductinconjunctionwithTable1,andaccordingtotheformulaSIPVDmax25=(SIP=1.0VDmax25)+(SIPDoseReductionFactorxlogSIP)步驟4:完成驗證劑量實驗Step4:Completetheverificationdoseexperiment以VDmax25輻照10個單元產(chǎn)品，要求輻照劑量合格，應滿足如下條件：Irradiate10unitproductswithVDmax25,therequiredradiationdoseisqualified,andthefollowingconditionsshouldbemet實施到單元產(chǎn)品上的最高劑量 <VDnax25*(1.0+10%)；Thehighestdoseappliedtotheunitproduct<VDmax25Thehighestdoseappliedtotheunitproduct<VDmax25*(1.0+10%)2）實施到單元產(chǎn)品上的最高劑量與最低劑量的算術(shù)平均值〉 90%ofVDmax25Thearithmeticmeanofthehighestandlowestdosesappliedtotheunitproductis>90%ofVDmax25按照ISO11737-2完成10個單元產(chǎn)品的無菌檢測。Completethesterilitytestof10unitsaccordingtoISO11737-2步驟5:結(jié)果判定Step5:Resultsjudgment如果10個單元產(chǎn)品的無菌檢測的陽性份數(shù)不多于 1.0個，則證實25kGy作為滅菌劑量，即日常輻照加工的最低吸收劑量要求為 25.0kGy;Ifthenumberofpositivetestsforaseptictestingof10unitproductsisnotmorethan1.0,then25kGyisconfirmedasthesterilizationdose,thatis,theminimumabsorbeddoserequiredfordailyirradiationprocessingis25.0kGy如果10個單元產(chǎn)品的無菌檢測的陽性份數(shù)為 2.0個，則執(zhí)行劑量驗證實驗；Ifthenumberofpositivetestsforthesterilitytestof10unitproductsis2.0,thenperformadoseverificationexperiment如果10個單元產(chǎn)品的無菌檢測的陽性份數(shù)多于 2.0個，則驗證無效。Ifthenumberofpositivetestsforsterilitytestof10unitproductsismorethan2.0,theverificationisinvalid.表1對于平均生物負載W1000CFU時VDmax25和劑量減少因子的值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湖南佑華醫(yī)療用品有限公司輻照火菌過程控制規(guī)范Irradiationsterilizationprocesscontrolspecification版權(quán)所有，注意保密YH-MOS-QP-111RevA第7頁共12頁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 廠一i.u丿 isusedandhencetheSIPDoseReductionFactorisnotgiven.確認滅菌工藝（滅菌供方完成）Confirmsterilizationprocess（completedbysterilizationsupplier）1） 設備安裝確認（IQ）；2） 設備運行確認（OQ）；3） 產(chǎn)品合格性確認（PQ）the該部分最主要的是確定劑量場分布，從而確定滅菌工藝。theThemainthinginthispartistodeterminethedistributionofthedosefieldandthussterilizationprocess.? 在輻照容器中，呈網(wǎng)絡分布的劑量計的分布圖；Distributiondiagramofdosimetersdistributedinanetworkinanirradiationcontainer?最大、最小劑量；Maximumandminimumdoses?最大、最小劑量的位置；Locationofmaximumandminimumdoses?使用的輻照裝置；Irradiationdevice?產(chǎn)品的裝箱模式；Productpackingmode? 劑量場分布或源排列的編號。Numberofdosefielddistributionorsourcearrangement滅菌確認的審核和批準Reviewandapprovalofsterilizationconfirmation質(zhì)量法規(guī)部將整個滅菌確認過程進行總結(jié)、形成滅菌確認報告，并與滅菌供方確定常規(guī)滅菌工藝參數(shù)。TheQualityLawDepartmentsummarizestheentiresterilizationconfirmationprocess,formsasterilizationconfirmationreport,anddeterminesthegeneralsterilizationprocessparameterswiththesterilizationsupplier.常規(guī)滅菌控制Routinesterilizationcontrol4.5.1滅菌供應商根據(jù)滅菌確認形成的滅菌工藝參數(shù)和裝載方式等，進行滅菌。bySterilizeaccordingtosterilization processparametersandloadingmethodsconfirmedbysterilization湖南佑華醫(yī)療用品有限公司輻照火菌過程控制規(guī)范Irradiationsterilizationprocesscontrolspecification版權(quán)所有，注意保密YH-MOS-QP-111RevA第9頁共12頁4.5.2生產(chǎn)人員按照SOP進行日常滅菌裝箱操作。 滅菌裝箱方式如有變動， 由質(zhì)量法規(guī)部人員進行評估對滅菌有效性的影響。DailysterilizationandpackingoperationsinaccordaneewithSOP .Ifthereisachangeinthesterilizationandpackingmethod,theimpactoftheevaluationbythequalityandregulationsdepartmentontheeffectivenessofsterilization4.5.3采購應與滅菌供方形成滅菌委托協(xié)議，在協(xié)議中明確滅菌要求和質(zhì)量責任。Procurementshouldformasterilizationentrustmentagreementwiththesterilizationsupplier,specifyingthesterilizationrequirementsandqualityresponsibilityintheagreement4.5.4生產(chǎn)部負責整理滅菌產(chǎn)品清單，并填寫《委外滅菌單》 ，將滅菌產(chǎn)品運送或快遞至滅菌供方，滅菌供方根據(jù)滅菌協(xié)議進行滅菌。Theproductiondepartmentisresponsibleforsortingthelistofsterilizedproducts,andfillingoutthe “ExternalSterilizationOrder ”,transportingordeliveringthesterilizpcbductstothesterilizingsupplier,andthesterilizingsuppliersterilizesaccordingtothesterilizationprotocol.4.5.5滅菌供方完成滅菌過程和劑量檢測后返回本公司，同時出具《輻照證明書》 。Thesterilizationsupplierreturnstothecompanyaftercompletingthesterilizationprocessanddosetesting,andissuesan"IrradiationCertificate"4.5.6質(zhì)量法規(guī)部負責對滅菌后的產(chǎn)品進行檢驗。Thequalityregulationdepartmentisresponsibleforinspectingthesterilizedproducts.滅菌有效性的保持 Maintenanceofsterilizationeffectiveness通過生物負載監(jiān)測、劑量審核及產(chǎn)品族的保持來確定滅菌劑量的持續(xù)有效，通過輻照條件的保持來確認輻照加工的持續(xù)有效。Determine thecontinuedeffectiveness ofsterilization dosesthroughbioburdenmonitoring,doseaudits,andmaintenanceofproductfamilies,andconfirmthecontinuedeffectivenessofirradiationprocessingbymaintainingirradiationconditions產(chǎn)品生物負載的監(jiān)測 Productbioburdenmonitoring? 當產(chǎn)品的平均生物負載大于或等于 1.5時，生物負載檢測的最大時間間隔為 3個月。Whentheaveragebioburdenoftheproductisgreaterthanorequalto1.5,themaximumtimeintervalforbioburdendetectionis3months? 當產(chǎn)品的平均生物負載小于 1.5時，并且按Whentheaveragebioburdenoftheproductislessthan1.5,使用方法2(見GB18280.2)建立滅菌劑量，或Usemethod2(seeGB18280.2)toestablishasterilizationdose選用25kGy為滅菌劑量，生物負載檢測的最大時間間隔為 3個月。25kGyisselectedasthesterilizationdose,andthemaximumtimeintervalforbioburdendetectionis3months?當產(chǎn)品的平均生物負載小于1.5時，并且按a)使用方法1(見GB18280.2)建立滅菌劑量，或b)選用15kGy為滅菌劑量，生物負載檢測的最大時間間隔為 1個月。Whentheaveragebioburdenoftheproductislessthan1.5,andaccordingtoa)usemethod1(seeGB18280.2)toestablishthesterilizationdose,orb)select15kGyasthesterilizationdose,themaximumtimeintervalforbioburdendetectionis1month.?如果產(chǎn)品批的時間間隔大于1個月，如適用，每個產(chǎn)品批應檢測生物負載。Ifthebatchintervalisgreaterthan1month,eachproductbatchshouldbetestedforbioburden,ifapplicable? 如果生物負載實驗的結(jié)果超過規(guī)定的限值， 則依據(jù)ISO11737-1的方法進行調(diào)查。如果調(diào)查的結(jié)果顯示生物負載實驗的結(jié)果是真實的，則采取措施并立即進行滅菌劑量審核。Iftheresultsofthebioburdenexperimentexceedthespecifiedlimits,investigateaccordingtothemethodofISO11737-1.Iftheresultsoftheinvestigationshowthattheresultsofthebioburdenexperimentarereal,take actionandimmediatelyperformasterilization dosereview滅菌劑量審核 Sterilizationdoseconfirmation建立滅菌劑量后，在產(chǎn)品連續(xù)生產(chǎn)階段， 質(zhì)量法規(guī)部應每3個月應組織抽取代表產(chǎn)品進行劑量審核，在連續(xù)生產(chǎn)一年后，如產(chǎn)品的生物負載監(jiān)測和劑量審核連續(xù)有效， 劑量審核的頻率減可少為半年一次， 但每年至少一次；在產(chǎn)品不連續(xù)生產(chǎn)階段， 質(zhì)量法規(guī)部負責在生產(chǎn)正式產(chǎn)品前應完成劑量審核。 劑量審核按照ISO11137-2要求需完成生物負載實驗、 劑量實驗及無菌實驗。如劑量審核成功，則滅菌劑量持續(xù)有效。Afterthesterilizationdoseisestablished,inthecontinuousproductionphaseoftheproduct,theQualityandLawDepartmentshallorganizerepresentativeproductstobedosedevery3monthsforadoseaudit.Thefrequencyreductioncanbeaslowashalfayear,butatleastonceayear.Inthediscontinuousproductionstageoftheproduct,thequalityregulations departmentisresponsibleforcompletingthedoseauditbeforeproducingtheformalproduct.Thedoseauditshallcompletethebioburdentest,dosetestandsterilitytestinaccordaneewiththerequirementsofISO11137-2.Ifthedoseauditissuccessful,thesterilizationdosewillcontinuetobeeffective產(chǎn)品族的保持Productfamilyretention質(zhì)量法規(guī)部每年應對產(chǎn)品族進行審查，以確保產(chǎn)品族和代表產(chǎn)品族的產(chǎn)品持續(xù)有效。生產(chǎn)過程中，應對生產(chǎn)條件、生產(chǎn)工藝發(fā)生改變的產(chǎn)品及新產(chǎn)品應進行初始污染檢測，確保代表產(chǎn)品的持續(xù)有效。湖南佑華醫(yī)療用品有限公司輻照火菌過程控制規(guī)范Irradiationsterilizationprocesscontrolspecification版權(quán)所有，注意保密YH-MOS-QP-111RevA第11頁共12頁Thequalityregulationsdepartmentshallreviewtheproductfamilyeveryyeartoensurethattheproductfamilyandtheproductsrepresentingtheproductfamilyarecontinuouslyeffective.Duringtheproduction process,productsthathavechangedproductionconditionsandproductionprocessesandnewproductsshouldbetestedforinitialpollutiontoensurethecontinuedeffectivenessoftherepresentativeproduct464輻照條件的保持 Maintenanceofirradiationconditions滅菌供方的輻照條件發(fā)生變化時，質(zhì)量法規(guī)部根據(jù)影響的結(jié)果進行劑量分布實驗或再確認或更換輻照機構(gòu)。Whentheirradiationconditionsofthesterilizationsupplierchange,thequalityregulationsdepartmentwillconductdosedistributionexperimentsorreconfirmorreplacetheirradiationmechanismaccordingtotheresultsoftheimpact.滅菌過程重新確認 Reconfirmationofsterilizationprocess在發(fā)生以下情況時，質(zhì)量法規(guī)部需要評定影響并形成文件，需要時進行重新確認：Inthefollowingcases,thequalityregulationsdepartment needstoassesstheimpactanddocumentit,andreconfirmitifnecessary1） 輻照機構(gòu)發(fā)生變化時，需進行輻照機構(gòu)確認、輻照加工確認；Whentheirradiationmechanismchanges,itisnecessaryto confirmthe irradiationmechanismandtheirradiationprocessing.2） 當代表產(chǎn)品發(fā)生變化、劑量審核失敗導致重新建立滅菌劑量時，需進行輻照劑量確認；Whentherepresentativeproductchangesa