2.0Glossaryofterms3.0processsimulationconceptsandpri3.1numberandfrequencyofsimulatio4.0processsimulationfo4.1asepticcompoundingacti 4.3lyophilizedprod4.3.1simulatedload/unloadwithshortenedh4.3.2simulatedlyop4.3.3specialconsiderationsuniquetotheproductionoflyophilizedproductsfreezingofmedia vacuumlevelsandduranaerobiccondit4.5ointments/creams/emulsions/4.6powder4.6.1liquidmediumfilledbythepowderfillingeq4.6.2drypowderfillerwithsupplementaryliquidfillcapab4.6.3on-lineliquidfillfollowedbyon-lin4.6.4on-linepowderfillfollowedbyon-linemed4.6.5specialconsiderationsuniquetothesimulationofasepticfillingofsterilepowders4.7otherdosageformsanddevice/drug4.8otherasepticprocessingtechnologies4.8.1restrictedaccessbarriers4.8.2form-fill-sealandblow-fill4.8.3isolationtechno5.2protocol/procedure5.5processsimulatio6.0microbiologicalenvironment7.0elementsofasepticprocesssimulations7.1facilityandfillingmachineconsid7.3mediaselectionandp7.6container/closureco7.10durationandnumberofunitsfilled7.12pre-incubationcontainerins7.14post-incubationi7.17postsimulation 8.2identifyinginterventionsassociatedwithanase8.5handingofintervention-relatedcontainers9.0personnelquali9.4accesswithoutpriorqu9.5lossofqualification13.1selectionandsterilizationofplacebopowder/mate FiguresandtablesindTable7.10.1durationandnumberofuni ThisdocumentreplacestheoriginalPDATechnicalReportNo.22,ProcessSimulationTestingforAsepticallyFilledProducts,publishedin1996.Theintentofthecurrenteffortistoupdatethatdocumenttoreflectthecontinuingchangesthathaveoccurredinasepticprocessingtechnologynotablecontributionsbyotherorganizations,reguthisarea.Inadditionthereportprovidesguidancewhereriskbasedapproachesmaybeapplied.更新這個(gè)文件反映全球產(chǎn)業(yè)無菌加工技術(shù)在發(fā)生不斷的變化。我們盡可能的將這個(gè)話題覆蓋的更加全面，總結(jié)其他那些在這個(gè)領(lǐng)域工作的著名的組織、管理者、摘要和個(gè)人。此外，該報(bào)告提供基于Thistechnicalreportwasdisseminatedindraftforpublicreviewandcommentpriortopublicationofthesubmittedcommentshavebeenincludedinthefinaldocument.Webelievethisapproachaccomplishedthewidestpossiblereviewofthedocumentandensuresitssuitabilityasavaluableguidetoindustryintheareaofprocesssimulationforasepticprocessingoperations.這份報(bào)告以草案的形式由公眾進(jìn)行了討論并在出版前征求了公眾的意見。一些意見的內(nèi)終的文件中。我們相信這個(gè)方法結(jié)合了最廣泛的討論意見，并確保這份文件對(duì)于從事無impliedstandard.Thereadermustrecognizethattheremaybeadditionalrequirementsimposedbecauseofneworlocalizedregulatoryexpectationsthatarenotincludedinthisdocument.Thistechnicalreportdoesnotprovideauniversallyappropriatetemplatefortheexecutionofprocesssimulationstudies.Eachcompanymustdeterminetheappropriaterationaleandapproachesapplicabletotheiruniqueoperations.本技術(shù)報(bào)告應(yīng)被視為一份指南；它無意于建立任何強(qiáng)制性的或隱含的標(biāo)準(zhǔn)。對(duì)于管強(qiáng)制的附加要求，并未涵蓋在本文之中，讀者應(yīng)與以充分考慮。本技術(shù)報(bào)適當(dāng)執(zhí)行工藝模擬研究的模板。每一個(gè)企業(yè)必須根據(jù)自己的實(shí)際情況選擇適當(dāng)?shù)膽?yīng)用原理及方法。Arecurringthemeinthisreportistheconsiderationofrisktoproductsterilityandpatientsafetyascriteriaforthedesignoftheasepticprocesssimulationstudies.Regulatoryauthoritieshaveissuedrecommendationsforasepticprocessstudydesignandcompaniesshourecommendationswhenplanningtheirstudies.However,thasameanstoprovideinformationusedtomakedecisishouldresultinbetterunderstandingoftheasepticprocessanditscapabilities.Theuseofriskassessmentsandrelatedinformationmayresultinstudieswhichgobeyondtherecommendationsofregulatoryauthorities.Itmayalsoresultinstudieswhichdifferfromresultinstudieswhicharelesseffectivethanthoserecommendedbyregulatoryauthor本報(bào)告將產(chǎn)品無菌性風(fēng)險(xiǎn)條件及病人用藥安全作為設(shè)計(jì)無菌工藝模擬研究的標(biāo)準(zhǔn)及科學(xué)評(píng)估信息有助于對(duì)無菌工藝及其能力的充分理解，利于研究設(shè)計(jì)的決議。含有關(guān)信息的研究成果可高于監(jiān)管建議要求，也可與建議略有差 Thistechnicalreportaddressesprocesscapabilconsistofoneormoreasepticprocesssimulationformulationandfillingactivities(rAsepticoperationsrequiredinthepreparationofsterilebulkmaterialsandbiotechnologyfeedmaterialsarenotapartofthisdocument;refertoPDATechnicalReportNo.28:ProcessSimulationTestingforSterileBulkPharmaceuticalChemicals(1).本報(bào)告涉及無菌加工過程能力的評(píng)估。本評(píng)估由制藥，生物制藥及灌裝活動(dòng)（世輔助制造）過程中一種以上無菌工藝模擬（APS）構(gòu)成。有無菌操作的無菌原料藥、生物技術(shù)種菌Whilethefocusofthisdocumentisonasepticprocessinginthepharmaindustry,applicationoftheconceptsandprinciplestotheprdiagnosticsmaybeappro雖然本文的重點(diǎn)是在制藥和生物制藥產(chǎn)業(yè)的無菌工藝上，將ofAsepticFillingforSolutionDrugProducts;TechnicalReportNo.6:ValidationofAsepticDrugPowderFillingProcesses,andthe1996editionofthisreport.TechnicalReportNo.22:ProcessSimulationTestingforAsepticallyFilledProducts(2,3,4).Sincetheabovereportswereissued,therehavebeencontinuedadvancessuchastheuseofbarrier,isolationandblow-fill-sealtechnologies.Theunderstandingandphilosophiesofasepticprocessqualificatandstandardsauthoritieshaverevisedtheirownguidance'sonasepticprocessing(5,6,7和吹灌封技術(shù)。無菌工藝確認(rèn)理解和理念、驗(yàn)證和控制逐漸成熟。此外,全球法規(guī)和標(biāo)準(zhǔn)The2011versionofTechnicalReportNo.22featuresthefollowingneworrevise ?RiskManagement:ThisreportfrequentlyreferencestheuseofqualityriskmanagementconceptsinthedesignofAPSprograms風(fēng)險(xiǎn)管理：這份報(bào)告頻繁的提出在設(shè)計(jì)無菌模擬工藝方案時(shí)使用質(zhì)量風(fēng)險(xiǎn)分析的?ConceptsandPrinciples:Therehavebeenclarificationsandenhancementsofwithcurrentscientificknowledge,experienceandregulatoryexpectatio?LyophilizedProducts:Thesectionon"LyophilizationofDilAPSapproachisgenerallynotconsideredappropriate.?FreezingofMedia:Forsimilarreasonsreferencestofreezingofmediahavebeenremoved.培養(yǎng)基的冷凍：出于類似的原因在關(guān)于培養(yǎng)基冷凍的?PowderFilling:CertainAPSapproachesforpowderfillinghavebeenremove—On-linepowderfillfollowedbyoff-lineliquid—Non-asepticliquidfill,sterilized,andfollowedbyon-linepowder—Off-lineliquidfillfollowedbyon-linepowder?Isolators,restrictedaccessbarriersystems(RABS),blow-fill-seal(BPS):Updatedinform?ElementsofAPS:Enhancedinformationisincludedfor:fillingspeed,interventions,anddunumberofunitsfilled?Interventions:Thisreportdifferentiatesasepticprocessinter"corrective,"adistinctionthatishelpfulinunderstandingtheirrelationshiptomicrobiaandthedesignoftheAPSprogram.APS程序設(shè)計(jì)的相互關(guān)系。?AcceptanceCriteria:Section10includesbackground,currensettingacceptancecriteri可接受標(biāo)準(zhǔn)：在10.0章節(jié)包括了背景、當(dāng)前推薦和設(shè)定無?On-goingProcessEvaluation:Formerlyreferredtoas'Validationupdatedtoreflectthatthestateofcontrolisanongoingprocess. Note:This2011revisionofTechnicalReportNo.22representsasignificantupdateofthecontentofthereport.Thisversionshouldbetreatshouldfullyreviewthisedition.Withthepublicationofthe2011versionofTechnicalRPDAnolongersupportsorconsAsepticprocesssimulation(sometimesreferredtoasamediafilcapabilityofasepticprocessingactivities.Fortheresultstobemeaningful,engineeringandmanufacturingcontrols,maintenanceactivities,qualitenvironmentalcontrol,environmecontrolsshouldbeinplace.APSsimulatestheasepticprocessfromtheposterilizationtoclosureofthecontainer(inclumightimpactcontainerintegrity),substitutingamicrobiologicalgrowthmediumfortheTheasepticprocesssimulationalsoprovidesameansfortheevaluationofchangesmadetoanasepticprocessingoperationwhichmightimpactthesterilityofthefinalproduct.Anasepticprocesssimulationcanbeusefulinidentifyingpocontributetothemicrobiologicalcontaminationoftheproductduringprocessing.可有助于識(shí)別在無菌過程中產(chǎn)品可能易于被微生物污染的潛在薄弱環(huán)節(jié)。Thepurposeofanasepticprocesssimulationisto:?Assessthecapabilityofanasepticprocessunderagivenmanufacturingenvironmentandprocess評(píng)估一個(gè)給定的生產(chǎn)環(huán)境和過程控制無菌工藝?Demonstratethatappropriatelydesignedandimplementedprocessc?Evaluatetheproficiencyofasepticprocessingpersonnel?DemonstratecompliancewithcurrentGoodManufacturi?Demonstratetheappropriatenessofoperatingpracticesusedinsupportofasepticprocessing ?ChallengetheasepticprocessformicrobialcontaminationvThesuccessfulcompletionofanAPScannotbeconsideredavalidationofasepticsensethataperformancequalificationeffortinvolvingbiologicalchallengeandtemperaturemeasurementcansupportasteamsterilizationprocess.Asepticpropractices,equipmentfeatures,facilitydesign/controlandproceduresthamicroorganismsfromsterilecomponentsandproducts.Theseelementsofasepticprocessingcannotrigorouslycontrolledasasterilizationprocess;resultinginaprocesssimulationisonlyademonstrationofthecapabilityoftheprocesstoproduceasepticallyatthetimeofitsexecutionusingthedefinedprocpersonnel.作依賴于人員干預(yù)實(shí)踐，設(shè)備、設(shè)施的設(shè)計(jì)/控制和程序。對(duì)無菌操作要素的要求不如滅菌工藝嚴(yán)TheAPSdoesnotprovideinformationwhichrelatesdirectlytothesteriliTherefore,thefactthataspecificAPSdoesnotmeettherequiredacceptancecriteriadoesnotnecindicateasterilityproblemforaeventhasoccurredduringtheAPSleadingtocontaminationofoneormoreunits.Thepotentialimpactoftheeventonproductionmaterialsmustbedetermin表明所有特定產(chǎn)品批存在無菌問題。然而，但它表明APS過程中發(fā)生了一Similarly,thesuccessfulperformanceofahigh-riskasepticinterventsimulationdoesnotinitselfjustifyitsuseoracceptabilityduringproduction.Theasepticprocesssimulationisonetoolforevaluatingtheprocessingstepsusedtomanufactureastprovidessupportingdatademonstratingtheon-goingcapabilityofproducingprocessingAholisticapproachmustbeusedtocontrolasepticprocesses.Anasepsystemstoassureandcontrolsterilityofthematerialsproduced.Thesesys?Product,equipmentandcomponents?Personneltrainingandcertificationofasepticgowningandaseptictechniques ?Equipmentandfacilitysaniti環(huán)境系統(tǒng)：微生物水平、壓差、氣流組織、風(fēng)速、溫濕度、?Personnel,materialande?Standardoperatingprocedures/workinstruct?AunderlyingqualitysystemapproachtoprThesesystemsmustberoutinelymonitoredtoprovideverificationoftheircontinuedacceptableperformance,bywhichthesterilityassuranceofamanufacturedproductcanbeestablished.Therefore,itisimportanttovalidatealloftherelindependently,suchassterilization/depyrogenationcontactandindirectproductcontactsurfaces(e.g.stoppers,hoppers).這些系統(tǒng)必須定期監(jiān)測，以提供確認(rèn)其持續(xù)可接受建立一個(gè)制造產(chǎn)品的無菌保證的性能。因此， ActionLevel(environmentalmonitAnestablishedmicrobialornon-viableparticlelevelthinvestigationandcorrectiveactionbasedontheinvestigActionPlanAwrittenplanconsistingofelementstobearesponsibilityforeachelementandatargAmicroorganismthatutilizesoxygethatwillgrowprimarilyinthepresenceofoxygen.Forthepurposeofthisreport,thisdefinitionencompassesfacultativeanaerobe微生物在新陳代謝中利用氧作為最終的電子接受體，只有在有氧條件下微生物才能AlertLevel(environmentalmoniEstablishedmicrobialornon-viableparticlelevelgivingearlywarningofpotentoperatingconditions;notnecessarilygroundsfordefinitivecorrectiveactionbuttypicallyre建立的微生物或非活性粒子標(biāo)準(zhǔn)，為正常操作條件下潛在的漂移提供早期的Amicroorganismthatdoesnotutilizemicroorganismthatwillgrowonlyintheabsenceofoxygen.微生物在新陳代謝中不利用氧作為最終的電子受Thepartofasepticprocessingwhereapre-sterilizedproductisfilledand/orpackagedintos 無菌工藝的一部分，即預(yù)先滅菌的產(chǎn)品灌和/或裝到無菌容Handlingsterilemateriaequipmentandpersonnelareregulatedtocontrolmicrobialandparticulatecontaminationtoacce在對(duì)供給空氣、設(shè)施、物料、設(shè)備及人員進(jìn)行微生物和顆粒物污染嚴(yán)格控制的環(huán)境下Controlledenvironment,consistingofseveralzones,andpersonnelareregulatedtocontrolmicrobialandparticulatecontaminationtoaccAsepticProcessingSimulation(Ameansforestablishingthecapabilityofanasepticprocessasperformedusingagrowthmedium.Note:Asepticprocessingsimulationsareunderstoodtobesynonymouswithmediafills,psimulations,simulatedproductfills,brothtrials,brothfil注意：無菌工藝模擬也可稱為培養(yǎng)基灌裝，工藝模擬，模擬產(chǎn)品灌裝，液體培AsystemofphysicalpartitionsthataffordsISO5psurroundingenvironmentutiliz通過氣流將內(nèi)部與外部環(huán)境進(jìn)行部分隔離，以滿足ISO5保護(hù)的物理分TotalnumberofviablemicroorganismsonorinahealthcareproductpriorAseriesofconsecutiveproductionbatchesmanufacturedwithoutinterveningcleaningandsterilization.過程中無清潔及滅菌活動(dòng)介入的一系列連續(xù)產(chǎn)品批 Aformalprogramthatdescribesevaluationandactionstobetakenifachangeisproposedorcompletedtofacilities,materials,equipment,and/orprocessesusedinthefabricatiooraproposedorcompletedchangethatmayaffecttheoperationofmicrobiologicalmediuAprocessinwhichabulkdrugsubstadrugsubstancetoproduceadrugprod將某種原料藥物與其他輔料物和/或原料藥物混合，生產(chǎn)藥物的工ThepercentageofunitsfilledinaprocesssimulationthatarepositiveformicrobialgrowthaAnareadesignedtomaintainsterilityofsterileequipmentmaybeexposedincritic為無菌物料專門設(shè)計(jì)的無菌區(qū)。無菌產(chǎn)品，容器，封裝件，以及設(shè)備可暴露于此關(guān)鍵EnvironmentalFlora(iMicroorganismsassociatedwithaprocessingenviroEnvironmentalMonitorintedprogramwhichdescribestheroutineparticulateandmicrobiologicalfprocessingandmanufacturingareas.(Note:Theprogramshouldreferenceacwhereactionlevelsareexc TestperformedtodemonstratethatmediawillsuppoTesttodeterminethefunctionalperformanceofamembranefilterorcontainer/Anasepticmanipulationoractivityperformedbyperstechnicalreportregardsinterventionsaseithercorrectiveorinherent.關(guān)鍵區(qū)域內(nèi)，由人員執(zhí)行的無菌操作或活動(dòng)。本技術(shù)報(bào)告中的干預(yù)措施或?yàn)锳ninterventionthatisincludesuchactivitiesas:clearingcomponentmisfeed,adju執(zhí)行過程中糾正或調(diào)整無菌工藝的干預(yù)措施。例如：清Aninterventionthatisanintegralpartoftheasepticprocessandisrequiredforsetand/ormonitoring,e.g.,asepticassembly,containerrepletc.Inherentinterventionsarerequiredbybatchrecconductoftheasepticprocess.樣等。根據(jù)批記錄，規(guī)程，或工作指令，計(jì)劃內(nèi)介入應(yīng)對(duì)無菌工藝進(jìn)行適當(dāng)?shù)闹笇?dǎo)。EnvironmentaloperatingconditionsdefinedinISO1GMPAnnexl"ManufactureofSterileMedicinalProducts.") AdecontaminatedunitmeetingISO5conditionsthatprovidesuncompromised,continuous,isolationofitsinteriorfromthesurroundingenvironplaceonlythroughmicrobiallyretentivefiltAdecontaminatedunitmeetingISO5conditionsthatprovidesuncompromised,continuous,isolationofitsinteriorfromthesurroundthroughopening?(e.g,"mouseholes")thatprecludetheingressofmicrobialcontamination.MicrobiologicalIdentifBiochemicalcharacterizationofisolatedcoloniestodUnitfilledinanasepticprocesssimulationthatexhibitsdetectablemiRestrictedAccessBarrierSysteRABSareasepticprocessingsystems(ISO5)intendedtosubstantiallyredtheuseofseparativedevicesanddefinedmechanicalfeaturesandoperatingprocedures.封裝件及設(shè)備的人員帶來的污染，確定機(jī)械的性能及執(zhí)行規(guī)ShiftScheduledperiodsofworkorproduction,usuallylessthan12hoursinlength,staffedbyofworkers.工作和生產(chǎn)的預(yù)定周期，通常少于12小時(shí)，工 EstablishedperiodforcollectingsamAbsenceoflife;usuallyreferstoabsenceofviablemicroorganisms.Note:Inpractice,nosuchabsolutestatementregardingtheabsenceofmicroorganismscanbeproven(seesterilization).注意：實(shí)際上沒有這種狀態(tài)，不能夠?qū)崿F(xiàn)絕對(duì)的沒有微生物的狀態(tài)（見TestperformedtodetermineifviablemicroorganismsarepreseValidatedprocessusedtorenderaproductfreeofviablemicroNote:Inasterilizationprocess,thenatureofmicrobiologicaldeathorreductionisdescribedbyanexponentialfunction.Therefore,thenumberofmineverbereducedtozero.注意：在滅菌過程中，微生物死亡或減少以指數(shù)函數(shù)形勢表示。在滅菌工藝后，仍Establishingdocumentedevidencethatprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspredeterminedspecificationsandqualityatt(Note:Therehasbeenwide-spreadevolutionintReadersshouldrefertotheU.S.FDA,ECandotherrelatedregulator)'definitionsandguidanceregard建立文件提供高等級(jí)的保障，證明某種特定的工藝可以持續(xù)生產(chǎn)滿足預(yù)定標(biāo)準(zhǔn)及質(zhì)量屬性的產(chǎn)品。Asetofconditionsencompassingupperandlowerprocessiwithinstandardoperatingprocedures,thatposethegreatestchance comparedtoidealconditions).Suchconditionsdonotnecessarilyinduceproduct 3.0processsimulationconceThevalidationofanasepticprocessingoperationshouldincludeasepticprocesssimicrobiologicalgrowthmediuminplaceoftheproduct.Tnormallyincludesexposingthemicrobiologicalgrowthmediumtoproductcontactsurfacesofequipment,containerclosuresystpotentialforaunitofdrugproducttobecomecontaminatedduringactualoperations無菌工藝操作驗(yàn)證應(yīng)包括使用微生物成長培養(yǎng)基替代產(chǎn)品的無菌工藝模擬。無基灌裝，正常情況下包括將微生物成長培養(yǎng)基暴露于設(shè)備接觸表面，容器，封裝系統(tǒng)，關(guān)鍵環(huán)境，3.1numberandfrequencyofsimulationsThenumberandtypeofasepticprocesssimulationpeposedbytheprocessorsignificantchangestotheprocess.Newfacilitiesandprocessesareregarddifferentlybasedonthedeterminationofthoserisks.無菌工藝模擬的數(shù)量和類型應(yīng)當(dāng)是建立在工藝或者重大工藝變更的風(fēng)險(xiǎn)評(píng)估基Foranewfacilityorproductionprocess,processsimulationsareperformedaspartoftheoverallvalidationactivities.Initialprocesssimulationsaregenerallyconductedaftercompletionof:一個(gè)新的設(shè)施或生產(chǎn)工藝，工藝模擬應(yīng)該作為所有驗(yàn)證的一部分。最初的·Implementationofenvironmentaldecontaminationpro·Personneltraining stateofcontrol.Historically,therehasbeenaregulatoryexpectationthatatleastthreeconssuccessfulprocesssimulationsareperformedwhenqThismaybeanappropriateactivitytoutilizeriskmanagementappro無菌工藝模擬是在理想控制狀態(tài)下，為新的設(shè)備、生產(chǎn)線或是工藝操作提供支 模擬?？蛇m當(dāng)使用風(fēng)險(xiǎn)管理方法。Thereisaregulatoryexpectationfora(6,7,8,9).Additionalprocesssimulevaluationofanymajorchangestoprocedures,practicesorequipmentconfiguration(SeeSection12.0-OngoingProcessEvaluation).Flexibilityinmediafilldesignmaybeappropriatofferrobustseparation(builtinbydesign)andconsistentlyheightenedlevelofproductprotection.裝設(shè)計(jì)應(yīng)具有靈活性，便于隔離裝置提供穩(wěn)健的分離（專門3.2worstcaseAusefultechniqueinthevalidationofpharmaceuticalprocessistheemploymentof”worstcase”scenarios.Theuseof“worstcase”situationsisintendedtochallengetheprocessunmaybeontheedgeofnormaloperatingconditions.If,underthecircumstanchallenge,acceptableresultsareachieved,thenthereisgreaterconfidenceinthereliabilityofthesystemundermoreroutinecondition.Worstcasedoesnotmeancreationofartificialconditionsorewhichexceedallowedoperatingconditionsandw在制藥工業(yè)驗(yàn)證中一個(gè)有用的技術(shù)就是采用“最差條件”。采用“最差條件”意在正常工作條件邊緣下對(duì)工藝條件進(jìn)行挑戰(zhàn)。如果在“最差條件”的挑戰(zhàn)下，仍然能達(dá)到預(yù)期的接受標(biāo)準(zhǔn)，那么在正常的條件下，系統(tǒng)的可靠性將有更高的信心。最差條件并非意味著人WorstcaseconditionsvarydependingontheoperationsorriskexecutingtheAPSusingthemaximumnumberofpersonnelmaybeworstcaseatcgownedpersonnelarethegreatestsourceofsituationsworstcasemayincludeexecutingtheprocesswithfewerpeopleifthisresultinmoremovementbytheprocessoperato人員更衣可能是在無菌過程中微生物最大的污染源。在其他情況下，最差中，更少的人，如果這樣作會(huì)導(dǎo)致更多活動(dòng)在操Otherexamplesof“worstcase”practicesmayinclude:·Usingroom/equipmentatthemaximumtimeperiodaftercompletionofsanitization/ster ·Usingtheslowestfillspeedfo·UsingthehighestfillspeedfortTheworstcaseconditionsselectedforinclusioninancharacteristicsoftheoperation.TheidentificationofappropriateworstcaseconditionsshouldbeaccomplishedbyconductinganassessmentoftheAPScoveringtherelevantvariablesandtheirmicrobiologicalimpactontheprocess.Suchassessmentscanbenefitfromtheapplicationofriskmanagementprincipleandconsiderations/rationalefortheirselecti由此對(duì)最差條件進(jìn)行恰當(dāng)?shù)淖R(shí)別。評(píng)估可借鑒風(fēng)險(xiǎn)管理原理相關(guān)內(nèi)容，評(píng)估結(jié)Riskisdefinedasthecombinationoftheimpactofahazardorunwantedevenoccurringandharmingthepatient(10,11).Thehazardassocofthistechnicalreportisthelossofsterilityassuranceorpotentialforpyrogens.Theuseassessmentprinciplesshouldbeofbenefitinmakingdecisionsresimulation.ItwouldbebeneficialconfirmingthedesignoftheAPSstudy.風(fēng)險(xiǎn)是指危險(xiǎn)或不必要的事件的影響，可能發(fā)生事故和危害加工相關(guān)的危害是無菌保證或潛在熱源的失控。風(fēng)險(xiǎn)評(píng)估原則的使用有利于決Anumberofriskassessmentmethodsspecificforasepticprocessinghavebeendefinedasepticprocessstepsandinterventionsthatcanpotentiallyadverselyaffectthesterilityastheproduct.Riskassessmentscanrelatedtocontainersize,configuration,linespeed,batchsize,andoperateffortsshouldbemadetomitigateidecommunicatedtostakeholdersandmanagementintheorganizationincludingtheQ識(shí)別和評(píng)估無菌工藝步驟和對(duì)產(chǎn)品無菌保障有潛在不利影響的干預(yù)措施。風(fēng)險(xiǎn)定與容器大小、外形、生產(chǎn)線速度、批量和操作條件相關(guān)的最差條件。在努力以減輕確定的風(fēng)險(xiǎn)通過消除或改變工序的風(fēng)險(xiǎn)和完善的設(shè)施、設(shè)備、和 應(yīng)記錄并傳達(dá)組織的利益相關(guān)者和管理層，包括質(zhì)量Anassessmentofongoingcontrolsandchangestotheasepticprocescomputerizedsystems,facilityandcriticalutilitiesmaybepchangestotheassuranceofsterility.Thisassessmentmaybeusedtojustifythetypeofresponseorsimulationoftheprocesschangeneededtoassurethatthechangehasnotadverselyaffectedtheasepticprocess.Riskassessmentmaybebeneficialtopresentarationalefortheneeprocesssimulationasaresultofchangecontrol.shouldberecorded,approvedandincorporatedintothechangecontroldocumentat對(duì)無菌工藝，人員，設(shè)備，計(jì)算機(jī)系統(tǒng)，設(shè)施和關(guān)鍵設(shè)施應(yīng)進(jìn)行持續(xù)控制和變更這些以保證無菌的變更的風(fēng)險(xiǎn)。評(píng)估通?？梢杂脕碜C明反應(yīng)類型或工藝變更保變更沒有對(duì)無菌工藝產(chǎn)生不良影響。作為變更控制的結(jié)果，風(fēng)險(xiǎn)評(píng)估有利需求和范圍的呈現(xiàn)。風(fēng)險(xiǎn)評(píng)估和風(fēng)險(xiǎn)管理決策應(yīng)記錄、批準(zhǔn)，并納入變更控制 4.0ProcesssimulatTheconductofprocesssimulationsofasepticallyproducedparenteralproductsentailssimulationoftheprocessfromthepointofsterilizationoftheproductandproductcontactsurface,includinandclosures,throughsealingoffilledconcompoundingareanecessarypartoftheAPS.Thefollowinmadeinthedesignandperformanceofprocesssimulationsforasepticallyplyophilizedproducts,suspensions,ointmentsandpowders.對(duì)于采用無菌生產(chǎn)工藝的注射藥品的工藝模擬，必須模擬從產(chǎn)品和產(chǎn)品容器包括部分。下面的章節(jié)總結(jié)性的描述了在設(shè)計(jì)和性能上必須要進(jìn)行工藝模擬的產(chǎn)品：無菌生產(chǎn)溶液、Theasepticprocessissimulatedthroughtheuseofprand/orplaceboishandledinamanroutineproduction.Theapplicationofthisprincipletoaasepticprocessoradaptationofshouldbeaccomplishedinamannerwhichwillnotreducsimulationand,asaresult,appeartoimprovetheresultsofthesimulationrelativetoroutinepoperations.相近。此項(xiàng)無菌工藝或規(guī)程的原理應(yīng)用要求適當(dāng)，不能降低模擬的有效挑戰(zhàn)ItisimportanttonotethatwheremediaisutilizedintheprocesssimulationitssteForexample,asepticprocesssimulationsdonotsupportthefiltrbeingsimulated,sodifferencesinthefilterarea,fchangesdonotenhancetheasepticprocessoreliminateaprocessstepwhisterilityassuranceoftheproduct.Thisdocu