.,ProcessValidationtheinterlockofthecapintothetubewaschangedtoimprovethepullstrengthtesting;andshortcapswereaddedtoaccommodatedifferentsizesyringes.Verificationsand/orvalidations,designreviews,designreleases,anddesignapprovalswerenotperformedforanyofthesechanges.對于這些變更沒有實施確認和/或確認，設計評審，設計發(fā)布，以及設計批準。Specifically,recordswerenotavailabletoshowthatthebursttestonlot31255wasperformedatthemaximumsterilizationdose.特別是，沒有記錄可以表明批號為31255的產(chǎn)品按照最大滅菌劑量進行了爆裂測試。Yourfirmfailedtoverify/validateseveralprocessdeviationsasrequiredby21CFR820.75.你們沒有按照21CFR820.75的要求進行驗證/確認過程偏差。,.,SomeFDAComplianceOfficerCommentsFDA符合官員的一些評論,“Specificationsneedtobedevelopedbeforeyougettothevalidationstage.”“進行確認之前，需要制訂技術規(guī)范?！薄癕anufacturerssometimesmissthestepofcompletingadequateprotocolsbeforeproceedingwithvalidationactivities.”“制造商有時會忘記在開始確認之前完成充分的方案?！薄癕anufacturerssometimesfailtorevisitthevalidationprocesswhenmodificationsaremadeinproductsorprocesses.”“當發(fā)生產(chǎn)品或過程變更時，制造商有時沒有重新進行過程確認。”,.,SoWhyDontCompaniesJustDoIt?為什么我們不能馬上進行過程確認呢？,Misunderstandingoftheregulation對法規(guī)的誤解Lackofknowledgeinexecution缺乏實施的知識Lackofresourcestoexecute缺乏實施的資源Fearoffailure害怕失敗Lackofmanagementsupport缺乏管理層支持Fearofdelaytomarket擔心延誤了上市Inhibitsprocesschange隱藏了過程變化,.,過程確認的要素,確認,安裝鑒定,操作鑒定,性能鑒定,開發(fā),.,何時確認,A過程輸出可驗證嗎？,B驗證是充分及成本可接受嗎？,C驗證并控制過程,D確認,E重新設計產(chǎn)品和/或過程,.,ProcessesWhichShouldBeValidated需要確認的過程,Sterilization滅菌Cleanroomambientconditions凈化室周圍的環(huán)境Asepticfillingprocesses無菌填充過程Sterilepackagingsealingprocesses無菌包裝密封過程Lyophilizationprocess（低壓）凍干過程Heattreatingprocesses熱處理過程Plasticinjectionmoldingprocess注塑成型過程2004GHTF,.,ProcessesThatMayBeVerified可以驗證的過程,Manualcuttingprocesses手動切割過程Testingforcolor,turbidity,totalpHforsolutions測試溶液的顏色，混濁度，總的pH值Visualinspectionofprintedcircuitboards印制電路板的目視檢驗Manufacturingandtestingofwiringharnesses電纜線束的制造和測試2004GHTF,.,WhatisaValidationMasterPlan?什么是確認主計劃（VMP）,Amastervalidationplanidentifiesthoseprocessestobevalidated,thescheduleforvalidations,interrelationshipsbetweenprocessesrequiringvalidationandtimingforrevalidations.Oncethesehavebeenestablished,andthepurposeandscopeforvalidationsareclearlystatedandknown,protocoldevelopmentcancommence確認主計劃用以明確哪些過程要確認，確認（過程）的進度表，要求確認的過程和再確認（過程）時間選定上的相互關系。一旦確定了上述內(nèi)容、清楚地規(guī)定確認的目的和范圍并對外告知，方案的編制便可以著手進行了。Itdocumentsspecificallythevalidationofequipment,processes,software,facilities,etc.它記錄了要被確認的設備、過程、軟件、設施等。Itsamapoftheprocessvalidationprocessfortheteamtofollow.它是團隊要遵守的過程確認主線圖。AVMPisanindexthatFDAcanfollowinunderstandingyourvalidations.確認主計劃是FDA用來理解你的確認的索引,.,WhyUseaValidationMasterPlan?為什么要用確認主計劃,AlthoughthesearenotrequiredbytheFDAregulationsitisoneofthefirstthingsthatanauditormayaskforduringaninspection.盡管這不是FDA法規(guī)所要求的，但是它是審核員在檢查過程中所要求的首要東西之一。IfacompanyholdstruetoitsVMPanditsdocumentedevidence,credibilityisestablishedandFDAwillhavemoreconfidenceinonesoutcomes.如果公司能夠按照VMP做并且記錄了證據(jù)，信任就建立起來了，F(xiàn)DA對其結(jié)果就會更有信心。,.,WhyUseaValidationMasterPlan?為什么要用確認主計劃,Allowsonetobeproactiveratherthanreactive.考慮前瞻性而不是事后反應Providesdefinition,scopecreep,andcommitmenttoresponsibilities.提供了定義、范圍以及對職責的承諾Itprovidesamaporguidetotheauditordefininghowthecompanyistyingtheirconcepttorealityinordertosuccessfullyachieveuserrequirements.它為審核員提供了公司為了成功的滿足用戶的要求而如何將公司的觀念和實際聯(lián)系在一起的路線圖或指導方向,.,ComponentsofaValidationMasterPlan?確認主計劃的組成,Definitionoftheproject項目定義Strategyorapproachtotheproject項目的策略或方法Scopeoftheproject項目的范圍Whatprocesseswillbevalidated?將被確認的過程Whatprocesseswillbeverified?將被驗證的過程Responsibilities職責,.,ComponentsofaValidationMasterPlan?確認主計劃的組成,Arethereanyspecialconsiderations?是否有任何特殊的考慮？Keymilestones關鍵的里程碑Validationprotocolnumbers確認方案的編號AVMP,perse,isnotthesameasaprojectplan!,.,WhatisinaValidationMasterPlan?確認主計劃是什么,.,WhatisRequiredtoBeOutstandinginProcessValidation?過程確認中需要強調(diào)什么？,Planning計劃CrossfunctionalteamTHATCANWORKTOGETHER!相關職能部門，一起合作Profoundprocessknowledge淵博的過程知識Havingalongtermcommitment長期的承諾Roadmapreflectingregulatoryguidelines能反映法規(guī)指導的路標圖Metricstomapprogress進展的指標Passionforexcellence追求卓越的激情,.,StepstoValidationofaProcess過程確認的步驟,Formamulti-disciplinaryteam組建一個多功能小組Plantheapproachanddefinerequirements制定步驟并定義要求Identifyanddescribetheprocess識別和描述過程Specifyprocessparametersanddesiredoutput規(guī)定過程參數(shù)和希望的輸出Decideonverificationandorvalidation就驗證和（或）確認做出決定CreateaValidationMasterPlan制定一個主要確認方案,.,StepstoValidationofaProcess,Selectmethodsandtoolsforvalidations選擇確認的方法和工具Createvalidationprotocols編制確認方案PerformIQ,OQ,PQanddocumentresults執(zhí)行IQ、OQ、PQ并將結(jié)果形成文件Determinecontinuousprocesscontrols確定連續(xù)的過程控制Controltheprocesscontinuously連續(xù)地控制過程,.,Protocoldevelopment方案編制,Processvalidationprotocolsshouldincludethefollowingelements:過程確認方案應該包括如下元素：Completedescriptionoftheprocess過程的完整描述Identificationoftheprocesstobevalidated要確認的過程標識Selecttheworstcase選擇最差條件（產(chǎn)品）Identificationofdevice(s)tobemanufacturedusingthisprocess在這個過程下產(chǎn)出的器械的標識Objectiveandmeasurablecriteriaforasuccessfulvalidation一個成功確認的目標和可測量的標準Lengthanddurationofthevalidation確認的用時和有效期限Shifts,operators,equipmenttobeusedintheprocess過程中采用的輪班制、操作人員和設備Identificationofutilitiesfortheprocessequipmentandqualityoftheutilities過程設備中使用器具(utilities)的標識和質(zhì)量Identificationofoperatorsandrequiredoperatorqualification操作員識別和要求的操作員資格（證）,.,Protocoldevelopment方案編制,、Relevantspecificationsthatrelatetotheproduct,components,manufacturingmaterials,etc產(chǎn)品、元件、生產(chǎn)材料等的相關規(guī)格Anyspecialcontrolsorconditionstobeplacedonprecedingprocessesduringthevalidation在（過程）確認中，對先發(fā)生的過程所設置的任何特殊控制或條件Processparameterstobemonitored,andmethodsforcontrollingandmonitoring要監(jiān)控的過程參數(shù)和監(jiān)控方法Productcharacteristicstobemonitoredandmethodformonitoring監(jiān)視的產(chǎn)品特性和方法Anysubjectivecriteriausedtoevaluatetheproduct用來評估產(chǎn)品的主觀標準Definitionofwhatconstitutesnon-conformanceforbothmeasurableandsubjectivecriteria對于可測量標準和主觀標準，定義什么是不合格Statisticalmethodsfordatacollectionandanalysis數(shù)據(jù)收集和分析的統(tǒng)計方法Considerationofmaintenanceandrepairsofmanufacturingequipment生產(chǎn)設備保養(yǎng)和修理方面的考慮IQ、OQ&PQCriteriaforrevalidation再確認標準,.,Protocoldevelopment方案編制,Forallthreephases,IQ,OQ,andPQ,basedonproduct/processrequirements:對于三個階段，IQ、OQ和PQ都要基于產(chǎn)品或過程的要求：Determinewhattoverify/measure決定驗證或測量什么Determinehowtoverify/measure決定如何驗證或測量Determinehowmanytoverify/measure,i.e.statisticalsignificance決定驗證或測量多少，如統(tǒng)計量Determinewhentoverify/measure決定何時驗證或測量Defineacceptance/rejectioncriteria規(guī)定接受或拒絕的標準Definerequireddocumentation規(guī)定要求的文件Remember:protocolmustbereviewedandapprovedbeforeexecution記住，在實施前，方案必須被評審和批準。,.,Protocoldevelopment方案編制,Generally,protocolincludes4sections:一般來講，方案可分為四大部分：The1stsection:validationoverview,includingvalidationscope,processdescription,background,worstcases,lengthanddurationofthevalidation,objectiveetc.第一部分：確認概述部分，包含確認范圍，過程描述，背景介紹，最差條件挑選，確認的用時和有效期限，目標等等；The2ndsection:qualificationreadiness,includingtherequirementsforman,machine,material,method,environment,testandlabel&traceability,PFMEAetc.第二部分：鑒定準備階段，包含所有的人、機、料、法、環(huán)、測及標志和追溯,PFMEA等要求和準備；The3rdsection:qualification(IQ,OQ&PQ),includingqualificationplananddeviationdisposaletc.第三部分：鑒定階段(IQ,OQ&PQ)，包含鑒定計劃及偏差處理等；The4thsection:documentrequirements，includingtheinputandoutputdocumentsrequiredbythisprotocol.第四部分：文件要求，包含本方案所需的文件及輸出文件要求。,.,QualificationTypes鑒定的類型,Howdorequirementsapply?怎樣應用這些要求,.,TheImportanceofGaging量具的重要性,Yourmeasurementmethodismostimportantindeterminingyourprocessparameters.在確定你的過程參數(shù)的過程中，你的測量方法是最重要的。Gagesmeasurevariationandprovidesignalsforchangesinvariation.量具用來測量變差并提供變差變化的信號。Gagesarethecompasstohelpnavigatethroughthevalidationprocess.量具是整個確認過程中幫助我們導航的羅盤。,.,InstallationQualification(IQ)安裝鑒定（IQ）,Establishingbyobjectiveevidencethatallkeyaspectsoftheprocessequipmentandancillarysysteminstallationadheretothemanufacturersapprovedspecificationandthattherecommendationsofthesupplieroftheequipmentaresuitablyconsidered.用客觀證據(jù)來支持證明，所安裝的過程設備和輔助系統(tǒng)的關鍵安裝方面，能滿足制造商已批準的技術規(guī)范，且供應商的建議也被恰當?shù)目紤]了。2004GHTF,.,InstallationQualification(IQ)安裝鑒定（IQ）,“Istheequipmentinstalledcorrectly?”設備已經(jīng)正確的安裝了嗎？IQGoal：IQ目的Verifyandproveallkeyaspectsoftheprocessequipmentandancillarysysteminstallationadheretothemanufacturersapprovedspecificationandthattherecommendationsofthesupplieroftheequipmentaresuitablyconsidered.驗證并證明所安裝的過程設備和輔助系統(tǒng)的關鍵安裝方面，能滿足制造商已批準的技術規(guī)范，且供應商的建議也被恰當?shù)目紤]了。TheIQreducesriskbyreducingthenumberofrootcausessuspectedwhentroubleoccursintheOQandPQ.IQ通過消減在OQ和PQ過程中出現(xiàn)的麻煩的可疑原因數(shù)量來減少風險Makesureequipmentstomeetintendeduse.確保設備滿足預期用途,.,InstallationQualification(IQ)安裝鑒定（IQ）,.,InstallationQualification(IQ)安裝鑒定（IQ）,Importantconsiderationsare:IQ考慮事項：Equipmentdesignfeatures(constructionmaterials,cleanability)設備設計特點（如清潔裝置的結(jié)構(gòu)材料等）Installationconditions(wiring,utilities)安裝條件（布線、實用性、功能性等）Calibration,PreventiveMaintenance,cleaningschedules校準、預防性保養(yǎng)、清潔計劃Safety安全特性Supplierdocumentation供應商文件Softwaredocumentation軟件文件Sparepartslist零部件清單Environmentalconditions(temperature,humidity)環(huán)境條件（如清潔室的要求、溫度和濕度）2004GHTF,.,AcceptanceCriteria接受標準,Considerations考慮點:Makethemclearandobjective清晰、客觀Bedescriptive可描述的Attributesshouldreferenceastandardwhenpossible.可能時，定性參數(shù)應該作為參考標準Specificationscanbeatolerance,maximumorminimum規(guī)格應該有公差，最大或最小Theymustmakesense，必須能講的清楚TheymustkeeptheOQandPQinmind必須一直把OQ和PQ記在心里Acceptancecriteriaarecreatedbeforetheprotocolisapprovednotafterward接受標準要在方案批準之前制定出來而不是之后制定出來,.,InstallationQualification(IQ)安裝鑒定（IQ）,Protocolcomponents:方案構(gòu)成Purpose目的Equipmentdescription設備描述Scope范圍Processdescription過程描述Itemstobeverifiedineachinstallationcategory在每個安裝類別里所要驗證的項目,.,OperationalQualification(OQ)操作鑒定（OQ）,Establishingbyobjectiveevidenceprocesscontrollimitsandactionlevelswhichresultinproductthatmeetsallpredeterminedrequirements用客觀證據(jù)確定能夠生產(chǎn)出滿足所有預定要求的產(chǎn)品的過程控制極限和行動標準。-2004GHTF,.,OperationalQualification(OQ)操作鑒定（OQ）,OQGoal：OQ目的：TheOQisintendedtocreateaprocessscope(limits)withinwhichanoperatorcontrolstheprocess.Thiswillchallengetheworstcase(Limits)OQ用于創(chuàng)建過程范圍(極限）,操作工可在此過程范圍內(nèi)控制過程。它將會挑戰(zhàn)過程的最差條件按（極限）。Usinggoodscienceisessentialtoestablishingreliableprocessparameters.使用正確的科學知識是建立可靠地過程參數(shù)的基本條件。,.,OperationalQualification(OQ)操作鑒定（OQ）,Sometime,limitscanbegottenherefromexperienceandothersourceinadvance有時，此處可由經(jīng)驗或其他來源預先獲得極限。,.,OperationalQualification(OQ)操作鑒定（OQ）,Importantconsiderationsare:重要的考慮點：Processparameterscontrollimits過程參數(shù)控制線Defineproductionrunsbatchqty/productqtyandsequenceforeachgroupofparameters確定每組參數(shù)的生產(chǎn)批次/產(chǎn)品的數(shù)量以及順序Acceptancecriteria接受標準Gagingortestmethods測量或測試方法Rawmaterials原材料Processchangecontrol過程變更控制ThelimitsandconditionsestablishedintheOQwillbethesamelimitsandconditionsusedinthePQ.在OQ中建立的極限和條件將是用在PQ中所使用的極限和條件相同的。,.,OperationalQualification(OQ)操作鑒定（OQ）,Importantconsiderations:重要的考慮點：Training培訓Methodfordeterminingshorttermstabilityandcapabilityofprocess確定短期穩(wěn)定性和過程能理的方法Potentialfailuremodes,actionlevels,andworstcaseconditions可能的故障狀態(tài)、作用程度和最壞情況條件UseofstatisticaltechniquestoidentifykeyprocessvariablesandDOEforoptimization統(tǒng)計學有效技術的使用來識別關鍵過程變差及用DOE進行優(yōu)化,.,OperationalQualification(OQ)操作鑒定（OQ）,TheOQmusttestproductattheworsecaseprocessconditions.OQ必須測試在最差過程條件中生產(chǎn)的產(chǎn)品Theworsecaseconditionsmustalsoincludeworsecaseproductwhenmorethanoneproductisinvolved(i.e.aproductfamily).當涉及到不止一個產(chǎn)品時（比如一個產(chǎn)品族）最差條件也要包含最差條件的產(chǎn)品。TheprocessparametersestablishedintheOQwillestablishtherevalidationcriteria.OQ中建立的過程參數(shù)要建立再確認標準。,.,DeterminationofProcessScope過程范圍的確定,Conventionalapproach:Usebesttechnicaljudgmentstodeterminekeyparametersandoperatingscope傳統(tǒng)的方法：使用最好的技術判斷來決定關鍵參數(shù)和操作范圍。Enhancedapproach:UseDesignofExperimentstodetermineoperationalscope先進的方法：使用DOE來確定操作范圍。,.,AdditionalOQConsiderations額外的OQ考慮點,Thisisthetimetofindthelimitsofyourprocess這是發(fā)現(xiàn)你們的過程極限的時間。Thisisalsothetimetodemonstrateyouknowhowchangesininputswilleffectyourkeyprocesscharacteristics這是證明你們知道當輸入如何變化時會影響你們關鍵的過程特性的時間。Remember:Oncethekeyprocesscontrolsareestablishedtheycannotbeviolatedbytheoperatorortheengineerwithoutrevalidation!記?。阂坏┙⒘岁P鍵的過程控制，如果沒有再確認，任何操作工或工程師都不能違背他們。,.,PerformanceQualification(PQ)性能鑒定（PQ）,establishingbyobjectiveevidencethattheprocess,underanticipatedconditions,consistentlyproducesaproductwhichmeetsallpredeterminedrequirements.用客觀證據(jù)確定，在預期條件下，過程能連續(xù)地產(chǎn)出符合所有預定要求的產(chǎn)品。2004GHTF,.,PerformanceQualification(PQ)性能鑒定（PQ）,PQGoal：PQ目標：establishingbyobjectiveevidencethattheprocess,underanticipatedconditions,consistentlyproducesaproductwhichmeetsallpredeterminedrequirements.用客觀證據(jù)確定，在預期條件下，過程能連續(xù)地產(chǎn)出符合所有預定要求的產(chǎn)品。Normally,anticipatedconditionsarethebestconditions(NominalParameters).通常情況下，預期的條件就是最好的條件（名義參數(shù)）,.,PerformanceQualification(PQ)性能鑒定（PQ）,Inthisphasethekeyobjectiveistodemonstratetheprocesswillconsistentlyproduceacceptableproductundernormaloperatingconditions.在此階段，要用關鍵的目標來證明在正常的操作條件下過程能持續(xù)的生產(chǎn)出可接受的產(chǎn)品。2004GHTFThePQmustbeperformedbytheoperator!PQ必須要由操作工來執(zhí)行！,.,PerformanceQualification(PQ)性能鑒定（PQ）,WhileFDAbelievesthatthreeproductionrunsduringprocessvalidationistheacceptedstandard,FDArecognizesthatallprocessesmaynotbedefinedintermsoflotsorbatches.Thenumberthreeis,however,currentlyconsideredtobetheacceptablestandard.FDA相信在過程確認中三個生產(chǎn)循環(huán)是可接受的標準，F(xiàn)DA認識到所有的過程不可能根據(jù)批次來進行定義的。然而，三這個數(shù)字當前被認為是可接受的標準。FDAPreamble,.,PerformanceQualification(PQ)性能鑒定（PQ）,.,PQconsiderationsinclude:PQ應該考慮：ActualproductandprocessparametersandproceduresestablishedinOQOQ階段的真實產(chǎn)品、過程參數(shù)和建立的程序Acceptabilityoftheproduct產(chǎn)品的可接受性AssuranceofprocesscapabilityasestablishedinOQ就像OQ階段那樣建立的對過程能力的保證Processrepeatability,longtermprocessstability過程的重復能力和長期過程的穩(wěn)定能力,PerformanceQualification(PQ)性能鑒定（PQ）,.,PQExecutionPQ實施,1.Manufacturethepredeterminednumberoflots.生產(chǎn)預先確定批次數(shù)量的產(chǎn)品2.Collectdataoneachlot.收集每一批的數(shù)據(jù)3.Analyzethedataapplyingtheproperstatisticaltechnique.使用恰當?shù)慕y(tǒng)計方法分析數(shù)據(jù)4.Documentallfindings.記錄所有的發(fā)現(xiàn)5.Dispositiontheprotocol.方案處理Note:Alllotsmustpasstoconsidertheprocessvalidated!注意：所有的批次必須通過將要被確認的過程！,.,TheFinalReport最終報告,Prepareatendofvalidationactivities在確認活動的最后準備Summarizethefindingsandanydeviationstotheprotocol.總結(jié)發(fā)現(xiàn)和任何對方案的偏離Includeallattachmentsrisenfromprotocol.包含由方案所引起的所有附件ConsiderwhethertheOQisstillvalid.考慮是否OQ仍然有效Deriveconclusionsregardingthevalidationstatusoftheprocess.應得出關于過程確認狀態(tài)的結(jié)論Obtainfinalapprovalsignatures.獲得最終的批準簽字Releaseprocesstomanufacturing.將過程放行給生產(chǎn)過程,.,FailedStudy失效研究,Summarizethereport.總結(jié)報告Investigateanddocumenttherootcauses.調(diào)查并記錄根本原因DeterminewhethertheOQparametersaretherootcause.確定是否OQ參數(shù)是根本原因DeterminewhethertheOQneedstobere-run.決定是否要重新進行OQDeterminewhetherthePQwillberunagain.決定是否再進行PQ,.,FailedStudy失效研究,Deviationsfromtheprotocol對方案的偏離Deviationscanbeacceptable.偏離是否是可接受的Statethedeviation.陳述偏離Statehowitdoesnotaffecttheprotocol陳述偏離不影響方案Havethedeviationapproved.讓偏離獲得批準,.,DiscussionQuestions問題討論,Whathappensiftwooutofthreelotsfailduetooperatorerror?Caneachlotbedispositionedoneatatime?Candifferentproductsberunin-betweeneachvalidationlot?Whathappensiftheparametersneedtobetemporarilychangedduetoarawmaterialchange?Doesanewoperatorrequiretheprocesstoberevalidated?Whenequipmentismovedtoanewlocationdoestheprocessneedtoberevalidated?Doesnewgaugingormeasurementmethodrequiretheprocesstoberevalidated?,.,Revalidation再確認,Aslongastheprocessoperatesinastateofcontrolandnochangeshavebeenmadetotheprocessoroutputproduct,theprocessdoesnothavetoberevalidated.一旦過程在受控狀態(tài)內(nèi)操作且沒有對過程或輸出的產(chǎn)品沒有變更，過程不需要再確認。FDAConditionsforrevalidationshouldbeclearlydefinedanddocumented.必須清楚地定義出再確認的條件并文件化。,.,WhenisRevalidationappropriateorrequired?什么時候要求再確認,change(s)intheactualprocessthatmayaffectqualityoritsvalidationstatus可能影響質(zhì)量或其確認狀態(tài)的真實過程的改變negativetrend(s)inqualityindicators質(zhì)量指示器的負面動向change(s)intheproductdesignwhichaffectstheprocess對過程有影響的產(chǎn)品設計上的改變transferofprocessesfromonefacilitytoanother從一臺裝置到另一臺裝置的過程轉(zhuǎn)換changeoftheapplicationoftheprocess過程應用的改變2004GHTF,.,WhenisRevalidationappropriateorrequir