2023年FDA工藝驗證指南(中文版)

GuidanceforIndustry行業(yè)指南ProcessValidation:GeneralPrinciplesandPractices工藝驗證：一般原則與標(biāo)準(zhǔn)U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforBiologicsEvaluationandResearch(CBER)CenterforVeterinaryMedicine(CVM)January2023CurrentGoodManufacturingPractices(CGMP)Revision1美國衛(wèi)生與人類效勞部食品藥品治理局藥物評價和爭論中心〔CDER〕生物制品評價和爭論中心〔CBER〕獸藥中心〔CVM〕2023年1月現(xiàn)行藥品質(zhì)量生產(chǎn)治理標(biāo)準(zhǔn)〔CGMP〕1包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@GuidanceforIndustry行業(yè)指南ProcessValidation:GeneralPrinciplesandPractices工藝驗證：一般原則與標(biāo)準(zhǔn)Additionalcopiesareavailablefrom:OfficeofCommunicationsDivisionofDrugInformation,WO51,Room220110903NewHampshireAve.SilverSpring,MD20993Phone:301-796-3400;Fax:301-847-8714“mailto:druginfo@“druginfo@另外的副本可從以下部門得到：馬里蘭州銀泉市罕布什爾大道10193號2201室藥品信息處，對外信息辦公室，郵政編碼：20993：301-796-3400;：301-847-8714“mailto:druginfo@“druginfo@TableofContents名目\l“_TOC_250029“INTRODUCTION 1一.簡介 1\l“_TOC_250028“BACKGROUND 3二.背景 3\l“_TOC_250027“A.ProcessValidationandDrugQuality 4\l“_TOC_250026“工藝驗證與藥品質(zhì)量 4\l“_TOC_250025“ApproachtoProcessValidation 5B.工藝驗證方法 5STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION 7\l“_TOC_250024“三.對工藝驗證的法規(guī)和監(jiān)管要求 7\l“_TOC_250023“RECOMMENDATIONS 9四.建議 9\l“_TOC_250022“A.GeneralConsiderationsforProcessValidation 9\l“_TOC_250021“對工藝驗證的總體考慮 9\l“_TOC_250020“Stage1-ProcessDesign 10B.第一階段-工藝設(shè)計 10\l“_TOC_250019“1.BuildingandCapturingProcessKnowledgeandUnderstanding 11\l“_TOC_250018“建立和捕獲工藝學(xué)問與理解 11\l“_TOC_250017“EstablishingaStrategyforProcessControl 122.建立工藝掌握策略 12\l“_TOC_250016“C.Stage2-ProcessQualification 14C.其次階段-工藝確認 14\l“_TOC_250015“1.DesignofaFacilityandQualificationofUtilitiesandEquipment 14\l“_TOC_250014“廠房設(shè)施設(shè)計以及公用設(shè)施與設(shè)備確認 14\l“_TOC_250013“ProcessPerformanceQualification 16\l“_TOC_250012“工藝性能確認 16\l“_TOC_250011“PPQProtocol 17\l“_TOC_250010“工藝性能確認方案 17\l“_TOC_250009“PPQProtocolExecutionandReport 194.工藝性能確認執(zhí)行與報告 19\l“_TOC_250008“D.Stage3-ContinuedProcessVerification 20D.第三階段-持續(xù)工藝驗證 20\l“_TOC_250007“CONCURRENTRELEASEOFPPQBATCHES 22\l“_TOC_250006“五.工藝性能確認批次的同時放行 22\l“_TOC_250005“DOCUMENTATION 24六.文件記錄 24\l“_TOC_250004“ANALYTICALMETHODOLOGY 24七.分析方法 24\l“_TOC_250003“GLOSSARY 26\l“_TOC_250002“術(shù)語表 26\l“_TOC_250001“REFERENCES. 28\l“_TOC_250000“參考資料 28包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@1GuidanceforIndustry1行業(yè)指南1ProcessValidation:GeneralPrinciplesandPractices工藝驗證：一般原則與實施ThisguidancerepresentstheFoodandDrugAdministration’s(FDA’s)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheappropriatenumberlistedonthetitleofthisguidance.本指南表達了食品藥品治理局〔FDA〕關(guān)于這一主題的最見解。本指南不為任何人或?qū)θ魏稳瞬胖圃旎蛸n予任何權(quán)利，不起束縛FDA或公眾的作用。假設(shè)替代方法能夠滿足適用法律、法規(guī)的要求，您可以使用替代方法。假設(shè)您期望爭論一種替代性方法，請與負責(zé)執(zhí)行本指南的FDA工作人員聯(lián)系。假設(shè)您不能確定相應(yīng)的FDA工作人員，請撥打本指南標(biāo)題頁所列的相應(yīng)號碼。INTRODUCTION一.簡介ThisguidanceoutlinesthegeneralprinciplesandapproachesthatFDAconsidersappropriateelementsofprocessvalidationforthemanufactureofhumanandanimaldrugandbiologicalproducts,includingactivepharmaceuticalingredients(APIsordrugsubstances),collectivelyreferredtointhisguidanceasdrugsorproducts.Thisguidanceincorporatesprinciplesandapproachesthatallmanufacturerscanusetovalidatemanufacturingprocesses.本指南概述了FDA認為是包括原料藥在內(nèi)的人與動物用藥和生物制品〔在本指南中合稱為藥品或制品〕生產(chǎn)工藝驗證相應(yīng)要素的一般原則和方法。該指南收編了全部生產(chǎn)商可用于驗證生產(chǎn)工藝的多種原則和方法。ThisguidancealignsprocessvalidationactivitieswithaproductlifecycleconceptandwithexistingFDAguidance,includingtheFDA/InternationalConferenceonHarmonisation(ICH)guidancesforindustry,Q8(R2)l,9yk,d0ly2Althoughthisguidancedoesnotrepeattheconceptsandprinciplesexplainedinthoseguidances,FDAencouragestheuseofmodernpharmaceuticaldevelopmentconcepts,qualityriskmanagement,andqualitysystemsatallstagesofthemanufacturingprocesslifecycle.本指南將工藝驗證活動與產(chǎn)品生命周期概念和現(xiàn)有FDA指南進展了對齊，包括FDA/人用藥1ThisguidancehasbeenpreparedbytheDivisionofManufacturingandProductQuality,CenterforDrugEvaluationandResearch(CDER),incooperationwithCDER’sOfficeofPharmaceuticalSciences,theCenterforBiologicsEvaluationandResearch(CBER),theOfficeofRegulatoryAffairs(ORA)andtheCenterforVeterinaryMedicine(CVM)attheFoodandDrugAdministration.1.本指南由FDA制造與產(chǎn)品質(zhì)量處、藥物評價與爭論中心〔CDER〕與CDER藥物科學(xué)辦公室、生物制品評價與爭論中心〔CBER〕、監(jiān)管事物辦公室(ORA)和獸藥中心〔CVM〕合作編制。包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@2品注冊技術(shù)標(biāo)準(zhǔn)國際協(xié)調(diào)會議(ICH)行業(yè)指南，Q8(R2)《藥品開發(fā)》、Q9《質(zhì)量風(fēng)險治理》和Q10《藥品質(zhì)量體系》。2盡管本指南不復(fù)述那些指南解釋的概念或原則，但FDA鼓舞在藥物工藝生命周期全部階段使用現(xiàn)代藥物開發(fā)概念、質(zhì)量風(fēng)險治理和質(zhì)量體系。Thelifecycleconceptlinksproductandprocessdevelopment,qualificationofthecommercialmanufacturingprocess,3andmaintenanceoftheprocessinastateofcontrolduringroutinecommercialproduction.Thisguidancesupportsprocessimprovementandinnovationthroughsoundscience.生命周期概念連接產(chǎn)品和工藝開發(fā)、商品化生產(chǎn)工藝確認3、以及日常商品化制造中處于受控狀態(tài)的過程維護。本指南通過牢靠的科學(xué)為工藝改進和創(chuàng)供給支持。Thisguidancecoversthefollowingcategoriesofdrugs:HumandrugsVeterinarydrugsBiologicalandbiotechnologyproductsFinishedproductsandactivepharmaceuticalingredients(APIsordrugsubstances)4Thedrugconstituentofacombination(drugandmedicaldevice)product本指南涵蓋以下類別的藥物：人用藥獸用藥生物和生物技術(shù)制品制劑產(chǎn)品和活性藥物成分〔原料藥或藥用物質(zhì)〕4組合產(chǎn)品〔藥物和醫(yī)療器械〕的藥物組分Thisguidancedoesnotcoverthefollowingtypesofproducts:TypeAmedicatedarticlesandmedicatedfeedMedicaldevices5DietarysupplementsHumantissuesintendedfortransplantationregulatedundersection361ofthePublicHealthService2Tomakesureyouhavethemostrecentversionofaguidance,checktheCDERguidanceat3Act6本指南不涵蓋以下類型產(chǎn)品：A類添加藥物產(chǎn)品或添加藥物飼料醫(yī)療器械5膳食補充劑受《公共衛(wèi)生效勞法》第361節(jié)監(jiān)管的擬用于移植的人體組織6Thisguidancedoesnotspecifywhatinformationshouldbeincludedaspartofaregulatorysubmission.InterestedpersonscanrefertotheappropriateguidanceorcontacttheappropriateCenterindeterminingthetypeofinformationtoincludeinasubmission.本指南沒有具體說明哪些信息應(yīng)當(dāng)包括在監(jiān)管提交文件局部中。有興趣的人士可以參考相應(yīng)指南或聯(lián)系相應(yīng)中心以確定應(yīng)包括在提交文件中的信息類型。Thisguidancealsodoesnotspecificallydiscussthevalidationofautomatedprocesscontrolsystems(i.e.,computerhardwareandsoftwareinterfaces),whicharecommonlyintegratedintomoderndrugmanufacturingequipment.Thisguidanceisrelevant,however,tothevalidationofprocessesthatincludeautomatedequipmentinprocessing.本指南也沒有具體爭論自動化工藝掌握系統(tǒng)驗證〔即計算機硬件和軟件界面〕，這些自動化掌握系統(tǒng)通常集成在現(xiàn)代化藥物生產(chǎn)設(shè)備中。然而，該指南與包括工藝過程自動設(shè)備在內(nèi)的工藝驗證有關(guān)。FDA’sguidancedocuments,includingthisguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.FDA的指南文件，包括本指南在內(nèi)，沒有規(guī)定依法強制執(zhí)行責(zé)任。相反，除非引述具體的監(jiān)管或法規(guī)要求，指南描述的是本機構(gòu)目前對該主題的看法，應(yīng)當(dāng)僅僅被視為建議。在本機構(gòu)指南中所使用的“應(yīng)當(dāng)”一詞，指建議或推舉某事，并非必需的。BACKGROUND二.背景IntheFederalRegisterofMay11,1987(52FR17638),FDAissuedanoticeannouncingtheavailabilityofaedenlsfse77then,wehaveobtainedadditionalexperiencethroughourregulatoryoversightthatallowsustoupdateourrecommendationstoindustryonthistopic.ThisrevisedguidanceconveysFDA’scurrentthinkingonprocessvalidationandisconsistentwithbasicprinciplesfirstintroducedinthe1987guidance.TherevisedguidancealsoprovidesrecommendationsthatreflectsomeofthegoalsofFDA’sinitiativeentitled“Pharmaceutical5Guidanceonprocessvalidationformedicaldevicesisprovidedinaseparatedocument,QualityManagementSystems–ProcessValidation,edition2,availableat4CGMPsforthe21stCentury―ARisk-BasedApproach,”particularlywithregardtotheuseoftechnologicaladvancesinpharmaceuticalmanufacturing,aswellasimplementationofmodernriskmanagementandqualitysystemtoolsandconcepts.8Thisrevisedguidancereplacesthe1987guidance.1987年5月11日，F(xiàn)DA在聯(lián)邦公告(52FR17638)上公布公告，宣布題為《工藝驗證一般原則指導(dǎo)原則》的指南〔1987年版指南〕面世。7從那時起，通過監(jiān)管監(jiān)視，我們能夠在此主題上更對業(yè)界的建議，使我們獲得了更多閱歷。該指南傳達了FDA目前對工藝驗證的看法，并與1987年版指南首次提出的根本原則相全都。指南還提出了一些反映FDA“21世紀(jì)制藥行業(yè)現(xiàn)行藥品生產(chǎn)治理標(biāo)準(zhǔn)——一種基于風(fēng)險的方法”打算的假設(shè)干目標(biāo)的建議，特別是關(guān)于藥品生產(chǎn)中技術(shù)進步的應(yīng)用，以及對現(xiàn)代風(fēng)險治理和質(zhì)量體系的工具及概念的實施。8該指南取代1987年版指南。FDAhastheauthorityandresponsibilitytoinspectandevaluateprocessvalidationperformedbymanufacturers.TheCGMPregulationsforvalidatingpharmaceutical(drug)manufacturingrequirethatdrugproductsbeproducedwithahighdegreeofassuranceofmeetingalltheattributestheyareintendedtopossess(21CFR211.100(a)and211.110(a)).FDAcGMP法規(guī)要求藥品在高度保證符合全部預(yù)期擁有屬性的狀況下生產(chǎn)(《聯(lián)邦法規(guī)21編122.100〔a〕和211.110〔a〕》)。A.ProcessValidationandDrugQuality工藝驗證與藥品質(zhì)量Effectiveprocessvalidationcontributessignificantlytoassuringdrugquality.Thebasicprincipleofqualityassuranceisthatadrugshouldbeproducedthatisfitforitsintendeduse.Thisprincipleincorporatestheunderstandingthatthefollowingconditionsexist:Quality,safety,andefficacyaredesignedorbuiltintotheproduct.Qualitycannotbeadequatelyassuredmerelybyin-processandfinished-productinspectionortesting.Eachstepofamanufacturingprocessiscontrolledtoassurethatthefinishedproductmeetsallqualityattributesincludingspecifications.有效的工藝驗證對保證藥品質(zhì)量做出了重要奉獻。質(zhì)量保證的根本原則在于生產(chǎn)出來的藥品符合其預(yù)定用途。該原則包括對存在以下狀況的理解：質(zhì)量、安全性和成效被設(shè)計或構(gòu)建于產(chǎn)品之中。7The1987guidancewaspreparedbyaworkinggroupthatincludedrepresentationfromtheCenterforDevicesandRadiologicalHealth(CDRH).Sincethattime,CDRHelectedtoreferenceaprocessvalidationguidancepreparedincooperationwiththeGlobalHarmonizationTaskForce(GHTF).Theprinciplesandrecommendationsinthatdocument,QualityManagementSystems–ProcessValidation,edition2(availableontheInternetat5質(zhì)量不能僅通過生產(chǎn)中檢查或檢測以及成品檢查或檢測賜予充分保證。生產(chǎn)工藝的每一步均予以掌握，確保成品符合包括規(guī)格在內(nèi)全部質(zhì)量屬性。ApproachtoProcessValidationB.工藝驗證方法Forpurposesofthisguidance,processvalidation isdefinedasthecollectionandevaluationofdata,fromtheprocessdesignstagethroughcommercialproduction,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproduct.Processvalidationinvolvesaseriesofactivitiestakingplaceoverthelifecycleoftheproductandprocess.Thisguidancedescribesprocessvalidationactivitiesinthreestages.就本指南而言，工藝驗證被定義為從工藝設(shè)計階段到商業(yè)生產(chǎn)的整個過程中，對數(shù)據(jù)進展收集和評價，建立能夠使工藝能夠始終如一地傳遞到優(yōu)質(zhì)產(chǎn)品中的科學(xué)證據(jù)。工藝驗證涉及整個產(chǎn)品生命周期和生產(chǎn)中發(fā)生的一系列活動。本指南分三個階段對工藝驗證進展說明。Stage1–ProcessDesign:Thecommercialmanufacturingprocessisdefinedduringthisstagebasedonknowledgegainedthroughdevelopmentandscale-upactivities.第一階段 工藝設(shè)計:在開發(fā)和放大活動過程中獲得的學(xué)問根底上，在此階段對商品化制造工藝進展定義。Stage2–ProcessQualification:Duringthisstage,theprocessdesignisevaluatedtodetermineiftheprocessiscapableofreproduciblecommercialmanufacturing.其次階段 工藝確認:在此階段，對工藝設(shè)計進展評估，以確認工藝是否具備可重現(xiàn)的商品化制造力量。Stage3–ContinuedProcessVerification:Ongoingassuranceisgainedduringroutineproductionthattheprocessremainsinastateofcontrol.第三階段 持續(xù)工藝核實:在日常生產(chǎn)中獲得工藝保持處于受控狀態(tài)的持續(xù)和不斷進展的保證。Thisguidancedescribesactivitiestypicalofeachstage,butinpractice,someactivitiesmightoccurinmultiplestages.本指南對每個階段的典型活動進展了說明，但在實踐中，有些活動可能發(fā)生于多個階段。Beforeanybatchfromtheprocessiscommerciallydistributedforusebyconsumers,amanufacturershouldhavegainedahighdegreeofassuranceintheperformanceofthemanufacturingprocesssuchthatitwillconsistentlyproduceAPIsanddrugproductsmeetingthoseattributesrelatingtoidentity,strength,quality,purity,andpotency.Theassuranceshouldbeobtainedfromobjectiveinformationanddatafromlaboratory-,pilot-,and/orcommercial-scalestudies.Informationanddatashoulddemonstratethatthecommercialmanufacturingprocessiscapableofconsistentlyproducingacceptablequalityproductswithincommercialmanufacturingconditions.經(jīng)工藝生產(chǎn)出任何批次產(chǎn)品經(jīng)過商業(yè)流通給消費者使用之前，生產(chǎn)商應(yīng)在生產(chǎn)工藝性能方面取得高度保證，以始終如一地生產(chǎn)出滿足與鑒別、含量、質(zhì)量、純度和效價相關(guān)的那些屬性的原料藥和藥品。這些保證應(yīng)當(dāng)從來自于試驗室小試、中試、和/或商品化大生產(chǎn)爭論的客觀信息或數(shù)據(jù)獲得。信息和數(shù)據(jù)應(yīng)當(dāng)顯示，商品化制造工藝應(yīng)能在商品化制造條件下始終如包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@6一地生產(chǎn)出合格的優(yōu)質(zhì)產(chǎn)品。Asuccessfulvalidationprogramdependsuponinformationandknowledgefromproductandprocessdevelopment.Thisknowledgeandunderstandingisthebasisforestablishinganapproachtocontrolofthemanufacturingprocessthatresultsinproductswiththedesiredqualityattributes.Manufacturersshould:一個成功的驗證方案取決于來自產(chǎn)品和工藝開發(fā)的學(xué)問。這種學(xué)問和理解是建立能夠生產(chǎn)出具備期望得到的質(zhì)量屬性產(chǎn)品生產(chǎn)工藝掌握方法的根底。制造商應(yīng)當(dāng)：Understandthesourcesofvariation了解變異來源Detectthepresenceanddegreeofvariation探測變異存在和程度Understandtheimpactofvariationontheprocessandultimatelyonproductattributes了解變異對工藝和最終對產(chǎn)品屬性的影響Controlthevariationinamannercommensuratewiththeriskitrepresentstotheprocessandproduct用與代表工藝與產(chǎn)品風(fēng)險相稱的方式掌握變異。Eachmanufacturershouldjudgewhetherithasgainedsufficientunderstandingtoprovideahighdegreeofassuranceinitsmanufacturingprocesstojustifycommercialdistributionofthemanufacturingprocessandassociatedvariationsmaynotleadtoadequateassuranceofquality.Afterestablishingandconfirmingtheprocess,manufacturersmustmaintaintheprocessinastateofcontroloverthelifeoftheprocess,evenasmaterials,equipment,productionenvironment,personnel,andmanufacturingprocedureschange.9全部生產(chǎn)商均應(yīng)推斷是否已經(jīng)對生產(chǎn)工藝供給高度保證獲得足夠理解，為產(chǎn)品商業(yè)流通供給保證。只是專注于確認努力，而無視對生產(chǎn)工藝和相關(guān)變異的關(guān)注，不能導(dǎo)致對質(zhì)量的充分保證。在建立和確認工藝之后，生產(chǎn)商必需保持工藝在工藝生命期內(nèi)處于受控狀態(tài)，即便是材料、設(shè)備、生產(chǎn)環(huán)境、人員和生產(chǎn)工序發(fā)生變更的狀況下。9Manufacturersshoulduseongoingprogramstocollectandanalyzeproductandprocessdatatoevaluatethestateofcontroloftheprocess.TheseprogramsmayidentifyprocessorproductproblemsoropportunitiesforprocessimprovementsthatcanbeevaluatedandimplementedthroughsomeoftheactivitiesdescribedinStages1and2.生產(chǎn)商應(yīng)使用持續(xù)和不斷進展的方案收集分析產(chǎn)品和工藝數(shù)據(jù)，對工藝受控狀態(tài)進展評估。這些方案可以確定工藝或產(chǎn)品問題，或找出工藝改善的適當(dāng)時機，這些時機可以通過在第一階段和其次階段中描述的一些活動進展評估和實施。Manufacturersoflegacyproductscantakeadvantageoftheknowledgegainedfromtheoriginalprocessdevelopmentandqualificationworkaswellasmanufacturingexperiencetocontinuallyimprovetheir9ThestatuteandregulationsdescribedinsectionIIIofthisguidanceexplaintherequirementthatthemethodsandfacilitiesusedforthemanufacturingofdrugsbeoperatedandadministeredundercontrolsufficienttoassurethattheidentity,strength,purity,andqualityofadrugareastheypurportorarerepresentedtopossess.9本指南第三節(jié)描述的法規(guī)和章程，對處于掌握之下的用于制藥的方法與設(shè)施的操作及治理要求作出了說明，掌握應(yīng)足以保證其聲稱或據(jù)稱具有的鑒別、含量、質(zhì)量、純度和效價。包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@7processes.ImplementationoftherecommendationsinthisguidanceforlegacyproductsandprocesseswouldlikelybeginwiththeactivitiesdescribedinStage3.傳統(tǒng)產(chǎn)品生產(chǎn)商可利用從原先的工藝開發(fā)和確認工作、以及生產(chǎn)閱歷中獲得的學(xué)問，不斷改進工藝。本指南中對傳統(tǒng)產(chǎn)品和工藝建議的實施，可能會始于第三階段所描述的活動。STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION三.對工藝驗證的法規(guī)和監(jiān)管要求Processvalidationfordrugs(finishedpharmaceuticalsandcomponents)isalegallyenforceablerequirementundersection501(a)(2)(B)oftheAct(21U.S.C.351(a)(2)(B)),whichstatesthefollowing:依據(jù)法令〔《美國聯(lián)邦法典U.S.C.351(a)(2)(B),21編》〕501(a)(2)(B)節(jié)，藥物〔藥物成品與組分〕工藝驗證依法強制執(zhí)行，其規(guī)定如下：Adrug...shallbedeemedtobeadulterated...if...themethodsusedin,orthefacilitiesorcontrolsusedfor,itsmanufacture,processing,packing,orholdingdonotconformtoorarenotoperatedoradministeredinconformitywithcurrentgoodmanufacturingpracticetoassurethatsuchdrugmeetstherequirementsofthisActastosafetyandhastheidentityandstrength,andmeetsthequalityandpuritycharacteristics,whichitpurportsorisrepresentedtopossess.一種藥品……應(yīng)當(dāng)被視為摻假藥品……假設(shè)……使用于制造、加工、包裝或置放的方法或設(shè)施、掌握裝置不符合或沒有遵照在安全性上保證藥品符合本法令的規(guī)定，并保證符合其聲稱或據(jù)稱的鑒別和含量、質(zhì)量和純度特征的現(xiàn)行藥品生產(chǎn)質(zhì)量管理標(biāo)準(zhǔn)操作和治理。FDAregulationsdescribingcurrentgoodmanufacturingpractice(CGMP)forfinishedpharmaceuticalsareprovidedin21CFRparts210and211.對用于成品的現(xiàn)行藥品生產(chǎn)質(zhì)量治理標(biāo)準(zhǔn)〔CGMP〕進展說明的FDA法規(guī)，見《美國聯(lián)邦法規(guī)第21編》第210和211節(jié)。TheCGMPregulationsrequirethatmanufacturingprocessesbedesignedandcontrolledtoassurethatin-processmaterialsandthefinishedproductmeetpredeterminedqualityrequirementsanddosoconsistentlyandreliably.Processvalidationisrequired,inbothgeneralandspecificterms,bytheCGMPregulationsinparts210and211.Thefoundationforprocessvalidationisprovidedin§211.100(a),whichstatesthat“[t]hereshallbewrittenproceduresforproductionandprocesscontroldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess...”(emphasisadded).Thisregulationrequiresmanufacturerstodesignaprocess,includingoperationsandcontrols,whichresultsinaproductmeetingtheseattributes.CGMP法規(guī)要求對生產(chǎn)工藝進展設(shè)計與掌握以保證在加工材料和成品符合預(yù)訂的質(zhì)量要求并始終如一和確實地這樣做。依據(jù)CGMP第210和211節(jié)，在一般條款和具體條款中，工藝驗證是必需的。在§211.100(a)中，規(guī)定了工藝驗證的根底，其中規(guī)定“應(yīng)當(dāng)有用于保證藥品具有其宣稱或據(jù)稱全部的鑒別、含量、質(zhì)量、純度的生產(chǎn)和工藝掌握的書面程序……”〔強調(diào)〕。該法規(guī)要求生產(chǎn)商設(shè)計包括操作和掌握在內(nèi)的工藝，使產(chǎn)品符合這些屬性。OtherCGMPregulationsdefinethevariousaspectsofvalidation.Forexample,§211.110(a),Samplingandgfsmaterialsdg,stls“...establishedtomonitortheoutputandtovalidatetheperformanceofthosemanufacturingprocessesthatmaybe包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@8responsibleforcausingvariabilityinthecharacteristicsofin-processmaterialandthedrugproduct”(emphasisadded).Underthisregulation,evenwell-designedprocessesmustincludein-processcontrolprocedurestoassurefinalproductquality.Inaddition,theCGMPregulationsregardingsamplingsetforthanumberofrequirementsforvalidation:samplesmustrepresentthebatchunderanalysis(§211.160(b)(3));thesamplingplanmustresultinstatisticalconfidence(§211.165(c)and(d));andthebatchmustmeetitspredeterminedspecifications(§211.165(a)).其它的CGMP法規(guī)對驗證的不同方面進展了定義。例如，§211.110(a)在加工材料和藥品的抽樣和檢測，要求掌握程序“……應(yīng)被建立以監(jiān)測產(chǎn)量和驗證可能是引起在加工材料和藥品特性變異緣由的那些生產(chǎn)工藝進展驗證?！薄矎娬{(diào)〕。依據(jù)這一法規(guī)，即便設(shè)計周到的工藝也必需包括中間工藝掌握程序以保證成品質(zhì)量。此外，有關(guān)抽樣的CGMP規(guī)定對驗證提出假設(shè)干要求：樣品必需代表承受分析的批次(§211.160(b)(3));抽樣方法必需產(chǎn)生統(tǒng)計學(xué)置信度(§211.165(c)和(d));批次必需符合其預(yù)設(shè)規(guī)格。Inadditiontosamplingrequirements,theCGMPregulationsalsoprovidenormsforestablishingin-processspecificationsasanaspectofprocessvalidation.Section211.110(b)establishestwoprinciplestofollowwhenestablishingin-processspecifications.Thefirstprincipleisthat“...in-processspecificationsforsuchcharacteristics[ofin-processmaterialandthedrugproduct]shallbeconsistentwithdrugproductfinalspecifications...”Accordingly,in-processmaterialshouldbecontrolledtoassurethatthefinaldrugproductwillmeetitsqualityrequirements.Thesecondprincipleinthisregulationfurtherrequiresthatin-processspecifications“...shallbederivedfrompreviousacceptableprocessaverageandprocessvariabilityestimateswherepossibleanddeterminedbytheapplicationofsuitablestatisticalprocedureswhereappropriate.”Thisrequirement,inpart,establishestheneedformanufacturerstoanalyzeprocessperformanceandcontrolbatch-to-batchvariability.10除抽樣要求之外，作為工藝驗證的一個方面，CGMP法規(guī)也規(guī)定了建立中間工藝標(biāo)準(zhǔn)。211.110(b)節(jié)規(guī)定了建立中間工藝標(biāo)準(zhǔn)時的兩個原則。第一個原則是，“……對這些〔在加工材料和藥品〕特性的中間工藝規(guī)格，應(yīng)當(dāng)與藥品成品規(guī)格全都?！币虼耍诩庸げ牧蠎?yīng)進展控制，以保證藥品成品符合其質(zhì)量要求。這份法規(guī)的其次個原則最中間工藝標(biāo)準(zhǔn)做了進一步要求“……應(yīng)當(dāng)源于之前認可的工藝均值和工藝變異性估量值。這項要求，局部地建立了生產(chǎn)商分析工藝性能和掌握批間變異的需求。10TheCGMPregulationsalsodescribeanddefineactivitiesconnectedwithprocessdesign,development,andmaintenance.Section211.180(e)requiresthatinformationanddataaboutproductqualityandmanufacturingexperiencebeperiodicallyreviewedtodeterminewhetheranychangestotheestablishedprocessarewarranted.Ongoingfeedbackaboutproductqualityandprocessperformanceisanessentialfeatureofprocessmaintenance.CGMP法規(guī)還說明和定義了與工藝設(shè)計、開發(fā)和維護有關(guān)的活動。211.180(e)節(jié)要求對有關(guān)產(chǎn)品質(zhì)量和制造閱歷的信息和數(shù)據(jù)進展定期審查，以打算對已建立工藝的全部變革是否合理和必要。對產(chǎn)品質(zhì)量與工藝性能不連續(xù)的反響是工藝維護的根本特征。Inaddition,theCGMPregulationsrequirethatfacilitiesinwhichdrugsaremanufacturedbeofsuitablesize,10TheAgencyfurtherexplainsthisprincipleinthepreambletothefinalruleon“CurrentGoodManufacturingPracticeinManufacture,Processing,Packing,orHolding”(43FR45013at45052,September29,1978)(availableontheInternetat9construction,andlocationtofacilitateproperoperations(§211.42).Equipmentmustbeofappropriatedesign,adequatesize,andsuitablylocatedtofacilitateoperationsforitsintendeduse(§211.63).Automated,mechanical,andelectronicequipmentmustbecalibrated,inspected,orcheckedaccordingtoawrittenprogramdesignedtoassureproperperformance(§211.68).此外，CGMP法規(guī)要求，生產(chǎn)藥品的設(shè)施具有適當(dāng)?shù)囊?guī)模、建筑和位置，以利于正確操作(§211.42)。設(shè)備必需擁有合理的設(shè)計、足夠的尺寸、放置位置適當(dāng)，以利于預(yù)期操作(§211.63)。自動化、機械和電子設(shè)備必需依據(jù)設(shè)計用來保證正確性能的書面打算校準(zhǔn)、檢查或核實(§211.68)。Insummary,theCGMPregulationsrequirethatmanufacturingprocessesbedesignedandcontrolledtoassurethatin-processmaterialsandthefinishedproductmeetpredeterminedqualityrequirementsanddosoconsistentlyandreliably.總之，CGMP法規(guī)要求生產(chǎn)工藝應(yīng)進展設(shè)計與掌握，與保證在加工材料與成品符合預(yù)設(shè)的質(zhì)量要求，并始終如一和確實地這樣做。RECOMMENDATIONS四.建議Inthefollowingsections,wedescribegeneralconsiderationsforprocessvalidation,therecommendedstagesofprocessvalidation,andspecificactivitiesforeachstageintheproductlifecycle.在下述局部中，我們對工藝驗證的總體考慮、建議的工藝驗證和產(chǎn)品生命周期內(nèi)每一階段的特別活動進展說明。A.GeneralConsiderationsforProcessValidation對工藝驗證的總體考慮Inallstagesoftheproductlifecycle,goodprojectmanagementandgoodarchivingthatcapturescientificknowledgewillmaketheprocessvalidationprogrammoreeffectiveandefficient.Thefollowingpracticesshouldensureuniformcollectionandassessmentofinformationabouttheprocessandenhancetheaccessibilityofsuchinformationlaterintheproductlifecycle.在產(chǎn)品生命周期的全部階段，捕獲科學(xué)學(xué)問的良好工程治理和良好歸檔將使得工藝驗證更為有效和更具效率。下述標(biāo)準(zhǔn)應(yīng)保證與工藝有關(guān)的信息收集和評價全都性，并在其后的產(chǎn)品生命周期中，提高這些信息的可獲得性。Werecommendanintegratedteamapproach11toprocessvalidationthatincludesexpertisefromavarietyofdisciplines(e.g.,processengineering,industrialpharmacy,analyticalchemistry,microbiology,statistics,manufacturing,andqualityassurance).Projectplans,alongwiththefullsupportofseniormanagement,areessentialelementsforsuccess.?我們建議工藝驗證承受包括來自多個學(xué)科特地學(xué)問的綜合團隊方法11〔例如工藝學(xué)、制藥工程、分析化學(xué)、微生物學(xué)、統(tǒng)計學(xué)、制造以及質(zhì)量保證〕。工程打算、以及高級管理團隊的全力支持，是成功的根本要素。stsdnmorelnser,yshltdge,e10Throughouttheproductlifecycle,variousstudiescanbeinitiatedtodiscover,observe,correlate,orconfirminformationabouttheproductandprocess.Allstudiesshouldbeplannedandconductedaccordingtosoundscientificprinciples,appropriatelydocumented,andapprovedinaccordancewiththeestablishedprocedureappropriateforthestageofthelifecycle.在整個產(chǎn)品生命周期，可啟動不同的爭論，覺察、觀看、關(guān)聯(lián)或確認有關(guān)產(chǎn)品和工藝的信息。全部的爭論，應(yīng)依據(jù)牢靠的科學(xué)原則來打算和進展，妥當(dāng)記錄，并依據(jù)適用于生命周期階段的既定程序予以批準(zhǔn)Thetermsattribute(s)(e.g.,quality,product,component)andparameter(s)(e.g.,process,operating,andequipment)arenotcategorizedwithrespecttocriticalityinthisguidance.Withalifecycleapproachtoprocessvalidationthatemploysriskbaseddecisionmakingthroughoutthatlifecycle,theperceptionofcriticalityasacontinuumratherthanabinarystateismoreuseful.Allattributesandparametersshouldbeevaluatedintermsoftheirrolesintheprocessandimpactontheproductorin-processmaterial,andreevaluatedasnewinformationbecomesavailable.Thedegreeofcontroloverthoseattributesorparametersshouldbecommensuratewiththeirrisktotheprocessandprocessoutput.Inotherwords,ahigherdegreeofcontrolisappropriateforattributesorparametersthatposeahigherrisk.TheAgencyrecognizesthatterminologyusagecanvaryandexpectsthateachmanufacturerwillcommunicatethemeaningandintentofitsterminologyandcategorizationtotheAgency.?專業(yè)名詞屬性〔例如質(zhì)量、產(chǎn)品、組分〕和參數(shù)〔例如工藝、操作和設(shè)備〕，在本指南中，不以其關(guān)鍵程度加以分類。在整個生命周期中，使用基于風(fēng)險的決策的生命周期方法進展工藝驗證，將關(guān)鍵程度視為連續(xù)態(tài)而不是非此即彼的二元態(tài)更為有用。全部的屬性和參數(shù)，應(yīng)當(dāng)從它們在工藝中發(fā)揮作用和對產(chǎn)品或在加工材料發(fā)生影響的角度進展評估，并在信息變得合用時重進展評估。對這些屬性或參數(shù)的掌握程度，應(yīng)當(dāng)與其對工藝和工藝輸出的風(fēng)險相稱。換句話說，對風(fēng)險較高的屬性或參數(shù)，更高程度的掌握是恰當(dāng)?shù)摹１緳C構(gòu)生疏到，專業(yè)名詞的使用可能有差異，并期望全部生產(chǎn)商就其專業(yè)名詞及歸類的內(nèi)涵和含義與本機構(gòu)溝通。Manyproductsaresingle-sourceorinvolvecomplicatedmanufacturingprocesses.Homogeneitywithinabatchandconsistencybetweenbatchesaregoalsofprocessvalidationactivities.Validationoffersassurancethataprocessisreasonablyprotectedagainstsourcesofvariabilitythatcouldaffectproductionoutput,causesupplyproblems,andnegativelyaffectpublichealth.?很多產(chǎn)品是單一來源或涉及簡單的生產(chǎn)工藝。一個批次內(nèi)的均一性和批間全都性是工藝驗證活動的目標(biāo)。驗證為一個工藝合理防止可能影響生產(chǎn)產(chǎn)出、引起供給問題、以及對公共安康造成負面影響的變異來源賜予保證。Stage1-ProcessDesignB.第一階段-工藝設(shè)計Processdesignistheactivityofdefiningthecommercialmanufacturingprocessthatwillbereflectedinplannedmasterproductionandcontrolrecords.Thegoalofthisstageistodesignaprocesssuitableforroutinecommercialmanufacturingthatcanconsistentlydeliveraproductthatmeetsitsqualityattributes.工藝設(shè)計是界定商品化制造工藝的活動，將通過打算中的主生產(chǎn)和掌握記錄中反映。本階段的目的在于，設(shè)計適合可以始終如一地產(chǎn)出符合其質(zhì)量屬性產(chǎn)品的日常商品化制造工藝。包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程爭論中心“mailto:info@“info@111.BuildingandCapturingProcessKnowledgeandUnderstanding建立和捕獲工藝學(xué)問與理解Generally,earlyprocessdesignexperimentsdonotneedtobeperformedundertheCGMPconditionsrequiredfordrugsintendedforcommercialdistributionthataremanufacturedduringStage2(processqualification)andStage3(continuedprocessverification).Theyshould,however,beconductedinaccordancewithsoundscientificmethodsandprinciples,includinggooddocumentationpractices.ThisnsthH0lysjustificationofthecontrolsshouldbesufficientlydocumentedandinternallyreviewedtoverifyandpreservetheirvalueforuseoradaptationlaterinthelifecycleoftheprocessandproduct.通常，早期工藝設(shè)計試驗不需在CGMP條件下進展，CGMP為擬用于商業(yè)流通的藥品在其次階段〔工藝確認〕和第三階段〔持續(xù)工藝核實所必需〕。但是，早期工藝設(shè)計試驗應(yīng)當(dāng)依照牢靠的科學(xué)方法和原則進展，包括藥品文件編制治理標(biāo)準(zhǔn)。該建議與ICHQ10《藥品質(zhì)量體系》全都。12掌握的決策和正值理由應(yīng)有足夠文件證明并經(jīng)內(nèi)部審核，以核實和維護決策及正值理由在隨后的工藝和產(chǎn)品生命周期內(nèi)的應(yīng)用和改編價值。Althoughoftenperformedatsmall-scalelaboratories,mostviralinactivationandimpurityclearancestudiescannotbeconsideredearlyprocessdesignexperiments.Viralandimpurityclearancestudiesintendedtoevaluateandestimateproductqualityatcommercialscaleshouldhavealevelofqualityunitoversightthatwillensurethatthestudiesfollowsoundscientificmethodsandprinciplesandtheconclusionsaresupportedbythedata.盡管常常在小型試驗室中開展，絕大局部的病毒滅活和雜質(zhì)去除爭論不能被視為早期工藝設(shè)計試驗。原打算用來與商品化大生產(chǎn)對產(chǎn)品質(zhì)量進展評估和估量病毒和雜質(zhì)去除爭論應(yīng)當(dāng)具備質(zhì)量部門監(jiān)視水準(zhǔn)，這樣的監(jiān)視水準(zhǔn)將保證爭論遵照牢靠的科學(xué)方法和原則，并保證結(jié)論由數(shù)據(jù)支持。Productdevelopmentactivitiesprovidekeyinputstotheprocessdesignstage,suchastheintendeddosageform,thequalityattributes,andageneralmanufacturingpathway.Processinformationavailablefromproductdevelopmentactivitiescanbeleveragedintheprocessdesignstage.Thefunctionalityandli