2023年FDA工藝驗(yàn)證指南(中文版)

GuidanceforIndustry行業(yè)指南ProcessValidation:GeneralPrinciplesandPractices工藝驗(yàn)證：一般原則與標(biāo)準(zhǔn)U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforBiologicsEvaluationandResearch(CBER)CenterforVeterinaryMedicine(CVM)January2023CurrentGoodManufacturingPractices(CGMP)Revision1美國(guó)衛(wèi)生與人類效勞部食品藥品治理局藥物評(píng)價(jià)和爭(zhēng)論中心〔CDER〕生物制品評(píng)價(jià)和爭(zhēng)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(zhēng)論中心“mailto:info@“info@GuidanceforIndustry行業(yè)指南ProcessValidation:GeneralPrinciplesandPractices工藝驗(yàn)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(mén)得到：馬里蘭州銀泉市罕布什爾大道10193號(hào)2201室藥品信息處，對(duì)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(jiǎn)介 1\l“_TOC_250028“BACKGROUND 3二.背景 3\l“_TOC_250027“A.ProcessValidationandDrugQuality 4\l“_TOC_250026“工藝驗(yàn)證與藥品質(zhì)量 4\l“_TOC_250025“ApproachtoProcessValidation 5B.工藝驗(yàn)證方法 5STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION 7\l“_TOC_250024“三.對(duì)工藝驗(yàn)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(duì)工藝驗(yàn)證的總體考慮 9\l“_TOC_250020“Stage1-ProcessDesign 10B.第一階段-工藝設(shè)計(jì) 10\l“_TOC_250019“1.BuildingandCapturingProcessKnowledgeandUnderstanding 11\l“_TOC_250018“建立和捕獲工藝學(xué)問(wèn)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(rèn) 14\l“_TOC_250015“1.DesignofaFacilityandQualificationofUtilitiesandEquipment 14\l“_TOC_250014“廠房設(shè)施設(shè)計(jì)以及公用設(shè)施與設(shè)備確認(rèn) 14\l“_TOC_250013“ProcessPerformanceQualification 16\l“_TOC_250012“工藝性能確認(rèn) 16\l“_TOC_250011“PPQProtocol 17\l“_TOC_250010“工藝性能確認(rèn)方案 17\l“_TOC_250009“PPQProtocolExecutionandReport 194.工藝性能確認(rèn)執(zhí)行與報(bào)告 19\l“_TOC_250008“D.Stage3-ContinuedProcessVerification 20D.第三階段-持續(xù)工藝驗(yàn)證 20\l“_TOC_250007“CONCURRENTRELEASEOFPPQBATCHES 22\l“_TOC_250006“五.工藝性能確認(rèn)批次的同時(shí)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(yǔ)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(zhēng)論中心“mailto:info@“info@1GuidanceforIndustry1行業(yè)指南1ProcessValidation:GeneralPrinciplesandPractices工藝驗(yàn)證：一般原則與實(shí)施ThisguidancerepresentstheFoodandDrugAdministration’s(FDA’s)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheappropriatenumberlistedonthetitleofthisguidance.本指南表達(dá)了食品藥品治理局〔FDA〕關(guān)于這一主題的最見(jiàn)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(zhēng)論一種替代性方法，請(qǐng)與負(fù)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(qǐng)撥打本指南標(biāo)題頁(yè)所列的相應(yīng)號(hào)碼。INTRODUCTION一.簡(jiǎn)介T(mén)hisguidanceoutlinesthegeneralprinciplesandapproachesthatFDAconsidersappropriateelementsofprocessvalidationforthemanufactureofhumanandanimaldrugandbiologicalproducts,includingactivepharmaceuticalingredients(APIsordrugsubstances),collectivelyreferredtointhisguidanceasdrugsorproducts.Thisguidanceincorporatesprinciplesandapproachesthatallmanufacturerscanusetovalidatemanufacturingprocesses.本指南概述了FDA認(rèn)為是包括原料藥在內(nèi)的人與動(dòng)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(yàn)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(yàn)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(yàn)證活動(dòng)與產(chǎn)品生命周期概念和現(xiàn)有FDA指南進(jìn)展了對(duì)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(píng)價(jià)與爭(zhēng)論中心〔CDER〕與CDER藥物科學(xué)辦公室、生物制品評(píng)價(jià)與爭(zhēng)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(zhēng)論中心“mailto:info@“info@2品注冊(cè)技術(shù)標(biāo)準(zhǔn)國(guó)際協(xié)調(diào)會(huì)議(ICH)行業(yè)指南，Q8(R2)《藥品開(kāi)發(fā)》、Q9《質(zhì)量風(fēng)險(xiǎn)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(kāi)發(fā)概念、質(zhì)量風(fēng)險(xiǎn)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(kāi)發(fā)、商品化生產(chǎn)工藝確認(rèn)3、以及日常商品化制造中處于受控狀態(tài)的過(guò)程維護(hù)。本指南通過(guò)牢靠的科學(xué)為工藝改進(jìn)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(bǔ)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(méi)有具體說(shuō)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(méi)有具體爭(zhēng)論自動(dòng)化工藝掌握系統(tǒng)驗(yàn)證〔即計(jì)算機(jī)硬件和軟件界面〕，這些自動(dòng)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(guò)程自動(dòng)設(shè)備在內(nèi)的工藝驗(yàn)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(méi)有規(guī)定依法強(qiáng)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(jī)構(gòu)目前對(duì)該主題的看法，應(yīng)當(dāng)僅僅被視為建議。在本機(jī)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(yàn)證一般原則指導(dǎo)原則》的指南〔1987年版指南〕面世。7從那時(shí)起，通過(guò)監(jiān)管監(jiān)視，我們能夠在此主題上更對(duì)業(yè)界的建議，使我們獲得了更多閱歷。該指南傳達(dá)了FDA目前對(duì)工藝驗(yàn)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(xiǎn)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(jìn)步的應(yīng)用，以及對(duì)現(xiàn)代風(fēng)險(xiǎn)治理和質(zhì)量體系的工具及概念的實(shí)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(yàn)證與藥品質(zhì)量Effectiveprocessvalidationcontributessignificantlytoassuringdrugquality.Thebasicprincipleofqualityassuranceisthatadrugshouldbeproducedthatisfitforitsintendeduse.Thisprincipleincorporatestheunderstandingthatthefollowingconditionsexist:Quality,safety,andefficacyaredesignedorbuiltintotheproduct.Qualitycannotbeadequatelyassuredmerelybyin-processandfinished-productinspectionortesting.Eachstepofamanufacturingprocessiscontrolledtoassurethatthefinishedproductmeetsallqualityattributesincludingspecifications.有效的工藝驗(yàn)證對(duì)保證藥品質(zhì)量做出了重要奉獻(xiàn)。質(zhì)量保證的根本原則在于生產(chǎn)出來(lái)的藥品符合其預(yù)定用途。該原則包括對(duì)存在以下?tīng)顩r的理解：質(zhì)量、安全性和成效被設(shè)計(jì)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(guò)生產(chǎn)中檢查或檢測(cè)以及成品檢查或檢測(cè)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(yàn)證方法Forpurposesofthisguidance,processvalidation isdefinedasthecollectionandevaluationofdata,fromtheprocessdesignstagethroughcommercialproduction,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproduct.Processvalidationinvolvesaseriesofactivitiestakingplaceoverthelifecycleoftheproductandprocess.Thisguidancedescribesprocessvalidationactivitiesinthreestages.就本指南而言，工藝驗(yàn)證被定義為從工藝設(shè)計(jì)階段到商業(yè)生產(chǎn)的整個(gè)過(guò)程中，對(duì)數(shù)據(jù)進(jìn)展收集和評(píng)價(jià)，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(yàn)證涉及整個(gè)產(chǎn)品生命周期和生產(chǎn)中發(fā)生的一系列活動(dòng)。本指南分三個(gè)階段對(duì)工藝驗(yàn)證進(jìn)展說(shuō)明。Stage1–ProcessDesign:Thecommercialmanufacturingprocessisdefinedduringthisstagebasedonknowledgegainedthroughdevelopmentandscale-upactivities.第一階段 工藝設(shè)計(jì):在開(kāi)發(fā)和放大活動(dòng)過(guò)程中獲得的學(xué)問(wèn)根底上，在此階段對(duì)商品化制造工藝進(jìn)展定義。Stage2–ProcessQualification:Duringthisstage,theprocessdesignisevaluatedtodetermineiftheprocessiscapableofreproduciblecommercialmanufacturing.其次階段 工藝確認(rèn):在此階段，對(duì)工藝設(shè)計(jì)進(jìn)展評(píng)估，以確認(rèn)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(shí):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(jìn)展的保證。Thisguidancedescribesactivitiestypicalofeachstage,butinpractice,someactivitiesmightoccurinmultiplestages.本指南對(duì)每個(gè)階段的典型活動(dòng)進(jìn)展了說(shuō)明，但在實(shí)踐中，有些活動(dòng)可能發(fā)生于多個(gè)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(guò)商業(yè)流通給消費(fèi)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(jià)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(lái)自于試驗(yàn)室小試、中試、和/或商品化大生產(chǎn)爭(zhēng)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(zhēng)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(gè)成功的驗(yàn)證方案取決于來(lái)自產(chǎn)品和工藝開(kāi)發(fā)的學(xué)問(wèn)。這種學(xué)問(wèn)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(lái)源Detectthepresenceanddegreeofvariation探測(cè)變異存在和程度Understandtheimpactofvariationontheprocessandultimatelyonproductattributes了解變異對(duì)工藝和最終對(duì)產(chǎn)品屬性的影響Controlthevariationinamannercommensuratewiththeriskitrepresentstotheprocessandproduct用與代表工藝與產(chǎn)品風(fēng)險(xiǎn)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(duì)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(rèn)努力，而無(wú)視對(duì)生產(chǎn)工藝和相關(guān)變異的關(guān)注，不能導(dǎo)致對(duì)質(zhì)量的充分保證。在建立和確認(rèn)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(jìn)展的方案收集分析產(chǎn)品和工藝數(shù)據(jù)，對(duì)工藝受控狀態(tài)進(jìn)展評(píng)估。這些方案可以確定工藝或產(chǎn)品問(wèn)題，或找出工藝改善的適當(dāng)時(shí)機(jī)，這些時(shí)機(jī)可以通過(guò)在第一階段和其次階段中描述的一些活動(dòng)進(jìn)展評(píng)估和實(shí)施。Manufacturersoflegacyproductscantakeadvantageoftheknowledgegainedfromtheoriginalprocessdevelopmentandqualificationworkaswellasmanufacturingexperiencetocontinuallyimprovetheir9ThestatuteandregulationsdescribedinsectionIIIofthisguidanceexplaintherequirementthatthemethodsandfacilitiesusedforthemanufacturingofdrugsbeoperatedandadministeredundercontrolsufficienttoassurethattheidentity,strength,purity,andqualityofadrugareastheypurportorarerepresentedtopossess.9本指南第三節(jié)描述的法規(guī)和章程，對(duì)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(shuō)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(jià)。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(zhēng)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(kāi)發(fā)和確認(rèn)工作、以及生產(chǎn)閱歷中獲得的學(xué)問(wèn)，不斷改進(jìn)工藝。本指南中對(duì)傳統(tǒng)產(chǎn)品和工藝建議的實(shí)施，可能會(huì)始于第三階段所描述的活動(dòng)。STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION三.對(duì)工藝驗(yàn)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(guó)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(yàn)證依法強(qiáng)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(méi)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(duì)用于成品的現(xiàn)行藥品生產(chǎn)質(zhì)量治理標(biāo)準(zhǔn)〔CGMP〕進(jìn)展說(shuō)明的FDA法規(guī)，見(jiàn)《美國(guó)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(duì)生產(chǎn)工藝進(jìn)展設(shè)計(jì)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(shí)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(yàn)證是必需的。在§211.100(a)中，規(guī)定了工藝驗(yàn)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(shū)面程序……”〔強(qiáng)調(diào)〕。該法規(guī)要求生產(chǎn)商設(shè)計(jì)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(zhēng)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(duì)驗(yàn)證的不同方面進(jìn)展了定義。例如，§211.110(a)在加工材料和藥品的抽樣和檢測(cè)，要求掌握程序“……應(yīng)被建立以監(jiān)測(cè)產(chǎn)量和驗(yàn)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(jìn)展驗(yàn)證。”〔強(qiáng)調(diào)〕。依據(jù)這一法規(guī)，即便設(shè)計(jì)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(duì)驗(yàn)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(jì)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(yàn)證的一個(gè)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(shí)的兩個(gè)原則。第一個(gè)原則是，“……對(duì)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(jìn)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(gè)原則最中間工藝標(biāo)準(zhǔn)做了進(jìn)一步要求“……應(yīng)當(dāng)源于之前認(rèn)可的工藝均值和工藝變異性估量值。這項(xiàng)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(shuō)明和定義了與工藝設(shè)計(jì)、開(kāi)發(fā)和維護(hù)有關(guān)的活動(dòng)。211.180(e)節(jié)要求對(duì)有關(guān)產(chǎn)品質(zhì)量和制造閱歷的信息和數(shù)據(jù)進(jìn)展定期審查，以打算對(duì)已建立工藝的全部變革是否合理和必要。對(duì)產(chǎn)品質(zhì)量與工藝性能不連續(xù)的反響是工藝維護(hù)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(jì)、足夠的尺寸、放置位置適當(dāng)，以利于預(yù)期操作(§211.63)。自動(dòng)化、機(jī)械和電子設(shè)備必需依據(jù)設(shè)計(jì)用來(lái)保證正確性能的書(shū)面打算校準(zhǔn)、檢查或核實(shí)(§211.68)。Insummary,theCGMPregulationsrequirethatmanufacturingprocessesbedesignedandcontrolledtoassurethatin-processmaterialsandthefinishedproductmeetpredeterminedqualityrequirementsanddosoconsistentlyandreliably.總之，CGMP法規(guī)要求生產(chǎn)工藝應(yīng)進(jìn)展設(shè)計(jì)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(shí)地這樣做。RECOMMENDATIONS四.建議Inthefollowingsections,wedescribegeneralconsiderationsforprocessvalidation,therecommendedstagesofprocessvalidation,andspecificactivitiesforeachstageintheproductlifecycle.在下述局部中，我們對(duì)工藝驗(yàn)證的總體考慮、建議的工藝驗(yàn)證和產(chǎn)品生命周期內(nèi)每一階段的特別活動(dòng)進(jìn)展說(shuō)明。A.GeneralConsiderationsforProcessValidation對(duì)工藝驗(yàn)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(wèn)的良好工程治理和良好歸檔將使得工藝驗(yàn)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(píng)價(jià)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(yàn)證承受包括來(lái)自多個(gè)學(xué)科特地學(xué)問(wèn)的綜合團(tuán)隊(duì)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(jì)學(xué)、制造以及質(zhì)量保證〕。工程打算、以及高級(jí)管理團(tuán)隊(duì)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(gè)產(chǎn)品生命周期，可啟動(dòng)不同的爭(zhēng)論，覺(jué)察、觀看、關(guān)聯(lián)或確認(rèn)有關(guān)產(chǎn)品和工藝的信息。全部的爭(zhēng)論，應(yīng)依據(jù)牢靠的科學(xué)原則來(lái)打算和進(jìn)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(gè)生命周期中，使用基于風(fēng)險(xiǎn)的決策的生命周期方法進(jìn)展工藝驗(yàn)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?cè)诠に囍邪l(fā)揮作用和對(duì)產(chǎn)品或在加工材料發(fā)生影響的角度進(jìn)展評(píng)估，并在信息變得合用時(shí)重進(jìn)展評(píng)估。對(duì)這些屬性或參數(shù)的掌握程度，應(yīng)當(dāng)與其對(duì)工藝和工藝輸出的風(fēng)險(xiǎn)相稱。換句話說(shuō)，對(duì)風(fēng)險(xiǎn)較高的屬性或參數(shù)，更高程度的掌握是恰當(dāng)?shù)?。本機(jī)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(jī)構(gòu)溝通。Manyproductsaresingle-sourceorinvolvecomplicatedmanufacturingprocesses.Homogeneitywithinabatchandconsistencybetweenbatchesaregoalsofprocessvalidationactivities.Validationoffersassurancethataprocessisreasonablyprotectedagainstsourcesofvariabilitythatcouldaffectproductionoutput,causesupplyproblems,andnegativelyaffectpublichealth.?很多產(chǎn)品是單一來(lái)源或涉及簡(jiǎn)單的生產(chǎn)工藝。一個(gè)批次內(nèi)的均一性和批間全都性是工藝驗(yàn)證活動(dòng)的目標(biāo)。驗(yàn)證為一個(gè)工藝合理防止可能影響生產(chǎn)產(chǎn)出、引起供給問(wèn)題、以及對(duì)公共安康造成負(fù)面影響的變異來(lái)源賜予保證。Stage1-ProcessDesignB.第一階段-工藝設(shè)計(jì)Processdesignistheactivityofdefiningthecommercialmanufacturingprocessthatwillbereflectedinplannedmasterproductionandcontrolrecords.Thegoalofthisstageistodesignaprocesssuitableforroutinecommercialmanufacturingthatcanconsistentlydeliveraproductthatmeetsitsqualityattributes.工藝設(shè)計(jì)是界定商品化制造工藝的活動(dòng)，將通過(guò)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(jì)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(zhēng)論中心“mailto:info@“info@111.BuildingandCapturingProcessKnowledgeandUnderstanding建立和捕獲工藝學(xué)問(wèn)與理解Generally,earlyprocessdesignexperimentsdonotneedtobeperformedundertheCGMPconditionsrequiredfordrugsintendedforcommercialdistributionthataremanufacturedduringStage2(processqualification)andStage3(continuedprocessverification).Theyshould,however,beconductedinaccordancewithsoundscientificmethodsandprinciples,includinggooddocumentationpractices.ThisnsthH0lysjustificationofthecontrolsshouldbesufficientlydocumentedandinternallyreviewedtoverifyandpreservetheirvalueforuseoradaptationlaterinthelifecycleoftheprocessandproduct.通常，早期工藝設(shè)計(jì)試驗(yàn)不需在CGMP條件下進(jìn)展，CGMP為擬用于商業(yè)流通的藥品在其次階段〔工藝確認(rèn)〕和第三階段〔持續(xù)工藝核實(shí)所必需〕。但是，早期工藝設(shè)計(jì)試驗(yàn)應(yīng)當(dāng)依照牢靠的科學(xué)方法和原則進(jìn)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(shí)和維護(hù)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(jià)值。Althoughoftenperformedatsmall-scalelaboratories,mostviralinactivationandimpurityclearancestudiescannotbeconsideredearlyprocessdesignexperiments.Viralandimpurityclearancestudiesintendedtoevaluateandestimateproductqualityatcommercialscaleshouldhavealevelofqualityunitoversightthatwillensurethatthestudiesfollowsoundscientificmethodsandprinciplesandtheconclusionsaresupportedbythedata.盡管常常在小型試驗(yàn)室中開(kāi)展，絕大局部的病毒滅活和雜質(zhì)去除爭(zhēng)論不能被視為早期工藝設(shè)計(jì)試驗(yàn)。原打算用來(lái)與商品化大生產(chǎn)對(duì)產(chǎn)品質(zhì)量進(jìn)展評(píng)估和估量病毒和雜質(zhì)去除爭(zhēng)論應(yīng)當(dāng)具備質(zhì)量部門(mén)監(jiān)視水準(zhǔn)，這樣的監(jiān)視水準(zhǔn)將保證爭(zhēng)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