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1、GuidanceforIndustry行业指南ProcessValidation:GeneralPrinciplesandPractices工艺验证:一般原则与标准U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforBiologiesEvaluationandResearch(CBER)CenterforVeterinaryMedicine(CVM)January2023CurrentGoodManufacturingPra
2、ctices(CGMP)Revision1美国卫生与人类效劳部食品药品治理局药物评价和争论中心(CDER)生物制品评价和争论中心(CBER)兽药中心(CVM)2023年1月现行药品质量生产治理标准(CGMP)1包含不具约束力的建议中文译稿:北京大学药物信息与工程争论中心GuidanceforIndustry行业指南ProcessValidation:GeneralPrinciplesandPractices工艺验证:一般原则与标准Additionalcopiesareavailablefrom:OfficeofCommunicationsDivisionofDrugInformation,W0
3、51,Room220110903NewHampshireAve.SilverSpring,MD20993Phone:301-796-3400;Fax:301-847-8714另外的副本可从以下部门得到:马里兰州银泉市罕布什尔大道10193号2201室药品信息处,对夕He息办公室,邮政编码:20993:301-796-3400;:301-847-8714TableofContents名目I.一简介1.二.背景3A.B.B.工艺验证方法5I11.STATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION7IV.四.建议9A.B.B.第一阶段-工艺i
4、S101.2.2.建立工艺掌握策略12C.其次阶段-工艺确认141.2.3.4.5.6.4.工艺性能确认执行与报告19D.第三阶段-持续工艺验证20V .VI六.文件记录24VII.七.分析方法24包含不具约束力的建议中文译稿:北京大学药物信息与工程争论中心1GuidanceforIndustryi行业指南1ProcessValidation:GeneralPrinciplesandPractices工艺验证:一般原则与实施ThisguidancerepresentstheFoodandDrugAdministration/s(FDA*s)currentthinkingonthistopic.
5、ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.Ifyoucannoti
6、dentifytheappropriateFDAStaftcalltheappropriatenumberlistedonthetitleofthisguidance.本指南表达了食品药品治理局(FDA)关于这一主题的最见解。本指南不为任何人或对任何人才制造或赐予任何权利,不起束缚FDA或公众的作用。假设替代方法能够满足适用法律、法规的要求,您可以使用替代方法。假设您期望争论一种替代性方法,请与负责执行本指南的FDA工作人员联系。假设您不能确定相应的FDA工作人员,请拨打本指南标题页所列的相应号码。I.INTRODUCTION一简介Thisguidanceoutlinesthegeneralp
7、rinciplesandapproachesthatFDAconsidersappropriateelementsofprocessvalidationforthemanufactureofhumanandanimaldrugandbiologicalproducts,includingactivepharmaceuticalingredients(APIsordrugsubstances),collectivelyreferredtointhisguidanceasdrugsorproducts.Thisguidanceincorporatesprinciplesandapproachest
8、hatallmanufacturerscanusetovalidatemanufacturingprocesses.本指南概述了FDA认为是包括原料药在内的人与动物用药和生物制品在本指南中合称为药品或制品生产工艺验证相应要素的一般原则和方法。该指南收编了全部生产商可用于验证生产工艺的多种原则和方法。ThisguidancealignsprocessvalidationactivitieswithaproductlifecycleconceptandwithexistingFDAguidance,includingtheFDA/InternationalConferenceonHarmonisa
9、tion(ICH)guidancesforindustry,Q8(R2)PharmaceuticalDeVeloPmenQ9QualityRiskManagemepbndQlOPharmaceuticalQualitySySte叨Althoughthisguidancedoesnotrepeattheconceptsandprinciplesexplainedinthoseguidances,FDAencouragestheuseofmodernpharmaceuticaldevelopmentconcepts,qualityriskmanagement,andqualitysystemsat
10、allstagesofthemanufacturingprocesslifecycle.本指南将工艺验证活动与产品生命周期概念和现有FDA指南进展了对齐,包括FDA/人用药1ThisguidancehasbeenpreparedbytheDivisionofManufacturingandProductQuality,CenterforDrugEvaluationandResearch(CDER),incooperationwithCDER,SOfficeofPharmaceuticalSciences,theCenterforBiologiesEvaluationandResearch(CB
11、ER),theOfficeofRegulatoryAffairs(ORA)andtheCenterforVeterinaryMedicine(CVM)attheFoodandDrugAdministration.】本指南由FDA制造与产品质量处、药物评价与争论中心CDER与CDER药物科学办公室、生物制品评价与争论中心(CBER、监管事物办公室(ORA)和兽药中心(CVM)合作编制。包含不具约束力的建议中文译稿:北京大学药物信息与工程争论中心2品注册技术标准国际协调会议(ICH)行业指南,Q8(R2)药品开发、Q9质量风险治理和QlO药品质量体系。2尽管本指南不复述那些指南解释的概念或原则,但
12、FDA鼓舞在药物工艺生命周期全部阶段使用现代药物开发概念、质量风险治理和质量体系。Thelifecycleconceptlinksproductandprocessdevelopment,qualificationofthecommercialmanufacturingprocess,3andmaintenanceoftheprocessinastateofcontrolduringroutinecommercialproduction.Thisguidancesupportsprocessimprovementandinnovationthroughsoundscience.生命周期概念连接
13、产品和工艺开发、商品化生产工艺确认3、以及日常商品化制造中处于受控状态的过程维护。本指南通过牢靠的科学为工艺改进和创供给支持。Thisguidancecoversthefollowingcategoriesofdrugs: Humandrugs Veterinarydrugs Biologicalandbiotechnologyproducts Finishedproductsandactivepharmaceuticalingredients(APIsordrugsubstances Thedrugconstituentofacombination(drugandmedicaldevice)
14、product本指南涵盖以下类别的药物: 人用药 兽用药 生物和生物技术制品 制剂产品和活性药物成分原料药或药用物质4 组合产品药物和医疗器械的药物组分Thisguidancedoesnotcoverthefollowingtypesofproducts: TypeAmedicatedarticlesandmedicatedfeed Medicaldevices5 Dietarysupplements Humantissuesintendedfortransplantationregulatedundersection361ofthePublicHealthService2Tomakesure
15、youhavethemostrecentversionofaguidance,checktheCDERguidanceat3Act6本指南不涵盖以下类型产品: A类添加药物产品或添加药物饲料 医疗器械5 膳食补充剂 受公共卫生效劳法第361节监管的拟用于移植的人体组织6Thisguidancedoesnotspecifywhatinformationshouldbeincludedaspartofaregulatorysubmission.InterestedpersonscanrefertotheappropriateguidanceorcontacttheappropriateCenter
16、indeterminingthetypeofinformationtoincludeinasubmission.本指南没有具体说明哪些信息应当包括在监管提交文件局部中。有兴趣的人士可以参考相应指南或联系相应中心以确定应包括在提交文件中的信息类型。Thisguidancealsodoesnotspecificallydiscussthevalidationofautomatedprocesscontrolsystems(i.e.,computerhardwareandsoftwareinterfaces),whicharecommonlyintegratedintomoderndrugmanuf
17、acturingequipment.Thisguidanceisrelevant,however,tothevalidationofprocessesthatincludeautomatedequipmentinprocessing.本指南也没有具体争论自动化工艺掌握系统验证即计算机硬件和软件界面,这些自动化掌握系统通常集成在现代化药物生产设备中。然而,该指南与包括工艺过程自动设备在内的工艺验证有关。FDA,sguidancedocuments,includingthisguidance,donotestablishlegallyenforceableresponsibilities.Inst
18、ead,guidancesdescribetheAgencyscurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.FDA的指南文件,包括本指南在内,没有规定依法强制执行责任。相反,除非引述具体的监管或法规要求,指南描述的是本
19、机构目前对该主题的看法,应当仅仅被视为建议。在本机构指南中所使用的应当一词,指建议或推举某事,并非必需的。ILBACKGROUNDIntheFederalRegisterofMay11,1987(52FR17638),FDAissuedanoticeannouncingtheavailabilityofaguidanceentitledGuidelineonGeneralPrinciplesofProcessVaIidatie1987guidance).7Sincethen,wehaveobtainedadditionalexperiencethroughourregulatoryoversi
20、ghtthatallowsustoupdateourrecommendationstoindustryonthistopicThisrevisedguidanceconveysFDA,scurrentthinkingonprocessvalidationandisconsistentwithbasicprinciplesfirstintroducedinthe1987guidance.TherevisedguidancealsoprovidesrecommendationsthatreflectsomeofthegoalsofFDA,sinitiativeentitledPharmaceuti
21、cal5Guidanceonprocessvalidationformedicaldevicesisprovidedinaseparatedocument,QualityManagementSystemsProcessValidation,edition2,availableat4CGMPsforthe21stCentury-ARisk-BasedApproach/particularlywithregardtotheuseoftechnologicaladvancesinpharmaceuticalmanufacturing,aswellasimplementationofmodernris
22、kmanagementandqualitysystemtoolsandConCePtS用ThiSrevisedguidancereplacesthe1987guidance.1987年5月11日,FDA在联邦公告(52FR17638)上公布公告,宣布题为工艺验证一般原则指导原则的指南1987年版指南面世。7从那时起,通过监管监视,我们能够在此主题上更对业界的建议,使我们获得了更多阅历。该指南传达了FDA目前对工艺验证的看法,并与1987年版指南首次提出的根本原则相全都。指南还提出了一些反映FDA21世纪制药行业现行药品生产治理标准种基于风险的方法打算的假设干目标的建议,特别是关于药品生产中技术
23、进步的应用,以及对现代风险治理和质量体系的工具及概念的实施。8该指南取代1987年版指南。FDAhastheauthorityandresponsibilitytoinspectandevaluateprocessvalidationperformedbymanufacturers.TheCGMPregulationsforvalidatingpharmaceutical(drug)manufacturingrequirethatdrugproductsbeproducedwithahighdegreeofassuranceofmeetingalltheattributestheyareint
24、endedtopossess(21CFR211.100(a)and211.110(a).FDA有权力和责任对由生产商实施的工艺验证进展检蛰和评估。用于验证制药的CGMP法规要求药品在高度保证符合全部预期拥有属性的状况下生产(联邦法规21编122.100(a)和211.110(a)。A.ProcessValidationandDrugQualityA.工艺验证与药品质量Effectiveprocessvalidationcontributessignificantlytoassuringdrugquality.Thebasicprincipleofqualityassuranceisthatad
25、rugshouldbeproducedthatisfitforitsintendeduse.Thisprincipleincorporatestheunderstandingthatthefollowingconditionsexist: Quality,safety,andefficacyaredesignedorbuiltintotheproduct. Qualitycannotbeadequatelyassuredmerelybyin-processandfinished-productinspectionortesting. Eachstepofamanufacturingproces
26、siscontrolledtoassurethatthefinishedproductmeetsallqualityattributesincludingspecifications.有效的工艺验证对保证药品质量做出了重要奉献。质量保证的根本原则在于生产出来的药品符合其预定用途。该原则包括对存在以下状况的理解: 质量、安全性和成效被设计或构建于产品之中。The1987guidancewaspreparedbyaworkinggroupthatincludedrepresentationfromtheCenterforDevicesandRadiologicalHealth(CDRH),Sinc
27、ethattime,CDRHelectedtoreferenceaprocessvalidationguidancepreparedincooperationwiththeGlobalHarmonizationTaskForce(GHTF),Theprinciplesandrecommendationsinthatdocument,QualityManagementSystems-ProcessValidation,edition2(availableontheInternetat5 质量不能仅通过生产中检查或检测以及成品检杳或检测赐予充分保证。 生产工艺的每一步均予以掌握,确保成品符合包括规
28、格在内全部质量属性。B.ApproachtoProcessValidationB.工艺验证方法Forpurposesofthisguidance,processvalidationisdefinedasthecollectionandevaluationofdata,fromtheprocessdesignstagethroughcommercialproduction,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproduct.Processvalidationin
29、volvesaseriesofactivitiestakingplaceoverthelifecycleoftheproductandprocess.Thisguidancedescribesprocessvalidationactivitiesinthreestages.就本指南而言,工艺验证被定义为从工艺设计阶段到商业生产的整个过程中,对数据进展收集和评价,建立能够使工艺能够始终如一地传递到优质产品中的科学证据。工艺验证涉及整个产品生命周期和生产中发生的一系列活动。本指南分三个阶段对工艺验证进展说明。 Stage1-ProcessDesign:Thecommercialmanufactur
30、ingprocessisdefinedduringthisstagebasedonknowledgegainedthroughdevelopmentandscale-upactivities. 第一阶段工艺设计:在开发和放大活动过程中获得的学问根底上,在此阶段对商品化制造工艺进展定义。 Stage2-ProcessQualification:Duringthisstage,theprocessdesignisevaluatedtodetermineiftheprocessiscapableofreproduciblecommercialmanufacturing. 其次阶段工艺确认:在此阶段,
31、对工艺设计进展评估,以确认工艺是否具备可重现的商品化制造力量。 Stage3-ContinuedProcessVerification:Ongoingassuranceisgainedduringroutineproductionthattheprocessremainsinastateofcontrol. 第三阶段持续工艺核实:在日常生产中获得工艺保持处于受控状态的持续和不断进展的保证。Thisguidancedescribesactivitiestypicalofeachstage,butinpractice,someactivitiesmightoccurinmultiplestages
32、.本指南对每个阶段的典型活动进展了说明,但在实践中,有些活动可能发生于多个阶段。Beforeanybatchfromtheprocessiscommerciallydistributedforusebyconsumers,amanufacturershouldhavegainedahighdegreeofassuranceintheperformanceofthemanufacturingprocesssuchthatitwillconsistentlyproduceAPIsanddrugproductsmeetingthoseattributesrelatingtoidentity,stre
33、ngth,quality,purity,andpotency.Theassuranceshouldbeobtainedfromobjectiveinformationanddatafromlaboratory-,pilot-,and/orcommercial-scalestudies.Informationanddatashoulddemonstratethatthecommercialmanufacturingprocessiscapableofconsistentlyproducingacceptablequalityproductswithincommercialmanufacturin
34、gconditions.经工艺生产出任何批次产品经过商业流通给消费者使用之前,生产商应在生产工艺性能方面取得高度保证,以始终如一地生产出满足与鉴别、含量、质量、纯度和效价相关的那些属性的原料药和药品。这些保证应当从来自于试验室小试、中试、和/或商品化大生产争论的客观信息或数据获得。信息和数据应当显示,商品化制造工艺应能在商品化制造条件下始终如包含不具约束力的建议中文译稿:北京大学药物信息与工程争论中心6一地生产出合格的优质产品。Asuccessfulvalidationprogramdependsuponinformationandknowledgefromproductandprocessd
35、evelopment.Thisknowledgeandunderstandingisthebasisforestablishinganapproachtocontrolofthemanufacturingprocessthatresultsinproductswiththedesiredqualityattributes.Manufacturersshould:一个成功的验证方案取决于来自产品和工艺开发的学问。这种学问和理解是建立能够生产出具备期望得到的质量属性产品生产工艺掌握方法的根底。制造商应当: Understandthesourcesofvariation 了解变异来源 Detectt
36、hepresenceanddegreeofvariation 探测变异存在和程度 Understandtheimpactofvariationontheprocessandultimatelyonproductattributes了解变异对工艺和最终对产品属性的影响Controlthevariationinamannercommensuratewiththeriskitrepresentstotheprocessandproduct用与代表工艺与产品风险相称的方式掌握变异。Eachmanufacturershouldjudgewhetherithasgainedsufficientunders
37、tandingtoprovideahighdegreeofassuranceinitsmanufacturingprocesstojustifycommercialdistributionofthemanufacturingprocessandassociatedvariationsmaynotleadtoadequateassuranceofquality.Afterestablishingandconfirmingtheprocess,manufacturersmustmaintaintheprocessinastateofcontroloverthelifeoftheprocess,ev
38、enasmaterials,equipment,productionenvironment,personnel,andmanufacturingprocedureschange.9全部生产商均应推断是否已经对生产工艺供给高度保证获得足够理解,为产品商业流通供给保证。只是专注于确认努力,而无视对生产工艺和相关变异的关注,不能导致对质量的充分保证。在建立和确认工艺之后,生产商必需保持工艺在工艺生命期内处于受控状态,即便是材料、设备、生产环境、人员和生产工序发生变更的状况下。9Manufacturersshoulduseongoingprogramstocollectandanalyzeproduc
39、tandprocessdatatoevaluatethestateofcontroloftheprocess.TheseprogramsmayidentifyprocessorproductproblemsoropportunitiesforprocessimprovementsthatcanbeevaluatedandimplementedthroughsomeoftheactivitiesdescribedinStages1and2.生产商应使用持续和不断进展的方案收集分析产品和工艺数据,对工艺受控状态进展评估。这些方案可以确定工艺或产品问题,或找出工艺改善的适当时机,这些时机可以通过在第
40、一阶段和其次阶段中描述的一些活动进展评估和实施。Manufacturersoflegacyproductscantakeadvantageoftheknowledgegainedfromtheoriginalprocessdevelopmentandqualificationworkaswellasmanufacturingexperiencetocontinuallyimprovetheir9ThestatuteandregulationsdescribedinsectionI11ofthisguidanceexplaintherequirementthatthemethodsandfaci
41、litiesusedforthemanufacturingofdrugsbeoperatedandadministeredundercontrolsufficienttoassurethattheidentity,strength,purity,andqualityofadrugareastheypurportorarerepresentedtopossess.9本指南第三节描述的法规和章程,对处于掌握之下的用于制药的方法与设施的操作及治理要求作出了说明,掌握应足以保证其声称或据称具有的鉴别、含量、质量、纯度和效价。包含不具约束力的建议中文译稿:北京大学药物信息与工程争论中心7processe
42、s.ImplementationoftherecommendationsinthisguidanceforlegacyproductsandprocesseswouldlikelybeginwiththeactivitiesdescribedinStage3.传统产品生产商可利用从原先的工艺开发和确认工作、以及生产阅历中获得的学问,不断改进工艺。本指南中对传统产品和工艺建议的实施,可能会始于第三阶段所描述的活动。IILSTATUTORYANDREGULATORYREQUIREMENTSFORPROCESSVALIDATION.对工艺验证的法规和监管要求Processvalidationford
43、rugs(finishedpharmaceuticalsandcomponents)isalegallyenforceablerequirementundersection501(B)oftheAct(21U.S.C.351(a)(2)(B),whichstatesthefollowing:依据法令美国联邦法典U.S.C.351(B),21编)501(a)(B)节,药物药物成品与组分工艺验证依法强制执行,其规定如下:Adrug.shallbedeemedtobeadulterated.if.themethodsusedin,orthefacilitiesorcontrolsusedfor,it
44、smanufacture,processing,packing,orholdingdonotconformtoorarenotoperatedoradministeredinconformitywithcurrentgoodmanufacturingpracticetoassurethatsuchdrugmeetstherequirementsofthisActastosafetyandhastheidentityandstrength,andmeetsthequalityandpuritycharacteristics,whichitpurportsorisrepresentedtoposs
45、ess.一种药品应当被视为掺假药品假设使用于制造、加工、包装或置放的方法或设施、掌握装置不符合或没有遵照在安全性上保证药品符合本法令的规定,并保证符合其声称或据称的鉴别和含量、质量和纯度特征的现行药品生产质量管理标准操作和治理。FDAregulationsdescribingcurrentgoodmanufacturingpractice(CGMP)forfinishedpharmaceuticalsareprovidedin21CFRparts210and211.对用于成品的现行药品生产质量治理标准CGMP进展说明的FDA法规,见美国联邦法规第21编第210和211节。TheCGMPregu
46、lationsrequirethatmanufacturingprocessesbedesignedandcontrolledtoassurethatin-processmaterialsandthefinishedproductmeetpredeterminedqualityrequirementsanddosoconsistentlyandreliably.Processvalidationisrequired,inbothgeneralandspecificterms,bytheCGMPregulationsinparts210and211.Thefoundationforprocess
47、validationisprovidedin211.100(a)zwhichstatesthatothereshallbewrittenproceduresforproductionandprocessControldesignedtoassurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess.”(emphasisadded).Thisregulationrequiresmanufacturerstodesignaprocess,includingoperationsandcontrols,whichresultsinaproductmeetingtheseattributes.CGMP法规要求对生产工艺进展设计与掌握以保证在加工材料和成品符合预订的质量要求并始终如一和确实地这样做。依据CGMP第210和211节,在一般条款和具体条款中,工艺验证是必需的。在211.100(a)中,规定了工艺验证的根底,其中规定应当有用于保证药品具有其宣称或据称全部的鉴别、含量、质量、纯度的生产和工艺掌握的书面程序”强调。该法规要
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