Q7A 活性藥物成分(API)的GMP指南

EC_Q7aPAGEPAGE63Q7a（中英文對照）FDA原料藥GMP指南TableofContents目錄1.INTRODUCTION1.簡介1.1Objective1.1目的1.2RegulatoryApplicability1.2法規(guī)的適用性1.3Scope1.3范圍2.QUALITYMANAGEMENT2.質(zhì)量管理2.1Principles2.1總則2.2ResponsibilitiesoftheQualityUnit(s)2.2質(zhì)量部門的責(zé)任2.3ResponsibilityforProductionActivities2.3生產(chǎn)作業(yè)的職責(zé)2.4InternalAudits(SelfInspection)2.4內(nèi)部審計(jì)（自檢）2.5ProductQualityReview2.5產(chǎn)品質(zhì)量審核3.PERSONNEL3.人員3.1PersonnelQualifications3.人員的資質(zhì)3.2PersonnelHygiene3.2人員衛(wèi)生3.3Consultants3.3顧問4.BUILDINGSANDFACILITIES4.建筑和設(shè)施4.1DesignandConstruction4.1設(shè)計(jì)和結(jié)構(gòu)4.2Utilities4.2公用設(shè)施4.3Water4.3水4.4Containment4.4限制4.5Lighting4.5照明4.6SewageandRefuse4.6排污和垃圾4.7SanitationandMaintenance4.7衛(wèi)生和保養(yǎng)5.PROCESSEQUIPMENT5.工藝設(shè)備5.1DesignandConstruction5.1設(shè)計(jì)和結(jié)構(gòu)5.2EquipmentMaintenanceandCleaning5.2設(shè)備保養(yǎng)和清潔5.3Calibration5.3校驗(yàn)5.4ComputerizedSystems5.4計(jì)算機(jī)控制系統(tǒng)6.DOCUMENTATIONANDRECORDS6.文件和記錄6.1DocumentationSystemandSpecifications6.1文件系統(tǒng)和質(zhì)量標(biāo)準(zhǔn)6.2EquipmentcleaningandUseRecord6.2設(shè)備的清潔和使用記錄6.3RecordsofRawMaterials,Intermediates,APILabelingandPackagingMaterials6.3原料、中間體、原料藥的標(biāo)簽和包裝材料的記錄6.4MasterProductionInstructions(MasterProductionandControlRecords)6.4生產(chǎn)工藝規(guī)程（主生產(chǎn)和控制記錄）6.5BatchProductionRecords(BatchProductionandControlRecords)6.5批生產(chǎn)記錄（批生產(chǎn)和控制記錄）6.6LaboratoryControlRecords6.6實(shí)驗(yàn)室控制記錄6.7BatchProductionRecordReview6.7批生產(chǎn)記錄審核7.MATERIALSMANAGEMENT7.物料管理7.1GeneralControls7.1控制通則7.2ReceiptandQuarantine7.2接收和待驗(yàn)7.3SamplingandTestingofIncomingProductionMaterials7.3進(jìn)廠物料的取樣與測試7.4Storage7.4儲存7.5Re-evaluation7.5復(fù)驗(yàn)8.PRODUCTIONANDIN-PROCESSCONTROLS8.生產(chǎn)和過程控制8.1ProductionOperations8.1生產(chǎn)操作8.2TimeLimits8.2時限8.3In-processSamplingandControls8.3工序取樣和控制8.4BlendingBatchesofIntermediatesorAPIs8.4中間體或原料藥的混批8.5ContaminationControl8.5污染控制9.PACKAGINGANDIDENTIFICATIONLABELINGOFAPIsANDINTERMEDIATES9.原料藥和中間體的包裝和貼簽9.1General9.1總則9.2PackagingMaterials9.2包裝材料9.3LabelIssuanceandControl9.3標(biāo)簽發(fā)放與控制9.4PackagingandLabelingOperations9.4包裝和貼簽操作10.STORAGEANDDISTRIBUTION10.儲存和分發(fā)10.1WarehousingProcedures10.1入庫程序10.2DistributionProcedures10.2分發(fā)程序11.LABORATORYCONTROLS11.實(shí)驗(yàn)室控制11.1GeneralControls11.1控制通則11.2TestingofIntermediatesandAPIs11.2中間體和原料藥的測試11.3ValidationofAnalyticalProcedures11.3分析方法的驗(yàn)證11.4CertificatesofAnalysis11.4分析報(bào)告單11.5StabilityMonitoringofAPIs11.5原料藥的穩(wěn)定性監(jiān)測11.6ExpiryandRetestDating11.6有效期和復(fù)驗(yàn)期11.7Reserve/RetentionSamples11.7留樣12.VALIDATION12.驗(yàn)證12.1ValidationPolicy12.1驗(yàn)證方針12.2ValidationDocumentation12.2驗(yàn)證文件12.3Qualification12.3確認(rèn)12.4ApproachestoProcessValidation12.4工藝驗(yàn)證的方法12.5ProcessValidationProgram12.5工藝驗(yàn)證的程序12.6PeriodicReviewofValidatedSystems12.6驗(yàn)證系統(tǒng)的定期審核12.7CleaningValidation12.7清洗驗(yàn)證12.8ValidationofAnalyticalMethods12.8分析方法的驗(yàn)證13.CHANGECONTROL13.變更的控制14.REJECTIONANDRE-USEOFMATERIALS14.拒收和物料的再利用14.1Rejection14.1拒收14.2Reprocessing14.2返工14.3Reworking14.3重新加工14.4RecoveryofMaterialsandSolvents14.4物料與溶劑的回收14.5Returns14.5退貨15.COMPLAINTSANDRECALLS15.投訴與召回16.CONTRACTMANUFACTURERS(INCLUDINGLABORATORIES)16.協(xié)議生產(chǎn)商（包括實(shí)驗(yàn)室）17.AGENTS,BROKERS,TRADERS,DISTRIBUTORS,REPACKERS,ANDRELABELLERS17.代理商、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者17.1Applicability17.1適用性17.2TraceabilityofDistributedAPIsandIntermediates17.2已分發(fā)的原料藥和中間體的可追溯性17.3QualityManagement17.3質(zhì)量管理17.4Repackaging,Relabeling,andHoldingofAPIsandIntermediates17.4原料藥和中間體的重新包裝、重新貼簽和待檢17.5Stability17.5穩(wěn)定性17.6TransferofInformation17.6信息的傳達(dá)17.7HandlingofComplaintsandRecalls17.7投訴和召回的處理17.8HandlingofReturns17.8退貨的處理18.SpecificGuidanceforAPIsManufacturedbyCellCulture/Fermentation18.用細(xì)胞繁殖/發(fā)酵生產(chǎn)的原料藥的特殊指南18.1General18.1總則18.2CellBankMaintenanceandRecordKeeping18.2細(xì)胞庫的維護(hù)和記錄的保存18.3CellCulture/Fermentation18.3細(xì)胞繁殖/發(fā)酵18.4Harvesting,IsolationandPurification18.4收取、分離和精制18.5ViralRemoval/Inactivationsteps18.5病毒的去除/滅活步驟19.APIsforUseinClinicalTrials19.用于臨床研究的原料藥19.1General19.1總則19.2Quality19.2質(zhì)量19.3EquipmentandFacilities19.3設(shè)備和設(shè)施19.4ControlofRawMaterials19.4原料的控制19.5Production19.5生產(chǎn)19.6Validation19.6驗(yàn)證19.7Changes19.7變更19.8LaboratoryControls19.8實(shí)驗(yàn)室控制19.9Documentation19.9文件20.Glossary20.術(shù)語Q7aGMPGuidanceforAPIsQ7a原料藥的GMP指南1.INTRODUCTION1.簡介1.1Objective1.1目的Thisdocumentisintendedtoprovideguidanceregardinggoodmanufacturingpractice(GMP)forthemanufacturingofactivepharmaceuticalingredients(APIs)underanappropriatesystemformanagingquality.ItisalsointendedtohelpensurethatAPIsmeetthequalityandpuritycharacteristicsthattheypurport,orarerepresented,topossess.本文件旨在為在合適的質(zhì)量管理體系下制造活性藥用成分（以下稱原料藥）提供有關(guān)優(yōu)良藥品生產(chǎn)管理規(guī)范（GMP）提供指南。它也著眼于幫助確保原料藥符合其旨在達(dá)到或表明擁有的質(zhì)量與純度要求。Inthisguidance,thetermmanufacturingisdefinedtoincludealloperationsofreceiptofmaterials,production,packaging,repackaging,labeling,relabeling,qualitycontrol,release,storageanddistributionofAPIsandtherelatedcontrols.Inthisguidance,thetermshouldidentifiesrecommendationsthat,whenfollowed,willensurecompliancewithCGMPs.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatues.Forthepurposesofthisguidance,thetermscurrentgoodmanufacturingpracticesandgoodmanufacturingpracticesareequivalent.本指南中所指的“制造”包括物料接收、生產(chǎn)、包裝、重新包裝、貼簽、重新貼簽、質(zhì)量控制、放行、原料藥的儲存和分發(fā)及其相關(guān)控制的所有操作。本指南中，“應(yīng)當(dāng)”一詞表示希望采用的建議，除非證明其不適用或者可用一種已證明有同等或更高質(zhì)量保證水平的供選物來替代。本指南中的“現(xiàn)行優(yōu)良生產(chǎn)管理規(guī)范（cGMP）”和“優(yōu)良生產(chǎn)管理規(guī)范（GMP）”是等同的。Theguidanceasawholedoesnotcoversafetyaspectsforthepersonnelengagedinmanufacturing,noraspectsrelatedtoprotectingtheenvironment.Thesecontrolsareinherentresponsibilitiesofthemanufacturerandaregovernedbynationallaws.本指南在總體上未涉及生產(chǎn)人員的安全問題，亦不包括環(huán)保方面的內(nèi)容。這方面的管理是生產(chǎn)者固有的責(zé)任，也是國家法律規(guī)定的。Thisguidanceisnotintendedtodefineregistrationand/orfilingrequirementsormodifypharmacopoeialrequirements.Thisguidancedoesnotaffecttheabilityoftheresponsibleregulatoryagencytoestablishspecificregistration/filingrequirementsregardingAPIswithinthecontextofmarketing/manufacturingauthorizationsordrugapplications.Allcommitmentsinregistration/filingdocumentsshouldbemet.本指南未規(guī)定注冊/歸檔的要求、或修改藥典的要求。本指南不影響負(fù)責(zé)藥政審理部門在原料藥上市/制造授權(quán)或藥品申請方面建立特定注冊/歸檔要求的能力。注冊/歸檔的所有承諾必須做到。1.2RegulatoryApplicability1.2法規(guī)的適用性Withintheworldcommunity,materialsmayvaryastotheirlegalclassificationasanAPI.WhenamaterialisclassifiedasanAPIintheregionorcountryinwhichitismanufacturedorusedinadrugproduct,itshouldbemanufacturedaccordingtothisguidance.在世界范圍內(nèi)對原料藥的法定定義是各不相同的。當(dāng)某種物料在其制造或用于藥品的地區(qū)或國家被稱為原料藥，就應(yīng)該按照本指南進(jìn)行生產(chǎn)。1.3Scope1.3范圍ThisguidanceappliestothemanufactureofAPIsforuseinhumandrug(medicinal)products.ItappliestothemanufactureofsterileAPIsonlyuptothepointimmediatelypriortotheAPIsbeingrenderedsterile.ThesterilizationandasepticprocessingofsterileAPIsarenotcoveredbythisguidance,butshouldbeperformedinaccordancewithGMPguidancesfordrug(medicinal)productsasdefinedbylocalauthorities.本文件適用于人用藥品（醫(yī)療用品）所含原料藥的生產(chǎn)。它適用于無菌原料藥在滅菌前的步驟。本指南不包括無菌原料藥的消毒和滅菌工藝，但是，應(yīng)當(dāng)符合地方當(dāng)局所規(guī)定的藥品（醫(yī)療用品）生產(chǎn)的GMP指南。ThisguidancecoversAPIsthataremanufacturedbychemicalsynthesis,extraction,cellculture/fermentation,recoveryfromnaturalsources,oranycombinationoftheseprocesses.SpecificguidanceforAPIsmanufacturedbycellculture/fermentationisdescribedinSection18.本文件適用于通過化學(xué)合成、提取、細(xì)胞培養(yǎng)/發(fā)酵，通過從自然資源回收，或通過這些工藝的結(jié)合而得到的原料藥。通過細(xì)胞培養(yǎng)/發(fā)酵生產(chǎn)的原料藥的特殊指南則在第18章論述。Thisguidanceexcludesallvaccines,wholecells,wholebloodandplasma,bloodandplasmaderivatives(plasmafractionation),andgenetherapyAPIs.However,itdoesincludeAPIsthatareproducedusingbloodorplasmaasrawmaterials.Notethatcellsubstrates(mammalian,plant,insectormicrobialcells,tissueoranimalsourcesincludingtransgenicanimals)andearlyprocessstepsmaybesubjecttoGMPbutarenotcoveredbythisguidance.Inaddition,theguidancedoesnotapplytomedicalgases,bulk-packageddrug(medicinal)products(e.g.,tabletsorcapsulesinbulkcontainers),orradiopharmaceuticals.本指南不包括所有疫苗、完整細(xì)胞、全血和血漿、全血和血漿的衍生物（血漿成分）和基因治療的原料藥。但是卻包括以血或血漿為原材料生產(chǎn)的原料藥。值得注意的是細(xì)胞培養(yǎng)基（哺乳動物、植物、昆蟲或微生物的細(xì)胞、組織或動物源包括轉(zhuǎn)基因動物）和前期生產(chǎn)可能應(yīng)遵循GMP規(guī)范，但不包括在本指南之內(nèi)。另外，本指南不適用于醫(yī)用氣體、散裝的制劑藥（例如，散裝的片劑和膠囊）和放射性藥物的生產(chǎn)。Section19containsguidancethatonlyappliestothemanufactureofAPIsusedintheproductionofdrug(medicinal)productsspecificallyforclinicaltrials(investigationalmedicinalproducts).第19章的指南只適用于用在藥品（醫(yī)療用品）生產(chǎn)中的原料藥制造，特別是臨床實(shí)驗(yàn)用藥（研究用醫(yī)療產(chǎn)品）的原料藥制造。AnAPIstartingmaterialisarawmaterial,anintermediate,oranAPIthatisusedintheproductionofanAPIandthatisincorporatedasasignificantstructuralfragmentintothestructureoftheAPI.AnAPIstartingmaterialcanbeanarticleofcommerce,amaterialpurchasedfromoneormoresuppliersundercontractorcommercialagreement,orproducedin-house.APIstartingmaterialsnormallyhavedefinedchemicalpropertiesandstructure.“原料藥的起始物料”是指一種原料、中間體或原料藥，用來生產(chǎn)一種原料藥，或者以主要結(jié)構(gòu)單元的形式被結(jié)合進(jìn)原料藥結(jié)構(gòu)中。原料藥的起始物料可能是在市場上有售、能夠通過合同或商業(yè)協(xié)議從一個或多個供應(yīng)商處購得，或由生產(chǎn)廠家自制。原料藥的起始物料一般來說有特定的化學(xué)特性和結(jié)構(gòu)。ThecompanyshoulddesignateanddocumenttherationaleforthepointatwhichproductionoftheAPIbegins.Forsyntheticprocesses,thisisknownasthepointatwhichAPIstartingmaterialsareenteredintotheprocess.Forotherprocesses(e.g.,fermentation,extraction,purification),thisrationaleshouldbeestablishedonacase-by-casebasis.Table1givesguidanceonthepointatwhichtheAPIstartingmaterialisnormallyintroducedintotheprocess.生產(chǎn)廠商要指定并用書面文件說明原料藥的生產(chǎn)從何處開始的理論依據(jù)。對于合成工藝而言，就是“原料藥的起始物料”進(jìn)入工藝的那一點(diǎn)。對其他工藝（如：發(fā)酵，提取，純化等）可能需要具體問題具體對待。表1給出了原料藥的起始物料從哪一點(diǎn)引入工藝過程的指導(dǎo)原則。Fromthispointon,appropriateGMPasdefinedinthisguidanceshouldbeappliedtotheseintermediateand/orAPImanufacturingsteps.ThiswouldincludethevalidationofcriticalprocessstepsdeterminedtoimpactthequalityoftheAPI.However,itshouldbenotedthatthefactthatacompanychoosestovalidateaprocessstepdoesnotnecessarilydefinethatstepsascritical.從這步開始，本指南中的有關(guān)GMP規(guī)范應(yīng)當(dāng)應(yīng)用在這些中間體和/或原料藥的制造中。這包括對原料藥質(zhì)量有影響的關(guān)鍵工藝步驟的驗(yàn)證。但是，值得注意的是廠商選擇某一步驟進(jìn)行驗(yàn)證，并不一定將該步驟定為關(guān)鍵步驟。TheguidanceinthisdocumentwouldnormallybeappliedtothestepsshowningrayinTable1.However,allstepsshownmaynotbecompleted.ThestringencyofGMPinAPImanufacturingshouldincreaseastheprocessproceedsfromearlyAPIstepstofinalsteps,purification,andpackaging.PhysicalprocessingofAPIs,suchasgranulation,coatingorphysicalmanipulationofparticlesize(e.g.,milling,micronizing)shouldbeconductedaccordingtothisguidance.本文件的指南通常適用于表1中的灰色步驟。但在表中體現(xiàn)的所有步驟并不是將應(yīng)用GMP管理的所有步驟全部體現(xiàn)出來了。原料藥生產(chǎn)中的GMP要求應(yīng)當(dāng)隨著工藝的進(jìn)行，從原料藥的前幾步到最后幾步，精制和包裝，越來越嚴(yán)格。原料藥的物理加工，如制粒、包衣或顆粒度的物理處理（例如制粉、微粉化）應(yīng)當(dāng)按本指南的標(biāo)準(zhǔn)進(jìn)行。ThisGMPguidancedoesnotapplytostepspriortotheintroductionofthedefinedAPIstartingmaterial.本GMP指南不適用于引入定義了的“原料藥的起始物料”以前的步驟。Table1:ApplicationofthisGuidancetoAPIManufacturingTypeofManufacturingApplicationofthisguidancetosteps(showningray)usedinthistypeofmanufacturingChemicalmanufacturingProductionoftheAPIStartingmaterialIntroductionoftheAPIstartingmaterialintoprocessProductionofIntermediate(s)IsolationandpurificationPhysicalprocessing,andpackagingAPIderivedfromanimalsourcesCollectionoforgan,fluid,ortissueCutting,mixing,and/orinitialprocessingIntroductionoftheAPIstartingmaterialintoprocessIsolationandpurificationPhysicalprocessing,andpackagingAPIextractedfromplantsourcesCollectionofplantCuttingandinitialextraction(s)IntroductionoftheAPIstartingmaterialintoprocessIsolationandpurificationPhysicalprocessing,andpackagingHerbalextractsusedasAPICollectionofplantsCuttingandinitialextractionFurtherextractionPhysicalprocessing,andpackagingAPIconsistingofcomminutedorpowderedherbsCollectionofplantsand/orcultivationandharvestingCutting/comminutingPhysicalprocessing,andpackagingBiotechnology:fermentation/cellcultureEstablishmentofmastercellbankandworkingcellbankMaintenanceofworkingcellbankCellcultureand/orfermentationIsolationandpurificationPhysicalprocessing,andpackaging“Classical”fermentationtoproduceanAPIEstablishmentofcellbankMaintenanceofthecellbankIntroductionofthecellsintofermentationIsolationandpurificationPhysicalprocessing,andpackagingIncreasingGMPrequirementsIncreasingGMPrequirements表1:本指南在原料藥生產(chǎn)中的應(yīng)用生產(chǎn)類型本指南在用于各類生產(chǎn)的工藝步驟（灰色背景）中的應(yīng)用化學(xué)品的生產(chǎn)原料藥起始物料的生產(chǎn)原料藥起始物料引入工藝過程中間體的生產(chǎn)分離和純化物理加工和包裝動物源原料藥器官、分泌物或組織的收集切割、混合和/或初步加工原料藥起始物料引入工藝過程分離和純化物理加工和包裝從植物源提取的原料藥植物的收集切割和初步提取原料藥起始物料引入工藝過程分離和純化物理加工和包裝草藥提取物用作原料藥植物的收集切割和初步提取進(jìn)一步提取物理加工和包裝由粉碎的或粉末狀草藥組成的原料藥植物的收集和/或培養(yǎng)和收獲切割/粉碎物理加工和包裝生物技術(shù)：發(fā)酵/細(xì)胞培養(yǎng)主細(xì)胞庫和工作細(xì)胞庫的建立工作細(xì)胞庫的維護(hù)細(xì)胞培養(yǎng)和/或發(fā)酵分離和純化物理加工和包裝“經(jīng)典”發(fā)酵生產(chǎn)原料藥細(xì)胞庫的建立細(xì)胞庫的維護(hù)細(xì)胞引入發(fā)酵分離和純化物理加工和包裝GMP的要求增加GMP的要求增加2.QUALITYMANAGEMENT2．質(zhì)量管理2.1Principles2.1總則2.10Qualityshouldbetheresponsibilitiesofallpersonsinvolvedinmanufacturing.2.10參與原料藥生產(chǎn)的每一個人都應(yīng)當(dāng)對質(zhì)量負(fù)責(zé)。2.11Eachmanufacturershouldestablish,document,andimplementaneffectivesystemformanagingqualitythatinvolvestheactiveparticipationofmanagementandappropriatemanufacturingpersonnel.2.11每一個生產(chǎn)商都應(yīng)當(dāng)建立并執(zhí)行一套有管理人員和有關(guān)員工積極參與的有效的質(zhì)量管理體系，并使其文件化。2.12Thesystemformanagingqualityshouldencompasstheorganizationalstructure,procedures,processandresources,aswellasactivitiestoensureconfidencethattheAPIwillmeetitsintendedspecificationsforqualityandpurity.Allquality-relatedactivitiesshouldbedefinedanddocumented.2.12質(zhì)量管理體系應(yīng)當(dāng)包括組織機(jī)構(gòu)、規(guī)程、工藝和資源，以及確保原料藥會符合其預(yù)期的質(zhì)量與純度要求所必需的活動。所有涉及質(zhì)量管理的活動都應(yīng)當(dāng)明確規(guī)定，并使其文件化。2.13Thereshouldbeaqualityunit(s)thatisindependentofproductionandthatfulfillsbothqualityassurance(QA)andqualitycontrol(QC)responsibilities.ThequalityunitcanbeintheformofseparateQAandQCunitsorasingleindividualorgroup,dependinguponthesizeandstructureoftheorganization.2.13應(yīng)當(dāng)設(shè)立一個獨(dú)立于生產(chǎn)部門的質(zhì)量部門，同時履行質(zhì)量保證(QA)和質(zhì)量控制(QC)的職責(zé)。依照組織機(jī)構(gòu)的大小，可以是分開的QA和QC部門，或者只是一個人或小組。2.14ThepersonsauthorizedtoreleaseintermediatesandAPIsshouldbespecified.2.14應(yīng)當(dāng)指定授權(quán)發(fā)放中間體和原料藥的人員。2.15Allquality-relatedactivitiesshouldberecordedatthetimetheyareperformed.2.15所有有關(guān)質(zhì)量的活動應(yīng)當(dāng)在其執(zhí)行時就記錄。2.16Anydeviationfromestablishedproceduresshouldbedocumentedandexplained.Criticaldeviationsshouldbeinvestigated,andtheinvestigationanditsconclusionsshouldbedocumented.2.16任何偏離既定規(guī)程的情況都應(yīng)當(dāng)有文字記錄并加以解釋。對于關(guān)鍵性偏差應(yīng)當(dāng)進(jìn)行調(diào)查，并記錄調(diào)查經(jīng)過及其結(jié)果。2.17Nomaterialsshouldbereleasedorusedbeforethesatisfactorycompletionofevaluationbythequalityunit(s)unlessthereareappropriatesystemsinplacetoallowforsuchuse(e.g.,releaseunderquarantineasdescribedinSection10ortheuseofrawmaterialsorintermediatespendingcompletionofevaluation).2.17在質(zhì)量部門對物料完成滿意的評價之前，任何物料都不應(yīng)當(dāng)發(fā)放或使用，除非有合適的系統(tǒng)允許此類使用（如10.20條款所述的待檢情況下的使用，或是原料或中間體在等待評價結(jié)束時的使用）。2.18Proceduresshouldexistfornotifyingresponsiblemanagementinatimelymannerofregulatoryinspections,seriousGMPdeficiencies,productdefectsandrelatedactions(e.g.,quality-relatedcomplaints,recalls,andregulatoryactions).2.18應(yīng)當(dāng)有規(guī)程能確保公司的責(zé)任管理部門能及時得到有關(guān)藥政檢查、嚴(yán)重的GMP缺陷、產(chǎn)品缺陷及其相關(guān)活動（如質(zhì)量投訴，召回，藥政活動等）的通知。2.2ResponsibilitiesoftheQualityUnit(s)2.2質(zhì)量部門的責(zé)任2.20Thequalityunit(s)shouldbeinvolvedinallquality-relatedmatters.2.20質(zhì)量部門應(yīng)當(dāng)參與所有與質(zhì)量有關(guān)的事物。2.21Thequalityunit(s)shouldreviewandapproveallappropriatequality-relateddocuments.2.21所有與質(zhì)量有關(guān)的文件應(yīng)當(dāng)由質(zhì)量部門審核批準(zhǔn)。2.22Themainresponsibilitiesoftheindependentqualityunit(s)shouldnotbedelegated.Theseresponsibilitiesshouldbedescribedinwritingandshouldinclude,butnotnecessarilybelimitedto:ReleasingorrejectingallAPIs.ReleasingorrejectingintermediatesforuseoutsidethecontrolofthemanufacturingcompanyEstablishingasystemtoreleaseorrejectrawmaterials,intermediates,packaging,andlabelingmaterialsReviewingcompletedbatchproductionandlaboratorycontrolrecordsofcriticalprocessstepsbeforereleaseoftheAPIfordistributionMakingsurethatcriticaldeviationsareinvestigatedandresolvedApprovingallspecificationsandmasterproductioninstructionsApprovingallproceduresaffectingthequalityofintermediatesorAPIsMakingsurethatinternalaudits(self-inspections)areperformedApprovingintermediateandAPIcontractmanufacturersApprovingchangesthatpotentiallyaffectintermediateorAPIqualityReviewingandapprovingvalidationprotocolsandreportsMakingsurethatquality-relatedcomplaintsareinvestigatedandresolvedMakingsurethateffectivesystemsareusedformaintainingandcalibratingcriticalequipmentMakingsurethatmaterialsareappropriatelytestedandtheresultsarereportedMakingsurethatthereisstabilitydatatosupportretestorexpirydatesandstorageconditionsonAPIsand/orintermediates,whereappropriatePerformingproductqualityreviews(asdefinedinSection2.5)2.22獨(dú)立的質(zhì)量部門的主要職責(zé)不應(yīng)當(dāng)委派給他人。這些責(zé)任應(yīng)當(dāng)以文字形式加以說明，而且應(yīng)當(dāng)包括，但不限于：所有原料藥的放行與否。用于生產(chǎn)商控制范圍以外的中間體的放行與否；建立一個放行與拒收原材料、中間體、包裝材料和標(biāo)簽的系統(tǒng)；在供銷售的原料藥放行前，審核已完成的關(guān)鍵步驟的批生產(chǎn)記錄和實(shí)驗(yàn)室檢驗(yàn)記錄；確保已對重大偏差進(jìn)行了調(diào)查并已解決；批準(zhǔn)所有的規(guī)格標(biāo)準(zhǔn)和主生產(chǎn)指令；批準(zhǔn)所有可能影響原料藥和中間體質(zhì)量的規(guī)程；確保進(jìn)行內(nèi)部審計(jì)（自檢）；批準(zhǔn)中間體或原料藥的委托生產(chǎn)商；批準(zhǔn)可能影響到中間體或原料藥質(zhì)量的變更；審核并批準(zhǔn)驗(yàn)證方案和報(bào)告；確保調(diào)查并解決質(zhì)量問題的投訴；確保用有效的體系來維護(hù)和校驗(yàn)關(guān)鍵設(shè)備；確保物料都經(jīng)過了適當(dāng)?shù)臋z驗(yàn)并報(bào)告結(jié)果；確保有穩(wěn)定性數(shù)據(jù)支持中間體或原料藥的復(fù)驗(yàn)期或有效期和儲存條件；開展產(chǎn)品質(zhì)量審核（詳見2.5節(jié)）。2.3ResponsibilityforProductionActivities2.3生產(chǎn)作業(yè)的職責(zé)Theresponsibilityforproductionactivitiesshouldbedescribedinwritingandshouldinclude,butnotnecessarilybelimitedto:Preparing,reviewing,approving,anddistributingtheinstructionsfortheproductionofintermediatesorAPIsaccordingtowrittenproceduresProducingAPIsand,whenappropriate,intermediatesaccordingtopre-approvedinstructionsReviewingallproductionbatchrecordsandensuringthatthesearecompletedandsignedMakingsurethatallproductiondeviationsarereportedandevaluatedandthatcriticaldeviationsareinvestigatedandtheconclusionsarerecordedMakingsurethatproductionfacilitiesarecleanand,whenappropriate,disinfectedMakingsurethatthenecessarycalibrationsareperformedandrecordskeptMakingsurethatthepremisesandequipmentaremaintainedandrecordskeptMakingsurethatvalidationprotocolsandreportsarereviewedandapprovedEvaluatingproposedchangesinproduct,processorequipmentMakingsurethatnewand,whenappropriate,modifiedfacilitiesandequipmentarequalified生產(chǎn)作業(yè)的職責(zé)應(yīng)當(dāng)以文字形式加以說明，并應(yīng)當(dāng)包括，但不限于以下內(nèi)容：按書面程序起草、審核、批準(zhǔn)和分發(fā)中間體或原料藥的生產(chǎn)指令；按照已批準(zhǔn)的指令生產(chǎn)原料藥或者中間體；審核所有的批生產(chǎn)記錄確保其完整并有簽名；確保所有的生產(chǎn)偏差都已報(bào)告、評價，對關(guān)鍵的偏差已做了調(diào)查，并記錄結(jié)論；確保生產(chǎn)設(shè)施的清潔，必要時要消毒；確保進(jìn)行必要的校驗(yàn)，并有記錄；確保對廠房和設(shè)備進(jìn)行保養(yǎng)，并有記錄；確保驗(yàn)證方案和報(bào)告的審核與批準(zhǔn)；對產(chǎn)品、工藝或設(shè)備擬作的變更進(jìn)行評估；確保新的或已改進(jìn)的生產(chǎn)設(shè)施和設(shè)備經(jīng)過了確認(rèn)。2.4InternalAudits(SelfInspection)2.4內(nèi)部審計(jì)（自檢）2.40ToverifycompliancewiththeprinciplesofGMPforAPIs,regularinternalauditsshouldbeperformedinaccordancewithanapprovedschedule.2.40為確實(shí)符合原料藥GMP原則，應(yīng)當(dāng)按照批準(zhǔn)的計(jì)劃進(jìn)行定期的內(nèi)部審計(jì)。2.41Auditfindingsandcorrectiveactionsshouldbedocumentedandbroughttotheattentionofresponsiblemanagementofthefirm.Agreedcorrectiveactionsshouldbecompletedinatimelyandeffectivemanner.2.41審計(jì)結(jié)果及整改措施應(yīng)當(dāng)形成文件，并引起公司責(zé)任管理人員的重視。獲準(zhǔn)的整改措施應(yīng)當(dāng)及時、有效地完成。2.5ProductQualityReview2.5產(chǎn)品質(zhì)量審核2.50Regularquality-reviewsofAPIsshouldbeconductedwiththeobjectiveofverifyingtheconsistencyoftheprocess.Suchreviewsshouldnormallybeconductedanddocumentedannuallyandshouldincludeatleast:Areviewofcriticalin-processcontrolandcriticalAPItestresultsAreviewofallbatchesthatfailedtomeetestablishedspecification(s)AreviewofallcriticaldeviationsornonconformancesandrelatedinvestigationsAreviewofanychangescarriedouttotheprocessesoranalyticalmethodsAreviewofresultsofthestabilitymonitoringprogramAreviewofallquality-relatedreturns,complaintsandrecallsAreviewofadequacyofcorrectiveactions2.50原料藥的定期質(zhì)量審核應(yīng)當(dāng)以證實(shí)工藝的一致性為目的來進(jìn)行。此種審核通常應(yīng)當(dāng)每年進(jìn)行一次，并記錄，內(nèi)容至少應(yīng)當(dāng)包括：關(guān)鍵工藝控制以及原料藥關(guān)鍵測試結(jié)果的審核；所有不符合既定質(zhì)量標(biāo)準(zhǔn)的產(chǎn)品批號的審核；所有關(guān)鍵的偏差或違規(guī)行為及有關(guān)調(diào)查的審核；任何工藝或分析方法變動的審核；穩(wěn)定性監(jiān)測的審核；所有與質(zhì)量有關(guān)的退貨、投訴和召回的審核；整改措施的適當(dāng)性的審核。2.51Theresultsofthisreviewshouldbeevaluatedandanassessmentmadeofwhethercorrectiveactionoranyrevalidationshouldbeundertaken.Reasonsforsuchcorrectiveactionshouldbedocumented.Agreedcorrectiveactionsshouldbecompletedinatimelyandeffectivemanner.2.51應(yīng)當(dāng)對質(zhì)量審核結(jié)果進(jìn)行評估，并做出是否需要整改或做任何再驗(yàn)證的評價。此類整改措施的理由應(yīng)當(dāng)文件化。獲準(zhǔn)的整改措施應(yīng)當(dāng)及時、有效地完成。3.PERSONNEL3.人員3.1PersonnelQualifications3.1員工的資質(zhì)3.10Thereshouldbeanadequatenumberofpersonnelqualifiedbyappropriateeducation,training,and/orexperiencetoperformandsupervisethemanufactureofintermediatesandAPIs.3.10應(yīng)當(dāng)有足夠數(shù)量的員工具備從事和監(jiān)管原料藥和中間體生產(chǎn)的教育、培訓(xùn)和/或經(jīng)歷等資格。3.11TheresponsibilitiesofallpersonnelengagedinthemanufactureofintermediatesandAPIsshouldbespecifiedinwriting.3.11參與原料藥和中間體生產(chǎn)的所有人員的職責(zé)應(yīng)當(dāng)書面規(guī)定。3.12Trainingshouldberegularlyconductedbyqualifiedindividualsandshouldcover,ataminimum,theparticularoperationsthattheemployeeperformsandGMPasitrelatestotheemployee’sfunctions.Recordsoftrainingshouldbemaintained.Trainingshouldbeperiodicallyassessed.3.12應(yīng)當(dāng)由有資格的人員定期進(jìn)行培訓(xùn)，內(nèi)容至少應(yīng)當(dāng)包括員工所從事的特定操作和與其職能有關(guān)的GMP。培訓(xùn)記錄應(yīng)當(dāng)保存，并應(yīng)當(dāng)定期對培訓(xùn)進(jìn)行評估。3.2PersonnelHygiene3.2員工的衛(wèi)生3.20Personnelshouldpracticegoodsanitationandhealthhabits.3.20員工應(yīng)當(dāng)養(yǎng)成良好的衛(wèi)生和健康習(xí)慣。3.21Personnelshouldwearcleanclothingsuitableforthemanufacturingactivitywithwhichtheyareinvolvedandthisclothingshouldbechanged,whenappropriate.Additionalprotectiveapparel,suchashead,face,hand,andarmcoverings,shouldbeworn,whennecessary,toprotectintermediatesandAPIsfromcontamination.3.21員工應(yīng)當(dāng)穿著適合其所從事生產(chǎn)操作的干凈服裝，必要時應(yīng)當(dāng)更換。其它保護(hù)性用品如頭、臉、手和臂等遮護(hù)用品必要時也應(yīng)當(dāng)佩帶，以免原料藥和中間體受到污染。3.22PersonnelshouldavoiddirectcontactwithintermediatesandAPIs.3.22員工應(yīng)當(dāng)避免與中間體或原料藥的直接接觸。3.23Smoking,eating,drinking,chewingandthestorageoffoodshouldberestrictedtocertaindesignatedareasseparatefromthemanufacturingareas.3.23吸煙、吃、喝、咀嚼及存放食品僅限于與生產(chǎn)區(qū)隔開的指定區(qū)域。3.24PersonnelsufferingfromaninfectiousdiseaseorhavingopenlesionsontheexposedsurfaceofthebodyshouldnotengageinactivitiesthatcouldresultincompromisingthequalityofAPIs.Anypersonshownatanytime(eitherbymedicalexaminationorsupervisoryobservation)tohaveanapparentillnessoropenlesionsshouldbeexcludedfromactivitieswheretheconditioncouldadverselyaffectthequalityoftheAPIsuntiltheconditioniscorrectedorqualifiedmedicalpersonneldeterminethattheperson’sinclusionwouldnotjeopardizethesafetyorqualityoftheAPIs.3.24患傳染性疾病或身體表面有開放性創(chuàng)傷的員工不應(yīng)當(dāng)從事危及原料藥質(zhì)量的生產(chǎn)活動。在任何時候（經(jīng)醫(yī)學(xué)檢驗(yàn)或監(jiān)控檢查）任何患有危及到原料藥質(zhì)量的疾病或創(chuàng)傷的人員都不應(yīng)當(dāng)參與作業(yè)，直到健康狀況已恢復(fù)，或者有資格的醫(yī)學(xué)人員確認(rèn)該員工不會危及到原料藥的安全性和質(zhì)量。3.3Consultants3.3顧問3.30ConsultantsadvisingonthemanufactureandcontrolofintermediatesorAPIsshouldhavesufficienteducation,training,andexperience,oranycombinationthereof,toadviseonthesubjectforwhichtheyareretained.3.30中間體或原料藥生產(chǎn)和控制的顧問應(yīng)當(dāng)有足夠的學(xué)歷，受訓(xùn)和經(jīng)驗(yàn)，能勝任所承擔(dān)的工作。3.31Recordsshouldbemaintainedstatingthename,address,qualifications,andtypeofserviceprovidedbytheseconsultants.3.31顧問的姓名、地址、資格和提供服務(wù)的類型都應(yīng)當(dāng)有文字記錄。4.BUILDINGSANDFACILITIES4.建筑和設(shè)施4.1DesignandConstruction4.1設(shè)計(jì)和結(jié)構(gòu)4.10BuildingsandfacilitiesusedinthemanufactureofintermediatesandAPIsshouldbelocated,designed,andconstructedtofacilitatecleaning,maintenance,andoperationsasappropriatetothetypeandstageofmanufacture.Facilitiesshouldalsobedesignedtominimizepotentialcontamination.WheremicrobiologicalspecificationshavebeenestablishedfortheintermediateorAPI,facilitiesshouldalsobedesignedtolimitexposuretoobjectionablemicrobiologicalcontaminants,asappropriate.4.10用于中間體和原料藥生產(chǎn)的廠房和設(shè)施的選址、設(shè)計(jì)和建造應(yīng)當(dāng)便于清潔，維護(hù)和適應(yīng)一定類型和階段的生產(chǎn)操作。設(shè)施的設(shè)計(jì)應(yīng)盡量減少潛在的污染。如果中間體或原料藥的生產(chǎn)有微生物限度要求，那么設(shè)施設(shè)計(jì)應(yīng)相應(yīng)的限制有害微生物的污染。4.11Buildingsandfacilitiesshouldhaveadequatespacefortheorderlyplacementofequipmentandmaterialstopreventmix-upsandcontamination.4.11廠房和設(shè)施應(yīng)有足夠空間，以便有秩序地放置設(shè)備和物料，防止混淆和污染。4.12Wheretheequipmentitself(e.g.,closedorcontainedsystem)providesadequateprotectionofthematerial,suchequipmentcanbelocatedoutdoors.4.12自身能對物料提供足夠保護(hù)的設(shè)備（如關(guān)閉的或封閉的系統(tǒng)），可以在戶外放置。4.13Theflowofmaterialsandpersonnelthroughthebuildingorfacilitiesshouldbedesignedtopreventmix-upsandcontamination.4.13通過廠房和設(shè)施的物流和人流的設(shè)計(jì)應(yīng)當(dāng)能防止混雜和污染。4.14Thereshouldbedefinedareasorothercontrolsystemsforthefollowingactivities:Receipt,identification,sampling,andquarantineofincomingmaterials,pendingreleaseorrejectionQuarantinebeforereleaseorrejectionofintermediatesandAPIsSamplingofintermediatesandAPIsHoldingrejectedmaterialsbeforefurtherdisposition(e.g.,return,reprocessingordestruction)StorageofreleasedmaterialsProductionoperationsPackagingandlabelingoperationsLaboratoryoperations4.14以下活動應(yīng)當(dāng)有指定區(qū)域或其它控制系統(tǒng)：來料的接收、鑒別、取樣和待驗(yàn)，等待放行或拒收；中間體和原料藥放行或拒收前的待驗(yàn)；中間體和原料藥的取樣不合格物料處理（如退貨、返工或銷毀）前的貯存；已放行物料的貯存；生產(chǎn)操作；包裝及貼標(biāo)簽操作；實(shí)驗(yàn)室操作。4.15Adequateandcleanwashingandtoiletfacilitiesshouldbeprovidedforpersonnel.Thesefacilitiesshouldbeequippedwithhotandcoldwater,asappropriate,soapordetergent,airdryers,orsingleservicetowels.Thewashingandtoiletfacilitiesshouldbeseparatefrom,buteasilyaccessibleto,manufacturingareas.Adequatefacilitiesforshoweringand/orchangingclothesshouldbeprovided,whenappropriate.4.15應(yīng)當(dāng)為員工提供足夠和清潔的盥洗設(shè)施。這些盥洗設(shè)施應(yīng)當(dāng)裝有冷熱水（視情況而定）、肥皂或洗滌劑，干手機(jī)和一次性毛巾。盥洗室應(yīng)當(dāng)與生產(chǎn)區(qū)隔離，但要便于達(dá)到。應(yīng)當(dāng)根據(jù)情況提供足夠的淋浴和/或更衣設(shè)施。4.16Laboratoryareas/operationsshouldnormallybeseparatedfromproductionareas.Somelaboratoryareas,inparticularthoseusedforin-processcontrols,canbelocatedinproductionareas,providedtheoperationsoftheproductionprocessdonotadverselyaffecttheaccuracyofthelaboratorymeasurements,andthelaboratoryanditsoperationsdonotadverselyaffecttheproductionprocess,intermediate,orAPI.4.16實(shí)驗(yàn)室區(qū)域/操作通常應(yīng)當(dāng)與生產(chǎn)區(qū)隔離。有些實(shí)驗(yàn)室區(qū)域，特別是用于中間控制的，可以位于生產(chǎn)區(qū)內(nèi)，只要生產(chǎn)工藝操作對實(shí)驗(yàn)室測量的準(zhǔn)確性沒有負(fù)面影響，而且，實(shí)驗(yàn)室及其操作對生產(chǎn)過程，或中間體，或原料藥也沒有負(fù)面影響。4.2Utilities4.2公用設(shè)施4.20Allutilitiesthatcouldaffectproductquality(e.g.,steam,gas,compressedair,heating,ventilation,andairconditioning)shouldbequalifiedandappropriatelymonitoredandactionshouldbetakenwhenlimitsareexceeded.Drawingsfortheseutilitysystemsshouldbeavailable.4.20對產(chǎn)品質(zhì)量會有影響的所有公用設(shè)施（如蒸汽，氣體，壓縮空氣和加熱，通風(fēng)及空調(diào)）都應(yīng)當(dāng)確認(rèn)合格，并進(jìn)行適當(dāng)監(jiān)控，在超出限度時應(yīng)當(dāng)采取相應(yīng)措施。應(yīng)當(dāng)有這些公用設(shè)施的系統(tǒng)圖。4.21Adequateventilation,airfiltrationandexhaustsystemsshouldbeprovided,whereappropriate.Thesesystemsshouldbedesignedandconstructedtominimizerisksofcontaminationandcross-contaminationandshouldincludeequipmentforcontrolofairpressure,microorganisms(ifappropriate),dust,humi