（醫(yī)療藥品管理）美國FDA原料藥生產(chǎn)質(zhì)量管理規(guī)范(中英文)DIRECTIONOFGMP(GOODMANUFACTURINGPRACTICE)OFRAWMATERIALSBYFDA美國FDA原料藥生產(chǎn)質(zhì)量管理規(guī)范（中英文）TableofContents目錄1.INTRODUCTION簡介1.1Objective目的1.2RegulatoryApplicability法規(guī)的適用性1.3Scope范圍2.QUALITYMANAGEMENT.質(zhì)量管理2.1Principles總則2.2ResponsibilitiesoftheQualityUnit(s)質(zhì)量部門的責(zé)任2.3ResponsibilityforProductionActivities生產(chǎn)作業(yè)的職責(zé)2.4InternalAudits(SelfInspection)內(nèi)部審計(jì)（自檢）2.5ProductQualityReview產(chǎn)品質(zhì)量審核3.PERSONNEL人員3.1PersonnelQualifications人員的資質(zhì)3.2PersonnelHygiene人員衛(wèi)生3.3Consultants顧問4.BUILDINGSANDFACILITIES建筑和設(shè)施4.1DesignandConstruction設(shè)計(jì)和結(jié)構(gòu)4.2Utilities公用設(shè)施4.3Water水4.4Containment限制4.5Lighting照明4.6SewageandRefuse排污和垃圾4.7SanitationandMaintenance衛(wèi)生和保養(yǎng)5.PROCESSEQUIPMENT工藝設(shè)備5.1DesignandConstruction設(shè)計(jì)和結(jié)構(gòu)5.2EquipmentMaintenanceandCleaning設(shè)備保養(yǎng)和清潔5.3Calibration.校驗(yàn)5.4ComputerizedSystems計(jì)算機(jī)控制系統(tǒng)6.DOCUMENTATIONANDRECORDS文件和記錄6.1DocumentationSystemandSpecifications文件系統(tǒng)和質(zhì)量標(biāo)準(zhǔn)6.2EquipmentcleaningandUseRecord設(shè)備的清潔和使用記錄6.3RecordsofRawMaterials,Intermediates,APILabelingandPackagingMaterials原料、中間體、原料藥的標(biāo)簽和包裝材料的記錄6.4MasterProductionInstructions(MasterProductionandControlRecords)生產(chǎn)工藝規(guī)程（主生產(chǎn)和控制記錄）6.5BatchProductionRecords(BatchProductionandControlRecords)批生產(chǎn)記錄（批生產(chǎn)和控制記錄）6.6LaboratoryControlRecords實(shí)驗(yàn)室控制記錄6.7BatchProductionRecordReview批生產(chǎn)記錄審核7.MATERIALSMANAGEMENT物料管理7.1GeneralControls控制通則7.2ReceiptandQuarantine接收和待驗(yàn)7.3SamplingandTestingofIncomingProductionMaterials進(jìn)廠物料的取樣與測試7.4Storage儲(chǔ)存7.5Re-evaluation復(fù)驗(yàn)8.PRODUCTIONANDIN-PROCESSCONTROLS生產(chǎn)和過程控制8.1ProductionOperations生產(chǎn)操作8.2TimeLimits時(shí)限8.3In-processSamplingandControls工序取樣和控制8.4BlendingBatchesofIntermediatesorAPIs中間體或原料藥的混批8.5ContaminationControl污染控制9.PACKAGINGANDIDENTIFICATIONLABELINGOFAPIsANDINTERMEDIATES原料藥和中間體的包裝和貼簽9.1General總則9.2PackagingMaterials包裝材料9.3LabelIssuanceandControl標(biāo)簽發(fā)放與控制9.4PackagingandLabelingOperations包裝和貼簽操作10.STORAGEANDDISTRIBUTION.儲(chǔ)存和分發(fā)10.1WarehousingProcedures入庫程序10.2DistributionProcedures分發(fā)程序11.LABORATORYCONTROLS實(shí)驗(yàn)室控制11.1GeneralControls控制通則11.2TestingofIntermediatesandAPIs中間體和原料藥的測試11.3ValidationofAnalyticalProcedures分析方法的驗(yàn)證11.4CertificatesofAnalysis分析報(bào)告單11.5StabilityMonitoringofAPIs原料藥的穩(wěn)定性監(jiān)測11.6ExpiryandRetestDating有效期和復(fù)驗(yàn)期11.7Reserve/RetentionSamples留樣12.VALIDATION.驗(yàn)證12.1ValidationPolicy驗(yàn)證方針12.2ValidationDocumentation驗(yàn)證文件12.3Qualification確認(rèn)12.4ApproachestoProcessValidation工藝驗(yàn)證的方法12.5ProcessValidationProgram工藝驗(yàn)證的程序12.6PeriodicReviewofValidatedSystems驗(yàn)證系統(tǒng)的定期審核12.7CleaningValidation清洗驗(yàn)證12.8ValidationofAnalyticalMethods分析方法的驗(yàn)證13.CHANGECONTROL變更的控制14.REJECTIONANDRE-USEOFMATERIALS.拒收和物料的再利用14.1Rejection拒收14.2Reprocessing返工14.3Reworking重新加工14.4RecoveryofMaterialsandSolvents物料與溶劑的回收14.5Returns退貨15.COMPLAINTSANDRECALLS投訴與召回16.CONTRACTMANUFACTURERS(INCLUDINGLABORATORIES)協(xié)議生產(chǎn)商（包括實(shí)驗(yàn)室）17.AGENTS,BROKERS,TRADERS,DISTRIBUTORS,REPACKERS,ANDRELABELLERS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17.1Applicability適用性17.2TraceabilityofDistributedAPIsandIntermediates已分發(fā)的原料藥和中間體的可追溯性17.3QualityManagement質(zhì)量管理17.4Repackaging,Relabeling,andHoldingofAPIsandIntermediates原料藥和中間體的重新包裝、重新貼簽和待檢17.5Stability穩(wěn)定性17.6TransferofInformation信息的傳達(dá)17.7HandlingofComplaintsandRecalls投訴和召回的處理17.8HandlingofReturns退貨的處理18.SpecificGuidanceforAPIsManufacturedbyCellCulture/Fermentation用細(xì)胞繁殖/發(fā)酵生產(chǎn)的原料藥的特殊指南18.1General總則18.2CellBankMaintenanceandRecordKeeping細(xì)胞庫的維護(hù)和記錄的保存18.3CellCulture/Fermentation細(xì)胞繁殖/發(fā)酵18.4Harvesting,IsolationandPurification收取、分離和精制18.5ViralRemoval/Inactivationsteps病毒的去除/滅活步驟19.APIsforUseinClinicalTrials用于臨床研究的原料藥19.1General總則19.2Quality質(zhì)量19.3EquipmentandFacilities設(shè)備和設(shè)施19.4ControlofRawMaterials原料的控制19.5Production生產(chǎn)19.6Validation驗(yàn)證19.7Changes變更19.8LaboratoryControls實(shí)驗(yàn)室控制19.9Documentation文件20.Glossary術(shù)語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(chǔ)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(cè)/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(qǐng)方面建立特定注冊(cè)/歸檔要求的能力。注冊(cè)/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(duì)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(dòng)物、植物、昆蟲或微生物的細(xì)胞、組織或動(dòng)物源包括轉(zhuǎn)基因動(dòng)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(gè)或多個(gè)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(duì)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(duì)其他工藝（如：發(fā)酵，提取，純化等）可能需要具體問題具體對(duì)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(duì)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。2.QUALITYMANAGEMENT2．質(zhì)量管理2.1Principles2.1總則2.10Qualityshouldbetheresponsibilitiesofallpersonsinvolvedinmanufacturing.參與原料藥生產(chǎn)的每一個(gè)人都應(yīng)當(dāng)對(duì)質(zhì)量負(fù)責(zé)。2.11Eachmanufacturershouldestablish,document,andimplementaneffectivesystemformanagingqualitythatinvolvestheactiveparticipationofmanagementandappropriatemanufacturingpersonnel.每一個(gè)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.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(huì)符合其預(yù)期的質(zhì)量與純度要求所必需的活動(dòng)。所有涉及質(zhì)量管理的活動(dòng)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(gè)獨(dú)立于生產(chǎn)部門的質(zhì)量部門，同時(shí)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(gè)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(dòng)應(yīng)當(dāng)在其執(zhí)行時(shí)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(duì)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(duì)物料完成滿意的評(píng)價(jià)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(shí)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(dòng)（如質(zhì)量投訴，召回，藥政活動(dòng)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:1.ReleasingorrejectingallAPIs.Releasingorrejectingintermediatesforuseoutsidethecontrolofthemanufacturingcompany2.Establishingasystemtoreleaseorrejectrawmaterials,intermediates,packaging,andlabelingmaterials3.ReviewingcompletedbatchproductionandlaboratorycontrolrecordsofcriticalprocessstepsbeforereleaseoftheAPIfordistribution4.Makingsurethatcriticaldeviationsareinvestigatedandresolved5.Approvingallspecificationsandmasterproductioninstructions6.ApprovingallproceduresaffectingthequalityofintermediatesorAPIs7.Makingsurethatinternalaudits(self-inspections)areperformed8.ApprovingintermediateandAPIcontractmanufacturers9.ApprovingchangesthatpotentiallyaffectintermediateorAPIquality10.Reviewingandapprovingvalidationprotocolsandreports11.Makingsurethatquality-relatedcomplaintsareinvestigatedandresolved12.Makingsurethateffectivesystemsareusedformaintainingandcalibratingcriticalequipment13.Makingsurethatmaterialsareappropriatelytestedandtheresultsarereported14.MakingsurethatthereisstabilitydatatosupportretestorexpirydatesandstorageconditionsonAPIsand/orintermediates,whereappropriate15.Performingproductqualityreviews(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：1.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；2.建立一個(gè)放行與拒收原材料、中間體、包裝材料和標(biāo)簽的系統(tǒng)；3.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；4.確保已對(duì)重大偏差進(jìn)行了調(diào)查并已解決；5.批準(zhǔn)所有的規(guī)格標(biāo)準(zhǔn)和主生產(chǎn)指令；6.批準(zhǔn)所有可能影響原料藥和中間體質(zhì)量的規(guī)程；7.8.批準(zhǔn)中間體或原料藥的委托生產(chǎn)商；9.批準(zhǔn)可能影響到中間體或原料藥質(zhì)量的變更；10.審核并批準(zhǔn)驗(yàn)證方案和報(bào)告；11.確保調(diào)查并解決質(zhì)量問題的投訴；12.確保用有效的體系來維護(hù)和校驗(yàn)關(guān)鍵設(shè)備；13.確保物料都經(jīng)過了適當(dāng)?shù)臋z驗(yàn)并報(bào)告結(jié)果；14.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(chǔ)存條件；15.開展產(chǎn)品質(zhì)量審核（詳見2.52.3ResponsibilityforProductionActivities2.3生產(chǎn)作業(yè)的職責(zé)Theresponsibilityforproductionactivitiesshouldbedescribedinwritingandshouldinclude,butnotnecessarilybelimitedto:1.Preparing,reviewing,approving,anddistributingtheinstructionsfortheproductionofintermediatesorAPIsaccordingtowrittenprocedures2.ProducingAPIsand,whenappropriate,intermediatesaccordingtopre-approvedinstructions3.Reviewingallproductionbatchrecordsandensuringthatthesearecompletedandsigned4.Makingsurethatallproductiondeviationsarereportedandevaluatedandthatcriticaldeviationsareinvestigatedandtheconclusionsarerecorded5.Makingsurethatproductionfacilitiesarecleanand,whenappropriate,disinfected6.Makingsurethatthenecessarycalibrationsareperformedandrecordskept7.Makingsurethatthepremisesandequipmentaremaintainedandrecordskept8.Makingsurethatvalidationprotocolsandreportsarereviewedandapproved9.Evaluatingproposedchangesinproduct,processorequipment10.Makingsurethatnewand,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：1.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；2.按照已批準(zhǔn)的指令生產(chǎn)原料藥或者中間體；3.審核所有的批生產(chǎn)記錄確保其完整并有簽名；4.確保所有的生產(chǎn)偏差都已報(bào)告、評(píng)價(jià)，對(duì)關(guān)鍵的偏差已做了調(diào)查，并記錄結(jié)論；5.確保生產(chǎn)設(shè)施的清潔，必要時(shí)要消毒；6.確保進(jìn)行必要的校驗(yàn)，并有記錄；7.確保對(duì)廠房和設(shè)備進(jìn)行保養(yǎng)，并有記錄；8.確保驗(yàn)證方案和報(bào)告的審核與批準(zhǔn)；9.對(duì)產(chǎn)品、工藝或設(shè)備擬作的變更進(jìn)行評(píng)估；10.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(shí)、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(hào)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(dòng)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.應(yīng)當(dāng)對(duì)質(zhì)量審核結(jié)果進(jìn)行評(píng)估，并做出是否需要整改或做任何再驗(yàn)證的評(píng)價(jià)。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(shí)、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(duì)培訓(xùn)進(jìn)行評(píng)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(shí)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(shí)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(dòng)。在任何時(shí)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(huì)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.4.124.13Theflowofmaterialsandpersonnelthroughthebuildingorfacilitiesshouldbedesignedtopreventmix-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:以下活動(dòng)應(yīng)當(dāng)有指定區(qū)域或其它控制系統(tǒng)：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(duì)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(duì)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(duì)產(chǎn)品質(zhì)量會(huì)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(shí)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,humidity,andtemperature,asappropriatetothestageofmanufacture.ParticularattentionshouldbegivingtoareaswhereAPIsareexposedtotheenvironment.4.21應(yīng)當(dāng)根據(jù)情況，提供足夠的通風(fēng)、空氣過濾和排氣系統(tǒng)。這些系統(tǒng)應(yīng)當(dāng)根據(jù)相應(yīng)的生產(chǎn)階段，設(shè)計(jì)和建造成將污染和交叉污染降至最低限度，并包括控制氣壓、微生物（如果4.22Ifairisrecirculatedtoproductionareas,appropriatemeasuresshouldbetakentocontrolrisksofcontaminationandcross-contamination.4.22如果空氣再循環(huán)到生產(chǎn)區(qū)域，應(yīng)當(dāng)采取適當(dāng)?shù)目刂莆廴竞徒徊嫖廴镜娘L(fēng)險(xiǎn)。4.23Permanentlyinstalledpipeworkshouldbeappropriatelyidentified.Thiscanbeaccomplishedbyidentifyingindividuallines,documentation,computercontrolsystem,oralternativemeans.PipeworkshouldbelocatedtoavoidrisksofcontaminationoftheintermediateorApI.4.23永久性安裝的管道應(yīng)當(dāng)有適宜的標(biāo)識(shí)。這可以通過標(biāo)識(shí)每根管道、提供證明文件、計(jì)算機(jī)控制系統(tǒng)，或其它替代方法來達(dá)到。管道的安裝處應(yīng)當(dāng)防止污染中間體或原料藥。4.24Drainsshouldbeofadequatesizeandshouldbeprovidedwithanairbreakorasuitabledevicetopreventback-siphonage,whenappropriate.4.24排水溝應(yīng)當(dāng)有足夠的尺寸，而且應(yīng)當(dāng)根據(jù)情況裝有空斷器或適當(dāng)?shù)难b置，防止倒虹吸。4.3Water4.3水4.30WaterusedinthemanufactureofAPIsshouldbedemonstratedtobesuitableforitsintendeduse.4.30原料藥生產(chǎn)中使用的水應(yīng)當(dāng)證明適合于其預(yù)定的用途。4.31Unlessotherwisejustified,processwatershould,ataminimum,meetWorldHealthOrganization(WHO)guidelinesfordrinking(portable)waterquality.除非有其它理由，工藝用水最低限度應(yīng)當(dāng)符合世界衛(wèi)生組織（WHO）的飲用水質(zhì)量指南。4.32Ifdrinking(portable)waterisinsufficienttoensureAPIqualityandtighterchemicaland/ormicrobiologicalwaterqualityspecificationsarecalledfor,appropriatespecificationsforphysical/chemicalattributes,totalmicrobialcounts,objectionableorganisms,and/orendotoxinsshouldbeestablished.4.32如果飲用水不足以確保原料的質(zhì)量，并要求更為嚴(yán)格的化學(xué)和/或微生物水質(zhì)規(guī)格標(biāo)準(zhǔn)，應(yīng)當(dāng)指定合適的物理/化學(xué)特性、微生物總數(shù)、控制菌和/或內(nèi)毒素的規(guī)格標(biāo)準(zhǔn)。4.33Wherewaterusedintheprocessistreatedbythemanufacturertoachieveadefinedquality,thetreatmentprocessshouldbevalidatedandmonitoredwithappropriateactionlimits.4.33在工藝用水為達(dá)到規(guī)定質(zhì)量由制造商進(jìn)行處理時(shí)，處理工藝應(yīng)當(dāng)經(jīng)過驗(yàn)證，并用合適的處置限度來監(jiān)測。4.34WherethemanufacturerofanonsterileAPIeitherintendsorclaimsthatitissuitableforuseinfurtherprocessingtoproduceasteriledrug(medicinal)product,waterusedinthefinalisolationandpurificationstepsshouldbemonitoredandcontrolledfortotalmicrobialcounts,objectionableorganisms,andendotoxins.4.34當(dāng)非無菌原料藥的制造商打算或者聲稱該原料藥適用于進(jìn)一步加工生產(chǎn)無菌藥品（醫(yī)療用品）時(shí)，最終分離和精制階段的用水應(yīng)當(dāng)進(jìn)行微生物總數(shù)、致病菌和內(nèi)毒素方面的監(jiān)測和控制。4.4Containment4.4限制4.40Dedicatedproductionareas,whichcanincludefacilities,airhandlingequipmentand/orprocessequipment,shouldbeemployedintheproductionofhighlysensitizingmaterials,suchaspenicillinsorcephalosprins.4.40在高致敏性物質(zhì)，如青霉素或頭孢菌素類的生產(chǎn)中，應(yīng)當(dāng)使用專用的生產(chǎn)區(qū)，包括設(shè)施、空氣處理設(shè)備和/或工藝設(shè)備。4.41Theuseofdedicatedproductionareasshouldalsobeconsideredwhenmaterialofaninfectiousnatureorhighpharmacologicalactivityortoxicityisinvolved(e.g.,certainsteroidsorcytotoxicanti-canceragents)unlessvalidatedinactivationand/orcleaningproceduresareestablishedandmaintained.4.41慮專用的生產(chǎn)區(qū)，除非已建立并維持一套經(jīng)驗(yàn)證的滅活和/或清洗程序。4.42Appropriatemeasuresshouldbeestablishedandimplementedtopreventcross-contaminationfrompersonnelandmaterialsmovingfromonededicatedareatoanother.4.42應(yīng)當(dāng)建立并實(shí)施相應(yīng)的措施，防止由于在各專用區(qū)域間流動(dòng)的人員和物料而造成的交叉污染。4.43Anyproductionactivities(includingweighing,milling,orpackaging)ofhighlytoxicnonpharmaceuticalmaterials,suchasherbicidesandpesticides,shouldnotbeconductedusingthebuildingsand/orequipmentbeingusedfortheproductionofAPIs.HandlingandstorageofthesehighlytoxicnonpharmaceuticalmaterialsshouldbeseparatefromAPIs.4.43劇毒的非藥用物質(zhì)，如除草劑、殺蟲劑的任何生產(chǎn)活動(dòng)（包括稱重、研磨或包裝）都不應(yīng)當(dāng)使用生產(chǎn)原料藥所使用的廠房和/或設(shè)備。這類劇毒非藥用物質(zhì)的處理和儲(chǔ)存都應(yīng)當(dāng)與原料藥分開。4.5Lighting4.5照明4.50Adequatelightingshouldbeprovidedinallareastofacilitatecleaning,maintenance,andproperoperations.4.50所有區(qū)域都應(yīng)當(dāng)提供充足的照明，以便于清洗、保養(yǎng)或其它操作。4.6SewageandRefuse4.6排污和垃圾4.60Sewage,refuse,andotherwaste(e.g.,solids,liquids,orgaseousby-productsfrommanufacturing)inandfrombuildingsandtheimmediatesurroundingareashouldbedisposedofinasafe,timely,andsanitarymanner.Containersand/orpipesforwastematerialshouldbeclearlyidentified.4.60進(jìn)入和流出廠房及鄰近區(qū)域的污水、垃圾和其它廢物（如生產(chǎn)中的固態(tài)、液態(tài)或氣態(tài)/或管道應(yīng)當(dāng)顯著地標(biāo)明。4.7SanitationandMaintenance4.7衛(wèi)生和保養(yǎng)4.70BuildingsusedinthemanufactureofintermediatesandAPIsshouldbeproperlymaintainedandrepairedandkeptinacleancondition.4.70生產(chǎn)中間體和原料藥的廠房應(yīng)當(dāng)適當(dāng)?shù)乇ｐB(yǎng)、維修并保持清潔。4.71Writtenproceduresshouldbeestablishedassigningresponsibilityforsanitationanddescribingthecleaningschedules,methods,equipment,andmaterialstobeusedincleaningbuildingsandfacilities.4.71應(yīng)當(dāng)制定書面程序來分配衛(wèi)生工作的職責(zé)，并描述用于清潔廠房和設(shè)施的清潔的計(jì)劃、方法、設(shè)備和材料。4.72Whennecessary,writtenproceduresshouldbeestablishedfortheuseofsuitablerodenticides,insecticides,fungicides,fumigatingagents,andcleaningandsanitizingagentstopreventthecontaminationofequipment,rawmaterials,packaging/labelingmaterials,intermediates,andAPIs..72必要時(shí)，還應(yīng)當(dāng)對(duì)合適的滅鼠藥、殺蟲劑、殺真菌劑、煙熏劑和清潔消毒劑的使用制定書面程序，以避免對(duì)設(shè)備、原料、包裝/標(biāo)簽、中間體和原料藥的污染。5.PROCESSEQUIPMENT5.工藝設(shè)備5.1DesignandConstruction5.1設(shè)計(jì)和結(jié)構(gòu)5.10EquipmentusedinthemanufactureofintermediatesandAPIsshouldbeofappropriatedesignandadequatesize,andsuitablylocatedforitsintendeduse,cleaning,sanitation(whereappropriate),andmaintenance.5.10中間體和原料藥生產(chǎn)中使用的設(shè)備應(yīng)當(dāng)有合理的設(shè)計(jì)和足夠的尺寸，并且放置在適宜于其使用、清潔、消毒（根據(jù)情況而定）和保養(yǎng)的地方。5.11Equipmentshouldbeconstructedsothatsurfacesthatcontactrawmaterials,intermediates,orAPIsdonotalterthequalityoftheintermediatesandAPIsbeyondtheofficialorotherestablishedspecifications.5.11設(shè)備的構(gòu)造中與原料、中間體或原料藥接觸的表面不會(huì)改變中間體和原料藥的質(zhì)量而使其不符合法定的或其他已規(guī)定的質(zhì)量標(biāo)準(zhǔn)。5.12Productionequipmentshouldonlybeusedwithinitsqualifiedoperatingrange.5.12生產(chǎn)設(shè)備應(yīng)該只在其確認(rèn)的操作范圍內(nèi)運(yùn)行。5.13Majorequipment(e.g.,reactors,storagecontainers)andpermanentlyinstalledprocessinglinesusedduringtheproductionofanintermediateorAPIshouldbeappropriatelyidentified.5.13中間體或原料藥生產(chǎn)過程中使用的主要設(shè)備（如反應(yīng)釜、貯存容器）和永久性安