EU-GMP指南-第1部分第4章：文件.docx

EUROPEANCOMMISSIONHEA1.THANDCONSUMERSDIRECTORATE-GENERA1.PublicHealthandRiskAssessmentPharmaceuticalsBrussels.SANCOC8AMslares(2010)1064587Eudra1.exTheRulesGoverningMedicinalProductsintheEuropeanUnionVolume4G<m)(1ManufacturingPracticeMedicinalProductsforHumanandVeterinaryUseChaDter4:DOCUmentation第四章：文件lx?galbasisforpublishingthedetailedguidelines:Article47ofDirective2OOI83EContheCommunitycoderelatingtomedicinalproductsforhumanuseandArticle51ofDirective200182EContheCommunitycoderelatingtoveterinarymedicinalplucts.Thisdocumentprovidesguidancefortheinterpretationof(heprinciplesandguidelinesofgo<lmanufacturingpractice(GMP)formedicinalproductsaslaiddowninDirective2(X)394ECformedicinalproductsIbrhumanuseandDirective9I412EECforVCICrinaryuse.立法基础：2001/83/EC法令第47款对人用药品的相关要求，2001/82/EC法令第51款售用药相关的欧共体法规。本文件主要是2003/94/EC法令对人用药和91/4I2/EEC对兽用药品的GMP原则和指南的说明.Statusofthedocument:revision1文件状态：第一次修订Reasonsforchanges:thesectionson,generationandcontrolofdocumcnlation"and"retentionofdocu11wnls”havebeenrevised,inIhclightoftheincreasinguseofdcclrnicdocumentswithintheGMPenvironment.变更理由:鉴于GMP环境下电子文档的增加,对“文件的生成和限制”和“文件和保存''进行修订Deadlineforcomingintooperation:30June2011实施时间：2011年6月30日TableofContents书目Principle原则RequiredGMPDocumentation要求的GMP文件GenerationandControlofDocumentation文件生成和限制GoodDocumentationPnKtices优良KetentionofDocuments记录保存Specifications质汽标准ManufacturingFormulaandi1rocessingInstructions生产处方和工艺规程Proceduresandrecords程序和记录Principle原则GooddocumentationconstitutesanessentialpartofthequalityassurancesystemandiskeytooperatingincompliancewithGMPrequirements.Tlievarioustypesofdocumentsandmediausedshouldbefullydetmedinthemanufacturer'sQualityManagementSySIem.好的文件管理，是质量:保证系统的一个关键部分,对fGMP符合性操作至关重要。在生产商的质量管理体系中应对所运用的各种文件和媒侦的类型进行全面界定。Documentationmayexistinavarietyoffo11ns,includingpaper-based,electronicorphotographicmedia.ThemainobjectiveofthesystemOfdocuinentationutilizedmustbetoestablish,control,monitorandrecordallactivitieswhichdirectlyorindirectlyimpactonallaspectsofthequalityofmedicinalproducts.TheQualityManagementSystemshouldincludesufficientinstructionaldetailtofacilitateaCOmmOnunderstandingoftherequirements,inadditiontoprovidingforsufficientrecordingofthevariousprocessesandevaluationofanyobservations,sothatongoingapplicationoftherequirementsmaybedemonstrated.文件可以各种形式存在，包括纸质、电子的或图像，公司应建立、限制、监督文件记录系统所采纳的主要方法，并记录卜全部会对药品质量各方面产生干脆或间接影响的活动。质量管理系统应对记录方式有足够的细致操作说明，这样除了对各工艺有充分记录，对各缺陷有评价外，还便利对记录要求有一般性了解，才可以达到应用目的。TherearetwoprimarytypesofdocumentationusedtomanageandrecordGMPcompliance:instructions(directions,requirements)andrccordsrcports.Appropriategddocumentationpracticeshouldbeappliedwithrespecttothetypeofdocument.这里有两种基本记录方式应用于GMP符合性管理和记录中：操作说明(指令、要求)和记录，报告，公司应依据不同文件类型，采纳相应的优良文件规范。Suitablecontrolsshouldbeimplementedloensuretheaccuracy,integrity,availabilityandlegibilityofdocuments.Instructiondocumentsshouldbefreefromerrorsandavailableinwriting.Tlieterm'written-meansrecorded,ordocumentedonmediafromwhichdatamayberenderedinahumanreadablefbrm.应对文件进行适当的限制以保证文件的精确、完整、有效及清晰易读。操作说明类文件应没有错误并有书面版本发行.术语“书面”意思是在某种介质上记录或记载，以使数据形式可以被人们读出。RequiredGMPdocumentation（bytype）:所须要的GMP文件（接类型）SiteMasterFile:AdocumentdescribingtheGMPrelatedactivitiesofthemanufacturer.工厂主文件：描述生产商与GMP相关活动的文件。Instructions（directions,orrequirements）type:规程（指令,或要求）类型SpecificationsDescribeindetailtherequirementswithwhichlhcProduClSormaterialsusedorobtainedduringmanufacturehavetoconlb11n.Theyserveasabasisforqualityevaluation.质量标准：是对产品或所用原料或中间产品所必需符合的要求的具体说明。这是质量评价的一个基础。ManacturingFormulae,Processing,PackagingandTestingInstructions:生产处方，生产、包装和检测说明，Providedetailallthestartingmaterials,equipmentandcomputerisedsystems（ifany）tobeusedandspecifyallprocessing,packaging,samplingandtestinginst11ctions.InprciccsscontrolsandPrOeCSSanalyticaltechnologiestobeemployedshouldbespecifiedwhererelevant,togetherwithacceptancecriteria.规定全部运用的起始物料、设备和计算机系统（如有）的具体要求，并说明全部工艺、包装、取样和检测规程，还须要说明相关的中控和所运用的过程分析技术及可接受标准。Procedures:（OiheruiseknownasStandardOperatingProcedures,orSOPs也称为标准操作规程或SOPs）,givedirectionsforperformingcertainoperations.规程：是时某一项工作的说明.Protocols:Giveinstructionsforpcrfo11uingandrecordingcertaindiscreetoperations.记录：是形成每一批产品的历史，包括发送给客户，也包括其他相关的可能会影响最终产品质量的因崇.TechnicalAgreements:Areagreedbetweencontractgiversandacceptorsforoutsourcedactivities.技术协议：外包活动中，外包方和承包方达成的协议.RecordZReporttype:记录/报告类型Records:Provideevidenceofvariousactionstakentodemonstratecompliancewihinstructions,e.g.activities,events,investigations,andinthecaseofmanufacturedbatchesahistoryofeachbatchofProdUCl*includingitsdistribution.Recordsincludetherawdatawhichisusedtogenerateotherrecords.Forelectronicrecordsregulatedusersshoulddefinewhichdataarctobeusedasrawdata.Atleast,alldataonwhichqualitydecisionsarebasedshouldbedefinedasrawdata.记录：供应各种依据操作要求实施行动的证据，例如，活动、事务、调查、己生产产品的各批次历史，包括销售。记录包括用于产生其它记录的原始数据。对于采纳电子记录的用户，应界定该电了记录为原始数据，至少全部用于作出版量确定的数据应界定为原始数据。Certificatesof.Analysis:Provideasummaryoftestingresultsonsamplesofproductsormaterials")togetherWiIhIhCevaluationIbrcompliancetoastatedspecification.分析报告：给产品或原料样品供应一个检测结果的总结，以及是否符合指定标准的评价。Reports:Oxrumenttheconductofparticularexercises,projectsorinvestigations,togetherwithresults,conclusionsandrecommendations.报告：记录实施特定活动、项目或调查及结果、结论和建议的文件.GenerationandControlofDocumentation文件生成和限制4.1 Alltypesot'docunentshouldbedefinedandadheredto.Therequirementsapplyequally(oallformsofdocumentmediatypes.Complexsystemsneedtobeunderstood,welldocumented,validated,andadequatecontrolsshouldbeinplace.Manydocuments(instructionsan<b'orrecords)mayexistinhybridforms,i.e.someelementsaselectronicandOIherSaspaperbased.Relationshipsandcontrolmeasuresformasterdocuments,officialcopies,datahandlingandrecordsneedtobestatedforbothhybridandhomogenoussystems.Appropriatecontrolsforelectronicdocumentssuchastemplates,forms,andmasterdocunwntsshouldbeimplemented.Appropriatecontrolsshouldbeinplacetoensuretheintegrityoftherecordthroughoutihcrcntionperiod.全部类型文件均应定义并执行，对全部以文件形式制定的表格也一样。困难的系统应能被理解、记录、脸证，并进行充分限制。很多文件(指令和/或记录)可能以混合方式存在，即一些为电子的，而另一些为纸质的.不管是混合方式还是同一方式，母版本文件、正式第印件、数据处理和记录之间的关系及限制方式均应明确说明。对于电子文件应进行适当限制，如文件模板、表格、须要实施的母版本文件.必需有适当的限制以保证记录在整个保存期间均完整.4.2 Docunwntsshouldbedesigned,prepared,reviewed,and(IistributcxlwithCarc.TheyshouldcomplywiththerelevantpartsofProductSpecificationFiles.ManufacturingandMarketingAuthorisationdossiers,asappropriate.Therer<Hiuciionofworkingdocumentsfrommasterdocumentsshouldnotallowanyerrorobeintroducedthroughtherer<xluctionPrOCeSS.文件应细致设计、起草、审核、发放，其内容应符合产品质量标准文件、生产文件和上市许可文件的相关部分要求。须耍执行填写的文件记录母版在复制时不允许有差错.4.3 Documentscontaininginstructionsshouldbeapproved,signedanddatedbyappropriateandauthorisedpersons.Docunwnisshouldhaveunambiguouscontentsandbeuniquelyidentifiable.Theeffectivedateshouldbedefined.包含指令的文件应经过适当的有授权的人批准、卷字、签署日期“文件内容应清晰、唯一、可识别，生效日期应明确.4.4 Documentscontaininginstructionsshouldbelaidoutinanorderlyfashionandbeeasytocheck.Thestyleandlanguageofdocumentsshouldfitwiththeirintendeduse.StandardOpcnitingProcedures,WorkInstnictionsandMethodsshouldbewritteninanimperativemandatoryslylc.包含指令的文件应有序编制，易于检杳。文件的形式和用词应与其用途相适应。标准操作规程、工作指令和方法应形成强制实施的书面文件。4.5 DocumentswithintheQualityManagementSystemshouldberegularlyreviewedandkeptup-to-date.文件管理体系内的文件应定期进行审核并保持更新。4.6 Documentsshouldnotbehand-written;although,wheredocumentsrequiretheentryofdata,sufficientspaceshouldbeprovidedforsuchentries.文件不应手写，假如有些地方须要手动填写，应保密足够的空间以便填入.GoodDocumentationPractices优良文件规范4.7 Handwrittenentriesshouldbemadeinclear,legible,indelibleway.全部书写应清晰、易读且不易擦除。4.8 RecordsshouldbemadeorcompletedatthetimeeachactionistakenandinsuchawaythatallsignificantactivitiesconcerningthemanufactureOfmedicinalproductsaretraceable.全部操作完成后应即进行记录，以保证与药品生产有关的重大活动均可追踪.4.9 Anyalterationmadetothecntrj,onadocumentshouldbesignedanddated:thealte11tionshouldpermitthereadingoflhcoriginalino11nalion.Whereappropriate,thereasonforthealterationshouldberecorded.任何修改必需有签名和日期,修改后原内容必需清晰可读。必要时要对修改缘由进行说明和记录。KetentionofDocuments文件保留4.10 Itshouldbeclearlydefinedwhichrecordisrelatedtoeachmanufacturingactivityandwherethisrecordislocated.Securecontrolsmustbeinplaceoensuretheintegrityofherecordthroughouttheretentionperiodandvalidatedwhere叩ProPriaIe.必需明确定义哪些记录与某生产活动相关，记录放置在什么地方。对放置文件的区域应有安保限制，以保证记录在整个保招期间的完整性，必要时应进行验证。4.11 SpecificrequirementsapplytobatchdocumentationwhichmustbekeptforoneyearafterexpiryofthebatchtowhichitrelatesoratleastfiveyearsaftercertificationofthebatchbytheQualifiedPerson,whicheveristhelonger.Forinvestigationalmedicinalproducts,thebatchdocumentationmustbekeptforatleastfiveyearsafterthecompletionorformaldiscontinuationofthelastclinicaltrialinwhichthebatchwasused.Otherrequirementsforretentionofdocumentationmaybedescribedinlegislationinrelationtospecifictypesofproduct(c.g.AdvancedTherapyMedicinalProducts)andspecifythatlongerretentionperiodsbeappliedtocertaindocuments.批记录必需保留至该批有效期后一年，或在QP放行该产品后至少5年，选其中更长者。对于临床探讨药品，批生产记录应保留至少临床试验完成后5年，或该批次所用于的最迟的临床试验正式结束时。如有相关法规对特殊类型的产品(例如先进的治疗用药品)的文件保留时间有特殊规定，则应符合这些法规要求。4.12 Forothertypesofdocumentation,theretentionperiodwilldependonthebusinessactivitywhichthedocumentationsupports.Criticaldocunwntation.includingrawdata(forexamplerelatingtovalidationorstability),whichsupportsinformationintheMarketingAuthorisationshouldberetainedwhilsttheauthrizalionremainsinforvc.Itmaybeconsideredacceptabletoretirecertaindocumentation(c.g.rawdatasupportingvalidationreportsorstabilityreports)wherethedatahasbeensupersededbyafullsetOfneWdata.Justificationforthisshouldbedocumentedandshouldtakeintoaccountherequirementsforretentionofbatchdocumentation;forexample,inthecaseofprocessvalidationdata,iheaccompanyingrawdatashouldberetainedforaperiodatleastaslongastherecordstorallbatcheswhosereleasehasbeenSUPPOnedonthebasisofthatvalidationexercise.对于其它类型的文件，保存期限依据文件所支持的商业活动而定。关键文件，包括原始数据（例如与验证和稳定性有关），支持上市批准信息，则应在上市批准有效期间均保留。假如有些数据己被新的全套数据替代，则可以考虑对这些数据进行销毁（例如支持验证报告或稳定性报告的原始数据）。对此的判定应记录，并考虑批文件的保留要求。例如,假如是工艺验证数据，原始数据至少应保留至其验证所支持的全部放行批次的记录一样长。Thefollowingsectiongivessomeexamplesofrequireddocuments.ThequalitymanagementsystemshoulddescribealldocunenisrequiredtoensurePrOdUClqualityandpatientsafely.下列部分对于要求的文件给出j'一些例子，质砧管理体系应描述全部要求的文件，以保证产品侦量和患者平安Specifications质量标准4.13 Thereshouldbeappropriatelyauthorisedanddatedspecificationsforstartingandpackagingmaterials,andfinishedPrOdUCtS.起始原料、包装物料和成品陶仃适当批准并标明日期的质量标准Specificationsforstartingandpackagingmaterials起始物料和包装材料的质状标准4.14 Specificationsforstartingandprimaryorprintedpackagingmaterialsshouldincludeorprovidereferenceto.ifapplicable:起始物料、内包材料、印字包材应对包括或对以下.项目供应参考（适用时a）Adescriptionofthematerials,inc】Uding:对物料的描述，包括Thedesignatednameandtheinternalcodereference：给定名称和内部参考代码11ereference,ifany,toaPhannaCCPOeialmonograph;参照物，如有时，Theapprovedsuppliersand.ifreasonable,theoriginalproducerofthematerial:批准的供应商，合理状况卜.，原料的牛产商Aspecimenofprintedmaterials;印刷包材的样本b)Directionsforsamplingandtesting;取样和检测要求c) QualitativeandquantitativerequirementswithacceptanceIinliIs;定量和定性要求及可接受标准d) StorageconditionsandPreCautiOns;贮存条件和警示e) Themaximumperiodofstoragebetorere-examinaiion.可以不需复;则的最长存贮期Specificationsforintermediateandbulkproducts中间体和原料药产品的质量标准4.15 Specificationsforintermediateandbulkproductsshouldbeavailableforcriticalstepsorifthesearepurchasedordispatched.I-hespecificationsshouldbesimilartospecificationsforstartingmaterialsorforfinishedp11lucts,asappropriate.关键步骤，或选购及销件的中间体和原料药产品的历员:标准，适用时，该质量标准应与起始原料或成品质址标准类似。Specificationsforfinishedproducts成品版量标准4.16 Specificationsforfinishedp11xluctsshouldincludeorprovidereferenceo:成品质信标准应包括或供应以下项目的参照物a) Thedesignatednameoftheproductandthecodereferencewhereapplicable;产品名称和索引代码(适用时)b) Tlieformula;分子式c) Adescriptionofthepharmaceuticalformandpackagedetails;药品形态和包装细微环节描述d)Directionsforsamplingandtesting取样和检测要求e)Thequalitativeandquantitativerequirements,withtheacceptancelimits;定性和定要求及可接受限度OThestorageconditionsandanyspecialhandlingprecautions,whereapplicable;存贮条件及特殊处理警示(须要时)g)TheSheIf-Iife.有效期ManufacturingFormulaandProcessingInstructions生产配方和工艺规程Approved,writtenManufacturingFormulaandProcessingInstructionsshouldexistforeachproductandbatchsizetobemanufactured.每产11l和批£.应有经批准的书面生产配和工艺规程4.17TheManufacturingFormulashouldinclude;生产配方应包括a)Thenameoftheproduct,withaproductreferencecoderelatingtoitsspecification：产品名称,包括与其质显标准相关的产品索引代码b>Adescriptionofthepharmaceuticalfo11n,strengthofthePrOdUClandbatchsize;药品形态描述、产品剂量和批地c) Alistofallstartingmaterialstobeused,withtheamountofeach,described:mentionshouldbemadeofanysubstancethatmaydisappearinthecourseofprocessing;全部运用的起始物料，包括各物料投料量的描述；任何在工艺过程中会消逝的物料也应提及d) statementoftheexpeciedfinalyieldwiththeacceptablelimits,andofrelevantintermediateyields,whereapplicable最终产品期里收率的可接受限度说明，以及相关的中间体收率(适用时)4.18TheProcessingInstructionsshouldinclude:工艺规程应包括a) statementoftheprocessinglocationandtheprincipalequipmenttobeused:将要运用的生产场所和主要设备的说明b) Tliemethods,orreference(oIhemethods,tobeusedforpreparingthecriticalequipment(e.g.cleaning,assembling,calibrating,sterilising);将要用F关键设着处理的方法或方法引用的文件(如清洁、装配、校正、消毒)c) ChecksthattheequipmentandworkstationarcclearofpreviousPr(KIUcis.documentsormaterialsnotrequiredfortheplannedprocess,andthatcquipnntiscleanandsuitableforuse;对设备和工作场所的检隹，包括本次生产不须要的前批产品、文件或物料消除，设备清洁并相宜运用d) Detailedstepwiseprocessinginstructionsc.g.checksonmaterials.pre-treatments,sequenceforaddingmaterials,criticalprocessparameters(tinw.tempetc);具体的逐步操作指令例如，物科检查、前处理、加料依次、关键工艺参数(时间、温度等)】.e) Theinstructionsforanyin-processcontrolswiththeirlimits;全部中控指令及其限度OWherenecessary,therequirementsforbulkstorageoftheProdUCIs;includingthecontainer,labelingandspecialstorageconditionswhereapplicable;必要时，未包装产品的贮存要求，包括容器、标卷和特殊的贮存条件(适用时)g)?nyspecialprecautionstobeobserved.其它特殊留意事项PackagingInstructions包装指令4.19ApprovedPackagingInstructionsforeachproduct,packsizeandtypeshouldexist.Theseshouldinclude,orhaveareferenceto.thefollowing:每个产品、包装规格和类型应有批准的包装指导，应包括以卜.项目，或有一份样品进行比照a) Nameoftheproduct;includingthebatchnumberofbulkandfinishedproduce产品名称，包括未包装产品和成品的批号b) Descriptionofitspharmaceuticalform,andstrengthwhereapplicable:其成品剂型、剂量(适用时)的描述c) Thepacksizeexpressedinte11nsofthenumber,weightorvolumeoftheroduc(inthefinalcontainer;最小包装容器上注明以数字形式表达的包装规格，产品重量或体积d) Acompletelistofallthepackagingmaterialsrequired,includingquantities,sizesandtypes,withthecodeorreferencenumberrelatingtothespecificationsofeachpackagingmaterial;须要的完整包材清单,包括数址、尺寸和类型，以及与每一包材质量标准对应的代码或索引号e) Whereappropriate,anexampleorreproductionoftherelevantprintedpackagingmaterials,andspecimensindicatingwheretoapplybatchnumberreferences,andshelflifeoftheproduct;适用时,应供应一个相关印刷包材的样品或现制品，以及样原来显示在何处标示产品批号和有效期11Checksthattheequipmentandworkstationareclearofpreviousproducts,documentsormaterialsnotrequiredfortheplannedpackagingoperations(lineclearance),andthatequipmentiscleanandsuitableforuse.对设备和工作场所的检查，包括本次将要进行的包装操作(包装线清场)不须要的前批产品、文件或物料清除，设符清沽并相宜运用g) Specialprecautionstobeobserved,includingacarefulexaminationoftheareaandequipmentinordertoascertaintheline