GMP确保产品生产和控制一致性减少那些不能通过制品检定来控制的风险交叉污染混淆GMP的基础质量管理要素1)质量保证 在一个组织内,QA是一个管理的工具。在契约(合同)情况下,它提供对供应商的保证.QA不是公司内某一部门单独的责任,而 是所有可能影响制品质量的员工的责任QA体系的要求–II确保成品进行正确加工,并在放行前进行检查(检验)7.确保制品经 授权者审核后放行8.储存储存和分发9.组织自检质量控制部门(QC)每个有生产许可证的企业都应该有QC部门独 立于生产和其它部门是最基本的要求由一个授权的有资格的经验丰富的人员管理,包括一个或几个质控实验室质量控制的基本要求 资 源足够的设施培训的人员经验证并批准的程序质量控制的基本要求-I 对象起始材料包装材料中间产品半成品成 品环境条件质量控制的基本要求–II1.QC部门批准的取样2.经验证的实验方法3.记录4.对生产记 录进行审查和评估5.对所有偏差的差错原因调查6.所有成分符合市场准入的要求质量控制的基本要求–III7. 成分达到要求的纯度8. 正确的容器9. 正确的标签10.由授权人签发11.原材料和成品的留样质控 部门的其它职责1.建立质控程序2.参考标准品3.正确的标签4.稳定性实验5.投诉调查6.环 境监测成品的评价应包含所有相关因素,如:生产条件生产过程的检测结果生产文件符合成品标准对最终包装的检验如何 对企业进行检查?申请许可证的新企业:检查所有GMP必须的要素是否有现场主文件(SMF)?是否有企业主文件(FMF)?是 否有质量手册?该手册是否包含GMP所有的要素以及如何用于衡量操作?如何处理不符合的情况?该手册是否详细描述了质量管理 问题?是否有产品概要文件(ProductSummaryFile)?References1.GoodManufact uringPracticesforpharmaceuticalproducts.In:WHOExpertCommi tteeonSpecificationsforPharmaceuticalPreparations.Twenty-se condreport.Geneva,WorldHealthOrganization,1992Annex1(WHO TechnicalReportSeries,No.823).2.Validationofanalyticalp roceduresusedintheexaminationofpharmaceuticalmaterials.In :WHOExpertCommitteeonSpecificationsforPharmaceuticalPrepa rations.Thirty-secondreport.Geneva,WorldHealthOrganization, 1992:Annex5(WHOTechnicalReportSeries,No.823).3.Goodma nufacturingpracticeformedicinalproductsintheEuropeanCommu nity.Brussels,CommissionoftheEuropeanCommunities,1992.4. PharmaceuticalInspectionConvention,PharmaceuticalInspectionC ooperationScheme(PIC/S).In:Guidetogoodmanufacturingpracti ceformedicinalplants,Geneva,PIC/SSecretariat,2000.5.Qual ityassuranceofpharmaceuticals.Acompendiumofguidelinesand relatedmaterials.Volume2.Goodmanufacturingpracticesandins pection.Geneva,WorldHealthOrganization,1999.6.Modelcertif icateofanalysis.In:WHOExpertCommitteeonSpecificationsfor PharmaceuticalPreparations.Thirty-sixthreport.Geneva,World HealthOrganization,2002,Annex10(WHOTechnicalReportSeries, No.902).通过GMP认可的企业::在一个常规检查期间,由于时间有限,并不能对要素的所有方面进行检查。但是 ,有些方面必须结合审核进行检查。WORKSHOPONGOODMANUFACTURINGPRACTICES(GMPs )INSPECTIONFORVACCINESWHOThefirstWHOdrafttextongoodm anufacturingpractices(GMP)waspreparedin1967byagroupofc onsultantsattherequestoftheTwentiethWorldHealthAssembly (resolutionWHA20.34).ItwassubsequentlysubmittedtotheTwent y-firstWorldHealthAssemblyunderthetitle“Draftrequirements forgoodmanufacturingpracticeinthemanufactureandqualityc ontrolofdrugsandpharmaceuticalspecialities”andwasaccepted .TherevisedtextwasdiscussedbytheWHOExpertCommitteeonS pecificationsforPharmaceuticalPreparationsin1968andpublish ed38asanannextoitstwenty-secondreport.Thetextwasthen reproduced(withsomerevisions)in1971intheSupplementtothe secondeditionofTheInternationalPharmacopoeia.In1969,when theWorldHealthAssemblyrecommendedthefirstversionoftheW HOCertificationSchemeontheQualityofPharmaceuticalProducts MovinginInternationalCommerceinresolutionWHA22.50,itacce ptedatthesametimetheGMPtextasanintegralpartoftheSch eme.RevisedversionsofboththeCertificationSchemeandtheGM Ptextwereadoptedin1975byresolutionWHA28.65.TheObjectiv eofthismoduleistogivetheInspectorabroadviewoftheess entialelementsofGMP,withemphasisonQualityManagement,defi nitionsofGMPandhowtheelementsmustbeconsideredduringthe licensingofnewfacilitiesandduringtheroutineinspectionso ffacilities.本模块的目的是使检查员对GMP的基本要素有一个全面的了解。重点是:质量管理;GMP的定义;以及在 新企业的认证和常规检查中如何考虑这些要点?FailuresofGMPinthePharmaceuticalindu strieshavecausedseverehumandiscomfortanddeathandthesetw oexamplesreflecttheimportanceofGMP.在药品生产企业,不遵守GMP,就会引起严重的人 类健康问题甚至死亡。这2个案例反映了GMP的重要性。HistoryofGMPandevolutionofGMPre flectsthecooperationofworldregulatorybodiessuchasWHOan dtheFDAandtheneedtoensuretheseregulationsaremadeavail abletoinspectorsandmanufacturerstoconformto.GMP的历史和发展反映了国 际上各管理机构之间的相互合作,如WHO和FDA之间的合作,以及确保这些条例的制定适用于检查员和生产企业的执行的需要。GMP是质 量保证的一部分,它确保制品一致性的生产和按其预期的用途进行质量控制,并且是进入市场所必需。GMP的目的在于在任何药品的生产过 程中,尽可能减少其内在的风险。一般包括:交叉污染(特别是意外的污染物);和混淆(混乱)。原因如:贴错标签等。通过GMP:(a )对所有的生产过程明确定义,根据经验进行系统的审查,并且表明能够保证制品生产的一致性,并符合其所要求的规定的质量。(b) 进行资格认证和验证;(c)通过所有必需的资源,包括:(i)适当的合格的、经培训的人员;(ii)适当 的厂房设施和空间;(iii)适当的设备和服务;(iv)适当的材料、容器和标签;(v)批准 的程序和规定;(vi)适当的储存和运输;(vii)生产过程的适当的人员,实验室和设备,控制(d) 明确的书面的规定和程序,并且适用;(e)员工经培训可进行正确操作;(f)生产过程的记录(手写和/或记录的设备),以表明 所有的步骤按规定进行,产品的数量和质量符合预期的目标;记录所有明显的偏差并进行调查。(g)覆盖整个生产和分发全过程的记录可反映 一批制品的全部历史,可追溯性,批记录应简明易懂,信息完整。(h)产品正确的储存和运输分发可将质量问题减至最小(i)还需要 一个能够从销售和供应召回任何制品的系统;(j)对上市制品的投诉进行调查,调查质量问题的原因,有针对性的采取适当的措施,以防止 再发生。hebasicelementsofqualitymanagementare:—anappropriat einfrastructureor“qualitysystem”,encompassingtheorganizati onalstructure,procedures,processesandresources;—systematic actionsnecessarytoensureadequateconfidencethataproduct( orservice)willsatisfygivenrequirementsforquality.Thetota lityoftheseactionsistermed“qualityassurance”.Withinanor ganization,qualityassuranceservesasamanagementtool.Incon tractualsituations,qualityassurancealsoservestogenerateco nfidenceinthesupplier.Theconceptsofqualityassurance,GMP andqualitycontrolareinterrelatedaspectsofqualitymanagemen t.Theyaredescribedhereinordertoemphasizetheirrelationsh ipandtheirfundamentalimportancetotheproductionandcontrol ofpharmaceuticalproducts.ThesearetheEssentialElementsof QualityManagement,andareneededforanycompanytobecomelice nsed.Principle.“Qualityassurance”isawide-rangingconceptco veringallmattersthatindividuallyorcollectivelyinfluenceth equalityofaproduct.Itisthetotalityofthearrangementsm adewiththeobjectofensuringthatpharmaceuticalproductsare ofthequalityrequiredfortheirintendeduse.Qualityassurance thereforeincorporatesGMPandotherfactors,includingthoseou tsidethescopeofthisguidesuchasproductdesignanddevelopm ent.1.2Thesystemofqualityassuranceappropriatetothemanuf actureofpharmaceuticalproductsshouldensurethat:(a)pharmac euticalproductsaredesignedanddevelopedinawaythattakesa ccountoftherequirementsofGMPandother1Goodmanufacturing practicesforpharmaceuticalproducts,PartOne.In:WHOExpertC ommitteeonSpecificationsforPharmaceuticalPreparations.Thirt y-secondreport.Geneva,WorldHealthOrganization,1992,Annex1 (WHOTechnicalReportSeries,No.823).1Thisisacodegovern ingthetestingofchemicalstoobtaindataontheirpropertiesa ndensuringsafetywithrespecttohumanhealthandtheenvironme nt.Itisdifferentfromthatdescribedin“Goodlaboratorypract icesingovernmentaldrugcontrollaboratories”intheThirtieth reportoftheWHOExpertCommitteeonSpecificationsforPharmace uticalPreparations(WHOTechnicalReportSeries,No.748,1987, Annex1).associatedcodessuchasthoseofgoodlaboratorypract ice(GLP)1andgoodclinicalpractice(GCP);(b)productionandc ontroloperationsareclearlyspecifiedinawrittenformandGMP requirementsareadopted;(c)managerialresponsibilitiesarecl earlyspecifiedinjobdescriptions;(d)arrangementsaremadefo rthemanufacture,supplyanduseofthecorrectstartingandpac kagingmaterials;(e)allnecessarycontrolsonstartingmaterial s,intermediateproducts,andbulkproductsandotherin-process controls,calibrations,andvalidationsarecarriedout;(f)the finishedproductiscorrectlyprocessedandchecked,accordingto thedefinedprocedures;(g)pharmaceuticalproductsarenotsold orsuppliedbeforetheauthorizedpersons(seealsosections9.1 1&9.12)havecertifiedthateachproductionbatchhasbeenprod ucedandcontrolledinaccordancewiththerequirementsofthema rketingauthorizationandanyotherregulationsrelevanttothep roduction,controlandreleaseofpharmaceuticalproducts;(h)sa tisfactoryarrangementsexisttoensure,asfaraspossible,that thepharmaceuticalproductsarestoredbythemanufacturer,dist ributed,andsubsequentlyhandledsothatqualityismaintainedt hroughouttheirshelf-life;(i)thereisaprocedureforself-ins pectionand/orqualityauditthatregularlyappraisestheeffecti venessandapplicabilityofthequalityassurancesystem;(j)dev iationsarereported,investigatedandrecorded;(k)thereisas ystemforapprovingchangesthatmayhaveanimpactonproductqu ality;(l)regularevaluationsofthequalityofpharmaceuticalp roductsshouldbeconductedwiththeobjectiveofverifyingthec onsistencyoftheprocessandensuringitscontinuousimprovement .1.3Themanufacturermustassumeresponsibilityforthequality ofthepharmaceuticalproductstoensurethattheyarefitfort heirintendeduse,complywiththerequirementsofthemarketing authorizationanddonotplacepatientsatriskduetoinadequate safety,qualityorefficacy.Theattainmentofthisqualityobje ctiveistheresponsibilityofseniormanagementandrequiresthe participationandcommitmentofstaffinmanydifferentdepartme ntsandatalllevelswithinthecompany,thecompany’ssupplier s,andthedistributors.Toachievethequalityobjectivereliabl ytheremustbeacomprehensivelydesignedandcorrectlyimplemen tedsystemofqualityassuranceincorporatingGMPandqualitycon trol.Itshouldbefullydocumentedanditseffectivenessmonitor ed.Allpartsofthequalityassurancesystemshouldbeadequatel ystaffedwithcompetentpersonnel,andshouldhavesuitableand sufficientpremises,equipment,andfacilities.Goodmanufactur ingpracticesforpharmaceuticalproducts(GMP)2.1Goodmanufact uringpracticeisthatpartofqualityassurancewhichensuresth atproductsareconsistentlyproducedandcontrolledtothequali tystandardsappropriatetotheirintendeduseandasrequiredby themarketingauthorization.GMPareaimedprimarilyatdiminish ingtherisksinherentinanypharmaceuticalproduction.Suchris ksareessentiallyoftwotypes:cross-contamination(inparticul arofunexpectedcontaminants)andmix-ups(confusion)causedby, forexample,falselabelsbeingputoncontainers.UnderGMP:(a )allmanufacturingprocessesareclearlydefined,systematically reviewedinthelightofexperience,andshowntobecapableof consistentlymanufacturingpharmaceuticalproductsoftherequire dqualitythatcomplywiththeirspecifications;(b)qualificatio nandvalidationareperformed;(c)allnecessaryresourcesarep rovided,including:(i)appropriatelyqualifiedandtrainedperso nnel;(ii)adequatepremisesandspace;(iii)suitableequipment andservices;(iv)appropriatematerials,containersandlabels; (v)approvedproceduresandinstructions;(vi)suitablestoragea ndtransport;(vii)adequatepersonnel,laboratoriesandequipmen tforin-processcontrols;(d)instructionsandproceduresarewr itteninclearandunambiguous()language,specificallyapplicabl etothefacilitiesprovided;(e)operatorsaretrainedtocarry outprocedurescorrectly;(f)recordsaremade(manuallyand/orb yrecordinginstruments)duringmanufacturetoshowthatallthe stepsrequiredbythedefinedproceduresandinstructionshavein factbeentakenandthatthequantityandqualityoftheproduct areasexpected;anysignificantdeviationsarefullyrecordeda ndinvestigated;(g)recordscoveringmanufactureanddistributio n,whichenablethecompletehistoryofabatchtobetraced,are retainedinacomprehensibleandaccessibleform;(h)theprope rstorageanddistributionoftheproductsminimizesanyriskto theirquality;(i)asystemisavailabletorecallanybatchofp roductfromsaleorsupply;(j)complaintsaboutmarketedproduct sareexamined,thecausesofqualitydefectsinvestigated,anda ppropriatemeasurestakeninrespectofthedefectiveproductsto preventrecurrence.Qualitycontrollaboratoriesshouldbesepar atedfromproductionareas.Areaswherebiological,microbiologic alorradioisotope(放射性同位素)testmethodsareemployedshouldbese paratedfromeachother.Qualitycontrollaboratoriesshouldbed esignedtosuittheoperationstobecarriedoutinthem.Suffici entspaceshouldbegiventoavoidmix-upsandcross-contaminatio n.Thereshouldbeadequatesuitablestoragespaceforsamples,r eferencestandards(ifnecessary,withcooling),solvents,reagen tsandrecords.Thedesignofthelaboratoriesshouldtakeintoa ccountthesuitabilityofconstructionmaterials,preventionoff umesandventilation.Thereshouldbeseparateairsupplytolabo ratoriesandproductionareas.Separateair-handlingunitsandot herprovisionsareneededforbiological,microbiologicalandrad ioisotopelaboratories.Aseparateroommaybeneededforinstrum entstoprotectthemagainstelectricalinterference,vibration振动 ,contactwithexcessive过多的moistureandotherexternalfactors, orwhereitisnecessarytoisolatetheinstruments.Qualitycont rolisthepartofGMPconcernedwithsampling,specificationsan dtesting,andwiththeorganization,documentationandreleasep rocedureswhichensurethatthenecessaryandrelevanttestsare actuallycarriedoutandthatmaterialsarenotreleasedforuse, norproductsreleasedforsaleorsupply,untiltheirqualityha sbeenjudgedtobesatisfactory.Qualitycontrolisnotconfined 限制tolaboratoryoperationsbutmustbeinvolvedinalldecisions concerningthequalityoftheproduct.Theindependenceofquali tycontrolfromproductionisconsideredfundamental.Eachmanufa cturer(theholderofamanufacturingauthorization)shouldhave aqualitycontrolfunction.Thequalitycontrolfunctionshouldb eindependentofotherdepartmentsandundertheauthorityofap ersonwithappropriatequalificationsandexperience,whohasone orseveralcontrollaboratoriesathisorherdisposal.Adequate resourcesmustbeavailabletoensurethatallthequalitycontr olarrangementsareeffectivelyandreliablycarriedout.Thebas icrequirementsforqualitycontrolareasfollows:(a)adequate facilities,trainedpersonnelandapprovedproceduresmustbeava ilableforsampling,inspecting,andtestingstartingmaterials, packagingmaterials,andintermediate,bulk,andfinishedproduct s,andwhereappropriateformonitoringenvironmentalconditions forGMPpurposes;(b)samplesofstartingmaterials,packagingma terials,intermediateproducts,bulkproductsandfinishedproduc tsmustbetakenbymethodsandpersonnelapprovedofbythequal itycontroldepartment;(c)qualificationandvalidationmustbe performed;(d)recordsmustbemade(manuallyand/orbyrecording instruments)demonstratingthatalltherequiredsampling,inspe ctingandtestingprocedureshaveactuallybeencarriedoutandt hatanydeviationshavebeenfullyrecordedandinvestigated;(e) thefinishedproductsmustcontainingredientscomplyingwithth equalitativeandquantitativecompositionoftheproductdescrib edinthemarketingauthorization;theingredientsmustbeofthe requiredpurity,intheirpropercontainerandcorrectlylabelle d;(f)recordsmustbemadeoftheresultsofinspectingandtest ingthematerialsandintermediate,bulkandfinishedproductsag ainstspecifications;productassessmentmustincludeareviewan devaluationoftherelevantproductiondocumentationandanasse ssmentofdeviationsfromspecifiedprocedures;(g)nobatchofp roductistobereleasedforsaleorsupplypriortocertificatio nbytheauthorizedperson(s)thatitisinaccordancewithther equirementsofthemarketingauthorization.Incertaincountries, bylaw,thebatchreleaseisataskoftheauthorizedpersonfro mproductiontogetherwiththeauthorizedpersonfromqualitycon trol;(h)sufficientsamplesofstartingmaterialsandproductsm ustberetainedtopermitfutureexaminationoftheproductifne cessary;theretainedproductmustbekeptinitsfinalpackunle ssthepackisexceptionallylarge.Qualitycontrolasawholewi llalsohaveotherduties,suchastoestablish,validateandimp lementallqualitycontrolprocedures,toevaluate,maintain,and storethereferencestandardsforsubstances,toensurethecorr ectlabellingofcontainersofmaterialsandproducts,toensure thatthestabilityoftheactivepharmaceuticalingredientsandp roductsismonitored,toparticipateintheinvestigationofcomp laintsrelatedtothequalityoftheproduct,andtoparticipate inenvironmentalmonitoring.Alltheseoperationsshouldbecarri edoutinaccordancewithwrittenproceduresand,wherenecessary ,recorded.Assessmentoffinishedproductsshouldembraceallre levantfactors,includingtheproductionconditions,theresults ofin-processtesting,themanufacturing(includingpackaging)do cumentation,compliancewiththespecificationforthefinishedp roduct,andanexaminationofthefinishedpack.Qualitycontrol personnelmusthaveaccesstoproductionareasforsamplingandi nvestigationasappropriate.Controlofstartingmaterialsandin termediate,bulkandfinishedproductsAlltestsshouldfollowth einstructionsgivenintherelevantwrittentestprocedurefore achmaterialorproduct.Theresultshouldbecheckedbythesupe rvisorbeforethematerialorproductisreleasedorrejected.Sa mplesshouldberepresentativeofthebatchesofmaterialfromwh ichtheyaretakeninaccordancewiththeapprovedwrittenproced ure.Samplingshouldbecarriedoutsoastoavoidcontamination orotheradverseeffectsonquality.Thecontainersthathavebee nsampledshouldbemarkedaccordinglyandcarefullyresealedaft ersampling.Careshouldbetakenduringsamplingtoguardagains tcontaminationormix-upof,orby,thematerialbeingsampled. Allsamplingequipmentthatcomesintocontactwiththematerial shouldbeclean.Someparticularlyhazardousorpotentmaterials mayrequirespecialprecautions.Samplingequipmentshouldbecl eanedand,ifnecessary,sterilizedbeforeandaftereachuseand storedseparatelyfromotherlaboratoryequipment.Eachsamplec ontainershouldbearalabelindicating:(a)thenameofthesamp ledmaterial;(b)thebatchorlotnumber;(c)thenumberofthe containerfromwhichthesamplehasbeentaken;(d)thenumberof thesample;(e)thesignatureofthepersonwhohastakenthesa mple;(f)thedateofsampling.Out-of-specificationresultsobta inedduringtestingofmaterialsorproductsshouldbeinvestigat edinaccordancewithanapprovedprocedure.Recordsshouldbema intained.TestrequirementsStartingandpackagingmaterialsBef orereleasingastartingorpackagingmaterialforuse,thequali tycontrolmanagershouldensurethatthematerialshavebeentes tedforconformitywithspecificationsforidentity,strength,pu rityandotherqualityparameters.Anidentitytestshouldbecon ductedonasamplefromeachcontainerofstartingmaterial(see alsosection14.14).Eachbatch(lot)ofprintedpackagingmateri alsmustbeexaminedfollowingreceipt.Inlieuoftestingbythe manufacturer,acertificateofanalysismaybeacceptedfromthe supplier,providedthatthemanufacturerestablishesthereliabi lityofthesupplier’sanalysisthroughappropriateperiodicvali dationofthesupplier’stestresults(seesections8.8and8.9) andthroughon-siteauditsofthesupplier’scapabilities.(This doesnotaffectsection17.15).Certificatesmustbeoriginals(n otphotocopies)orotherwisehavetheirauthenticityassured.Cer tifi-catesmustcontainatleastthefollowinginformation(6): (a)identification(nameandaddress)oftheissuingsupplier;(b )signatureofthecompetentofficial,andstatementofhisorhe rqualifications;(c)thenameofthematerialtested;(d)theba tchnumberofthematerialtested;(e)thespecificationsandmet hodsused;(f)thetestresultsobtained;(g)thedateoftesting .In-processcontrolIn-processcontrolrecordsshouldbemaintai nedandformapartofthebatchrecords(seesection15.25).Fin ishedproductsForeachbatchofdrugproduct,thereshouldbean appropriatelaboratorydeterminationofsatisfactoryconformity toitsfinishedproductspecificationpriortorelease.Products failingtomeettheestablishedspecificationsoranyotherrelev antqualitycriteriashouldberejected.BatchrecordreviewProd uctionandqualitycontrolrecordsshouldbereviewedaspartof theapprovalprocessofbatchrelease.Anydivergenceorfailure ofabatchtomeetitsspecificationsshouldbethoroughlyinvest igated.Theinvestigationshould,ifnecessary,extendtootherb atchesofthesameproductandotherproductsthatmayhavebeen associatedwiththespecificfailureordiscrepancy.Awrittenre cordoftheinvestigationshouldbemadeandshouldincludethec onclusionandfollow-upaction.Retentionsamplesfromeachbatch offinishedproductshouldbekeptforatleastoneyearaftert heexpirydate.Finishedproductsshouldusuallybekeptintheir finalpackagingandstoredundertherecommendedconditions.If exceptionallylargepackagesareproduced,smallersamplesmight bestoredinappropriatecontainers.Samplesofactivestartingm aterialsshouldberetainedforatleastoneyearbeyondtheexpi rydateofthecorrespondingfinishedproduct.Otherstartingmat erials(otherthansolvents,gases,andwater)shouldberetained foraminimumoftwoyearsiftheirstabilityallows.Retention samplesofmaterialsandproductsshouldbeofasizesufficient topermitatleasttwofullre-examinations.StabilitystudiesQu alitycontrolshouldevaluatethequalityandstabilityoffinish edpharmaceuticalproductsand,whennecessary,ofstartingmater ialsandintermediateproducts.17.24Qualitycontrolshouldesta blishexpirydatesandshelf-lifespecificationsonthebasisof stabilitytestsrelatedtostorageconditions.Awrittenprogramm eforongoingstabilitydeterminationshouldbedevelopedandimp lementedtoincludeelementssuchas:(a)acompletedescription ofthedruginvolvedinthestudy;(b)thecompletesetoftestin gparametersandmethods,describingalltestsforpotency,purit y,andphysicalcharacteristicsanddocumentedevidencethatthes etestsindicatestability;(c)provisionfortheinclusionofa sufficientnumberofbatches;(d)thetestingscheduleforeachd rug;(e)provisionforspecialstorageconditions;(f)provision foradequatesampleretention;(g)asummaryofallthedatagene rated,includingtheevaluationandtheconclusionsofthestudy. Stabilityshouldbedeterminedpriortomarketingandfollowing anysignificantchangesinprocesses,equipment,packagingmateri als,etc.药品GMP管理概述WORKSHOPONGOODMANUFACTURINGPRACTICES(GM Ps)INSPECTION介绍疫苗的质量管理和GMP的基本要素生产中的GMP要求在检查中要寻找的内容培训班的目的 GMP失败的教训-案例分析?“神奇的药物”投入使用。作为小儿科的万能药上市。是一种悬于液体工业溶剂-双烯乙 二醇中的芳香溶液.通常被认为是以酒精为基础的产品,但特殊配方为双烯乙二醇.摄取后,乙烯乙二醇代谢为草酸. 358中毒107死亡251发病但存活1938–磺胺,一种甘香洒剂(甜的芳香的酒精与水的溶液,用作药 物的赋形剂)1955–脊灰疫苗(CutterLabs,USA)(Lamber t,E.C.,MedicalMistakes,IndianaUniversityPress,1978)案例分析5 1儿童麻痹10死亡几个可能的原因:病毒灭活过程批间存在差异.·未经适当的病毒灭活工艺验证而急于放大生产·现行的 活病毒生产工艺采用热灭活步骤.对于病毒;加热灭活步骤的放大可能并不充分GMP的历史WH0-GMPEC-GMPFD A-无菌加工FDA-cGMPFDA-GMPPIC-GMP德国国家法律强制实施GMP19681971197819 83198519871989GMP的历史PIC-改编的GMP根据EC-GMPWHO-修订的GMPWHO-生物 制品的GMPWHO-检查指南附件1的修订EC-GMPWHO-无菌药品的GMP1992199219921996 199720022003WHO-修订的GMP什么是GMP?世界卫生组织将GMP定义为:“质量保证 的一部分。确保制品按照适合拟使用目的的质量标准进行一致性生产和质量控制,并且满足市场许可的要求”质量管理制定和 贯彻“质量方针”基本要素是:适当的基础或“质量体系”,包括程序,步骤和资源确保对产品(或服务)符合既定的“质量”要求有 足够信任所必需采取的总体行为.这些行为总称为“质量保证”质量管理定义为管理功能中制定和贯彻质量方针的方面质量方针是公司 上层管理对其有关质量的总体意图的说明,以总体方针正式表达.质量关系质量管理质量控制GMP质量保证管理方面质量体系 质量方针…人员培训验证自检质量目标质量手册取样标准检测设施人员生产优良规范培训的人员和卫生质量控 制优良规范文件培训质量管理的基本基础自检和质量检查合同生产和分析产品收回投诉资格和验证卫生和卫生设施GM P质量保证材料设备质量保证体系要求–I1. 确保产品正确生产2. 区分管理职责3. 为生产和质控提供SOPs 4. 组织供应和使用正确的原材料5. 规定生产和包装所有环节的质量控制GMP的基本要求–I1. 明确定义并系统审核 生产过程2. 关键步骤的验证3. 适当的资源:人员,建筑,设备,材料4. 明确的书写程序5. 经培训的操作者 GMP的基本要求–II6. 完整的记录,差错调查7. 正确的保存和分发8. 制品召回系统9 . 投诉的处理WORKSHOPONGOODMANUFACTURINGPRACTICES(GMPs)INSPEC TIONFORVACCINESWHOThefirstWHOdrafttextongoodmanufactu ringpractices(GMP)waspreparedin1967byagroupofconsultan tsattherequestoftheTwentiethWorldHealthAssembly(resolut ionWHA20.34).ItwassubsequentlysubmittedtotheTwenty-first WorldHealthAssemblyunderthetitle“Draftrequirementsforgoo dmanufacturingpracticeinthemanufactureandqualitycontrolo fdrugsandpharmaceuticalspecialities”andwasaccepted.There visedtextwasdiscussedbytheWHOExpertCommitteeonSpecifica tionsforPharmaceuticalPreparationsin1968andpublished38as anannextoitstwenty-secondreport.Thetextwasthenreproduc ed(withsomerevisions)in1971intheSupplementtothesecond editionofTheInternationalPharmacopoeia.In1969,whentheWor ldHealthAssemblyrecommendedthefirstversionoftheWHOCerti ficationSchemeontheQualityofPharmaceuticalProductsMoving inInternationalCommerceinresolutionWHA22.50,itacceptedat thesametimetheGMPtextasanintegralpartoftheScheme.Rev isedversionsofboththeCertificationSchemeandtheGMPtextw ereadoptedin1975byresolutionWHA28.65.TheObjectiveofthi smoduleistogivetheInspectorabroadviewoftheessentiale lementsofGMP,withemphasisonQualityManagement,definitions ofGMPandhowtheelementsmustbeconsideredduringthelicensi ngofnewfacilitiesandduringtheroutineinspectionsoffacili ties.本模块的目的是使检查员对GMP的基本要素有一个全面的了解。重点是:质量管理;GMP的定义;以及在新企业的认证和常 规检查中如何考虑这些要点?FailuresofGMPinthePharmaceuticalindustriesh avecausedseverehumandiscomfortanddeathandthesetwoexampl esreflecttheimportanceofGMP.在药品生产企业,不遵守GMP,就会引起严重的人类健康问题甚至死 亡。这2个案例反映了GMP的重要性。HistoryofGMPandevolutionofGMPreflectst hecooperationofworldregulatorybodiessuchasWHOandtheFD Aandtheneedtoensuretheseregulationsaremadeavailableto inspectorsandmanufacturerstoconformto.GMP的历史和发展反映了国际上各管理机构之 间的相互合作,如WHO和FDA之间的合作,以及确保这些条例的制定适用于检查员和生产企业的执行的需要。GMP是质量保证的一部分, 它确保制品一致性的生产和按其预期的用途进行质量控制,并且是进入市场所必需。GMP的目的在于在任何药品的生产过程中,尽可能减少 其内在的风险。一般包括:交叉污染(特别是意外的污染物);和混淆(混乱)。原因如:贴错标签等。通过GMP:(a)对所有的生产 过程明确定义,根据经验进行系统的审查,并且表明能够保证制品生产的一致性,并符合其所要求的规定的质量。(b)进行资格认证和验 证;(c)通过所有必需的资源,包括:(i)适当的合格的、经培训的人员;(ii)适当的厂房设施和空间 ;(iii)适当的设备和服务;(iv)适当的材料、容器和标签;(v)批准的程序和规定; (vi)适当的储存和运输;(vii)生产过程的适当的人员,实验室和设备,控制(d)明确的书面的规定 和程序,并且适用;(e)员工经培训可进行正确操作;(f)生产过程的记录(手写和/或记录的设备),以表明所有的步骤按规定 进行,产品的数量和质量符合预期的目标;记录所有明显的偏差并进行调查。(g)覆盖整个生产和分发全过程的记录可反映一批制品的全部历 史,可追溯性,批记录应简明易懂,信息完整。(h)产品正确的储存和运输分发可将质量问题减至最小(i)还需要一个能够从销售和 供应召回任何制品的系统;(j)对上市制品的投诉进行调查,调查质量问题的原因,有针对性的采取适当的措施,以防止再发生。he basicelementsofqualitymanagementare:—anappropriateinfras tructureor“qualitysystem”,encompassingtheorganizationalstr ucture,procedures,processesandresources;—systematicactions necessarytoensureadequateconfidencethataproduct(orservi ce)willsatisfygivenrequirementsforquality.Thetotalityof theseactionsistermed“qualityassurance”.Withinanorganizati on,qualityassuranceservesasamanagementtool.Incontractual situations,qualityassurancealsoservestogenerateconfidence inthesupplier.Theconceptsofqualityassurance,GMPandqual itycontrolareinterrelatedaspectsofqualitymanagement.They aredescribedhereinordertoemphasizetheirrelationshipandt heirfundamentalimportancetotheproductionandcontrolofphar maceuticalproducts.ThesearetheEssentialElementsofQuality Management,andareneededforanycompanytobecomelicensed.Pr inciple.“Qualityassurance”isawide-rangingconceptcoveringa llmattersthatindividuallyorcollectivelyinfluencethequalit yofaproduct.Itisthetotalityofthearrangementsmadewith theobjectofensuringthatpharmaceuticalproductsareoftheq ualityrequiredfortheirintendeduse.Qualityassurancetherefo reincorporatesGMPandotherfactors,includingthoseoutsideth escopeofthisguidesuchasproductdesignanddevelopment.1.2 Thesystemofqualityassuranceappropriatetothemanufactureo fpharmaceuticalproductsshouldensurethat:(a)pharmaceutical productsaredesignedanddevelopedinawaythattakesaccounto ftherequirementsofGMPandother1Goodmanufacturingpractice sforpharmaceuticalproducts,PartOne.In:WHOExpertCommittee onSpecificationsforPharmaceuticalPreparations.Thirty-second report.Geneva,WorldHealthOrganization,1992,Annex1(WHOTe chnicalReportSeries,No.823).1Thisisacodegoverningthe testingofchemicalstoobtaindataontheirpropertiesandensur ingsafetywithrespecttohumanhealthandtheenvironment.Iti sdifferentfromthatdescribedin“Goodlaboratorypracticesin governmentaldrugcontrollaboratories”intheThirtiethreporto ftheWHOExpertCommitteeonSpecificationsforPharmaceuticalP reparations(WHOTechnicalReportSeries,No.748,1987,Annex1) .associatedcodessuchasthoseofgoodlaboratorypractice(GLP )1andgoodclinicalpractice(GCP);(b)productionandcontrolo perationsareclearlyspecifiedinawrittenformandGMPrequire mentsareadopted;(c)managerialresponsibilitiesareclearlysp ecifiedinjobdescriptions;(d)arrangementsaremadeforthema nufacture,supplyanduseofthecorrectstartingandpackagingm aterials;(e)allnecessarycontrolsonstartingmaterials,inter mediateproducts,andbulkproductsandotherin-processcontrols ,calibrations,andvalidationsarecarriedout;(f)thefinished productiscorrectlyprocessedandchecked,accordingtothedef inedprocedures;(g)pharmaceuticalproductsarenotsoldorsupp liedbeforetheauthorizedpersons(seealsosections9.11&9.12 )havecertifiedthateachproductionbatchhasbeenproducedand controlledinaccordancewiththerequirementsofthemarketing authorizationandanyotherregulationsrelevanttotheproductio n,controlandreleaseofpharmaceuticalproducts;(h)satisfacto ryarrangementsexisttoensure,asfaraspossible,thatthepha rmaceuticalproductsarestoredbythemanufacturer,distributed, andsubsequentlyhandledsothatqualityismaintainedthroughou ttheirshelf-life;(i)thereisaprocedureforself-inspection and/orqualityauditthatregularlyappraisestheeffectivenessa ndapplicabilityofthequalityassurancesystem;(j)deviations arereported,investigatedandrecorded;(k)thereisasystemfo rapprovingchangesthatmayhaveanimpactonproductquality;( l)regularevaluationsofthequalityofpharmaceuticalproducts shouldbeconductedwiththeobjectiveofverifyingtheconsisten cyoftheprocessandensuringitscontinuousimprovement.1.3Th emanufacturermustassumeresponsibilityforthequalityofthe pharmaceuticalproductstoensurethattheyarefitfortheirint endeduse,complywiththerequirementsofthemarketingauthoriz ationanddonotplacepatientsatriskduetoinadequatesafety, qualityorefficacy.Theattainmentofthisqualityobjectiveis theresponsibilityofseniormanagementandrequiresthepartici pationandcommitmentofstaffinmanydifferentdepartmentsand atalllevelswithinthecompany,thecompany’ssuppliers,andt hedistributors.Toachievethequalityobjectivereliablythere mustbeacomprehensivelydesignedandcorrectlyimplementedsyst emofqualityassuranceincorporatingGMPandqualitycontrol.It shouldbefullydocumentedanditseffectivenessmonitored.All partsofthequalityassurancesystemshouldbeadequatelystaffe dwithcompetentpersonnel,andshouldhavesuitableandsufficie ntpremises,equipment,andfacilities.Goodmanufacturingprac ticesforpharmaceuticalproducts(GMP)2.1Goodmanufacturingpr acticeisthatpartofqualityassurancewhichensuresthatprodu ctsareconsistentlyproducedandcontrolledtothequalitystand ardsappropriatetotheirintendeduseandasrequiredbythemar ketingauthorization.GMPareaimedprimarilyatdiminishingthe risksinherentinanypharmaceuticalproduction.Suchrisksaree ssentiallyoftwotypes:cross-contamination(inparticularofun expectedcontaminants)andmix-ups(confusion)causedby,forexa mple,falselabelsbeingputoncontainers.UnderGMP:(a)allma nufacturingprocessesareclearlydefined,systematicallyreviewe dinthelightofexperience,andshowntobecapableofconsiste ntlymanufacturingpharmaceuticalproductsoftherequiredqualit ythatcomplywiththeirspecifications;(b)qualificationandva lidationareperformed;(c)allnecessaryresourcesareprovided, including:(i)appropriatelyqualifiedandtrainedpersonnel;(i i)adequatepremisesandspace;(iii)suitableequipmentandserv ices;(iv)appropriatematerials,containersandlabels;(v)appr ovedproceduresandinstructions;(vi)suitablestorageandtrans port;(vii)adequatepersonnel,laboratoriesandequipmentforin -processcontrols;(d)instructionsandproceduresarewrittenin clearandunambiguous()language,specificallyapplicabletothe facilitiesprovided;(e)operatorsaretrainedtocarryoutproc edurescorrectly;(f)recordsaremade(manuallyand/orbyrecord inginstruments)duringmanufacturetoshowthatallthestepsre quiredbythedefinedproceduresandinstructionshaveinfactbe entakenandthatthequantityandqualityoftheproductareas expected;anysignificantdeviationsarefullyrecordedandinves tigated;(g)recordscoveringmanufactureanddistribution,which enablethecompletehistoryofabatchtobetraced,areretaine dinacomprehensibleandaccessibleform;(h)theproperstorag eanddistributionoftheproductsminimizesanyrisktotheirqu ality;(i)asystemisavailabletorecallanybatchofproductf romsaleorsupply;(j)complaintsaboutmarketedproductsareex amined,thecausesofqualitydefectsinvestigated,andappropria temeasurestakeninrespectofthedefectiveproductstoprevent recurrence.Qualitycontrollaboratoriesshouldbeseparatedfro mproductionareas.Areaswherebiological,microbiologicalorra dioisotope(放射性同位素)testmethodsareemployedshouldbeseparated fromeachother.Qualitycontrollaboratoriesshouldbedesigned tosuittheoperationstobecarriedoutinthem.Sufficientspac eshouldbegiventoavoidmix-upsandcross-contamination.There shouldbeadequatesuitablestoragespaceforsamples,reference standards(ifnecessary,withcooling),solvents,reagentsandr ecords.Thedesignofthelaboratoriesshouldtakeintoaccountt hesuitabilityofconstructionmaterials,preventionoffumesand ventilation.Thereshouldbeseparateairsupplytolaboratories andproductionareas.Separateair-handlingunitsandotherprov isionsareneededforbiological,microbiologicalandradioisotop elaboratories.Aseparateroommaybeneededforinstrumentsto protectthemagainstelectricalinterference,vibration振动,contac twithexcessive过多的moistureandotherexternalfactors,orwhere itisnecessarytoisolatetheinstruments.Qualitycontrolist hepartofGMPconcernedwithsampling,specificationsandtestin g,andwiththeorganization,documentationandreleaseprocedure swhichensurethatthenecessaryandrelevanttestsareactually carriedoutandthatmaterialsarenotreleasedforuse,norpro ductsreleasedforsaleorsupply,untiltheirqualityhasbeenj udgedtobesatisfactory.Qualitycontrolisnotconfined限制tola boratoryoperationsbutmustbeinvolvedinalldecisionsconcern ingthequalityoftheproduct.Theindependenceofqualitycontr olfromproductionisconsideredfundamental.Eachmanufacturer( theholderofamanufacturingauthorization)shouldhaveaqualit ycontrolfunction.Thequalitycontrolfunctionshouldbeindepe ndentofotherdepartmentsandundertheauthorityofapersonwi thappropriatequalificationsandexperience,whohasoneorseve ralcontrollaboratoriesathisorherdisposal.Adequateresourc esmustbeavailabletoensurethatallthequalitycontrolarran gementsareeffectivelyandreliablycarriedout.Thebasicrequi rementsforqualitycontrolareasfollows:(a)adequatefaciliti es,trainedpersonnelandapprovedproceduresmustbeavailablef orsampling,inspecting,andtestingstartingmaterials,packagin gmaterials,andintermediate,bulk,andfinishedproducts,andw hereappropriateformonitoringenvironmentalconditionsforGMP purposes;(b)samplesofstartingmaterials,packagingmaterials, intermediateproducts,bulkproductsandfinishedproductsmust betakenbymethodsandpersonnelapprovedofbythequalitycont roldepartment;(c)qualificationandvalidationmustbeperforme d;(d)recordsmustbemade(manuallyand/orbyrecordinginstrum ents)demonstratingthatalltherequiredsampling,inspectingan dtestingprocedureshaveactuallybeencarriedoutandthatany deviationshavebeenfullyrecordedandinvestigated;(e)thefin ishedproductsmustcontainingredientscomplyingwiththequalit ativeandquantitativecompositionoftheproductdescribedinth emarketingauthorization;theingredientsmustbeoftherequire dpurity,intheirpropercontainerandcorrectlylabelled;(f)r ecordsmustbemadeoftheresultsofinspectingandtestingthe materialsandintermediate,bulkandfinishedproductsagainstsp ecifications;productassessmentmustincludeareviewandevalua tionoftherelevantproductiondocumentationandanassessmento fdeviationsfromspecifiedprocedures;(g)nobatchofproducti stobereleasedforsaleorsupplypriortocertificationbythe authorizedperson(s)thatitisinaccordancewiththerequireme ntsofthemarketingauthorization.Incertaincountries,bylaw, thebatchreleaseisataskoftheauthorizedpersonfromproduc tiontogetherwiththeauthorizedpersonfromqualitycontrol;(h )sufficientsamplesofstartingmaterialsandproductsmustber etainedtopermitfutureexaminationoftheproductifnecessary; theretainedproductmustbekeptinitsfinalpackunlessthep ackisexceptionallylarge.Qualitycontrolasawholewillalso haveotherduties,suchastoestablish,validateandimplementa llqualitycontrolprocedures,toevaluate,maintain,andstoret hereferencestandardsforsubstances,toensurethecorrectlabe llingofcontainersofmaterialsandproducts,toensurethatthe stabilityoftheactivepharmaceuticalingredientsandproducts ismonitored,toparticipateintheinvestigationofcomplaintsr elatedtothequalityoftheproduct,andtoparticipateinenvir onmentalmonitoring.Alltheseoperationsshouldbecarriedouti naccordancewithwrittenproceduresand,wherenecessary,record ed.Assessmentoffinishedproductsshouldembraceallrelevantf actors,includingtheproductionconditions,theresultsofin-pr ocesstesting,themanufacturing(includingpackaging)documentat ion,compliancewiththespecificationforthefinishedproduct, andanexaminationofthefinishedpack.Qualitycontrolpersonne lmusthaveaccesstoproductionareasforsamplingandinvestiga tionasappropriate.Controlofstartingmaterialsandintermedia te,bulkandfinishedproductsAlltestsshouldfollowtheinstru ctionsgivenintherelevantwrittentestprocedureforeachmate rialorproduct.Theresultshouldbecheckedbythesupervisorb eforethematerialorproductisreleasedorrejected.Samplessh ouldberepresentativeofthebatchesofmaterialfromwhichthey aretakeninaccordancewiththeapprovedwrittenprocedure.Sam plingshouldbecarriedoutsoastoavoidcontaminationorother adverseeffectsonquality.Thecontainersthathavebeensample dshouldbemarkedaccordinglyandcarefullyresealedaftersampl ing.Careshouldbetakenduringsamplingtoguardagainstcontam inationormix-upof,orby,thematerialbeingsampled.Allsamp lingequipmentthatcomesintocontactwiththematerialshouldb eclean.Someparticularlyhazardousorpotentmaterialsmayrequ irespecialprecautions.Samplingequipmentshouldbecleanedan d,ifnecessary,sterilizedbeforeandaftereachuseandstored separatelyfromotherlaboratoryequipment.Eachsamplecontainer shouldbearalabelindicating:(a)thenameofthesampledmate rial;(b)thebatchorlotnumber;(c)thenumberofthecontaine rfromwhichthesamplehasbeentaken;(d)thenumberofthesam ple;(e)thesignatureofthepersonwhohastakenthesample;(f )thedateofsampling.Out-of-specificationresultsobtaineddur ingtestingofmaterialsorproductsshouldbeinvestigatedinac cordancewithanapprovedprocedure.Recordsshouldbemaintained .TestrequirementsStartingandpackagingmaterialsBeforerele asingastartingorpackagingmaterialforuse,thequalitycontr olmanagershouldensurethatthematerialshavebeentestedfor conformitywithspecificationsforidentity,strength,purityand otherqualityparameters.Anidentitytestshouldbeconductedo nasamplefromeachcontainerofstartingmaterial(seealsosec tion14.14).Eachbatch(lot)ofprintedpackagingmaterialsmust beexaminedfollowingreceipt.Inlieuoftestingbythemanufac turer,acertificateofanalysismaybeacceptedfromthesupplie r,providedthatthemanufacturerestablishesthereliabilityof thesupplier’sanalysisthroughappropriateperiodicvalidationo fthesupplier’stestresults(seesections8.8and8.9)andthro ughon-siteauditsofthesupplier’scapabilities.(Thisdoesnot affectsection17.15).Certificatesmustbeoriginals(notphoto copies)orotherwisehavetheirauthenticityassured.Certifi-ca tesmustcontainatleastthefollowinginformation(6):(a)identification(nameandaddress)oftheissuingsupplier;(b)signatureofthecompetentofficial,andstatementofhisorherqualifications;(c)thenameofthematerialtested;(d)thebatchnumberofthematerialtested;(e)thespecificationsandmethodsused;(f)thetestresultsobtained;(g)thedateoftesting.In-processcontrolIn-processcontrolrecordsshouldbemaintainedandformapartofthebatchrecords(seesection15.25).FinishedproductsForeachbatchofdrugproduct,thereshouldbeanappropriatelaboratorydeterminationofsatisfactoryconformitytoitsfinishedproductspecificationpriortorelease.Productsfailingtomeettheestablishedspecificationsoranyotherrelevantqualitycriteriashouldberejected.BatchrecordreviewProductionandqualitycontrolrecordsshouldbereviewedaspartoftheapprovalprocessofbatchrelease.Anydivergenceorfailureofabatchtomeetitsspecificationsshouldbethoroughlyinvestigated.Theinvestigationshould,ifnecessary,extendtootherbatchesofthesameproductandotherproductsthatmayhavebeenassociatedwiththespecificfailureordiscrepancy.Awrittenrecordoftheinvestigationshouldbemadeandshouldincludetheconclusionandfollow-upaction.Retentionsamplesfromeachbatchoffinishedproductshouldbekeptforatleastoneyearaftertheexpirydate.Finishedproductsshouldusuallybekeptintheirfinalpackagingandstoredundertherecommendedconditions.Ifexceptionallylargepackagesareproduced,smallersamplesmightbestoredinappropriatecontainers.Samplesofactivestartingmaterialsshouldberetainedforatleastoneyearbeyondtheexpirydateofthecorrespondingfinishedproduct.Otherstartingmaterials(otherthansolvents,gases,andwater)shouldberetainedforaminimumoftwoyearsiftheirstabilityallows.Retentionsamplesofmaterialsandproductsshouldbeofasizesufficienttopermitatleasttwofullre-examinations.StabilitystudiesQualitycontrolshouldevaluatethequalityandstabilityoffinishedpharmaceuticalproductsand,whennecessary,ofstartingmaterialsandintermediateproducts.17.24Qualitycontrolshouldestablishexpirydatesandshelf-lifespecificationsonthebasisofstabilitytestsrelatedtostorageconditions.Awrittenprogrammeforongoingstabilitydeterminationshouldbedevelopedandimplementedtoincludeelementssuchas:(a)acompletedescriptionofthedruginvolvedinthestudy;(b)thecompletesetoftestingparametersandmethods,describingalltestsforpotency,purity,andphysicalcharacteristicsanddocumentedevidencethatthesetestsindicatestability;(c)provisionfortheinclusionofasufficientnumberofbatches;(d)thetestingscheduleforeachdrug;(e)provisionforspecialstorageconditions;(f)provisionforadequatesampleretention;(g)asummaryofallthedatagenerated,includingtheevaluationandtheconclusionsofthestudy.Stabilityshouldbedeterminedpriortomarketingandfollowinganysignificantchangesinprocesses,equipment,packagingmaterials,etc. 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