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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