Questions and Answers on cGMP about productionprocess control part.docx
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Questions and Answers on cGMP about productionprocess control part.docx
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QuestionsandAnswersoncGMPaboutproductionprocesscontrolpart
QuestionsandAnswersonCurrentGoodManufacturingPractices,GoodGuidancePractices,Level2Guidance-ProductionandProcessControls
1.DotheCGMPsrequireafirmtoretaintheequipmentstatusidentificationlabelswiththebatchrecordorotherfile?
Assumingeachmajorpieceofequipmenthasaunique"CleaningandUseLog"thatisadequatelyretained,isitacceptabletodiscardthese'quickreference'equipmentlabels?
2.Cancontainers,closures,andpackagingmaterialsbesampledforreceiptexaminationinthewarehouse?
3.Afirmhasmultiplemediafillfailures.TheyconductedtheirmediafillsusingTSB(trypticsoybroth)preparedbyfiltrationthrough0.2micronsterilizingfilter. Investigationdidnotshowanyobviouscauses. Whatcouldbethesourceofcontamination?
4.Someproducts,suchastransdermalpatches,aremadeusingmanufacturingprocesseswithhigherin-processmaterialrejectratesthanforotherproductsandprocesses. Isthisokay?
5.DoCGMPsrequirethreesuccessfulprocessvalidationbatchesbeforeanewactivepharmaceuticalingredient(API)orafinisheddrugproductisreleasedfordistribution?
6.IsitgenerallyacceptablefromacGMPperspectiveforamanufacturerofsteriledrugproductsproducedbyasepticprocessingtorelysolelyonISO14644-1andISO14644-2whenqualifyingtheirfacility?
7.In2004,FDAissuedaguidanceentitled“PAT-AFrameworkforInnovativePharmaceuticalDevelopment,Manufacturing,andQualityAssurance”thatencouragedindustrytomodernizemanufacturingthroughenhancementsinprocesscontrol. HowcanIimplementPAT(ProcessAnalyticalTechnology)?
8.HowdoIcontactCDERwithquestionsaboutProcessAnalyticalTechnology?
9.HowdoIcontactCBERwithquestionsaboutProcessAnalyticalTechnology?
10.Whatistheacceptablemediafillfrequencyinrelationtothenumberofshifts?
Normally,mediafillsshouldberepeatedtwicepershiftperlineperyear.Isthesamefrequencyexpectedofaprocessconductedinanisolator?
11.WhyistheFDAconcernedabouthumantopicalantisepticdrugproducts?
12.Whatspecificcurrentgoodmanufacturingpractice(CGMP)regulationsmightbeusefultomanufacturersoftopicalantisepticdrugproducts?
13.Howcanmanufacturersassessandaddresstheriskofmicrobiologicalcontaminationoftopicalantiseptics?
14.CanLeptospiraspeciespenetratesterilizing-gradefilters?
Ifso,whatshouldmanufacturerskeepinmindintheirongoinglifecycleriskmanagementeffortstoassuremicrobialcontrol?
15.FDArecentlyannouncedthewithdrawalofitsdraftguidanceforindustryonPowderBlendsandFinishedDosageUnits—StratifiedIn-ProcessDosageUnitSamplingandAssessment.WhatweretheAgency’smajorconcernswiththisguidance?
16.WhyisFDAconcernedaboutpropersamplingofpowderblends?
17.Whataresomerecommendedinnovativeapproachestoensuringadequacyofmixingofpowderblends?
18.WhataretheAgency’srecommendationsregardingin-processstratifiedsamplingoffinisheddosageunits?
19.Foranonsterilecompendialdrugproductthatincludesanantimicrobialpreservativeinitsformulation,mayIreleaseandmarketlotsofthisdrugproductwithinitialout-of-specificationtotalaerobicplatecountsiftheselotstestwithinspecification2weekslater?
20.Dopharmaceuticalmanufacturersneedtohavewrittenproceduresforpreventinggrowthofobjectionablemicroorganismsindrugproductsnotrequiredtobesterile?
Whatdoesobjectionablemeananyway?
21.Fordrugproductsformulatedwithpreservativestoinhibitmicrobialgrowth,isitnecessarytotestforpreservativesaspartofbatchreleaseandstabilitytesting?
1.DothecGMPsrequireafirmtoretaintheequipmentstatusidentificationlabelswiththebatchrecordorotherfile?
Assumingeachmajorpieceofequipmenthasaunique"CleaningandUseLog"thatisadequatelyretained,isitacceptabletodiscardthese'quickreference'equipmentlabels?
ThecGMPregulationsforfinishedpharmaceuticalsrequiretheretentionofcleaninganduselogsfornon-dedicatedequipment,butnosimilarrequirementexistsforretainingwhatareintendedtobe"quickreference"ortemporarystatuslabels. Examplesofthesekindsofstatuslabelsinclude"mixinglot###";"clean,readyforuseasofd/M/y";"notclean." Weseenovalueintheretentionofsuchlabelsinadditiontotherequiredequipmentlogorbatchrecorddocumentation. Thelabelsserveavaluable,temporarypurposeofpositivelyidentifyingthecurrentstatusofequipmentandthematerialunderprocess. Anystatuslabelshouldbecorrect,legible,readilyvisible,andassociatedwiththecorrectpieceofequipment. Theinformationonthetemporarystatuslabelshouldcorrespondwiththeinformationrecordedintheequipmentcleaninganduselog,orthepreviousbatchrecordfornon-dedicatedequipment.
Labelsaremerelyonewaytodisplaytemporarystatusinformationaboutapieceofequipment. Itisconsideredacceptablepracticetodisplaytemporaryequipmentstatusinformationondry-eraseboardsorchalkboards. AnditwouldbeappropriateforanFDAinvestigatortoverifythattheinformationonatemporarystatuslabelisconsistentwiththelog.
References:
∙21CFR211.182:
Equipmentcleaninganduselog
∙21CFR211.105:
Equipmentidentification
2.Cancontainers,closures,andpackagingmaterialsbesampledforreceiptexaminationinthewarehouse?
Yes. Generally,webelievethatsamplinginatypicaldrugmanufacturingfacilitywarehousewouldnotrepresentarisktothecontainer/closureoraffecttheintegrityofthesampleresults.ButwhethertheactofcollectingasampleinthewarehouseviolatestheCGMPsrequirementthatcontainers"beopened,sampled,andsealedinamannerdesignedtopreventcontaminationoftheircontents..."willdependonthepurportedqualitycharacteristicsofthematerialundersampleandthewarehouseenvironment.Forcontainer/closurespurportingtobesterileordepyrogenated,samplingshouldbeunderconditionsequivalenttothepurportedqualityofthematerial:
awarehouseenvironmentwouldnotsuffice(see211.94and211.113(b)). Thisistopreservethefitnessforuseoftheremainingcontainer/closuresaswellasensuresampleintegrity,iftheyaretobeexaminedformicrobialcontamination. Ataminimum,anysamplingshouldbeperformedinamannertolimitexposuretotheenvironmentduringandafterthetimesamplesareremoved(i.e.,wipingoutsidesurfaces,limitingtimethattheoriginalpackageisopen,andproperlyresealingoriginalpackage).Well-writtenandfollowedproceduresarethecriticalelements.
NotethattheCGMPsat211.84permitamanufacturertoreleaseforuseashipmentofcontainers/closuresbasedonthesupplier'scertificateofanalysisandavisualidentificationofthecontainers/closures. Onceasupplier'sreliabilityhasbeenestablishedbyvalidationoftheirtestresults,amanufacturercouldperformthevisualexaminationentirelyinthewarehouse.
References:
∙21CFR211.84:
Testingandapprovalorrejectionofcomponents,drugproductcontainers,andclosures
∙21CFR211.94:
Drugproductcontainersandclosures
∙21CFR211.113(b):
Controlofmicrobiologicalcontamination
∙21CFR211.122:
Materialsexaminationandusagecriteria
3.Afirmhasmultiplemediafillfailures.TheyconductedtheirmediafillsusingTSB(trypticsoybroth)preparedbyfiltrationthrough0.2micronsterilizingfilter. Investigationdidnotshowanyobviouscauses. Whatcouldbethesourceofcontamination?
Afirmrecentlyhadmultiplemediafillfailures. Themediafillruns,simulatingthefillingprocessduringproduction,wereconductedinsideanisolator. ThefirmusedTSB(non-sterilebulkpowder)fromacommercialsource,andpreparedthesterilesolutionbyfilteringthrougha0.2micronsterilizingfilter. Aninvestigationwaslaunchedtotracethesourceofcontamination. Theinvestigationwasnotsuccessfulinisolatingorrecoveringthecontaminatingorganismusingconventionalmicrobiologicaltechniques,includingtheuseofselective(e.g.,bloodagar)andnonselective(e.g.,TSBandtrypticsoyagar)media,andexaminationunderamicroscope. ThecontaminantwaseventuallyidentifiedtobeAcholeplasmalaidlawiibyusing16SrRNAgenesequence. ThefirmsubsequentlyconductedstudiestoconfirmthepresenceofAcholeplasmalaidlawiiinthelotofTSBused. Therefore,itwasnotacontaminantfromtheprocess,butfromthemediasource.
Acholeplasmalaidlawiibelongstoanorderofmycoplasma.Mycoplasmacontainonlyacellmembraneandhavenocellwall. Theyarenotsusceptibletobeta-lactamsanddonottakeupGramstain. Individualorganismsarepleomorphic(assumevariousshapefromcoccitorodstofilaments),varyinginsizefrom0.2to0.3micronsorsmaller. IthasbeenshownthatAcholeplasmalaidlawiiiscapableofpenetratinga0.2micronfilter,butisretainedbya0.1micronfilter(seeSundaram,etal.).Acholeplasmalaidlawiiisknowntobeassociatedwithanimal-derivedmaterial,andmicrobiologicalmediaisoftenfromanimalsources. Environmentalmonitoringofmycoplasmarequiresselectivemedia(PPLObrothoragar).
Resolution:
Fornow,thisfirmhasdecidedtofilterpreparedTSB,foruseinmediafills,througha0.1micronfilter(note:
wedonotexpectorrequirefirmstoroutinelyuse0.1micronfiltersformediapreparation). Inthefuture,thefirmwillusesterile,irradiatedTSBwhenitbecomesavailablefromacommercialsupplier. (Firm'sautoclaveistoosmalltopermitprocessingofTSBformediafills,sothiswasnotaviableoption.) Thefirmwillcontinuemonitoringformycoplasmaandhasreva
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