EU GMP 附录12：药品生产中电离辐射的应用-英文

IntroductionIonisingradiationmaybeusedduringthemanufacturingprocessforvariouspurposesincludingthereductionofbioburdenandthesterilisationofstartingmaterials,packagingcomponentsorproductsandthetreatmentofbloodproducts.Therearetwotypesofirradiationprocess:GammaIrradiationfromaradioactivesourceandhighenergyElectronIrradiation(Betaradiation)fromanaccelerator.GammaIrradiation:twodifferentprocessingmodesmaybeemployed:Batchmode:theproductisarrangedatfixedlocationsaroundtheradiationsourceandcannotbeloadedorunloadedwhiletheradiationsourceisexposed.Continuousmode:anautomaticsystemconveystheproductsintotheradiationcell,pasttheexposedradiationsourcealongadefinedpathandatanappropriatespeed,andoutofthecell.ElectronIrradiation:theproductisconveyedpastacontinuousorpulsedbeamofhighenergyelectrons(Betaradiation)whichisscannedbackandforthacrosstheproductpathway.ResponsibilitiesTreatmentbyirradiationmaybecarriedoutbythepharmaceuticalmanufacturerorbyanoperatorofaradiationfacilityundercontract(a“contractmanufacturer”)，bothofwhommustholdanappropriatemanufacturingauthorisation.Thepharmaceuticalmanufacturerbearsresponsibilityforthequalityoftheproductincludingtheattainmentoftheobjectiveofirradiation.Thecontractoperatoroftheradiationfacilitybearsresponsibilityforensuringthatthedoseofradiationrequiredbythemanufacturerisdeliveredtotheirradiationcontainer(i.e.theoutermostcontainerinwhichtheproductsareirradiated).Therequireddoseincludingjustifiedlimitswillbestatedinthemarketingauthorisationfortheproduct.DosimetryDosimetryisdefinedasthemeasurementoftheabsorbeddosebytheuseofdosimeters.Bothunderstandingandcorrectuseofthetechniqueisessentialforthevalidation,commissioningandcontroloftheprocess.Thecalibrationofeachbatchofroutinedosimetersshouldbetraceabletoanationalorinternationalstandard.Theperiodofvalidityofthecalibrationshouldbestated,justifiedandadheredto.Thesameinstrumentshouldnormallybeusedtoestablishthecalibrationcurveoftheroutinedosimetersandtomeasurethechangeintheirabsorbanceafterirradiation.Ifadifferentinstrumentisused,theabsoluteabsorbanceofeachinstrumentshouldbeestablished.Dependingonthetypeofdosimeterused,dueaccountshouldbetakenofpossiblecausesofinaccuracyincludingthechangeinmoisturecontent,changeintemperature,timeelapsedbetweenirradiationandmeasurement,andthedoserate.Thewavelengthoftheinstrumentusedtomeasurethechangeinabsorbanceofdosimetersandtheinstrumentusedtomeasuretheirthicknessshouldbesubjecttoregularchecksofcalibrationatintervalsestablishedonthebasisofstability,purposeandusage.ValidationoftheprocessValidationistheactionofprovingthattheprocess,i.e.thedeliveryoftheintendedabsorbeddosetotheproduct,willachievetheexpectedresults.Therequirementsforvalidationaregivenmorefullyinthenoteforguidanceon“theuseofionisingradiationinthemanufactureofmedicinalproducts”.Validationshouldincludedosemappingtoestablishthedistributionofabsorbeddosewithintheirradiationcontainerwhenpackedwithproductinadefinedconfiguration.Anirradiationprocessspecificationshouldincludeatleastthefollowing:detailsofthepackagingoftheproduct;theloadingpattern(s)ofproductwithintheirradiationcontainer.Particularcareneedstobetaken,whenamixtureofproductsisallowedintheirradiationcontainer,thatthereisnounderdosingofdenseproductorshadowingofotherproductsbydenseproduct.Eachmixedproductarrangementmustbespecifiedandvalidated;theloadingpatternofirradiationcontainersaroundthesource(batchmode)orthepathwaythroughthecell(continuousmode);maximumandminimumlimitsofabsorbeddosetotheproduct[andassociatedroutinedosimetry];maximumandminimumlimitsofabsorbeddosetotheirradiationcontainerandassociatedroutinedosimetrytomonitorthisabsorbeddose;otherprocessparameters,includingdoserate,maximumtimeofexposure,numberofexposures,etc.Whenirradiationissuppliedundercontractatleastparts(d)and(e)oftheirradiationprocessspecificationshouldformpartofthatcontract.CommissioningoftheplantGeneralCommissioningistheexerciseofobtaininganddocumentingevidencethattheirradiationplantwillperformconsistentlywithinpredeterminedlimitswhenoperatedaccordingtotheprocessspecification.Inthecontextofthisannex,predeterminedlimitsarethemaximumandminimumdosesdesignedtobeabsorbedbytheirradiationcontainer.Itmustnotbepossibleforvariationstooccurintheoperationoftheplantwhichgiveadosetothecontaineroutsidetheselimitswithouttheknowledgeoftheoperator.Commissioningshouldincludethefollowingelements:Design;Dosemapping;Documentation;Requirementforre-commissioning.GammairradiatorsDesignTheabsorbeddosereceivedbyaparticularpartofanirradiationcontaineratanyspecificpointintheirradiatordependsprimarilyonthefollowingfactors:theactivityandgeometryofthesource;thedistancefromsourcetocontainer;Thedurationofirradiationcontrolledbythetimersettingorconveyorspeed;Thecompositionanddensityofmaterial,includingotherproducts,betweenthesourceandtheparticularpartofthecontainer.Thetotalabsorbeddosewillinadditiondependonthepathofcontainersthroughacontinuousirradiatorortheloadingpatterninabatchirradiator,andonthenumberofexposurecycles.Foracontinuousirradiatorwithafixedpathorabatchirradiatorwithafixedloadingpattern,andwithagivensourcestrengthandtypeofproduct,thekeyplantparametercontrolledbytheoperatorisconveyorspeedortimersetting.DoseMappingForthedosemappingprocedure,theirradiatorshouldbefilledwithirradiationcontainerspackedwithdummyproductsorarepresentativeproductofuniformdensity.Dosimetersshouldbeplacedthroughoutaminimumofthreeloadedirradiationcontainerswhicharepassedthroughtheirradiator,surroundedbysimilarcontainersordummyproducts.Iftheproductisnotuniformlypacked,dosimetersshouldbeplacedinalargernumberofcontainers.Thepositioningofdosimeterswilldependonthesizeoftheirradiationcontainer.Forexample,forcontainersupto1x1x0.5m,athree-dimensional20cmgridthroughoutthecontainerincludingtheoutsidesurfacesmightbesuitable.Iftheexpectedpositionsoftheminimumandmaximumdoseareknownfromapreviousirradiatorperformancecharacterisation,somedosimeterscouldberemovedfromregionsofaveragedoseandreplacedtoforma10cmgridintheregionsofextremedose.Theresultsofthisprocedurewillgiveminimumandmaximumabsorbeddosesintheproductandonthecontainersurfaceforagivensetofplantparameters,productdensityandloadingpattern.Ideally,referencedosimetersshouldbeusedforthedosemappingexercisebecauseoftheirgreaterprecision.Routinedosimetersarepermissiblebutitisadvisabletoplacereferencedosimetersbesidethemattheexpectedpositionsofminimumandmaximumdoseandattheroutinemonitoringpositionineachofthereplicateirradiationcontainers.Theobservedvaluesofdosewillhaveanassociatedrandomuncertaintywhichcanbeestimatedfromthevariationsinreplicatemeasurements.Theminimumobserveddose,asmeasuredbytheroutinedosimeters,necessarytoensurethatallirradiationcontainersreceivetheminimumrequireddosewillbesetintheknowledgeoftherandomvariabilityoftheroutinedosimetersused.Irradiatorparametersshouldbekeptconstant,monitoredandrecordedduringdosemapping.Therecords,togetherwiththedosimetryresultsandallotherrecordsgenerated,shouldberetained.ElectronbeamirradiatorsDesignTheabsorbeddosereceivedbyaparticularportionofanirradiatedproductdependsprimarilyonthefollowingfactors:thecharacteristicsofthebeam,whichare:electronenergy,averagebeamcurrent,scanwidthandscanuniformity;theconveyorspeed;theproductcompositionanddensity;thecomposition,densityandthicknessofmaterialbetweentheoutputwindowandtheparticularportionofproduct;theoutputwindowtocontainerdistance.Keyparameterscontrolledbytheoperatorarethecharacteristicsofthebeamandtheconveyorspeed.DoseMappingForthedosemappingprocedure,dosimetersshouldbeplacedbetweenlayersofhomogeneousabsorbersheetsmakingupadummyproduct,orbetweenlayersofrepresentativeproductsofuniformdensity,suchthatatleasttenmeasurementscanbemadewithinthemaximumrangeoftheelectrons.Referenceshouldalsobemadetosections18to21.Irradiatorparametersshouldbekeptconstant,monitoredandrecordedduringdosemapping.Therecords,togetherwiththedosimetryresultsandallotherrecordsgenerated,shouldberetained.Re-commissioningCommissioningshouldberepeated讦thereisachangetotheprocessortheirradiatorwhichcouldaffectthedosedistributiontotheirradiationcontainer(e.g.changeofsourcepencils).Theextenttore-commissioningdependsontheextentofthechangeintheirradiatorortheloadthathastakenplace.Ifindoubt,re-commission.PremisesPremisesshouldbedesignedandoperatedtosegregateirradiatedfromnon-irradiatedcontainerstoavoidtheircross-contamination.Wherematerialsarehandledwithinclosedirradiationcontainers,itmaynotbenecessarytosegregatepharmaceuticalfromnonpharmaceuticalmaterials,providedthereisnoriskoftheformerbeingcontaminatedbythelatter.Anypossibilityofcontaminationoftheproductsbyradionuclidefromthesourcemustbeexcluded.ProcessingIrradiationcontainersshouldbepackedinaccordancewiththespecifiedloadingpattern(s)establishedduringvalidation.Duringtheprocess,theradiationdosetotheirradiationcontainersshouldbemonitoredusingvalidateddosimetryprocedures.Therelationshipbetweenthisdoseandthedoseabsorbedbytheproductinsidethecontainermusthavebeenestablishedduringprocessvalidationandplantcommissioning.Radiationindicatorsshouldbeusedasanaidtodifferentiatingirradiatedfromnonirradiatedcontainers.Theyshouldnotbeusedasthesolemeansofdifferentiationorasanindicationofsatisfactoryprocessing.Processingofmixedloadsofcontainerswithintheirradiationcellshouldonlybedonewhenitisknownfromcommissioningtrialsorotherevidencethattheradiationdosereceivedbyindividualcontainersremainswithinthelimitsspecified.Whentherequiredradiationdoseisbydesigngivenduringmorethanoneexposureorpassagethroughtheplant,thisshouldbewiththeagreementoftheholderofthemarketingauthorisationandoccurwithinapredeterminedtimeperiod.Unplannedinterruptionsduringirradiationshouldbenotifiedtotheholderofthemarketingauthorisation讦thisextendstheirradiationprocessbeyondapreviouslyagreedperiod.Non-irradiatedproductsmustbesegregatedfromirradiatedproductsatalltimes.Methodsofdoingthisincludetheuseofradiationindicators(31.)andappropriatedesignofpremises(28.).GammairradiatorsForcontinuousprocessingmodes,dosimetersshouldbeplacedsothatatleasttwoareexposedintheirradiationatalltimes.Forbatchmodes,atleasttwodosimetersshouldbeexposedinpositionsrelatedtotheminimumdoseposition.Forcontinuousprocessmodes,thereshouldbeapositiveindicationofthecorrectpositionofthesourceandaninterlockbetweensourcepositionandconveyormovement.Conveyorspeedshouldbemonitoredcontinuouslyandrecorded.Forbatchprocessmodessourcemovementandexposuretimesforeachbatchshouldbemonitoredandrecorded.Foragivendesireddose,thetimersettingorconveyorspeedrequiresadjustmentforsourcedecayandsourceadditions.Theperiodofvalidityofthesettingorspeedshouldberecordedandadheredto.ElectronBeamIrradiatorsAdosimetershouldbeplacedoneverycontainer.Thereshouldbecontin