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1、1664ASSESSMENTOFDRUGPRODUCTLEACHABLESASSOCIATEDWITHPHARMACEUTICALPACKAGINGDELIVERYSYSTEMSPURPOSEThisgeneralchapterpresentsaframewkfthedesignjustificationimplementationofassessmentsfdrugproductleachablesderivedfrompharmac
2、euticalpackagingdeliverysystems.Ascientificallysoundleachablesassessmentisimptanttomanufacturerstheirvarioussuppliersprimarilyasameansofestablishingthesuitabilityfuseofpharmaceuticalpackagingdeliverysystemsasleachablesca
3、npotentiallyaffectdrugproductefficacysafetyquality.Additionallysuchaleachablesassessmentcouldprovideanunderstingofthesourcesofleachableshowtoevaluatemanageleachablesduringthedrugdevelopmentmanufacturingprocesses.Thechapt
4、erestablishescriticaldimensionsofaleachablesassessmentdiscussespracticaltechnicalaspectsofeachdimension.Thechapterdoesnotestablishspecificanalyticalmethodsleachablesspecificationsacceptancecriteriafanyparticulardosagefmp
5、ackagingsystemdrugproductcombinationndoesitdelineateeverysituationinwhichaleachablesassessmentisrequired.Itisnotpossiblefageneraldiscussionofdrugproductleachablestoanticipatecoverallsituationswhichcanoccurinthepharmaceut
6、icalindustrywherealeachablesassessmentmightberequired.Designinganindividualleachablesassessmentisaprocessthatstrikesabalancebetweensoundscienceprudentresourceallocationeffectiveriskmanagementwithanemphasisonpatientsafety
7、productquality.Achievingthisbalanceistheresponsibilityobligationofthedrugproductmanufacturerassumesdueconsiderationofapplicablelegalregulatyrequirements.Theprinciplesbestdemonstratedpracticesoutlinedinthisgeneralchapterr
8、epresentaconsensusinterpretationofsoundsciencecantherefebeextrapolatedappliedtoanysituationinwhichaleachablesassessmentisrequiredfpharmaceuticalapplication.Inmanycasesdrugproductleachablesassessmentsarebasedonfacilitated
9、byknowledgefromextractablesassessmentsaccomplishedondrugproductpackagingsystemspackagingcomponentspackagingmaterialsofconstruction(seeAssessmentofExtractablesAssociatedwithPharmaceuticalPackagingDeliverySystems1663).KEYT
10、ERMSThisgeneralchapterusesthefollowingkeyterms(12alsoseePackagingStageRequirements659).NotethatthetermsPackagingSystemPackagingComponentPrimaryPackagingComponentSecondaryPackagingComponentMaterialsofConstructionarealsode
11、finedin659thedefinitionsbelowareintendedfclarificationpurposeswithinthecontextofthischapterarenotintendedtosupersedethoseprovidedin659.PackagingSystemsarethesumofpackagingcomponentsthattogethercontainprotectthedosagefm.P
12、ackagingsystemsarealsoreferredtoasContainerClosureSystemsmayincludeprimarysecondarytertiarypackaging.AContainerisareceptaclethatholdsanintermediatecompoundactivepharmaceuticalingredientexcipientdosagefmisindirectcontactw
13、iththeproduct.AClosureisamaterialthatsealsanotherwiseopenspaceonacontainerprovidesprotectionfthecontents.Italsoprovidesaccesstothecontentsofthecontainer.APackagingComponentisanysinglepartofthepackagecontainer–closuresyst
14、emincludingthecontainer(e.g.ampulsprefilledsyringesvialsbottles)closures(e.g.screwcapsstoppers)ferrulesoversealsclosurelinersinnersealsadministrationptsoverwrapsadminstrationaccessieslabelscardboardboxesshrinkwrap.APrima
15、ryPackagingComponentisindirectcontactmaycomeintodirectcontactwiththeproduct(e.g.IVbag).ASecondaryPackagingComponentisindirectcontactwithaprimarypackagingcomponentmayprovideadditionalprotectionoftheproduct(e.g.overpouchdu
16、stcoverfanIVbag).ATertiaryPackagingComponentisindirectcontactwithasecondarypackagingcomponentmayprovideadditionalprotectionoftheproductduringtransptationstage(e.g.shippingcartonfanoverpouchedIVbag).AnAncillaryComponentis
17、acomponententitythatmaycomeintocontactwithatertiarypackagingcomponentduringthedistributionstagetransptationofthepackagedproduct(e.g.palletsskidsshrinkwrapactivecontainers).PackagingMaterialsofConstructionaresubstancesuse
18、dtomanufacturepackagingcomponents.ThesearealsoreferredtoasRawMaterials.ADeliverySystemisthesumofcomponentsmaterialsthatareusedtotransptadrugproductfromitspackagingtothepointofadministrationintothepatient.Fexampleanadmini
19、strationsetisadeliverysystemthatisusedtotransferliquiddrugproductsfromtheirplasticpackagingsystemtothesiteofadministrationtothepatient.Extractablesareganicinganicchemicalentitiesthatcanbereleasedfromapharmaceuticalpackag
20、ingdeliverysystempackagingcomponentpackagingmaterialofconstructionintoanextractionsolventunderlabatyconditions.Dependingonthespecificpurposeoftheextractionstudy(discussedbelow)theselabatyconditions(e.g.solventtemperature
21、stoichiometryetc.)mayaccelerateexaggeratethenmalconditionsofstageusefapackageddosagefm.Extractablesthemselvessubstancesderivedfromextractableshavethepotentialtoleachintoadrugproductundernmalconditionsofstageusebecomeleac
22、hables.Thusextractablesarepotentialleachables.GeneralChapters18501664AssessmentofDrugProductLeachablesGeneralInfmationUSP39OfficialfromDecember12016Copyright(c)2016TheUnitedStatesPharmacopeialConvention.Allrightsreserved
23、.Accessedfrom10.6.1.1bycopps4onTueDec2720:14:28EST2016actionwithpackagingcomponents.Remainingrelativelyhighriskdosagefmsinclude:inhalationaerosolssolutionsinjectablesinjectablesuspensionsophthalmicstransdermalointmentspa
24、tches.Itisimptanttonotehoweverthatevenlowriskdosagefmspresentsomeriskthatappropriatelyrigousleachablesassessmentscanbeimptanttoparticulardrugproductsinlowerriskdosagefmcategies(e.g.topicalsaldosagefmsetc.).Table1.Modifie
25、dFDACDERCBERRiskBasedApproachtoConsiderationofLeachablesa(1)ExamplesofPackagingConcernsfCommonClassesofDrugProductsDegreeofConcernAssociatedwiththeRouteofAdministrationLikelihoodofPackagingComponentDosageFmInteractionHig
26、hMediumLowHighestInhalationAerosolsSpraysInjectionsInjectableSuspensionsInhalationSolutionsSterilePowdersPowdersfInjectionInhalationPowdersHighTransdermalOintmentsPatchesOphthalmicSolutionsSuspensionsNasalAerosolsSprays—
27、LowTopicalSolutionsSuspensionsTopicalLingualAerosolsalSolutionsSuspensions—alTabletsal(HardSoftGelatin)CapsulesTopicalPowdersalPowdersaWhilethistableprovidesaconvenientoverviewofthegenerallevelofregulatyconcernwithvariou
28、sdosagefmsregardingleachablesitshouldnotbeinferredthat“l(fā)owrisk”dosagefms(e.g.altablets)bythatdefinitioncarrynoriskfleachablesissues.Thischapterwilldescribescientificprinciplesbestpracticesftheassessmentofdrugproductleach
29、ableswillcovervariousimptantconceptsincluding:1)therequirementfleachablesstudies2)fundamentalconceptsfleachablesstudies3)thebasisofthresholdsfleachablesgeneralguidanceaboutapplicationofthesethresholds4)designimplementati
30、onofleachablesstudies5)leachablesmethoddevelopmentvalidation6)crelationofresultsfromextractablesassessmentsroutineextractablestestingwithleachablesstudies7)establishmentofleachablesspecificationsincludingacceptancecriter
31、ia.Thesescientificprinciplesbestpracticesapplytoallganizationsindividualsinvolvedinthemanufacturemarketingqualificationofdrugproductsintheirstabilitystudiesincludingbutnotlimitedto:?Manufacturersofdrugproductsfhumanveter
32、inaryusewheremanufacturingmayinvolveoperationsattheapplicantholdersfacilities(i.e.facilitiesthatbelongtotheholderofanapprovedNewDrugApplicationAbbreviatedNewDrugApplication)atthoseofacontractftheapplicantholder?Manufactu
33、rersofcombinationdrugproducts?Packagingoperationsbythemanufactureradesignatedcontractftheapplicantholder?Repackagingoperationsinwhichthedrugproductmaybeownedbyanganizationotherthantheprimarymanufacturer.Althoughitisultim
34、atelythedrugproductapplicantsresponsibilitytoensurethatappropriateleachablesassessmentsarecompletedmanufacturersfabricatsofpharmaceuticalpackagingdeliverysystemspackagingcomponentsmaterialsofconstructionshouldalsoapplyth
35、esescientificprinciplesbestpracticesasappropriateapplicantsareencouragedtowkwithcomponentmanufacturersfabricatstothisend.CONCEPTSGeneralConceptsfLeachablesAssessmentDuringthecourseofmanufacturingpackagingstagedistributio
36、nadministrationdosagefmstheirfmulationconstituentscontactcomponentsmaterialsofconstructionofmanufacturingpackagingequipmentprimarysecondarypackagingcomponentssystems.Suchcontactmayresultininteractionsbetweenthedosagefmth
37、esecomponentsmaterials.Onesuchinteractionisthemigrationleachingofsubstancesfromanyofthesecomponentsmaterialsintothedosagefm.Leachableswhichcanincludebothganicinganic(i.e.elemental)chemicalentitieswithwidechemicaldiversit
38、yareofconcernduetotheirpotentialsafetyrisktopatientspotentialcompatibilityrisksfthedrugproduct.Indertoassesstheserisksmanagethepotentialissuesposedbyleachablesitisnecessarytoknowtheiridentitiesthelevelstowhichtheywillacc
39、umulateinthefinisheddrugproductoveritsshelflife.Thesetwopiecesofinfmationcanbeusedtoestablishthemagnitudeofpatientexposure(dose)therefethesafetyriskposedbyanindividualleachableaswellasthelikelihoodofanydrugproductcompati
40、bilityissues.Regulatyguidelinesrequirementsvariousbestpracticerecommendationsallstatethatthedefinitiveassessmentofthepotentialimpactofcontactbetweenapackagingdeliverysystemafinaldosagefminvolvestestingthefinaldrugproduct
41、fleachables.Initsmostessentialfmthisimpactassessmentinvolvesperfmingamigrationleachablesstudywhosepurposeistodiscoveridentifyquantitateleachablesthathavemigratedfromthecontactedsystemcomponentsmaterialsaccumulatedinthefi
42、nisheddosagefmundertheproductsactualmanufacturingstageclinicaluseconditions.Aleachablesstudyisalabatyinvestigationintothequalitativequantitativenatureofaparticularleachablesprofile(s)overtheproposedshelflifeofaparticular
43、drugproduct.Thepurposeofaleachablesstudyistosystematicallyrationallyidentifyquantify(i.e.acterize)drugproductleachablestotheextentpracticablewithincertainGeneralChapters18521664AssessmentofDrugProductLeachablesGeneralInf
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