usp-1664-leachable-包材析出物研究方法

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