questionstatanano

QualityConsiderationsandRegulatoryPerspectivesforDrugProductsContainingNanomaterialsKatherineTyner,Ph.
D.
USFoodandDrugAdministrationOctober5,2015DisclaimerThistalkreflectstheviewsoftheauthorandshouldnotbeconstruedtorepresentFDA'sviewsorpoliciesThementionofcommercialproducts,theirsources,ortheiruseinconnectionwithmaterialreportedhereinisnottobeconstruedaseitheranactualorimpliedendorsementofsuchproductsbytheDepartmentofHealthandHumanServices.
2Originalimagefromhttp://www.
aubrey-organics.
com/images/Resources/nanometer_1208.
jpgModifiedimagefromStephens,O.
CMCreviewconsiderationsfornanotechnologyproducts,presentedMarch19,2012WhatQualifiesas"nano"iPodNanoTataNanoMe3ConsideringWhetheranFDA-RegulatedProductInvolvestheApplicationofNanotechnologyPointstoConsider–Whetheramaterialorendproductisengineeredtohaveatleastoneexternaldimension,oraninternalorsurfacestructure,inthenanoscalerange(approximately1nmto100nm);–Whetheramaterialorendproductisengineeredtoexhibitpropertiesorphenomena,includingphysicalorchemicalpropertiesorbiologicaleffects,thatareattributabletoitsdimension(s),evenifthesedimensionsfalloutsidethenanoscalerange,uptoonemicrometer(1,000nm)http://www.
fda.
gov/RegulatoryInformation/Guidances/ucm257698.
htm4WhyApplyNanotechnologytoDrugsCombinationofsizeandsurfaceeffects→novelpropertiesIncreasebioavailabilityChangebiodistributionIncreaseddrugactionStabilizeeasilydegradabledrugsDeliverdrugs–Targeted/controlled/smartdeliveryofAPIMultifunctionalcapabilitiesLiversidgeGG&CundyKC.
InternationalJournalofPharmaceutics.
1995125,91-9756PlatformExampleNameNDAApprovalIndicationLiposomeDOXIL(Doxorubicin)19951CancerInorganicnanoparticleFERRLECIT(Sodiumferricgluconatecomplex)19992AnemiaProteinnanoparticleABRAXANE(Paclitaxel)2005CancerPolymernanoparticleMACUGEN(Pegaptanibsodium)2004Maculardegeneration.
EmulsionRESTASIS(Cyclosporine)2002ToincreasetearproductionLipidcomplexAMPHOTEC(AmphotericinB)1996InvasiveaspergillosisNanotubeSOMATULINEDEPOT(Lanreotideacetate)2007AcromegalyNanocrystalTRICOR(Fenofibrate)20043HypercholesterolemiaMicelleTAXOTERE(Docetaxel)1996Cancer1FirstANDAapprovalin20132FirstANDAapprovalin20113FirstANDAapprovalin2011NanomaterialsinDrugProducts:CDERExamplesTynerKTetal.
WIRESNanomedicineandNanotechnology2015.
EvolutionofDrugProductsContainingNanomaterials7Reformulationstoincreasebioavailabilityandbiodistribution-Liposomes-Nanocrystals-IroncolloidsMultifunctional,multicomponent-Complexmicrostructures-ANDAsCDER'squestionsandunderstandinghasevolvedwiththetechnology8EvolutionofDrugProductsContainingNanomaterialsFDA-NanotechnologyCoordinationNanotechnologyTaskForceCFSANCVMCTPORANCTRCDRHCDERNanotechnologyWorkingGroupGuidanceInternalandexternalcommunicationNanotechnologyReviewer'sNetworkTechnicalProfileOCNationalNanotechnologyInitiativeUSGovernmentAgenciesInternationalRegulatorsForumWhataretheNanoIssuesCDERcurrentregulatoryframeworkandreviewprocesscanadequatelyidentifyandmanagepotentialrisksassociatedwiththeuseofnanomaterialsindrugproducts–SowhatisdifferentPhysicochemicalproperties(suchasparticlesize)cansignificantlyaffectproductperformanceandsafetySpecializedanalyticalmethodsareneededtocharacterizenanomaterialsappropriatelyCruzCNetal.
TheAAPSJournal.
15(3)623-8(2013).
10CommonChallengesandPotentialRisksPKprofilesoftheparentdrugandthedrugencapsulatedinthenanoparticlesareoftendifferentNanomaterialsmayalsoenhancethedeliveryofdrugstocertaintissuesandthus,causenewsideeffectsNanomaterialsmayhavephysicalandchemicalstabilitychallenges.
CHARACTERIZATIONAppropriateCharacterizationCharacterizationisfundamental–NeedtoknowwhatyouhaveadministeredbeforeyoucandiscussanyobservationsRegulationsandLawdoNOTseparatenanotechnologyproducts–"nano"productsarenottreateddifferently–LooktoRegulationsandGuidances21CFR314.
50(d)requiresafulldescriptionofphysicalandchemicalcharacteristicsandstabilityforthedrugsubstance–Particlesize,crystallineform,surfacearea/volume,etc…–Identity,strength,quality,purity,etc.
–ManufacturingProcessandControls–AnalyticalproceduresNanomaterialPhysicochemicalPropertiesPKADMEToxicityFDAGuidancesmaybefoundat:http://www.
fda.
gov/RegulatoryInformation/Guidances/default.
htmWhattoCharacterizeAgglomeration/aggregationChemicalcompositionCrystalstructure/crystallinityParticlesize/sizedistributionPurityShapeSurfaceareaPorositySurfacechargeSurfacechemistry(compositionandreactivity)EndotoxincontentSolubilityStabilityConcentrationZetapotentialSurfaceenergyCatalyticpropertiesDustinessOleophilicity/hydrophilicityGrainsizePhotocatalytyicactivityOctanol-waterpartitioncoefficientRedoxpotentialRadicalformationpotentialCardandMagnuson,J.
FoodSci.
,74,vi-vii,2009;MinCHARproject;www.
characterizationmatters.
or;http://www.
toxicology.
org/isot/ss/nano/docs/Ostraat_guest_presentation.
pdfDrugProductWhattoCharacterizeThereareusuallyspecificreasonswhyaproductisbeingdevelopedtoincludenanoscalematerials.
ThenanomaterialpropertiesthatarebeingexploitedforthedrugproductwilloftentranslateintoCQAs,whichwill,inturn,havetobefurthercharacterizedandcontrolled.
Changesinnanomaterialpropertiesmaychangepharmacokinetics,biodistributionandtoxicity,affectingthetherapeuticeffect–Particlesize&shape–Charge–Surfacecoating–Encapsulationefficiency(e.
g.
liposomes)–Drugreleaserate–Stability(chemicalandphysical)Keene,A.
M.
,etal.
Nanomedicine.
7(2)199-209(2012).
LungSternum/MarrowHeart0.
00.
51.
0PPAGRAGLPPAGLAGR525456585***%dose/gtissuePhysicochemicalproperty(agglomeration)Biologicalresponse(biodistribution)14HowtoCharacterizeSpecializedanalyticalmethods–TraditionalmethodsmaynotbeadequateforcharacterizationofnanomaterialsExample:Chromatographyformolecularweight(mayalsoneedparticlesizeandsizedistribution)–CommonmethodsmaybreakdownornotbesuitableforthissizerangeExample:Laserdiffractionmethodsusedformicron-sizedparticlesappliedtonanomaterials–Techniquesmaybenew,orapplieddifferentlyExample:Nanoparticletrackinganalysis(new)Example:XRDforparticlesizevscrystalstructure(old)Method/systemsuitability–Adissolutionmethodwitha0.
2m(200nm)filterwillnotbesuitabletodiscriminatedissolutionof100nmparticles–Evensmallparticlesmayinteractwithfilters(robustness)TynerKMetalWIREsNanomedicine&Nanobiotechnology.
Accepted20141510nmparticles200nmfilterAnExampleofSizeStockSolutionDLS–Zave:51.
0±0.
5nmTEMDosingSolutionWeek1DLS–Zave:51.
8±0.
5nmTEMDLS–Zave:50.
6±0.
7nmTEMDosingSolutionWeek7AnExampleofSizeStockSolutionDLS–Zave:51.
0±0.
5nm–pdi:0.
141±0.
004TEM–Feretdiameter:50±4nmNAA–1.
12g/L–1.
0g/L(theoretical)DosingSolution—Week1DLS–Zave:51.
8±0.
5nm–pdi:0.
231±0.
005TEM–Feretdiameter:42±6nmNAA–0.
36g/L–0.
46(theoretical)StockSolutionDosingSolution—Week1AnExampleofSizeZave:51.
0±0.
5nmPdi:0.
141±0.
004Zave:51.
8±0.
5Pdi:0.
231±0.
00518WhataboutGenericsExamplesofapprovedgenericdrugproductscontainingnanomaterials–Sodiumferricgluconateinjection–DoxorubicinHClinjectionFDAproduct-specificequivalenceguidancesdeveloped:–DoxorubicinHClliposomeinjection–Verteporfinliposomeinjection–AmphotericinBliposomeinjection–Daunorubicinliposomeinjection–Sodiumferricgluconateinjection–Ferumoxytolinjection–Ironsucroseinjection–Paclitaxelalbumin-boundparticlesforinjectablesuspensionhttp://www.
fda.
gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.
htmHowdoesthisfitintotherestoftheworldDefinitions–1-100nm–Nanomedicine–NanosimilarsPlatforms–Drug/Device/Cosmetic–Liposomes–Nanocrystals–SPIOs–Protein-drugcomplexesInternationalPharmaceuticalRegulator'sForum–US,EMA,Japan,HealthCanada,TGAAustralia20HaubenreisserS.
EMAperspectivesonthedevelopmentofnanomedicine.
PQRINanotechnologyWorkshopJanuary2015AdvicetotheReviewSideHaveallthecriticalqualityattributesbeenidentifiedandcontrolledHavethepotentialriskstoqualitybeenidentifiedIsthereanadequatelevelofprocessknowledgeandunderstandingtoaddressthepotentialrisksandtojustifytheproposedcontrolsAretheproposedcontrolssufficienttoassureproductqualityduringroutineproduction21AdvicetoIndustryCommunicateearly(PIND,INDandEoP2b)anddiscusscharacteristicsandcharacterizationoftheformulationandanyimpactofnanomaterialqualityattributesonsafetyandefficacy.
FollowtheprinciplesofICHQ8,Q9,andQ10whicharebasedonthelinkofcriticalqualityattributes(characterization)andarisk-basedapproachtodevelopment.
Discusschallengingmethodsearlyinthedevelopment,sothatnon-clinicalstudiesandpivotalclinicalbatchesareadequatelycharacterizedandrelevanttothefinalcontrolstrategy.
22ConclusionsThestateofnanotechnologyindrugproductshasevolvedandmatured–Firstgeneration:nanocrystals,liposomes,ironcolloids–Newgeneration:complex,multicomponent,multifunctionalDespitethediversityindrugproductscontainingnanomaterials,therearestillcommonissuesFDAandCDERcontinuetofosterinnovationandtheresponsibledevelopmentofdrugproductscontainingnanomaterialsCurrentreviewpracticesandregulatoryframeworkarecapableofdetectingandmanagingthepotentialriskstoquality,safetyandefficacyduetonanomaterialsindrugproductAsthenanotechnologyfieldcontinuestomature,thecomplexityofnanomaterialswithindrugproductsisexpectedtoincreaseCharacterizationplaysacriticalroleinestablishingthequalityofthedrugproduct23AcknowledgementsCeliaCruz,OPF/OPQ/CDERSau(Larry)Lee,OPQ/IOWenleiJiang,OGDSheetalD'Mello,OPQ/IOCDERNanotechnologyWorkingGroup24