5最新北大医学部复习资料精品FDA Extended Release Oral Dosage Forms In VitroIn Vivo Correlations.docx
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5最新北大医学部复习资料精品FDA Extended Release Oral Dosage Forms In VitroIn Vivo Correlations.docx
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5最新北大医学部复习资料精品FDAExtendedReleaseOralDosageFormsInVitroInVivoCorrelations
DRUGRELEASE
ExtendedReleaseOralDosageForms:
Development,Evaluation,andApplicationofInVitro/InVivoCorrelations
Introduction
Thisguidanceprovidesrecommendationstopharmaceuticalsponsorswhointendtodevelopdocumentationinsupportofaninvitro/invivocorrelation(IVIVC)foranoralextendedrelease(ER)drugproductforsubmissioninanewdrugapplication(NDA),abbreviatednewdrugapplication(ANDA),orantibioticdrugapplication(AADA).Theguidancepresentsacomprehensiveperspectiveon
(1)methodsofdevelopinganIVIVCandevaluatingitspredictability;
(2)usinganIVIVCtosetdissolutionspecifications;and(3)applyinganIVIVCasasurrogateforinvivobioequivalencewhenitisnecessarytodocumentbioequivalenceduringtheinitialapprovalprocessorbecauseofcertainpre-orpostapprovalchanges(e.g.,formulation,equipment,process,andmanufacturingsitechanges).
Categoriesofinvitro/invivocorrelations
A.LevelA
ALevelAcorrelationisusuallyestimatedbyatwo-stageprocedure:
deconvolution2followedbycomparisonofthefractionofdrugabsorbedtothefractionofdrugdissolved.Acorrelationofthistypeisgenerallylinearandrepresentsapoint-to-pointrelationshipbetweeninvitrodissolutionandtheinvivoinputrate(e.g.,theinvivodissolutionofthedrugfromthedosageform).Inalinearcorrelation,theinvitrodissolutionandinvivoinputcurvesmaybedirectlysuperimposableormaybemadetobesuperimposablebytheuseofascalingfactor.Nonlinearcorrelations,whileuncommon,mayalsobeappropriate.
AlternativeapproachestodevelopingaLevelAIVIVCarepossible.Onealternativeisbasedonaconvolutionprocedurethatmodelstherelationshipbetweeninvitrodissolutionandplasmaconcentrationinasinglestep.Plasmaconcentrationspredictedfromthemodelandthoseobservedarecompareddirectly.Forthesemethods,areferencetreatmentisdesirable,butthelackofonedoesnotprecludetheabilitytodevelopanIVIVC.
WhateverthemethodusedtoestablishaLevelAIVIVC,themodelshouldpredicttheentireinvivotimecoursefromtheinvitrodata.Inthiscontext,themodelreferstotherelationshipbetweeninvitrodissolutionofanERdosageformandaninvivoresponsesuchasplasmadrugconcentrationoramountofdrugabsorbed.
B.LevelB
ALevelBIVIVCusestheprinciplesofstatisticalmomentanalysis.Themeaninvitrodissolutiontimeiscomparedeithertothemeanresidencetimeortothemeaninvivodissolutiontime.ALevelBcorrelation,likeaLevelA,usesalloftheinvitroandinvivodata,butisnotconsideredtobeapoint-to-pointcorrelation.ALevelBcorrelationdoesnotuniquelyreflecttheactualinvivoplasmalevelcurve,becauseanumberofdifferentinvivocurveswillproducesimilarmeanresidencetimevalues.
C.LevelC
ALevelCIVIVCestablishesasinglepointrelationshipbetweenadissolutionparameter,forexample,t50%,percentdissolvedin4hoursandapharmacokineticparameter(e.g.,AUC,Cmax,Tmax).ALevelCcorrelationdoesnotreflectthecompleteshapeoftheplasmaconcentrationtimecurve,whichisthecriticalfactorthatdefinestheperformanceofERproducts.
D.MultipleLevelC
AmultipleLevelCcorrelationrelatesoneorseveralpharmacokineticparametersofinteresttotheamountofdrugdissolvedatseveraltimepointsofthedissolutionprofile.
Generalconsiderations:
ThefollowinggeneralstatementsapplyinthedevelopmentofanIVIVCinanNDAorANDA/AADA:
1.HumandatashouldbesuppliedforregulatoryconsiderationofanIVIVC.
2.BioavailabilitystudiesforIVIVCdevelopmentshouldbeperformedwithenoughsubjectstocharacterizeadequatelytheperformanceofthedrugproductunderstudy.Inprioracceptabledatasets,thenumberofsubjectshasrangedfrom6to36.Althoughcrossoverstudiesarepreferred,parallelstudiesorcross-studyanalysesmaybeacceptable.Thelattermayinvolvenormalizationwithacommonreferencetreatment.ThereferenceproductindevelopinganIVIVCmaybeanintravenoussolution,anaqueousoralsolution,oranimmediatereleaseproduct.
3.IVIVCsareusuallydevelopedinthefastedstate.Whenadrugisnottoleratedinthefastedstate,studiesmaybeconductedinthefedstate.
4.AnyinvitrodissolutionmethodmaybeusedtoobtainthedissolutioncharacteristicsoftheERdosageform.Thesamesystemshouldbeusedforallformulationstested.
5.ThepreferreddissolutionapparatusisUSPapparatusI(basket)orII(paddle),usedatcompendiallyrecognizedrotationspeeds(e.g.,100rpmforthebasketand50-75rpmforthepaddle).Inothercases,thedissolutionpropertiesofsomeERformulationsmaybedeterminedwithUSPapparatusIII(reciprocatingcylinder)orIV(flowthroughcell).
6.Anaqueousmedium,eitherwaterorabufferedsolutionpreferablynotexceedingpH6.8,isrecommendedastheinitialmediumfordevelopmentofanIVIVC.SufficientdatashouldbesubmittedtojustifypHgreaterthan6.8.Forpoorlysolubledrugs,additionofsurfactant(e.g.,1%sodiumlaurylsulfate)maybeappropriate.Ingeneral,nonaqueousandhydroalcoholicsystemsarediscouragedunlessallattemptswithaqueousmediaareunsuccessful.AppropriatereviewstaffinCDERshouldbeconsultedbeforeusinganyothermedia.
7.Thedissolutionprofilesofatleast12individualdosageunitsfromeachlotshouldbedetermined.Asuitabledistributionofsamplingpointsshouldbeselectedtodefineadequatelytheprofiles.Thecoefficientofvariation(CV)formeandissolutionprofilesofasinglebatchshouldbelessthan10%.
8.ALevelAIVIVCisconsideredtobethemostinformativeandisrecommended,ifpossible.
9.MultipleLevelCcorrelationscanbeasusefulasLevelAcorrelations.However,ifamultipleLevelCcorrelationispossible,thenaLevelAcorrelationisalsolikelyandispreferred.
10.LevelCcorrelationscanbeusefulintheearlystagesofformulationdevelopmentwhenpilotformulationsarebeingselected.
11.LevelBcorrelationsareleastusefulforregulatorypurposes.
12.Rankordercorrelationsarequalitativeandarenotconsideredusefulforregulatory
purposes.
Generalinformationsforalevelainvitro/invivocorrelation
1.TheIVIVCrelationshipshouldbedemonstratedconsistentlywithtwoormoreformulationswithdifferentreleaseratestoresultincorrespondingdifferencesinabsorptionprofiles.AlthoughanIVIVCcanbedefinedwithaminimumoftwoformulationswithdifferentreleaserates,threeormoreformulationswithdifferentreleaseratesarerecommended.Exceptionstothisapproach(i.e.,useofonlyoneformulation)maybeconsideredforformulationsforwhichinvitrodissolutionisindependentofthedissolutiontestconditions(e.g.,medium,agitation,pH).
2.Ideally,formulationsshouldbecomparedinasinglestudywithacrossoverdesign.
3.Ifoneormoreoftheformulations(highestorlowestreleaserateformulations)doesnotshowthesamerelationshipbetweeninvitrodissolutionandinvivoperformancecomparedwiththeotherformulations,thecorrelationmaystillbeusedwithintherangeofreleaseratesencompassedbytheremainingformulations.
4.Theinvitrodissolutionmethodologyshouldadequatelydiscriminateamongformulations.Dissolutiontestingcanbecarriedoutduringtheformulationscreeningstageusingseveralmethods.Onceadiscriminatingsystemisdeveloped,dissolutionconditionsshouldbethesameforallformulationstestedinthebiostudyfordevelopmentofthecorrelationandshouldbefixedbeforefurtherstepstowardscorrelationevaluationareundertaken.
5.Duringtheearlystagesofcorrelationdevelopment,dissolutionconditionsmaybealteredtoattempttodevelopa1-to-1correlationbetweentheinvitrodissolutionprofileandtheinvivodissolutionprofile.
6.Timescalingmaybeusedaslongasthetimescalingfactoristhesameforallformulations.DifferenttimescalesforeachformulationindicateabsenceofanIVIVC.
Evaluatingthepredictabilityofalevelacorrelation
AnIVIVCshouldbeevaluatedtodemonstratethatpredictabilityofinvivoperformanceofadrugproductfromitsinvitrodissolutioncharacteristicsismaintainedoverarangeofinvitrodissolutionreleaseratesandmanufacturingchanges.SincetheobjectiveofdevelopinganIVIVCistoestablishapredictivemathematicalmodeldescribingtherelationshipbetweenaninvitropropertyandarelevantinvivoresponse,theproposedevaluationapproachesfocusontheestimationofpredictiveperformanceor,conversely,predictionerror.DependingontheintendedapplicationofanIVIVCandthetherapeuticindexofthedrug,evaluationofpredictionerrorinternallyand/orexternallymaybeappropriate.EvaluationofinternalpredictabilityisbasedontheinitialdatausedtodefinetheIVIVCmodel.Evaluationofexternalpredictabilityisbasedonadditionaltestdata7sets.ApplicationofoneormoreoftheseprocedurestotheIVIVCmodelingprocessconstitutesevaluationofpredictability.AnimportantconceptisthatthelessdataavailableforinitialIVIVCdevelopmentandevaluationofpredictability,themoreadditionaldatamaybeneededtodefinecompletelytheIVIVC'spredictability.Somecombinationofthreeormoreformulationswithdifferentreleaseratesisconsideredoptimal.Anothersignificantfactoristherangeofreleaseratesstudied.Thereleaserates,asmeasuredbypercentdissolved,foreachformulationstudied,shoulddifferadequately(e.g.,by10%).Thisshouldresultininvivoprofilesthatshowacomparabledifference,forexample,a10%differenceinthepharmacokineticparametersofinteres
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