Conducting-Forced-Degradation-Studies-

orceddegradationorstresstestingisundertakentodemon-stratespecificitywhendevelopingstability-indicatingmethods,particularlywhenlittleinformationisavailableaboutpotentialdegradationproducts.Thesestudiesalsoprovideinformationaboutthedegradationpathwaysanddegra-dationproductsthatcouldformduringstorage.Forceddegra-dationstudiesmayhelpfacilitatepharmaceuticaldevelopmentaswellinareassuchasformulationdevelopment,manufactur-ing,andpackaging,inwhichknowledgeofchemicalbehaviorcanbeusedtoimproveadrugproduct.Theavailableregulatoryguidanceprovidesusefuldefinitionsandgeneralcommentsaboutdegradationstudies.However,guidanceconcerningthescope,timing,andbestpracticesfordegradationstudiesisverygeneral.Variousissuesrelatedtostresstestingareaddressedinnumerousguidancedocumentsbutnotalwaysinthecontextofstresstesting.Forexample,theavailableguidancediscussesissuessuchasstereochemicalsta-bility,degradationproductidentificationthresholds,polymor-phismandcrystalforms,stabilityof(parenteral)combinationproducts,andmassbalancebutdoesnotaddresstheseissuesinthecontextofdegradationstudies.TheFDAandInternationalConferenceonHarmonization(ICH)guidanceprovidesverylittleinformationaboutstrate-giesandprinciplesforconductingforceddegradationstudies,includingproblemsofpoorlysolubledrugsandexceptionallystablecompounds.Inparticular,theissueofhowmuchstressisadequateinstresstestingisnotaddressedspecifically.Over-stressingamoleculecanleadtodegradationprofilesthatarenotrepresentativeofrealstorageconditionsandperhapsnotrele-vanttomethoddevelopment.Therefore,stress-testingcondi-tionsshouldberealisticandnotexcessive.Inthisregard,itistheamountofstressthatisimportantandnotnecessarilytheex-tentofdegradation.Indeed,somecompoundsmaynotdegradesignificantlyafterconsiderableexposuretostressconditions.Alsosomewhatuncleariswhatshouldbedoneateachde-velopmentphasefrombotharegulatoryandascientificper-spective.AlthoughFDAdoesnotrequiredegradationstudiesforaninvestigationalnewdrug(IND)application,prelimi-48PharmaceuticalTechnologyFEBRUARY2002*KevinL.Facchine,JuneF.Mullaney,KarenM.Alsante,ToddD.Hatajik,andMichaelG.MottoDanW.Reynolds,PhD,isaresearchinvestigatorII,andKevinL.Facchine,PhD,isateammanagerinthechemicaldevelopmentanalyticalsciencesdepartmentatGlaxoSmithKline.JuneF.Mullaney,PhD,isvice-presidentatthepharmaceuticaldevelopmenttechnicaloperationsatGlaxoSmithKline,FiveMooreDr.,POBox13398,ResearchTrianglePark,NC27709.KarenM.Alsante,PhD,isaseniorresearchinvestigator,ToddD.Hatajikisascientist,andMichaelG.Motto,PhD,isadirectorintheanalyticalresearchanddevelopmentdepartmentatPfizerGlobalResearchandDevelopment(Groton,CT).*Towhomallcorrespondenceshouldbeaddressed.FThisarticlesummarizesthecollectiveviewsofindustryparticipantsataPharmaceuticalResearchandManufacturersofAmericaAnalyticalResearchandDevelop-mentSteeringCommitteeworkshoponacceptableanalyticalpracticesonthetopicofforceddegradationstudies.Thearticleincludesanoverviewofavailableguidanceandsomesuggestionsforbestpractices.PHOTODISC,INC.50PharmaceuticalTechnologyFEBRUARY2002(1–3),forceddegradationstudiesarecarriedoutforthefollowingreasons:●developmentandvalidationofstability-indicatingmethod-ology●determinationofdegradationpathwaysofdrugsubstancesanddrugproducts●discernmentofdegradationproductsinformulationsthatarerelatedtodrugsubstancesversusthosethatarerelatedtonon–drugsubstances(e.g.,excipients)●structureelucidationofdegradationproducts●determinationoftheintrinsicstabilityofadrugsubstancemolecule.Degradationstudieshaveseveraldefiningcharacteristics.They●arecarriedoutinsolutionand/orthesolidstate●involveconditionsmoreseverethanacceleratedtesting(e.g.,
40C;75%relativehumidity;inexcessofICHlightcon-ditions;highandlowpH,oxidation,etc.)(1,2)●aretypicallycarriedoutononebatchofmaterial(1,2)●includeconditionsthatanalyzethermolytic,hydrolytic,ox-idative,andphotolyticdegradationmechanismsinthedrugsubstanceanddrugproduct(asappropriate)(1,2)●arenotpartoftheformalstabilityprogram.SummaryofrequirementsattheINDphaseAlthoughthereportingofdegradationstudiesisnotrequiredinINDapplications,preliminarystudiesmaybecarriedouttofacilitatethedevelopmentofstability-indicatingmethodology.Studiescanbeconductedonthedrugsubstanceanddevelop-m