qualification--verification-or-validation

1100LCGCNORTHAMERICAVOLUME23NUMBER10OCTOBER2005“validation”and“qualification,”sometimesareusedtodescribethesamethings.Tofurtherconfusetheissue,athirdterm,“verification,”alsohasbeenthrownintothemix.Threerecentdocumentshelptodefineanddelineatethesethreetermstostemthepotentialforconfusion.MichaelSwartzandIraKrullValidationViewpointEditorshenitwasfirstconvened14yearsago,theInternationalConferenceonHarmonization(ICH)usheredinaneweraofincreasedglobalcommunicationintheregulatedpharmaceuticalindustrythatcontinuestothisday(1).Butthesedaysitseemsthatnotamonthgoesbythatthereisnotatleastoneconferenceorsymposiumfocusingononeaspectoranotheroftheregulatorylandscape.Indeed,avirtualcottageindus-tryhasdevelopedspecializinginmethoddevelopmentandvalidation.However,likemostsituationsinlife,thereisgoodnewsandbad.Thegoodnews:moreinformationcontainingmoredetailsisavailablenowthaneverbefore.TheU.S.FoodandDrugAdministration(FDA)continuestoissuenewguidancesandupdates,theUnitedStatesPharmacopeia(USP)continuestoupdateitsgeneralchapterstofurtherreflectimplementationoftheICHguidelines,andindustrygroupscontinuetomeetwithreg-ulatoryrepresentativestohelpclarifyissues.Thebadnews:allofthisnewinformationcanleadtoconfusionandsometimescanbeoverwhelming.Inthismonth’sinstall-mentof“ValidationViewpoint,”wetakealookatthreerecentlypublisheddocumentsinthevalidationliteraturefromgroupsworkingtoclearupsomeofthepotentialforconfusion.Somebasicdefinitions—validation,qualification,andverification:Inthemostgeneralsense,validationreferstoaprocessthatconsistsofatleastfourdistinctcompo-nentsorsteps:software,instruments,meth-odsorprocedures,andsystemsuitability(2).Thesystem,thesoftware,andthemethodmustallbevalidated,andsystemsuitabilityisusedtokeeptheprocessincheck.Butwhiletheoverallprocessiscalledvalidation,someofthestepsalsoarereferredtobythatsameterm,aswellasothers,suchasqualificationandverification.InMarch2003,theAmericanAssocia-tionofPharmaceuticalChemists(AAPS),theInternationalPharmaceuticalFedera-tion(FIP),andtheInternationalSocietyforPharmaceuticalEngineering(ISPE)cosponsoredaworkshoptitled“AScientificApproachtoAnalyticalInstrumentValida-tion.”Amongotherobjectives,thevariousparties(theeventdrewacross-sectionofattendees,users,qualityassurancespecial-ists,regulatoryscientists,consultants,andvendors)agreedthatprocessesare“vali-dated”andinstrumentsare“qualified,”finallyreservingthetermvalidationforprocessesthatincludeanalyticalmethodsandproceduresandsoftwaredevelopment(3).Useofthetermqualificationinthissense,however,shouldnotbeconfusedwiththesametermusedtorefertothequalificationofimpuritiesintheICHguidelineonimpuritiesindrugsubstances(4).Qualificationinthissensereferstotheprocessofacquiringandevaluatingdataforthebiologicalsafetyofimpurities.Verificationisamorerecenttermthatreferstothesuitabilityofacompendialprocedureunderactualconditionsofuse.TheInternationalOrganizationforStan-dardization(ISO)putsitthisway:“Valida-tionisconfirmation,throughtheprovisionofobjectiveevidencethattherequirementsforaspecificintendeduseorapplicationhavebeenfulfilled”(5).“Verificationisconfirmation,throughtheprovisionofobjectiveevidencethatspecifiedrequire-mentshavebeenfulfilled”(6).Putsimply,ifyouareusingacompendialmethod,youverify;anoncompendialoralternativeana-WValidationViewpointValidation1102LCGCNORTHAMERICAVOLUME23NUMBER10OCTOBER2005!Method(Procedure)ValidationEarlierthisyear,theUSPproposedrevi-sionstothemethodvalidationguidelinespublishedinChapter1225(7).Forthemostpart,therevisionsweremadetocon-tinuetoharmonizewithICHterminology,forexample,usingtheword“procedures”insteadof“methods.”Theterm“pharma-ceuticalproducts”isreplacedbytheterm“pharmaceuticalarticles”toindicatethattheguidelinesapplytobothdrugsub-stancesanddrugproducts.Amajorwel-comechangeistheuseoftheterm“inter-mediateprecision”andthedeletionofthesectionanduseoftheterm“ruggedness,”whichmostpeopleusuallyconfusedwithrobustnessanyway.Useofthetermrugged-nesshasbeenfallingoutoffavoreversinceimplementationoftheoriginalICHguide-lineonterminology(8).However,confu-sionstillexistsastoexactlywhatconstitutesrobustnessversusintermediateprecision.Therobustnessofananalyticalprocedureisameasureofitscapacitytoremainunaf-fectedbysmallbutdeliberatevariationsinproceduralparameterslistedintheproce-duredocumentationandprovidesanindi-cationofitssuitabilityduringnormalusage.Robustnessusuallyisinvestigatedduringthedevelopmentofaprocedureandisusefultoestablishsystemsuitabilityparameters.Intermediateprecisionreferstorandomeventsorwithin-laboratoryvaria-tionsduetosuchthingsasdifferentana-lystsorinstrumentsandresultsondifferentdays.Aruleofthumb:ifitiswrittenintothemethod(forexample,30°C,1.0mL/min,254nm),itisarobustnessissue.Ifitisnotspecifiedinthemethod(forexample,youwouldneverspecify:SteverunsthemethodonTuesdaysoninstru-mentsix),itisanint