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1225VALIDATIONOFCOMPENDIALPROCEDURES
Testproceduresforassessmentofthequalitylevelsofpharmaceuticalarticlesaresubjecttovariousrequirements.AccordingtoSection501oftheFederalFood,Drug,andCosmeticAct,assaysandspecificationsinmonographsoftheUnitedStatesPharmacopeiaandtheNationalFormularyconstitutelegalstandards.TheCurrentGoodManufacturingPracticeregulations[21CFR211.194(a)]requirethattestmethods,whichareusedforassessingcomplianceofpharmaceuticalarticleswithestablishedspecifications,mustmeetproperstandardsofaccuracyandreliability.Also,accordingtotheseregulations[21CFR211.194(a)(2)],usersofanalyticalmethodsdescribedinUSP–NFarenotrequiredtovalidatetheaccuracyandreliabilityofthesemethods,butmerelyverifytheirsuitabilityunderactualconditionsofuse.RecognizingthelegalstatusofUSPandNFstandards,itisessential,therefore,thatproposalsforadoptionofneworrevisedcompendialanalyticalproceduresbesupportedbysufficientlaboratorydatatodocumenttheirvalidity.
Thetextofthisinformationchapterharmonizes,totheextentpossible,withtheTripartiteInternationalConferenceonHarmonization(ICH)documentsValidationofAnalyticalProceduresandtheMethodologyextensiontext,whichareconcernedwithanalyticalproceduresincludedaspartofregistrationapplicationssubmittedwithintheEC,Japan,andtheUSA.
SUBMISSIONSTOTHECOMPENDIA
SubmissionstothecompendiaforneworrevisedanalyticalproceduresshouldcontainsufficientinformationtoenablemembersoftheUSPCouncilofExpertsanditsExpertCommitteestoevaluatetherelativemeritofproposedprocedures.Inmostcases,evaluationsinvolveassessmentoftheclarityandcompletenessofthedescriptionoftheanalyticalprocedures,determinationoftheneedfortheprocedures,anddocumentationthattheyhavebeenappropriatelyvalidated.Informationmayvarydependinguponthetypeofmethodinvolved.However,inmostcasesasubmissionwillconsistofthefollowingsections.
Rationale—Thissectionshouldidentifytheneedfortheprocedureanddescribethecapabilityofthespecificprocedureproposedandwhyitispreferredoverothertypesofdeterminations.Forrevisedprocedures,acomparisonshouldbeprovidedoflimitationsofthecurrentcompendialprocedureandadvantagesofferedbytheproposedprocedure.
ProposedAnalyticalProcedure—Thissectionshouldcontainacompletedescriptionoftheanalyticalproceduresufficientlydetailedtoenablepersons“skilledintheart”toreplicateit.Thewrite-upshouldincludeallimportantoperationalparametersandspecificinstructionssuchaspreparationofreagents,performanceofsystemsuitabilitytests,descriptionofblanksused,precautions,andexplicitformulasforcalculationoftestresults.
DataElements—Thissectionshouldprovidethoroughandcompletedocumentationofthevalidationoftheanalyticalprocedure.Itshouldincludesummariesofexperimentaldataandcalculationssubstantiatingeachoftheapplicableanalyticalperformancecharacteristics.Thesecharacteristicsaredescribedinthefollowingsection.
VALIDATION
Validationofananalyticalprocedureistheprocessbywhichitisestablished,bylaboratorystudies,thattheperformancecharacteristicsoftheproceduremeettherequirementsfortheintendedanalyticalapplications.Typicalanalyticalperformancecharacteristicsthatshouldbeconsideredinthevalidationofthetypesofproceduresdescribedinthisdocumentarelistedin
Table1
.Becauseopinionsmaydifferwithrespecttoterminologyanduse,eachoftheperformancecharacteristicsisdefinedinthenextsectionofthischapter,alongwithadelineationofatypicalmethodormethodsbywhichitmaybemeasured.Thedefinitionsreferto“testresults.”Thedescriptionoftheanalyticalprocedureshoulddefinewhatthetestresultsfortheprocedureare.AsnotedinISO5725-1and3534-1,atestresultis“thevalueofacharacteristicobtainedbycarryingoutaspecifiedtestmethod.Thetestmethodshouldspecifythatoneoranumberofindividualmeasurementsbemade,andtheiraverage,oranotherappropriatefunction(suchasthemedianorthestandarddeviation),bereportedasthetestresult.Itmayalsorequirestandardcorrectionstobeapplied,suchascorrectionofgasvolumestostandardtemperatureandpressure.Thus,atestresultcanbearesultcalculatedfromseveralobservedvalues.Inthesimplecase,thetestresultistheobservedvalueitself.”Atestresultalsocanbe,butneednotbe,thefinal,reportablevaluethatwouldbecomparedtotheacceptancecriteriaofaspecification.Validationofphysicalpropertymethodsmayinvolvetheassessmentofchemometricmodels.However,thetypicalanalyticalcharacteristicsusedinmethodvalidationcanbeappliedtothemethodsderivedfromtheuseofthechemometricmodels.
Theeffectsofprocessingconditionsandpotentialforsegregationofmaterialsshouldbeconsideredwhenobtainingarepresentativesampletobeusedforvalidationofprocedures.
Table1.TypicalAnalyticalCharacteristics
UsedinMethodValidation
Accuracy
Precision
Specificity
DetectionLimit
QuantitationLimit
Linearity
Range
Robustness
Inthecaseofcompendialprocedures,revalidationmaybenecessaryinthefollowingcases:asubmissiontotheUSPofarevisedanalyticalprocedure;ortheuseofanestablishedgeneralprocedurewithanewproductorrawmaterial(seebelowinDataElementsRequiredforValidation).
TheICHdocumentsgiveguidanceonthenecessityforrevalidationinthefollowingcircumstances:changesinthesynthesisofthedrugsubstance;changesinthecompositionofthedrugproduct;andchangesintheanalyticalprocedure.
Chapter1225isintendedtoprovideinformationthatisappropriatetovalidateawiderangeofcompendialanalyticalprocedures.Thevalidationofcompendialproceduresmayusesomeorallofthesuggestedtypicalanalyticalcharacteristicsusedinmethodvalidationasoutlinedin
Table1
andcategorizedbytypeofanalyticalmethodinTable2.ForsomecompendialproceduresthefundamentalprinciplesofvalidationmayextendbeyondcharacteristicssuggestedinChapter1225.Fortheseprocedurestheuserisreferredtotheindividualcompendialchapterforthosespecificanalyticalvalidationcharacteristicsandanyspecificvalidationrequirements.
AnalyticalPerformanceCharacteristics
accuracy
Definition—Theaccuracyofananalyticalprocedureistheclosenessoftestresultsobtainedbythatproceduretothetruevalue.Theaccuracyofananalyticalprocedureshouldbeestablishedacrossitsrange.[Anoteonterminology:Thedefinitionofaccuracyin1225andICHQ2correspondstounbiasednessonly.IntheInternationalVocabularyofMetrology(VIM)anddocumentsoftheInternationalOrganizationforStandardization(ISO),“accuracy”hasadifferentmeaning.InISO,accuracycombinestheconceptsofunbiasedness(termed“trueness”)andprecision.]
Determination—Inthecaseoftheassayofadrugsubstance,accuracymaybedeterminedbyapplicationoftheanalyticalproceduretoananalyteofknownpurity(e.g.,aReferenceStandard)orbycomparisonoftheresultsoftheprocedurewiththoseofasecond,well-characterizedprocedure,theaccuracyofwhichhasbeenstatedordefined.
Inthecaseoftheassayofadruginaformulatedproduct,accuracymaybedeterminedbyapplicationoftheanalyticalproceduretosyntheticmixturesofthedrugproductcomponentstowhichknownamountsofanalytehavebeenaddedwithintherangeoftheprocedure.Ifitisnotpossibletoobtainsamplesofalldrugproductcomponents,itmaybeacceptableeithertoaddknownquantitiesoftheanalytetothedrugproduct(i.e.,“tospike”)ortocompareresultswiththoseofasecond,well-characterizedprocedure,theaccuracyofwhichhasbeenstatedordefined.
Inthecaseofquantitativeanalysisofimpurities,accuracyshouldbeassessedonsamples(ofdrugsubstanceordrugproduct)spikedwithknownamountsofimpurities.Whereitisnotpossibletoobtainsamplesofcertainimpuritiesordegradationproducts,resultsshouldbecomparedwiththoseobtainedbyanindependentprocedure.Intheabsenceofotherinformation,itmaybenecessarytocalculatetheamountofanimpuritybasedoncomparisonofitsresponsetothatofthedrugsubstance;theratiooftheresponsesofequalamountsoftheimpurityandthedrugsubstance(relativeresponsefactor)shouldbeusedifknown.
Accuracyiscalculatedasthepercentageofrecoverybytheassayoftheknownaddedamountofanalyteinthesample,orasthedifferencebetweenthemeanandtheacceptedtruevalue,togetherwithconfidenceintervals.
TheICHdocumentsrecommendthataccuracyshouldbeassessedusingaminimumofninedeterminationsoveraminimumofthreeconcentrationlevels,coveringthespecifiedrange(i.e.,threeconcentrationsandthreereplicatesofeachconcentration).
Assessmentofaccuracycanbeaccomplishedinavarietyofways,includingevaluatingtherecoveryoftheanalyte(percentrecovery)acrosstherangeoftheassay,orevaluatingthelinearityoftherelationshipbetweenestimatedandactualconcentrations.Thestatisticallypreferredcriterionisthattheconfidenceintervalfortheslopebecontainedinanintervalaround1.0,oralternatively,thattheslopebecloseto1.0.Ineithercase,theintervalorthedefinitionofclosenessshouldbespecifiedinthevalidationprotocol.Theacceptancecriterionwilldependontheassayanditsvariabilityandontheproduct.Settinganacceptancecriterionbasedonthelackofstatisticalsignificanceofthetestofthenullhypothesisthattheslopeis1.0isnotanacceptableapproach.
Accuracyofphysicalpropertymethodsmaybeassessedthroughtheanalysisofstandardreferencematerials,oralternatively,thesuitabilityoftheaboveapproachesmaybeconsideredonacase-by-casebasis.
precision
Definition—Theprecisionofananalyticalprocedureisthedegreeofagreementamongindividualtestresultswhentheprocedureisappliedrepeatedlytomultiplesamplingsofahomogeneoussample.Theprecisionofananalyticalprocedureisusuallyexpressedasthestandarddeviationorrelativestandarddeviation(coefficientofvariation)ofaseriesofmeasurements.Precisionmaybeameasureofeitherthedegreeofreproducibilityorofrepeatabilityoftheanalyticalprocedureundernormaloperatingconditions.Inthiscontext,reproducibilityreferstotheuseoftheanalyticalprocedureindifferentlaboratories,asinacollaborativestudy.Intermediateprecision(alsoknownasruggedness)expresseswithin-laboratoryvariation,asondifferentdays,orwithdifferentanalystsorequipmentwithinthesamelaboratory.Repeatabilityreferstotheuseoftheanalyticalprocedurewithinalaboratoryoverashortperiodoftimeusingthesameanalystwiththesameequipment.
Determination—Theprecisionofananalyticalprocedureisdeterminedbyassayingasufficientnumberofaliquotsofahomogeneoussampletobeabletocalculatestatisticallyvalidestimatesofstandarddeviationorrelativestandarddeviation(coefficientofvariation).Assaysinthiscontextareindependentanalysesofsamplesthathavebeencarriedthroughthecompleteanalyticalprocedurefromsamplepreparationtofinaltestresult.
TheICHdocumentsrecommendthatrepeatabilityshouldbeassessedusingaminimumofninedeterminationscoveringthespecifiedrangefortheprocedure(i.e.,threeconcentrationsandthreereplicatesofeachconcentration)orusingaminimumofsixdeterminationsat100%ofthetestconcentration.
specificity
Definition—TheICHdocumentsdefinespecificityastheabilitytoassessunequivocallytheanalyteinthepresenceofcomponentsthatmaybeexpectedtobepresent,suchasimpurities,degradationproducts,andmatrixcomponents.Lackofspecificityofanindividualanalyticalproceduremaybecompensatedbyothersupportinganalyticalprocedures.[Note—Otherreputableinternationalauthorities(IUPAC,AOAC-I)havepreferredtheterm“selectivity,”reserving“specificity”forthoseproceduresthatarecompletelyselective.]Forthetestsdiscussedbelow,theabovedefinitionhasthefollowingimplications:
IdentificationTests:ensuretheidentityoftheanalyte.
PurityTests:ensurethatalltheanalyticalproceduresperformedallowanaccuratestatementofthecontentofimpuritiesofananalyte(e.g.,relatedsubstancestest,heavymetalslimit,organicvolatileimpurities).
Assays:provideanexactresult,whichallowsanaccuratestatementonthecontentorpotencyoftheanalyteinasample.
Determination—Inthecaseofqualitativeanalyses(identificationtests),theabilitytoselectbetweencompoundsofcloselyrelatedstructurethatarelikelytobepresentshouldbedemonstrated.Thisshouldbeconfirmedbyobtainingpositiveresults(perhapsbycomparisontoaknownreferencematerial)fromsamplescontainingtheanalyte,coupledwithnegativeresultsfromsamplesthatdonotcontaintheanalyteandbyconfirmingthatapositiveresponseisnotobtainedfrommaterialsstructurallysimilartoorcloselyrelatedtotheanalyte.
Inthecaseofanalyticalproceduresforimpurities,specificitymaybeestablishedbyspikingthedrugsubstanceorproductwithappropriatelevelsofimpuritiesanddemonstratingthattheseimpuritiesaredeterminedwithappropriateaccuracyandprecision.
Inthecaseoftheassay,demonstrationofspecificityrequiresthatitcanbeshownthattheprocedureisunaffectedbythepresenceofimpuritiesorexcipients.Inpractice,thiscanbedonebyspikingthedrugsubstanceorproductwithappropriatelevelsofimpuritiesorexcipientsanddemonstratingthattheassayresultisunaffectedbythepresenceoftheseextraneousmaterials.
Ifimpurityordegradationproductstandardsareunavailable,specificitymaybedemonstratedbycomparingthetestresultsofsamplescontainingimpuritiesordegradationproductstoasecondwell-characterizedprocedure(e.g.,aPharmacopeialorothervalidatedprocedure).Thesecomparisonsshouldincludesamplesstoredunderrelevantstressconditions(e.g.,light,heat,humidity,acid/basehydrolysis,andoxidation).Inthecaseoftheassay,theresultsshouldbecompared;inthecaseofchromatographicimpuritytests,theimpurityprofilesshouldbecompared.
TheICHdocumentsstatethatwhenchromatographicproceduresareused,representativechromatogramsshouldbepresentedtodemonstratethedegreeofselectivity,andpeaksshouldbeappropriatelylabeled.Peakpuritytests(e.g.,usingdiodearrayormassspectrometry)maybeusefultoshowthattheanalytechromatographicpeakisnotattributabletomorethanonecomponent.
Forvalidationofspecificityforqualitativeandquantitativedeterminationsbyspectroscopicmethods,chaptersrelatedtotopicssuchasnear-infraredspectrophotometry,ramanspectroscopy,andX-raypowderdiffractionshouldbeconsulted.
detectionlimit
Definition—Thedetectionlimitisacharacteristicoflimittests.Itisthelowestamountofanalyteinasamplethatcanbedetected,butnotnecessarilyquantitated,underthestatedexperimentalconditions.Thus,limittestsmerelysubstantiatethattheamountofanalyteisaboveorbelowacertainlevel.Thedetectionlimitisusuallyexpressedastheconcentrationofanalyte(e.g.,percentage,partsperbillion)inthesample.
Determination—Fornoninstrumentalprocedures,thedetectionlimitisgenerallydeterminedbytheanalysisofsampleswithknownconcentrationsofanalyteandbyestablishingtheminimumlevelatwhichtheanalytecanbereliablydetected.
Forinstrumentalprocedures,thesameapproachmaybeusedasfornoninstrumentalprocedures.Inthecaseofproceduressubmittedforconsiderationasofficialcompendialprocedures,itisalmostnevernecessarytodeterminetheactualdetectionlimit.Rather,thedetectionlimitisshowntobesufficientlylowbytheanalysisofsampleswithknownconcentrationsofanalyteaboveandbelowtherequireddetectionlevel.Forexample,ifitisrequiredtodetectanimpurityatthelevelof0.1%,itshouldbedemonstratedthattheprocedurewillreliablydetecttheimpurityatthatlevel.
Inthecaseofinstrumentalanalyticalproceduresthatexhibitbackgroundnoise,theICHdocumentsdescribeacommonapproach,whichistocomparemeasuredsignalsfromsampleswithknownlowconcentrationsofanalytewiththoseofblanksamples.Theminimumconcentrationatwhichtheanalytecanreliablybedetectedisestablished.Typicallyacceptablesignal-to-noiseratiosare2:1or3:1.Otherapproachesdependonthedeterminationoftheslopeofthecalibrationcurveandthestandarddeviationofresponses.Whatevermethodisused,thedetectionlimitshouldbesubsequentlyvalidatedbytheanalysisofasuitablenumberofsamplesknowntobenear,orpreparedat,thedetectionlimit.
quantitationlimit
Definition—Thequantitationlimitisacharacteristicofquantitativeassaysforlowlevelsofcompoundsinsamplematrices,suchasimpuritiesinbulkdrugsubstancesanddegradationproductsinfinishedpharmaceuticals.Itisthelowestamountofanalyteinasamplethatcanbedeterminedwithacceptableprecisionandaccuracyunderthestatedexperimentalconditions.Thequantitationlimitisexpressedastheconcentrationofanalyte(e.g.,percentage,partsperbillion)inthesample.
Determination—Fornoninstrumentalprocedures,thequantitationlimitisgenerallydeterminedbytheanalysisofsampleswithknownconcentrationsofanalyteandbyestablishingtheminimumlevelatwhichtheanalytecanbedeterminedwithacceptableaccuracyandprecision.
Forinstrumentalprocedures,thesameapproachmaybeusedasfornoninstrumentalprocedures.Inthecaseofproceduressubmittedforconsiderationasofficialcompendialprocedures,itisalmostnevernecessarytodeterminetheactualquantitationlimit.Rather,thequantitationlimitisshowntobesufficientlylowbytheanalysisofsampleswithknownconcentrationsofanalyteaboveandbelowthequantitationlevel.Forexample,ifitisrequiredthatananalytebeassayedatthelevelof0.1mgpertablet,itshouldbedemonstratedthattheprocedurewillreliablyquantitatetheanalyteatthatlevel.
Inthecaseofinstrumentalanalyticalproceduresthatexhibitbackgroundnoise,theICHdocumentsdescribeacommonapproach,whichistocomparemeasuredsignalsfromsampleswithknownlowconcentrationsofanalytewiththoseofblanksamples.Theminimumconcentrationatwhichtheanalytecanreliablybequantifiedisestablished.Atypicallyacceptablesignal-to-noiseratiois10:1.Otherapproachesdependonthedeterminationoftheslopeofthecalibrationcurveandthestandarddeviationofresponses.Whateverapproachisused,thequantitationlimitshouldbesubsequentlyvalidatedbytheanalysisofasuitablenumberofsamplesknowntobenear,orpreparedat,thequantitationlimit.
linearityandrange
DefinitionofLinearity—Thelinearityofananalyticalprocedureisitsabilitytoelicittestresultsthataredirectly,orbyawell-definedmathematicaltransformation,proportionaltotheconcentrationofanalyteinsampleswithinagivenrange.Thus,inthissection,“linearity”referstothelinearityoftherelationshipofconcentrationandassaymeasurement.Insomecases,toattainlinearity,theconcentrationand/orthemeasurementmaybetransformed.(Notethattheweightingfactorsusedintheregressionanalysismaychangewhenatransformationisapplied.)Possibletransformationsmayincludelog,squareroot,orreciprocal,althoughothertransformationsareacceptable.Iflinearityisnotattainable,anonlinearmodelmaybeused.Thegoalistohaveamodel,whetherlinearornonlinear,thatdescribescloselytheconcentration-responserelationship.
DefinitionofRange—Therangeofananalyticalprocedureistheintervalbetweentheupperandlowerlevelsofanalyte(includingtheselevels)thathavebeendemonstratedtobedeterminedwithasuitablelevelofprecision,accuracy,andlinearityusingtheprocedureaswritten.Therangeisnormallyexpressedinthesameunitsastestresults(e.g.,percent,partspermillion)obtainedbytheanalyticalprocedure.
DeterminationofLinearityandRange—Linearityshouldbeestablishedacrosstherangeoftheanalyticalprocedure.Itshouldbeestablishedinitiallybyvisualexaminationofaplotofsignalsasafunctionofanalyteconcentrationofcontent.Ifthereappearstobealinearrelationship,testresultsshouldbeestablishedbyappropriatestatisticalmethods(e.g.,bycalculationofaregressionlinebythemethodofleastsquares).Datafromtheregressionlineitselfmaybehelpfultoprovidemathematicalestimatesofthedegreeoflinearity.Thecorrelationcoefficient,y-intercept,slopeoftheregressionline,andresidualsumofsquaresshouldbesubmitted.
Therangeoftheprocedureisvalidatedbyverifyingthattheanalyticalprocedureprovidesacceptableprecision,accuracy,andlinearitywhenappliedtosamplescontaininganalyteattheextremesoftherangeaswellaswithintherange.
ICHrecommendsthat,fortheestablishmentoflinearity,aminimumoffiveconcentrationsnormallybeused.Itisalsorecommendedthatthefollowingminimumspecifiedrangesshouldbeconsidered:
AssayofaDrugSubstance(orafinishedproduct):from80%to120%ofthetestconcentration.
DeterminationofanImpurity:from50%to120%oftheacceptancecriterion.
ForContentUniformity:aminimumof70%to130%ofthetestconcentration,unlessawiderormoreappropriaterangebasedonthenatureofthedosageform(e.g.,metered-doseinhalers)isjustified.
ForDissolutionTesting:±20%overthespecifiedrange(e.g.,iftheacceptancecriteriaforacontrolled-releaseproductcoveraregionfrom30%,after1hour,andupto90%,after24hours,thevalidatedrangewouldbe10%to110%ofthelabelclaim).
Thetraditionaldefinitionoflinearity,i.e.,theestablishmentofalinearormathematicalrelationshipbetweensampleconcentrationandresponse,isnotapplicabletoparticlesizeanalysis.Forparticlesizeanalysis,aconcentrationrangeisdefined(instrument-andparticlesize-dependent)suchthatthemeasuredparticlesizedistributionisnotaffectedbychangesinconcentrationwithinthedefinedconcentrationrange.Concentrationsbelowthedefinedconcentrationrangemayintroduceanerrorduetopoorsignal-to-noiseratio,andconcentrationsexceedingthedefinedconcentrationrangemayintroduceanerrorduetomultiplescattering.
robustness
Definition—Therobustnessofananalyticalprocedureisameasureofitscapacitytoremainunaffectedbysmallbutdeliberatevariationsinproceduralparameterslistedintheproceduredocumentationandprovidesanindicationofitssuitabilityduringnormalusage.Robustnessmaybedeterminedduringdevelopmentoftheanalyticalprocedure.
systemsuitability
Ifmeasurementsaresusceptibletovariationsinanalyticalconditions,theseshouldbesuitablycontrolled,oraprecautionarystatementshouldbeincludedintheprocedure.Oneconsequenceoftheevaluationofrobustnessandruggednessshouldbethataseriesofsystemsuitabilityparametersisestablishedtoensurethatthevalidityoftheanalyticalprocedureismaintainedwheneverused.Typicalvariationsarethestabilityofanalyticalsolutions,differentequipment,anddifferentanalysts.Inthecaseofliquidchromatography,typicalvariationsarethepHofthemobilephase,themobilephasecomposition,differentlotsorsuppliersofcolumns,thetemperature,andtheflowrate.Inthecaseofgaschromatography,typicalvariationsaredifferentlotsorsuppliersofcolumns,thetemperature,andtheflowrate.
Systemsuitabilitytestsarebasedontheconceptthattheequipment,electronics,analyticaloperations,andsamplestobeanalyzedconstituteanintegralsystemthatcanbeevaluatedassuch.Systemsuitabilitytestparameterstobeestablishedforaparticularproceduredependonthetypeofprocedurebeingevaluated.Theyareespeciallyimportantinthecaseofchromatographicprocedures.SubmissionstotheUSPshouldmakenoteoftherequirementsundertheSystemSuitabilitysectioninthegeneraltestchapterChromatography621.
DataElementsRequiredforValidation
Compendialtestrequirementsvaryfromhighlyexactinganalyticaldeterminationstosubjectiveevaluationofattributes.Consideringthisbroadvariety,itisonlylogicalthatdifferenttestproceduresrequiredifferentvalidationschemes.Thischaptercoversonlythemostcommoncategoriesoftestsforwhichvalidationdatashouldberequired.Thesecategoriesareasfollows:
CategoryI—Analyticalproceduresforquantitationofmajorcomponentsofbulkdrugsubstancesoractiveingredients(includingpreservatives)infinishedpharmaceuticalproducts.
CategoryII—Analyticalproceduresfordeterminationofimpuritiesinbulkdrugsubstancesordegradationcompoundsinfinishedpharmaceuticalproducts.Theseproceduresincludequantitativeassaysandlimittests.
CategoryIII—Analyticalproceduresfordeterminationofperformancecharacteristics(e.g.,dissolution,drugrelease,etc.).
CategoryIV—Identificationtests.
Foreachcategory,differentanalyticalinformationisneeded.ListedinTable2aredataelementsthatarenormallyrequiredforeachofthesecategories.
Table2.DataElementsRequiredforVali
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