USP化學(xué)藥物質(zhì)量控制分析方法驗(yàn)證技術(shù)指導(dǎo)原則

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,“l(fā)inearity”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.DataElementsRequiredforValidation

Analytical

Performance

Characteristics

CategoryI

CategoryII

CategoryIII

CategoryIV

Quantitative

Limit

Tests

Accuracy

Yes

Yes

*

*

No

Precision

Yes

Yes

No

Yes

No

Specificity

Yes

Yes

Yes

*

Yes

DetectionLimit

No

No

Yes

*

No

QuantitationLimit

No