USP化学药物质量控制分析方法验证技术指导原则.docx
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USP化学药物质量控制分析方法验证技术指导原则
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VALIDATIONOFCOMPENDIALPROCEDURES
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.TypicalanalyticalperformancecharacteristicsthatshouldbeconsideredinthevalidationofthetypesofproceduresdescribedinthisdocumentarelistedinTable1.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.
Chapter
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isintendedtoprovideinformationthatisappropriatetovalidateawiderangeofcompendialanalyticalprocedures.ThevalidationofcompendialproceduresmayusesomeorallofthesuggestedtypicalanalyticalcharacteristicsusedinmethodvalidationasoutlinedinTable1andcategorizedbytypeofanalyticalmethodinTable2.ForsomecompendialproceduresthefundamentalprinciplesofvalidationmayextendbeyondcharacteristicssuggestedinChapter
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.Fortheseprocedurestheuserisreferredtotheindividualcompendialchapterforthosespecificanalyticalvalidationcharacteristicsandanyspecificvalidationrequirements.
AnalyticalPerformanceCharacteristics
accuracy
Definition—Theaccuracyofananalyticalprocedureistheclosenessoftestresultsobtainedbythatproceduretothetruevalue.Theaccuracyofananalyticalprocedureshouldbeestablishedacrossitsrange.[Anoteonterminology:
Thedefinitionofaccuracyin
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andICHQ2correspondstounbiasednessonly.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.Settinganacceptancecriterionbasedonthelackofstatisticalsignificanceofthetestofthenullhypothes