色谱分析方法验证-FDA

CenterforDrugEvaluationandResearch(CDER)ReviewerGuidanceValidationofChromatographicMethodsNovember1994CMC3TABLEOFCONTENTSI.INTRODUCTION...............................................1II.TYPESOFCHROMATOGRAPHY.................................2A.HighPerformanceLiquidChromatography(HPLC)...............21.ChiralChromatography...............................22.Ion-exchangeChromatography.........................33.Ion-pair/AffinityChromatography........................34.NormalPhaseChromatography.........................35.ReversedPhaseChromatography.......................36.SizeExclusionChromatography........................4B.GasChromatography(GC)..................................4C.Thin-LayerChromatography(TLC)............................5III.REFERENCESTANDARDS......................................5IV.PARAMETERSFORVALIDATIONOFHPLCHROMATOGRAPHICMETHODSFORDRUGSUBSTANCEANDDRUGPRODUCT..........7A.Accuracy................................................8B.DetectionLimitandQuantitationLimit.........................8C.Linearity................................................11D.Precision................................................131.Repeatability........................................13a.InjectionRepeatability...........................13b.AnalysisRepeatability...........................152.IntermediatePrecision................................153.Reproducibility......................................16E.Range..................................................16F.Recovery................................................16G.Robustness..............................................16H.SampleSolutionStability...................................17I.Specificity/selectivity.......................................17J.SystemSuitabilitySpecificationsandTests.....................211.Capacityfactor......................................222.Precision/Injectionrepeatability.........................223.Relativeretention....................................224.Resolution.........................................225.Tailingfactor........................................236.Theoreticalplatenumber..............................26K.GeneralPointstoConsider..................................28V.COMMENTSANDCONCLUSIONS................................29VI.ACKNOWLEDGEMENTS........................................29VII.REFERENCES................................................29ThisguidancehasbeenpreparedbytheAnalyticalMethodsTechnical1CommitteeoftheChemistryManufacturingControlsCoordinatingCommittee(CMCCC)oftheCenterforDrugEvaluationandResearchattheFoodandDrugAdministration.AlthoughthisguidancedoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAortheindustry,itdoesrepresenttheagency’scurrentthinkingonthevalidationofchromatographicmethods.Foradditionalcopiesofthisguidance,contacttheDivisionofCommunicationsManagement,HFD-210,CDER,FDA,5600FishersLane,Rockville,MD20857(Phone:[phone]).Sendoneself-addressedadhesivelabeltoassisttheofficesinprocessingyourrequest.AnelectronicversionofthisguidanceisalsoavailableviaInternettheWorldWideWeb()(connecttotheFDAHomePageat“RegulatoryGuidance”section).REVIEWERGUIDANCE1VALIDATIONOFCHROMATOGRAPHICMETHODSI.INTRODUCTIONThepurposeofthistechnicalreviewguideistopresenttheissuestoconsiderwhenevaluatingchromatographictestmethodsfromaregulatoryperspective.ThedocumentdiscussesthepointstonoteandweaknessesofchromatographysothatCDERreviewerscanensurethatthemethod'sperformanceclaimsareproperlyevaluated,andthatsufficientinformationisavailableforthefieldchemisttoassessthemethod.Analyticalterms,asdefinedbytheInternationalConferenceofHarmonization(ICH),1993,havebeenincorporatedinthisguide.Chromatographicmethodsarecommonlyusedforthequantitativeandqualitativeanalysisofrawmaterials,drugsubstances,drugproductsandcompoundsinbiologicalfluids.Thecomponentsmonitoredincludechiralorachiraldrug,processimpurities,residualsolvents,excipientssuchaspreservatives,degradationproducts,extractablesandleachablesfromcontainerandclosureormanufacturingprocess,pesticideindrugproductfromplantorigin,andmetabolites.Theobjectiveofatestmethodistogeneratereliableandaccuratedataregardlessofwhetheritisforacceptance,release,stabilityorpharmacokineticsstudy.Dataaregeneratedforthequalitativeandquantitativetestingduringdevelopmentandpost-approvalofthedrugproducts.Thetestingincludestheacceptanceofrawmaterials,releaseofthedrugsubstancesandproducts,in-processtestingforqualityassurance,andestablishmentoftheexpirationdatingperiod.Validationofamethodistheprocessbywhichamethodistestedbythedeveloperoruserforreliability,accuracyandprecisenessofitsintendedpurpose.DatathusgeneratedbecomepartofthemethodsvalidationpackagesubmittedtoCDER.Methodsvalidationshouldnotbeaone-timesituationtofulfilAgencyfilingrequirements,butthemethodsshouldbevalidatedandalsodesignedbythedeveloperorusertoensureruggednessorrobustness.Methodsshouldbereproduciblewhenusedbyotheranalysts,onotherequivalentequipment,onotherdaysorlocations,andthroughoutthelifeofthed