生物样品分析方法验证指导原则--欧洲

EuropeanMedicinesAgency7WestferryCircus,CanaryWharf,London,E144HB,UKTel.(44-20)74188400Fax[phone]E-mail:[e-mail]©EMEA2009Reproductionand/ordistributionofthisdocumentisauthorisedfornoncommercialpurposesonlyprovidedtheEMEAisacknowledged123London,19November2009Doc.Ref:EMEA/CHMP/EWP/192217/2009COMMITTEEFORMEDICINALPRODUCTSFORHUMANUSE4(CHMP)56DRAFTGUIDELINEONVALIDATIONOFBIOANALYTICALMETHODS78DRAFTAGREEDBYTHEEFFICACYWORKINGPARTYSeptember2009ADOPTIONBYCHMPFORRELEASEFORCONSULTATION19November2009ENDOFCONSULTATION(DEADLINEFORCOMMENTS)31M[e-mail]10KEYWORDSCHMP,EMEA,Guideline,validation,bioanalyticalmethod,analyses2/17GUIDELINEONVALIDATIONOFBIOANALYTICALMETHODS11121314151617181920212223242526272829303132333435363738TABLEOFCONTENTS1.INTRODUCTION(BACKGROUND)........................................................................................32.SCOPE............................................................................................................................................33.LEGALBASIS..............................................................................................................................34.METHODVALIDATION............................................................................................................44.1COMPLETEVALIDATIONOFANANALYTICALMETHOD...........................................................44.1.1Selectivity.........................................................................................................................44.1.2Carry-over.......................................................................................................................54.1.3Lowerlimitofquantitation..............................................................................................54.1.4Calibrationcurve............................................................................................................54.1.5Accuracy..........................................................................................................................64.1.6Precision..........................................................................................................................74.1.7Dilutionintegrity.............................................................................................................74.1.8Matrixeffect....................................................................................................................74.1.9Stability............................................................................................................................84.2PARTIALVALIDATION..............................................................................................................94.3CROSSVALIDATION.................................................................................................................94.4LIGAND-BINDINGASSAYS........................................................................................................95.ANALYSISOFSTUDYSAMPLES..........................................................................................105.1ANALYTICALRUN..................................................................................................................115.2ACCEPTANCECRITERIAOFANANALYTICALRUN.................................................................115.3CALIBRATIONRANGE............................................................................................................125.4REANALYSISOFSTUDYSAMPLES..........................................................................................125.5INTEGRATION.........................................................................................................................136.INCURREDSAMPLESREANALYSIS...................................................................................137.STUDYREPORT........................................................................................................................13DEFINITIONS....................................................................................................................................163/1739404142434546474849505152535456575859606162646566676869707172737475767778EXECUTIVESUMMARYThisguidelinedefineskeyelementsandprovidesrecommendationsforthevalidationofbioanalyticalmethods.Theguidelinefocusesonthevalidationoftheanalyticalmethodsusedforpharmacokineticsampleanalysis.Inaddition,guidancewillbeprovidedwithregardtotheactualanalysisofstudysamples.1.INTRODUCTION(background)44Measurementofdrugconcentrationsinbiologicalmatricesisanimportantaspectofmedicinalproductdevelopmentforthoseproductscontainingnewactivesubstancesaswellasforlineextensionsandgenericproducts.Suchdatamayberequiredtosupportnewapplicationsaswellasvariationstoauthoriseddrugproducts.Theresultsoftoxicokinetic,pharmacokineticandbioequivalencestudiesareusedtomakecriticaldecisionssupportingthesafetyandefficacyofamedicinaldrugsu