大分子生物药物生物分析方法验证_解读欧洲药品管理局指导原则_张双庆

.199.Q5A1001-8751(2012)05-0199-05BioanalyticalMethodValidationforMacromolecules:InterpretationofGuidelineofEuropeanMedicinesAgencyZhangShuang-qing,FanYu-mingNationalInstitutesforFoodandDrugControl,Beijing100176Abstract:Thereviewcoversfullvalidation,partialvalidation,cross-validationandincurredsampleanalysisaspectsofbioanalyticalmethodformacromolecules.Keywordsmacromolecule;bioanalyticalmethod;validation2012-08-20EuropeanMedicinesAgencyEMA201221Guidelineonbioanlyticalmethodvalidation,EMEA/CHMP/EWP/192217/200912015[1]20052010IIXIXB20129335.200.[4]11.1[2]1.2LLOQULOQ25%[2,5]1.310LLOQLLOQ80%20%LLOQ25%1[2-3]Table1Comparisonofthecharacteristicsofsmall-moleculeandmacromoleculecompounds(characteristic)(smallmolecules)(macromolecules)(size)1000Da(small)5000Da(large)(structure)(organicmolecules)(aminoacidbiopolymers;couldbemultimeric)(purity)(homogeneous)(heterogeneous)(solubility)(oftenhydrophobic)(oftenhydrophilic)(stability)(chemical)(chemical,physicalandbiological)(presenceinmatrix)(xenobiotic)(endogenous)(synthesis)(organicsynthesis)(biologicalproduction)(metabolism)(defined)(notwelldefined;couldbebiotransformeddependingontheenvironmentaswellasinvivoconditions)(serumbinding)(albumin)(specificcarrierproteins)WorldNotesonAntibiotics,2012,Vol.33,No.5.201.1.4ULOQLLOQ20%1.51.6100%[2]1.7626LLOQULOQ25%20%75%LLOQULOQ45LLOQULOQ[5-6]1.8LLOQ3LLOQ75%-85%ULOQULOQ620%LLOQULOQ25%20%LLOQULOQ25%RE+CV30%LLOQULOQ40%[2]1.9ULOQHBsAgAFPhCG20%20%1.10[2,7]20129335.202.Cmax330%1.113LLOQ75%-85%ULOQ220%12h1.12[2,5-8]RobustnessRuggedness2315%67%20%44.120%LLOQULOQ25%675%LLOQULOQ3267%50%20%4.2Incurredsample2003FDA300%[9][10]WorldNotesonAntibiotics,2012,Vol.33,No.5.203.100010%10005%Cmax67%30%[10]%=-/×100%5GarofoloF,MichonJ,LeclaireV,etal.USFDA/EMA[1]harmonizationoftheirbioanalyticalguidance/guidelineandactivitiesoftheGlobalBioanalyticalConsortium[J].Bioanalysis,2012,4(3):231KelleyM,DeSilvaB.Keyelementsofbioanalyticalmethod[2]validationformacromolecules[J].AAPSJ,2007,9(2):E156ViswanathanCT,BansalS,BoothB,etal.Quantitative[3]bioanalyticalmethodsvalidationandimplementation:bestpracticesforchromatographicandligandbindingassays[J].PharmRes,2007,24(10):1962SavoieN,GarofoloF,vanAmsterdamP,etal.2010white[4]paperonrecentissuesinregulatedbioanalysis&globalharmonizationofbioanalyticalguidance[J].Bioanalysis,2010,2(12):1945SmolecJ,DeSilvaB,SmithW,etal.Bioanalyticalmethod[5]validationformacromoleculesinsupportofpharmacokineticstudies[J].PharmRes,2005,22(9):1425ViswanathanCT,BansalS,BoothB,etal.Quantitative[6]bioanalyticalmethodsvalidationandimplementation:bestpracticesforchromatographicandligandbindingassays[J].PharmRes,2007,24(10):1962DeSilvaB,SmithW,WeinerR,etal.Recommendations[7]forthebioanalyticalmethodvalidationofligand-bindingassaystosupportpharmacokineticassessmentsofmacromolecules[J].PharmRes,2003,20(11):1885FindlayJW,SmithWC,LeeJW,etal.Validationof[8]immunoassaysforbioanalysis:apharmaceuticalindustryperspective[J].JPharmBiomedAnal,2000,21(6):1249TimmermanP,LuedtkeS,vanAmsterdamP,etal.Incurred[9]samplereproducibility:viewsandrecommendationsbytheEuropeanBioanalysisForum[J].Bioanalysis,2009,1(6):1049RocciMLJr,DevanarayanV,HaugheyDB,etal.[10]Confirmatoryreanalysisofincurredbioanalyticalsamples[J].AAPSJ,2007,9(3):E3362013()()-2512.007262-88168610052()028-84216030E-mail:[e-mail]20129335