化学药品杂质谱控制的现状与展望_胡昌勤

ChineseJournalofNewDrugs2015,24(15)172720152415。[e-mail]。··100050。、。2010。Ｒ917A1003－3734201515－1727－08CurrentsituationandthetrendinimpurityprofilingofchemicaldrugsHUChang-qinNationalInstitutesforFoodandDrugControlBeijing100050ChinaAbstractThesafetyofmedicationtherapyiscloselyrelatedtothequalityofdrugs．Impurityprofilinghasbecomethemostimportantactivityinassuringthehighqualityofdrugsmeanwhileitisthekeyfactorforpromotingthedomesticnewdrugresearchanddevelopment．SupportedbytheNationalKeyNewDrugＲ＆DProgramduringthe12thFiveYearPlanofstateinChinathetechniquesusedinimpurityprofilingwithemphasisonimpuritydeter-minationidentificationaswellasqualificationhavebeendevelopingrapidlyandmadegreatprogressintheappli-cation．Theprogressinimpurityprofilingofchemicaldrugssince2010wasreviewedandthetrendofthisfieldinChinawasoutlined．Keywordschemicaldrugsimpurityprofileimpuritydeterminationimpurityidentificationimpurityqual-ificationspecification、3。impurityprofile。1－3。“impurityprofiling”4。2010、35。《》2015。2010。1ICH、ICHQ3AICHQ3B、ICHQ3CICHQ3DNDAs。ICHChineseJournalofNewDrugs2015,24(15)172820152415。FDAICHQ3AICHQ3B200920106－7。20137ICHQ3Dmetalimpuritieselementalim-purities1AsCdHgPb。2。2AVMoSeCo2BAuTlPdPtIrOsＲhAgＲu。3SbBaLiCrCuSnNi。4AlBFeZnKCaNaMnMgWPDEs。20141216ICHQ3D4STEP4//。。EMA200682007ViraceptEMA、、、910TTC1.5μg·d－1。FDA200811。ICHICHM720147154ICH。ICHQ3AICHQ3BEMA2010512。2、。QbD/13－16APILC-MS1718－19。。20、β-21、22。ＲP-HPLC。、C2、C3、2008－2012C18C862%9%50%1。HILICＲP-HPLC23--ZIC-ＲP-HILICβ-MS24。UVaerosol-based、ELSD、chargedaerosoldetectorsCADNQADnanoquantityanalytedetector25。NQADCAD26CADng～μg272829ELSD《》/0．5%/30。elec-tro-chemicaldetectorECDChineseJournalofNewDrugs2015,24(15)172920152415pulsedamperometricdetectionPADEPUSPECD31－33。《》2015ELSDPAD。ECD。LC-MS/MSn34－37。LC-MSLC-MS。UVHPLCLC-MS38－39MSMS40。。。calibratedlineshapeisotopeprofilesearchCLIPS41MassWorksTMCLIPS3942。NMＲ43－45NMＲ46CD345。。、ESI-MS47－49。β-、50－52Z/E53Δ-3、infraredmultiplepho-tondissociationspectroscopy54。LC-MS55。56－57、58－59、60、61－62、62－6364API65－69。6h6-hpf3d3-dpfLC-MS/MS56。375770topologicalpolarsurfaceareaTPSA70。。MMS、EMS、IMS。EPGC、、、、LC-MSMMSEMSIMS70、ChineseJournalofNewDrugs2015,24(15)17302015241571－73。productsoffermentation。、Bradford1ppm74。GpenicillinGacylasePGAHILIC-FDPGATSKgelOctadecyl-4PW4．6mm×150mmi．d--Agilent2100BioanalyzerHighSensitivityProtein250kit、。ICP-AES75。19ICHQ3D13ICP-AES760．5μg·g－177。ICP-MS78－79。80《》8181－82。3。83。84－9091－92《》2015。93、94、95。96。。。97－98ZIC-ＲP-HILIC2499。designofexperimentsDoEcriticalprocessparametersCPPs、pH、criticalqualityat-tributesCQAs、100－102。DoE《》2010G28《》201540。《》2015DoE。relativeretentiontimeＲＲT。、103－104。Sny-der/Dolan-、Euerby、HoogmartensUSP-105。-HSABCAhydrogen-bondacidityβ-A0．1β-104。《》2015β-A。ChineseJournalofNewDrugs2015,24(15)173120152415。35“〈1224〉”OkamotoHPLC、106。verified“”qualification。//、LOQ/LOD。。UV107。《》2005。。、、107。UVMSNMＲnormalizationfactor108。ＲＲTUVrelativeresponsefactorＲＲF109。4“”。。、specializedimpu-rity。。。。/。、。110--QSAＲ。。1JAINDBASNIWALPK．Forceddegradationandimpurityprofi-lingrecenttrendsinanalyticalperspectivesJ．JPharmBi-omedAnal20138611－35．2NAＲAYANAMMHANDATSHAＲMAPetal．Criticalpracti-calaspectsintheapplicationofliquidchromatography-massspec-trometricstudiesforthecharacterizationofimpuritiesanddegra-dationproductsJ．JPharmBiomedAnal201487191－217．3MAGGIOＲMCALVONLVIGNADUZZOSEetal．Pharma-ceuticalimpuritiesanddegradationproductsUsesandapplica-tionsofNMＲtechniquesJ．JPharmBiomedAnal2014101102－122．4GＲGS．Theimportanceandthechallengesofimpurityprofi-linginmodernpharmaceuticalanalysisJ．TrendsAnalChem2006258755－757．5．J．2010406679－687．6USFoodandDrugAdministration．GuidanceforIndustryAN-DAsImpuritiesinDrugSubstancesEB/OL．2009．http//．fda．gov/downloads/drugs/guidancecomplianceregulatory-information/guidances/ucm072862．pdf．7USFoodandDrugAdministration．GuidanceforIndustryAN-DAsImpuritiesinDrugProductsEB/OL．2010．http//．fda．gov/downloads/drugs/guidancecomplianceregulatory-information/guidances/ucm072861．pdf．8TheEuropeanMedicalControlAgencyCommitteeforMedicinalProductsforHumanUse．Guidelineonthelimitsofgenotoxicim-puritiesEB/OL．2006．http//．ema．europa．eu/ema/index．jspcurl=pages/regulation/general/general_content_000356．jsp＆mid=WC0b01ac0580028e8c．9EuropeanMedicinesAgencyCommitteeforMedicinalProductsforHumanUseCHMP．Ｒequesttoassesstheriskofoccurrenceofcontaminationwithmesilateestersandrelatedcompoundsinphar-maceuticalsEB/OL．2008．http//．ema．europa．eu/ema/pages/includes/document/open_document．jspwebCon-tentId=WC500015375．ChineseJournalofNewDrugs2015,24(15)17322015241510TheEuropeanMedicalControlAgencyCommitteeforMedicinalProductsforHuman．Questionsandanswersonthe‘Guidelineonthelimitsofgenotoxicimpurities’EB/OL．2010．http//．ema．europa．eu/docs/en_GB/document_library/Other/2009/11/WC500015375．pdf．11USDepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandＲesearchCDEＲ．GuidanceforIndustryGenotoxicandCarcinogenicIm-puritiesinDrugSubstancesandProductsＲecommendedApproa-chesEB/OL．2008．http//．fda．gov/cder/guidance/index．htm．12European