肖柏明PPT—杂质研究色谱体系的建立、优化与疑难问题分析(1)

同写意论坛41期专题讲座江苏先声药业有限公司南京百家汇科技创业社区有限公司执行技术总监肖柏明2015.11.231杂质研究色谱体系的建立、优化与疑难问题分析药物分析的新趋向-杂质谱研究杂质分类及我们的主要关注点杂质谱研究的思维及流程案例分享：1.稳定性研究中物料缺失调查(原研药-NDA前)2.不稳定降解物-“鬼峰”的来龙去脉(原研药-NDA前)3.碱性药物的色谱分离挑战及解决方法(原研药-早期)4.仿药：标准与无标准的有关物质研究(6种情况)略谈科学地建立快速液相色谱方法色谱方法的验证及技术转移中的要点问题讨论2药物质量定义：从“含量”到“杂质”的悄然变化Overthelastoneandahalfdecade,fromthetimewhenICHQ3seriesofguidelineswerefirstintroduced,aseachangehasgoneintothedefinitionof‘quality’ofpharmaceuticals.Thefocushasdefinitelyshiftedfrom‘purity’to‘impurities’(IMPs)indrugsubstancesand‘degradationproducts’(DPs)infinishedpharmaceuticalproducts.ReviewAcriticalreviewontheuseofmodernsophisticatedhyphenatedtoolsinthecharacterizationofimpuritiesanddegradationproductsSaranjitSingh∗et.AlJournalofPharmaceuticalandBiomedicalAnalysis69(2012)148–173药品原料、产品杂质有关指导原则humanuse.Q3A(R2):ImpsinNewDS25-Oct-06Q3B(R2):ImpsinNewDP2-Jun-06Q3C(R5):Imps:ResidualSolvents4-Feb-11Q3D:Imps:MetalImpurities(finalconceptpaper)29-Oct-09M7:AssessmentandControlofDNAReactive(Mutagenic)ImpuritiesinPharmaceuticalstoLimitPotentialCarcinogenicRisk(finalconceptpaper)9-Jun-10EMEA/CHMP/CVMP/QWP/450653/2006:AssessmentofQualityofMedicinalProductsContainingExisting/KnownActiveSubstances10-Jul-07CPMP/QWP/1529/04:ControlofImpuritiesofPharmacopoeialSubstances22-Apr-04CPMP/SWP/5199/02andEMEA/CHMP/QWP/251344/2006:GuidelineontheLimitsofGenotoxicImpurities28-Jun-07CPMP/SWP/QWP/4446/00corr.:GuidelinesonSpecificationLimitsforResiduesofMetalCatalystsJan-07EMA/CHMP/CVMP/QWP/199250/2009:GuidelineonSettingSpecificationsforRelatedImpuritiesinAntibiotics(draft)14-Jul-10ICH(USA,EUandJapan)EMA(Europe)药品原料、产品杂质有关指导原则NDAs:ImpuritiesinDrugSubstancesFeb2000June2009GenotoxicandCarcinogenicImpuritiesinDrugSubstancesandProducts:RecommendedApproaches(draft)Dec-08ANDAs:ImpuritiesinDrugProductsNov-10TGA(Canada)ImpuritiesinExistingDrugSubstancesandProducts(draft)6-Sep-05TPD(Australia)AustralianRegulatoryGuidelinesforPrescriptionMedicines;Appendix18:ImpuritiesinActivePharmaceuticalIngredientsandFinishedProductsJun-04USFDA(USA)Continuedfrompreviouspage由于杂质问题美国被FDA召回药品的案例(September2011–March2012)ProductVolumeDeclaredreasonClassAdagen(Pegademasebovine)injection,250units/ml,1.5mlsingle-dosevials,4vials/carton249cartonsIMPs/DPs:Duringroutinestabilitytesting,levelsofIMPCwereoutofspecification.IIAzelastinhydrochlorideophthalmic(sterile),6mlbottlessolution,0.05%155,363bottlesIMPs/DPs:TotalIMPresultswereoutofspecificationduringtheanalysisof18monthssamples.controlledIIIBrimonidineTartrateophthalmicsolution0.2%(Sterile),0.2%(sterile),15mlbottles18,137bottlesIMPs/DPs:9monthsstabilitysampledoesnotcomplyspecification.IIIBudeprionXL(BuproprionHClERTablets),300mg7718tabletsIMPs/DPs:RecallisbeingcarriedoutduetothepotentialthatlotsmaynotmeetIMPspecificationoverproductshelflife.IIICyclopiroxGel,0.77%,45gtube24,664tubesIMPs/DPs:TwolotsdidnotconformtoproductspecificationsforanunspecifiedIMPatthe9monthstabilityteststation.IIIDiflorasoneDiacetateCreamUSP,0.05%,(a)15gtube;(b)30gtube;(c)60gtube27,557tubesIMPs/DPs:Out-of-specificationresults,0.05%wereobtainedforknownandtotalDPs.IIIFludeoxyglucoseF18injections,20–300mCi/ml,multi-dosevials8dosesIMPs/DPs:Productcontainsresidualby-productsofthemanufacturingprocessaboveallowancesIIHydroxyzineHydrochlorideOralSolution,USP,10mg/5ml,120ml&Pint(473ml)bottles30,740bottlesIMPs/DPs:OutofSpecificationresultsforanindividualIMPatthe12monthroomtemperaturetimepoint.III由于杂质问题美国被FDA召回药品的案例(September2011–March2012)ContinuedfrompreviouspageLeflunomideTablets,10mg,30-countBottle32,325bottlesIMPs/DPs:OnelotofthisproductdoesnotmeetIMPspecifications.IIMigergot(ErgotamineTartrateandCaffeine)RectalSuppositoriesUSP10,968boxesIMPs/DPs:ProductwasoutofspecificationforaknownDP,ergotaminine.IIIPediatricAtropineSulfateInjection,USP,0.05mg/ml;SingleDose37,100syringesIMPs/DPs;OOSresultfortotalIMPsatthe8monthstabilitytestinginterval.IIPrednisoloneSodiumPhosphateOralSolution,15mg(base)/5ml24,980bottlesIMPs/DPs:Outofspecificationforrelatedcompoundsatthe12-monthroomtemperaturestabilitytimepoint.IIRopiniroleHydrochlorideTablets,0.25mg,0.5mg,1mgand2mg,100-counttabletsperbottle1,103,813bottlesIMPs/DPs:RopiniroleHydrochlorideTabletsmaynotmeetthespecificationforaknownIMPovertheproductshelflife.IIITopiramate25mg&200mgtablets82,653tabletsIMPs/DPs:HighoutofspecificationresultsforIMP.IIIITYLENOL®ColdMulti-SymptomNighttime/RapidReleaseGelcaps2,372,472cartonsIMPs/DPs;thelevelofchlorpheniramineammonioacetate(CPAA)wasslightlyhigherthanexpectedinsomeTYLENOL®ColdMulti-SymptomNighttimeRapidReleaseGelcaps.II药品原料、产品杂质限度有关规定ImpurityThresholdinNewAPI&DPThresholdforDegradationProductsinNewDrugProducts(ICHQ3B)MaxDailyDoseReportingThresholdIdentificationThresholdQualificationThreshold≤2g/day0.05%0.10%or1.0mg0.15%or1.0mg2g/day0.03%0.05%0.05%MaximumDailyDoseThreshold≤1g0.10%1g0.05%MaximumDailyDoseThreshold1mg1.0%or5μgTDI1mg-10mg0.5%or20μgTDI10mg-2g0.2%or2mgTDI2g0.10%MaximumDailyDoseThreshold10mg1.0%or50μgTDI10mg-100mg0.5%or200μgTDI100mg-2g0.2%or3mgTD2g0.15%ReportingThresholdsIdentificati