精鼎法规专家张明平谈创新药全球同步开发时中美欧FIH申报的CMC要求对比前沿创新/法规与上市咨询服务

中美欧FIH申报的CMC要求对比 FIHCMCRequirementsin China/US/EU MingpingZhangVPsTechnicalCMCJuly.2024 ©2024ParexelInternational(MA)Corporation/CONFIDENTIAL ©2024ParexelInternational(MA)Corporation/CONFIDENTIAL ZhangMingping VicePresident(technical) ParexelInternational M+86–18911811665 Mingping.zhang@Parexel.com 张明平 副总裁（技术） •现任精鼎医药研究开发（上海）有限公司咨询部门副总裁 （技术） •曾任苏州瑞博副总经理，负责产品管线管理与法规 •前百济神州CMC高级总监，管理创新药物研发过程中的药学相关事务 •前中国外商投资企业协会药品研制和开发行业委员会 （RDPAC）CMC专业组委员会成员 •前诺华DRACMC高级经理；负责所有与中国申报相关的药 学事务 •前国家药监局药学审评员，曾负责外科，心血管，抗生素等药物的药学审评 •新加坡国立大学化学工程硕士 •北京化工大学生物化学工程学士 GlobalFIHRegulatorySubmissionTimelineComparison July Aug Sept Oct Nov Dec Jan Feb Mar Apr May CMC Non-clinical ProtocolIB Pre-INDmeeting INDPreparation IND/CTASubmissionTechnicalReview ClinicalTrialsMay Begin EUQPisonthecriticalpath USPre-clinicaldocumenttranslationisoncriticalpath China USEU AUS Consistence Quality Sponsor:PhaseAdaptedCMCactivities PhaseIQC HA perspective RiskBenefit PhaseII Quality Consisten ce PhaseIII 4©2024ParexelInternational(MA)Corporation/CONFIDENTIAL4 CMCinPharmaceuticalDev. I CSP*sPoC*Phase PhaseII PhaseIII DiscoveryExploratoryDevelopmentFullDevelopment FrequencyofDrugSubstance/ProductChangesDuringDevelopment ImpactofDrugSubstance/ProductChanges DuringDevelopmentMostoftheCMCdevelopmentshouldbedonebefore PhaseIII *CSP:CANDIDATESELECTIONPOINT(SeveralCompound) sPoC:SELECTEDPROOFOFCONCEPT(OneCompound) KeyCMCConsiderationforPhaseI 新药Ⅰ期临床试验申请 Q 申请人首先应声明原料药或制剂的化学性质或生产过程是否显示出任何潜在的人体风险信号。如果出现上述信号，那么应对这些潜在的风险信号进行讨论，并阐述为监测该风险所计划采取的步骤，或对这个（些）信号不予以考虑的原因进行分析。 IdentifiedthepotentialriskinCMC C 另外，申请人应介绍拟进行临床试验用制剂与动物毒理试验用制剂，在化学和生产方面的任何差异，其将作为申请人对研究药物继续进行人体临床试验安全性结论的基础。如存在差异，则需讨论这些差异可能对制剂安全性方面造成的影响程度。如两种制剂之间无差异，也应进行说明。 ThedifferencebetweentheclinicalbatchandToxbatchshouldbewelljustified PointstoconsiderinCMCReviewQ APISynthesisprocess(Platformapproachaccept): organicsolvents,toxicreagents,heavymetals,andcrudeproductspurification Preliminaryqualitycontrolstrategyofthekeymaterials Keyphysicochemicalpropertiesthatmayaffectthemanufactureandqualityattributesofdrugproduct(limitedbatch&priorknowledge): Solubility,permeability,crystalform,particlesize,hygroscopicityandstereochemicalconfigurationetcFolding,monomerpurity,lowPRIsandabsenceofclipping QualitycontrolofAPI(Platformapproachaccept) Itemsrelatedtosafety,suchasrelatedsubstances(identifiedimpurities,unknownimpurities,potentialgenotoxicimpurities);testitemsetting&limitsjustification. BindingassayacceptforMabs(onlyPhaseIinUS) PreliminarystabilityoftheAPI; Coverproposedclinicalperiod(minimum2batches:Tox+Clinical) Q PointstoconsiderinCMCReview Formulation&Manufactureofdrugproduct Specialexcipientandagentused Specialmanufactureprocesses;e.g.sterileassuranceofinjectionsDifferencesandsimilaritiesbetweenthetoxbatchandclinicalbatch Qualitycontrolofdrugproduct Itemsrelatedtosafety,suchasimpurityprofile,StresstestproductsDegradationproductsobservedinlong-term&acceleratedstabilitystudiesItemsrelatedtoclinicalefficacy,suchasdissolution/sustained-release,etcanalyticalmethodcouldbeverify(withoutrobustnessrequirement) Stability(limitedbatchandextrapolationaccept) StorageStability&in-usestability(minimum1pilot+1clinical) Q PointstoconsiderinCMCReview ContainerClosureSystem Normally,extractablesstudycansupportFIHapplicationforbio Stopper: Compatibilitywithdrugs Theparticleexceedsthestandard,puncturechips Siliconeoilcontamination Glass:only“doubleIclass”wasallowed PointstoconsiderinCMCReviewQ ViralClearance&Validationrequirement PlatformValidation(PV)couldbeacceptedif*: Formonoclonalantibodies,theplatformtechnologydefinedastheprocess,whichbasedonthevalidationresearchresultsof3-5specificproductswithsimilarcharacteristicattributesandsimilarprocesses. Virusclearanceeffectshouldbeusedthesamedetectionmethodwiththe sameprinciple(suchascell-baseddetectionornucleicacidbaseddetection). Theoperationcondition&CPPshouldbewithintheplatformtechnologydefinespace. Invirusfiltrationvalidation,parvovirusshouldbeusedastheindicatorvirusat leastoncetoconductavalidationstudyofspecificproducts. *NMPAguideline-Technicalguidelinesforclinicaltrialapplicationofrecombinantproteinproductsforviralclearanceprocessplatformvalidation(Trial)2024January PotentialRiskforPhaseIApplication Safetyconcernmayraisebecause*: Productspreparedfromunknownorimpurecomponents; Thechemicalstructureoftheproductisknowntobetoxicorhighlylikelytobetoxic; Duringtheproposedclinicalperiod,theproductmaynotbestable; Theimpurityprofilesindicatepotentialtoxicityorhavenotbeenfullyidentifiedandevaluatedthepotentialtoxicity;micro/viralsafetyaswell; Themaincellbank(MCB)orworkingcellbank(WCB)hasnotbeenfully characterized;e.g.notenoughorrighttypeofvirusormycoplasmatesting *《新药I期临床试验申请技术指南》 ©2024ParexelInternational(MA)Corporation/CONFIDENTIAL 11©2024ParexelInternational(MA)Corporation/CONFIDENTIAL Reviewerperspective: CommonCMCissuesinPhaseIApplication(SM) Limitedmanufactureprocessinfo.provided* complexAPIs(suchaspolypeptides,smallmoleculenucleicacids,polymer,