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

MingpingZhangVPs Technical CMCJuly. 2024 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DRA CMC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 Zhang MingpingVice President (technical) Parexel InternationalM +86–18911811665Mingping.zhang@Parexel.com CMC in Pharmaceutical Dev. * CSP: CANDIDATE SELECTION POINT (Several Compound)sPoC: SELECTED PROOF OF CONCEPT (One Compound) Key CMC Consideration for Phase I新药Ⅰ期临床试验申请 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。 Q Identified the potential risk in CMC 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。 The difference between the clinical batch and Tox batch should be welljustified PointstoconsiderinCMCReview API Synthesis process(Platform approach accept): organic solvents, toxic reagents, heavy metals, and crude products purification Preliminary quality control strategy of the key materials Key physicochemical properties that may affect the manufacture and quality attributes of drugproduct (limited batch & prior knowledge): Solubility, permeability, crystal form, particle size, hygroscopicity and stereochemical configurationetc Folding, monomer purity, low PRIs and absence of clipping Items related to safety, such as related substances (identified impurities, unknown impurities,potential genotoxic impurities); test item setting & limits justification. Binding assay accept for Mabs (only Phase I in US) Preliminary stability of the API; Cover proposed clinical period (minimum 2 batches: Tox + Clinical) PointstoconsiderinCMCReview Formulation & Manufacture of drug product Special excipient and agent usedSpecial manufacture processes; e.g. sterile assurance of injectionsDifferences andsimilaritiesbetween the tox batch and clinical batch Quality control of drug product Items related to safety, such as impurity profile, Stress test productsDegradation products observed in long-term & accelerated stability studiesItems related to clinical efficacy, such as dissolution/sustained-release,etcanalytical method could be verify (without robustness requirement) Stability (limited batch and extrapolation accept) Storage Stability & in-use stability (minimum 1 pilot + 1 clinical) PointstoconsiderinCMCReview Container Closure System Normally, extractables study can support FIH application for bio Stopper: Compatibility with drugs Silicone oil contamination Glass: only “double I class” was allowed PointstoconsiderinCMCReview Viral Clearance & Validation requirement Platform Validation (PV) could be accepted if*: For monoclonal antibodies, the platform technology defined as the process,which based on the validation research results of 3-5 specific products withsimilar characteristic attributes and similar processes. Virus clearance effect should be used the same detection method with thesame principle (such as cell-based detection or nucleic acid based detection). The operation condition & CPP should be within the platform technologydefine space. In virus filtration validation, parvovirus should be used as the indicator virus atleast once to conduct a validation study of specific products. * NMPA guideline-Technical guidelines for clinical trial application of recombinant protein products forviral clearance process platform validation (Trial) 2024 January Potential Risk forPhase I Application Safety concern may raise because*: Products prepared from unknown or impure components; The chemical structure of the product is known to be toxic or highly likelyto be toxic; During the proposed clinical period, the product may not be stable; The impurity profiles indicate potential toxicity or have not been fullyidentified and evaluated the potential toxicity; micro/viral safety as well; The main cell bank(MCB) or working cell bank(WCB) has not been fullycharacterized; e.g. not enough or right type of virus or mycoplasma testing Reviewer perspective:Common CMC issues in Phase I Application (SM) Limited manufacture process info. provided* complex APIs (such as polypeptides, small molecule nucleic acids, polymer, drugs containingmultiple chiral centers, fermentation processes or natural sources) complex drug products (such as microspheres/microemulsions/liposomes, micelles, transdermal,inhalation, etc.) complex drug delivery routes (such as preparation of suspensions, lotion or gel for topicaladministration through dermatology, ophthalmology and otology, etc.) complex combination of drugs and device Solution:More detailed description of important manufacture steps, equipment, andprocess parameters. For sterile preparations, sterile conditions and sterilization/sterilizationmethods should be provided, and sterile assurance measures should be provided in details. Revi