【作者】 周婷；

【导师】 曾苏；

【作者基本信息】 浙江大学 ， 药学， 2018， 硕士

【摘要】 原料药的起始物料(API Starting Material)是欧美日等ICH国家提出的针对原料药合成工艺和药品生产管理规范(GMP)的起点,在ICHQ11中关于起始物料的选择和确定有明确的基本原则。国家食品药品监督管理局于2005年首次提出起始物料的基本要求,适用于药品研发和生产注册申请的资料要求,但法规对于起始物料的选择和界定不够明确,在实际药品注册中存在一定混淆和争议。本论文首先总结和分析人用药物注册技术要求国际协调会议(ICH)关于起始物料选择的要求和实施案例。然后结合起始物料选择应用于药品注册的实践,通过对比国内外对起始物料细节的要求,剖析国内企业进行原料药研发和注册过程中起始物料选择的模式和遇到的问题。最后针对目前国内法规要求及其实践中存在的问题,对进一步改进我国起始物料选择确认和原料药开发关注的内容进行了探讨,建议完善法规指南,参考ICH进行注册申报,更好地与国际注册接轨。总之,本论文以ICH Q11对于原料药起始物料选择的原则为切入点,详细分析了现行合成原料药起始物料选择在国内外药品注册中的实践情况,研究了国际药品申报过程中出现的问题和解决方案,运用QbD理念和风险评估理论,初步建立了风险评估策略,用于评判起始物料选择的合理性,并提出了我国与国际接轨的改进建议。上述研究结果可为提高我国原料药生产工艺开发研究水平和注册申报审评的技术要求提供参考,使药品申报企业和管理者深入理解原料药生产工艺起始物料的研究内容和技术要求,有利于推进我国原料药开发和起始物料确定按ICH国际要求进行国内外同步注册,促进产品生命周期的管理,提升我国药品开发和研究的整体质量。更多还原

【Abstract】 As proposed by ICH countries in Europe,the United States and Japan,an active pharmaceutical integrant(API)starting material is the starting point of API synthesis.The ICH Q11 defines the general principles of the definition and selection of starting materials,from both technology and good manufacturing practices(GMP).The China Food and Drug Administration(CFDA)has issued the general principles about starting material in 2005,which provides the guidance to pharmaceutical development and data collection required for regulatory submission.Nevertheless,this guidance apparently has not yet clearly defined the criteria of selecting starting materials and not clearly set a standard of defining the starting point,that could cause some confusion in development and negatively affecting the quality of submission.First of all,this paper investigates the ICH requirements and studies cases study of starting material selection.Then combining with the starting material selection applied in the practice of the drug application,this paper compares different requirements for starting materials based on regulations in China and ICH,analyzes the model and problems occurred from drug substance development and registration for Chinese enterprises.Finally,aiming to the problems existed in the domestic regulations,this paper discusses how to improve the starting material selection&definition and drug substance development focus,also suggests completing domestic relevant guidelines to match the international registration requirement,and introduce ICH reference in regulatory submission.In conclusion,from the ICH Q11 general principles,this paper investigates the practice of current starting material selection for synthetic drug substance based on the regulatory submission for China and overseas,deficiencies cited from the reviewers and responses are also reviewed.This paper applies the QbD concept and risk assessment theory and preliminarily establishes a risk assessment strategy to evaluate the suitability of starting material selection,and proposes suggestions of compliance with the international standards.The research results could raise the level of API production process development research in China,and provide reference to improve the technical requirements of regulatory submission and review.This paper helps drug enterprises and managers better understand the research content and technical requirements for the starting material in drug substance manufacturing.It is beneficial to register drugs in domestic and overseas market synchronically according to the ICH concept of drug substance development and starting material selection,improve product lifecycle management and the overall quality of the pharmaceutical research in China.更多还原