The designation and justification of active pharmaceutical ingredient starting materials (API SMs) is a crucial aspect of the drug substance (DS) commercialization process. Over the past decade, significant efforts have been made by both the pharmaceutical industry and regulatory authorities to clarify and harmonize requirements for API SM selection and justification, including the introduction of the ICH Q11 guideline in 2011 and the Q&A document to Q11 in 2017. In 2018, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) established the API SM Working Group to evaluate the impact of the ICH Q11 Q&A on API SM selection and approval, as well as cross-regulatory alignment. The API SM Working Group collected metrics from 19 IQ member companies on drug substances marketing applications submitted since 2014, including the associated API SM selection, justification, and associated ICH regulatory approval experiences. Data representing a total of 115 API SMs used to manufacture 38 new chemical entities were obtained. The outcomes of API SM proposals in initial marketing applications across ICH countries and regions prior to and following the publication of the ICH Q11 Q&A document are presented. The data showed significant differences in acceptance rates of API SM proposals across ICH regulatory agencies, with the highest proportion of API SMs being rejected by the European Medicines Agency (EMA). The data also revealed a higher proportion of rejections for API SMs that contain impurities impacting the DS quality and when a lower number of solid isolations exist between the point of introduction of the API SM and the DS. Feedback received from health authorities during development phases prior to marketing application submissions generally aided sponsor companies in their strategic approach to API SM designation and resulted in improved overall acceptance rates of API SMs in marketing applications. The data indicated that subjectivity and variability of the interpretation of guidelines persists and that greater alignment among ICH health authorities is still needed to achieve a single, global API SM designation approach and facilitate the timely delivery and continued global supply of innovative medicines to patients through a unified supply chain.

中文翻译：

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ICH Q11 问答对 ICH 监管成员接受活性药物成分原料提案结果的影响

活性药物成分起始原料 (API SM) 的指定和合理性是原料药 (DS) 商业化过程的一个重要方面。在过去的十年中，制药行业和监管机构都做出了重大努力，以澄清和统一 API SM 选择和论证的要求，包括 2011 年推出 ICH Q11 指南和 2017 年 Q11 的问答文件。 2018年，国际药物开发创新与质量联盟（IQ联盟或IQ）成立了API SM工作组，以评估ICH Q11问答对API SM选择和批准以及跨监管协调的影响。 API SM 工作组收集了 19 家 IQ 成员公司自 2014 年以来提交的原料药营销申请的指标，包括相关的 API SM 选择、理由和相关的 ICH 监管审批经验。获得了代表用于制造 38 种新化学实体的总共 115 个 API SM 的数据。介绍了 ICH Q11 问答文件发布之前和之后 API SM 提案在 ICH 国家和地区的初始营销应用中的结果。数据显示，ICH 监管机构对 API SM 提案的接受率存在显着差异，其中被欧洲药品管理局 (EMA) 拒绝的 API SM 比例最高。数据还显示，当 API SM 和 DS 的引入点之间存在较少数量的固体隔离时，含有影响 DS 质量的杂质的 API SM 的报废比例较高。在提交营销申请之前的开发阶段，从卫生当局收到的反馈通常有助于申办公司制定 API SM 指定的战略方法，并提高营销申请中 API SM 的总体接受率。数据表明，指南解释的主观性和可变性仍然存在，ICH 卫生当局仍需要加强协调，以实现单一的全球 API SM 指定方法，并通过统一供应链。