Impact of ICH Q11 Questions and Answers on the Outcome of Active Pharmaceutical Ingredient Starting Material Proposal Acceptance by ICH Regulatory Members

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.