[co-author: Eftychia Sideri]

The European Medicines Agency (“EMA”) has released a reflexion paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances. The reflexion paper provides clarification with respect to Section 5 of ICH guideline Q11 on Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). This Section 5 provides the information that should be submitted in marketing authorisation applications to justify the selection of starting materials.

EMA’s reflexion paper aims to expand some of the points of Section 5 of ICH Q11 in order to harmonise opinions between assessors and clarify the requirements for applicants. EMA also recognises that the information submitted by applicants or Active Substance Master File (ASMF) holders to justify the selection of starting materials is often insufficient to allow adequate assessment of suitability. According to EMA, the description of the manufacturing process should be sufficiently detailed to demonstrate that the process and its associated control strategy will consistently provide active substance of satisfactory quality. 

The reflexion paper recalls that, in relation to synthetic drug substances, a sufficient number of chemical transformation steps, as defined in the glossary of ICH Q11 need to be included so that the generation, fate and control of impurities can be understood. According to EMA, short synthetic routes will not normally be accepted. The detailed description of the manufacturing process should cover all the synthetic steps critical to the quality of the active substance.

The reflexion paper defines a “critical step” as one where the process conditions, test requirements or other relevant parameters must be controlled within pre-determined limits to ensure that the active substance meets its specification.

In addition, the reflexion paper underlines that the term “significant structural fragment” is frequently misinterpreted by applicants as meaning structural proximity to the active substance. However, EMA explains, that the phrase applies to materials which contribute to the final molecular structure of the active substance, as opposed to reagents, catalysts, or solvents.

EMA’s reflexion paper also provides explanatory notes on the content of information of starting materials that applicants should submit as well as explanatory notes on the content of justification of starting materials.

EMA highlights that this reflexion paper is not intended as a revision of ICH Q11.