EMA: Reflection Paper on API Starting Materials
This month the EMA released a “Reflection paper in the requirements for selection and justification of starting materials for the manufacture of chemical active substances”. It aims to clarify some of the expectations of EU competent authorities arising from the guidance found in ICH Q11 regarding the information to be submitted in marketing authorisation dossiers to justify the selection of starting materials.
Disagreements between applicants and quality assessors on the suitability of proposed starting materials have become more frequent in recent times. This suggests that the current guidelines, intentionally high level to allow application to the wide range of chemical syntheses submitted to regulatory authorities, are open to interpretation.
Furthermore, it is increasingly common for applicants to propose very short synthetic routes with complex custom-synthesized starting materials. Another trend is for some, or all, of the active substance manufacture to be outsourced to third parties. The use of external sources for any steps in a manufacturing process may lead to a higher degree of risk to quality of the active substance than would be expected were the full manufacturing process to be carried out by the applicant or a single active substance manufacturer alone.
A set of eleven explanatory notes strives to expand on some of the points in ICH Q11 in order to clarify the requirements for applicants. Some of these include:
The synthesis route indicated should include as many synthesis steps to clearly follow the formation of the efficient principle of the API
Critical steps that have to be carried out under GMP, require an appraisal of the criticality of all transformations in the full synthetic route on the quality of the active substance
Changes to the synthesis route always have to be assessed for quality impact on the API
All principles described for synthetic starting materials also apply to semi-synthetic starting materials
A statement that a starting material is commercially available is not enough to justify its selection.
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