New EMA's Reflection Paper on API Starting Materials

Recommendation

22/23 February 2024
Munich, Germany

API Regulatory Starting Materials
Definition, Manufacture, Assessment and handling post-approval Changes

According to the Guideline ICH Q11 "Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities", the chemical substance must be defined in the early drug product development phase  which is used as the starting material for the manufacture of the API. This "Starting Material" marks the point in the route of synthesis where GMP conditions have to be applied. According to ICH Q11, the criterion for the definition of a starting material is its molecular structure and it should already contain a significant structural element of the subsequent API. Yet, the further statements in Chapter 5 of the ICH Q11 Guideline on starting materials aren't so straightforward and have led to misunderstandings and misinterpretations in the months following the publication of the guideline. Disagreements between applicants and the assessors of the regulatory authorities processing the applications are rather almost the rule.

This situation drove the EMA to release a document entitled "Reflection paper in the requirements for selection and justification of starting materials for the manufature of chemical active substances". The paper was published on 10 October 2014 on the website of the Agency and aims to clarify the selection of starting materials for synthetic and semi-synthetic APIs as well as the justification of such a selection. Within in total 11 so-called "explanatory notes" the Agency presents its expectations from the applicants regarding the information about an API starting material in a marketing authorisation application. Find below some examples:

• The route of synthesis indicated should include so many synthesis steps to clearly and unambiguously follow the formation of the efficient principle of the API. Short synthetic routes related to the argument that the efficient structural element in the molecule is already available won't normally be accepted.
• A detailed description is required of how the quality-relevant synthesis steps are controlled.
• All the principles described for synthetic starting materials also apply to semi-synthetic starting materials.
• Changes to the synthetic route should always be assessed for their impact on the quality of the active substance.
• A statement that a starting material is commercially available isn't sufficient to justify its selection.

The future will show to what extent EMA's document contributes to the clarification of misunderstandings between applicants and regulatory authorities.

Note: At the 17th APIC Conference on 5 - 7 November 2014 in Vienna, Austria, you will get first-hand information on the topic from an EMA representative.