New EMA and FDA guidance

EMA has published a draft of the new Guideline on the chemistry of active substances (EMA/321776/2024). You can find it under the link https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-chemistry-active-substances-revision-1_en.pdf

The new guidance replaces "Note for guidance on 52 chemistry of new active substances" (CPMP/QWP/130/96, Rev 1) and "Chemistry of active substances' (3AQ5a)". The aim of the new guideline is to merge both original guidelines into one document.

The requirements listed in the Guideline on the chemistry of active substances also include an assessment of the risks associated with nitrosamines and impurities with a mutagenic effect according to ICH M7 ( Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk ).

A new guidance regarding nitrosamines was also issued in September 2024 by the FDA - Control of Nitrosamine Impurities in Human Drugs Guidance for Industry https://www.fda.gov/media/141720/download . The FDA guidance also makes references to ICH Q7 ( Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients ), ICh Q11 ( Development and Manufacture of Drug Substances ) and ICH M7.

The FDA guidance states that each manufacturer of synthetically produced APIs must evaluate the risks of the possible presence of nitrosamines. If such a risk is identified, the instruction sets out further steps to control the risk. The entire document is quite extensive, it lists the chemical reactions leading to the formation of nitrosamines and the chemical structure of small molecules - potential impurities in API. In the appendix to the instruction, we can also find the procedure for determining the acceptable limit (Acceptable intake limit) and an example of the control and specification of the acceptable intace limit.

The entire evaluation requires a comprehensive approach - from knowledge of the synthetic route, production process, supply chain, analytical methods and toxicological evaluation . Our motto is " to be useful to clients " - so use our experts - we remain available for all the tricky questions.