Marketing authorisation holders (MAHs) currently need to test all chemically synthesised medicinal products for nitrosamine contamination. This requirement extends to innovative products, generics and over-the-counter (OTC) products alike. The EMA recently released a list of potential sources of nitrosamine impurities that can help MAHs to identify risks in the manufacturing process.
As we previously reported, MAHs have only six months to perform individual risk assessments for N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) contamination for all of their medicinal products. We therefore welcome the EMA’s efforts to publish and regularly update a list of potential contamination sources in its Q&A on ‘Information on nitrosamines for marketing authorisation holders’. [Update 28.10.2019] The CMDh provides a "practical guide" as well as templates for reporting nitrosamines for national and DCP/MRP marketing authorisations. [Update ends]
Potential sources of nitrosamine impurities, according to the EMA:
- Use of sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts within the same or different process steps (if carry over can occur).
- Use of sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines, within the same or different process steps (if carry over can occur).
- Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts).
- Use of recovered materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment.
- Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials which may allow nitrosamine formation.
- Cross-contaminations due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
- Degradation processes of starting materials, intermediates and drug substances, including those induced by inherent reactivity in combination with carry-over of sodium nitrite (NaNO2), or other nitrosating agents. This could potentially occur also during finished product formulation or storage.
- Use of certain packaging materials. Nitrosamine contamination has been observed by one MAH in a finished product stored in blister. The MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions.
Only six months left for the risk assessment of all medicinal products
The result of the risk assessment will decide whether additional steps are necessary: intensified GMP audits of the supply chain, adaptations to laboratory analyses or even changes to the production process, including the related regulatory consequences. Do you want to find out more? Contact us!