Nitrosamines Regulations

In the EU, guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines are provide by:

1. The EMA review under Article 5(3) of Regulation (EC) No 726/2004 for Nitrosamine Impurities in Human Medicinal Products EMA/369136/2020
2. The implementation plan European Medicines Regulatory Network Approach for the Implementation of the CHMP Opinion Pursuant to Article 5(3) of Regulation (EC) No 726/2004 for Nitrosamine Impurities in Human Medicines EMA/425645/2020 agreed by EMA
3. Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products EMA/409815/2020 Rev.19 which is updated regularly

The CHMP asked marketing authorisation holders to review and assess their manufacturing processes for all drug products containing chemically synthesized or biologically active substances to avoid the presence of nitrosamine impurities in human medicines and test products at risk in a 3 steps procedure:

§  Step 1 − Risk evaluation

Conduct a risk evaluation to identify active substances and finished products at risk of N-nitrosamine formation or (cross-)contamination and report the outcome

§  Step 2 − Confirmatory testing

Perform further confirmatory testing on the products identified to be at risk of N-nitrosamine formation or (cross-)contamination and report confirmed presence of nitrosamines

§  Step 3 − Update marketing authorisations

Apply for any necessary changes to the manufacturing process resulting from this review, by requesting a variation to the marketing authorisation via standard regulatory procedures

EMA has asked the marketing authorization holders and the manufacturer of drug products to consider these three possible sources of nitrosamine impurities:

§  API synthetic route: formation of nitrosamine impurities during the API synthetic process

§  Manufacturing process: formation of nitrosamine impurities during the manufacture of drug products or during shelf life

§  Contamination: formation of nitrosamine impurities due to contamination from equipment degradation, recovered materials such as solvents, reagents, catalysts and intermediates

Companies are required to have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, to improve their manufacturing processes.