At its 174th session in November 2022, the European Pharmacopoeia (Ph. Eur.) Commission adopted the revised general monographs Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619), which now include a paragraph explaining the Ph. Eur. approach to N-nitrosamine impurities. This approach was defined based on the comments received during the last round of public consultation in Pharmeuropa together with recent feedback from Heads of Medicines Agency¹ and European Medicines Agency² 

groups and from the national competent authorities of non-EU Ph. Eur. member states.

The following paragraph has been added to 2034 under “Production”:

“N-Nitrosamines. As many N-nitrosamines are classified as probable human carcinogens, manufacturers of active substances for human use are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and during storage. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy should be implemented to detect and control these impurities. General chapter 2.5.42 N-Nitrosamines in active substances is available to assist manufacturers.”

A similar paragraph has been added to the same section in 2619:

“N-Nitrosamines. As many N-nitrosamines are classified as probable human carcinogens, manufacturers of medicinal products, except products for veterinary use only and unlicensed pharmaceutical preparations, are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and throughout their shelf-life, according to the requirements of the relevant competent authorities. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy must be implemented to detect and control these impurities. General chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.”

The revised monographs will be published in Ph. Eur. Supplement 11.3 and implemented as from 1 January 2024. The Ph. Eur. Commission will now start reflecting on how to address the issue of nitrosamine control in individual monographs.

See also:

• N-nitrosamine contamination in brief
• European Pharmacopoeia Commission
• European Pharmacopoeia 11th Edition