N-nitrosamine contamination in drugs: European Pharmacopoieia review and practical applications

N-nitrosamines are organic compounds that are possibly carcinogenic to humans. They are contained in some foods, in drink water supplies, and some classes of drugs. As of 2019, several EMA and AIFA guidelines have stressed that prolonged exposure above specific levels of N-nitrosamines increases the risk of cancer in humans, urgently requiring an accurate review of medicinal products to all MA holders of drugs containing chemical or biological active pharmaceutical ingredients (APIs), in order to prevent and contain N-nitrosamines content.

The determination of the potential risk of N-nitrosamine formation/contamination is possible thanks to the support of the European Pharmacopoeia, that is continuously updated by EMA guidelines. The impurity control can be carried out consulting the monographs of the individual substances, the general monographs (e.g. “Substances for pharmaceutical use”, 2034;Pharmaceutical preparations”, 2619), the general chapters and texts (e.g. “Control of impurities in substances for pharmaceutical use”, 5.10), defining the structures at risk of being classified as “mutagenic impurities”, that may cause tumours, and the appropriate specifications to be implemented in case of formation of such substances.

Risk management of mutagenic impurities, such as N-nitrosamines can be planned as follows:

  • according to the EMA principles of the International Council on Harmonisation (ICH) M7 for the assessment and control of DNA-reactive species;
  • according to Art. 5(3) of the Referral on N-nitrosamines, published by EMA following the initial identification of these impurities in the pharmaceutical class of sartans in 2018.

The review of the content of medicinal products has allowed a significant updating of sartan monographs as well as of the sections on analytical testing and manufacturing, then implemented with the addition of a new general chapter named “2.5.42, N-Nitrosamines in active substances”; consequently, a change was determined in the approach required to control and manufacture medicinal products.

So far, in order to define an N-nitrosamine contamination risk as non-existent, the content of these impurities in drugs (for a single N-nitrosamine or as a sum of N-nitrosamines) should be ≤ 10% of the acceptability limit (Acceptable Intake, AI) calculated for the concerned API.

MA holders are called to demonstrate their awareness of the risks of N-nitrosamines in drugs, by defining and reporting – in the Certificates of Conformity of the European Pharmacopoeia – the limits within which N-nitrosamine impurities can be tolerated in order to minimise any potential tumour formation. In the definition of these limits, it is also important that CEPs report the minimum values for which such impurities are detected, and justify if and why it is not possible to provide a classification of the risk and/or threshold values (e.g. method-related technical limitations, values that are too small to be measured, etc. )

National authorities have not yet established which are the cases where the omission of N-nitrosamine detecting testing can be justified, therefore a review of analytical and manufacturing methods is highly recommended so that any potential presence of these impurities can be verified.

In the case a risk of N-nitrosamine formation/contamination is detected, it could be necessary to change some aspects of the drug manufacturing. If this change does not affect the quality profile of the finished product (e.g. no addition of further solvents to be reported in the CEP), but it only decreases the risk of N-nitrosamine presence, it will be considered as a method replacement. Differently, for manufacturing process changes affecting the finished product (such as the case of use of substitute solvents), it will be required to submit a separate “sister file” to the EDQM for transparency, traceability and management of the substance life-cycle.

Much information was learnt in the last two years, following the review of medicinal products to exclude the presence of N-nitrosamines, or to contain at least the threat of these mutagenic impurities, potentially causing tumours.

For any further information, latest updated reference can be consulted at: Q&As sui prodotti medicinali del 26/02/2021; Q&As sui sartani del 05/03/2021.

Written by: Valeria Cardinale