Are nitrosamines still a concern for a drug product?
In June 2018 it was recognized that some active substances used in manufacturing of medicinal product contained undesired levels of potentially carcinogenic nitrosamine impurities (e.g. NDMA, NDEA). Immediately afterwards, EU regulators started to establish ways of minimizing that risk. As a result, MAHs were requested to review their manufacturing process and evaluate the risk of the presence and possible sources and formation of nitrosamine impurities in their medicinal products (CHMP opinion under Article 5 (3) of Regulation (EC) No. 726/2004). From that point onwards, MAH should subsequently inform the competent authorities about the outcome of such risk assessment. Depending on the outcome, if the presence of impurity is indeed of a concern, further steps, such as confirmatory testing or even changes in the manufacturing process and subsequent post-approval variations, may be required.
IS YOUR DEADLINE DUE? CHEMICAL, BIOLOGICAL OR NEW APPLICATIONS.
WHAT ARE NITROSAMINES AT ALL?
WHAT TRIGGERS NITROSAMINES FORMATION?
- primary, secondary and tertiary amines (aliphatic or aromatic);
- 4th order ammonium salts;
- drugs with amino groups (eg. penicillin, ephedrine, promethazine);
- compounds containing groups with a nitrogen atom (III).
The kinetics of the nitrosamine formation reaction is influenced by:
- concentration of substrates (especially the presence of "nitro" species);
- basicity of the amine (the higher the pKb, the more basic the amine);
- pH of the environment (acidic pH, typical pH 3.3);
- temperature (in general, its increase increases the concentration of the product);
- presence of reaction catalysts, eg. formaldehyde, nitrogen oxides or thiocyanates
BRIEF GUIDE THROUGH RISK ASSESSMENT
- Highlighting the stages, where amines or nitrite agents are used or demonstrating its lack.
- Analyzing raw materials used, like quaternary ammonium salts.
- Taking into account and reviewing any catalysts used.
- Demonstrating presence or lack of nitrogen-based impurities.
- Considering purification methods in relation to their the potential (or real) effectiveness in nitrosamine impurity removal (compare with ).