Contaminação de medicamentos por N-nitrosaminas: bases regulatórias para controle

Abstract

N-nitrosamines are impurities that have an aliphatic N-nitroso chemical group of chemical structure R2N–N=O. These impurities are formed from the reaction of amines, amides or amino derivatives with nitrosating agents. In face of carcinogenicity risk due to long-term exposure promoted by this type of impurity, it is essential to control the formation of these impurities at all stages of the drug manufacturing process. Consequently, regulatory agencies around the world, such as ANVISA and FDA, have established protocols for risk assessment of N-nitrosamines, in order to determine the possibility of formation of N-nitrosamines in the API synthesis process, observing factors such as the combination of reagents, solvents, and starting materials used, the intermediates formed, the possible impurities and degradation products. Other steps involved in risk assessment are associated with the manufacturing process of the finished product, compatibility with excipients, storage throughout its useful life and possible degradation or interaction with excipients and packaging material. In this context, the present manuscript presents a systematic review for (1) risk assessment; (2) confirmatory tests; and (3) post-registration changes associated with the formation of N- nitrosamines in medications. In parallel, criteria for toxicological evaluation of N- nitrosamines with unknown mutagenic potential were also established.