Impurezas de nitrosaminas em medicamentos: um panorama geral

Abstract

In 2018, medicines containing valsartan were reviewed due to contamination by an impurity called NDMA, which belongs to the class of nitrosamines known for their carcinogenic potential. This study aims to understand the risks associated with the presence of nitrosamines in medications, including their chemical and toxicological aspects. A documentary analysis was conducted on regulatory authority websites and scientific databases. The presence of impurities in medications affects their safety, quality, and efficacy. In order to harmonize regulations and promote a global standard of quality, the ICH was established in 1990, and since then, several guidelines for the evaluation and control of impurities have been developed. Nitrosamines are highly potent mutagenic impurities and are described as part of the "concern group" in the ICH M7 guideline. Due to their mutagenic potential, the TTC limits are not applicable to compounds belonging to this group. An in vitro mutagenicity test, the bacterial reverse mutation test, may be necessary to determine the mutagenic potential and the control strategy to be adopted for these compounds. Nitrosamines are a class of compounds characterized by a nitroso group linked to an amino functional group. Their genotoxicity depends on metabolic activation, which occurs via alpha-hydroxylation by cytochrome P450-dependent enzymes, generating highly reactive carbocations or diazonium compounds capable of alkylating cellular macromolecules such as DNA, RNA, and chromosomes. Nitrosamines are formed through a N-N bond known as Nnitrosation, where a nitroso functional group is introduced into a molecule containing NH (e.g., amines) by a nitrosating agent under specific reaction conditions. The formation of nitrosamines can occur from various sources, such as during the synthesis of the active pharmaceutical ingredient (e.g., valsartan), drug-excipient interactions (e.g., metformin), or due to drug instability (e.g., ranitidine). Therefore, a detailed risk assessment is necessary, considering the entire process from the synthesis of the active pharmaceutical ingredient to the production of the finished product, in order to establish acceptable limits and develop control strategies for these impurities, which represent a public health issue.