Risk assessment of potentially mutagenic impurities in anti-hypertensive drug products approved in Brazil

• Ano de defesa: 2021
• Autor(a) principal: Waechter, Fernanda
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Ensaios toxicológicos in silico; ICH M7; Impurezas farmacêuticas; in silico toxicological assays; Mutagenicidade; Mutagenicity; Pharmaceutical impurities
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/9/9143/tde-05082021-111631/

The presence of impurities in drug products has been controlled according to international guidelines in Brazil and the entire world. Impurities with mutagenic potential tend to show a greater toxicity and consequently need to be controlled to lower limits than the other regular impurities. The international guideline for control of mutagenic impurities (ICH M7) is not applicable for drug products which are already approved. However, some mutagenic impurities have recently been found above the permitted limits in valsartan, losartan, ranitidine, and other drug products which were already approved by regulatory agencies. The objective of this project is to identify the possible mutagenic impurities in anti-hypertensive drugs approved in Brazil and perform the risk assessment proposing control strategies for such impurities. The possible impurities in each drug substance were identified based on the drug master file, a document where the manufacturer describes the manufacturing process and potential impurities of the drug substance. For the mutagenicity prediction of the impurities, in silico systems were used, and in one inconclusive case the Ames test was performed. For evaluation of the levels of the impurities in the drug substance, in silico tools such as the purge factor approach, as well as validated analytical procedures were used. A total of 15 drug substances was evaluated, and 262 impurities were identified. The results show that 22% of these impurities are potentially mutagenic, however all of them, except for impurities described in a pharmacopoeial monograph, are below the acceptable limits. This suggests that although mutagenic impurities are present at low levels in drug substances, the current manufacturing processes seem to be adequate to keep the negligible risk. Nonetheless, there is an evident need to establish control strategies which ensure the levels of mutagenic impurities are below the acceptable limits throughout all manufactured batches. Moreover, it is recommended to evaluate the potential mutagenicity of impurities described in pharmacopoeial monographs, understanding whether there is a need to tighten limits.