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Master's Dissertation
Full name
Fernanda Waechter
Knowledge Area
Date of Defense
São Paulo, 2021
Nascimento, Elizabeth de Souza (President)
Barros, Silvia Berlanga de Moraes
Bercu, Joel Paul
Rodrigues, Maria Augusta Carvalho
Title in English
Risk assessment of potentially mutagenic impurities in anti-hypertensive drug products approved in Brazil
Keywords in English
in silico toxicological assays
Pharmaceutical impurities
Abstract in English
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.
Title in Portuguese
Avaliação do risco de impurezas potencialmente mutagênicas em medicamentos anti-hipertensivos registrados no Brasil
Keywords in Portuguese
Ensaios toxicológicos in silico
Impurezas farmacêuticas
Abstract in Portuguese
A presença de impurezas em medicamentos tem sido controlada conforme guias internacionais no Brasil e ao redor do mundo. Impurezas com potencial mutagênico tendem a apresentar uma maior toxicidade e consequentemente limites mais baixos do que os aplicados às demais impurezas. O guia internacional para controle de impurezas mutagênicas (ICH M7) não é aplicável a medicamentos já aprovados. Porém, recentemente algumas impurezas mutagênicas foram encontradas acima dos limites permitidos na valsartana, losartana, ranitidina, e outros medicamentos que já eram aprovados por agências reguladoras. O objetivo desse trabalho é identificar as possíveis impurezas mutagênicas em medicamentos anti-hipertensivos aprovados no Brasil e realizar a avaliação do risco propondo estratégias de controle para tais impurezas. As possíveis impurezas em cada fármaco foram identificadas com base no arquivo mestre do fármaco, um documento no qual o fabricante descreve o processo de fabricação e as impurezas potenciais do fármaco. Visando prever a mutagenicidade das impurezas, sistemas in silico foram utilizados, e para um caso inconclusivo o teste de Ames foi realizado. Para avaliar os níveis das impurezas no fármaco, foram utilizadas tanto ferramentas in silico (fator de purga), como métodos analíticos validados. Um total de 15 fármacos foi avaliado, e 262 impurezas foram identificadas. Os resultados mostram que 22% dessas impurezas são potencialmente mutagênicas, porém, com exceção das impurezas farmacopeicas, em todos os casos os níveis encontrados são inferiores aos limites aceitáveis. Isso sugere que apesar de haver a presença de impurezas mutagênicas em baixos níveis nos fármacos, os processos de fabricação atualmente utilizados parecem ser adequados para manter o risco negligenciável. É necessário estabelecer estratégias de controle que garantam que os níveis das impurezas mutagênicas permanecerão abaixo dos limites aceitáveis em todos os lotes produzidos. Além disso, recomenda-se a avaliação do potencial mutagênico de impurezas descritas em monografias farmacopeicas, a fim de definir se existe a necessidade de restrição dos limites.
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