RESUMO
Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.
Assuntos
Anti-Hipertensivos , Contaminação de Medicamentos , Mutagênicos , Brasil , Medição de Risco , Anti-Hipertensivos/toxicidade , Mutagênicos/toxicidade , Mutagênicos/análise , Estudos Retrospectivos , Humanos , Guias como AssuntoRESUMO
The objective of this study was to verify the possible inclusion of the Salmonella/microsome mutagenicity assay in a groundwater monitoring program as a complementary assay to assess water quality. Groundwater samples belonging to seven wells from different types of aquifers were analyzed. Three different methods for sample preparation were used: membrane filtration; liquid-liquid and XAD-4 extraction. The filtered samples were tested using TA98, TA100, YG1041 and YG1042 and the water extracts only with TA98 and TA100. No mutagenic activity was observed in any of the 16 filtered samples tested. Out of the 10 samples analyzed using XAD-4 extraction, five showed mutagenic activity with potency ranging from 130 to 1500 revertants/L. Concerning the liquid-liquid extraction, from the 11 samples analyzed, 3 showed mutagenicity. The XAD-4 extraction was the most suitable sample preparation. TA98 without S9 was found to be the most sensitive testing condition. The wells presenting water samples with mutagenic activity belonged to unconfined aquifers, which are more vulnerable to contamination. The data suggest that Salmonella/microsome assay can be used as an efficient screening tool to monitor groundwater for mutagenic activity.
Assuntos
Monitoramento Ambiental/métodos , Água Doce/análise , Microssomos Hepáticos/metabolismo , Salmonella typhimurium/genética , Animais , Brasil , Geografia , Microssomos Hepáticos/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Ratos , Reprodutibilidade dos Testes , Salmonella typhimurium/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Purificação da Água/métodos , Purificação da Água/normasRESUMO
Urinary 2,5-hexanedione (2,5-HD) is used as a biomarker for biological monitoring of workers exposed to n-hexane. The purpose of this study was to compare two types of treatment of urine samples during clean-up (with and without acidic hydrolysis) and to study the exposure situation of workers exposed to n-hexane during shoe manufacturing. There, various glues containing n-hexane are used. Quantification of 2,5-HD was carried out by gas chromatography and flame ionization detection (GC-FID). Fifty-two urine samples taken from workers of seven shoe factories were analyzed. Thirty-four persons from the administrative staff of the same factories served as controls. They were not known to be exposed to n-hexane. The samples treated with acidic hydrolysis showed levels (average 0.94 mg/l) approximately 10 times higher than samples without acidic hydrolysis (0.09 mg/l). The difference is predominantly caused by the conversion of other metabolites of n-hexane (e.g. 4,5-dihydroxy-2-hexanone) to 2,5-HD in the presence of acids. Our results also show, that exposure to n-hexane is different between various industries. Levels of 2,5-HD in urine are predominantly dependent on the type of operation (how the glue is applied on the leather during shoe manufacturing). Simple measures, e.g. using a glue handgun instead of a paintbrush significantly decreased exposure to n-hexane.