A carregar...
Publicação
Impacto de impurezas genotóxicas na indústria farmacêutica
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 912.3 KB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
A maioria dos fármacos resulta de processos de síntese que envolvem um conjunto complexo de reações químicas, recorrendo-se muitas vezes a reagentes altamente reativos. Como resultado desses processos surgem impurezas, incluindo as Impurezas Genotóxicas (IG), que, mesmo em níveis residuais, podem prejudicar a segurança e efetividade dos fármacos.
As IG, dividindo-se entre mutagénicas e cancerígenas, podem originar graves problemas de segurança, concentrando em si uma grande preocupação por parte da Indústria Farmacêutica. Todo o sector desenvolveu esforços no sentido de otimizar o processo de controlo das mesmas, tentando ao máximo mitigar os seus possíveis efeitos.
Várias normas têm sido publicadas sobre esta temática, culminando na publicação da guideline ICH M7(R1), intitulada “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potencial Carcinogenic Risk”. Esta norma, amplamente citada e analisada na presente revisão, surgiu no sentido de harmonizar os conceitos abordados nos restantes documentos disponíveis e fazer face a diversas questões levantadas na abordagem adequada a estas impurezas. Para além das orientações presentes no documento referido, a guideline ICH S2(R1) caracteriza a bateria de ensaios de curto-termo que devem ser realizados no sentido de se avaliar a genotoxicidade dos compostos e predizer potenciais riscos para a saúde humana.
Um dos maiores desafios para a Indústria Farmacêutica reside no desenvolvimento e implementação de metodologias com um grau de sensibilidade e de especificidade adequado para a quantificação das IG, devendo, idealmente, permitir limites de deteção na ordem de 1 a 5 ppm. Neste contexto, diversas metodologias analíticas baseadas na Espetrometria de Massa têm sido utilizadas.
Em resumo, é inequívoco afirmar que as IG trouxeram novos desafios, por vezes de grande complexidade, para a Indústria Farmacêutica, destacando-se a necessidade de existir um equilíbrio entre as exigências regulamentares e o impacto das mesmas no tempo e custo de desenvolvimento dos novos fármacos.
The majority of drugs result from synthesis routes that involve a complex set of reactions, often using highly reactive reagents. As a result of those routes, impuritites can emerge, including Genotoxic Impurities (GI), that, even in residual quantities, can affect the satety and efficiency of drugs. GI, that can be divided into mutagenic and carcinogenic, can cause severe safety problems, being a major concern for the Pharmaceutical Industry. Therefore, the entire sector has made efforts to optimize their control process, trying as much as possible to mitigate GI’s possible effects. Several guidelines have been published on this subject, culminating with the publication of the ICH Guideline M7(R1), entitled ““Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potencial Carcinogenic Risk”. This guideline, widely quoted and analyzed in this review, appeared in order to harmonize the concepts adressed in the remaining documents and cope with several issues raised about the appropriate approach to these impurities. In addition to the general orientations in the mentioned document, the ICH Guideline S2(R1) caractherizes the amount of short-term tests that must be performed in order to assess the genotoxicity of the compounds and predict potencial risks to human health. One of the biggest challenges for the Pharmaceutical Industry lies in the development and implementation of methodologies that have an adequate level of sensitivity and specificity for the quantification of GI, ideally allowing detection limits in the scale of 1 to 5 ppm. In this context, several analytical methodologies based on Mass Spectrometry have been used. Concluding, it is unequivocal to say that GI brought new challenges, sometimes of great complexity, for the Pharmaceutical Industry, emphasising the need for a balance between regulatory demands and their impact on the time and costs required to develop new drugs.
The majority of drugs result from synthesis routes that involve a complex set of reactions, often using highly reactive reagents. As a result of those routes, impuritites can emerge, including Genotoxic Impurities (GI), that, even in residual quantities, can affect the satety and efficiency of drugs. GI, that can be divided into mutagenic and carcinogenic, can cause severe safety problems, being a major concern for the Pharmaceutical Industry. Therefore, the entire sector has made efforts to optimize their control process, trying as much as possible to mitigate GI’s possible effects. Several guidelines have been published on this subject, culminating with the publication of the ICH Guideline M7(R1), entitled ““Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potencial Carcinogenic Risk”. This guideline, widely quoted and analyzed in this review, appeared in order to harmonize the concepts adressed in the remaining documents and cope with several issues raised about the appropriate approach to these impurities. In addition to the general orientations in the mentioned document, the ICH Guideline S2(R1) caractherizes the amount of short-term tests that must be performed in order to assess the genotoxicity of the compounds and predict potencial risks to human health. One of the biggest challenges for the Pharmaceutical Industry lies in the development and implementation of methodologies that have an adequate level of sensitivity and specificity for the quantification of GI, ideally allowing detection limits in the scale of 1 to 5 ppm. In this context, several analytical methodologies based on Mass Spectrometry have been used. Concluding, it is unequivocal to say that GI brought new challenges, sometimes of great complexity, for the Pharmaceutical Industry, emphasising the need for a balance between regulatory demands and their impact on the time and costs required to develop new drugs.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Impurezas genotóxicas Normas ICH Processo sintético Estratégias de controlo Monotorização Mestrado integrado - 2020