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Continuous development methodologies to enhance pharmaceutical R&D productivity
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A questão da produtividade em investigação e desenvolvimento (I&D) é um assunto de grande debate, principalmente porque um importante resultado destas actividades é intangível. Algo que é transversal a todo o I&D é a incerteza e o risco de falhar, que forçam a que a produtividade seja medida como a média entre o falhanço e o sucesso. Na industria farmacêutica, para ambos os ramos de negócio (inovadores e genéricos), o tempo necessário para chegar ao mercado e o custo em I&D são factores-chave de sucesso, impulsionados grandemente pela produtividade da I&D. Quality by Design (QbD) e produção em contínuo são dois conceitos sobre os quais a FDA expressou o desejo que as empresas construam e apliquem nos seus processos e produtos para melhorar a qualidade, conhecimentos de processo, flexibilidade e robustez na manufactura de produtos farmacêuticos.
Nesta tese, a implementação de química em fluxo e a metodologia de desenvolvimento em contínuo são apresentados através de casos de estudo baseados na pipeline da Hovione em fase de desenvolvimento e comercial. Estes casos de estudo incluem diferentes transformações químicas, tais como N-alquilações, ciclizações intramoleculares, reacções organometálicas e formação de sais para a preparação de ingredientes farmacêuticos activos (trifenatato de vilanterol e brometo de umeclidínio) que envolvem desvantagens, como longo tempo de reacção, reacção em condições criogénicas, reagentes perigosos, intermediários sensíveis, formação de impurezas ou longos tempos de separação e purificação do produto. De modo a entender a mudança de mentalidade entre desenvolvimento de processos em descontinuo e em contínuo, os casos de estudo foram desenvolvimentos e optimizados começando com o procedimento descrito em patentes e considerando as vantagens de operar em modo contínuo. A implementação de química de micro-ondas, tecnologia analítica de processo (PAT), desenho de experiências (DoE) e modelação cinética suportaram a redução do tempo, custo, risco de falha do desenvolvimento, aumentando consequentemente a produtividade e o conhecimento do processo. Os casos de estudo resultaram em maior rendimento, menor tempo de reação, menor preocupação com segurança, em alguns casos maior pureza e menor teor de impurezas. As melhorias no processo através dos casos de estudo mostraram que a produção em contínuo pode ser uma alternativa à produção em descontínuo.
A metodologia desenvolvida demonstrou ser uma nova estratégia que fornece um fluxo de trabalho para desenvolvimento de processos químicos que explora oportunidade de produção em contínuo seguindo o conceito de QbD.
The question of research and development (R&D) productivity is a matter of a great debate, mainly because an important outcome of these activities is intangible. Transversal to all R&D is the uncertainty and risk of failure, which forces the productivity to be measured as an average between failure and success. In the pharmaceutical industry, for both innovator and generic branches of the business, time to market and R&D cost are key success factors, largely driven by R&D productivity. Quality by Design (QbD) and continuous manufacturing are two concepts that FDA expressed desire that companies build in and apply for their processes and products to improve quality, process understanding, flexibility and robustness in the manufacture of pharmaceuticals. In this thesis the implementation of flow chemistry and the continuous development methodology are presented through case studies based on the development and commercial pipeline of Hovione. These case studies include different chemical transformations, such as N-alkylations, intramolecular cyclization, organometallic reaction and salt formation for the preparation of active pharmaceutical ingredients (vilanterol trifenatate and umeclidinium bromide), that involve drawbacks, such as long reaction time, cryogenic reaction conditions, hazardous reagents, sensitive intermediates, impurity formation or time-consuming downstream processing. In order to understand the mindset difference between batch and continuous process development, the case studies were developed and optimized starting from previously described procedure of patents and considering the drivers of operating in continuous mode. The implementation of microwave chemistry, process analytical technology (PAT), Design of Experiments (DoE) and kinetic modelling supported the reduction of development time, cost and risk of failure, therefore increased productivity and process understanding. The case studies resulted in higher yield, shorter reaction time, reduced safety concerns, in some cases higher purity and lower impurity content. The process improvements showcased that continuous manufacturing could be the alternative of traditional batch production. The developed methodology demonstrated to be a novel strategy that provided a workflow for chemical process development exploring the opportunities for continuous manufacturing following the QbD concept.
The question of research and development (R&D) productivity is a matter of a great debate, mainly because an important outcome of these activities is intangible. Transversal to all R&D is the uncertainty and risk of failure, which forces the productivity to be measured as an average between failure and success. In the pharmaceutical industry, for both innovator and generic branches of the business, time to market and R&D cost are key success factors, largely driven by R&D productivity. Quality by Design (QbD) and continuous manufacturing are two concepts that FDA expressed desire that companies build in and apply for their processes and products to improve quality, process understanding, flexibility and robustness in the manufacture of pharmaceuticals. In this thesis the implementation of flow chemistry and the continuous development methodology are presented through case studies based on the development and commercial pipeline of Hovione. These case studies include different chemical transformations, such as N-alkylations, intramolecular cyclization, organometallic reaction and salt formation for the preparation of active pharmaceutical ingredients (vilanterol trifenatate and umeclidinium bromide), that involve drawbacks, such as long reaction time, cryogenic reaction conditions, hazardous reagents, sensitive intermediates, impurity formation or time-consuming downstream processing. In order to understand the mindset difference between batch and continuous process development, the case studies were developed and optimized starting from previously described procedure of patents and considering the drivers of operating in continuous mode. The implementation of microwave chemistry, process analytical technology (PAT), Design of Experiments (DoE) and kinetic modelling supported the reduction of development time, cost and risk of failure, therefore increased productivity and process understanding. The case studies resulted in higher yield, shorter reaction time, reduced safety concerns, in some cases higher purity and lower impurity content. The process improvements showcased that continuous manufacturing could be the alternative of traditional batch production. The developed methodology demonstrated to be a novel strategy that provided a workflow for chemical process development exploring the opportunities for continuous manufacturing following the QbD concept.
Descrição
Palavras-chave
química em fluxo produção em contínuo desenvolvimento de processos químicos ingredientes farmacêuticos activos flow chemistry continuous manufacturing Quality by Design chemical process development active pharmaceutical ingredientes