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Impact of successive post-authorisation changes on the dissolution profile of solid oral dosage forms
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A equivalência terapêutica de medicamentos genéricos (MG) é a principal premissa para a obtenção da autorização de introdução do medicamento no mercado (AIM). Aquando a apresentação de um pedido de AIM, a prova de equivalência do medicamento genérico em comparação com o seu medicamento de referência (MR) deve ser irrefutavél. A mesma é confirmada através de testes in-vitro, incluindo testes de desempenho, como por exemplo, o perfil de dissolução comparativo. Quando aplicável no âmbito do pedido de AIM, a confirmação da bioequivalência é confirmada através de testes in-vivo. Este tipo de ensaios permite a extrapolação tanto dos dados de eficácia (clínicos) como de segurança (pré-clínicos e farmacovigilância) do MR comparativamente ao produto genérico proposto.
Durante o ciclo de vida do produto, o desempenho do mesmo deve ser reavaliado a cada necessidade de alteração de qualquer condição aprovada na AIM, provando que o medicamento genérico continua a ser um equivalente terapêutico ao seu MR. Testes comparativos de desempenho, tais como a dissolução, são úteis na simulação do comportamento do medicamento no corpo humano, tornando possível a comparação da sua absorção com a de um MR. A necessidade de repetir o estudo alargado de bioequivalência (BE) pode ser substancialmente reduzida quando se estabelece uma relação entre dados de desempenho in-vitro e dados de desempenho in-vivo.
O controlo destas características é da responsabilidade dos titulares da AIM, e cada autoridade reguladora tem a sua própria regulamentação, o que permite avaliar o nível de impacto da alteração e apresentar as provas adequadas durante a gestão do ciclo de vida do medicamento.
Contudo, após sucessivas alterações menores ao medicamento genérico e medicamento de referência, devido a directrizes e regulamentos de testes não padronizados, é possível o surgimento de uma potencial bio-inequivalência do medicamento genérico após a sua aprovação inicial.
O presente trabalho pode ser dividido em três objectivos principais. Primeiramente, confirmar a presença de divergências de desempenho entre MR e MG, que potencialmente resultam em bio-inequivalencia, após mudanças pós-AIM sucessivas durante todo o ciclo de vida do medicamento. Simultaneamente, identificar lacunas no panorama regulamentar das autoridades reguladoras ANVISA (Agência Nacional de Vigilância Sanitária) do Brasil, a EMA (Agência Europeia de Medicamentos) da Europa e a FDA (Food and Drug Administration) dos Estados Unidos da América, que potenciam possíveis divergências de desempenho e, portanto, bio-inequivalência. O último objectivo deste trabalho é sugerir e analisar possíveis alterações de regulação que atenuem este risco.
Para este efeito, foi realizada uma pesquisa bibliográfica aprofundada, analisando regulamentação local, directrizes, documentação e publicações oficiais, bases de dados públicas das autoridades de saúde com AIM aprovadas e teses académicas, utilizando termos, definições e linguagem adaptados para os efeitos desta pesquisa. Os principais instrumentos de pesquisa aplicados às publicações indexadas foram PubMed, Science.gov, Google books, Science Direct e Research Gate. Esta pesquisa permitiu a comparação dos critérios de aceitação de BE, perfil comparativo de dissolução (PCD), requisitos para o desenvolvimento do método de dissolução juntamente com a regulamentação da alteração dos termos do AIM no que respeita à sua classificação, provas a apresentar e forma de apresentação para a implementação de alterações.
Em termos de critérios de aceitação do perfil comparativo de dissolução e bioequivalência, não foram observadas diferenças entre as directrizes das autoridades reguladoras estudadas. Entre as principais semelhanças nos diferentes regulamentos para alterações aos termos da AIM estão: a necessidade de realizar o PCD entre a condição anterior aprovada e a condição proposta; e a exigência de factor de semelhança, f2, com um valor superior a 50. Estas conclusões estão de acordo com a hipótese proposta para este trabalho, isto é, após sucessivas pequenas alterações ao medicamento genérico e ao MR, para as quais apenas foram apresentadas provas comparativas in-vitro versus a condição previamente aprovada, o perfil de dissolução pode se tornar distinto do perfil do seu MR, o que pode levar à bio-inequivalência do medicamento genérico após a sua aprovação inicial.
Uma simulação de PCD foi proposta, considerando um aumento de 10 vezes no tamanho do lote do medicamento genérico em comparação com o bio-lote, concomitantemente com uma pequena alteração no processo de produção e uma mudança no equipamento. Neste cálculo, foram consideradas mesma classe e subclasse de um produto com principios activos de baixa solubilidade (classe II ou IV) do sistema de classificação biofarmacêutico, para o qual a dissolução é sempre um factor crítico. Este conjunto de alterações foi classificado como menor e moderado pelas autoridades de saúde avaliadas neste trabalho. Considerando que o critério de semelhança entre o PCD proposto e o aprovado se restringia ao valor f2 superior a 50, através da simulação de uma única alteração, foi possível demonstrar que, quando comparado com a referência, a curva de dissolução proposta divergia da curva da mesma.
Numa tentativa de mitigação dos riscos encontrados, várias soluções foram estudadas e propostas, desde a simples realização do estudo contra o medicamento de referência no seu estado actual (assumindo todas as alterações) para qualquer tipo de alteração, até um programa de monitorização específico para avaliar uma possível bio-inequivalência dos medicamentos do mercado.
Atendendo à premissa desta obra de avaliar os requisitos regulamentares para a hipótese levantada de perda de bioequivalência, foi considerado confirmado que existe uma lacuna regulamentar para a prova de comparação necessária para alterações menores e moderadas na AIM de uma forma farmacêutica sólida genérica de libertação imediata.
Foi possível concluir que, tendo em consideração que a isenção da necessidade de bioequivalência utiliza principalmente o critério f2, genéricos das classes II e IV BCS, podem ser introduzidos no mercado com perfis de dissolução que diferem dos do seu medicamento de referência. Foi possível constatar, também, que os produtos de libertação imediata são mais vulneráveis do que os produtos de libertação modificada, tendo em vista um menor número de condicionantes para a classificação da mudança como menores e moderadas.
Therapeutic equivalence is the main premise for obtaining Marketing Authorization (MA) for generic drugs. Proof of equivalence is presented in the submission of an MA application. Pharmaceutical equivalence is confirmed through in vitro testing, including performance tests such as comparative dissolution profile. When applicable in the scope of the MA application, bioequivalence confirmation is asserted by in vivo testing. This testing supports the extrapolation of both efficacy (clinical) and safety (pre-clinical and pharmacovigilance) data of the reference product (RP) to the proposed generic product. During its life cycle, product performance must be re-evaluated at every need to change any condition approved in the MA, proving that the generic product continues to be a therapeutic equivalent to its RP. Comparative performance tests, such as dissolution, are useful in simulating the behaviour of the drug in the human body, making it possible to compare its absorption against a RP. The need to repeat the extended bioequivalence study (BE) can be substantially reduced when a relationship between in-vitro performance data and in-vivo performance data is established. The monitoring of these characteristics is responsibility of the MA holders, and each regulatory agency has its own regulation, which allows the level of impact of the change to be assessed and the appropriate evidence to be submitted during the life cycle management of the drug. However, after successive minor changes to the generic drug and RP, due to unstandardized guidelines and regulations of testing, a potential bio-inequivalence of the generic drug after its initial approval may arise. The present work is axed in three main goals. The first to attest the presence of performance divergences between RP and generic solid oral products, after successive post-authorisation changes throughout their lifecycle, possibly resulting in bio-inequivalence. This while identifying gaps in the regulatory landscape of the regulatory authorities ANVISA (Agência Nacional de Vigilância Sanitária) from Brazil, the EMA (European Medicines Agency) from Europe and the FDA (Food and Drug Administration) from the United States of America that potentiate possible performance divergences and thus, bio-inequivalence. The last goal of this body of work is to suggest and analyse possible regulation changes that mitigate this risk. A comprehensive literature search was performed by analysing local regulations, guidelines, official documentation and publications, health authorities’ public online databases of approved MAs, academic thesis, using adapted terms, definitions, and language for the research purpose. Main research tools applied to indexed publications were PubMed, Science.gov, Google books, Science Direct and Research Gate. This allowed for the comparison of the acceptance criteria of BE, comparative dissolution profile (CDP), requirements for development of the dissolution method along with the regulation of change to the terms of the MA regarding its classification, evidence to be presented and form of submission for the implementation of changes. In terms of acceptance criteria for comparative dissolution profile and bioequivalence, no differences between regulatory authorities’ guidelines were observed. Among the main similarities in the different regulations for changes to the terms of the MA researched are: the need to perform the CDP between the previous approved condition and the proposed condition; and requiring similarity factor, f2, with a value greater than 50. These findings are in line with the proposed hypothesis of this work, that is, after successive minor changes to the generic drug and RP, for which only in-vitro comparative evidence has been presented against the previously approved condition, this dissolution profile may no longer be similar to its reference drug, which may lead to bio-inequivalence of the generic drug after its initial approval. A simulation of CDP was performed considering a 10-fold increase in the batch size of the generic drug compared to the bio-batch, concomitant with a minor change in the production process and a change in equipment. Same class and subclass of a product with low solubility assets (class II or IV) of the biopharmaceutical classification system, for which dissolution is always a critical factor was assumed. This set of changes was rated as minor and moderate by the health authorities subject in this work. Considering that the similarity criterion between proposed and approved CDP was restricted to f2 value greater than 50, by simulating a single change, it was possible to demonstrate that, when compared to the reference, the proposed dissolution curve diverged from the curve of the reference drug. To mitigate the risks found, a number of solutions were studied and proposed, ranging from simply conducting the study against the RP in its current condition (assuming all changes) for all of the changes categories, to a specific monitoring program for possible bio-inequivalence. As the aim of this research was to assess the regulatory requirements for the hypothesis raised, it was considered confirmed that there is a regulatory gap for the evidence of comparison required for minor and moderate changes in the MA acceptance of an immediate release generic solid dosage form. It was possible to conclude that, taking into consideration that the exemption of the need for bioequivalence uses mainly the f2 criterion, generics of classes II and IV BCS, may be available the market with dissolution profiles that differ from those of their reference product during its lifecycle. Immediate release products were found to be more vulnerable than modified release products, given fewer constraints on the classification of change as minor and moderate.
Therapeutic equivalence is the main premise for obtaining Marketing Authorization (MA) for generic drugs. Proof of equivalence is presented in the submission of an MA application. Pharmaceutical equivalence is confirmed through in vitro testing, including performance tests such as comparative dissolution profile. When applicable in the scope of the MA application, bioequivalence confirmation is asserted by in vivo testing. This testing supports the extrapolation of both efficacy (clinical) and safety (pre-clinical and pharmacovigilance) data of the reference product (RP) to the proposed generic product. During its life cycle, product performance must be re-evaluated at every need to change any condition approved in the MA, proving that the generic product continues to be a therapeutic equivalent to its RP. Comparative performance tests, such as dissolution, are useful in simulating the behaviour of the drug in the human body, making it possible to compare its absorption against a RP. The need to repeat the extended bioequivalence study (BE) can be substantially reduced when a relationship between in-vitro performance data and in-vivo performance data is established. The monitoring of these characteristics is responsibility of the MA holders, and each regulatory agency has its own regulation, which allows the level of impact of the change to be assessed and the appropriate evidence to be submitted during the life cycle management of the drug. However, after successive minor changes to the generic drug and RP, due to unstandardized guidelines and regulations of testing, a potential bio-inequivalence of the generic drug after its initial approval may arise. The present work is axed in three main goals. The first to attest the presence of performance divergences between RP and generic solid oral products, after successive post-authorisation changes throughout their lifecycle, possibly resulting in bio-inequivalence. This while identifying gaps in the regulatory landscape of the regulatory authorities ANVISA (Agência Nacional de Vigilância Sanitária) from Brazil, the EMA (European Medicines Agency) from Europe and the FDA (Food and Drug Administration) from the United States of America that potentiate possible performance divergences and thus, bio-inequivalence. The last goal of this body of work is to suggest and analyse possible regulation changes that mitigate this risk. A comprehensive literature search was performed by analysing local regulations, guidelines, official documentation and publications, health authorities’ public online databases of approved MAs, academic thesis, using adapted terms, definitions, and language for the research purpose. Main research tools applied to indexed publications were PubMed, Science.gov, Google books, Science Direct and Research Gate. This allowed for the comparison of the acceptance criteria of BE, comparative dissolution profile (CDP), requirements for development of the dissolution method along with the regulation of change to the terms of the MA regarding its classification, evidence to be presented and form of submission for the implementation of changes. In terms of acceptance criteria for comparative dissolution profile and bioequivalence, no differences between regulatory authorities’ guidelines were observed. Among the main similarities in the different regulations for changes to the terms of the MA researched are: the need to perform the CDP between the previous approved condition and the proposed condition; and requiring similarity factor, f2, with a value greater than 50. These findings are in line with the proposed hypothesis of this work, that is, after successive minor changes to the generic drug and RP, for which only in-vitro comparative evidence has been presented against the previously approved condition, this dissolution profile may no longer be similar to its reference drug, which may lead to bio-inequivalence of the generic drug after its initial approval. A simulation of CDP was performed considering a 10-fold increase in the batch size of the generic drug compared to the bio-batch, concomitant with a minor change in the production process and a change in equipment. Same class and subclass of a product with low solubility assets (class II or IV) of the biopharmaceutical classification system, for which dissolution is always a critical factor was assumed. This set of changes was rated as minor and moderate by the health authorities subject in this work. Considering that the similarity criterion between proposed and approved CDP was restricted to f2 value greater than 50, by simulating a single change, it was possible to demonstrate that, when compared to the reference, the proposed dissolution curve diverged from the curve of the reference drug. To mitigate the risks found, a number of solutions were studied and proposed, ranging from simply conducting the study against the RP in its current condition (assuming all changes) for all of the changes categories, to a specific monitoring program for possible bio-inequivalence. As the aim of this research was to assess the regulatory requirements for the hypothesis raised, it was considered confirmed that there is a regulatory gap for the evidence of comparison required for minor and moderate changes in the MA acceptance of an immediate release generic solid dosage form. It was possible to conclude that, taking into consideration that the exemption of the need for bioequivalence uses mainly the f2 criterion, generics of classes II and IV BCS, may be available the market with dissolution profiles that differ from those of their reference product during its lifecycle. Immediate release products were found to be more vulnerable than modified release products, given fewer constraints on the classification of change as minor and moderate.
Descrição
Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Solid dosage forms Dissolution Bioequivalence Generic product Teses de mestrado - 2021