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Quality and regulatory considerations for the manufacture and banking of clinical GRADE iPSCs: The EU AND US perspectives
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Resumo(s)
Introdução: A descoberta de células estaminais pluripotentes induzidas (induced pluripotent stem cells) e a sua capacidade de diferenciação em diferentes tipos de células, revolucionou a medicina regenerativa, tornando-se crucial o desenvolvimento de protocolos que permitam o seu fabrico em conformidade com as Boas Práticas de Fabrico. As terapias celulares alogénicas derivadas de iPSCs, são neste momento a opção de fabrico preferencial. Esta opção requer o estabelecimento de bancos celulares mestre de iPSCs qualificados para aplicação clínica.
Objetivos: No presente estudo pretendeu-se rever os requisitos Regulamentares e de Qualidade das duas principais jurisdições mundiais – Europa e Estados Unidos – no que diz respeito ao fabrico de bancos celulares mestre de iPSCs para aplicação clínica. Os requisitos mínimos aplicáveis às iPSCs para validar a sua utilização em ensaios clínicos iniciais “first-in-human” foram também revistos, bem como as melhores práticas atualmente seguidas pelos fabricantes para a caraterização analítica de iPSCs.
Metodologia: A metodologia seguida neste trabalho foi a revisão de diferentes fontes de informação que incluíram a literatura científica, orientações publicadas e disponíveis nos sites da EMA e da FDA, orientações GMP e ICH, e as monografias compendiais aplicáveis.
Conclusão: Os fabricantes de bancos celulares de iPSCs que pretendem a sua qualificação para aplicação clínica, fundamentam-se nas orientações ICH procurando adaptar os seus os seus requisitos. Com especial impacto, as áreas seguintes deveriam ser objeto de orientação e harmonização: i) os vetores de expressão autorizados para a criação das iPSCs; ii) testagem mínima para identificação; iii) testagem mínima para avaliação de pureza (incluindo testagem de agentes adventícios) e iv) avaliação da estabilidade. As ICH atuais referentes a produtos biotecnológicos/biológicos deveriam ter o seu âmbito alargado para incluir a aplicação a bancos de células usados para terapias celulares.
Introduction: The discovery of induced pluripotent stem cells (iPSCs) and the development of protocols for their differentiation in different cell types have revolutionized regenerative medicine. Developing manufacturing protocols for safe and GMP-compliant final products has become crucial. The allogeneic iPSCs-derivative cell therapies are now the preferred production alternative. This option requires the establishment of clinical-grade Master Cell Banks of iPSCs. Objectives: The present study aimed to review the Quality and Regulatory requirements from the two main jurisdictions in the world - Europe and the United States - concerning the manufacture of clinical grade Master Cell Banks (iPSCs). The minimum requirements applicable to iPSCs for use in “first-in-human” clinical trials, were also reviewed, as well as current best practices followed currently by manufacturers of iPSCs banks, for final product characterization. Methodology: The methodology used for this work was the review of different sources of information ranging from scientific literature; published guidance documents available on the EMA and FDA websites; GMP and ICH guidelines; and applicable compendial monographs. Conclusion: The manufacturers of iPSC cell banks looking to qualify them for clinical use, turn to ICH guidelines and try to adapt their requirements. Specifically with impact in the field of iPSC cell banks, the following areas should be the object of orientation and harmonization: i) expression vectors authorized for iPSC creation; ii) minimum identity testing; iii) minimum purity testing (including adventitious agents testing) and iv) stability testing. Current ICH guidelines for biotechnological/biological products should be expanded to include application to cell banks used for advanced cell therapies.
Introduction: The discovery of induced pluripotent stem cells (iPSCs) and the development of protocols for their differentiation in different cell types have revolutionized regenerative medicine. Developing manufacturing protocols for safe and GMP-compliant final products has become crucial. The allogeneic iPSCs-derivative cell therapies are now the preferred production alternative. This option requires the establishment of clinical-grade Master Cell Banks of iPSCs. Objectives: The present study aimed to review the Quality and Regulatory requirements from the two main jurisdictions in the world - Europe and the United States - concerning the manufacture of clinical grade Master Cell Banks (iPSCs). The minimum requirements applicable to iPSCs for use in “first-in-human” clinical trials, were also reviewed, as well as current best practices followed currently by manufacturers of iPSCs banks, for final product characterization. Methodology: The methodology used for this work was the review of different sources of information ranging from scientific literature; published guidance documents available on the EMA and FDA websites; GMP and ICH guidelines; and applicable compendial monographs. Conclusion: The manufacturers of iPSC cell banks looking to qualify them for clinical use, turn to ICH guidelines and try to adapt their requirements. Specifically with impact in the field of iPSC cell banks, the following areas should be the object of orientation and harmonization: i) expression vectors authorized for iPSC creation; ii) minimum identity testing; iii) minimum purity testing (including adventitious agents testing) and iv) stability testing. Current ICH guidelines for biotechnological/biological products should be expanded to include application to cell banks used for advanced cell therapies.
Descrição
Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2024, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Induced pluripotent stem cells Master cell banks Quality requirements Regulatory requirements Manufacture Clinical grade Teses de Mestrado -2024