Implementation of the quality-by-design concept for an adeno-associated viral vector-based gene therapy

INTRODUCTION. Currently, manufacturers of adeno-associated virus (AAV)-based gene therapy products are facing a number of systemic problems stemming from the difficulties in assessing the quality of medicinal products due to insufficient scientific data, limited experience, and imperfect regulatory requirements. However, a risk-based approach to assessing critical quality attributes (CQAs) within the the framework of Quality by Design (QbD) can ensure improved efficiency in the development and production of advanced therapy medicinal products.

AIM. This study aimed to identify QbD-based CQAs and associated specifications for the development of AAV-based gene therapy products for Duchenne muscular dystrophy.

DISCUSSION. This study involved an analysis of QbD-based approaches to the development of AAV production technologies. The authors substantiated a list of the main AAV characteristics and collated available data on their impact on patients in terms of the efficacy and safety of gene therapy products and, in particular, the immune response to treatment. Following a risk assessment, the authors identified a list of CQAs for AAVs. When developing an AAV production process, the authors determined specifications for AAV CQAs, including viral and infectious titres, the presence of replication-competent AAVs, the percentage of empty capsids, and residual impurities (proteins, plasmid DNA, and residual host-cell DNA). A comprehensive risk assessment was conducted to determine the quality target product profile for an AAV-based gene therapy product for Duchenne muscular dystrophy. The authors listed the CQAs, developed the basic requirements for the applicable analytical procedures, and established the CQA specifications for the gene therapy product.

CONCLUSIONS. The use of QbD principles and risk-based approaches is an important step in CQA identification during the development of gene therapy products. The QbD methodology facilitates drafting new regulatory standards for the evaluation of the safety and efficacy of gene therapy products and helps with the development and commercial-scale manufacturing of such products.

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