Biomanufacturing of Gene Therapy Vectors

Abstract

Cristina Peixoto Otto-Wilhelm Merten The progress from clinical development toward product licensure of several programs presents challengesmainly to gene therapy product manufacturing. These include challenges in viral vector-manufacturing capacity but also in process variability, difficulty characterizing complex materials, and lack of knowledge of critical process parameters and their effect on critical quality attributes of the viral vector products. In the viral vector production, scale-up is a critical task due to the limited scalability of traditional laboratory systems and the demand for high volumes of viral vector manufactured following current goodmanufacturing practice. Furthermore, the expanding potential commercial product pipeline in the last years and the continuously advancing development of viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency, and safety. Finally, there is an increase in regulatory scrutiny that involves also the academic researchers and manufacturers of investigational drugs for early-phase clinical trials engaged in industry collaborations. This trend has led to a greater demand for both pre-clinical and clinical-grade viral vector-manufacturing capacity to support the increasing number of gene therapy clinical development programs. As these programs advance toward licensure, more rigorous product characterization using improved analytical methods and progressively higher regulatory compliance will be expected. The solution to increasing viral vector capacity involves both scientific and technical issues. The manufacturing should be robust, scalable, and more automated to fit GMP solutions for both small-scale and large-scale production. In clinical manufacturing, procedures must produce consistent results with a minimum lot to lot variability. For example, variability in transfection efficiency and the lack of scalability and consistency is therefore problematic and requires rigorous control. Ferreira et al.[1] review recent progress in stable cell line development to overcome this challenge in the manufacturing of lentiviral vectors (LV). Similar developments are performed for the production of AAV vectors (development of stable virus-free inducible AAV producer cell lines based on CAP cells[2] and in the future in the context of the baculovirus/insect cell system.[3] Alternatively, Lesch et al.[4] evaluate the use of single-use fixed-bed bioreactors for large-scale