JUNE 2023LIFE SCIENCES REVIEW8Platform approach for intensify virus-based therapeutics process manufacturingExpanding the disease indications of gene therapies beyond rare diseases as well as developing more complex but also more fragile target viral vectors require not only expanding existing manufacturing facilities but also developing new capacities. The manufacturing processes that enabled the first landmark gene therapies to successfully complete clinical trials and regulatory approvals lack the efficiency and productivity required to meet current and future demand. Special requirements on the viral vector manufacturing processes, such as low cell density, low production and instability create challenges in their scale-up that cannot be solve by traditional platform approaches. Advanced technologies are needed to meet the vector demand and provide the required reliability and robustness for manufacturing enabling gene therapies to meet their full potential. Challenges across the vector process workflow A key challenge in the field of therapeutic viral vector manufacturing is maximizing vector yield during the entire process at all scales. Current upstream viral vector manufacturing processes primarily are based on transient expression, using multiple plasmid DNA, typically suffer from low productivity and a complexity that can challenge manufacturing reproducibility. Current FDA approved Adeno-associated Virus (AAV)-based gene therapies are facing scalability challenge since they are mainly generated by adherent cell culture using either flatware's or fixed-bed bioreactors.Operation with non-fit platform during purification leads to low recovery yield of viral vectors. Translation of filtration and chromatography platforms used for biological drug processes to viral vector processes does in fact lead to product loss and low recovery yield due to hold up volume, unfit pump, aggregation, or shear stress. Affinity resins efficiently remove host cell proteins (HCPs) and DNA impurities from AAV but are challenged by the diversity of AAV serotypes. Because the product itself is a virus or viral vector, therapeutic protein-based contaminant (bacteria or adventitious viruses) removal techniques such low pH viral inactivation and sterile/virus filtrations are not compatible. This drives a strong need for contamination prevention strategy over removal. Furthermore, analytical technologies for in-line monitoring of the product critical quality attributes (CQAs) are limited for gene therapy. Most gene therapy analytical methods are conducted off-line with high turnaround time eliminating the ability to make smart decisions during the process development, leading to more development cycles and therefore the cost and slow time to market.Traditional upstream, downstream, and analytic platforms are not able to overcome those challenges. IN MY OPINIONBy Rachel Legmann, PhD Senior director of technology, gene therapy, Repligen Corp.EVOLUTION OF VIRAL VECTOR ANALYTICS FOR GENE THERAPYRachel Legmann
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