JANUARY 2025LIFE SCIENCES REVIEW8IN MY OPINIONPlatform approach for intensifying 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 solved 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 are primarily based on transient expression, using multiple plasmid DNA, and typically suffer from low productivity and complexity that can challenge manufacturing reproducibility. Current FDA-approved Adeno-associated Virus (AAV)-based gene therapies are facing scalability challenges since they are mainly generated by adherent cell culture using either flatware or fixed-bed bioreactors.Operation with a non-fit platform during purification leads to a 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 as low pH viral inactivation and sterile/virus filtrations are not compatible. This drives a strong need for a 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 offline with high turnaround time, eliminating the ability to make smart GENE THERAPY--THERAPEUTIC VIRAL VECTORS; MANUFACTURING, CHALLENGES, AND INNOVATIONBy Rachel Legmann, PhD, Senior Director of Technology, Gene Therapy, Repligen Corporation [NASDAQ: RGEN]Rachel Legmann
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