Gene therapy can target the underlying causes of disease and even cure previously untreatable conditions. But despite this potential, the market remains small with only a handful of approved products.

In part, the slow growth reflects a lack of maturity in the manufacturing techniques, says Paul Young, director of process science at Pharmaron, who suggests developers take cues from the monoclonal antibody industry.

“Market analysis not only demonstrates that the gene therapy sector has strong growth potential, but also indicates infancy with the number of currently approved products,” he continues. “To be able to realize the full potential of AAV-based gene therapy, focus has shifted to the ability to manufacture and deliver high titer, high quality, and efficacious product.

“However, manufacturing is not simple, with multiple complex challenges ranging from starting material generation, ensuring cellular production of high titers of viral vectors, to purification, where not all AAV particles contain the intended genetic payload.”

Young took a closer look at the challenges facing developers using adeno associated virus (AAV) vectors in a study last month.

Improving product quality

And his conclusion is that each of the commonly used AAV vector production methods—transient transfection, baculovirus-based methods, or herpes simplex virus (HSV) production systems—can be improved, particularly in terms of product quality.

“All AAV production processes require starting material, either plasmid or baculoviral/HSV starting viruses. With the prevalence of triple transfection-based AAV manufacture, the plasmid used is crucial,” according to Young.

“Plasmid generation typically requires a standalone manufacturing process based on microbial expression technology. Focus on quality is required, not only for the quality of plasmid used in the manufacturing process, but also for the impact on the quality of the resultant viral vector produced.”

Young identified vector purification as another area where improvement is needed. However, rather than developing a standard approach, he says, gene therapy developers will need to create several different methodologies.

“Different AAV serotypes present different challenges driven by the capsid structure and associated properties. Advanced manufacturers are using a tailored approach depending on the serotype used, a ‘toolbox’ approach.”

More generally Young believes the gene therapy sector needs to focus on process standardization, scaleup, and innovation.

“As an industry, we must learn from established manufacturing processes, such as for monoclonal antibodies, to deliver rapidly scalable, robust, and cost-effective platform solutions that can be truly multiproduct, while working hand-in-hand with regulatory agencies,” he explains. “Additionally future innovation remains important and there are several opportunities for disruptive and further advanced manufacturing approaches. With a true end in mind approach, can we turn the tide from treatment to cure?”

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