Viral Vector Manufacturing for Gene Therapy

Show Notes

I began the interview by asking Dr. Lundgren what he saw as the main challenges in viral vector manufacturing today. He sees several challenges to producing high quality vectors at larger scale while maintaining cost effectiveness. He lists the advanced cell culture systems required for virus production and the fact that vectors must be infectious in order to be efficacious as two factors. He also discusses increasing regulatory considerations, including the avoidance of animal sourced raw materials such as serum. Scale up can also be difficult depending on the system being used, but he believes all these challenges can be overcome by using the right technologies.

I went on to ask why it is so difficult to create manufacturing platforms for viral vectors. Mats said it is due to the diversity of viruses used. Depending on the virus used one may use different cell lines, the viruses themselves could be different sizes and some may be enveloped as well. These differences require different processing technologies. As certain viruses like lentivirus and adeno-associated virus become more commonly used, there is the opportunity to create more virus specific platforms.

We then moved on to discuss the production capacity crunch that exists in viral vector manufacturing and Mats described how he thinks this could be addressed. Due to the increase in indications and the high demand on contract manufacturing, there is the need to build more capacity for viral vector production. He suggests pre-designed modular facilities for viral vector manufacturing that can be implemented quickly to build up production capacity as a solution.

I then asked if there are lessons that the cell and gene therapy industry can learn and apply from monoclonal antibody production. He explained that monoclonal antibody production uses a well-defined platform that results in high yields, which is something that we would like to emulate in gene therapy manufacturing. They also use chemically defined media, which would be best for viral vector manufacturing as well. However, with the different viruses used this kind of platform approach can be difficult.

I followed up with a question about the start to finish adenovirus manufacturing process that Dr. Lundgren and his colleagues at GE Healthcare created and he provided an overview of the process. The goal was to meet the regulatory, process economics, and scalability demands for viral vector manufacturing in one process. The team carefully selected technologies that would support these goals, such as single-use bioreactors and chemically defined media. They also implemented media filtration and chromatography techniques that resulted in a highly purified final bulk that met regulatory requirements. In addition they incorporated upstream and downstream technologies that were compatible with pre-designed and modular manufacturing facilities. Everything that was used was compatible with GE Healthcare’s Flex Factory™ solution.

I asked why they chose adenovirus and if it was possible that this process could be applied to other virus types? Mats said that currently adenovirus is being developed as both a vector for vaccines and an oncolytic therapy. With oncolytic viruses the goal is to infect the cancer cells with a modified virus to kill the cancer cells. This adenovirus process could be applied to other virus types as a toolbox approach. Depending on the type of virus, the virus properties and the host cell line being used, then different tools from the process could be incorporated.

We then discussed the challenges, highlights and ultimate outcome of the developed process. Mats explained that what was clear right away was a need for improved analytics. They had to develop two new assays – one for quantification of infectious virus particles that was based on automated microscopy and the other to measure the total number of virus particles. It was quite important as some of the analytical tools available were old and not very precise. They also found by looking with electron microscopy at the purified virus that the new chromatography purification process they employed would remove much of the smaller cell debris particles. This result was quite different from the older published process that they used for comparison. Ultimately, they created a scalable process with very good process economy and most importantly met regulatory requirements.

I wanted to follow up on scalability and how it was incorporated into the process. Mats stated that they used only technologies that they knew were scalable. For instance they used single-use bioreactors, filtration systems and chromatography solutions that they had previous experience scaling up to ensure it was a scalable process overall and compatible with an automated facility solution such as FlexFactory.

Next we discussed cost of goods and how important it is in the commercialization of gene therapies. I asked how a platform approach can help with cost of goods. Mats said that a platform approach can significantly reduce the development timeline and move a product to market faster. Naturally, a process with high expression and yield will help reduce cost of goods as well. A platform approach also helps make a facility more flexible in that companies can more easily switch between batches and products.

I mentioned how in our recent publication on gene therapy manufacturing, it became clear that the relationships between drug developers/manufacturers/CMOs and their suppliers are critically important. I asked how he thought these groups could work together to increase the production output and quality of viral vector manufacturing. He said that customers are looking to suppliers for more than just individual products now; they want manufacturing solutions. So it is important that vendors understand the process and product requirements. Conversations between developers, manufacturers and CMOs are critical. Single-use is state of the art in this field so good relationships with vendors to ensure security of supply is also important. Additionally, vendors can be a source of extensive expertise on equipment and various processes.

Lastly, I asked what are the most exciting upcoming enabling technologies in downstream viral vector manufacturing. He told me that there were many new developments in purification. One was a recent acquisition for a fiber-based purification technology that will be well-suited for virus production. Virus will bind to the surface of the fibers, thereby creating very high binding capacity. Other exciting developments will be announced in the near future.

I closed by asking Mats if he had anything else to add for our listeners. He stressed the importance of advanced analytics to increase process understanding and to characterize the product. Also, he recommended the use of process economy modeling at relevant scales early in development to evaluate commercial viability of the product.

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