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Bioprocessing and Bioproduction Trends in Cell and Gene Therapies

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Cell and gene therapies hold great promise for treating human diseases, for which current therapeutics are lacking. However, the research and development process for delivering these therapies to the clinic is complex, comprising various bioprocessing and bioproduction steps that must be fulfilled and optimized to ensure the safety and efficacy of the final product. The process continues to evolve to meet increasing demand and to overcome unexpected obstacles, such as the impact of the COVID-19 global pandemic on supply chains and manufacturing efforts in the biotech and biopharma industries.

In this interview, Technology Networks spoke with Neal Goodwin, PhD, Chief Scientific Officer at Teknova, to learn more about current bioprocessing and bioproduction trends in the cell and gene therapy space. Goodwin also discusses the impact of the COVID-19 pandemic on the biopharmaceutical sector and highlights how the industry has united to contribute to the development of vaccines at this critical time.

Molly Campbell (MC): You have 20 years of experience working in biotechnology and therapeutics. Can you talk about the evolution of the field through this time?

Neal Goodwin (NG):
 It has been a great 20 years! The human genome release is one of the most dramatic events during those 20 years. Once we had the human genome at our disposal, the field burgeoned. We've seen targeted therapeutics make a significant impact in personalized healthcare – imatinib, erlotinib, and the new KRAS inhibitors, among other targeted therapeutics for oncology, come to mind. Also, the first immuno-oncology therapeutics are now positively affecting large numbers of patients – which is terrific.

The ability to move into gene therapy and address severe genetic disorders and conduct gene replacement therapy is fantastic. The progress in gene delivery viral vectors and non-viral nanoparticle delivery contributed to the rapid advancement of prominent COVID-19 vaccines. The mRNA-based vaccines and non-viral nanoparticle-based gene delivery technologies have validated a promising approach to gene therapy that is being expanded to rare genetic diseases. The ability to mass-produce mRNA vaccines demonstrated the feasibility of mRNA treatments and gene therapies for more widespread use for treating broader therapeutic targets and conditions.

MC: Can you talk to us about some of the current trends you are seeing in the bioprocessing and bioproduction space?

First of all, there is a considerable demand for bioprocessing and commercial production of viral and non-viral vectors. These efforts must support what is now well over 1,000 clinical development programs in gene therapy alone. There is a need to develop better individualized processes that are readily scalable for GMP production matched to specific therapeutics. This effort will require the implementation of new strategies, new technologies, and increased global manufacturing capacity. It is an exciting place to be, but there is a great deal of development left to achieve streamlined processes and optimized capacity.

MC: Cell and gene therapies are key emerging markets. What are some of the key challenges that exist when developing these products from the lab, through to clinical testing and eventually authorization?

NG: There is a wide breadth of requirements – I will try to narrow them down to a few of the essential points. Some autologous cellular therapies require cells to be genetically modified ex vivo. This genetic modification is usually done with viral vectors, and a crucial aspect is the delivery of the gene, i.e., the active pharmaceutical ingredient, to the cells. There is a need for more advanced lentiviral vector systems that are safer for use in systemic gene delivery.

Among the non-cellular gene delivery segment, adeno-associated virus (AAV) vector gene delivery is the most widely used viral gene delivery platform. AAV production relies on the efficient expression in human cell lines of plasmids that encode viral packaging, capsid and replication genes, and expression plasmids encoding the therapeutic gene. One of the drawbacks of AAV vectors employed for gene therapy is they generally cannot deliver larger gene fragments required for optimal treatments. So, better viruses or non-viral gene delivery systems are needed.

In turn, choosing the best cell manufacturing conditions that provide the most efficient viral vector production is essential. A key challenge is how to scale up with reproducibility and efficiency.

MC: How can we look to overcome the challenge of scale-up in cell and gene therapies?

Because therapeutic programs are each different, having adaptable processes to individual programs is vital. Some strategies focus on gene delivery into autologous cells or allogeneic cells that become expanded and transplanted into patients. In contrast, other strategies require direct delivery of viral or non-viral gene therapy products into patients. In viral gene delivery, matching the most suitable virus to achieve the best target tissue tropism is essential. To date, AAV has been successfully used in two FDA-approved gene therapies, with many in advanced clinical trials. Traditionally, there have been few available AAV serotypes available for gene delivery. However, now we can use a directed evolution approach to manipulate and generate AAV capsids that have better target tissue tropism with reduced host immunogenicity.

Concerning AAV production, the purification processes of viruses need optimized, which is a focus of Teknova. We are barcoding different AAV serotypes with specific processes to achieve higher purity and viral vector yield.

MC: How has the COVID-19 impacted the biotech sector?

COVID-19 motivated and united the biotech sector. It remains a worldwide effort where enormous challenges are being addressed rapidly and collaboratively. The field appears more collaborative, almost cheering once competitive firms and laboratories. Teknova experienced this by retooling and supplying GMP viral transport media for COVID-19 testing and providing the global research community with research reagents and custom GMP manufactured products. This transformation is something that instils pride.

MC: How do you envision the biotech sector will change over the next few years? Are there any areas, aside from cell and gene therapies, that excite you?

The biotech sector's attitude is positive and more confident than 20 years ago, and this spirit enables us to tackle problems once considered unsolvable.

One of the most exciting biotech advancement areas is precision therapeutics. For example, a difficult hurdle to overcome was treating cancers linked to specific mutant KRAS alleles in a high percentage of cancers. Multiple firms have recently advanced precision therapeutics to late-stage clinical trials to treat this historically untreatable cancer type precisely. I think this can-do attitude will continue.

Another area where I expect to see progress is gene therapy delivery that will increasingly evolve non-viral delivery technologies. This evolution will allow precise targeting of therapeutics delivery and undoubtedly improve human health through this process.

Neal Goodwin was speaking to Molly Campbell, Science Writer for Technology Networks.