Written by expert: Kai, Technical Lead
The obstacles of viral vector production
Over the last decade, the scientific community has witnessed several breakthroughs in the field of gene therapy and immuno-oncology. These breakthroughs have propelled the interest in the development of Advanced Therapy Medicinal Products (ATMPs), i.e., medicinal products for human use, based on genes, tissues or cells (see figure 1). Such products currently offer hope in the treatment of genetic disorders and cancer where previously there was none.
Fig. 1 Market development of viral vector therapies
Many ATMPs under development rely on the delivery of genetic material to cells of a patient using so-called viral vectors. Viral vectors are usually derived from parental wild type viruses whose viral genes (essential for replication and virulence) have been replaced with the heterologous genes intended for cell manipulation. In vitro and clinical use of viral vectors is based on RNA and DNA viruses that differ in their genomic structures and host range. Specific viruses have been picked as gene delivery vehicles according to their capacity to carry foreign genes, as well as their ability to conveniently deliver genes that are linked to efficient gene expression.
Here, we address some of the challenges in viral vector manufacturing that manufacturers are tackling, specifically to the production of viral vector based ATMPs. Although we focus on two viral vectors, i.e., adeno-associated virus (AAV) and lentivirus derived vectors as these two systems are mostly selected for the development of ATMPs (see figure 2), most vector systems under development face similar challenges.
Figure 2: Distribution of gene based ATMPs in development based on platform.
In a nutshell, the challenges in manufacturing AAV and lentiviral vectors are across the board meaning that production, purification, and product quality is up for improvement. In production, it’s the viral vector titer that needs to be drastically increased, in purification recovery of product needs to be drastically improved, while ensuring other critical quality attributes (such as the transducing titer for lentiviruses or the number of empty particles when working with AAV) are not affected. Substantial improvements in all fields are deemed essential to reduce cost of goods, increase manufacturing success by limiting batch-batch inconsistencies, and lower the therapeutic dose to improve product safety profile.
How Batavia is hurdling the obstacles of viral vector production
To start tackling these issues, industry is turning its focus on the development of automation and the development of Process Analytical Tools. Recent advances using DOE approaches to optimize the cell culture and transfection processes have been described as well as the development of specific technologies to increase downstream recovery. In addition, an exciting new prospect is provided by the generation of stable vector producer cell lines, capable of expressing complete viral vector particles upon induction. This technology delivers higher titers and, so far, seems to deliver more consistent product quality compared to transfection processes.
At Batavia, we focus on scalability of viral vector manufacturing processes, using our HIP-Vax® platform. This platform uses fixed-bed bioreactors and is based on the principles of process intensification. In the field of monoclonal antibody production, process intensification has already been adopted as one of the key manufacturing strategies to realize low cost of goods. Now it’s time to do the same for viral vector products.
It has been demonstrated that fixed-bed systems are suitable for both adherent cell lines and suspension cell lines in manufacturing AAV and lentiviral vectors.
Due to the high productivity of this production platform, it requires only limited sized clean rooms, making this manufacturing platform well suitable to produce viral vectors for ex vivo therapies for which only small volumes are required for individual patient treatment protocols. However, the technology also provides a vector yield output at approximately 50-liter scale equivalent to a 1000-liter suspension reactor owing to the high cell density culture.
This advantage of the HIP-Vax manufacturing platform, i.e., the ability to manufacture product at a small facility footprint has been amply demonstrated to substantially lower the costs-of-goods of the production process, due to the increase in batch output, and a decrease of costs associated with raw materials.
Our HIP-Vax platform modernizes viral vector production by increasing both yield and improving product quality. Additionally, owing to its low footprint, it helps solve the current capacity constraints in the viral vector industry.