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Do fixed-bed bioreactors provide a solution to viral vector shortage?

Meet the Expert: Yang, Bioprocess Scientist

In 2017, the New York Times wrote an article to report the critical shortage in the global viral vector manufacturing capacity. Next to the shortage of experienced manufacturing organizations capable of producing viral vectors, the high costs to produce this material is a main challenge for patients awaiting a viral vector treatment. Novartis was the first company that marketed a viral vector-based gene therapy product and is charging $475.000 for a one-time treatment per patient. Given the production issues it can be expected that novel gene therapy products will be launched at comparable market prices. The high production costs are due to (1) the high dose needed for the treatment of one patient, and (2) the low viral vector production yields obtained in current manufacturing campaigns. Therefore, there is an urgent demand to scale-up the manufacturing to produce sufficient product for the patients in a phase 1 clinical study. Additionally, a breakthrough innovation is needed to improve the viral vector yield in current production processes, which is a major factor for the high cost of goods. A recent development has been the rise of novel fixed-bed bioreactors, and herewith I would like to guide you through some of my team’s experiences with this equipment in the manufacturing of viruses.

The challenge for viral vectors production

Most protein-based biopharmaceuticals are produced using suspension mammalian cell cultures. In contrast, most viral vectors are produced using cells that will only proliferate and produce a desired product when attached to a surface. Therefore,  static systems, such as T-flasks, Cell Stacks, Roller Bottles, or Cell Factories, are traditionally used. Unfortunately, such systems are very labor intensive, require a large footprint, and only allow very limited in-process control. The biggest issue is, however, the fact that these systems only allow increased production capacity through out-scaling instead of up-scaling. In the 1970’s, the microcarrier system was development by van Wezel et al. The advantage of the microcarrier system is that cells are grown on beads which are suspended in a tank and agitated, providing a homogeneous environment and the possibility to scale-up, like suspension cells. Nowadays, several viral vaccines, are produced using a microcarrier system. Expert know-how and experience with this system is required, in particular at larger scales, to avoid reduced cell growth. Reduced cell growth has been a common observation due to the agitation needed to keep the microcarriers in suspension. In addition, separating the virus product from the microcariers upon harvest requires an extra step and can therefore reduce the overall yield of the viral product.

Fixed-bed bioreactors for viral vectors

Fixed-bed bioreactors are two-phase systems in which the medium flows continuously through a stationary bed made of a porous polymer. Because the matrix on which the cells are growing is fixed, the cells have to endure substantially less shear stress, while process parameters such as pH and Dissolved Oxygen can still be tightly controlled. This set-up generally allows for high cell densities in a small-footprint bioreactor and easy recovery of the viral vector product.

My team at Batavia uses both the scale-X™ and iCELLis® fixed-bed bioreactors. We gathered a wealth of data on both systems. For example, the scale-X bioreactors have been successfully used for the Sabin poliovirus strains (PV1, PV2, PV3) production. As a direct comparison of our results in the scale-X bioreactor with the microcarrier production process described in literature, an average yield increase of 178% (in DU/cm2) was achieved for the 3 serotypes of poliovirus.3 In addition, the scale-X bioreactor was implemented for production of the VSV vector in our Lassa and Marburg vaccine programs.

Using iCELLis® bioreactors, lentiviral vectors have been successfully produced in our lab. We corroborated the conclusions of Valkema et al. that iCELLis® bioreactor based processes are much easier to be scaled up and use significantly less floorspace compared to the T-flask based production process.

Overall, our working experience with fixed-bed bioreactors is very positive, because it provides smooth scale-up, is less labor intensive, and we are able to reach very high cell densities which benefits transfection efficiency and product yield. We therefore believe that these systems may substantially contribute in overcoming viral vector manufacturing cost.

Batavia Biosciences offers a broad range of process development and manufacturing services for all major classes of biopharmaceuticals, i.e., viral vaccines, viral vectors, recombinant proteins and antibodies. As a company dedicated to help bringing biopharmaceuticals to the market at higher speed, with reduced costs, and with a higher success rate, Batavia Biosciences has vast experience in developing and manufacturing vector vaccines, gene therapy vectors and oncolytic vectors. With our team of experienced scientists and technicians, we are well equipped to take on any challenge associated with viral vector development.

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