Do Fixed-Bed Bioreactors Provide A Solution to Viral Vector Shortages?

A blog to guide you through some of our team’s experiences with fixed bed reactors for virus manufacturing.
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Written by 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 to market a viral vector-based gene therapy. They charge $475,000 for a one-time treatment per patient. Given the production issues, we expect that novel gene therapy products will be launched at comparable market prices. The production costs are high due to:

  1. the high dose needed for the treatment of a patient
  2. the low viral vector production yields obtained in current manufacturing campaigns

Therefore, there is an urgent demand to scale-up the manufacturing. This way sufficient product for the patients in a phase 1 clinical study can be produced. Additionally, we need a breakthrough innovation to improve the viral vector yield in current production processes. The yield is a major factor for the high cost of goods. A recent development which promises higher vector yields, is the rise of novel fixed-bed bioreactors. Herewith, I would like to guide you through some of my team’s experiences with this equipment for virus manufacturing.

The Challenge For Viral Vector Production

Most protein-based biopharmaceuticals are produced using suspension mammalian cell cultures. In contrast, most viral vectors are produced using adherent cells. Adherent cells will only proliferate and produce the desired product when attached to a surface. Therefore,  traditionally static systems, such as T-flasks, Cell Stacks, Roller Bottles, or Cell Factories, were used. Unfortunately, such systems are very labor intensive, require a large footprint, and only allow very limited in-process control. The biggest issue, however, is the fact that these systems only allow increased production capacity through out-scaling instead of up-scaling.

The first scale-up alternative was the microcarrier system. In the 1970’s, van Wezel et al. developed this technology. The advantage of this system is that cells are grown on beads. These beads are suspended in a tank and agitated, providing a homogeneous environment and the possibility to scale-up. Therefore, this technology provides similar characteristics to suspension cells. Nowadays, several viral vaccines are produced using a microcarrier system. There are, however, a few downsides to this system. Expert know-how and experience is absolutely required to avoid reduced cell growth. This is particularly true for production at larger scales. Reduced cell growth has been a common observation in microcarrier-based processes because of the agitation needed to keep the microcarriers in suspension. In addition, separating the virus product from the microcarriers upon harvest requires an extra step. Each extra step has the potential to reduce the overall yield of the viral product.

Fixed-Bed Bioreactors For Viral Vectors

The second scale-up alternative is the use of fixed-bed bioreactors. 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.

Our process development data

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 corroborate 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. These high cell densities benefit 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. We are dedicated to help bring 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. Our team of experienced scientists and technicians are well equipped to take on any challenge associated with viral vector development.


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