Continuous Cell Culture for Viral Vaccines

Development of a mechanistic model of vaccine production for the development and demonstration of the continuous operation of an upstream cell culture process for the production of a model vaccine.

Industry Need

The biopharmaceutical industry has shown significant interest in developing continuous manufacturing processes for therapeutic protein production.
Despite some progress, continuous manufacturing approaches have yet to be widely applied to cell-culture based vaccine manufacturing.
The production of viral vaccines is more biologically complex than the production of recombinant protein therapeutics because of the infection and replication cycle of the virus.
The development of a first principles/mechanistic model of the manufacturing process could be a key element in the design of a manufacturing process and feedback control system that will allow for extended operation of the production system and consistent effluent of virus titer of high quality.

Approach

MIT and participating organizations aimed to create a mechanistic model of vaccine production for the development of the continuous operation of an upstream cell culture process to produce a model vaccine. This approach could be generalizable to a variety of vaccine production systems based upon the characteristics of the host cell line being used and the vaccine being produced.

Impacts

Advancement of continuous processing and mechanistic models applied to vaccines.

Demonstrate the suitability of novel PAT in vaccine manufacture

Will enable a platform approach for the rapid development and commercialization of viral therapeutics

Advanced continuous processing and mechanistic models applied to vaccines

Demonstrated the suitability of novel PAT in vaccine manufacture

Enabled a platform approach for the rapid development and commercialization of viral therapeutics

Developed a mechanistic model that describes the production of a viral vaccine in mammalian cell culture, allowing greater understanding of viral production in continuous cell culture.

Demonstrated automatically controlled production of a viral vaccine over a 20-day continuous culture at process development scale at an FDA-licensed manufacturer of vaccines.

Positively correlated changes in cellular biophysical characteristics with viral vaccine production and measured in two flow-through systems, the Ovizio iLine F and MIT SMR; leveraging these technologies will allow for continuous monitoring of cellular biophysical attributes during viral vaccine production.

Value Statement/Outcomes

Continuous viral vaccine production will reduce the time that it takes to get a product from clinical into commercial production. This can dramatically impact the speed in which a new vaccine can be brought to market, especially to meet emerging viral threats. Second, this eliminates the need for time-consuming and expensive scale-up experiments and product comparability exercises.

Outputs/Deliverables

Mechanistic model that describes the production of a viral vaccine in mammalian cell culture, allowing greater understanding of viral production in continuous culture. MRL 5 was achieved through use of mechanistic models to drive development of a continuous vaccine manufacturing process which was experimentally demonstrated at development scale at MassBiologics. Technology is being transferred to Merck for a demonstration of continuous cell culture for viral vaccine production for further MRL advancement. MIT expanded analytical capabilities with a Malvern SoPAT MM2 and integrated SMR-fluorescence microscope. MassBiologics expanded process development capabilities with purchase of bioreactors and supporting equipment.

Posters

Braatz, R. D., McNally, D., Grippe, A., & Kudugunti, S.. Continuous Cell Culture for Viral Vaccines, August 2, 2021.

Ganko, K., Hong, M., Lee, S., Grippe, A., Wagner, J., Achwei, H., McNally, D., Springs, S., Barone, P. W., & Braatz, R. D., Model-based optimization of titers and infected cells in the two-stage continuous production of a viral vaccine, January 24, 2024.

Presentations

Continuous Cell Culture for Viral Vaccines (PC2.1-036), NIIMBL Member Forum, Virtual, March 24, 2022.

Ganko, K. & Braatz, R., Mechanistic modeling to predict titers and infected cells in the two-stage continuous production of a viral vaccine, BioMAN Workshop on Application of Models in Biomanufacturing, Cambridge, MA, June 6, 2023.

Ganko, K., Hong, M., Lee, S., Provenzano, J. R., Grippe, A., Wagner, J., Achwei, H., McNally, D., Springs, S., Barone, P., & Braatz, R., Mechanistic modeling to predict titers and infected cells in the two-stage continuous production of a viral vaccine, ECI Integrated Continuous Biomanufacturing V, Sitges, Spain, October 9, 2022.