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Achwei, Helen

Barone, Paul W.

Braatz,, Richard D.

Ganko, Krystian

Grippe, Anthony

Hong, Moo Sun

Lee, Sangmook

McNally, David

Provenzano, Joules

Schickel, Kaylee C.

Springs, Stacy L.

Wagner, James

English

Engineering Conferences International

Monday, October 10, 2022                    Session 2:  Continuous manufacturing of emerging therapeutic modalities MECHANISTIC MODELLING TO PREDICT TITERS AND INFECTED CELLS IN  THE TWO-STAGE CONTINUOUS PRODUCTION OF A VIRAL VACCINE   Krystian Ganko, Massachusetts Institute of Technology, USA kkganko@mit.edu Moo Sun Hong, Massachusetts Institute of Technology, USA Sangmook Lee, MassBiologics Kaylee C. Schickel, Massachusetts Institute of Technology, USA Joules Provenzano, Massachusetts Institute of Technology, USA Anthony Grippe, Merck and Co. James Wagner, Merck and Co. Helen Achwei, MassBiologics David McNally, MassBiologics Stacy L. Springs, Massachusetts Institute of Technology, USA Paul W. Barone, Massachusetts Institute of Technology, USA Richard D. Braatz, Massachusetts Institute of Technology, USA  Key Words: Continuous vaccine production, viral vaccine manufacturing, mechanistic modelling  The biopharmaceutical industry has shown significant interest in developing continuous manufacturing processes for therapeutic protein production [1]. Despite this progress, continuous manufacturing approaches have yet to be widely applied to cell cultures for live virus vaccine manufacturing, due in part to the increased biological complexity involved in the manufacture of viral vaccines relative to the production of recombinant protein therapeutics. The COVID-19 pandemic has highlighted a growing need for increased overall vaccine production capacity and improved approaches to rapid scale up. As such, there is a substantial need to improve the flexibility, reproducibility, scalability, cost, and speed of vaccine development and commercialization, which requires the development of next-generation vaccine manufacturing technologies. Continuous vaccine manufacturing, together with first-principles / mechanistic modeling of the manufacturing process, is one potential solution. This presentation describes the application of mechanistic modeling and systems engineering concepts to rigorously identify and reliably predict the aged-cell infection trajectories of a suspension-adapted Cutter Laboratories Dog Kidney (sCLDK) cell line infected with a recombinant Newcastle Disease Virus (NDV) based vaccine candidate in a two-stage continuous production setup (Figure 1). In this host-virus system, defective interfering particles (DIPs) of NDV are suspected to compete for host cells with the desired fully infectious standard virus (STV) product [2]. Moreover, cell aging effects due to extended time-scale process operation relative to batch production can contribute to poorer infection and lower infectious titers. PAT-enabled batch and continuous infection experiments, infectivity model numerical simulations, and domain knowledge are all combined to demonstrate that measured viral titers are best predicted in a two-stage continuous setup with a lytic death-modified, two-predator-type competition model. Moreover, host cell aging effects on infectious titers, which are demonstrated to decrease up to four-fold within 30 cell passages, are shown to be well-predicted by adding smooth exponential structures into sensitive infectivity model parameters. Overall, these results build our understanding of the infection processes taking place during continuous viral vaccine manufacturing, highlighting key considerations and potential limitations for continuous live virus production. This work was performed under a Project Award Agreement from the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and financial assistance award 70NANB17H002 from the U.S. Department of Commerce, National Institute of Standards and Technology.  [1] K.B. Konstantinov & C.L. Cooney. White paper on continuous bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci., 104(3), 813–820, 2015 [2] M. Vignuzzi & C.B. López. Defective viral genomes are key drivers of the virus–host interaction. Nature Microbiology, 4, 1075–1087, 2019 Figure 1 – A two-stage continuous platform for compartmentalizing suspension line growth and viral infection. 

Mechanistic modeling to predict titers and infected cells in the two-stage continuous production of a viral vaccine

https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1008&context=biomanufact_v&type=additional

Mechanistic modeling to predict titers and infected cells in the two-stage continuous production of a viral vaccine

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Engineering Conferences International