Max Planck Institute for Dynamics of Complex Technical Systems
Continuous Production of Cell Culture-derived Vaccines in a Plug-flow Tubular Bioreactor System
Using cascades of stirred tank bioreactors is a first approach for a continuous cell-culture based virus production. Another option for continuous virus production is the use of a plug-flow tubular bioreactor (PFBR) [1,2] within the cascade. As before, a chemostat is used for the continuous production of cells. However, in this set-up, virus seed is continuously added to the cells at the entry of a PFBR (Fig. 1). If the length of the tubing is adjusted to the MOI and the duration of the replication cycle, a virus harvest with defined passage number can be collected continuously at the tube outlet. The multiplicity of infection (MOI) at the point of entry is a function of the cell concentration in the chemostat, the virus concentration in the virus stock, and the flow rates, as described in Fig. 1. This has several advantages:
1) Elimination of the risk of viral antigenic variation as each cell that enters the tube is infected with a virus stock of defined passage number , and the number of additional virus passages inside the tube is limited
2) Steady-state operation allows harvesting of virus particles with defined quality attributes over extended time periods.
3) Suitable for production of viruses which show significant accumulation of defective interfering particles (DIPs) and display high mutation rates, i.e. influenza A virus [3,4,5]
Aim of the project
Design and optimization of a PFBR system for production of influenza A virus (Fig. 2)
Characterization of the system by monitoring the total number of virus particles, the concentration of infectious virions, cells and metabolites using flow cytometry, quantitative PCR, and virus assays 
Establishment of a mathematical model to describe process behavior
Process design and evaluation for other viruses and cells (optionsfor licensing and/or collaborations )
Tapia, F., Genzel, Y., Reichl U.:
Plug flow bioreactor, method containing the same and method for virus production.
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