Production of Bovine Ephemeral Fever Virus (BEFV)using TideCell Bioreactor System

Comparison study Due to significant difference in characteristics of virus strain and host cell line, the optimal process of virus production can be significantly different. In the following slides are requirement of conditions for this specific case of study, on which comparison of TideCell/BelloCell system and other commonly used systems are based.

1. High cell density is required to achieve high titer, and reduce medium consumption High surface area provided in TideCell increase cell density up to 10 folds. Roller bottle: low cell density due to limitation of surface area Microcarrier system: the bead density is limited Fixed bed bioreactor system: Yes, but the scale is limited.

2. Cells tend to detach during post- infection period. TideCell: Low shear stress enables cells protected inside the matrix and not detach after infection Roller bottles: Shear stress is low. Microcarrier system and fixed bed system. Shear stress is higher.Cells tend to detach during post-infection period

3. Infection time is crucial. Easy to take carrier sample for cell counting and MOI calculation. Roller bottle: Can decide the infection time by observing the confluency from the bottles. But no exact cell density. MOI calcuation is rough. Microcarrier system. Carrier sample can be taken for cell counting. Fixed bed bioreactor: cannot take sample. Indirect estimation by DO or GUR is required. Difficult to calculate MOI.

4. Glucose consumption rate is low which makes the perfusion process difficult. Batch or fed-batch process is thus required. TideCell: Able to adjust matrix to culture medium ratio to 1:25 and enable to perform a fed-batch to batch process. Microcarrier system. Not able to adjust matrix to medium volume ratio, unless to reduce microcarrier density for running batch process. Fixed bed bioreactor: Not able to adjust matrix to medium volume ratio. Fed batch or batch process is not possible.

5. Linear scale-up to reduce process development time BelloCell with 500 ml working volume and TideCell-020 with 500 L working volume reaches similar virus output (Log TCID50: 9.2 in BelloCell, 9.0 in TideCell -020) Roller bottle: directly increase bottle number for scale up. Microcarrier system: process development is time consuming. Fixed bed bioreactor: Not able to scale up due to scale limitation.

Final Results TideCell TCID50 log 9.0 (scale of 500 L) BelloCell: TCID50 Log 9.2 (scale of 0.5 L) Fixed bed bioreactor: TCID50 Log 8.5 (scale of 2 L)

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