Table 1. Productivity comparison of a continuous tubular bioreactor system versus a batch production system for production of influenza A virus.
| Bioreactor type | Description | Bioreactor working volume [mL] | Volumetric production rate [mL/h]2 | Volume produced [L] | Time required [h] | Maximum cell concentration [cells/mL] | Total cells produced [cells] | Average harvest HA titer log10 (HA units/100 μL)3 | Average harvest virus titer [virions/mL]4 | Virus production rate [virions/h] | Virus produced [virions] | TY [virions/h] | STY [virions /(L h)]5 | TY normalized [–]6 | STY normalized [–]6 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tubular bioreactor system A 1 | Bioreactor developed in this work | 711 | 12 | 7.1 | 592 | 3.0E+06 | 2.1E+10 | 2.50 | 6.4E+09 | 7.7E+10 | 4.5E+13 | 7.7E+10 | 1.4E+10 | 2.0 | 2.1 |
| Batch A 1 | Stainless steel batch | 711 | 5.93 | 7.1 | 1198 | 3.0E+06 | 2.1E+10 | 2.50 | 6.4E+09 | 3.8E+10 | 4.5E+13 | 3.8E+10 | 6.6E+09 | 1.0 | 1.0 |
| Batch B 1 | Single-use batch | 711 | 7.41 | 7.1 | 959 | 3.0E+06 | 2.1E+10 | 2.50 | 6.4E+09 | 4.7E+10 | 4.5E+13 | 4.7E+10 | 8.2E+09 | 1.3 | 1.3 |
Abbreviations: TY = time-yield; STY = space-time-yield; WV = working volume; PFBR = tubular plug flow bioreactor.
1 Continuous tubular bioreactor system with a 500 mL CSTR and 211 mL PFBR. Continuous tubular bioreactor system with 3 days of batch cell growth followed by continuous cell propagation. The virus propagation inside the PFBR takes 20 h (1 day); stainless steel batch culture (Batch A) with a cycle of 120 h or 5 days (3 days of cell growth, 1 day of virus propagation, 1 day of cleaning); single-use batch B has a 4 days cycle (no cleaning); the first harvest of both systems is assumed to be taken at 0 of culture (first harvest at outlet of tubular system and first complete batch harvest)
2 Production [mL/h] of the continuous tubular bioreactor system as used to design experiments; for batch culture, this value was calculated assuming a production of 711 mL in 4 or 5 days.
3 Average haemagglutinin (HA) titer refers to the HA of the total volume of harvest medium collected. For the continuous tubular system the HA value was estimated from HA titers between 336 and 422 h of the experiment with MDCK.SUS2 cells; for batch culture, the HA value was determined from an estimated HA titer at 24 h post infection as described by Lohr et al. 2010 [21].
4 Calculated assuming that 1 virus particle binds to 1 cell.
5 Liters [L] considers the total volume of medium consumed, including medium required to inoculate the cell bioreactors.
6 Normalized to the stainless steel batch culture (Batch A).