similar yields compared to an ATF-based process were achieved. The usage of a

heat exchanger was identified as a crucial parameter to obtain high virus titers [62].

However, at the used scale, the dead volume within this CRD was very large. How

this translates at large-scale processes still has to be investigated. Another study by

Alvim et al. applied an inclined settler to the production of yellow fever virus

like particles (VLPs) using suspension HEK293 cells. Cell concentrations of

42E06 cells/mL were obtained further highlighting the potential of inclined settlers

for the production of viruses and VLPs [85].

6.6.6

HYDROCYCLONE

The hydrocyclone is the simplest type of centrifugal separators, in which the ro-

tating motion is induced by the liquid flowing through one or more tangentially

arranged inlets at the head of the system. The apparatus consists of a conical section

connected to a cylindrical portion at the upper part through which clarified super-

natant can be harvested. A simplified overview and description of the hydrocyclone

setup is shown in Figure 6.9.

By injecting the cell broth tangentially at a high flow rate, a strong swirling

downward vortex is generated. Resulting centrifugal forces disperse cells radially

Feed pump

Balance

Weight control

Permeate pump

Spent medium

Inclined settler

Heat

exchanger

Feed

medium

FIGURE 6.8 Schematic illustration of an inclined settler setup for perfusion processes. The

cell broth is pumped through in the lower part of the settler and gravitational forces drive the

cells towards the lower surface of each lamella. Once settled, the cells slide down in a layer

towards the plate periphery and are transferred back into the bioreactor. Cell-free supernatant

is constantly removed from the top part of the settler, allowing fresh medium to be added to

the bioreactor. Figure adapted from [ 65].

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Bioprocessing of Viral Vaccines