Symbols

6.1

INTRODUCTION

In the previous chapter, general aspects of cell culture-based virus production were

presented. Increasing world population, pandemic threats, high costs, and new

applications demanding large virus quantities, i.e. gene or cancer therapy, increase

the pressure to identify innovative solutions to intensify the conventional virus

production processes. In 2019, the yearly global vaccine production was estimated

to be between 3.5 billion and 5.5 billion doses of all vaccines [1]. With the current

2019 outbreak of the coronavirus SARS-CoV-2, assuming a two-dose regiment just

for COVID-19 vaccines, approximately 12 billion doses would be required to

vaccinate the 6 billion vaccine-eligible humans worldwide. Moreover, emerging

markets for gene therapies and gene-modified cell therapies further escalate the

need for more efficient production processes. It becomes very clear that classical

virus production capacities are not sufficient to meet this increasing demand.

According to the EMA (European Medicines Agency), gene therapy medicines

consist of a “vector or delivery formulation/system containing a genetic construct

engineered to express a specific transgene (therapeutic sequence) for the regulation,

repair, replacement, addition, or deletion of a genetic sequence” [2]. While CAR T-

cell therapies (chimeric antigen receptor T-cell) already require a relatively high

CSVY

Cell-specific virus yield

virions/cell

cVir

Virus particle concentration

virions/mL

cS

Substrate concentration

mM

cX

Cell concentration

cells/mL

D

Dilution rate

1/h

kLa

Oxygen transfer coefficient

1/h

MOI

Multiplicity of infection

infectious units/cell

PFU

Plaque forming units

PFU/mL

pO2

Partial pressure of oxygen

%

RV

Reactor volume

mL

RT

Residence time

h

SRID

Single radial immunodiffusion

HAU/(µg/mL)

STY

Space-time yield

virions/RV/d

T

Temperature

°C

TCID50

Tissue culture infectious dose 50

TCID50/mL

TOH

Time of harvest

h

TOI

Time of infection

h

ttot

Total process time

h

VVP

Volumetric virus productivity

virions/L/d

Vtot

Total volume of spent medium

L

wv

Working volume

L

µ

Specific cell growth rate

1/h

µmax

Maximum specific cell growth rate

1/h

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Bioprocessing of Viral Vaccines