flexibility has led to new types of manufacturing facilities that can accommodate a

growing range of different types of VBVs and can be reconfigured easily to take

high clinical trial attrition rates into account. To meet these challenges, vaccine

manufacturers, for example, those developing SARS-CoV-2 vaccines in cell cul-

tures, are adopting strategies including process intensification as they believe this

will help achieve higher product titers while reducing manufacturing footprint thus

making larger numbers of doses of VBVs more readily available.

An advantage of using cell cultures to produce VBVs is that they could poten-

tially be manufactured using process intensification. This is an approach to process

development originally pioneered in the chemical industry by the Process

Technology Group at Imperial Chemical Industries (ICI) in the United Kingdom.

The aim was to reduce plant size while increasing productivity, thus decreasing the

cost of goods (CoGs) by lessening capital investment and overhead costs [2].

Today, multiple definitions of process intensification have been developed but all

have the ultimate goal of increasing productivity.

Process intensification could be used for vaccine manufacturing, to utilize fa-

cilities with a smaller plant footprint, and less scale-up volumes to rapidly produce a

large number of doses required for mass vaccination campaigns. This is because

there are more 2,000 L scale bioreactors than 20,000 L good manufacturing practice

(GMP) compliant bioreactors which can be accessed quickly. Therefore, utilizing

an intensified cell culture process could improve overall manufacturing yield to

produce 10–20 doses of vaccine/mL, making it possible to perform 2,000 L runs

and produce sufficient vaccine for small-scale trials. For example, by increasing the

final titer of VBVs by 1 log a potential scale-up could be reduced from 20,000 L to

2,000 L, which would have a significant effect on overall production timelines [78].

Process intensification also offers the opportunity for more localized production of

VBVs in low to middle income (LMI) countries because it can provide more doses/

mL, potentially making the cost per dose lower. This will help the transfer towards

LMI countries, where having a fully closed, high titer process is essential to facilitate

GMP requirements, prevent unwanted contamination, and avoid the need for scale-up.

In this case, a scale-out would be feasible and more easily manageable than a scale-up

especially in a setting where bioprocessing skills and knowledge may be lacking.

Process intensification for VBV production is built on three pillars: equipment,

mode of operation, and technology (Figure 7.7). Many manufacturers are assessing and

adopting these pillars around process intensification, generally in a step-wise approach.

For downstream clarification of VBVs produced in intensified cell cultures by

either enveloped, shear sensitive viruses, for example the SARS-CoV-2 or measles

virus, or lytic non-enveloped viruses including adenoviruses, cell harvest and

clarification can become a bottleneck. The development of high cell densities

processes (≥20 × 10⁶ cells/mL) present several challenges because increased cell

numbers produce an increase in host cell proteins (HCPs), DNA and protein ag-

gregates, which can foul and clog filters, requiring sizeable filter areas and large

buffer volumes for VBV purification.

The most common option to help remove the excess DNA before filtration is to

use nuclease, but this is an expensive enzyme, and if a large amount of DNA is

present then higher amounts of nuclease could be required making the

Downstream processing

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