5.6.3

CHOOSING A PRODUCTION VESSEL

Once the decision on the host cell line is made and the number of vaccine doses

required is known, the final volume of the production vessel can be chosen. Adherent

cells will need an attachment surface and large-scale production in STR requires the

use of microcarriers. In the case that packed-bed reactors are considered, macro-

carriers can be chosen. Nevertheless, some adherent cell lines are difficult to expand

in such systems, especially when serum-free or chemically defined media are re-

quired. Here, the use of roller bottles or cell stacks should be considered. Handling of

such systems with all their drawbacks can be cumbersome, but for some vaccine

production processes, especially where multiple harvesting allows to dramatically

increase virus yields, the cultivation of adherent cells can actually be advantageous.

Finally, many factors decide on the selection of production vessels: previous ex-

perience with similar manufacturing challenges, size of the facility and equipment

available, investment and running costs for equipment, utilities (electricity, water,

steam, cooling, etc.) and media, regulatory requirements, prizing of a vaccine, pro-

duction needs, location, speed to market, and qualification of staff.

With the change of using classical stainless-steel STR with up to 20,000 L to dif-

ferent disposable cultivation vessels in static or mixing mode, additional decision cri-

teria have come up. If parts of the production stream are disposable these parts will be

part of a supply chain. To be able to provide enough vaccine doses, this supply chain

needs to be guaranteed and a back-up solution needs to be available. All suppliers must

be audited and certified and should be able to guarantee a supply for at least the next 10

years. Delivery to all production facilities needs to be guaranteed and quality needs to be

constant and consistent throughout different batches. Just imagining that the disposable

bioreactor vessels of choice are not available, because they have been taken from the

market or the company selling them is not existing anymore. Or a change of supplier for

the production of the vessel is needed (plastic foil) and then the quality cannot be met

anymore. Such risks need to be well-considered and corresponding concerns might, of

course, slow down innovation at some point. Alternatively, such technology should

then be integrated into the manufacturing company or large batches of these vessels

need to be bought and for this, storage capacity needs to be considered. Nevertheless,

this explains also why currently many of these single-use technologies and new bior-

eactor designs are collected together at only a few companies.

5.7

VIRUS PRODUCTION AND PROCESS DEVELOPMENT

5.7.1

VIRUS PRODUCTION

This part now focuses on the virus production phase as the final stage of USP in cell

culture-based vaccine production (Figure 5.1). As discussed previously, viral vac-

cines can be produced in adherent or suspension cell lines. Nowadays, production

processes with suspension cells constitute the preferred choice due to an easy

scalability, improved monitoring and process control and the option for high-cell

density cultivations (see also next chapter).

In general, the cell-culture−based production of viral vaccines involves a bi-

phasic process divided into the cell growth phase (3−5 days) and the subsequent

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Bioprocessing of Viral Vaccines