manufacturing, biosafety measures during cultivation and for inactivation will need to

be considered carefully. From the manufacturing and regulatory perspective, guar-

antee of supply and the request for a back-up system is often limiting large-scale

production with highly innovative SUB systems. In addition, the environmental im-

pact of single-use technologies has to be considered.

6.8

CONCLUSION

Over the previous decades, a deeper understanding for animal cell culture was gained,

allowing the development of robust basal growth media. Cell concentrations ex-

ceeding 1E07 cells/mL are reached in batch operations with suspension cells growing

in serum-free or chemically defined media. This improved cell handling laid the

foundation for intensified process operations, which were already successfully im-

plemented for several approved biotherapeutics, i.e., recombinant proteins. For viral

vaccine and/or vector production, initial goals for process intensification comprised

increased cell concentrations, increased viral titers, and increased VVPs and STYs.

Although most vaccine production processes still rely on adherent cell cultures or

chicken eggs, the establishment of intensified virus production platforms offers many

advantages. Facilities with significantly reduced footprints and lower volumes could

be used, allowing a rapid production of large numbers of virions. Achieving higher

cell concentrations could reduce bioreactor sizes, and therefore the use of SUB for

commercial productions. This could give manufactures the opportunity to flexibly

adapt to product changeovers and remain in the same facility throughout the entire

clinical development. Higher VVPs could increase production capacities while si-

multaneously reducing costs. However, several challenges remain. In order to go for

process intensification, new upstream and downstream tools that are capable of cul-

turing and processing high cell concentrations and high virus titers are needed. Choice

of the right cell retention device will depend on the cell and virus type used. Critical

process parameters need to be identified for each cell retention device and in-

dividually optimized. Impact of high cell concentrations on productivity, quality and

efficacy, and process-related impurities, also on downstream applications, have to be

evaluated. Many lessons will be learned from the challenges of the COVID-19

pandemic and its implications for viral vaccine manufacturing. Limitations in supply

will impact regulations to guarantee supply chains and backup solutions. A better

process understanding and more flexibility regarding process options will be needed

to avoid production limitations due to supply chain limitations.

A tendency towards platform solutions provided by only a limited number of

global players will increase dependencies. This could ultimately reduce options for

alternative process solutions and hamper the establishment of vaccine manufacturing

processes in a growing number of countries that decide to produce their own vaccines

rather than relying on resources and timely supply from other countries.

The next years will be exiting for cell culture-based virus production for vac-

cination and therapy. We are convinced that the establishment of HCD cultures and

process intensification is mandatory to provide safe and potent vaccines to supply

an increasing world population and to support future developments in gene and

cancer therapy.

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