cooperation’s using existing infrastructures of similar vaccine production processes.

In contrast, academic approaches could only provide proof-of-principle alternatives,

but could not contribute to the establishment of manufacturing processes within the

required time frame [91,92]. Nevertheless, by integrating regulatory guidelines at

early stages of process development and establishment of a clear and focused

regulatory strategy, even academic approaches may be fast tracked at least for

animal testing and early clinical development.

5.10

OTHER POINTS TO CONSIDER

5.10.1

MANUFACTURING OPTIONS

If the vaccine type and host cell system is chosen, and dose input as well as booster

regime and annual demand are known, manufacturing scale and bioreactor vessel(s)

can be defined. Table 5.10 gives some examples of possible settings for such es-

timations for a scenario assuming a need of 1E07 infectious units/dose for a live-

attenuated vaccine and 1E09 total virions/dose for an inactivated vaccine, no

booster vaccination, a loss of 50% in downstream processing and the same CSVY

for all production modes. For an inactivated vaccine produced at 2,000 L wv in a

STR, this would require 2,667 bioreactor runs or handling of 1.3E08 roller bottles

(see Table 5.10) to cover the world supply. Even with the current SARS-CoV-2

vaccine production, one of the next vaccines designated for Europe will be pro-

duced in roller bottles using adherent Vero cells (Valneva). This exercise might help

to demonstrate that vaccine production is about producing many doses at low cost

and many parameters need to be considered at all time.

5.10.2

BIOSAFETY

Typically, viruses considered for production of vaccines will be wild type viruses

provided by WHO, NIBSC, and others. At early stages of vaccine development

even isolates from patients might be handled. If available, attenuated virus strains

will be preferred as their biosafety level will be BSL1 or BSL2. This also applies to

most of viral vectors. In the future, certainly more and more advanced methods for

genetic engineering including reverse genetics or CRISPR-Cas technologies will be

used to either modify virus strains, viral vectors or production cell lines. Then risk

assessments need to be updated accordingly. One risk that always needs to be

considered in this respect is the risk to generate a highly pathogenic virus instead of

an attenuated strain. Equally, for attenuated strains, the risk of reversion of the

attenuation will need to be addressed; likewise for inactivated vaccines, the in-

activation procedure needs to be carefully validated.

Therefore, not only efficacy and quality of vaccines, but also safety needs to be

controlled on a regular basis. Handling several viruses or subtypes in parallel could

promote unwanted recombinations or generation of new subtypes (i.e., for IAV).

Furthermore, cross-contaminations in cell culture as well as contaminations of

media, cell lines, or virus seeds should be checked on a regular basis.

Upstream processing for viral vaccines

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