Facing the Challenges in Vaccine Upstream Bioprocessing - 18

Facing the Challenges in Vaccine Upstream Bioprocessing * Integrated Continuous Manufacturing of Biologics: Trends in the Field

for integrated continuous manufacturing are
products for which there are particular challenges
in using batch operations. For example, a highly
labile product that degrades over time would
benefit dramatically from the use of a continuous
process-this is why perfusion bioreactors were
originally used for production of unstable clotting
factors. On the other hand, integrated continuous
manufacturing is well suited for products that
have very high-volume demand or significant cost
constraints. The successful development of integrated manufacturing systems will likely require
considerable product and process knowledge,
which today is most readily available for mAb
products due to the large number of these products already in commercial manufacture.
Dr. Lacki: I would rather ask a different question:
What type of expression systems or upstream
technologies are more suited for continuous
operation? And my answer would be perfusion
operation or even [use of] six-pack fed-batch
bioreactors would make an operation quasicontinuous. That said, I think that a successful
continuous biomanufacturing process must be
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as simple, or rather, as robust, as possible. For
instance, a downstream process that relies on
as few chromatography steps as possible will
be more suited for continuous operations. From
that perspective, one could argue that an affinity
step is an enabler for continuous downstream
operation. Cost of an affinity resin will be lower if
it is operated in a continuous manner, but even
without that, the benefit of normalizing a product
stream through a selective capture step would
deliver so many advantages from the process
reproducibility and controllability perspective that the cost of the resin need not even be
considered.
Mr. Zijlstra: I would say [the most feasible type
of therapies would be] primarily labile products
that require perfusion and immediate capture
from the cell broth to prevent product degradation. Some cost-model studies also suggest that
beyond certain annual production scales, integrated continuous biomanufacturing leads to
lower COGs for mAbs and are preferable in that
case. Finally, evidence is mounting that even for
mAbs, (critical) product quality attributes can be

controlled much more tightly [in continuous than]
in batch operational mode.
GEN: The manufacturers of Prezista (Janssen), a
small-molecule drug, got FDA approval to change
its processes to a continuous method. To your
knowledge, are any biologics manufacturers
looking into a similar manufacturing change?
Do you think manufacturers are more likely to
address the end-to-end manufacture of a totally
new product, rather than for an existing product?
Dr. Najera: While it is easy to understand why
people draw parallels between small molecules
and large molecules, it is important to note that
control of small vs. large molecules is significantly
different. For small molecules, it is relatively easy
to understand all impurities and variants through
analytical testing. This is not always possible
for large molecules. For this reason, continuous
processing and process analytical testing (PAT) are
often linked. Even with the challenges large molecules pose, there are many companies presenting
compelling small-scale data on continuous purification strategies. However, these processes are

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Facing the Challenges in Vaccine Upstream Bioprocessing

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