Discussion and Conclusion
The aim of this study was to asses a disposable bioreactor in combination with a disposable probe for a fed-batch MAb production
process. The equipment chosen was the HyClone SUB coupled to the TruLogic RDPD controller and the disposable TruFluor DO probe
by Finesse Solutions. The single-use DO sensor showed comparable results to conventional ones. The equipment was readily implemented
because the set-up time was only one day.
The SUB gave results comparable to the 5-L glass vessel bioreactor (small-scale reference for the process) for the seed train
and the production steps. This shows that despite different material, agitation, and aeration, the disposable bioreactor had
a performance similar to standard bioreactors, at least for the fed-batch process tested here. The scale-up to 50-L also was
straightforward. Given that all HyClone disposable bioreactors have the same overall reactor geometry ratio up to 2,000 L,
it can be expected that the scale-up to larger volumes such as 300 L could be performed using the same principles. The scale-up
to a higher volume such as 1,000 L could be more complex because process scale-up is rarely linear between such different
scales.
The single-use bioreactor showed the capacity to be used either as a seed train bioreactor or a production bioreactor, or
both. If this double use is to be implemented, the bag aeration configuration should be carefully defined to be able to cope
with different oxygen demand in cell expansion and production. In this case, the same bag was used for both phases, a limitation
in oxygen flow rate appeared toward the end of the culture.
The bioprocess container bag used for these experiments was equipped with a 20-mm sparger membrane. The bubbles released by
this system were small enough to have sufficient oxygen transfer to the culture, but big enough to strip CO2. The bag is now available with a dual sparge system, consisting in a 20-mm porous frit for the oxygen transfer and an open
pipe for CO2 stripping, enlarging the range for pCO2 stripping. Many different disposable bioreactors systems coexist on the market and new versions are frequently released,
showing the high dynamism of single-use technology. Each system presents its own features and advantages. Some other disposable
bioreactors currently are being assessed in our company.5
This study enabled us to demonstrate the applicability of using a single-use bioreactor for producing a MAb at 50-L scale,
and we can expect that further scale-up to at least 300-L can be achieved. In the future, it can be expected that disposable
bioreactors will become far more common in biopharmaceutical manufacturing. Their use is of specific interest when producing
material for early clinical trials to avoid a capital investment early, when the final production bioreactor volume, as well
as the future of the molecule, are unknown. Some people claim that the use of disposable bioreactors also has big advantages
when building a new facility, because the need for utilities might be reduced in a fully disposable environment, therefore
reducing start up time, installation costs, and campaign turnaround.6 On the other hand, some concerns exist about the environmental impact of disposables, although assessing the latter is far
from simple. The reduced use of purified water, clean and pure steam, and cleaning chemicals compared to stainless equipment
has to be balanced with the increased plastic waste. One way to reduce the impact of such waste could be to convert back part
of the 32.6 GJ/ton of energy stored in plastic in waste-to-energy incineration facilities, not necessarily solving the issue
of carbon footprint.7 The ultimate solution might reside in recycling these disposable products, requiring further development on innovative transformation
methods. Some other interesting future directions with respect to single-use bioreactors could be the development of systems
for perfusion process applications, as well as more insights on leachables and extractables.
Emmanuelle Cameau is a biotech process sciences upstream specialist, Georges De Abreu is a biotech central services manager, Alain Desgeorges, PhD, is a biotech process sciences upstream coordinator, Elodie Charbaut Taland, PhD, is a biotech process sciences manager, and Henri Kornmann, PhD, is a biotechnology production director, all at Merck Serono SA, Aubonne, Switzerland, +41(0)218217111, emmanuelle.cameau@merckserono.net
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