In the first scenario, a company operating Phase III clinical-trial manufacturing at full scale (10,000–15,000 L bioreactors
or larger) does not keep its process scale small or sufficient enough to make only the amount of product they require for
the study. The quantities of raw materials and consumables to be purchased at scale, as a result, constitute a significant
cost to the company's research and development (R&D) budget. Worse, resins and other consumables cannot be used for their
full lifetime.
In the second scenario, a company producing small quantities (as much as a few hundred kilograms) in the same size bioreactors
as the first company faces the same issue. Very few batches are run, and the resins are not used for their full lifetime.
Pricing of consumables, however, follows the economic value of the products where lifetime is a significant factor. In large
facilities, things can get quite expensive in this case.
Will these factors lead to the end of the dinosaurs in biopharmaceutical manufacturing? Or will they serve as the beginning
of a single-use age?
Most forecasters agree that very few new antibodies will require large, ton-scale production, or even more than a few hundred
kilograms. Product titers at 5 g/L will allow companies to manufacture annual quantities in bioreactors as small as 500 L,
certainly in 1000 L. This scale isssue cannot be ignored much longer. Companies will need to adopt the entire scale-up strategy,
including the planning of clinical manufacturing. Facilities of the future could be built with a few different bioreactor
sizes, none larger than 2000 L. Most future facility models may also include disposable equipment, assuming the equipment
can play an important role after a thorough cost-benefit analysis is completed for potential use. In some cases, the benefits
of disposables are small or nonexistent; individual case studies are necessary. There is also a scale limitation to consider
when thinking about using disposables.
Regardless of the presence of disposables, most important in new facility designs will be the responsiveness of the facility
to changing demands and its ability to accommodate new products at different scales while addressing cost concerns.
The real paradigm shift will happen when companies move new production away from the dinosaur bioreactor farms and leave it
to the first-generation legacy processes that industry has agreed may be suboptimal but "best to keep." Technical bottleneck
issues and related cost concerns would disappear momentarily.
This true "paradigm shift" would represent a fundamental change in manufacturing strategy. This article is not trying to talk
industry into keeping the status quo. Rather, it's about looking for improvements in the right places and following the good
old 80:20 rule, in which you solve 80% of the problem first and thereby gain 80% of the benefit. Relevant cost reductions
are not likely to be found in alternative technologies alone. Suboptimal, inherited facilities and process designs, as well
as overdimensioning of production, are today's true cost drivers.
Günter Jagschies, PhD, is a senior director of strategic customer relations at GE Healthcare Life Science Biotechnologies R&D, Björkgatan 30 S-75184,
Uppsala, Sweden, tel. +46 18 6120880, fax +46 18 6121863, guenter.jagschies@ge.com
Reference
1. B. Kelley, "Very Large Scale Monoclonal Antibody Purification: The Case for Conventional Unit Operations," Biotechnol. Prog.,
23, 995–1008 (2007).
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