Rational approaches for cell-line engineering, combined with a concise media selection program and straight process development
efforts, significantly increase the probability of generating such high-yielding cell lines. In most cases, dozens of grams
of clinical-grade protein can be provided for Phase I clinical trials 15 months after cell transfection. Growing the throughput
of different types of proteins through the facility by applying a combination of different approaches described earlier increases
the predictability of protein yields per batch. High flexibility, advanced process science, tailor-made processes, and significant
capacities are the major performance criteria of the plant.
Table 4. Experiences with Different Proteins at Berlin Pilot Plant
CHALLENGES FOR PLANTS WITH DISPOSABLE BIOREACTORS
Various disposable bioreactor systems are currently on the market. We have summarized our experiences with two of them. The
major obstacles both wave and hollow-fiber systems face are:
- Limitation in scale
- Limited supplier sources
- Limited experiences in facility design and operation.
The AcuSyst hollow-fiber bioreactor family is limited by its largest system (AcuSyst XCELLERATOR) to 20 simultaneous cartridges
in continuous perfusion. The WAVE family is limited to 500 L net culture volume per batch. The basic design of a commercial
plant, equipped with single-use technology, revealed low capital expenditures. This is in accord with independent estimates
for a biomanufacturing modular concept facility combined with single-use technology that was presented by Stedim and Applicon
Corporations at bioLOGICS 2004 in Geneva,20 and with other reports in the literature.21, 22
Validated processes are the prerequisites for construction and validation of such a commercial plant. Demands for low-volume,
highly potent proteins of a few kilograms net product per year will favor single-use technology.
Within the next 10 to 15 years, market trends will lead to a growing demand for highly flexible, multi-product plants that
can produce an average annual capacity of 10 to 100 kg of purified mammalian cell-expressed protein. A new generation of large-scale,
disposable, linear- scalable, high-performance bioreactors will meet the industry's growing need for fully disposable manufacturing
Rene Brecht, Ph.D., vice president process science and manufacturing, ProBioGen AG, Goethestrasse 54 13086 Berlin, Germany 49.30.924.006.40, fax 49.30.924.006.19 firstname.lastname@example.org
Volker Sandig, Ph.D., email@example.com
Susann Koch, firstname.lastname@example.org
Uwe Marx, Ph.D., email@example.com
Marco Riedel, Ph.D., firstname.lastname@example.org
1. Melmer G, Biopharmaceuticals and the industrial environment. In. G. Gelissen: Production of recombinant proteins. Wiley-VCH,
6. Sandig V, Rose Th, Winkler K, Brecht R: Mammalian cells. In. G. Gelissen: Production of recombinant proteins. Wiley-VCH,
7. Nagel A, Koch S, Valley U, Emmrich F, Marx U: Membrane based cell culture systems – an alternative to in vivo production of monoclonal antibodies. Dev. Biol. Stand., Karger, 1999; 101:57-64.