Twenty-five years ago, as today, selection of the bioreactor used for large-scale cell culture was a key component of the
success of the production process (1). Kim L. Nelson, PhD, the orginal author of the paper, now director of strategic consulting
at CRB Consulting Engineers talks to BioPharm International about bioreactor design for large-scale mammalian cell culture.
BioPharm: In 1988, the size limits for suspension mammalian-cell culture ranged from 8000–10,000 L. Is that still the case?
Nelson: Much has changed in the last 25 years, and the upper limits of mammalian cell-culture suspension bioreactors have increased
dramatically. Currently, the largest bioreactors are 25,000 L for suspension cell culture, and around 5,000 L for microcarrier
cell culture. It's ironic, however, the increasing titers being achieved in cell culture today may actually make these scale
systems unnecessary. The required scale of bioreactors necessary to meet market demands are coming down, in some cases to
the point where single-use bioreactors are feasible for commercial products (2).
BioPharm: Given the evolution of production-grade cell lines, is genetic stability still the most important determinant of scale-up
Nelson: Genetic stability is still paramount in a production cell line. If the cell line is unstable, it is unsuitable for large-scale
culture and GMP production. Metabolic potential, however, is also now a key requirement for production cell lines. Understanding
a cell line's metabolism and nutrient demands helps achieve successful commercial-scale production.. The fed-batch processes
used today are quite sophisticated in their feeding strategies, and have produced phenomenal results (2). Such productivity
has been achieved by numerous companies, and once developed, can often be rapidly re-optimized for subsequent projects that
use the same host cell line.
BioPharm: Is a stirred-tank bioreactor still the most common choice for a large-scale bioreactor?
Nelson: Yes, stirred-tank bioreactors are still the mainstay of cell-culture based biopharmaceutical production. There are also a
variety of other, specialized, bioreactors that have been marketed over the years, a number of which are intended for adherent
cells and vaccine production. The traditional stainless-steel bioreactor designs offered by the equipment suppliers have been
standardized, with a menu of options such as different impellers, or sparging systems. Even specialized (and effective) perfusion
systems are being marketed that allow very sizable perfusion bioreactor systems. The industry is increasingly turning toward
single-use bioreactors. In this area we are seeing an explosion of novel bioreactor designs each trying to gain a foothold
in this market. Again, the stirred-tank bioreactor is emerging as the single-use system of choice for larger volume commercial
1. K.L. Nelson, BioPharm. Int. 1 (2), 42–46 (1988).
2. J. P. Smelko et al., Biotechnol. Prog. 27 (5), 1358–1364 (2011).