Over the past decade, the use of disposable technologies has become an integral part of biotechnological processes. Currently,
disposable bioreactors with volumes up to 1,000 L of cell culture are commercially available.39 Disposable bioreactors with small volumes (up to 20 L) are particularly popular because they provide an alternative to using
multiple shake flasks or spinner flasks for cell expansion. The perceived benefits of using disposable (single-use) technologies
are listed in Table 2. The industry also has seen tremendous improvements in available technologies for cell growth and viability
measurements. Automatic instruments for cell counting and viability measurements are now commonplace, and the next phase will
likely involve the implementation of online probes for measuring viable cell density for commercial processes. The inclusion
of viable cell density probes is important because multiple decisions, including the sequential transfer of cultures in a
bioreactor scale-up train and the feeds addition in a production bioreactor, often are dependent on the viable cell density
of the culture.
Table 2. Rationale for using disposable systems
POST COMMERCIAL ACTIVITIES AND SCALE-DOWN
As the number of commercial products in the biotechnology industry continues to grow, so does the emphasis on maintaining
consistent process and product quality. The control of raw material consistency is critical and is often challenging in the
case of complex raw materials. For complex materials like fetal bovine serum, serum fractions, or hydrolysates, it may be
hard to pinpoint the reason an excursion is observed. This is because of a lack of sufficient understanding of the specific
components present in these complex raw materials and how they affect various cellular activities.
The operation of commercial biopharmaceutical processes generates large amounts of online and offline data that are often
underused. The management of these data is challenging; equally challenging is strategizing how best to use the data. The
use of multivariate analysis as a methodology has gained popularity recently.40 The technique is capable of incorporating raw material as well as process and product data and is useful in identifying
clusters and the state of control of a process. Most importantly, the analysis can be used to identify the potential levers
that can be used to troubleshoot or improve a process. When combined with analytical and experimental data, the technique
can also be used as a raw material control strategy.
Scale-down is an equally important area, because using a good laboratory-scale model is an easy way to troubleshoot and improve
an existing commercial-scale process. An ideal scale-down model will result in cell culture performance similar to that observed
at large scale, not only in terms of growth, viability, and titer, but also in consistent metabolism and product quality attributes.
Scale-down is an uncharted territory, however, and is generally not a straightforward task. As is the case for understanding
scale-up, combined analyses using computational, genomic, and proteomic approaches hold the key to thoroughly understanding
the issues related to scale-down.
There has been enormous growth in the areas of protein expression, and cell culture over the last 30 years. Although bacterial
systems are rather established, cell culture still remains poorly understood. Table 3 summarizes the historical practices,
current and future trends, and expectations for the cell culture processes used in the biotechnology industry. With the introduction
of newer methods and technologies targeted toward understanding the fundamental mechanisms of cell physiology and metabolism,
scientists are gradually inching toward a time when they will be able to maneuver cell culture to their needs rather than
letting the cells dictate their next path forward.
Table 3. Historical practices and future trends in protein expression and cell culture
Antonio R. Moreira, PhD, is vice provost for academic affairs and a professor of chemical and biochemical engineering at the University of Maryland,
Baltimore County, Baltimore, MD, 410.455.6576, firstname.lastname@example.org