Geoffrey Hodge
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Cell culture productivity has increased dramatically over the last few decades. This productivity increase is due in
large part to significant process development efforts in this area, efforts traditionally justified by the economic benefit
of improving productivity. The economic pressure to increase productivity has been highlighted in recent years by the success
of monoclonal antibodies, some of which have market requirements in the hundred-kilogram-per-year range. The demand for such
large quantities of protein has, in turn, triggered concerns about a potential shortage of manufacturing capacity, intensifying
the pressure to boost cell culture productivity.1
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Development scientists have responded to this challenge admirably. Monoclonal antibody titers in cell culture have increased
roughly tenfold, from a few hundred milligrams per liter a decade ago to grams per liter today, with reports of titers in
excess of 5 grams per liter. If an industry-wide shortage of bioreactor capacity fails to materialize, this will be due not
only to the recent burst in the construction of new manufacturing capacity, but also to the reduction of demand resulting
from improvements in cell culture productivity.2
Evolution of Mammalian Cell Culture Media
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In addition to the strategic advantage of reducing the requirement for bioreactor capacity, increasing titer can have a significant
impact on the cost of goods sold (COGS). Case studies show that a fourfold improvement in titer can cut COGS by one-half.3 Cell culture development has been so successful that downstream processing is beginning to surface in discussions as the
next bottleneck to be addressed. Although the gain in COGS from increasing cell culture productivity may diminish due to
the increasing impact of downstream steps as titers continue to improve, optimizing bioreactor output is still a primary concern
for most companies.
The steady increase in cell culture productivity is the result of intensive efforts to understand and optimize all aspects
of the cell culture production process.Improvements have been made in molecular biology, cell line construction and selection,
media and feed development, and bioreactor operating parameters. But arguably it is media and feed development, particularly
feed development, that has been responsible for the largest share of this improvement.
MEDIA DEVELOPMENT CONSIDERATIONS
While the strategic impact of decreasing capacity requirements and COGS makes boosting productivity a primary goal, it is
but one of several important aspects to be considered when selecting or developing media. Others include safety (to assure
patients are not adversely affected by therapeutics intended to improve quality of life), quality, robustness, economics,
and operability.
Safety
Safety and the related requirements of product quality and regulatory compliance are achieved mainly through control of raw
materials for media. Introduction of contaminants via raw materials may be possible at any step in a biomanufacturing process,
but cell culture media pose a higher risk because the cell culture processes provide an opportunity for co-cultivation of
microbes and replication of adventitious agents that may infect cells. This concern, which has been a driving force in the
trend toward eliminating serum from media, has been deepened by an increasing awareness of transmissible spongiform encephalopathies.
Through good processing, controls, and documentation, manufacturers of serum may reduce the risk of a transmissible pathogen
reaching patients. The impossibility of reducing the risk to zero, along with the increasing regulatory burden of assuring
safety, has led to a strong effort to eliminate serum from cell culture media. This same concern has expanded to other animal-derived
raw materials, and thus, many media are now "animal-free."
Quality
Comparability questions can arise from changing media in an established process. Changes in media may directly impact product
characteristics such as glycosylation, or may alter cell culture conditions, subsequently impacting downstream steps. Introduction
of new raw materials may also introduce new contaminants into the process stream. Even animal-free media may contain contaminants
such as endotoxins, mycotoxins, or immunogenic compounds.4 Changes to media in an established process must be carefully
assessed.
