With hundreds of products in development, and blockbusters already on the market, monoclonal antibodies (mAbs) remain the
single most important product group driving the biopharmaceutical industry's development today (1). The selectivity and flexibility
of their mode of action provide the potential for successful therapeutic strategies against medical conditions that, until
recently had no effective treatments, let alone a cure.
mAb therapies typically require relatively high doses. Thus, the necessary product quantities are associated with high-volume
production facilities in which mammalian-cell–culture processes running in multiple 10,000–20,000 L working-volume bioreactors
play an important role in the design and cost of the facility.
As a consequence, commercializing a mAb product has gone hand-in-hand with a significant capital expense if the market strategy
included a decision to build a production facility. Historically, the scale of the operation and the necessary technology
have led to considerable total installed costs that often are in or above the $100–300 million range. Although strategic decisions
to go this route have resulted in bringing important products to patients and mitigating risk of capacity limitations, price
tags are of such an order that the facility can represent a future burden (2).
The biopharmaceutical industry is now poised to undergo a transition influenced by trends such as market differentiation,
expiring patents, an increase in biosimilars, excess capacity, and governmental initiatives to reduce the cost of healthcare
(3). These trends are very real for mAbs because the product group continues to shape the biopharmaceutical industry and drive
the design of production facilities that will match this transformed landscape.
Dramatic increases in cell-culture yields make it possible to significantly reduce bioreactor volume, thereby making single-use
technology a viable alternative to stainless-steel bioreactors. Market segmentation resulting from personalized medicine and
biomarkers will result in smaller product campaigns. Not only will new facilities become smaller and more flexible, but also
new process technology will make these facilities more efficient, cost effective, and better able to adapt to changes in market
demand. Moreover, process intensification and single-use technology will result in greener facilities with a reduced CO2-footprint.
Advances in cell-culture technology ranging from new cell lines, improved media compositions, and optimized process conditions
have all contributed to a marked increase in mAb titers compared with the situation in the mid-to-late 1990s, when the first
production facilities where designed. Statements from industry leaders cite titers of 3–5 g/L as the new reality for products
in production, while some products in development come with titers of 8–10 g/L (4). Current state-of-the-art technologies
forecast that titers in the 10–15 g/L range are possible before process limitations come into play. The recent year's strong
focus on optimizing the upstream process has resulted in 10–100-fold increases during the past 10 years, even for the traditional
industry workhorse, the Chinese hamster ovary (CHO) cell line (5).
For next-generation cell lines such as the PER.C6 cell line from Percivia (Cambridge, MA), the perspective is further illustrated
by a combination with novel process technology. Derived from the human retina, the cell line is optimized for protein production,
and mAb titers of 8 g/L have been reported. In combination with Percivia's XD-process (a perfusion process with both cell
and product retention over a continually flushed, hollow-fiber membrane that allows feeding of fresh nutrients to the bioreactor
while waste products are being removed), the cell line has demonstrated concentrations of 27 g/L(6). Titers of this order
change the current understanding of a typical mAb process design that has settled on variations of the process generalization
(see Figure 1).
The future challenge will be to optimize the downstream processes in a design space confined by physical and chemical conditions
(e.g., mass transport, binding rates) as opposed to optimizing output from a biological system (volume driven) in which output
increases with cell viability and concentration. With high titers such as those from the XD-process, the industry enters a
level of processing where some loss in the subsequent capture process can be accepted. Alternatives to the classical protein
affinity capture column based on precipitation or membrane chromatography processes are thus becoming realistic (7).