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).
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).