The news today that DSM Biologics and Crucell N.V. had again scaled up production of the PER.C6 cell line was another sign that biopharma cell culture capacity concerns are (probably) a thing of the past, and that PER.C6 represents a breakthrough. Who better to consult with than Eric Langer of BioPlan Associates, whose annual biopharma capacity and production report is a key industrywide gauge. Langer was gracious enough to respond to our emailed questions:
Q: What is the general view on cell culture capacity at present? Are there still concerns of a "capacity crunch”?
Langer: The capacity crunch that occurred 5-6 years ago is long over, at least for the time being. But the solutions to that situation are debatable. Based on the results of our 5th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production this past year, capacity utilization has remained essentially steady for mammalian cell culture, at 63.3%, vs. 63.9% the year before. This leveling-off of the fluctuations in manufacturing capacity suggests that companies are either using their existing capacity more efficiently (planning more effectively), or are taking advantage of advances in production technology, especially upstream. It’s likely a combination of both. In 2003, the biopharmaceutical industry’s utilization rates exceeded 76%. This was a capacity-crunch time that led to facility build-outs by both biotherapeutic developers and contract manufacturers. The resulting expanded capacity brought the utilization rate down so that by 2006 it appeared that a stable capacity utilization rate would be around 63%. Today, smoothed-out biopharmaceutical industry utilization rates are due primarily to improved planning by manufacturers, and the lack of any major blockbuster drugs that might absorb substantial industry capacity.
Q: The PER.C6 cell development has been watched with interest for its potential to boost and simplify production of therapeutic proteins. Is this another significant step?
Langer: The human PER.C6 cell line is fast becoming a major host cell line and platform technology. In BioPlan’s newest report, “Biopharmaceutical Expression Systems: Current and Future Platforms,” we compare this with over 400 other platforms. The PER.C6 cell line was designed from the start for recombinant glycoprotein, including antibodies, manufacture at high yields, with human-like glycosylation. The cells harbor and express the adenovirus E1B gene; a well-known inhibitor of apoptosis (programmed cell death). The high cell number directly accounts for record high yields of antibody expression achieved with the cell line.
In June 2008, DSM Biologics and Crucell N.V. announced a breakthrough—the production of IgG antibodies using the PER.C6 cell line (and XD technology) to produce a record yield of an unspecified "regular" (presumably human or humanized) antibody at over 27 grams/Liter (with over 95% viability and unchanged product quality). In March 2008, achievement of 15 grams per liter had been reported. This new record surpasses all other mammalian cell recombinant protein production systems. Also, the production scale potential of the cell line has been demonstrated in an unprecedented successful bioreactor run of 20,000 liters.
In addition, the PER.C6 technology can be used in a variety of culture formats and has been made suitable to perform well in a variety of production processes including batch, fed-batch and perfusion. Most of the other technologies cited in our reference as relevant to or useful with CHO cells, NS0 cells, other human and mammalian host cell lines are useful with PER.C6 cells. Although no products using PER.C6 have been approved, many PER.C6 produced products have been in the clinic, with several in or heading for Phase III trials. Licensees to PER.C6 cells can review and refer to the FDA BMF in their regulatory submissions, thereby potentially saving time and cost for regulatory approvals. The Biologics Master File, initially filed with FDA in 1999, is updated on an annual basis in collaboration with Merck & Co., one of Crucell's PER.C6 licensees.