Gunter Jagschies, senior director of strategic customer relations at GE Healthcare BioSciences in Uppsala, Sweden, is less
swayed by stories of bottlenecks. "You hear these stories, and at the same time, they seem to come down to existing installations
built with too small downstream processing equipment to accommodate very much higher productivity upstream. This is not so
much a problem of the technology but more of the ability to predict what would happen with cell culture," he says. Jagschies
points to case studies that indicate that 10 metric tons of product—roughly 10 times today's highest production levels—can
be made with existing technologies. The problem, as he sees it, has to do with the rate at which high-yield supernatants can
be run through a column.
"You have to process monoclonal antibodies quickly," says Jagschies. "There are problems maintaining the antibodies' stability
in liquid." The protein product is vulnerable to enzymatic degradation by proteases, with the result that the composition
of a batch at the end of an 18-hour holding period may differ from the starting composition. Theoretically, product yields
could become so high as to require several days to purify the contents of just one bioreactor. "But no one is there yet. Current
[purification] technologies can handle a batch in 12 to 18 hours," Jagschies says.
Ironically, the purification problem may be more acute for contract manufacturers and niche manufacturers, who are producing
the smallest product quantities. Current blockbusters—Genentech's anticancer drug Rituxan (rituximab), for example, or Abbott's
arthritis drug Humira (adalimumab)—enjoy billion-dollar sales because they address diseases with large patient populations.
But the day of the blockbuster may be over—even for the relatively new mAb drugs.
In coming years, niche drugs for relatively rare conditions, or targeted therapeutics that are effective for subpopulations
of patients suffering from fairly common conditions such as arthritis, will require much smaller production batches to serve
the reduced markets. But smaller batches may mean very expensive purification equipment that is not used to its maximal capacity
or for its total life span, which raises the the cost per use of such equipment. Even producers of blockbusters are looking
for lower-cost options as pressure increases on them to lower drug prices, and as they stare down the specter of competition
from follow-on biologics. In fact, cost considerations have been as much of a driver of innovation as the high product yields.
Focus on capture
Of the steps in mAb purification, the capture step receives the most attention, possibly because it's so important in trapping
the product, but also possibly because of the expense associated with it. Standard protocol relies heavily on the affinity
of human antibodies for a compound called Protein A.
In the early years of antibody purification, manufacturers relied on "natural" Protein A; that is, the protein as it was isolated
from the cell walls of the bacterium Staphylococcus aureus. These days, most commercially available Protein A has been genetically engineered and molecularly cloned. As used in a chromatography
column, Protein A is part of a resin. Resins from different vendors differ markedly to respond to the distinctive needs of
their customers, but they all share some common features. In general, this resin consists of some kind of porous bead inside
of which is a gelatinous matrix to which the Protein A is chemically affixed. The antibody product is poured through the chromatography
column, diffuses inside the beads and through the gelatinous matrix where it finds and binds to Protein A. Almost all of the
contaminants, most of which do not have an affinity for Protein A or the resin components, exit the column. In subsequent
steps, buffers are run through the column to release the antibody product from Protein A, and the now somewhat purified product
is collected and shunted into subsequent "polishing" steps.