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Feature Articles : Apr 15, 2008 ( )
Downstream Bottlenecks: Are They Myth or Reality?
Throughput Isn’t Where It Should Be, and There Is Some Disagreement as to Why!--h2>
Like the story of the blind men describing an elephant, the answer to whether a downstream bioprocessing bottleneck exists is largely one of perception.
“The situation is even worse than it was two years ago,” according to Uwe Gottschalk, Ph.D., vp of purification technology, a business unit of Sartorius Stedim Biotech. Ann O’Hara, GM of life science services at GE Healthcare Life Sciences, counters that the presence or lack of a bottleneck “is a matter of optimization. The solutions are here.”
“The issue is partly a matter of optimization and partly the nature of operations,” elaborates Daniel Van Plew, vp and GM of industrial operations and product supply at Regeneron Pharmaceuticals.
Manufacturers generally seem to favor the optimization argument. Whatever it’s called, though, everybody agrees that throughput isn’t what it should be. Managers and scientists within the biotech community are finally aware of the challenge, and vendors are beginning to work to solve it.
The lack of awareness comes largely from the way scientists are trained. “You’re either an upstream expert or a downstream expert,” Dr. Gottschalk explains, “and managers don’t listen to both equally.” It’s similar to the long-touted disconnect between information technology and management, in which business units don’t speak the language of IT, and IT doesn’t speak the language of business. The outcome, in biotech, is a gap in which upstream cell culture advances have outpaced downstream separation and purification advances.
Upstream operations have been an area of focus for a long time because the industry feared a capacity shortage. As you may recall, about 10 years ago, manufacturers were bemoaning the lack of cell culture capacity, and conference presentations deftly outlined a capacity crunch that would leave mAb producers, in particular, woefully short, even if massive investments were made in new facilities. The industry rallied to the challenge. Batches were optimized to become more productive for longer periods. Titers increased.
“At the turn of the century, fermentation was very diluted, and water was the number one contaminant,” recounts O’Hara. Removing the water led to affinity chromatography. Improvements upstream led to much less water, perhaps one-tenth, being used. “Whenever you have improvements like that, the next step shows a burden, so even though the next step may become twice as effective, it doesn’t match.”
With those advances, Van Plew says, “sixty to seventy percent of the titers today are in the one to three grams per liter range.” At titers of one gram per liter, “we’re seeing large cell culture capacities of 15,000 to 25,000 liter bioreactors in sets of four or six,” says Duncan Lowe, Ph.D., scientific executive director, process development, at Amgen. But, he adds, “I’ve seen titers up to 10 grams per liter at small scale,” and titers are expected to reach 20 grams per liter soon.
These titers solved the immediate upstream need but diverted attention from downstream issues, leading to an imbalance between upstream and downstream capacities. Consequently, Dr. Gottschalk says, “we have five times more product coming from fermentation, which requires five times the columns and buffer volumes. Binding capacities, however, haven’t increased that much.”
Van Plew notes that “columns are thought of mechanically, something you can bolt on to expand production.” Until recently, vendors focused on making larger chromatography columns, therefore using more resin to handle the increased upstream yields. “These columns still often need to be cycled many times, which can also result in installing bigger buffer and product pool tanks,” explains Scott Carver, Ph.D., director of manufacturing sciences at Regeneron.
The larger columns are proving unwieldy, though, so they have been less widely adopted than their developers had hoped. “Theoretically, large columns work,” Dr. Gottschalk says, “but technical issues and costs make them impractical.”
Addressing the Issues
Now the industry is beginning to look at higher affinity columns and faster resins to yield more robust, scalable systems that increase throughput. GE Healthcare and other vendors are beginning to concentrate on increasing downstream throughput.
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