Günter Jagschies, Ph.D., at GE Healthcare, has long been outspoken in debunking the notion that upstream efficiencies unduly stress protein purification, that the problems are intractable, and the solution lies, at least in part, on alternative technologies.
For one thing, he is no fan of precipitation, crystallization, and extraction as solutions to downstream bottlenecks. “Switching from chromatography entails revamping your entire facility, and it’s questionable whether you’ll achieve the same level of process robustness.” These methods, he says, are a result of scientific irrational exuberance that overlooks basic economics. “And you could be sure that if someone came up with a general technique for crystallizing an antibody, they would patent it. Licensing fees, even if small on a percentage basis, would be much higher than anyone pays anybody these days for protein A resin.”
Dr. Jagschies does not deny upstream-downstream mismatches. But those, he says, are more a function of when a bioproduction plant was put into service than of inherent inabilities to deal with high titers.
He admits that plants coming online today were designed for lower-titer processes conceived between five and ten years ago, and that purification has not improved step-for-step with cell culture.
“But if you were to start from a blank slate, if you could build plants today based on modern purification technology, bottleneck issues would not arise,” he says.
Plants constructed in the early 2000’s were designed for protein titers below 1 g/L. Processors can make up for approximately a doubling of titers without changing much. Once a process crosses the 2–3 g/L titer level, however, operators must adopt newer, higher-capacity, and higher-throughput filtration and chromatography tools, as well as modern dilution, buffer, hold, analytic, and scheduling strategies.
Besides, the perception of gross mismatch depends on the point of reckoning. By comparison today’s processes are at least 100 times more product-intensive than the first bioprocesses, but only 10 times as product-dense as the first monoclonal antibody processes.
“This fact is lost in the sound bites we refer to as downstream bottlenecks,” observes Dr. Jagschies. “I’m not denying that bottlenecks exist—just trying to add perspective to the discussion.”
Relatively straightforward adjustments in purification technology, he says, can open up low-titer facilities to high-titer processes, without adding or eliminating unit operations. One such improvement is switching to high-performance resins providing three to four times the binding capacity and significantly higher throughput than first-generation resins. Moreover, when crossing the magical 2–3 g/L barrier, processors can analyze the entire process and implement changes at once to chromatography, filtration, buffer, and hold steps.
Most observers believe, however, that this is more easily recommended than done.
Many observers, though, now view upstream titer improvements as something of a mixed blessing. In manufacturing, more is usually better than less, but that is not always true for the manufacture of biotech drugs.
“If you plot a U-shaped cost curve, with the x-axis as product titer, you’ll see that it flattens out between three and five grams per liter,” Dr. Jagschies says.
That rising titers also raise the cost of goods flies in the face of conventional wisdom, but the logic is irrefutable.
Bioprocessors experiencing rising titers can exploit newly found efficiencies by running fewer batches or making more product. The latter is only viable if demand exists for the drug. Reducing the number of campaigns sounds attractive, but it is only cost-effective if the freed-up capacity can be filled with some other remunerative project.
“But almost nobody is operating at full capacity,” Dr. Jagschies observes. Genentech and Amgen, for example, are divesting themselves of capacity.
In the hypothetical case where two batches produce the same as three, fixed costs—which comprise up to 70% of all costs in classic stainless steel facilities—are apportioned to one-third fewer batches, which raises their nominal cost; the variable cost advantages from running one less batch pales in significance.
Instead of throwing R&D competence toward wringing out the last bit of production efficiency, Dr. Jagschies suggests devoting those resources toward higher-quality product. Reducing aggregates and improving drug potency are two such strategies. With material needs greatly reduced, biomanufacturers will become much more savvy about dimensioning future production facilities.