Easing the Bottleneck - Pharmaceutical Technology

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Easing the Bottleneck
Manufacturers of therapeutic monoclonal antibodies consider new paradigms in purification technologies.

Pharmaceutical Technology
Volume 33, Issue 5, pp. 44-50

Millipore (Billerica, MA) has gone the furthest with a disposable gambit. At the Interphex 2009 show in March, the company unveiled its suite of Mobius products. The Mobius line (marketed as Mobius Flex Ready Solutions) is made up of two components. The first is a metal cart, approximately the size and shape of your average New York City hotdog vendor's stand. Into these can be inserted the entire disposable purification train, with all of the bags and hoses already attached. (Disposable trains for other aspects of biopharmaceutical processing are also available to work in concert with the Mobius carts.)

The truly intrepid biopharmaceutical manufacturers may move away from column-chromatographic solutions entirely. In an attempt to reduce the footprint of the purification apparatus as well as costs, some vendors are developing membrane-based purification devices. Lisa Crossley, president and CEO of the Canadian firm Natrix Separations, described in January at the Biomanufacturing Summit in San Diego, CA, organized by WTG, a novel capture membrane the company has developed. Unlike other membrane-based capture technologies that put the affinity chemistry on the membrane's surface only, Natrix's membrane offers a more dimensional structure. The apparatus is composed of a support membrane that houses a porous hydrogel to which is affixed either Protein-A or synthetic ligands, depending on the customer's needs. It is available in both multicycle and single-use, disposable formats.

The dimensionality of the Natrix product is intended to increase the binding surface area, diffusion rates, and flow rates, all while reducing the equipment's footprint, and significantly reducing operating costs, Crossley says. In addition, the membranes can be used for simultaneous clarification and capture, eliminating the need for separate harvest and primary purification steps. "There's a big cost savings in combining two steps in one," Crossley says.

The Natrix membranes offer such an impressive combination of attributes that one person attending Crossley's San Diego presentation exclaimed that Natrix had delivered the "Holy Grail" of mAb purification. Others in the industry are not quite as moved. The pharmaceutical industry is slow to adopt any technology that might engender regulatory scrutiny, and so may take a "wait-and-see" stance on this and other technological developments. Furthermore, skeptics point out that the Natrix technology's robustness has not yet been proved for full commercial-scale use. To date, the technology has been used for commercial-scale manufacturing of nutraceuticals and veterinary vaccines in North America and Europe, but is still in the preclinical stage for biopharmaceutical applications.

Pressure toward greater efficiency and lower cost may, surprisingly, drive the industry back to the future as they explore alternative technologies, notes Sartorius's Gottschalk. "Because of the expense, many other industries don't use chromatography at all," he says. He points to technologies used to purify components from blood plasma. Typically, these manufacturers precipitate the desired products out of the plasma, a technique that Gottschalk offers might be adapted to mAb purification in the years ahead.

Jagschies, on the other hand, is dubious that chromatography will disappear. "Right now, the world leader in plasma-derived biopharmaceuticals, CSL from Australia, has put chromatography in place pretty much everywhere," he says. "This will not change back, not in my time at work for sure." Several players, notes Pall's Sellick, are also exploring fractionation and crystallization.

Putting the polish on polishing

Gottschalk doesn't stop there, though. He is looking at ways to improve purification beyond the capture step. "We need to shift our focus from product capture, where yields are increasing, to contaminant removal," he says. He suggests that it may be possible to remove more impurities—nucleic acids, for example—in the early clarification steps, thereby reducing the burden on the capture materials and possibly reducing the number of polishing steps required as well.

Millipore has also been considering ways to beef up impurity removal. For example, the company is specifically honing in on ways to improve the efficiency and lower costs of some initial clarification steps. Following centrifugation and before capture, the contents of a bioreactor go through depth-filtration.


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