Genetic Engineering & Biotechnology News

JUN15 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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GENengnews.com | Genetic Engineering & Biotechnology News | JUNE 15, 2018 | 23 eliminate downstream bottlenecks, ac- cording to James Stout, Ph.D., director of process science biologics at BioVectra. "There are different technologies today that take advantage of right-sizing the pro- cess, so one can match the upstream produc- tivity with the downstream productivity," he says. In doing this, a productivity through- put rate can be achieved for a particular pro- cess train. But while balancing capacity works to an extent, there are limitations. For example, it is difficult to increase downstream capacity for an established process if subsequent upstream process improvements yield higher titers. "You are in a fixed plant and cannot in- crease the size of columns, filters, or hold tanks. So, increasing the titer in the same bio- reactor dramatically affects the ability of the downstream process to be able to respond to the amount of protein to be processed," explains Dr. Stout. "You can stagger harvests for a run rate and process more per annum but with fixed columns, hardware, and tankage, there is only so much productivity you can gain be- fore the downstream is outpaced by the large upstream bioreactors." A better, and potentially disruptive, ap- proach is to combine capacity balancing with flexible process facility designs and dis- posable manufacturing technologies. "The flexible facility approach, new tech- nology downstream process options, and the ability to utilize run rate and or duplicate the manufacturing facility alleviates the bottle- neck in the process," Dr. Stout continues. "The best approach is to correctly pair the upstream process with the right-sized down- stream process. This can be achieved using disposable technology approaches." Product Capture Technologies Capture purification using Protein A is another bottleneck that is being addressed with disruptive technologies. "Protein A is a great workhorse and does an amazing job at capture purification. However, it is expensive and to improve flow through the column, the ProA resin is unde- rutilized and oversized," explains Dr. Stout. "It cannot be cycled quickly and therefore a large column is needed for large batches. To make it cost effective, many cycles need to be run across the resin to amortize the cost of the resin over many batches of protein." A number of non-resin Protein A alterna- tives with higher capacity are being devel- oped, according to Dr. Stout, who explains that there are follow-on benefits. "The ProA membranes can perform chromatography at membrane flow rates and cycle quickly. Therefore, the size of the column can be downsized and right-sized to the needs of the batch." Yuyi Shen, Ph.D., principal scientist at Spanish drug manufacturer Grifols, also backs the use of more modern membrane-based capture purification technologies, particularly when it comes to eliminating bottlenecks. "The higher titers and high cell densi- ties used upstream are driving the needs for greater downstream process efficiency and capacity. For example, mAb titers have in- creased two- to three-fold in the past several years," Dr. Shen says. Membrane chromatography has emerged as a potential alternative to resin-based cap- ture technologies and it continues to gain ground because it is more efficient and there are cost advantages, notes Dr. Shen. The method reduces downstream processing costs up to five-fold compared with resin- based technologies, he says. "For typical bioprocessing, the major driver for innovative technology will be pro- cess efficiency, higher quality, and low cost. 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