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March 15, 2017 (Vol. 37, No. 6)

Continuous Bioprocessing Skips a Beat

Bioprocessing Needs a Tuneup If It Is to Run Smoothly and At Full Power

  • In with the Old

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    Thermo Fisher Scientific has been focusing on its Poros capture and ion-exchange chromatography media for several continuous chromatography applications.

    Conventional chromatography resins are routinely adapted for use in continuous purification. For example, GE Healthcare has shown how its MabSelect SuRe LX protein A resin may serve as the medium for a three-column periodic countercurrent chromatography (PCC) operation. This particular operation is based on the company’s ÄKTA platform.

    In PCC, columns are switched between loading and nonloading steps consisting of column wash, elution, clean-in-place, and equilibration. At breakthrough, the first column in the loading zone is disconnected. Then, the load is redirected to the next column.

    Similarly, Thermo Fisher Scientific has been pushing its Poros capture and ion-exchange chromatography media in several continuous chromatography environments. “Perfusion and alternating tangential filtration have unlocked significant productivity improvements upstream,” asserts Kevin Tolley, the company’s senior field application specialist, “but downstream operations remain stuck in batch mode and have difficulty keeping up.”

    Thermo Fisher Scientific has not been developing hardware or software for continuous processing on its own, preferring to collaborate with companies possessing those specialized skills. Tolley believes that Poros resins have a lot to contribute, however, by enabling shorter bed heights while maintaining high binding capacities.

    In the absence of a chromatography resin specifically dedicated to continuous processing, advances in continuous chromatography will arise from the marriage of innovative hardware and the application (as we saw with Siemens) of control software.

  • Banking on Hardware

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    LEWA Bioprocess Technologies has developed the EcoPrime Twin, a GMP-ready, multicolumn chromatography system. It incorporates ChromaCon’s CaptureSMB, a two-column process. The integrated unit can perform batch, continuous batch, and continuous capturechromatography.

    Bioprocesses traditionally divide cleanly into upstream and downstream components. An analogous delineation exists for continuous processing. Thanks to perfusion cell culture and its many variants, upstream continuous operation is feasible at large scale. Downstream purification steps, however, have yet to catch up.

    To upgrade downstream processing, LEWA Bioprocess Technologies, a subsidiary of LEWA (itself a subsidiary, of Nikkiso), entered into a collaboration with ChromaCon in 2014. LEWA Bioprocess Technologies is working on the all-important capture step and eventually expects to tackle polishing chromatography operations in continuous formats.

    Continuous chromatography will likely not be adopted for established processes, but LEWA Bioprocess Technologies’ chief marketing officer Gerard Gach believes that “most” developers of new protein manufacturing processes, including biosimilars, are considering continuous chromatography to save time and cut costs.

    “Biomanufacturers are taking a pragmatic approach,” he explains. “They’re looking to incorporate one continuous step and get that going reliably, then a second step, then linking unit operations together.”

    Product capture is the most attractive entry point for continuous downstream processing because of the high volume/value of product at that stage, and the fact that conventional antibody purification employs protein A, which is arguably the most expensive “reagent” in the purification train.

    “Decreasing the volume of protein A used, and addressing potential debottlenecking,” notes Gach, “will significantly improve process economics.”

    He is referring here to the capacity mismatch that sometimes results from purification not maintaining parity with protein expression.

    Gach describes his firm’s continuous chromatography team as “hardware nerds,” meaning they operate for the most part behind the scenes on the hardware side of the business instead of by supplying chromatography resins.

    “We have a great corporate heritage of excellence in fluid dynamics and applying those highly precise fluid systems at GMP scale,” boasts Gach. “Our history is as a metering and pump company.”

    Gach has a point. Approximately 14,000 LEWA pumps (by his estimation) are in use today in chromatography systems. He believes that on that basis alone, plus recent acquisition of GMP technology, LEWA has already produced chromatography systems that improve productivity by a few percentage points, even without continuous processing. This was achieved, Gach says, by applying digital control to chromatography system operation.

    In June 2016, LEWA installed a scaled-up version of ChromaCon’s Contichrom Cube system at the Fraunhofer Institute in Stuttgart, Germany. The system was incorporated into a twin-column GMP-grade purification skid for continuous pilot-scale chromatography. According to Gach, the twin-column unit’s design significantly reduces system complexity.

    “Other companies use up to eight columns, which may involve the incorporation of up to 300 valves,” states Gach. “The two-column system uses just 20% of the valves, reducing complexity and risk by 80%.”

    LEWA also sells the EcoPrime Chromatography System, which doubles as a buffer dilution system.

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