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May 1, 2010 (Vol. 30, No. 9)

Leveling Downstream Process Bottlenecks

Alternatives to Traditional Unit Operations Are Now Available to Alleviate Very Real Logjams

  • Location, Location, Location

    Facilities play a substantial role in streamlining or bottlenecking bioprocess workflows. “Designers of new facilities have the luxury of designing everything  from the ground up, with upstream and downstream processes in mind,” says Dave Wareheim of Integrated Project Services.

    “Greenfield” facilities may even incorporate room to expand or bring in new equipment. But when retrofitting the building is the starting point,“cramming a process into an existing shell requires slightly different judgment regarding interstitial spaces, whether the process will stand on the ground floor or higher floor, how to deal with drainage. Here facility and services can get in the way,” Wareheim explains.

    Rising protein titers in mammalian cell culture bring higher upstream productivity and, potentially, lower cost of goods. The negatives are underutilization of upstream space and overtaxing downstream areas that were designed for less-productive cultures. In some situations, Wareheim reports that biomanufacturers have simply abandoned these facilities—not because of bottlenecks but because the plants have become too big for the process. “Utilization of 70 to 80 percent is fine, but when it gets down to 40 or 50 percent people start to worry.”

    Where upstream and downstream processing mismatches result in bottlenecks, adopting new separation technologies can help, provided these methods are adopted early enough in process development. An obvious option is high-capacity resins, but these are expensive and, many believe, approaching their theoretical capacity. Similarly, companies might consider ultra high-throughput virus filters, but processors have long complained about the cost and time involved—up to 15 hours per batch.

    Wareheim mentions several separation  methods that might help. One is fluidized bed chromatography that combines cell removal with affinity-based purification. The advantage, besides a smaller footprint due to replacement of two processes (filtration or centrifugation plus protein A chromatography) with one, is de-bottlenecking of the centrifugation/filtration step.

    Wareheim also likes simulated moving bed techniques employing multiple (but smaller) chromatography columns. “This technique takes longer but provides a two- to threefold reduction in resin costs.” Finally, he suggests in-line buffer dilution to minimize the number of storage tanks. “One or two companies are using this and doubling their productivity during buffer dilution with minimal added footprint.”

  • Chromatography Media

    Click Image To Enlarge +
    According to Xcellerex, FlexFactory downstream modules, which are fully disposable systems, can reduce downstream bottlenecks by shortening time to production and helping to delay capital investments until later in a drug's development cycle.

    Parrish M. Galliher, founder and CTO at Xcellerex, believes that downstream processing will be transformed over the next few years to a degree similar to the introduction of single-use products.

    “It has to happen because of the pressures placed on downstream operations by improvements upstream.” He acknowledges, however, that for the downstream revolution he envisions to occur, bioprocessors have to turn their thinking and current practices on their heads. “Our goal is 10-, 20-, or 30-fold improvements in throughput and productivity for protein purification.”

    The way to achieve this is not by improving resin capacities or enlarging chromatography columns, but by vastly increasing the workload on resins. “Chromatography resins are only working about 10 or 20 percent of the time. Our idea is to get less resin busy all the time, purifying all the time.”

    This, he believes, will shrink resin beds to a manageable size, to the point where discarding them after a single use makes sense. He mentions simulated moving bed and expanded bed chromatography as two systems that approach this ideal. “People shied away from these techniques because cleaning validation was problematic. But if you make them single-use, with resins cheap enough to justify throwing them away, you could sidestep validation.”

    Another area where disposables could create a breakthrough is in ultrafiltration, a technique used in several places downstream. The current problem, Galliher says, is that scaling ultrafiltration in single-use mode is problematic. “As soon as you go above a one-inch diameter recirculation system the pressures become too great for single-use tubing.” Xcellerex and a collaborator are working on an improvement that Galliher expects will eliminate the single-use issue for ultrafiltration.


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