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Dec 1, 2013 (Vol. 33, No. 21)

Filtration Technology Keeps Up with the Times

  • Early Pathogen Removal

    Click Image To Enlarge +
    To enhance a filter cartridge’s performance, the cartridge’s filter membrane may be pleated, enlarging the membrane’s surface area, which directly affects flow rate and total throughput. Twinpleat technology, from Sartorius Stedim Biotech, is characterized by an alternating sequence of longer and shorter membrane pleats, positioned in a specific angle.

    Bioprocessors must beware of pathogens inherent in their expression systems, potential pathogens in ingredients and buffers, and those that enter the process from the environment or through worker contact.

    Although viral clearance formally begins with the first purification step, definitive virus filtration occurs late downstream. Recent concerns regarding new viral and bacterial contaminants, however, have caused a whole-process rethinking of pathogen removal. For example Mycoplasma, the smallest known free-living and self-duplicating microorganisms, are particularly destructive and difficult to eradicate.

    Genentech’s 2012 presentation on Leptospira contamination opened the eyes of many to the dangers of complacency with regard to novel organisms that have not previously been encountered in cell culture and fermentation. A poster, presented by Genentech scientist Ting-Kuo Huang, Ph.D., described the pathogen as “adventitious,” having been discovered “during routine microscopic visual examination.” Genentech considered the problem serious enough to warrant publicly exposing what is typically considered a trade secret.

    “These concerns have led biomanufacturers to consider pathogen removal already at early process stages, which includes virus filtration, for certain cell culture media or media components,” says Holger Bromm, director of filtration technologies at Sartorius Stedim Biotech.

    But as Bromm notes, removal of small contaminants requires finer retention characteristics of the filter media, which causes throughput to fall and cost to rise: “Cost is a critical issue here. For the future, it will be critical for vendors to offer filtration options that capture and retain smaller organisms such as mycoplasma, viruses, and other small contaminants without compromising current production costs significantly.”

    Although virus filtration occurs late in purification, bioprocessors are uneasy with the notion of potential contamination persisting from one purification step to subsequent operations. “If you can detect contamination in your bioreactor, it is unacceptable to proceed further with downstream processing,” Bromm explains.

    Chemical or heat treatments are two alternatives to filtration for eliminating early-stage contamination. But not all products and processes stand up to such treatment, and at their best they complicate the process by adding steps.

  • Pre-Sterilized Filtration for Perfusion Cell Culture

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    Spectrum Lab’s KrosFlo® Perfusion Single-Use Flow-Path Assemblies and System.

    Tony MacDonald, president of Spectrum Labs, notes that a significant number of new bioprocesses employ continuous, perfusion cell culture. “Perfusion is no longer a specialty process,” he says. “Our focus has been to make single-use filtration an available, facile option for this segment of bioprocessing.”

    Most processes today autoclave or steam-sterilize perfusion-appropriate filtration devices before use. “That’s cumbersome,” MacDonald adds. “Our idea was to provide something already sterile, a plug-and-play filtration flow path.”

    Since perfusion cultures are continuous, filters must be capable of allowing product to flow through without harming cells or product.

    The special requirement of continuous processing has thus far limited options for companies simultaneously seeking the benefits of perfusion culture and single-use filtration. “Processors did what they could to extend filter life and extract as much product as possible,” accordingo to MacDonald.

    Spectrum’s assembles its filtration products, along with connectors and tubing, in a clean room, then double-bags and irradiates them to assure sterility. “When customers open it up they get a flow path that’s ready to go.”

    Spectrum uses industry-standard sterile barrier connectors from Colder Products as their default setup, but can accommodate customer preferences for other vendors’ connectors.

  • Continuously Upgraded Performance

    Direct filtration costs are quantified by performance—flow and throughput. Maximizing these characteristics helps users minimize the number of filter products they use, and thereby reduce costs.

    From the filter vendor’s perspective, this has involved what Holger Bromm of Sartorius refers to as “continuously upgraded performance” that involves improved membrane structures and incorporating greater surface area within filter elements. For example, the Sartorius Sartopore Platinum, which employs the company’s Twin Pleat technology, provides one square meter of surface area into a 10-inch cartridge.

    “The idea is not simply to incorporate more surface area, but to assure that it is effectively utilized,” Bromm says. “Some high surface pleated-filter products claim greater surface area, but they are not effectively utilized because the surface area is not accessible.”

    Bromm also mentions indirect costs as a critical decision-driver for selecting bioprocess filters. Integrity testing, for example, involves wetting for five minutes at 0.3 bar differential pressure. Practically speaking, this requires up to 120 liters of water for injection (WFI), at a cost of up to $3 per liter.

    “In 95% of cases where cartridges fail, the cause is insufficient wetting,” Bromm notes.

    By improving the wettability (hydrophilicity) of membrane materials, Sartorius claims to have reduced the WFI demand to five liters for a 10-inch cartridge going along with a significant cost saving for the user and eliminating troubleshooting and retesting of filters.

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