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Aug 1, 2010 (Vol. 30, No. 14)

Integrating Methods for mAb Production

Distinct Advantages Result from Combining a Broad Array of Tools and Technologies

  • Resource and Facility Utilization

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    ChromaSorb membrane adsorber provides robust impurity removal over a wide conductivity range, according to Millipore. This single-use device reportedly reduces validation requirements, capital equipment expenditures, and time and labor when compared to traditional column-based anion-exchange resins.

    Integration and utilization of manufacturing resources are an ongoing concern. “Antibody processing is maturing and changing,” explains Neil Soice, Ph.D., principal research scientist at Millipore. The company is seeking to help bioprocessors in their struggle with upstream-downstream misfit.

    Most bioprocess plants operating today were designed years ago to accommodate protein titers that were much lower than today’s. This has introduced limitations and constraints with respect to buffer and holding tanks, which, according to Dr. Soice, have become bottlenecks.

    “The larger manufacturers have invested heavily in their facilities, and are trying to leverage that investment by getting as many drugs as possible to the clinic,” he says.

    Millipore has introduced several purification products over the last three years that serve this end, specifically chromatography resins with high intrinsic capacity and flow rates. These include the ProSep® Ultra Plus capture resin, which provides 50 g/L of binding capacity for mAbs, the high-capacity ProRes™-S cation exchange media, and an anion-exchange membrane adsorber for polishing.

    Millipore has found that by optimizing each step, it’s possible to elute directly from the capture column to the cation-exchange column without intermediate hold. “And if you’re smart about the cation-exchange step, you can elute directly onto the membrane adsorber.” Dr. Soice stresses that while this purification scheme works with both single-use and stainless steel equipment, it is not 100% ironed out for every product, particularly at large scale.

    Will connected processing save time in a real-world, large-scale process? It certainly does at lab scale, but at manufacturing scale the hold tanks serve a purpose other than storing product between steps. Tanks enable process engineers to design the beginnings and ends of unit operations around the flow of human resources—to hold product between work shifts.

    “Connected processing would force you to optimize processes completely differently,” Dr. Soice says. “It would force bioprocessors to break the existing paradigm, and not let things sit around because they’re waiting for the next shift to come through.”

  • Sidebar: Applications for Ceramic Hydroxyapatite

    At BIT’s “International Congress of Antibodies” held earlier this year in Beijing, Larry Cummings, consulting scientist for Bio-Rad Laboratories, discussed the use of CHT™ ceramic hydroxyapatite media for antibody purification. According to Cummings, the value of CHT in the downstream processing of therapeutic antibodies is derived from its ability to remove antibody aggregates, protein A, endotoxin, host-cell proteins, nucleic acids, and viruses from the target protein in a single step.

    “The utility of this matrix derives from its mixed-mode binding, which combines both metal chelation and classical cation exchange,” explained Cummings, who added that Bio-Rad recently introduced two methods to further enhance the utility of CHT by extending column life through mitigation of pH drops that are often observed with salt elution on cation exchangers.

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