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April 01, 2010 (Vol. 30, No. 7)

Improving Productivity in Bioreactors

Process Aims to Boost Cell Culture Volumes

  • Case Studies

    Click Image To Enlarge +
    Figure 2. Cell growth and product concentration of a fusion protein-producing CHO clone

    Early trials applying the XD process for an IgG-producing CHO clone resulted in a viable cell density of approximately 60 x 106 cells/mL and 12.6 g/L of antibody. In addition, it was found that by shortening the cultivation period to 15 days, operational costs were reduced and risks associated with long processes (e.g., contamination and technical failures) diminished.

    Another advantage of XD is that as a result of production improvements, the overall capacity of a manufacturing plant may be reduced if the same output of product is desired, decreasing plant footprint, equipment, and facility-related investments. Also, because product is collected inside the bioreactor, only a small and concentrated batch is harvested, thus eliminating the need to collect and purify large, multiple volume harvest batches.

    In another experiment, a CHO clone engineered to produce and secrete a fusion protein was tested. The original fed-batch process from the customer utilized commercially available, chemically defined medium and feeds, and reported a maximum product concentration of only 1.2 g/L in fed-batch mode.

    By applying XD process technology, with the same basal medium, a biomass concentration of 130 x 106 cells/mL was attained (Figure 2). The high cell growth in the XD bioreactor translated into a 7.7-fold improvement in productivity (final product concentration of 9.2 g/L).

    The benefits of boosting the productivity of the bioreactor are obvious. The original fed-batch process utilized a 400 L bioreactor that delivered 480 grams of recombinant product. Using XD process technology the same amount of product was obtained by using a 50 L working volume bioreactor. Even higher productivity was obtained in a second run using the same CHO clone.

  • Click Image To Enlarge +
    Figure 3. Cells were adapted to a different medium. The same formulation was then used in the XD process.

    Cells were at first adapted into a different chemically defined formulation. An XD process was then performed using the same medium. A cell density of 175 x 106 cells/mL was achieved on day 12 (Figure 3). Product concentration of 11.3 g/L was measured on the same day, corresponding to a 9.5-fold factor improvement of the fed-batch productivity, while keeping the same length of the original process (12 days).

    XD process technology integrates cell culture and product retention. It is almost independent from the cell line.

    XD process technology may also boost cell densities and the productivity of CHO clones making different products (monoclonal antibody and fusion protein). By boosting volumetric productivity of bioreactors to high levels, XD process technology is ideal for situations in which large amounts of product needed to be made quickly and with minimum development and investment. XD is also ideal for manufacturing products that are difficult to produce at high titers in traditional fed-batch systems.

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