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Feb 15, 2010 (Vol. 30, No. 4)

Trends in Monoclonal Antibody Production

With Capacity Issues Resolved, Firms Direct Attention to Quality, Timelines, and Cost

  • Predictive Analytics

    Improved analytics is helping ensure that the active pharmaceutical ingredient quality attributes of antibodies are identified as early as possible, determining both the desirable and undesirable characteristics, according to Thomas Rohrer, senior director ADC and biochemical technologies at Lonza.

    Using protein aggregations as an example of an undesirable property that adds complexity to the purification process, Dr. Rohrer notes that Lonza has developed a software tool to accurately predict the aggregation propensity of proteins. Called AggreSolve™, “the tool can be used to screen product candidates or provide a rational basis for redesigning the primary sequence of the antibody or changing the conditions in the antibody modification and conjugation reaction to make aggregation less likely.

    “The AggreSolve technology platform can extract information from the primary sequence by calculating solvent accessibility, structural preferences, aggregation propensity, and potential intermolecular interaction.” That information, he continues, makes it possible to predict potential stability and aggregation issues that may occur during antibody drug conjugate process development.

    “We also have developed predictive scale-down models at milligram and gram scales to simulate the antibody modification and conjugation reactions. These models help reduce process-development costs and provide assurance that the large-scale process will meet the quality attributes necessary to prove clinical efficacy.”

    According to Dr. Rohrer, Lonza currently has a small-scale model of an ImmunoGen process that is predictive of the large-scale product quality and overall process yield, he says. Therefore, “it is useful as a process-validation tool when investigating critical process parameters.”

    Beyond modeling, Lonza is also improving the gene-expression system, methods used to ensure clonality, and screening techniques. “The single biggest issue has been the time taken to generate a clonally derived cell line suitable for product manufacturing.

    “In the case of the GS Gene-Expression System™ used at Lonza, the selection of cells is sufficiently stringent to avoid the need for additional time-consuming rounds of amplification. Additionally, a suspension-adapted variant of CHO cells is used, which eliminates the time taken to adapt cells to chemically defined animal component-free suspension culture. The use of automated cloning systems and modified screening procedures have further reduced the time taken to generate cell lines from 60 to 30 weeks.”

    In terms of reducing the cost of goods, Lonza has increased both capacity and scale. By advancing gene-expression technology and the design of its fed-batch systems, routine expression typically in the grams per liter range has occasionally exceeded 10 grams per liter, Dr. Rohrer says. Another approach is to reduce the need to manufacture large quantities of mAbs. For example, he says, when antibodies used for oncology therapies require receptor binding of compliment fixation to elicit apoptosis, the potency of antibody can be reduce 100-fold by conjugating it to a potent cytotoxic drug.

  • Overcapacity

    Click Image To Enlarge +
    Typical multiproduct facility: cost reduction through gradual increase of utilization and process improvement (GE Healthcare)

    In the early days, “most mAb therapies required high dosages,” recalls Günter Jagschies, Ph.D., senior director, R&D GE Healthcare Life Sciences. To meet those needs, bioreactor output improved about 10-fold, so that “optimized bioreactors today produce 3–4 grams per liter.” Currently installed capacity, combined with that being built, will yield a 120-ton capacity, which Dr. Jagschies says is sixfold more than is needed. Some new plants won’t be put into operation and “others are probably cancelling their building projects.”

    Several companies are now building smaller facilities to reduce capital outlay and are working with contract manufacturing organizations as needed. But, for companies with excess capacity in existing facilities, the options are to use the space to produce other proteins in smaller scales, to use disposable setups, and to “bring in other products if you can,” Dr. Jagschies says, recognizing that production lines and bioreactors are not necessarily interchangeable.

    “The issue of stainless steel versus disposable equipment is irrelevant.” Instead, flexibility is the issue. “You have to have several separate production lines and lines at different scales to hold different organisms, and to work in parallel. At 1,000 to 2,000 liters you can do that with roll-in/roll-out capacity.”

    Bioreactor advances have created a bottleneck downstream where purification steps are not providing higher capacities from new resins. People take this into consideration, Dr. Jagschies continues, and are always looking for increased productivity with newly developed downstream tools, which can resolve capacity bottlenecks.

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