THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 14

The cost of monoclonal antibody manufacturing includes the capital costs associated with building or modifying a production facility and operating costs associated with production. Fixed costs include depreciation, insurances, taxes, maintenance, and labor costs. Fixed costs are the major part of operating costs in a typical large scale manufacturing facility such that approximately 60 - 70% of the operating costs for a monoclonal antibody manufacturing facility are fixed but can be lower in older facilities that are fully depreciated. Fixed costs are incurred independent of facility utilization and the fixed cost allocation per dose is lower the higher the overall utilization of the manufacturing plant. For this reason, facility utilization is a key driver manufacturing costs for monoclonal antibodies. The second major cost component of manufacturing is variable costs, namely those operating costs that vary directly with the level of production, primarily comprised of consumables and raw materials required to run the production process as well as a small amount for utility and waste disposal. Variable costs are related to the specifics of the manufacturing process and are constant per unit of product produced.

…Recently, bioreactor capacity expansion and ongoing technical improvements in the productivity of mammalian cells has led to overcapacity in the industry. The globally installed bioreactor capacity may approach 4 million liters in 2013 provided all ongoing or planned construction projects come to fruition. At a product titer of 2 g/L, this installation base represents a production capacity of 120 tons; at 5 g/L it would be 300 tons, which is 12-30 times more than the 2008 production rate (see Table 3, worst case). With bioreactors capable of producing 3 to 5 g/L of product and a downstream process that has an overall yield of 70-80%, a single facility, with eight 12,000 L bioreactors and a maximum batch rate of approximately 170 batches per year, can produce between 4.5 and 7.5 tons of bulk monoclonal antibody annually. …If all product produced were sold at pharmacy list price, the manufacturing demand would have been below 5 tons in 2008.

Building a facility with significantly smaller bioreactors offers capital savings opportunities in the hundreds of million dollar range compared to historical norms. Including certain single-use options in this smaller scale facility can further reduce its capital requirements. However, the economy of use of single-use technology is largely dependent on the frequency of batch processing and on the complexity of the single-use device. At higher batch frequency processing, stainless steel based systems become relatively more favorable on an overall cost basis.

…Regulatory demands and company responses to them have created “dogma” in clinical manufacturing that turn out to be costly now that more highly productive processes are available at a relatively early stage of process development. Many companies produce monoclonal antibody for Phase 1 or Phase 2 trials in bioreactors ranging in scale from 200 L to 2,000 L while Phase 3 clinical trial material is usually produced in large scale bioreactors, up to 12,000 L in volume, in anticipation of launching the product at the same production scale. Assuming a product titer of 3 g/L and a downstream yield of 75%, one batch of clinical manufacturing at the largest of these volumes could produce enough material for the entire clinical study, i.e., 4.5 kilograms from a 2,000 L for a Phase 1/2 study and 27 kilograms from a 12,000 L bioreactor for a Phase 3 study. With just one batch, however, not enough data exists to set product and process specifications or to demonstrate process robustness. Therefore, companies need to produce more batches to meet regulatory requirements and obtain sufficient data from actual production runs. This suggests that for clinical manufacturing, smaller bioreactors and multiple batches should be considered, particularly late in clinical development in preparation for product launch, but there is a per batch cost that must be factored in.

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