Increasing titers in mammalian cell culture has recently shifted the focus of process development efforts toward improving the economics of product recovery and purification processes. Some argue that a paradigm shift may be required to ensure timely and cost-effective delivery of future antibody candidates. This paper discusses the key process economic drivers and the impact of scale and titer on downstream processing (DSP) economic trade-offs.
The success of therapeutic monoclonal antibodies (MAbs) in the treatment of indications such as cancer and autoimmune diseases has fuelled clinical trial activities; in recent years MAbs have become the fastest growing segment of the biopharmaceutical industry.1,2 Attractive returns coupled with the potential losses in revenue resulting from delays in product approval have made companies focus on speed-to-market rather than on improving process economics.3–5 However, MAbs are amongst the most expensive drugs—the annual cost per patient can reach $35,000 for antibodies that treat cancer conditions. With intensified competition on the way and increasing pressure from healthcare providers, the ultimate success of the next generation of MAb therapeutics will increasingly depend on economic factors.6 As a result, production costs and capacity use are becoming critical success factors for the industry.7,8
Economies of Scale
Lonza, Ltd., Basel, Switzerland
The relative importance of key process parameters on the overall economic feasibility of a process varies with both the scale of operation and the titer assumed. As annual output and scale increase at a given titer or combined with titer increases, the relative importance of different cost categories are expected to change as follows (Figure 1): Overall cost of goods/gram (COG/g) decreases; direct/indirect costs: material costs rise considerably and dominate COG/g, labor and capital-dependent costs (overheads) represent a less significant proportion of COG/g; and upstream/downstream processing costs: downstream processing costs become a major component of COG/g.
Figure 1. Typical cost trends as scale increases for (a) total COG/g, (b) material, labor, and indirect (capital-related) costs, and (c) upstream and downstream processing operating costs.
If the increase in annual output is also accompanied by titer increases, then the trends are expected to become even more pronounced. At small scales, fixed costs tend to dominate and any changes in raw materials will have minimal impact. However, as scale increases, the role of raw materials becomes more critical. It is therefore important to look at the distribution of the costs (upstream to downstream, and direct to indirect costs) and at the scale and titer of interest to prioritize optimization efforts.