Process Economic Trade-offs for DSP Bottlenecks
Current efforts to avoid downstream processing becoming a bottleneck when handling larger masses include intensifying existing
processes by enhancing capacity and speed. Such approaches can mitigate the need for extra investment in equipment and improve
the process economics. However, with each of these approaches there are trade-offs and uncertainties that need to be evaluated
to assess the impact on overall process economics.
Chromatography Resin Dynamic Binding Capacity
Increasing resin binding capacity reduces column size requirements with concomitant drops in resin volumes required and buffer
consumption [for equilibration, washing, elution, regeneration, and clean-in-place (CIP)] per batch. Novel resins have capacities
that are more than twice those of the first generation resins.24,31 This can lower consumables costs which are a major component of COG/g at higher titers and demands,9 although the impact on the consumable costs will depend on the price differential between first and second generation resins.
Increasing the binding capacity of affinity resins can have a greater influence on COG/g because affinity resins are more
expensive than ion-exchange resins. With the cheaper ion-exchange resins, Sommerfeld and Strube highlight that a trade-off
exists between the less pronounced drop in consumables cost and the increase in labor costs, which becomes more important
at higher binding capacities, because of the longer processing times. However, given that most of the novel resins also allow
higher flow rates, this may not be an issue.
Chromatography Flow Rates
The first generation of cell-culture–based MAb processes used compressible chromatography resins. However, these impose severe
limits on usable bed heights and flow rates when considering the expected increases in titer and scale.30,32 A move away from compressible resins and towards rigid resins that can handle higher flow rates reduces process cycle times
and turnaround time and increases productivity.24,30,31 Flow rates with rigid resins can be three to five times faster than conventional compressible agarose resins.24,31 However, their use can also lead to increased buffer demands, higher pressure drops, packing complications, and shear stresses.30 New ion-exchange resins have recently been developed that can handle high flow rates (700 cm/h) and low back pressures (<3
bar). If the productivity increases outweigh the increased buffer demands, this will positively influence the COG/g.
Chromatography Resin Cycle Limits
As mentioned earlier, resin and filter re-use can have a significant impact on the process economics at higher scales if the
materials are expensive, despite the CIP and cleaning validation costs. Re-use also reduces the frequency of column packing
which is time-consuming and costly when carried out on a large-scale.31 New resins are becoming available with increased stability when exposed to the harsh chemicals used for CIP; hence, they
have longer cycle limits and can contribute to reducing the raw material costs.
Platform processes provide a generic approach to antibody production that greatly reduces the development time while streamlining
the regulatory aspects of processing. They represent a useful starting point for customization depending on the antibody being
manufactured. Advances in resin properties have also allowed platform processes to emerge with two rather than three chromatography
steps.16,28 This can help to alleviate DSP bottlenecks in existing facilities because a two-chromatography–step process occupies less
floor space and consumes less buffer. Through such process intensification methods, Kelley predicted that a platform consisting
of two chromatography steps with high capacity resins would be able to handle an annual output of 10 tons.16 Newer resins with the combined attributes of longer lifetimes, higher flow rates, and improved dynamic binding capacities
will lead to improved platform processes for antibodies and contribute to significant reductions in downstream costs.28,31
Alternatives to Chromatography
Research into alternatives for column chromatography focuses on methods that have the potential to effectively handle increased
amounts of both the product and impurities (e.g., host cell proteins and antibody aggregates or isomers). Ideally, these alternatives
should achieve a separation power equal to that of column chromatography while reducing the COG/g.33 When assessing the cost-effectiveness of these alternatives, it is important to consider not only the equipment sizes and
resource consumption, but also the development and validation costs required.
Membrane chromatography operating in flow-through mode is emerging as a popular alternative to anion-exchange chromatography
steps in MAb purification,because of its rapid operation, ease of scale-up, and cost savings (Table 1).11,26,34–36 The dominant component in the distribution of raw material costs shifts from buffer costs in packed-bed chromatography to
membrane costs; a membrane suitable for processing a batch of several thousand liters can cost several thousands of dollars
and is disposable and not reusable. The key process economic trade-offs for anion-exchange applications therefore depends
on whether the savings in buffer, labor, and overheads outweigh the high cost of the membranes. Critical variables that will
affect the outcome of this cost comparison are the relative differences in the handling capacities assumed between anion-exchange
membranes and resins, which dictate the sizes required, and the assumed WFI and buffer costs; higher values of these variables
increase the economic attractiveness of membrane chromatography.26 The pace at which resin and membrane capacities improve will contribute to which operation secures its place in future platform
processes. In cases where packed-bed and membrane chromatography offer similar COG/g, the real cost advantages may be in the
development and validation costs that are significantly reduced with membrane chromatography because there is no column packing
or cleaning validation.26
Table 1. Example of downstream process economic trade-offs