Downstream process design can increase facility output through improved overall process yield or higher batch capacity in
mass and volume. Higher yields enable the production of more drug product or a reduction in the number of batches required
to satisfy the market need. Combining these changes could make room for production of additional products in the same facility.
Use of recent technology as well as state-of-the-art process engineering will be necessary to achieve significant improvement
in both of these categories.
The single most effective improvement of drug manufacturing costs comes from resin and filter re-use optimization, in spite
of cleaning and validation costs that need to be considered as a result. This view is particularly valid for the Protein A
step, but also applies to ion exchangers in large-scale production with high batch frequency. A scenario comparing a single-use
membrane adsorber with re-use column chromatography was recently published.9 This paper discusses the cost comparison in great detail and includes all related costs in the evaluation, yet it uses an
old ion exchange resin as the point of reference. Table 1 represents the main conclusion derived from this study as a cost
comparison for 10 years of use together with a calculation based on a modern anion exchanger. Data were obtained following
the same approach and using the raw data supplied in this comparison.9
Table 1. Importance of using recent technology in cost of use estimates: The most recent technology offers the best long-term
cost of use at slightly higher initial raw material investment combined with re-use and improved mass and volume capacity
Other incremental improvements of a process step, either through optimization of process parameters or exchange of one resin
for another or for a membrane, will only produce small cost reductions unless any of the following items can be achieved:
- Overall process productivity improvements or time savings (satisfying higher product needs in an existing plant),
- Sizeable reallocation of facility capacity for other productive purposes,
- Reduced number of failed batches through improved robustness and lower production risk.
An example in line with the priority ranking shown in Figure 3 would be doubling cell culture titre and binding capacity for
all steps in the purifications sequence, which could cut in half the number of batches required to meet market needs, thus
releasing the remaining capacity for other manufacturing or alternatively to double the output of one product. Comparing capacities
for first generation resins and recently introduced products makes it clear that such improvement is achievable when moving
from old resins to new. A novel cation exchange resin has binding capacity of 80–120 g/L IgG at residence times of 2 to 6
min and typical pH and conductivity values for the feed stream. This represents twice the amount of useful capacity for SP
Sepharose Fast Flow in a typical first generation process (Figures 2,5).
Figure 5. Large-scale Chromaflow columns are typically used in the downstream processing of recombinant proteins.
The Protein A step (in good company with virus removal filtration) is often considered the most cost-intensive step in current
platform downstream processes. Even this step, however, represents only about 3% of total manufacturing costs. Replacing Protein
A with a less costly resin will reduce the raw material cost, but will have little impact on the total product cost because
of resulting productivity losses. There is a risk that such a small cost improvement will be accompanied by lower process
performance of the new step; the benchmark would be tough: 95–97% yield and >99% purity. Similar constraints of improvement
options would hold true for subsequent downstream steps.