However, additional scale up yields much smaller time savings and much higher costs associated with very large systems and much greater buffer volumes. It is very unlikely that a column >1.4 m would be cost effective in this situation. It is likely, however, that a column <1.2 m would be most economical during clinical production. For a few runs of a product that may not gain approval, a long step-run time would be more cost effective than a larger-scale operation. So strategic decisions regarding likelihood of approval, anticipated demand, and the ability to make process changes later may override cost considerations.

Membrane Chromatography: In a facility constrained by buffer tank and CIP availability, use of membrane chromatography in flow-through mode may greatly reduce buffer consumption and is thus presents another debottlenecking option.

In each case the product was very pure before this step, which removes trace contaminants and provides additional log removal of viruses. Conventional chromatography columns of sufficient size to handle the product feed volume in a reasonable amount of time would have offered a huge excess of unused capacity. Filters used to replace these columns offer faster kinetics within their membrane pores than do chromatography media.

Use of membrane chromatography at this step reduced buffer consumption by >10×. This technology provides one more tool with which to address facility throughput constraints caused by limited buffer tank availability. As stated, increasing plant capacity will have the greatest potential for lowering COGM, and addressing bottlenecks in the process will have the greatest impact on increasing plant capacity.

A Holistic Approach

We have highlighted the impact of process development on manufacturing throughput and COGM in three different scenarios. In the first case, we demonstrated that lowest raw material cost did not necessarily lead to lowest COGM. In fact, when manufacturing run rate was accounted for, the more costly raw material and its associated unit operation were preferable. In the second case study, plant modeling was used to guide simultaneous process development and new facility design, resulting in a facility flexible enough to meet volatile projected demand at maximum run rate to minimize COGM. In the third case, COGM was used as a guide to determine multiple retrofitting options for a fully commercialized facility.

Based on our observations, coupled with the increasing cost pressure on biopharmaceuticals, we recommend that plant modeling to reasonably estimate the manufacturing run rate become an integral part of early — and particularly late — process development. This holistic approach enables companies to maximize the likelihood of commercial success of their costly development programs.