Today’s biomanufacturing industry is teetering at the limits of its capabilities. In contrast to the laissez-faire approach in the first 15 years, there is now intense economic and regulatory pressure to wring as much product from each batch as possible without compromising quality. This means that downstream process technology is being tested to its limits, both physically and economically.
The most pressing concern is that, because the same technologies have been used since the birth of the industry, we are in some cases reaching the operational limits of each platform.
Chromatography is the most often quoted example because the dynamic binding capacity (DBC) of a chromatography column can only be increased by scaling up the process. However, doing so while still maintaining the same process parameters such as the linear flow rate is impossible. Therefore, either new process parameters must be implemented or the entire process must be redesigned from the ground up.
The limitations of column chromatography have been exposed by increasing upstream titers because bind-and-elute operations are mass rather than volume driven. The amount of buffer can be varied as required but the total mass of API produced in each fermentation batch now often approaches the DBC of the columns and risks product breakthrough.
These risks are lower, but still evident, in polishing chromatography, where the larger fermentor offloads demand high performance to remove excess host-cell proteins, metabolites, and nucleic acids.
Manufacturers are facing the prospect of splitting batches over multiple processing runs, or adding extra columns to handle the increased titer, which significantly increases the production costs in terms of equipment purchase and facility size, while also affecting batch definition and regulatory approval.
The limitations of current downstream processing technology and the fact that manufacturers cannot simply expand out of trouble without increasing their costs in a linear fashion have forced manufacturers and their equipment suppliers to innovate. Some of these innovations have involved incremental improvements in process efficiency, e.g., by developing better resins and buffers to maximize the selective retention of target proteins while efficiently eliminating contaminants.
Some manufacturers have replaced expensive chromatography-based separations with simpler and less expensive solutions, such as precipitation steps that can be used to remove bulk contaminants or even to reversibly precipitate and recover the product.
New technological approaches also abound. Prominent examples include continuous chromatography platforms such as simulated moving bed chromatography to increase selectivity and resolution, the development of novel capture ligands, and new chromatography formats that allow product capture under unfavorable conditions (e.g., salt-tolerant interaction chromatography), and the use of membrane adsorbers in place of fixed columns to enhance convective transport during chromatographic separations.