This article is an updated version of a previously published article. This version was published in a special supplement to BioPharm International in August 2013.
Progress in the industry has been impressive, but most of the increases in productivity achieved in previous decades have resulted from improvements in the upstream production phase, with more efficient bioreactors and better media formulations sharing the limelight with cell lines that are intrinsically more productive because of the development of more effective screening technologies to identify the most productive clones (5). Downstream processing is now routinely found to be the bottleneck in biopharmaceutical manufacturing because its capacity has not kept pace with upstream production (1). This is largely due to the incremental nature of technological improvements in downstream processing, which do nothing to address the absence of economy of scale. Unlike upstream production, where a more productive cell line generates more of the product without increasing costs, the costs of upscaling downstream production are linear because a feed stream containing more of the product requires larger amounts of materials such as buffers and chromatography resins (i.e., higher titers), which translates linearly into higher manufacturing costs (6). The future success of downstream processing, therefore, depends on disruptive, game-changing innovations rather than incremental ones (1, 4). This need for innovation reflects the increased demand for biopharmaceutical products, the regulatory focus on quality in the manufacturing process, and the stratification of the market due to the advent of biosimilars or follow-on biologics (3).Running to stand still
The first 15 years of biomanufacturing can be considered as a golden era, where manufacturers had the luxury of using inefficient processes because the product itself was far more important (3). Most biopharmaceuticals were required in small doses and demand was sufficiently low to allow plenty of slack in the system. It was also pointless investing in process efficiency when any tweaks and modifications would arouse the suspicious eye of regulators. It was better to let sleeping dogs lie and be satisfied with the status quo. In this environment, innovation was considered a burden rather than a bonus.
Inevitably, this relaxed attitude to process efficiency resulted in an immense amount of wastage because up to 50% of product batches failed to come up to specifications (3). To address this waste, FDA ordered that processes should be designed with quality attributes taken into account (7, 8). The process was no longer simply a means to an end to generate the product, but became part of the product. As the economic screws began to tighten and demand increased, so manufacturers turned to the age old strategy of scaling up their production to achieve cost savings, and this is where the industry began to flounder. Whereas upstream production can be scaled up almost indefinitely by increasing the productivity of cells growing in a bioreactor, downstream processing has limits imposed by physics and chemistry. Downstream processing is driven by the mass of product; therefore, increased productivity requires corresponding larger volumes of buffer, larger storage tanks and preparation areas, larger filters, and most importantly larger amounts of chromatography media. For the production of antibodies (i.e., where Protein A resin is typically used in the primary capture step), the costs of scaling up are in some cases greater than the extra revenue made possible by the increased upstream productivity. Manufacturers find themselves in the paradoxical situation that there is no longer an economy scale in manufacturing, but rather an economic depression reflecting the physical limits that constrain the size of the apparatus used in separations (e.g., chromatography columns and the associated piping, skids, and buffer reservoirs). So far the extra demand has been absorbed by contract manufacturers offering their spare capacity to fulfill quotas, but this is a short-term measure that cannot cope with the predicted increases in demand from hundreds of products currently in clinical development, all requiring at least pilot-scale manufacture according to GMPs (9).
How can this productivity dilemma be addressed? With constant scaling up no longer a viable approach, the industry must return to its roots and innovate to succeed. Manufacturers are currently considering three solutions, all inspired in some way by the more encouraging regulatory landscape that rewards rather than punishes innovation. These solutions are the streamlining of existing processes, the revisiting of simple technology solutions currently employed in the bulk chemical industry, and the use of innovative technologies from the bleeding edge of biopharmaceutical research. These latter technologies have the potential to introduce game-changing processing options into an industry still mired in technologies that were state-of-the-art 20 years ago. On a cautionary note, however, technologies from the bleeding edge can fail, and the rash adoption of new and untested technology platforms can punish the eager company seeking innovative solutions. This is the new dilemma in downstream processing.