Expression Systems
Improved versions of currently-predominate expression systems (i.e., genetically-engineered cell lines such as Chinese hamster ovary [CHO], yeast, and E. coli) for recombinant protein expression are further making vaccine manufacture easier and cost-effective and reducing the scale and investment required to manufacture products. The BioPlan annual survey of bioprocessing professionals and other studies show a rather consistent doubling of mammalian-cell protein expression and product yield about every five years, with yields now typically in the upper 2-3 g/L (bioreactor volume) range. Newer expression systems coming on line promise even higher yields and/or cost-effectiveness, with yields of more than 30 g/L being reported. These upcoming systems include plants (both laboratory-grown and field-grown), such as from iBio (Newark, DE); transgenic animals; PER.C6 and other novel high-yield human-cell lines; and various bacteria other than the usual E. coli. Using the same manufacturing systems and culture media, these new systems produce the same amount of product at commensurately lower cost and often much faster. This higher yield has lead to US biodefense programs providing R&D support for diverse vaccine-expression systems.
Thus, the same equipment can essentially be used to manufacture twice as much product as what was possible only about five years ago. These improvements, however, come amidst intense regulation as major changes in products' bioprocessing are only implemented for new bioprocesses/products as they are developed with established processes rarely undergoing major changes. Upcoming new bioreactor technologies will further increase vaccine-manufacturing flexibility and reduce costs. This includes perfusion. Capillary hollow-fiber perfusion bioreactors being developed by FiberCell Systems, for example, are expected to comparably produce up to 1000 x (based on bioreactor size) the output from conventional bioreactor (e.g., a 50-L desktop perfusion bioreactor matching the overall output of a 5000-L bioreactor).
Purification Technologies
Novel purification technologies are also in development. These improvements are much needed, as advances in upstream manufacturing (everything through product formation in the bioreactor) causing capacity constraints and problems, because later downstream processing, primarily purification, have not advanced as rapidly as expression systems, and other upstream technologies have. The BioPlan study shows that many facilities are considering upgrading (i.e., adopting, new purification technologies). This trend includes 54% considering high-capacity chromatography resins; 44%, single-use filters; 38%, automated buffer dilution systems; and 35%, single-use tangential flow filtration.Other advances being adapted for large-scale use include simulated moving bed chromatography systems and membrane filters, which are starting to replace chromatography columns. Cast-in-place "monolithic" chromatography media, rather than labor-intensive packing of columns, are yet another example of improvements approaching adoption for commercial-scale manufacture.
Looking Ahead
Further practical advances and synergies can be expected when these technological advances are combined, thereby resulting in simpler, cheaper, and transportable vaccine manufacturing. A number of other vaccines currently in the development pipeline are being manufactured in SUS, are being developed for manufacturing using modular units, are using novel, higher-yield expression systems, and/or are adopting newer purification technologies. Besides federal biodefense programs funding, many of these efforts are independently funded or also being funded by PATH and other vaccine development-oriented philanthropic organizations.
The confluence and combination of ongoing bioprocessing technological advances will increasingly enable manufacture of vaccines quicker, simpler, and at significantly-reduced costs, often just pennies/dose, with many future vaccines likely to be sold at prices that are comparable or even below current manufacturing costs.
Ronald A. Rader is senior director, Technical Research, at BioPlan Associates. Eric Langer is president of BioPlan Associates, tel. 301.921.5979, elanger@bioplanassociates.com
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REFERENCE
1. BioPlan Associates, 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (Rockville, MD USA, April 2013), http://www.bioplanassociates.com/.