Going modular is the next advancement in bioprocessing hardware. It is closely related to the adoption of SUS technologies
and involves housing SUS bioprocessing equipment within their own cleanroom cabinets—whether portable prefabricated trailers
or equipment sealed within dedicated isolator cabinets—with these increasingly designed for plug-and-play simplicity. Bioprocessing
facilities that formerly required years for planning and construction can be brought on line in a matter of months or even
weeks. SUS have become common in less than a decade, in as short as 5 or 10 years; however, we may comparably be talking about
industry widespread adoption of flexible bioprocessing modules and plug-and-play factories. Vaccines are expected to be one
of the first product sectors affected by this trend. Modular technology will accelerate worldwide proliferation of vaccine
manufacturing, including transfer of bioprocessing to lesser-developed countries. Even easier than with SUS process lines,
modular systems allow whole plants to be essentially cloned, potentially allowing cGMP manufacture in many developing countries.
Many foreign countries are and can be expected to demand local vaccine manufacture, particularly once modular facilities become
commonplace, and equipment vendors plan to actively pursue this market.
Companies developing modular systems for vaccine manufacture include G-Con, which is working with partners, including Sartorius
Stedim Biotech and GE/Xcellerex. For example, Project GreenVax, a private–public consortium, is currently constructing an influenza vaccine manufacturing facility (to be operated by G-Con, developer
of the modular units being used) in Texas for manufacture of recombinant tobacco plant-expressed influenza vaccines, with
a projected final scale capacity of 100 million doses per month [1.2 billion doses/year], according to company projections
and production costs of pennies/dose compared with conventional dollars/dose for conventional egg-culture manufacturing. The
Project Greenvax influenza vaccine-manufacturing facility, subsidized by biodefense funding, uses single-use equipment, housed
within plug-and-play-type modular trailers, using tobacco plant expression technology. Medicago and other companies are also
developing vaccines using tobacco-plant expression.
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
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).
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 technolgies 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.
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, email@example.com
and a periodic contributor to Outsourcing Outlook.
1. BioPlan Associates, 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (Rockville, MD USA, April 2013),