Eric S. Langer
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Biosimilars manufacturers recognize that to compete and provide cost-savings relative to reference products, they must be
cost-effective. Some improvements for biosimilar manufacturers will include: improved expression systems, higher titers to
reduce capacity requirements, and better assay methods to permit process monitoring, and product characterization (1).
TECHNOLOGY NEEDS
Improved expression systems
Biosimilars manufacturers will need to increase expression-system yields to enable use of smaller bioreactors and lower cost
facilities. New expression-system technologies, along with large single-use bioreactors for late-stage and commercial manufacturing,
may begin to displace stainless steel for commercial manufacture. This shift is particularly true for recombinant monoclonal
antibodies (mAbs), where a large number of biosimilar products are in development. mAbs have high repeated dosing requirements,
and large amounts of protein in the magnitude of hundreds of kilograms per year often are needed.
New platforms (i.e., new host cells/organisms) and genetic-engineering advances applied to traditional platforms also can
offer advantages in product yield, product quality, lower operating, purification, and infrastructure costs (2). Some newer
technologies offer shorter times required to go from gene to transformed host cell line/organism to commercial-scale manufacture.
Currently, there are just a few major players promoting new expression-system technologies, but there are many advances ready
for adoption, adaptation, and further development.
Higher titers to reduce capacity requirements
Figure 1: Annual change in titre, commercial, and clinical-scale production of monoclonal antibodies, 2008–2011 (data, reference
1).
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The trend in increasing protein expression yields has had broad ramifications for biosimilars. From lowering construction
requirements to increasing bottlenecks at the downstream end of production, the effects of upstream advances and the availability
of more varied expression systems have created options and problems not previously seen. According to a recent BioPlan Associates
analysis, the overall average yield reported for commercial mAb manufacture in 2011 is 2.18 g/L, up from 1.94 g/L in 2009
(see Figure 1) (1). It was not that long ago that mammalian-cell culture commercial production yields were lucky to achieve
1 g/L or greater (1).
The next generation of commercial products will have an even greater average yield. For late-stage clinical manufacture, the
overall average in 2011 is 2.68 g/L, up from 1.96 g/L in 2008. Although protein yields over 30 g/L are being reported by expression
system developers and early adopters, these yields are the exception, and yields for commercial manufacture in the 5–10 g/L
range are more likely in coming years (1).
