In 2012, BioPlan Associates estimated the global market for biopharmaceuticals at $140 billion, of which $100 billion was for recombinant proteins. The monoclonal antibody (mAb) market, a subclass of recombinant proteins, was estimated at $40 billion.
The development of biopharmaceuticals, from initial lab work through production and final regulatory approval, is a complex process. Downstream processing steps can represent up to 60% of the production costs for a protein, illustrating the need to develop efficient processes that can cut costs and improve productivity at commercial scale.
Advances in downstream processing were one of the many technology topics at the recent IBC conference “Biopharmaceutical Development and Production”.
“Multimodal chromatography is a powerful tool for difficult separation challenges, including mAb-aggregate removal,” explained Peter Hagwall, product manager, bioprocess media, GE Healthcare Life Sciences.
“Aggregates are tricky; they are composed of the same mAb molecule so a lot of the properties are similar to the monomer. Size differences are difficult to exploit and general techniques like ion exchange and hydrophobic-interaction chromatography often give unsatisfactory results. Poor separation usually means that yield of pure product is compromised.”
MAbs, although all the same class of molecules, have individual properties. The tendency to aggregate can vary, and cannot always be genetically engineered-in or predicted.
A trend over the past five years has been to apply multimodal media to the difficult polishing challenges downstream of the Protein A capture step. This allows optimization of fewer steps and further reduction of aggregate levels.
“A rapidly growing part of the biological pipeline is antibody fragments (Fabs),” said Hagwall. “In Fab purification, Capto adhere is already established as a workhorse for aggregate removal. Additionally, Capto MMC does a good job separating domain antibodies (dAbs), the smallest functional entity of antibodies, and can be used as part of a platform with Capto L, which purifies conventional Fabs as well as dAbs.
“Our next-generation multimodal ligands, Capto adhere ImpRes and Capto MMC ImpRes, display improved capability to reduce aggregate content while maintaining high yields and, thereby, good process economy,” he continued. “The high yields are achieved through the combination of fast mass transport of the Capto ImpRes base matrix and high selectivity of multimodal ligands, resulting in high-resolution separations. The Capto ImpRes base matrix has a smaller bead size than the Capto base matrix without compromising industrial demands, such as pressure/flow properties.
“Although future polishing challenges will be similar to those of today, new challenges will emerge related to the removal of undesirable product variants such as charge variants, glycosylation-, folding-, and truncated mAb-variants.
“As biomanufacturing continues to grow along with cost and time pressures, process development issues will need to be resolved quickly, and we are already seeing the use of high-throughput approaches to enable more rapid screening and optimization. An improved coupling between upstream and downstream processing will, in the long run, further improve process economy.”