Regulatory demand for higher quality medicines is driving drug makers to search for better ways of separating product from the process stream. In recent years, mixed-mode chromatography (MMC) has emerged as a powerful potential solution.

In MMC, multiple binding mechanisms are used to mediate the interaction between proteins and ligands immobilized on a stationary phase. These secondary interactions improve separation power, which has attracted a lot of industry interest, according to John Milne, PhD, bioprocessing training director at National Institute for Bioprocessing Research and Training (NIBRT) in Ireland.

“High selectivity and resolution are key attributes in developing a robust purification strategy and hence the use of MMC resins that combine electrostatic and hydrophobic interactions can offer a more discrete purification when compared with using individual chromatography steps that utilize charge or hydrophobicity separation alone,” he says. “In essence MMC can provide unique selectivity and as these resins are based on multiple interactions, it affords the chromatographer greater options to purify certain analytes.”

Intensified production methods

MMC is also better suited to intensified production methods, including continuous manufacturing, than traditional chromatography, according to Milne.

“As the biopharmaceutical industry looks at newer innovations to address the need for greater process intensification in biologics manufacturing, alternative purification strategies are an obvious area of focus,” he continues. “As two or more types of interaction contribute significantly to the retention of solutes, MMC can offer many advantages in terms of achieving high resolution, high selectivity, and high sample loading when compared with conventional chromatography.

Milne and his NIBRT team examined industry use of MMC in a recent review. The simplicity of the approach is another factor in its favor, he points out.

“MMC is easy to implement,” Milne explains. “Essentially, you are packing a resin into a column shell. The column operates in traditional batch mode attached to a traditional column chromatography system, so nothing particularly unique to the operations. The infrastructure is similar it is just the selectivity offered by the resin that is more unique!”

He adds that, “Generally, MMC is not more expensive and time consuming than normal chromatographic operations that are common to all liquid chromatography operations. It’s just that the media itself offers an alternative type of separation.

“Resin costs may be higher than traditional resin costs (IEX, HIC) but they are still not as expensive as customized and or affinity-based resins and typically they are available off the shelf from suppliers.”

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