For years, biopharma separations have followed a familiar script: improve the column, push the pressure higher, and let mass spectrometry (MS) clean up what chromatography can’t resolve. That playbook is now reaching its limits. As therapeutic molecules become larger, more modified, and more structurally ambiguous, the industry is being forced to confront an uncomfortable truth—some problems simply cannot be solved in the liquid phase.
Josh McBee, PhD, mass spectrometry scientist lead at Advanced Materials Technology, sees ion mobility as a necessary evolution rather than an optional add-on. “There are classes of molecules now where liquid chromatography, or LC, just runs out of resolving power,” he says. “Once you move into the gas phase, you suddenly gain a completely different way of separating things.”
Ion mobility adds a structural dimension to analysis, separating ions based not only on mass but also on size and shape as they drift through a gas under an electric field. In practice, that means isomers and closely related variants that coelute and fragment identically by LC–MS can finally be distinguished. “You can have compounds that look identical by chromatography and MS/MS,” McBee explains, “but ion mobility will show you they are not the same species.”
This capability is increasingly relevant for RNA therapeutics, where chemical modifications designed to enhance stability create families of near-identical molecules. The challenge is not simply detecting impurities, but recognizing when analytical blind spots lead to misidentification. McBee points to metabolomics and nucleotide analysis as cautionary examples, where traditional workflows can confidently assign the wrong structure.
Yet ion mobility is not a silver bullet. Its adoption in biopharma has been slowed by data volume and complexity, particularly when coupled with high-resolution MS. “People underestimate how fast the data problem explodes,” McBee says. “You’re adding another dimension, and suddenly your analysis tools are the bottleneck, not the instrument.”
For now, ion mobility is finding its strongest footing in early characterization and problem-solving, rather than regulated manufacturing. But McBee expects that to change as software matures and workflows become more automated. “The hardware is ahead of the ecosystem,” he says. “Ion mobility is really an enhancement of chromatography, and you may see an HPLC-ion mobility box in a production environment as the first iteration of the technology. Once the data handling catches up, mass spectrometry may not be far behind.”
In an era where therapeutic innovation is outpacing analytical tradition, ion mobility represents a shift in mindset as much as technology. “Chromatography and mass spectrometry have been critical tools for the development of these biologic therapeutics, but we can’t keep asking chromatography to do everything,” McBee says. “Sometimes the only way forward is to change the dimension entirely.”
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