Recent Advances in Mass Spectrometry for Process Monitoring

March 2, 2021

The talks in this Monday morning session highlight recent advances in mass spectrometry (MS) for reaction monitoring approaches for small and large molecules. Presentation of both approaches is intended to cross-fertilize ideas and to be informative for both analytical and process scientists.

The session will kick off at 8:30 am with a talk by R. Graham Cooks of Purdue University on high throughput reaction monitoring and small scale synthesis. Cooks will describe an automated system based on desorption electrospray ionization (DESI) and its use for high density (6,144 reaction mixtures) small scale (50 n:, 1–5 ng) analysis at high speed (two samples/s), with MS and MS/MS data being acquired automatically. The system has been modified to allow small-scale synthesis with on-line analysis of bioactivity of the products of synthesis. The applications in bioanalysis, including enzyme assays, will be stressed.

Next, at 8:50 am, Steven Groskreutz of Eli Lilly & Company will discuss an online-liquid chromatography–mass spectrometry (LC–MS) workflow to enable manufacturing of synthetic peptides. He will present on the development and application of an online-LC–MS based process analytical technology (PAT) platform to support development and inform manufacture of linearly build synthetic peptides. Applications focus on monitoring amino acid couplings and deprotection reactions to ensure reaction completion, elucidating coupling–deprotection kinetics and identifying and tracking critical impurities. Further, Groskreutz will discuss how he leveraged this new PAT tool to assess resin washing online (resulting in significant reductions in solvent consumption) as well as ensure finished materials meet desired critical quality attributes.

Tony Bristow of AstraZeneca will then describe, at 9:10 am, the use of mass spectrometry for process monitoring of pharmaceutical processes, from preliminary research to implementation.This presentation will describe a journey that began with the evaluation of continuous on-line monitoring by small footprint MS of flow chemistry and dissolution, to the coupling of on-line nuclear magnetic resonance (NMR)–MS to monitor batch chemistry. The greatest impact of MS for process monitoring to date has been realized through the coupling to self-optimizing flow reactor technology. Despite this success, there remain challenges for the broader and routine implementation of on-line MS and these areas will also be explored.

This will be followed by a talk at 9:30 am by session organizer Mark Zell of Takeda Pharmaceuticals on recent applications of online tools for reaction monitoring in the pharmaceutical industry, including optical spectroscopy, NMR, and MS. Zell and his colleagues have been working to implement all of these technologies in parallel to provide a comprehensive overview of the chemical reactions occurring in their laboratories. An overview of some applications of their work around reaction monitoring will be outlined.

In the fifth talk, at 10:05 am, Andrei Federov of the Georgia Institute of Technology will give a talk on the monitoring of cell secretome and metabolome using a dynamic sampling platform coupled to electrospray ionization mass spectrometry (ESI-MS).Standard analytical methods work with relatively large samples and averaged (homogenized) biomarker concentrations, and have no ability to assess either the local heterogeneity or the transient nature of cell biochemical evolution and signaling. The dynamic sampling platform (DSP) overcomes both barriers by enabling local sampling of biomolecules for rapid, high fidelity, and label free identification via inline ESI-MS.

Gregory Pino of Takeda will then describe, at 10:25 am, online monitoring for rapid process development. A cross-functional team comprised of analytical scientists and upstream and downstream engineers successfully developed a 10-L bench scale bioreactor model with online product quality testing for titer, aggregation, charge variants, fragmentation, oxidation, glycation, glycosylation and process performance attributes. The technology implemented is scalable and agnostic to single-use perfusion or fed-batch processes. The utilization of online product quality monitoring has reduced data turnaround time from 10 d to less than 1 d and reduced resourcing needs 10 fold compared to traditional manual testing approaches.

The session will wrap up with a talk at 10:45 pm by Peng Li of West Virginia University on the development of vibrating sharp-edge spray ionization (VSSI) for MS analysis. This presentation will discuss the latest development of the VSSI method, and its applications in direct surface analysis, tandem MS native MS, and LC–MS

Link to the full session: