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Techniques & Tools Mass Spectrometry, Liquid Chromatography, Pharma & Biopharma, Data Analysis

Instrumental to Success

How can a company, in any sector, tell if a product resonates with prospective customers while it is still in development? I believe that the best way – perhaps the only way – is to get customers involved from the word go. Here’s an example from my company, Waters, of having customers actively participate in implementing and evaluating a sophisticated LC-MS system. In fact, this example even originates with a customer.

Steve Cohen

In 2004, we were approached by John Engen, then at the University of New Mexico. John is a pioneer in hydrogen-deuterium exchange mass spectrometry (HDX-MS), which is used to assess the solvent accessibility of protein amide protons. In HDX-MS, protein samples are placed in deuterated buffer to exchange amide protons with deuterons. After a specified time, the exchange is quenched by acidifying the sample at or near 0°C. The protein is then digested with the acid-stable protease pepsin, and the peptides separated and analyzed by LC-MS. The technique provides insights on protein stability, dynamics, the effects of additives, binding sites, and protein-ligand interactions.

Excessive back-exchange prior to MS was causing John problems. This process occurs readily during sample processing and analysis. Our Acquity UPLC system, which yields fast, efficient separations, limited back-exchange: the problem was solved. 

The story could have ended there, but John, now at Northeastern University, felt that other avenues for improving HDX-MS were ripe for development. He encouraged Waters to engineer a cooled sample preparation module that was compatible with UPLC, to replace ice baths; and he suggested that this module should interface with a robotic sample-handling module. Chemist-engineers in Waters' Instrument Research Group, first Keith Fadgen and later including Michael Eggertson and Martha Stapels, produced a prototype in short order that provided the necessary thermal control in a user-friendly configuration.

There was clearly commercial potential in this. Our next step was to involve a number of customer sites to help identify and iron out problems prior to delivery to paying customers. The application chemists in an instrument company normally work with readily available standard samples. Working in customers' labs allows us to analyze more exotic samples, for example, protein biopharmaceuticals, that offer far more insight into the typical use of the instruments after purchase. In this case, certain proteins yielded carryover of hydrophobic peptides that both interfered in subsequent runs and gave incorrect exchange values in the initial run. With staff from Waters and our customers working together, modifications in the chromatography provided a between-sample column wash that eliminated the problem. Further suggestions for improvements from customers extended to modifying the layout within the cooling module to improve access to key components, improving serviceability.

Initially, the ability to efficiently process and analyze this data and to visualize the results in a meaningful and timely fashion was missing. It became a critical element of the development process.

A significant roadblock that emerged was that, while sample analysis was streamlined, the system produced massive amounts of data. Initially, the ability to efficiently process and analyze this data and to visualize the results in a meaningful and timely fashion was missing. It became a critical element of the development process. Our solution was to adapt existing data-processing routines from proteomics workflows for use with HDX data and peptic peptide analysis. A novel processing method was developed that decreased processing time by several orders of magnitude, reducing what originally took months to hours and allowing complete data processing in approximately the same time that it takes to acquire the data. Based on suggestions from one of our collaborating customers – the biotechnology company BiogenIdec – we also enhanced data visualization and statistical analysis to produce a package for the comparability studies that are an essential part of the biopharmaceutical development process. 

These instances of customer insight were dependent on the customers actually working with prototype instruments. If we had waited for feedback until after commercialization, the system would have been clearly deficient, critical aspects would have caused field failures, and customer frustration from slow data processing would have seriously compromised our success. Instead, the early test site program provided valuable feedback that greatly enhanced the system, which we successfully introduced in 2011.

Needless to say, the mutually beneficial interaction between instrument developers and customers is at the heart of everything that Waters is doing.

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About the Author
Steve Cohen

RDE Life Sciences Director, Waters Corporation, Milford, MA, USA.

Steven Cohen is currently a director in Waters Life Sciences Research and Development Group. He began at Waters in 1982 as a Senior Scientist and has held several positions at Waters before his current one. He received his Bachelor’s degrees in Chemistry and Math from Clark University and a Ph.D. in Biochemistry from the University of Chicago studying protein structure and function. After graduation Steve had post-doctoral positions at Wesleyan University and the University of Connecticut. Prior to joining Waters, he was Senior Research Scientist at Northeastern University in the Institute of Chemical Analysis (now the Barnett Institute for Analytical Chemistry). Steve is the author of more than 50 peer reviewed publications and his extensive experience using multidimensional liquid chromatography has led to the recent publication of the book “Multidimensional Liquid Chromatography: Theory and Applications in Industrial Chemistry and the Life Sciences”, co-edited with Dr. Mark Schure.

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