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The Lifetime of LC-MS is, and Will Be, Constantly Evolving

With lightning-fast speed, LC-MS systems have rapidly evolved into today’s highly functional tools. But where did they begin?

by James Netterwald
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LC/MS Purification System | Gilson 

“When LC-MS instruments first came out 15 to 20 years ago, the main issue was just getting them to work,” says Bob Classon, LC-MS business development manager, Shimadzu Scientific Instruments (Columbia, MD). Back then, the early models were difficult to use and lacked the ionization sources needed, especially for small-molecule pharmaceuticals. “Once people learned how to make them work, the next step was making them reliable—making them work for weeks or months without having to do a lot of maintenance,” says Classon. About seven years ago, the trend in MS switched more to a focus on sensitivity, prompting the development of a number of LC-MS systems with large increases in sensitivity. “The trend now is more toward convenience and reliability, which means a number of systems were created that require less maintenance and can handle a wider variety of samples and sample matrices without difficulty,”says Classon.

One of the latest trends is a move toward improving operator convenience by reducing the training requirements needed to use LC-MS. “Right now we have a lot of people using them who have no analytical chemistry, mass spectrometry, or HPLC background,” says Classon. “Users might range from biomedical people or synthesis chemists to food chemists.” LC-MS users don’t want to know the technology or the physics of how it works. They want results, and fast. So the robustness and the ability to handle a dirty sample or dirty matrix, or compatibility with fast HPLC or UPLC, are of great interest to current end users. Recently introduced instruments are more robust than products from just five years ago, and the newest instruments are getting faster to be more compatible with UPLC and high-throughput requirements. Instruments now have to be able to perform quantitation on chromatographic peaks that are less than one second wide and have to be able to perform quantitative and qualitative analysis on fast peaks in a single one-minute run. Much of this is driven by clinical labs and CROs where the lab that runs the most samples per day makes the most profit. Even as pharmaceutical companies are producing fewer NDAs, they are trying to get better drugs into clinical trials faster. They don’t want the LC-MS analysis portion to slow down getting a drug to market.

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New compounds; lightning speed; complete solutions

The trend moving forward will probably place somewhat less emphasis on small molecule analysis and more on biotherapeutics, proteinbased compounds, and biosimilars. Here the selectivity is just as important as the sensitivity. Samples involving proteomic workflows generally incorporate many steps such as concentration, fractionation, digestion, and other types of cleanup that were never designed to be put together. In order to speed up analysis of these types of samples and to reduce cost per sample, there will be more emphasis on the systems to automate these steps so users gain not only speed but also quantitative transfer from step to step and much greater reproducibility. Systems are already available to allow for injection of whole-plasma samples for fast analysis of proteins. These systems use antibody binding and immobilized enzymes to perform analysis of targeted proteins for research applications such as finding markers for cancer and other diseases. One such system, the Perfinity Workstation, can select target proteins from a biological sample, perform a tryptic digest, and produce a peptide map, all automatically. If you were looking for the metabolism of a proteinbased drug or a low-abundance protein biomarker, this type of analysis would complement the LCMS significantly by allowing a biological sample to be processed, digested to peptides in under 10 minutes, and turned into a full peptide map in 30 to 60 minutes. In short, this type of system makes the LC-MS work better. The conventional approach to this is that a 24-hour analysis is much more expensive and is not as reproducible for quantitation.

Another trend is the life science industry's continued push for more efficiency and productivity,” says Lester Taylor, Ph.D., LC-MS product marketing, Agilent Technologies (Santa Clara, CA). "To that end, with mass spectrometry moving into other fields outside pharmaceutical or research fields, there is the need for ease of use in providing access of this data to non specialists." The push for efficiency is not only a push for greater ease of use but also for automation, particularly in front-end sample handling using highthroughput robotics.

LC-MS System | Flexar SQ 300 PerkinElmer | 

"The push for efficiency is not only a push for greater ease of use but also for automation".

A further trend in LC-MS is for vendors to provide complete solution kits, which include the mass spectrometer, the analytical methods, the HPLC conditions, and the mass spectrometry conditions, as well as a database containing reference spectral information. “That allows the user to run the samples, get the data back, and screen it against its library of spectra,” says Taylor. Another trend is the development of software tools to allow the inexpert LC-MS user to analyze samples and get streamlined summary reports.

New applications; personalization

According to Sal Iacono, vice president and general manager of mass spectrometry for PerkinElmer (Waltham, MA), one of the major trends in the LC-MS market is greater use of the instrument in preclinical research and food testing, and there is an increase in the ease of use of these systems. “Over the last few years, we have seen more multifunctional researchers. Having the time to learn every software package, every nuance of it, is rapidly disappearing. The capability to make one or two mouse clicks to generate a result is one of the major trends in the marketplace and is likely to accelerate further,” says Iacono.

Besides the traditional LC-MS users in basic life science research and pharmaceuticals, there are an increasing number of users in clinical diagnostics and in food safety who are using the technology for routine applications. “These users don’t want just a mass spectrum. They want yes-or-no answers,” says Steve Smith, senior director and mass spectrometry product manager, Waters Corporation (Milford,MA). "These are critical applications where the mass spec result could make the difference between life and death or making and losing millions of dollars.

Triple Quad Mass Spectrometer | LCMS-8030 | Shimadzu 

Another trend in LC-MS is to personalize the operation of the instrument. “If you have six scientists in the lab, then you have two ways to personalize those instruments: you could either buy a new instrument for each user, or you could schedule time for each individual to operate an instrument, says Iacono. “What we’ve designed is a separation probe that is about the size of a writing pen.

Each individual can be assigned a personalized separation probe. In this way, when a scientist is ready to use the instrument in a scheduled manner or via open access … the individual simply walks up to the instrument and places the separation probe onto the mass spectrometer with the click of one button.” A column can be preconfigured right down to the chromatographic separation. “When the scientist is finished with the analysis, the user disconnects the LC and walks away with that personalized application probe,” says Iacono. These novel solutions will reduce the cost of operation to the laboratory by maximizing efficiency, optimizing usage time, and ultimately requiring smaller numbers of instruments and solvents.

In summary, there is a wide variety of trends in the LC-MS market. Present and future end users should keep abreast of these trends in order to effectively make the most informed purchasing decisions.