A labortorian prepares a sample

 

As clinical laboratories embrace semiautomated solutions for mass spectrometry-based assays, a key question remains: Could a fully automated mass spectrometry analyzer boost adoption of this technology?

Drug testing and determining 25-hydroxyvitamin D (25(OH)D) levels are the two main uses for liquid chromatography-tandem mass spectrometry (LC-MS/MS) at large commercial laboratories, health systems, and drug testing laboratories. Some laboratories also deploy LC-MS/MS for neonatal metabolism screening, endocrine testing, and detecting monoclonal immunoglobulins.

Current LC-MS/MS methods are often lab-developed tests (LDTs) whose development and implementation can be challenging for some clinical laboratories because of labor-intensive and mostly manual workflows. To establish accurate and reproducible MS-based LDTs, a laboratory requires a significant level of expertise.

Consequently, LC-MS/MS has not gained traction in hospital laboratories as much as had been anticipated a decade ago, said Judith Stone, MT(ASCP), PhD, DABCC, a clinical chemist with experience developing tests and managing LC-MS/MS production at San Francisco General Hospital, Kaiser Regional Laboratories, Northern California, and the University of California, San Diego (UCSD) Center for Advanced Laboratory Medicine.

While the clinical use of LC-MS/MS technology is growing, most laboratories still rely on immunoassay-based methods for the majority of their workload, she noted. “Ten or 15 years ago, many people thought LC-MS was going to offer a revolution in hospital laboratory testing and that LC-MS would rapidly replace immunoassays, but that hasn’t happened,” Stone said. “It’s an interesting arc. If we are just talking about hospital laboratories, it’s still a relatively small percentage that use LC-MS.”

Clinical laboratorians prize both the sensitivity and versatility of LC-MS/MS. Stone conducted a small survey of hospital LC-MS laboratory directors in 2019 about their use of the technology, with results published in CLN (2019;45:24-7). When asked why they chose LC-MS/MS over another testing technique, respondents cited greater selectivity as the primary reason, followed by lack of an available assay on another in-house platform.

The survey also asked about whether laboratories had switched from LC-MS/MS to another technology and if so, why. Half of respondents said they had on occasion used automated immunoassays instead of LC-MS/MS primarily because of the workload and complexity of clinical mass spectrometry.

When asked whether they would transition all clinical mass spectrometry testing to a closed, fully automated Food and Drug Administration (FDA)-approved LC-MS/MS system if one became available, only one respondent would choose replacement. More than half said they would retain their open access lab-developed LC-MS/MS tests and continue to develop additional LDTs, as well as using a fully automated closed LC-MS/MS system.

SemiAutomated Solutions

Thus far, development of automated solutions in LC-MS/MS primarily has been focused on pre- and post-analytical areas. In recent years, some integrated systems to automate preanalytical steps in LC-MS/MS have been introduced by Shimadzu, Thermo Fisher, Tecan Group, Agilent, SCIEX, Waters, and Aurora. In Stone’s survey, about half of respondents said they had adopted automated liquid handling systems.

However, fewer laboratories indicated having adopted automated data analysis, which is also very labor intensive. Both Indigo BioAutomation and several LC-MS/MS vendors, including Waters, have developed automated data analysis solutions to facilitate data flow and analysis. One recent study found that Indigo BioAutomation’s ASCENT and Waters’ TargetLynx reduced manipulations by technologists during chromatogram review by 75% when compared to non-automated testing (Clin Chim Acta 2019;498:84-9).

“This eliminated manual result entry, repetitive transcription and unnecessary review of high-quality data while enabling systematic evaluation of data quality indicators,” wrote Shannon Haymond, PhD, DABCC, FAACC, a researcher and associate professor of pathology at Northwestern University Feinberg School of Medicine in Evanston, Illinois. “The new processes were accurate, improved the data review and processing times and helped reduce manual manipulations during chromatogram review.”

Fully Automated Systems Enter the Fray

Until recently, no fully automated LC-MS/MS system was available in the United States, but that changed in March with Thermo Fisher’s announcement that the company’s Cascadion SM Clinical Analyzer, a fully automated system, would be commercially available. Thermo Fisher first introduced this analyzer in Europe. Due to the highly competitive nature of innovation in this part of the industry, it’s not easy to forecast which company will be the next to introduce such an instrument.

Currently, the only test that can be run on Thermo Fisher’s analyzer is the Cascadion SM 25-Hydroxy Vitamin D Assay. The company has said publicly that it is developing an immunosuppressants panel for the analyzer. Thermo Fisher declined to be interviewed for this article.

According to a white paper published by Thermo Fisher, the Cascadion system enables a 70% reduction in the total time required to implement ready-made assays for routine clinical testing applications. The system is designed to minimize maintenance and possible delays in starting testing during clinical lab shifts. Maintenance checks can be scheduled off-hours so as not to interfere with laboratory throughput. Meanwhile, the daily start-up procedures take only 20 to 30 minutes and can be programmed to start just before working hours.

Roche also reportedly is working on an LC-MS/MS automation module for its cobas pro analyzer. Benjamin Lilienfeld, vice president and international leader of serum work area systems, said in a 2019 interview that the cobas pro will be the host for Roche’s integrated mass spectrometry analytical unit, although he noted that it’s still several years out. Roche also declined to be interviewed for this article.

Is This a Game Changer?

Might the introduction of a fully automated LC-MS/MS analyzer be a gamechanger for clinical diagnostics? Robert Fitzgerald, PhD, DABCC, NRCC, FAACC, a professor of pathology and director of toxicology at UCSD, believes it will.

“Clearly, a fully automated LC-MS/MS solution has the potential to change clinical diagnostics,” Fitzgerald said. “LC-MS/MS offers sensitivity and specificity not achievable with current automated chemistry platforms. Currently, most LC-MS/MS assays are run in a batch mode, and consequently turnaround times suffer. The ability to offer LC-MS/MS in a random-access high-volume analyzer will improve both turnaround times, as well as improve sensitivity and specificity of the assays.” He added, “The full impact of an automated LC-MS/MS system will depend on how feasible it is to install in a routine clinical laboratory. The hurdles to overcome include instrument challenges, assay menu, price, and ease of use.”

Stone believes a major driver for hospital labs to adopt Cascadion will be availability of a test menu with which immunoassays can’t compete. This could be through consolidating multiple tests on a single platform, significant differences in selectivity, or by saving money from internalizing testing previously sent out to reference laboratories.

References laboratories like Quest and LabCorp have large 25(OH)D testing volumes so might be able to justify the analyzer for just that one assay. But an instrument with only one FDA-approved test initially might be a tougher sell to smaller laboratories, Stone noted. “Once there are two or three high-workload tests available on analytical platforms, it is easier to financially justify adding more expensive, low-volume tests on that same instrument, perhaps assays that your health system wants but hasn’t previously been able to afford,” she said.

The main benefits of having a fully automated LC-MS/MS platform would be the ability to bring sendout testing back in-house and improve turnaround times, said Fitzgerald, who noted that UCSD clinicians would like to have tacrolimus measured by LC-MS/MS, but they want to have results back from the lab in a couple of hours. “This is not currently feasible, so we measure tacrolimus by immunoassay. If we had access to a fully automated LC-MS/MS system capable of measuring tacrolimus, that would be an ideal option.”

Lorin Bachmann, PhD, DABCC, associate professor of pathology and co-director of clinical chemistry and point-of-care testing at Virginia Commonwealth University in Richmond, emphasized the additional benefits of a fully automated system beyond increased efficiency. “Any time you have a fully automated system, it reduces the chance for human error,” she said. “Also, technologists don’t need to have a lot of training in LC-MS to run the system. If the system is completely walk away, they can multitask and perform other types of testing, so that is another way that efficiency is increased.”

While only being able to run one test might limit the Cascadion’s current marketability, Bachmann notes that availability of a fully automated LC-MS/MS solution is a start in making this technology more widely available to clinical laboratories. “This represents a step in the right direction,” she said. “As more tests are made available on fully automated systems, LC-MS/MS technology will move closer toward more widespread adoption.”

Kimberly Scott is a freelance writer who lives in Lewes, Delaware. +Email: kmscott2@verizon.net