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LC-MS/MS random access automation – a game changer for the 24/7 clinical laboratory

  • Ronda F. Greaves ORCID logo EMAIL logo
Published/Copyright: May 8, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 7

Keywords: epilepsy; automation; therapeutic drug monitoring (TDM); laboratory medicine; reference measurement procedure

Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has significantly grown over the last 20-plus years to become a routine clinical application [1]. As predicted, it has opened the field of analytes that could be successfully measured by mass spectrometry (MS) techniques, e.g. drugs, hormones, and newborn screening and importantly, this technology has provided opportunities to significantly address unmet clinical needs [1], [2], [3], [4], [5], [6]. However, the application in clinical laboratories is still considered highly technical and not applicable to routine 24/7 workflows. Whilst there have been significant process improvements, gaps remain across the total testing process, especially post-analytical, that have continued to limit instrumentation to the specialised areas of the laboratory.

Currently, there remain many challenges with LC-MS/MS that have limited its full translation to the core/central laboratory. These include:

  1. Throughput – LC-MS/MS is associated with batch mode processing that limits the ability to run assays with high sample numbers all by first tier testing e.g. congenital adrenal hyperplasia screening [7];

  2. Post-analytical processing – which remains for many laboratories based on spread sheets or similar as the “middleware” to review output parameters and import them into the laboratory information system;

  3. Service support – mass spectrometry companies have not adapted to the clinical needs of 24/7 support and continue to base their service support on a 9 to 5 model and slow response time for breakdowns; and

  4. Education, training and competence – the level required can be higher than the capacity and broad capability of teams to operate an LC-MS/MS system as a main frame instrument.

So, whilst the dictum of change to MS if it is better than immunoassay holds for the improved specificity, because of the issues noted above, immunoassay remains the predominant first-tier testing principle for steroid analysis, therapeutic drug monitoring (TDM) and toxicology screening. These challenges may be resolved for many routine tests soon.

Building on its Serum Work Area, Roche Diagnostics is making a leap of faith to incorporate automated LC-MS/MS[1] [8, 9]. This has in part been tried previously by others with limited success [10, 11]. With a larger planned initial test menu, the Roche approach pivots away from batch mode processing to a random access testing model, giving the central laboratory a choice between immunoassay and mass spectrometry for more tests. To anchor these methods, as part of the development of this automated solution, Roche is publishing candidate reference measurement procedures (RMP) in preparation for submission to the Joint Committee for Traceability in Laboratory Medicine (JCTLM) database,[2] and as an example, the RMP for methotrexate was published in 2023 and is now included in the database identified as C19RMP11 [12, 13]. The development of RMP to establish metrological traceability was the topic of the editorial associated with Roche’s first set of publications [13], [14], [15], [16], [17], [18], [19].

In this special issue of the Journal, the second collation of five methodology papers describing RMP is presented [20], [21], [22], [23], [24]. These papers continue to address the need for a greater number of Systeme International (SI)-traceable RMP for small molecules. Each paper presents a single analyte isotope dilution mass spectrometry method for the quantification of 1) carbamazepine [20], 2) its main metabolite carbamazepine 10,11-epoxide [21], 3) phenobarbital [22], 4) primidone (which is bio-transformed to phenobarbital) [23], and 5) zonisamide [24] in human serum and plasma. Of these five analytes, only phenobarbital had a RMP listed in the JCTLM previously and two of the Roche methods are newly listed RMP (i.e. carbamazepine – JCTLM ID C20RMP10 and zonisamide JCTLM ID C20RMP10) [12]. Clinically, each of these therapeutic drugs is used alone or in combination with other medications to control certain types of seizures in people with epilepsy.

Epilepsy affects around 50 million people worldwide, affecting individuals from birth through to adults, and contributes 0.5 % to the global burden of disease, and for 70 % of individuals there is the opportunity to live seizure-free if appropriately diagnosed and treated [25]. Antiepileptic TDM has been used to improve the effectiveness and patient safety since the 1960s. Immunoassay-based TDM replaced HPLC-based methods in the mid-1980s because they offered simplicity and sensitivity, but at the expense of specificity due to cross-reactivity [26], [27], [28]. As an example, carbamazepine 10,11-epoxide can interfere with carbamazepine immunoassays that may confound clinical interpretation, limiting the effectiveness of treatment and the potential for adverse outcomes [29]. Hence, with the introduction of LC-MS/MS into clinical laboratories 20-plus years ago, it seemed appropriate to move away from immunoassay. Despite this knowledge, the move to improve specificity has been hampered by the lack of adequate progression to full automation of LC-MS/MS [30, 31].

In summary, automation is a key component of the smart laboratory and its ability to have random access LC-MS/MS assays formatted for antiepileptic TDM is likely to bridge the chasm and allow its widespread adoption [2]. If this initiative is successful, many of the challenges faced by LC-MS/MS (i.e. throughput, post-analytical processing, service support and training requirements) will be dissipated. Whilst automation can bring its own challenges, this more sophisticated approach has the advantages of lean processing efficiency, greenness (through automation) and safety in handling of reagents [32], [33], [34]. The opportunity to have LC-MS/MS run as part of a laboratory’s 24/7 service delivery is likely to be a game changer, in that it is projected to have a profound impact on the central laboratory and its role in the clinical management of epilepsy and beyond.

Corresponding author: Prof. Ronda F. Greaves, Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia; and Department of Paediatric, University of Melbourne, Parkville, VIC 3052, Australia, E-mail:

Acknowledgments

RG has signed a non-disclosure agreement with Roche Diagnostics concerning their new LC-MS/MS system. The information provided in this editorial is in the public domain and provided in good faith to reflect the proposed mass spectrometry product at the time of writing.

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Published Online: 2024-05-08
Published in Print: 2024-06-25

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/cclm-2024-0501
Keywords for this article
epilepsy; automation; therapeutic drug monitoring (TDM); laboratory medicine; reference measurement procedure
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. LC-MS/MS random access automation – a game changer for the 24/7 clinical laboratory
  4. Reviews
  5. Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges
  6. Differential diagnosis of ascites: etiologies, ascitic fluid analysis, diagnostic algorithm
  7. Opinion Papers
  8. Clinical Decision Support System in laboratory medicine
  9. Blood over-testing: impact, ethical issues and mitigating actions
  10. General Clinical Chemistry and Laboratory Medicine
  11. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure for the quantification of zonisamide in human serum and plasma
  12. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure for the quantification of carbamazepine in human serum and plasma
  13. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of phenobarbital in human serum and plasma
  14. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of primidone in human serum and plasma
  15. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure for the quantification of carbamazepine-10,11-epoxide in human serum and plasma
  16. Should we depend on reference intervals from manufacturer package inserts? Comparing TSH and FT4 reference intervals from four manufacturers with results from modern indirect methods and the direct method
  17. Comparison of three chatbots as an assistant for problem-solving in clinical laboratory
  18. Evidence-based cutoffs for total and adjusted calcium: a major factor in detecting severe hypo- and hypercalcemia
  19. Minor head injury in anticoagulated patients: performance of biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in the detection of intracranial injury. A prospective observational study
  20. A comparative evaluation of the analytical performances of premier resolution-high-performance liquid chromatography (PR-HPLC) with capillary zone electrophoresis (CZE) assays for the detection of hemoglobin variants and the quantitation of HbA0, A2, E, and F
  21. Get reliable laboratory findings – how to recognize the deceptive effects of angiotensin-converting enzyme inhibitor therapy in the laboratory diagnostics of sarcoidosis?
  22. Reference Values and Biological Variations
  23. Vitamin D and vitamin K status in postmenopausal women with normal and low bone mineral density
  24. Hematology and Coagulation
  25. An automatic analysis and quality assurance method for lymphocyte subset identification
  26. Cancer Diagnostics
  27. Machine learning-based delta check method for detecting misidentification errors in tumor marker tests
  28. Cardiovascular Diseases
  29. Analytical evaluation of the novel Mindray high sensitivity cardiac troponin I immunoassay on CL-1200i
  30. Infectious Diseases
  31. A reactive monocyte subset characterized by low expression of CD91 is expanded during sterile and septic inflammation
  32. Letters to the Editor
  33. Inadvertent omission of a specimen integrity comment – an overlooked post-analytical error
  34. Falsely elevated T3 due to interference of anti-T3 autoantibodies: a case report
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