Victoria Zhang, PhD, MBA, DABCC, FADLM
Professor and Vice Chair, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is a vital tool in clinical diagnostics, offering superior specificity compared to immunoassays. However, its adoption has been limited by labor-intensive workflows, a lack of FDA-approved assays, and the need for technical expertise, all of which impede automation and high-throughput implementation in clinical laboratories (1,2). The development of automated, FDA-approved standalone LC-MS/MS has generated significant interest. A paper published in 2015 by Drs. Zhang and Rockwood proposed two possible models, standalone vs integrated, to achieve automation on LC-MS/MS (3). In 2017, the Cascadion™ SM Clinical Analyzer was introduced, marking a milestone in LC-MS/MS automation. Initially launched in Europe, it later gained FDA approval in the U.S. with its vitamin D assay (4).
Recently, Dr. Zhang’s laboratory evaluated this instrument and its vitamin D assay (5). The Cascadian is an automated LC-MS/MS platform with integrated automated sample handling, barcode reader, pipetting, centrifugation, online solid-phase extraction, and reporting. The standalone instrument is equipped with dual streams of HPLC interfaced to a triple quadrupole mass spectrometer and can process a serum sample every 3 minutes. The analytical measurement range (AMR) was 3.4 – 132 ng/mL. The manufacturer-specified precision and accuracy were within 10% and 15%, respectively. Calibration was performed once a month by running a six points calibrator, and three QCs were run twice daily. This study demonstrated that the automated platform simplified LC-MS/MS workflow and its vitamin D assay characteristics were comparable to traditional LC-MS/MS systems. The study also highlighted areas for improvement, such as overall throughput, truly random-access platform, and test menu expansion. Although discontinued in 2022, the Cascadian provided critical insights into transitioning from traditional LC-MS/MS to automated platforms.
In December 2024, Cobas Mass Spec solution received a CE mark approval in Europe. This instrument is considered an integrated and fully automated mass spectrometry system with a larger test menu, including immunosuppressants, anticonvulsants, antifungal, and hormones. With multiple HPLC streams running in parallel, a throughput of 100 samples per hour was achieved for therapeutic drug monitoring of mycophenolic acid (6). We look forward to learning more about instrument performance and its assay characteristics in future studies. Continued innovation in automated mass spectrometry systems will facilitate implementation of LC-MS/MS in routine clinical laboratories, where highly trained personnel may not be available.
迈向临床液相色谱串联质谱方法的自动化
液相色谱串联质谱法 (LC-MS/MS) 是临床诊断的重要工具，与免疫测定相比，它具有更高的特异性。然而，由于复杂的工作流程、缺乏 FDA 批准的定量方法以及对专业技术的要求，该技术在临床实验室的推广、采用受到了限制 (1,2)。近来FDA 批准的自动化临床质谱仪的开发引起了人们的极大兴趣。张博士和 Rockwood 博士在 2015 年发表的一篇文章中提出了两种模型, 独立型和集成型，来实现LC-MS/MS 的自动化 (3)。2017 年，Cascadion™ SM 临床分析仪问世，标志着 LC-MS/MS 自动化的一个里程碑。它最初在欧洲推出，后来该仪器及其维生素 D 检测方法在美国获得了 FDA 批准 (4)。
张博士的实验室评估了Cascadion 的性能及其维生素 D 定量方法 (5)。Cascadian 是一个独立型自动化 LC-MS/MS 平台，集成了条形码读取器、取样、离心、固相萃取和报告功能。该仪器配备两套 液相色谱，与三重四极杆质谱分析仪连接，每 3 分钟可处理一个样品。维生素D的定量范围 为 3.4 – 132 ng/mL。制造商指定的精密度和准确度分别在 10% 和 15% 以内。要求每月至少运行一次标准品以校准仪器，每天运行两次质控样品。这项研究表明，自动化平台简化了 临床质谱仪的工作流程，其维生素 D 定量方法可媲美传统 LC-MS/MS 方法。该研究也指出了需要改进的领域，例如提高总体通量、实现真正的随机访问和拓展临床适用的定量方法。尽管 Cascadian 于 2022 年停产，但它为从传统 LC-MS/MS 向自动化平台的过渡提供了重要经验。
2024 年 12 月，Cobas Mass Spec 在欧洲获得了 CE 标志认证。该仪器被视为集成型的全自动质谱系统，提供较多的临床测试方法，包括免疫抑制剂、抗惊厥药、抗真菌药和激素。通过配备多套液相色谱，用于治疗药物监测的霉酚酸定量方法每小时可以分析100 个样品 (6)。我们期待在未来的研究中进一步了解该仪器的性能及其测试方法。自动化质谱系统的持续创新将有助于常规临床实验室引进基于液相色谱串联质谱的精准定量方法。
References:
1. Vogeser M, Seger C. A decade of HPLC-MS/MS in the routine clinical laboratory--goals for further developments. Clin Biochem 2008 Jun;41 9:649-62. Epub 20080314 as doi: 10.1016/j.clinbiochem.2008.02.017.
2. Clarke W, Rhea JM, Molinaro R. Challenges in implementing clinical liquid chromatography-tandem mass spectrometry methods--the light at the end of the tunnel. J Mass Spectrom 2013 Jul;48 7:755-67 as doi: 10.1002/jms.3214.
3. Zhang YV, Rockwood A. Impact of automation on mass spectrometry. Clinica Chimica Acta 2015; 450:298-303.
4. Nguyen NN, Raju MNP, da Graca B, Wang D, Mohamed NA, Mutnal MB, Rao A, et al. 25-hydroxyvitamin D is a predictor of COVID-19 severity of hospitalized patients. PLoS One 2022;17 5:e0268038. Epub 20220503 as doi: 10.1371/journal.pone.0268038.
5. Gqamana,PP, Militello, L., McMaster, J.M., Daley, S.J., and Zhang, Y.Z., Analytical Concordance of Total Vitamin D on a Fully Automated Random-Access LC–MS/MS Platform. JALM, 2023;940-951. PMID: 37473445 DOI: 10.1093/jalm/jfad036
6. Vogeser M, Habler K, Reuter A, Schneider-Thauern C. Pilot study of a prototype fully automated mass spectrometry system for routine clinical laboratory use. JMSACL, 2024, 34:44-45.
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