LC-MS/MS Testing: Miss The Big Picture Stuff that FDA Cares About

Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a bioanalytical technique used in a multitude of diagnostic procedures in laboratory medicine. Over the years, LC-MS/MS analysis has matured with time and is often irreplaceable by alternative bioanalytical techniques. As the method evolved, the applications of LC-MS methods got increasingly well documented. Moreover, the in vitro diagnostic industry is coming up with certified instruments and assay kits, having LC-MS/MS method as its analytical core.

Even after the advent of newer technical specifications, the implementation of LC-MS/MS analysis is still burdensome in several lab settings. Often labs rely on a highly specialized technical staff for locally lab-developed analysis. Currently, researchers routinely employ LC-MS analysis for a wide range of compounds in toxicology, drug monitoring, and endocrinology. Thus, such a fundamental technique will require critical fulfillments of FDA criteria. Let us study some of the crucial aspects that the FDA truly cares about.

Robust LC-MS/MS validation

The primary goal of all FDA specifications is to produce a sound and robust bioanalytical method capable of providing reliable and reproducible results. FDA regulates all bioanalytical techniques, including LC-MS/MS instrumentation, so that the instruments are reliable and efficient in their intended uses. The intended use of LC-MS/MS analysis is critical to validate the test design and study performance to assist all marketing claims. For example, if clinical studies submitted to the FDA are conducted in the intended population, the subsequent results can support the marketing claims. Thus it proves that the results appropriately reflect the LC-MS/MS performance. Hence, LC MS method development and validation are crucial deciding factors for its successful implementation in routine drug analysis.

Regulation and streamlining lab developed systems

The lab-developed tests always lay the foundational stone for technological development from labs to routine practices. Hence, lab-based LC-MS/MS instrumentation is of utmost importance for maturation and technological advancements. Lab-developed LC-MS/MS methods were the only reason that several limitations were evident, and the groundwork for method design and validation was established. Lab-based tests are particularly indispensable, as there are several diagnostic analytes for whom industrialized or FDA-approved assays are not yet available.

During the development of lab-based LC-MS/MS methods, the FDA expects that the developer should mitigate all the associated risks involved in the testing procedure. Next, the FDA expects that the developer must define the intended use and determine the reference and target ranges. In 2014, the FDA issued draft guidance for lab-developed tests, followed by a discussion paper, later in 2017. FDA allows the development of lab-based LC-MS/MS methods, as long as no industrialized methods with similar performance characteristics are available for analysis.


To fulfill the ever-increasing need of the pharma and biomedical industry, LC-MS/MS has matured to such an extent that most small molecules are efficiently assessed. However, LC-MS/MS analysis predominantly relies on specialized personnel in research settings. Hence, to become a routine diagnostic, the pharma industry must come up with automated solutions for LC-MS/MS analysis. It is just a matter of time that LC-MS/MS instruments will be on a similar path to automated ligand-binding assays.

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