Matrix effect in bioanalytical assay development using supercritical fluid chromatography‐mass spectrometry

Abstract Matrix effect (ME) is commonly caused by coelution of compounds with target analytes, resulting in either suppression or enhancement of analyte ionization. Thus, to achieve the desired accuracy, precision, and sensitivity, ME needs to be evaluated and controlled during bioanalytical method development. As the application of supercritical fluid chromatography‐mass spectrometry (SFC‐MS) for analysis of biological samples has increased, ME using SFC‐MS has also been investigated with a focus on the difference in ME in SFC‐MS compared to other chromatographic techniques used for achiral separation in biological samples. Here, we provide a summary of the status of ME evaluation and mitigation in SFC‐MS methods. This review presents an overview of the phenomenon of ME and methods for evaluating ME in bioanalysis. Next, the factors that can impact ME in SFC‐MS‐based bioanalytical methods are discussed in detail with an emphasis on SFC. A literature review of the evaluation of ME in targeted bioanalytical methods using SFC‐MS is included at the end. Robust instrumentation, effective sample preparation, and superb separation selectivity are the foundations of reliable analytical methods as well as the ability to mitigate detrimental ME in SFC‐MS methods.