Very complex internal standard response variation in LC-MS/MS bioanalysis: Root cause analysis and impact assessment

Nico C Van De Merbel*, Remco A Koster, Corey Ohnmacht

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

6 Citations (Scopus)


Internal standards (ISs) are essential for the development and use of reliable quantitative bioanalytical LC-MS/MS methods, because they correct for fluctuations in the analytical response that are caused by variations in experimental conditions. Sample-to-sample differences in the IS response are thus to be expected, but a large variability often is an indication of nonoptimal sample handling or analysis settings. This paper discusses a number of cases of very complex variation of IS responses that could be attributed to analytical problems such as injection errors and sample inhomogeneity, and matrix-related issues such as degradation and increased ionization efficiency. A decision tree is proposed to help find the underlying root cause for extreme IS variability.
Original languageEnglish
Pages (from-to)1693-1700
Number of pages8
Issue number18
Publication statusPublished - 27-Nov-2019


  • internal standard
  • LC-MS
  • matrix effects
  • response variability
  • root cause analysis
  • decision tree
  • ionization
  • liquid chromatography-mass spectrometry
  • matrix effect
  • review
  • standard

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