LC-MS/MS bioanalytical challenge: ultra-high sensitivity assays.

Anne-Françoise Aubry is Director of Bioanalytical Sciences at Bristol-Myers Squibb Co., leading a team in developing bioanalytical methods for early development drug candidates in support of toxicology and clinical studies. Her main research interests are high-speed, high-resolution LC and new approaches for LC-MS/MS drug bioanalysis in regulated laboratories. Anne Aubry is on the executive board of the Eastern Analytical Symposium and on the organizing committee of the Applied Pharmaceutical Analysis and Chemical and Pharmaceutical Structure Analysis (Shanghai 2011) conferences. The challenges of developing and running low pg/ml LC-MS/MS bioanalytical assays in a regulated laboratory are reviewed. The practical problems encountered in implementing ultrasensitive assays are less in reaching a suitable sensitivity on the instrument than in implementing procedures to control losses and contamination, eliminate matrix interferences and ensure assay robustness so that the assay can be validated to industry standards. Solutions to these problems can be found in each of the three facets of the bioanalytical assay: the sample preparation, the chromatographic separation and the mass spectrometric detection. The key to developing an ultrasensitive assay is to optimize each of these elements. Progress in MS instrumentation has been essential in our ability to reach the low pg/ml limits.