Analytical Validation of Accelerator Mass Spectrometry for Pharmaceutical Development

Abstract

The validation parameters for pharmaceutical analyses were examined for the accelerator mass spectrometry measurement of ¹⁴C/C ratio, independent of chemical separation procedures. The isotope ratio measurement was specific (owing to the ¹⁴C label), stable across samples storage conditions for at least 1 year, linear over four orders of magnitude with an analytical range from 0.1 Modern to at least 2000 Modern (instrument specific). Furthermore, accuracy was excellent (between 1 and 3%), while precision expressed as coefficient of variation was between 1 and 6% determined primarily by radiocarbon content and the time spent analyzing a sample. Sensitivity, expressed as LOD and LLOQ was 1 and 10 attomoles of ¹⁴C, respectively (which can be expressed as compound equivalents) and for a typical small molecule labeled at 10% incorporated with ¹⁴C corresponds to 30 fg equivalents. Accelerator mass spectrometry provides a sensitive, accurate and precise method of measuring drug compounds in biological matrices.

Financial & competing interests disclosure

Some of this work was performed under the auspices of the US Department of Energy by University of California, Lawrence Livermore National Laboratory (LLNL) under Contract W-7405-Eng-48. Colleagues at LLNL who performed work leading to the data shown here include Kurt Haack, Bruce Buchholz, and Darren Hillegonds. Portions of this work were supported by the NIH National Center for Research Resources at the Research Resource for Biomedical AMS (P41-RR013641). Many samples, data, and carbon analyses were done by, or under contract with, Procter & Gamble Pharmaceuticals. Samples, data, and support in composing the manuscript were provided by Vitalea Science (Dr Steve Dueker).

Bradly D Keck is an employee of Vitalea Science (VS), which funds his authorship. Bradly D Keck was an employee of Procter & Gamble Pharmaceuticals during much of this work, who sponsored many of the sample analyses referenced. Ted Ognibene is an employee of Lawrence Livermore National Laboratory and holds a patent licensed by VS but no other financial interests. John S Vogel was an employee of LLNL during much of this work but is now an unpaid advisor to VS and possesses equity in the Company, which licenses several of his patents. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Some of this work was performed under the auspices of the US Department of Energy by University of California, Lawrence Livermore National Laboratory (LLNL) under Contract W-7405-Eng-48. Colleagues at LLNL who performed work leading to the data shown here include Kurt Haack, Bruce Buchholz, and Darren Hillegonds. Portions of this work were supported by the NIH National Center for Research Resources at the Research Resource for Biomedical AMS (P41-RR013641). Many samples, data, and carbon analyses were done by, or under contract with, Procter & Gamble Pharmaceuticals. Samples, data, and support in composing the manuscript were provided by Vitalea Science (Dr Steve Dueker).