European Bioanalysis Forum Recommendation: Scientific Validation of Quantification by Accelerator Mass Spectrometry

Abstract

Accelerator mass spectrometry (AMS) is being used more widely to provide PK data for early decision making or to generate absolute bioavailability data in later phases of development. Presently, there is no clear consensus on the level of the scientific validation required for these assays. The European Bioanalysis Forum (EBF) has conducted two surveys with its members and presented the results at its 4th Open Symposium. With AMS being used for discrete scientific assessment, method establishment of AMS assays should focus on science rather than trying to fit the assay parameters into validation criteria used for Regulated Bioanalysis guidance, and an amount of freedom of execution and interpretation is needed. Hence, the EBF focuses their recommendation on introducing terminology around scientific qualification or validation to be used in relation to AMS. Guidance is given on which parameters should be investigated when a qualified method is required. The recommendations of the EBF for scientific validation are described herein. The scientific validation of AMS assays will be different to that applied for LC-MS/MS assays, and an example is that accuracy and precision limits, as used for ligand-binding assays, would be more appropriate.

Evaluation of cAMS for 14 C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

“…Linearity, reproducibility and accuracy were demonstrated within a dynamic range in all matrices. Although the analyses were performed only in triplicate, the results were in accordance with required bioanalysis criteria for ADME studies (RD: ± 20% within dynamic range, ± 25% at LLOQ, [12]). The observed LLOQ (∼1, 0.5, ∼5 and ∼10 mBq/g for blood, plasma, urine and feces, respectively) were in line with the needs of microtracer ADME studies and with LLOQ from other cAMS instruments (Supplementary Table 6).…”

“…The validation criteria in target matrix (performed only in triplicate in this study) were following the recommendation of the European Bioanalysis Forum [12], whenever possible, and applied to determine the dynamic range, limit of detection [LOD] and lower limit of quantification [LLOQ] in biomatrices.…”

“…In the present study, we evaluate the direct measurement of sample CO 2 (cAMS) combined with MICADAS (MICADAS-cAMS) for ADME studies. Whenever possible, our investigations follow previous recommendations [8,12,20] on critical bioanalysis parameters needed to perform adequate radioactivity quantification in the scope of an ADME study.…”

“…In general, AMS using graphitization of sample carbon (gAMS) has been accepted by health authorities as a method to provide data for human ADME studies [10,11]. In a previous white paper, the application of gAMS for the measurement of parent compound and/or metabolites circulating in plasma was described [12]. However, the conversion of sample carbon to graphite makes gAMS slow, resource demanding and expensive and, therefore, is unsuitable for the analysis of large numbers of samples in an early clinical setting.…”

New Frontiers—Accelerator Mass Spectrometry (AMS): Recommendation for Best Practices and Harmonization from Global Bioanalysis Consortium Harmonization Team

“…The latter is currently not in use for any routine AMS operation. The EBF white paper on the scientific validation of quantitative AMS methods [1] formed the basis for initial discussions and provided a platform on which to build, although not all aspects of the recommendations in that paper are universally applied by AMS providers at this time nor indeed will all of them be applied in the future.…”