Fit-for-Purpose Quality Control System in Continuous Bioanalysis During Long-Term Pediatric Studies.

Abstract

Pharmacokinetic studies are key to evidence-based pharmacotherapy. The reliability of pharmacokinetic parameters is closely related to the quality of bioanalytical data. Bioanalytical method validation is fully described by regulatory guidelines; however, it is conducted just once. To ensure reliability and comparability of clinical data, appropriate quality control systems must be enforced to monitor post-validation bioanalytical runs. While single bioanalytical run evaluation is described in international guidelines, somehow, the long-term reproducibility of the bioanalytical method is unattended; it becomes pivotal with the involvement of pediatric population. Therefore, a customized quality control system was developed that addresses regulatory requirements and encompasses the specific demands of pediatric research. It consisted of continuous multi-parameter assessment, including calibration curves, quality control samples, incurred sample reanalysis, and internal standard data. The recommendations provided by the guidelines were combined with the additional Westgard rules, statistical evaluation, and graphical observations. The applicability of the developed quality control system was investigated by using data from three pediatric clinical trials, where the system was able to identify 16% of all analytical runs as invalid. Using a pooled standard deviation provided a better estimate of long-term reproducibility by calculating the %CV, which ranged from 3.6 to 10.3% at all quality control levels. Irrespective of the difficulties encountered owing to vulnerable pediatric populations, the incurred sample reanalysis fulfilled the regulatory requirement of at least 67%. This quality control approach ensured reliable and comparable results over a whole 31-month duration in relation to pediatric studies.