Application of the lifecycle approach to the development and validation of a chromatographic method for therapeutic drug monitoring of ceftazidime, meropenem, and piperacillin

Abstract

Herein, the analytical quality by design (AQbD) approach is employed to develop a novel bioanalytical method to determine the plasmatic levels of three beta-lactam antibiotics, ceftazidime, meropenem, and piperacillin, for therapeutic drug monitoring. The analytical target profile (ATP) is defined by the selective quantification of these drugs in the plasma of the polymedicated patients over a range of 0.25–8 times of their minimal inhibitory concentration breakpoints within an analysis time of ≤ 15 min, ensuring sufficient accuracy and precision such that the reportable results fall within ± 15% of the true value with at least 90% probability determined with 95% confidence. A fast, simple, and cost-effective reversed-phase high-performance liquid chromatography method with ultraviolet detection was developed, optimized, and validated. The critical method attributes and critical method parameters (CMPs) were established through risk assessment and preliminary experimentation. Thereafter, these were extensively investigated via a sequential methodology using different experimental designs. Mathematical predictive models were built and adjusted to define a method operable design region (MODR) and an optimal working point (OWP) inside the MODR. To validate the OWP and edge points in the MODR, the probability of failure was determined through Monte Carlo simulations by considering the CMPs variability and model coefficient errors. The method was then validated according to the FDA guidelines for bioanalytical methods, indicating compliance with the ATP. The control strategies were implemented for the routine use of the method consisting of system suitability parameters and relative bias limit criteria that were attained using a quality control sample.