Analytical quality by design and measurement uncertainty in the development of discriminative dissolution method for pediatric fixed-dose combination dispersible tablets of isoniazid and rifampicin

Abstract

Analytical Quality by Design (AQbD) is a proactive approach that ensures the consistent performance of analytical methods throughout the lifecycle. The application of AQbD in dissolution testing remains limited, particularly with the incorporation of measurement uncertainty to minimize risks for both consumers and producers. This study applied AQbD principles to develop a dissolution method for a fixed-dose combination of isoniazid (INH) and rifampicin (RIF) in dispersible tablets. The Analytical Target Profile was defined based on the dissolved percentage of INH and RIF. A risk-based approach was used to assess risks impacting the discriminative power and measurement uncertainty. design of experiments optimized medium pH, volume and rotation speed, considering two experimental batches. With Monte Carlo simulations, the Method Operable Design Region was constructed to allow batch A approval and batch B failure. Validation confirmed that the methods were selective, precise and accurate, with combined standard uncertainties of 1.7 % for INH and 3.8 % for RIF. The guard bands defined new acceptance limits in the three stages of dissolution, minimizing both consumer and producer risks. A hazard analysis and critical control point plan was established as a control strategy. If the dissolved percentage of RIF or INH leads to a batch failure, two options are possible: retesting or discarding the batch, considering guard bands to ensure a producer risk lower than 5 %. The study innovates by demonstrating the relevance of incorporating AQbD in dissolution testing, ensuring more reliable methods for controlling product quality.