Analytical Method Quality by Design for an On-Line Near-Infrared Method to Monitor Blend Potency and Uniformity

In this work, an example of analytical method quality by design (AQbD) principles applied to an in-line NIR method to monitor blend potency and uniformity in the manufacturing of an oral solid dosage product is presented. An integrated process analytical technology (PAT) method was developed following the AQbD workflow, including risk assessment, design of experiments (DoE), method control strategy, and method maintenance. Several aspects particular to partial least square (PLS) chemometric method development and validation (such as the combined use of DoE, optimization, and multivariate data analysis) are addressed. Results from the risk assessment showed that the active pharmaceutical ingredient (API) particle size was the most significant risk factor due to the presence of aggregates. This risk was reduced by introducing changes in the API crystallization procedure and by including a wide range of calibration blends within the expected range of particle size. Other potential risks related to the instrumentation, the API and excipient properties, and the environment were further studied and minimized. System suitability tests based on Mahalanobis distance and discriminant analysis (DA) techniques were developed to ensure the quality of the spectral data before blend potency calculation. The use of AQbD provided a robust and rugged method that has the potential to be used as part of the product real-time release (RTR) control strategy.