A Probability Based Equivalence Test of NIR Versus HPLC Analytical Methods in a Continuous Manufacturing Process Validation Study

Abstract

Continuous manufacturing processes rely on Process Analytical Technology (PAT) and chemometric Near Infrared (NIR) technologies to carry out real time release testing (RTRt). A critical requirement for this purpose is to establish the equivalence between the NIR analytical method with the gold standard analytical method, say an HPLC method. We propose a variance components model that acknowledges the inherent blocking across individual dosage units through a paired comparison. Variance terms corresponding to dosage unit, location effects due to a stratified sampling plan and heterogeneous residual terms provide estimates of the total measurement uncertainty in both methods free of dosage unit effects. Bayesian posterior parameter estimates and the posterior predictive distribution are used to assess the performance of the NIR method in relation to the HPLC gold standard method as a measure of equivalence, referred to as a Relative Performance Index (Rel_Pfm). An acceptably high probability of a Rel_Pfm of 1 (or greater) is proposed as the essential requirement for establishing equivalence (or superiority).