Impact of metrological correlation on the total combined risk in pharmaceutical equivalence evaluations

Abstract

Pharmaceutical equivalence evaluation requires a multiparametric conformity assessment for both generic and reference medicines. This paper investigates the impact of metrological correlations on the total combined risk in pharmaceutical equivalence evaluations. The study focused on the equivalence between ranitidine hydrochloride tablets, assessed by determining the average weight, the assay of the active pharmaceutical ingredient, and the uniformity of dosage units. The risks of false conformity decisions were evaluated using Monte Carlo method simulations across four scenarios, each reflecting different correlation conditions. The results of the study focus on evaluating pharmaceutical equivalence between ranitidine hydrochloride tablets from two manufacturers. The tablets were tested for three parameters: average weight, active pharmaceutical ingredient (API) assay, and uniformity of dosage units. The measured values were within the regulatory specifications for both medicines A and B. Four scenarios of metrological correlation were assessed: #1 – actual correlation from shared analytical steps, #2 – correlation between parameters within the same medicine, #3 – correlation between generic and reference medicines, and #4 – uncorrelated parameters. The study revealed that correlations significantly affect total and combined risk values. The correlations between different parameters of the same medicine affect the total risk values, while the correlations between generic and reference medicines for a given parameter influence the combined particular risk values. Correlations between parameters of the same medicine affect total risk values, while correlations between generic and reference medicines impact combined particular risk values. Both types of correlations significantly influence combined total risk values, making metrological correlations crucial in pharmaceutical equivalence evaluations. Proper consideration of these correlations ensures the quality, efficacy, and safety of generic and reference medicines.