A Quality by Design (QbD) Approach for Pharmaceutical Capsule Filling Unit Operation: Identifying Critical Process Variables and Detecting Possible Interactions

摘要

Capsule filling process performance is dependent on capsule filling machine and the formulation. Variation in capsule weight clearly results in variation in drug content. The purpose of this study was to use an integrated QbD approach to identify critical process variables and detect possible interactions between variables for a pharmaceutical capsule filling unit operation. The formulation consisted of 4% aspirin and 96% MCC. Two full factorial designs were created to include selected formulation [aspirin type (coarse and fine), filler MCC (Avicel~R PH 200 and PH 301), lubricant level (0 and 0.5%)], and process [(capsule size (#0 and #1), filling machine type (Zanasi and H&K)] variables. A total of 24 batches were manufactured. Ten capsule samples were collected at each of the predefined time points throughout each production run. Particle size, flowability, bulk density and tapped density were measured. The coefficient of variation (CV) for capsule weight and aspirin content were determined for each interval sampled (CV_i). Main effects and interactions were assessed by ANOVA. Principal component analysis (PCA) was used to analyze the variability in the powder’s physical properties.