(189a) Assessing Excipient Variability within QbD Drug Product Development

Understanding variability in excipient physico-chemical properties is becoming an important aspect of Quality-by-Design (QbD) drug product development.  However, present experimental methods are only able to study a few physico-chemical properties on a few excipient lots due to time, cost, and sample gathering considerations.  To improve the robustness of drug products to excipient variability, analysis methods are needed to examine a broader range of excipient physico-chemical properties.  An alternative analysis method is proposed which uses quantitative physico-chemical property data gathered by excipient vendors to evaluate excipient lot-to-lot variability in a comprehensive, low cost manner.  Microcrystalline cellulose, spray-dried lactose, and magnesium stearate were selected as commonly-used excipients for this demonstration.  The proposed analysis method, which is based on multivariate approaches, offers drug product developers several advantages over present experimental methods, including the ability to: 1) examine excipient products for manufacturing site and/or year-to-year variations, 2) quantify a domain of prior experience for each excipient by determining the percentage of excipient lots contained within a multi-dimensional ellipsoid described by the excipient lots used during drug product development, and 3) rationally select excipient lots from the vendors inventory to maximize the domain of prior experience throughout the drug development process.  Case studies will be reviewed illustrating successful application of this method supporting drug product robustness to critical excipient material properties.  Leveraging prior knowledge from excipient vendors’ experience with excipient lot-to-lot variability should be an integral part of a QbD drug product development program to understand the role of excipient variability on the robustness of drug product manufacturability and performance.