Utilizing quantitative certificate of analysis data to assess the amount of excipient lot-to-lot variability sampled during drug product development.

Kushner, Joseph

Understanding variability in excipient physico-chemical properties is becoming an important aspect of Quality-by-Design drug product development. However, present experimental methods have only been able to study a few physico-chemical properties for a few excipient lots due to time, cost, and sample gathering considerations. An alternative analysis method is proposed here that shows how quantitative physico-chemical property data reported in vendor certificates of analysis can evaluate excipient lot-to-lot variability in a comprehensive and low cost manner. Microcrystalline cellulose, spray-dried lactose, and magnesium stearate were selected as commonly-used excipients for this demonstration. The proposed analysis method 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. For cases where certificate of analysis data may contain insufficient information, drug product developers and excipient vendors should work together to identify more appropriate datasets for analysis.