Examining the Impact of Excipient Material Property Variation on Drug Product Quality Attributes: A Quality-By-Design Study for a Roller Compacted, Immediate Release Tablet

A quality-by-design study examining the impact of variability in excipient material properties on the quality attributes of an immediate release tablet was performed. A literature review and risk analysis identified particle size of microcrystalline cellulose (MCC), spray-dried lactose (SDL), and magnesium stearate (MgSt), and polymorph and specific surface area of MgSt as potential high-risk material properties. The following results were obtained with laboratory-scale processing equipment: (1) a 32-µm increase in d50 (mean particle diameter) of MCC and SDL led to a ∼30-µm increase in blend and granulation d50 and a statistically significant increase in the blend and granulation flow function coefficients, and (2) a 32-µm increase in d50 of MCC and SDL, a 4.4 m2/g increase in the surface area, and a 19-µm decrease in the particle size of MgSt yielded an 18%-28% increase in ribbon tensile strength and tablet hardness. Confirmatory experiments with kilo-scale equipment showed impact of excipient variability on granulation particle size and tablet hardness was ∼50% smaller. Although the impact of these differences on overall manufacturability and performance of the tablets examined here were deemed low, the presence of statistically significant effects supports examining excipient variability as part of the design and control strategy of new drug products. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2222-2239, 2011