Quality-By-Design Evaluation of an Immediate Release Tablet Platform

Excipient variability, and its impact on drug product performance, has been previously examined with risk-based, experiment-based, and data-based approaches.  However, there has been very little investigation into understanding how much variability in excipients impacts drug product performance relative to variability in API properties and processing parameters or method.  Therefore, the present study provides an example assessment of the relative impact of variability in API, excipients, and the manufacturing process on final performance of two, model, immediate release, drug products to aid those that pursue Quality-by-Design drug product development.  Ibuprofen and Theophylline served as the model APIs, microcrystalline cellulose (MCC) served as the ductile diluent, lactose (spray dried) served as a brittle diluent, croscarmellose sodium served as the disintegrant, and magnesium stearate served as the lubricant.  The impact of filler:lubricant particle size ratio variation (3.4 – 41.6) on the attributes of an immediate release tablet were compared to the impacts of the manufacturing method used (direct compression or dry granulation) and drug loading (1%, 5%, and 25%), particle size (D[4,3]: 8–114 microns), and drug type (Theophylline or Ibuprofen).  These factors were evaluated using a 2^5-1 fractional factorial statistical design. 5-kg batches of the various formulations were manufactured using suitably-scaled equipment.  All batches were successfully manufactured, except for the direct compression of 25% drug loading of 8 micron (D[4,3]) drug, which exhibited very poor flow properties.  All manufactured tablets possessed adequate quality attributes:  tablet weight uniformity < 4% RSD, tablet potency: 94-105%, content uniformity < 6% RSD, acceptance value < 15, solid fraction: 0.82-0.86, tensile strength > 1 MPa, friability < 0.2% weight loss, and disintegration time < 4 minutes.  The filler:lubricant particle size ratio exhibited the greatest impact on blend and granulation particle size and granulation flow, while drug property variation dominated blend flow, ribbon solid fraction and tablet quality attributes.  Although statistically significant effects were observed, the results of this study suggest that the manufacturability and performance of this immediate release tablet formulation is robust to a broad range of variation in drug properties, both within-grade and extra-grade excipient particle size variations, and the choice of manufacturing method.