A Demonstration of Mixing Robustness in a Direct Compression Continuous Manufacturing Process.

The purpose of this work was to assess the impact of continuous mixing on tablet critical quality attributes (CQAs) manufactured using a continuous, direct compression process. A 9-run design of experiments (DoE) that bracketed the range of commercially relevant mixer speeds, mixer orientations, and mass flow rates was executed using a formulation containing a cohesive drug substance at relatively low drug load. Drug substance dispensed concentration using loss-in-weight feeders was within 1% of target for each experiment with 30-s mass flow relative standard deviation values of 3.5% or less. Higher mass flow rates resulted in first off tablets closer to target potency, a shorter tablet potency startup phase, and greater assurance of passing content uniformity testing. Dissolution profiles from the DoE runs that bracketed mixer shear conditions were similar, indicating mixing had minimal impact on drug substance release from the tablets. None of the DoE parameters had a practical impact on the description CQA (tablet breaking force, friability, and appearance). Collectively, these results highlight that for this study continuous mixing within a direct compression process is robust and is assessed as low risk of adversely impacting drug product CQAs provided there is appropriate control of the continuous feeders.