(452a) Effects of Operating Parameters on Tablet Quality in a Continuous Manufacturing Line

As continuous manufacturing is gaining increasing importance within the pharmaceutical industry there still remains a knowledge gap in building quality into the final product. In the context of establishing continuous manufacturing technology, characterization of these processes becomes important.  As there are many parameters impacting the product quality, it is important to understand the interplay between these process parameters and tablet performance.  Hence, the present study evaluates experimentally the effect of variation in critical process parameters (CPP) on the critical quality attributes (CQA) of tablets produced by direct compression continuous manufacturing. The study was performed on a model API, acetaminophen (APAP), using lactose monohydrate and magnesium stearate (MgSt) as excipients. Multivariate effects were analyzed using Quality-by-design principles.  A fractional factorial design with 30 experiments, including 3 repeated center points, was used to study the influence of four process variables – drug concentration (%), compaction force (KN), blending speed (rpm), and feed frame speed (rpm) – on the final product.  Design of experiments was executed on a continuous tablet manufacturing line consisting of three feeders, a mill, a blender, and a tablet press. Tablets were characterized for hardness, dissolution, content uniformity, and weight variability.  Additionally, they were subjected to NIR transmission spectroscopy analysis and ultrasound testing.  The processed NIR spectral datasets were analyzed using PCA, and it was determined that the first and second principal components track tablet drug content and compaction force.  Analyses of designed experiments also revealed that drug concentration and compaction force significantly affect tablet dissolution. The results were further used to optimize the process and establish boundary limits for critical process parameters that influence the product to achieve desirable tablet quality.