Variation and Risk Analysis in Tablet Press Control for Continuous Manufacturing of Solid Dosage via Direct Compaction.

ABSTRACT

A continuous rotary tablet press is a multi-stage process with many punch stations running in parallel, in which each punch undergoes the following steps: die filling and metering, pre-compaction, main-compaction, tablet ejection, and tablet take-off from lower punch. Process uncertainties or disturbances within a punch station or among stations in the tablet press are a major source of variation in final product quality attributes, e.g., hardness, weight, etc., which in turn imposes challenges for the real-time release in pharmaceutical continuous manufacturing of solid dosage. In this study, the direct compression line at Purdue University was investigated and a Natoli BLP-16 tablet press was used to characterize powder compressibility, system dynamics and variation, as well as the interaction effects on process control development. The compressibility of tablets made from a blend of Acetaminophen (API), Avicel Microcrystalline Cellulose PH-200 (excipient), and SiO2 (lubricant) was found to be largely independent of tableting speed. By contrast, filling depth or dosing level, turret speed, feed-frame speed, and compression force were interacting and significantly affected the die-filling process and the final product quality attributes. Thus, the design of the process control structure plays an important role in reducing process and product quality variations. A hierarchical three-level control design was proposed and evaluated, consisting of Level 0 Natoli built-in control, Level 1 decoupled Proportional Integral Derivative (PID) cascaded control loops for tablet weight and production rate control, and Level 2 advanced model predictive control. Process variations, e.g., in powder bulk density changes, during continuous steady-state operation were also investigated. Finally, a risk analysis of the effects of the process dynamics on variation on the product quality control was briefly discussed and summarized.