Effect of tablet press residence time distribution on material traceability in a continuous direct compression...

Continuous Direct Compression via Mini-Batch Blending (CDC via MBB) is gaining traction as an innovative manufacturing technology in the pharmaceutical industry. According to the Roche design, mini-batches (MBs) are sequentially fed and blended, remaining separate until they come into contact with one another in the hopper above the tablet press after the first diversion point. Material tracking is crucial for understanding how unexpected disturbances propagate through a CDC via MBB line. While tracking is straightforward for separate MBs, assessing the residence time distribution (RTD) in the tablet press becomes necessary after the first diversion point. In this study, a methodological framework is presented where a RTD was characterized experimentally using a tracer (tartaric acid) step change, transmission Raman spectroscopy and in-silico modelling using Discrete Element Method (DEM) simulations. The experimental results indicated intermixing between adjacent MBs. The RTD-based simulations enabled the quantification of intermixing, revealing that the produced tablet consisted of a blend of multiple MBs at any given time during the characterization of the tablet press. Further simulations based on the corroborated RTD enabled testing of the sampling and disturbance management strategies. The RTD models were used to compare conservative and smart material diversion strategies. It was established that the smart strategy significantly reduced the amount of non-conforming material after minor disturbances. Understanding the process dynamics based on the RTD characterization of the tablet press allows for the development of sampling and material diversion strategies during the CDC via MBB drug product process development. Insights from this work can be applied to other tablet press variants as discussed in Part 2 of this study.