Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness.

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to manage the batch-to-batch variability of an active pharmaceutical ingredient (API) in a high drug loaded formulation on a continuous line was investigated to obtain consistent tablet CQAs. As the ultimate goal of continuous manufacturing is to produce 24/7, current study also aimed at guaranteeing long term stability of the process. To do so, previously identified API critical material attributes (CMAs) were varied together with granulation, drying and milling critical process parameters (CPPs) in a screening design of experiments to understand the influence of these factors upon product CQAs and process stability. To evaluate the factors affecting the process stability with a reduced amount of materials, process deviations recorded by process sensors were used. While product CQAs only depended on process CPPs, process stability was strongly affected by API CMAs. The effect of API batch-to-batch variability on process stability could nonetheless be managed by applying suitable granulation conditions. Therefore, appropriate ranges of CPPs were defined to ensure both product CQAs and process stability. By studying the fully integrated continuous manufacturing line, it was possible to highlight the interactions between the different unit operations and the API CMAs and to design a robust process.