(451d) Advanced Quality Control Method for a Continuous Wet Granulation Tableting Line

Recent success in academia in combination with the guidance and support of regulatory bodies (FDA, EMA, etc.) have increased the attractivity of continuous manufacturing for pharmaceutical producers. The acceptance and approval of continuous production methods is especially high in secondary production of solid oral dosage forms, which can be realized through a continuous wet granulation tableting line (GEA ConsiGma 25). The line consists of feeders for pre-mix and granulation liquid, a twin screw granulator, a fluid bed dryer, a mill, further feeders for dosing of an external phase, a blender and a tablet press. The material is either transported continuously (feeding, granulation and tableting) or in “mini-batches” (drying, milling and blending) through the single unit operations. The size of the “mini-batches” or so-called product keys (PKs) is defined by the line throughput and the filling time of the dryer cells. Those PKs are then kept separated from each other, i.e., intermixing between the PKs is avoided until the PKs enter the tablet press. From a material tracking point of view, this approach offers simplicity, since no residence time distribution (RTD) of the material has to be considered for the mentioned unit operations. However, the twin screw granulator and the tablet press (including hopper and feed frame) show a RTD. Knowledge of the complete RTD, and therefore, the behavior on material propagation through the line can be used to support quality assurance. Under application of split feeding or when API is dosed via granulation liquid, mass flow disturbances of the feeders or deviations in pre-mix concentration can lead to out of spec granules. By means of RTD modeling the PK and tablet concentration can be predicted after the granulation and the tableting, respectively.

In our study, we have experimentally captured the residence time distribution of the granulator and the tablet press. Mathematical models for single unit operations were parameterized and combined to a RTD model of the entire line, which enables material tracking as well as prediction of PK and tablet concentration. The model was validated by an experimental characterization of the complete line (from outlet of the first feeder until the tablets exiting the press). The presentation highlights the utilization of this model for quality assurance of the final dosage form.