Digital twin of a continuous direct compression line for drug product and process design using a hybrid flowsheet modelling approach.

The pharmaceutical industry is continuously overcoming ways to reduce its development times to market and bring new medicines to patients with the highest quality standards faster. This can be achieved with continuous manufacturing and digital design by minimising the amount of active pharmaceutical ingredient (API) needed in drug product design, early project de-risking, and reducing the use of clinical manufacturing equipment, rework, and quality investigations. This paper presents the digital twin of a continuous direct compression line combining first-principles models, residence time distribution (RTD) models obtained from discrete element method (DEM) simulations, science of scale tools and data-driven models from process data in a hybrid flowsheet approach. The flowsheet predicts critical process parameters in the feeders, blender, and tablet press, and critical quality attributes, like tablet composition, weight, thickness, and hardness. It allows the study of the steady state operation in the design space, the impact of operating conditions, material and process parameters, and the dynamic response to disturbances. This is used to de-risk and optimise drug product and process development while reducing the number of experiments. The digital twin also has the potential to guide manufacturing runs and respond to new drug product market approval queries using flowsheet modelling.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Twin screw wet granulation: the study of a continuous twin screw granulator using Positron Emission Particle Tracking (PEPT) technique.

In this paper, Positron Emission Particle Tracking (PEPT) techniques are utilised to track the trajectory of single particles through the mixing and conveying zones of a Twin Screw Granulator (TSG). A TSG consisting of conveying zones and mixing zones is used in this study. The mixing zones are arranged with kneading discs at an angle of 30°, 60° or 90°. Experiments were carried out using different mixing configurations with various screw speed and total mass flow rate. The PEPT data obtained were then utilised to obtain the residence time distribution (RTD) and the Peclet number in an attempt to gain some insight into the mixing of the process. The fill level of the granulator was also estimated to study the mechanism of granulation. As might be expected, it was shown that the residence time of the granulation process increases with decreasing screw speed. It also increases with increasing angle of the arrangement of kneading blocks in the mixing zones, but will decreases when powder feed rate is increased. The fill level of the mixing zone in particular increases when the screw speed decreases or when powder feed rate increases. Furthermore, the fill level of the granulator will increase when the mixing zone configuration changes from 30° to 90°. It is shown that the granulator is never fully filled, even using 90° mixer elements implying limited compaction which may explain why the granules produced are porous compared with those from a high shear mixer. Interestingly, the RTD analysis reveals that the extent of axial mixing in the mixing zone of the granulator does not change significantly for different configurations and process conditions. There is evidence of a tail in the RTD which implies some material hold up and channelling.