Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGmaTM-25: Part 2 Granule Size.

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of production processes can mitigate the effect of diverse process disturbances and enhance process efficiency, particularly in terms of production costs and environmental footprint. This paper explores the potential of QbC algorithms for optimizing twin-screw wet granulation in the ConsiGmaTM-25 manufacturing line, specifically addressing granule size. It represents the second part of a study (Celikovic et al. (2024)) focused on granule composition. The concepts proposed in this work rely on process analytical technology (PAT) equipment for real-time monitoring of the granulation CQAs and a dynamic process model linking the granulation process parameters and the monitored CQAs. The granule size model identified via the local-linear-model-tree (LoLiMoT) algorithm is used to develop both a model predictive controller (MPC) and a granule size soft sensor. The MPC employs this model as a core component for selecting optimal granulation parameters to ensure the production of granules with target size. A digital operator assistant is developed to address disturbances that cannot be mitigated via MPC but can be eliminated by the plant operators. This study systematically outlines a workflow, starting from conceptualization, moving through simulation development, and finally ending with real-world application on a production line. In this final step, all proposed concepts are transferred to the ConsiGmaTM-25 manufacturing line, where their performance is validated through selected disturbance scenarios.

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGmaTM-25: Part 1 Granule Composition.

Continuous manufacturing of pharmaceuticals offers several benefits, such as increased production efficiency, enhanced product quality control, and lower environmental footprint. To fully exploit these benefits, standard operation mode (production processes with no or minimal disturbance mitigation measures) should be supported by adopting novel quality-by-control (QbC) methodologies. The paper at hand is the first part of a study focused on developing QbC algorithms for optimizing twin-screw wet granulation in the industrial manufacturing line ConsiGmaTM-25, specifically addressing granule composition. This work relies on previously established process-analytical-technology (PAT) equipment for real-time monitoring of the granule composition, i.e., the active pharmaceutical ingredient (API) and liquid content in wet granules. The developed control platform integrates model-based process control algorithms that aim to keep the API- and liquid content at target values through real-time adjustments of the process parameters. Furthermore, the platform integrates a digital operator assistant, which aims to detect and classify granulation disturbances and provides messages and instructions for the plant operator. The present manuscript systematically outlines all design steps from the development phase in the simulation environment to the final real system application and validation. The control platform's performance is demonstrated through selected test scenarios on the ConsiGmaTM-25 manufacturing line. The obtained results indicate improved disturbance robustness and an increase in intermediate/final product quality (compared to conventional operating modes): The process control algorithms successfully maintained the API- and liquid content at target values despite process disturbances. Furthermore, realistic disturbances (feeder, pump, and material) were accurately detected and classified by the digital assistant algorithm. The information was provided through a user interface, offering real-time support for plant personnel.

Prediction of dissolution performance of uncoated solid oral dosage forms via optical coherence tomography.

Real-time prediction of the dissolution behavior of solid oral dosage forms is an important research topic. Although methods such as Terahertz and Raman can provide measurements that can be linked to the dissolution performance, they typically require a longer time off-line for analysis. In this paper, we present a novel strategy for analyzing uncoated compressed tablets by means of optical coherence tomography (OCT). Using OCT, which is fast and in-line capable, makes it possible to predict the dissolution behavior of tablets based on images. In our study, OCT images were obtained of individual tablets from differently produced batches. Differences between tablets or batches in these images were hardly visible to the human eye. Advanced image analysis metrics were developed to quantify the light scattering behavior captured by the OCT probe and depicted in the OCT images. Detailed investigations assured the repeatability and robustness of the measurements. A correlation between these measurements and the dissolution behavior was established. A tree-based machine learning model was used to predict the amount of dissolved active pharmaceutical ingredient (API) at certain time points for each immediate-release tablet. Our results indicate that OCT, which is a non-destructive and real-time technology, can be used for in-line monitoring of tableting processes.

Control oriented modeling of twin-screw granulation in the ConsiGmaTM-25 production plant.

ConsiGmaTM-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw granulation affect the quality of intermediate and final products. This paper proposes methods for real-time monitoring of these quantities and control-oriented modeling of the granulator. The PSD of wet granules is monitored via an in-line process analytical technology (PAT) probe based on the spatial velocimetry principle. The algorithm for signal processing and evaluation of PSD characteristics is developed and applied to the acquired PSD data. A dynamic process model predicting PSD characteristics from granulation parameters is trained via the local linear model tree (LoLiMoT) approach. The experimental data required for the model training are collected via systematically designed excitation runs. Finally, the performance of the identified model is examined and verified by means of a new set of validation runs. Furthermore, an in-line PAT probe based on Raman spectroscopy is developed and integrated after the granulator. The API- and liquid content of produced wet granules are evaluated from the spectral data by means of chemometric modeling, and chemometric models are validated on a separate set of experimental data. The solutions proposed in this research can be used as a reliable (and necessary) basis for the development of advanced quality-by-design control concepts (e.g., PSD process control). Such concepts would ultimately improve the ConsiGmaTM-25 process performance in terms of robustness against disturbances and quality of intermediate and final products.

Towards a novel continuous HME-Tableting line: Process development and control concept.

The objective of this study was to develop a novel closed-loop controlled continuous tablet manufacturing line, which first uses hot melt extrusion (HME) to produce pellets based on API and a polymer matrix. Such systems can be used to make complex pharmaceutical formulations, e.g., amorphous solid dispersions of poorly soluble APIs. The pellets are then fed to a direct compaction (DC) line blended with an external phase and tableted continuously. Fully-automated processing requires advanced control strategies, e.g., for reacting to raw material variations and process events. While many tools have been proposed for in-line process monitoring and real-time data acquisition, establishing real-time automated feedback control based on in-process control strategies remains a challenge. Control loops were implemented to assess the quality attributes of intermediates and product and to coordinate the mass flow rate between the unit operations. Feedback control for the blend concentration, strand temperature and pellet thickness was accomplished via proportional integral derivative (PID) controllers. The tablet press hopper level was controlled using a model predictive controller. To control the mass flow rates in all unit operations, several concepts were developed, with the tablet press, the extruder or none assigned to be the master unit of the line, and compared via the simulation.

Ensuring tablet quality via model-based control of a continuous direct compaction process.

Switching from batch to continuous pharmaceutical production offers several advantages, such as an increased productivity, a steady product quality, and decreased costs. This paper presents a control strategy for direct compaction on a continuous tablet production line consisting of two feeders, one blender, and a tablet press (TP). A data-driven, linear modeling approach is applied in order to develop a Smith predictor for active pharmaceutical ingredient concentration control and a model predictive controller responsible for the TP hopper level. Additionally, in case of severe concentration variations out-of-specification material can be discarded before it enters the TP. The effectiveness of the control concept is tested not only in simulations but also by implementing it on a real pilot plant.