Continuous Tablet Manufacturing Process Research Articles

Evaluation of the effect of granule size of raw tableting materials on critical quality attributes of tablets during the continuous tablet manufacturing process using near-infrared spectroscopy

Objective The effects of granule size of raw materials on tablet hardness (TH) and weight (TW) in the continuous tablet manufacturing process (CTMP) were investigated using near-infrared spectroscopy (NIRS). Methods Granule materials of different sizes were prepared by extrusion granulation from a standard granule formula powder containing lactose/starch and 4.5% acetaminophen. Large-, small-, and medium-sized granules were sequentially filled in a hopper, and tablets were produced continuously using a single-shot tableting machine. After arranging approximately 500 tablets in order, the tablets were subjected to NIRS. A total of 450 NIRS datasets were divided into three groups of 150 each (calibration, validation 1, and validation 2 datasets). Results The best fitted calibration models for predicting TH and TW were obtained, with sufficient accuracy, based on NIRS using the partial least squares regression, and comprised both physical and chemical information. The regression and loading vectors of the calibration models suggested that the models used to predict TH and TW involve physical information based on geometrical factors of the tablet and chemical information related to binder-related intermolecular interactions. Conclusions The changes in the predicted value profiles of TH and TW using NIRS reflected the changes in the measured values depending on the raw granule size during CTMP.

The transition from batch to continuous manufacturing for tablet manufacturing performance comparison and control system review

The pharmaceutical industry is motivated to improve tablet productivity in order to adapt to the expanding drug market. One innovative way is the transition of the traditional batch tablet manufacturing process to a continuous process. This paper aims to review the performance of continuous tablet manufacturing processes. From the comparison of continuous to traditional batch processes, the continuous tablet manufacturing process demonstrates improvements in production flexibility, robustness, and ultimately process profitability. The continuous process is proven to mix drug particles with more evenly distributed size and less segregation resulting in tablets with better quality compared to the traditional batch process. The improvement on the continuous tablet manufacturing process requires robust control system for process automation to counteract process noise and disturbances in process feed. A well-tuned Proportional Integral Derivative (PID) control is sufficient for the process to produce a desirable product. Developing a new algorithm for model predictive control (MPC) and enhancing the control system with MPC-PID control can further improve the system performance. Overall, the transition from batch to continuous tablet manufacturing is supported by pharmaceutical companies as well as organizations like Food and Drug Administration (FDA).

Assessment of blend uniformity in a continuous tablet manufacturing process

Blend uniformity was monitored throughout a continuous manufacturing (CM) process by near infrared (NIR) spectroscopic measurements of flowing blends and compared to the drug concentration in the tablets. The NIR spectra were obtained through the chute after the blender and within the feed frame, while transmission spectra were obtained for the tablets. The CM process was performed with semi-fine acetaminophen blends at 10.0% (w/w). The blender was operated at 250 RPM, for best performance, and 106 and 495 rpm where a lower mixing efficiency was expected. The variation in blender RPM increased the variation in drug concentration at the chute but not at the feed frame. Statistical results show that the drug concentration of tablets can be predicted, with great accuracy, from blends within the feed frame. This study demonstrated a mixing effect within the feed frame, which contribute to a 60% decrease in the relative standard deviation of the drug concentration, when compared to the chute. Variographic analysis showed that the minimum sampling and analytical error was five times less in the feed frame than the chute. This study demonstrates that the feed frame is an ideal location for monitoring the drug concentration of powder blends for CM processes.

Integrated Moving Horizon-Based Dynamic Real-Time Optimization and Hybrid MPC-PID Control of a Direct Compaction Continuous Tablet Manufacturing Process

In this manuscript, a moving horizon-based real-time optimization (MH-RTO) has been integrated with a hybrid model predictive control (MPC) system for a continuous tablet manufacturing process for quality by design (QbD)-based efficient continuous manufacturing. In the proposed approach, the integrated MH-RTO provides the optimal operational set points for the tablet production rate in real time. The MH-RTO takes into consideration the capital and operating cost, the market fluctuations, the product inventory, the product quality assurance strategy, the regulatory constraints, and the product rejections. An advanced hybrid model predictive control system then ensures that the required production rate with desired quality is met with minimum resources and time. A robust optimization strategy and an efficient control system have been integrated to achieve the maximum profit. The MH-RTO integrated with a hybrid control strategy ensures the maximum possible profit irrespective of the market demand fluctuations. The basic advantage of the MH-RTO framework is that it takes into consideration the future demand and thus can lead to increased profit compared to a standard real-time optimization approach.

A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process

Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic control of the end product quality as desired by QbD (quality by design)-based efficient manufacturing. The precise control of the quality of the pharmaceutical product requires corrective actions in the process/raw material variability before product quality can be influenced. In this manuscript, a combined feed-forward/feed-back control system has been developed for a direct compaction continuous tablet manufacturing process. The feed-forward controller takes into account the effect of process disturbances proactively while the feed-back control system ensures the end product quality consistently. The coupled feed-forward/feed-back control system ensures the minimum variability in the final product quality irrespective of process and raw material variations. The performance of the combined control strategy has been evaluated through process simulation and is found to be more effective in comparison with a feed-back only control strategy and, therefore, demonstrates potential to further improve pharmaceutical tablet manufacturing operations.

A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process

A novel manufacturing strategy based on continuous processing integrated with online/inline monitoring tools coupled with an advanced control system is highly desired for efficient Quality by Design (QbD)-based pharmaceutical manufacturing. A control system ensures the predefined end product quality, satisfies the high regulatory constraints, facilitates real time release of the product, and optimizes the resources. In this work, a systematic framework for the onsite design and implementation of the control system in continuous tablet manufacturing process has been developed. The framework includes a generic methodology and supporting tools through which the control system can be designed at the manufacturing site and can be implemented for closed-loop operation. The control framework has different novel features such as the option to run the plant in closed-loop (MPC/PID), open-loop and simulation mode. NIR sensor, an online prediction tool, a PAT data management tool, and a control platform have been used to close the control loop.

An integrated approach for dynamic flowsheet modeling and sensitivity analysis of a continuous tablet manufacturing process

Manufacturing of powder-based products is a focus of increasing research in the recent years. The main reason is the lack of predictive process models connecting process parameters and material properties to product quality attributes. Moreover, the trend towards continuous manufacturing for the production of multiple pharmaceutical products increases the need for model-based process and product design. This work aims to identify the challenges in flowsheet model development and simulation for solid-based pharmaceutical processes and show its application and advantages for the integrated simulation and sensitivity analysis of two tablet manufacturing case studies: direct compaction and dry granulation. The developed flowsheet system involves a combination of hybrid, population balance and data-based models. Results show that feeder refill fluctuations propagate downstream and cause fluctuations in the mixing uniformity of the blend as well as the tablet composition. However, this effect can be mitigated through recycling. Dynamic sensitivity analysis performed on the developed flowsheet, classifies the most significant sources of variability, which are material properties such as mean particle size and bulk density of powders.