New scopes of PAT for real time advanced control of continuous pharmaceutical manufacturing processes

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1 New scopes of PAT for real time advanced control of continuous pharmaceutical manufacturing processes Ravendra Singh, Marianthi Ierapetritou, Rohit Ramachandran Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA Abstract Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic feed-forward/feed-back 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 on the process/raw material variability proactively before they can influence the product quality. Therefore, PAT tools are needed to monitor the feedforward as well as feed-back process variables that need to be sent to the automatic real time control system. In this article, the scope of PAT for a combined feed-forward/feed-back control system has been highlighted. Keywords: PAT, QbD, Continuous pharmaceutical manufacturing, advanced control, MPC 1. Introduction Extensive development on Process Analytical Technology (PAT) in recent years provides a suitable platform for paradigm shift of QbD based pharmaceutical manufacturing [1-2]. Today, methods and tools are commercially available that make the application of PAT possible for real time pharmaceutical process control as desired for real time product release within a highly regulated environment. Moreover, recently developed continuous pharmaceutical manufacturing techniques involving solid dosage forms catalytically accelerate this revolutionary shift by enabling both feed-forward and feedback (FF/FB) control strategies. The feed-forward controller takes into account the effect of process disturbances and raw material variability proactively while the feed-back control system ensures consistency in end product quality. For a feed-forward control, the sensor (e.g. NIR) should be placed upstream to measure the process disturbances and the measured signal should be transmitted in real time to downstream unit operation to take the compensative actions. Variations in raw material properties (e.g. particle size), feeder hopper level, amount of lubrication, milling and blending action, applied shear in different processing stages can affect the blend density significantly and thereby tablet weight, dissolution and hardness. Therefore, the inline real time monitoring of the blend density and its incorporation into the control system so that it does not affect the end product quality is highly desired [3]. For a feed-back control, the sensor should be placed at downstream unit operations to measure the critical quality attributes (CQAs) and critical process parameters (CPPs) and based on that the process parameters need to be manipulated to control the measured variables. In the last few years, very few attempts have been made toward the control of a tablet manufacturing process in general utilizing a feed-back control algorithm [4-5] and PAT tools. Feed-forward control systems still need to be coupled with the feed-back control system. The coupled FF/FB control system ensures minimum variability in the final product quality irrespective of process and raw material variations and it is very successful in different manufacturing industries.

2 In this work, the scope of PAT for a combined feed-forward/feed-back (FF/FB) control system of continuous tablet manufacturing process has been highlighted. The feed-forward control loop is based on real time monitoring of the powder bulk density while the feed-back control loops are based on the drug concentration, powder level, tablet weight and hardness. An NIR (Near Infrared) based real time monitoring of the blend density for feed-forward control has been proposed.

3 2. Application of PAT for combined feed-forward/feed-back control of continuous tablet manufacturing process A continuous direct compaction tablet manufacturing pilot-plant has been installed and situated at C- SOPS, Rutgers University [5]. The process flowsheet model is shown in Figure 1. There are three gravimetric feeders, a co-mill, a continuous blender and a tablet press. The NIR sensor for inline monitoring of powder blend uniformity, powder blend composition and powder blend density has been integrated through a chute placed in between tablet press and blender. The local level controllers are inbuilt in each feeder in order to control the powder flow rate. A ratio controller has been added that provides the flow rate set points of API, Excipient and Lubricant feeders for a given total flow rate and API composition. Six supervisory control loops have been then added. First loop is for PAT based feed-forward control (FFC) which takes the corrective action on variations in powder bulk density. Powder blend is fed to the tablet press die through a feed frame. For a specific fill depth and punch displacement settings, the variation in blend density can lead to variations in the tablet weight, hardness and dissolution. The powder blend density during continuous tablet manufacturing operation can change at different processing units for several reasons: For example, the powder hopper level can change the powder bulk density. Powder particle size has significant effects on the powder bulk density. So, if the raw material specification has been changed then it can have significant effects on the final product quality if a suitable control strategy has not been implemented. The shear level can also change the powder bulk density. Furthermore, the powder bulk density can change during feeding operation because of shear introduced by helix. Milling operation can also change the powder bulk density because of change in particle size and applied shear force. The blending operation changes the bulk density because of shear force. The bulk density can also change during the powder flow for several reasons; for example segregation and compression. An NIR sensor together with chemometric tools have been used for real time inline monitoring of the powder blend density. The signal of powder blend density has then been sent to the feed-forward controller that manipulates the fill cam depth of the tablet press proactively. The second loop has been added to control the main compression force of the tablet press. This control loop is in cascade arrangement with a master controller (loop 3) specifically designed to control the tablet weight. The input of this master controller is weight and it generates the set point of main compression force. Loop four has been designed to control the tablet hardness by manipulating the punch displacement. Checkmaster (Fette) has been used for real time monitoring of tablet weight and hardness. Loop 5 has been added to control the powder level in instrumented hopper. A webcam has been used for online monitoring of the powder level. The drug concentration has been controlled through PAT based 6th control loop. The NIR sensor has been used for inline real time monitoring of drug concentration. The powder bulk density and drug concentration can be monitored using a single NIR probe. Two PLS models have been used to predict the powder bulk density and drug concentration separately. In order to implement the designed feed-forward/feedback control into the pilot-plant, the signal from the NIR sensor (raw spectrums) has to be sent to a chemometric tool that utilizes the NIR calibration models for blend density and drug concentration and a real time prediction tool to generate the signals for the control variables in real time. The generated signals are then sent to a commercially available control platform via an OPC (OLE process control) where the combined FF/FB control loop has been implemented. The blend density is the input for the feed-forward controller while the blend composition together with powder level, tablet weight and hardness are the inputs of the feedback control system.

4 Figure 1. Continuous tablet manufacturing process integrated with PAT and combined FF/FB control strategy. MPC: Model predictive control, PID: Proportional Integral Derivative, FFC: Feed-forward control. 3. Real time measurement of powder bulk density, drug concentration and blend uniformity using NIR sensor NIR has been used for the real time monitoring of powder bulk density, drug concentration and blend uniformity. Monitoring of drug concentration and blend uniformity has been previously reported [4-6]. Real time monitoring of powder bulk density using NIR sensor has been described here. For monitoring of powder density using NIR sensor, the first step is to calibrate the NIR. In order to develop the NIR calibration model, the spectrums need to be collected for powder samples of different densities. The powder has been filled in a graduated cylinder placed on the top of a tapping machine. Then the taps have been applied on the graduated cylinder. Tapping changes the bulk density of the powder and thereby the powder volume. Based on the change in the volume the reference values of the density have been calculated. The highest changes in density were obtained for the first 20 taps. The spectrums have been collected for each density. The PLS based calibration model for density then has been developed using a chamometric tool. An NIR sensor has been integrated with the direct compaction tablet manufacturing pilot-plant through a chute interface. The calibration models for density and drug concentration have been then integrated with a chamometric tool for real time prediction of density and concentration signals respectively. Blend uniformity (relative standard deviation) has then been calculated from the drug concentration signals.

5 A proprietary PAT data management tool (syntq) has been used for management of raw data and predicted signals. The data across different software tools communicate via OPC interface. In gravimetric mode of the operation of lose-in-weight feeder, the powder flow rate has been controlled by manipulating the feeder screw speed. So if there is variation in the powder bulk density then the screw speed needs to be adjusted automatically in order to deliver the same mass flow rate of the powder. Therefore, the feeder screw speed is the primary indication of the change in the powder bulk density. 4. Results and discussions The real time monitoring of powder bulk density along with feeder screw speed is shown in Figure 2. As shown in the figure, the screw rotational speed first decreases and then increases indicating that the powder density first slightly increases then decreases non-linearly. Figure shows that, how the change in bulk density affects the feeder screw rotational speed. The density measurement response is delayed in compare to feeder screw speed response. The result shown in Figure 2 demonstrates the proof of concept that NIR can be used for real time monitoring of powder bulk density. Figure 2. In-line monitoring of powder bulk density using NIR The effect of powder bulk density on tablet weight is shown in Figure 3. Step change in the powder bulk density has been introduced by switching the excipient from Avicel 101 to Avicel 301 and back to Avicel 301. Avicel 301 is known to be denser than Avicel 101. API (APAP) and lubricant (MgSt) remains same.

6 Figure 3 shows that powder bulk density has a significant impact on tablet weight. Similar effects have been observed on tablet hardness as well. Therefore, the powder bulk density is critical to monitor for real time feed-forward control. The effect of density variation is proposed to be compensated by adjustment the fill depth. Figure 4, shows the sensitivity of fill depth on tablet weight and hardness. The results demonstrate that the fill depth can be manipulated to compensate the variation in density so that a consistent tablet weight and hardness can be achieved. Figure 3. Effect of powder bulk density on tablet weight 5. Conclusions The scope of PAT for feed-forward/feed-back control to obtain a precise pre-defined end-product quality of a pharmaceutical product, as mandated by regulatory authorities, has been highlighted. NIR has been used for real time monitoring of powder bulk density, drug concentration and blend uniformity. Future work includes the implementation of an FF/FB control system into our pilot-plant.

7 Figure 4. Sensitivity of fill depth on tablet weight and hardness. Acknowledgements This work is supported by the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through Grant NSF-ECC References 1. FDA. (2004). PAT A framework for innovative pharmaceutical development, manufacturing, and quality assurance FDA. (2007). Guidance for industry, Q8 (R2) pharmaceutical development García-Munoz, S. Dolph, H. W. Ward II. Handling uncertainty in the establishment of a design space for the manufacture of a pharmaceutical product. Computers and Chemical Engineering 2010, 34, Singh, R.; Sahay, A.; Karry, K. M.; Muzzio, F.; Ierapetritou, M.; Ramachandran, R. Implementation of a hybrid MPC-PID control strategy using PAT tools into a direct compaction continuous pharmaceutical tablet manufacturing pilot-plant. International Journal of Pharmaceutics 2014, 473, Singh, R.; Sahay, A.; Muzzio, F.; Ierapetritou, M.; Ramachandran, R. Systematic framework for onsite design and implementation of the control system in continuous tablet manufacturing process. Computers & Chemical Engineering Journal 2014, 66, Vanarase, A.; Alcal, M.; Rozo, J.; Muzzio, F.; Romaach, R. Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy. Chem. Eng. Sci. 2010, 65 (21),