Optimized continuous pharmaceutical manufacturing via model-predictive control.

This paper demonstrates the application of model-predictive control to a feeding blending unit used in continuous pharmaceutical manufacturing. The goal of this contribution is, on the one hand, to highlight the advantages of the proposed concept compared to conventional PI-controllers, and, on the other hand, to present a step-by-step guide for controller synthesis. The derivation of the required mathematical plant model is given in detail and all the steps required to develop a model-predictive controller are shown. Compared to conventional concepts, the proposed approach allows to conveniently consider constraints (e.g. mass hold-up in the blender) and offers a straightforward, easy to tune controller setup. The concept is implemented in a simulation environment. In order to realize it on a real system, additional aspects (e.g., state estimation, measurement equipment) will have to be investigated.

[1]  Maitraye Sen,et al.  A Hybrid MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients , 2014 .

[2]  Fernando J. Muzzio,et al.  Plant-Wide Control of a Continuous Tablet Manufacturing for Quality-By-Design Based Pharmaceutical Manufacturing , 2015 .

[3]  J. Stoustrup,et al.  Optimal model-based control in HVAC systems , 2008, 2008 American Control Conference.

[4]  Marianthi G. Ierapetritou,et al.  A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process , 2014, Comput. Chem. Eng..

[5]  Chi-Tsong Chen,et al.  Analog and Digital Control System Design: Transfer-Function, State-Space, and Algebraic Methods , 1993 .

[6]  Daniel Markl,et al.  Supervisory Control System for Monitoring a Pharmaceutical Hot Melt Extrusion Process , 2013, AAPS PharmSciTech.

[7]  Manfred Morari,et al.  Model predictive optimal averaging level control , 1989 .

[8]  André L. Tits,et al.  Optimal averaging level control , 1986 .

[9]  D. Luenberger Observing the State of a Linear System , 1964, IEEE Transactions on Military Electronics.

[10]  Benjamin Paris,et al.  Heating control schemes for energy management in buildings , 2010 .

[11]  K. Plumb,et al.  Continuous Processing in the Pharmaceutical Industry: Changing the Mind Set , 2005 .

[12]  Patrick Wahl,et al.  PAT for Pharmaceutical Extrusion Monitoring and Supervisory Control , 2012 .

[13]  Krist V. Gernaey,et al.  ICAS-PAT: A software for design, analysis and validation of PAT systems , 2010, Comput. Chem. Eng..

[14]  Jan M. Maciejowski,et al.  Predictive control : with constraints , 2002 .

[15]  Marianthi Ierapetritou,et al.  Implementation of an advanced hybrid MPC-PID control system using PAT tools into a direct compaction continuous pharmaceutical tablet manufacturing pilot plant. , 2014, International journal of pharmaceutics.

[16]  Luiz Augusto da Cruz Meleiro,et al.  ANN-based soft-sensor for real-time process monitoring and control of an industrial polymerization process , 2009, Comput. Chem. Eng..

[17]  Marianthi Ierapetritou,et al.  Real time monitoring of powder blend bulk density for coupled feed-forward/feed-back control of a continuous direct compaction tablet manufacturing process. , 2015, International journal of pharmaceutics.

[18]  D. Luenberger Observers for multivariable systems , 1966 .

[19]  Brahim Benyahia,et al.  A Plant-Wide Dynamic Model of a Continuous Pharmaceutical Process , 2012 .

[20]  Amit Mehrotra,et al.  Real-Time Particle Size Analysis Using Focused Beam Reflectance Measurement as a Process Analytical Technology Tool for a Continuous Granulation–Drying–Milling Process , 2013, AAPS PharmSciTech.

[21]  Zoltan K. Nagy,et al.  Nonlinear Model-Based Control of a Semi-Industrial Batch Crystallizer Using a Population Balance Modeling Framework , 2012, IEEE Transactions on Control Systems Technology.

[22]  Marko Bacic,et al.  Model predictive control , 2003 .

[23]  J. Rantanen,et al.  The Future of Pharmaceutical Manufacturing Sciences , 2015, Journal of pharmaceutical sciences.

[24]  Marianthi Ierapetritou,et al.  System-wide hybrid MPC-PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[25]  Mahdi Zarghami,et al.  Model-based predictive control of wheeled omni-directional robots considering nonlinear dynamical constraints and input delay , 2014, 2014 13th International Conference on Control Automation Robotics & Vision (ICARCV).

[26]  Martin Horn,et al.  Model Predictive Control of Temperature and Humidity in Heating, Ventilating and Air Conditioning Systems , 2013, System Modelling and Optimization.

[27]  Fernando J. Muzzio,et al.  Characterizing continuous powder mixing using residence time distribution , 2011 .

[28]  Eva Roblegg,et al.  Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion. , 2013, International journal of pharmaceutics.

[29]  Rohit Ramachandran,et al.  Model-Based Control-Loop Performance of a Continuous Direct Compaction Process , 2011, Journal of Pharmaceutical Innovation.

[30]  Jakob Rehrl,et al.  Supply Air Temperature Control in an Industrial HVAC Pilot Plant Based on Smith Predictor and Inward Approach , 2009, 2009 International Conference on Computational Intelligence, Modelling and Simulation.

[31]  Hong Chen,et al.  Modeling and control of the air path system in turbocharged gasoline engine , 2015, The 27th Chinese Control and Decision Conference (2015 CCDC).

[32]  Tak-Fai Cheung Liquid-Level Control in Single Tanks and Cascades of Tanks with Proportional-Only and Proportional-Integral Feedback Controllers , 1979 .

[33]  Richard D. Braatz,et al.  Plant-wide model predictive control for a continuous pharmaceutical process , 2015, 2015 American Control Conference (ACC).

[34]  Tielong Shen,et al.  Model-based starting transient speed control scheme for automotive engines , 2013, 2013 10th IEEE International Conference on Control and Automation (ICCA).

[35]  Shen Tielong,et al.  Model-based design approach for gasoline engine control Part I: Modeling and validation , 2013, Proceedings of the 32nd Chinese Control Conference.

[36]  Martin Horn,et al.  Model predictive control of a HVAC system based on the LoLiMoT algorithm , 2013, 2013 European Control Conference (ECC).

[37]  David Q. Mayne,et al.  Constrained model predictive control: Stability and optimality , 2000, Autom..

[38]  B. Bequette,et al.  Process Control: Modeling, Design and Simulation , 2003 .

[39]  Martin Horn,et al.  Elimination of limit cycles in HVAC systems using the describing function method , 2009, Proceedings of the 48h IEEE Conference on Decision and Control (CDC) held jointly with 2009 28th Chinese Control Conference.

[40]  Lawrence X. Yu,et al.  Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production , 2015, Journal of Pharmaceutical Innovation.

[41]  T. Moe,et al.  Perspectives on traceability in food manufacture , 1998 .

[42]  Patrick Wahl,et al.  Hot Melt Extrusion as a Continuous Pharmaceutical Manufacturing Process , 2013 .

[43]  S. I. Denisov,et al.  Generalized Fokker-Planck equation: Derivation and exact solutions , 2008, 0808.0274.

[44]  Martin Horn,et al.  Temperature control for HVAC systems based on exact linearization and model predictive control , 2011, 2011 IEEE International Conference on Control Applications (CCA).

[45]  Hui Zhang,et al.  Model based control of industrial robot and implementation of its gain scheduling robust control , 2011, 2011 IEEE International Conference on Robotics and Biomimetics.

[46]  Fernando J. Muzzio,et al.  A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process , 2015 .

[47]  Peter Hippe Windup in Control: Its Effects and Their Prevention , 2006 .

[48]  William Engisch,et al.  Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing , 2015, Journal of Pharmaceutical Innovation.

[49]  Chi-Tsong Chen,et al.  Linear System Theory and Design , 1995 .

[50]  Marianthi Ierapetritou,et al.  An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction. , 2012, International journal of pharmaceutics.