(8i) Process System Engineering for Advanced Modular Continuous Pharmaceutical Manufacturing Platform

Authors: 
Singh, R., Rutgers, The State University of New Jersey
Research Interests:  My main research area is process system engineering with focus on continuous pharmaceutical manufacturing. I have contributed significantly in the field of process monitoring and control, process modelling and simulation, optimization, PAT, QbD, control hardware/software integration, new methodology and software tools development.

Process system engineering (PSE) is a very advanced field and has been very successful in solving complex problems of chemical based product manufacturing. However, the particulate systems are still poorly understood and there is different level of complexities involved, therefore new techniques and tools need to be developed for pharmaceutical manufacturing through extensive fundamental and applied research.

Currently, major pharmaceutical industries are shifting toward continuous manufacturing technology in which PSE can play a very significant role. Furthermore, there is a need of advanced modular continuous manufacturing platform technology for fast and robust development of solid oral products. Master formulations, process models, standardized sensing and control architecture, superior automation and novel methods and tools need to be developed to enable platform technology. Authorâ??s main research area is pharmaceutical process system engineering. This area of research and education are highly encouraged and supported by pharmaceutical companies, academic institutions, regulatory authority (FDA) and national science foundation (NSF). For example, national science foundation of USA has established a 100 million dollar research center for structured organic particulate systems (C-SOPS) at Rutgers University New Jersey. Furthermore, more than 40 companies are supporting this center economically and providing scientific inputs so that the research outcomes can be directly applied to the companies.

In this work, a scientific foundation for the optimal design, optimization and control of the modular continuous process involving structured organic particulate systems has been developed. The mathematical models for continuous manufacturing of active pharmaceutical ingredients and final product tablet, has been developed for virtual experimentation and applied for plant design, optimization and control. Advanced modelling techniques such as PBM, DEM and CFD have been applied for pharmaceutical process modeling. The developed continuous tablet manufacturing plant and process model has been adapted by several pharmaceutical companies. A flexible monitoring and control system incorporating different PAT techniques and tools and control strategies for continuous pharmaceutical manufacturing process has been designed and implemented to Rutgers plant. Different control strategies such as PID, PID coupled with dead time compensator, and MPC has been compared and evaluated practically for pharmaceutical process control in terms of set point tracking and disturbances rejection ability, robustness, and stability/instability. A new hybrid MPC-PID control strategy has been developed and implemented into the pharmaceutical tablet manufacturing plant and its performance has been found better than the other control strategies. For the first time, the closed-loop operation of the tablet manufacturing plant using NIR sensor has been demonstrated, which is a significant advancement in pharmaceutical manufacturing as endorsed by the Food and Drug Administration (FDA) and other regulatory authorities as part of the Quality by Design (QbD) paradigm. For the first time NIR has been applied for real time monitoring of powder bulk density. Feedforward control system has been integrated with feedback control system to take proactive mitigation actions on raw materials and process variability. A systematic generic framework including the methods and tools through which the cost and profit can be estimated and the Dynamic Real Time Optimization (DRTO) can be integrated with hybrid control system has been also developed. The integrated DRTO provides the optimal operational set points for the plant control system in real time optimizing an objective function. DRTO integrated with hybrid control strategy ensures the maximum possible profit irrespective of the market demand fluctuations.

Presently, I am working as an assistant research professor at Department of Chemical and Biochemical Engineering of Rutgers University and currently managing and leading ten projects funded by NSF, industries and regulator with total grants exceeding 18 million USD. I was involved in proposal writing of these projects and I am PI/Co-PI of some of these projects. Prior to this, I worked in a large scale European pharmaceutical project (F3 Factory project), which involves 25 partners from industry and Academia; where my responsibility was to manage and lead the DTUâ??s parts of the F3 Factory project and also to coordinate with the other partners associated with it. My doctoral research work, done at Department of Chemical and Biochemical Engineering, Technical University of Denmark, has been awarded for prestigious â??EFCE Excellence Award 2010â?, given in Recognition of an Outstanding PhD Thesis, from European Federation of Chemical Engineering. I have exemplary academic records, previous teaching experiences, and an established trail of valued research accreditationsâ??. I have published several peer reviewed scientific international Journal articles, popular reputed magazine articles, book chapters and presented in more than 80 international conferences. I am actively serving as a conference session chair, guest editor of Journal, manuscripts reviewer and bachelor, master and PhD projects supervisor.

The objective of this presentation is two-fold. First to give the overview of my research and teaching experience, and second to demonstrate the simulation, design, optimization, monitoring and control of advanced modular continuous pharmaceutical manufacturing plant.

Teaching Interests:  

My teaching experience that I acquired serving as a teaching assistant, lecturer, and assistant research professor makes me confidant to develop and teach any courses of chemical and biochemical engineering. The industrial invited crash courses that I have given provide me opportunity to extend my teaching skills to cover more applied courses and to interact with highly experienced scientist and operators from manufacturing companies. I demonstrated my skills to instruct hands-on exercise through several workshops that I conducted. Several training courses that I conducted for industrial and academic participants make me instrumented with additional capability of building highly skilled workforce. In my department, I am a lead organizer of postdoctoral training program with the aim of building highly skilled workforce for industry and academia. I developed two online course modules where I learn how to develop and give online courses. My unique research area- applied process system engineering- provides me dual ability to teach theoretical as well as practical courses. I am open to teach any courses that your university will assign me. I am especially interested to teach courses related to process control, process modeling and simulation, process monitoring, chemical reaction engineering, process and tool integration and pharmaceuticals. If needed then I can develop new courses based on my research outcomes.

Grants:

Extensive experience in funding proposals writing. Wrote several grants proposals for national science foundation (NSF), FDA, and pharmaceutical industries. 11 projects with total grant more than 18 million USD got funded in which I have contributed significantly.

Publications:

Scientific articles (43); Book chapters (4); International conference presentations (80); Invited industrial/academic lectures (8); Workshops (5); Thesis (3); Reports (>100).

Activities in AIChE 2015 conference:

Session co-chair

  1. 10B08 Process Control Applications I: 32339
  2. 10B12 Process Control Applications II: 34890
  3. 10C03 Dynamic Simulation and Optimization: 32320
  4. 10D01 Advances in Computational Methods and Numerical Analysis: 32306
  5. 10E02 Big Data Analytics in Chemical Engineering: 32315

Presenter (Oral presentations)

  1. Singh, R., Muzzio, F. J, Ramachandran, R. Ierapetritou, M. (2016). Advanced flexible control system implementation into direct compaction continuous pharmaceutical manufacturing pilot-plant. Oral presentation at AIChE annual meeting, San Francisco, CA, USA, 13 â?? 18 November. Session: Product Quality Attribute Monitoring and Control in Drug Product Manufacturing. Schedule: Thursday, November 17, 3: 59 PM.
  2. Singh, R., Cao, H., Mushnoori, S., Higgins, B., Kolipara, C., Fermier, A., Hausner, D., Jha, S., Ierapetritou, M., Ramachandran, R. (2016). Data management and integration for continuous pharmaceutical manufacturing. Oral presentation at AIChE annual meeting, San Francisco, CA, USA, 13 â?? 18 November. Session: Industrial Applications of Data Analysis, Information Management, and Intelligent Systems. Schedule: Wednesday, November 16, 9.46 AM.
  3. Singh, R., Pereira, G. C., Soni, N., Román-Ospino, A. D., Ierapetritou, M., Ramachandran, R. (2016). Feedforward control of continuous pharmaceutical manufacturing process. Oral presentation at AIChE annual meeting, San Francisco, CA, USA, 13 â?? 18 November. Session: Quality By Design in Drug Product Formulation, Design, & Process Development II. Schedule: Friday, November 18, 8.30 AM.

Co-author

  1. Wang, Z., Escotet-Espinoza, M. S., Singh, R., Muzzio, F. J., Ierapetritou, M. G. (2016). Surrogate-Based Optimization Methodology for Pharmaceutical Tablet Manufacturing Processes. Oral presentation at AIChE annual meeting, San Francisco, CA, USA, 13 â?? 18 November. Session: Design and Operations Under Uncertainty I. Schedule: Thursday, November 17, 8:30 AM.
  2. Wang, Z., Escotet-Espinoza, M. S., Singh, R., Muzzio, F. J., Ierapetritou, M. G. (2016). Feasibility Analysis of Flowsheet Models in Continuous Pharmaceutical Manufacturing Processes Considering the Effects of Noise. Poster presentation at AIChE annual meeting, San Francisco, CA, USA, 13 â?? 18 November. Poster Session: Pharmaceutical. Schedule: Monday, November 14, 3:15 - 5:45 PM.

Selected publications:

1. International scientific articles:

Year 2016

  1. Wu, S., Panikar, S. S., Singh; R., Zhang, J., Donepudi, A., Glasser, B., Ramachandran, R. (2016). Systematic framework to monitor mulling processes using Near Infrared spectroscopy. Advanced Powder Technology. doi:10.1016/j.apt.2016.03.022.
  2. Singh, R., Muzzio, F., Ierapetritou, M., Ramachandran, R. (2016). Systematic framework for design and implementation of plant-wide multilayer, sensing and control architecture into continuous pharmaceutical manufacturing plant. Computer Aided Chemical Engineering. Accepted.
  3. Román-Ospino, A. D., Singh, R., Ierapetritou, M., Ramachandran, R. Méndez, R., Ortega, C., Muzzio, F. J., Romañach, R. J., (2016). Near Infrared Spectroscopic Calibration Models For Real Time Monitoring Of Powder Density. International Journal of Pharmaceutics. Accepted.

Year 2015

  1. Singh, R., Román-Ospino, A. D., Romañach, R. J., Ierapetritou, M., Ramachandran, R. (2015). Real time monitoring of powder blend bulk density for coupled feed-forward/feed-back control of a continuous direct compaction tablet manufacturing process. International Journal of Pharmaceutics, 495, 612-625.
  2. Singh, R., Muzzio, F., Ierapetritou, M., Ramachandran, R. (2015). A combined feed-forward/feed-back control system for a QbD based continuous tablet manufacturing process. PROCESSES Journal, 3, 339-356.
  3. Singh, R., Sen, M., Ierapetritou, M., Ramachandran, R. (2015). Integrated moving horizon based dynamic real time optimization and hybrid MPC-PID control of a direct compaction continuous tablet manufacturing process. Journal of Pharmaceutical Innovation, 10 (3), 233-253.
  4. Simon, L. L., .. Singh, R., et al. (2015). Assessment of Recent Process Analytical Technology (PAT) Trends: A Multi-author Review. Organic Process Research & Development, 19, 3-62.
  5. Singh, R.,Zhang, J., Ierapetritou, M., Ramachandran, R. (2015). Designing a novel continuous manufacturing plant with superior monitoring and control. European Pharmaceutical Review, 20(6), 37-41.
  6. Sen, M., Singh, R., Ramachandran, R. (2015). Model Manufacturing. The Medicine Maker, February, 05, 42-45.
  7. Escotet-Espinoza, M. S., Singh, R., Sen, M., Oâ??Connor, T., Lee, S., Chatterjee, S., Ramachandran, R., Ierapetritou, M., Muzzio, F. (2015). Flowsheet Models Modernize Pharmaceutical Manufacturing Design and Risk Assessment, Pharmaceutical Technology 39 (4), 34-42.
  8. Singh, R., Muzzio, F., Ierapetritou, M., Ramachandran, R. (2015). Plant-wide control of a continuous tablet manufacturing for Quality-by-Design based pharmaceutical manufacturing. Computer Aided Chemical Engineering, 37, 2183 - 2188.
  9. Karry, K. M., Singh, R.,Muzzio, F. J. (2015). Fit-for-Purpose Miniature NIR Spectroscopy for Solid Dosage Continuous Manufacturing. American Pharmaceutical Review, 18(4), 64 - 67.
  10. Singh, R.,Ierapetritou, M., Ramachandran, R. (2015). The scopes of PAT in real-time advanced control of tablet quality. European Pharmaceutical Review 20(2), 76-80.

Year 2014

  1. Singh, R., Sahay, A., Karry, K. M., Muzzio, F., Ierapetritou, M., Ramachandran, R. (2014). 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, 473, 38â??54.
  2. Singh, R., Sahay, A., Fernando Muzzio, Ierapetritou, M., Ramachandran, R. (2014). Systematic framework for onsite design and implementation of the control system in continuous tablet manufacturing process. Computers & Chemical Engineering Journal, 66, 186-200.
  3. Singh, R., Barrasso, D., Chaudhury, A., Maitraye Sen, Ierapetritou, M., Ramachandran, R. (2014). Closed-Loop Feedback Control of a Continuous Pharmaceutical Tablet Manufacturing Process via Wet Granulation. Journal of Pharmaceutical Innovation, 9, 16-37.
  4. Sen, M., Barrasso, D., Singh, R., Ramachandran, R. (2014). A Multi-Scale Hybrid CFD-DEM-PBM Description of a Fluid-Bed Granulation Process. Processes Journal, 2(1), 89-111.
  5. Sen, M., Singh, R., Ramachandran, R. (2014). Simulation based design of an efficient control system for the continuous purification and processing of active pharmaceutical ingredients. Journal of Pharmaceutical Innovation, 9, 65-81.
  6. Sen, M., Singh, R., Ramachandran, R. (2014). A hybrid MPC-PID control system design for the continuous purification and processing of active pharmaceutical ingredients. PROCESSES Journal, 2, 392-418; doi:10.3390/pr2020392.
  7. Sen, M., Chaudhury, A., Singh, R., Ramachandran, R. (2014). Two-dimensional population balance model development and validation of pharmaceutical crystallization processes. American Journal of Modern Chemical Engineering, 1, 13-29.

Year 2013

  1. Singh, R., Ierapetritou, M., Ramachandran, R. (2013). System-wide hybrid model predictive control of a continuous pharmaceutical tablet manufacturing process via direct compaction. European Journal of Pharmaceutics and Biopharmaceutics, 85(3), Part B, 1164-1182.
  2. Singh, R., Godfrey, A., Gregertsen, B., Muller, F., Gernaey, K. V., Gani, R., Woodley, J. M. (2013). Systematic substrate adoption methodology (SAM) for future flexible, generic pharmaceutical production processes. Computers & Chemical Engineering Journal, 58, 344 - 368.
  3. Sen, M., Dubey, A., Singh, R., Ramachandran, R. (2013). Mathematical Development and Comparison of a Hybrid PBM-DEM description of a Continuous Powder Mixing Process. Journal of Powder Technology, http://dx.doi.org/10.1155/2013/843784.
  4. Sen, M., Chaudhury, A., Singh, R., John, J., Ramachandran, R. (2013). Multi-scale flowsheet simulation of an integrated continuous purificationâ??downstream pharmaceutical manufacturing process. International Journal of Pharmaceutics, 445 (1-2), 29-38.
  5. Sen, M., Rogers, A., Singh, R., Chaudhury, A., John, J., Ierapetritou, M., Ramachandran, R. (2013). Flowsheet optimization of an integrated continuous purification-processing pharmaceutical manufacturing operation. Chemical Engineering Science, 102, 56 â?? 66.
  6. Singh, R., Ierapetritou, M., Ramachandran, R (2013). Hybrid advanced control of a flexible multipurpose continuous pharmaceutical tablet manufacturing process via direct compaction. Computer Aided Chemical Engineering, 32, 757-762.
  7. Muzzio, F., Singh, R., Chaudhury, A., Rogers, A., Ramachandran, R. Ierapetritou, M. (2013). Model- predictive design, control and optimization of pharmaceutical process. Pharmaceutical Technology magazine, 37(6), 40-41, 77.
  8. Singh, R., Sahay, A., Oka, S., Liu, X., Ramachandran, R., Ierapetritou, M., Muzzio, F. (2013). Online monitoring, advanced control and operation of robust continuous pharmaceutical tablet manufacturing process. BioPharma magazine Asia, 2(5), 18-25.

Year 2012

  1. Singh, R., Ierapetritou, M., Ramachandran, R. (2012). An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction. International Journal of Pharmaceutics, 438 (1-2), 307-326.
  2. Sen, M., Singh, R., Vanarase, A., John, J., Ramachandran, R. (2012). Multi-dimensional population balance modeling and experimental validation of continuous powder mixing processes. Chemical Engineering Science, 18, 349-360.
  3. Singh, R., Raquel Rozada-Sanchez, R., Dean, W., Perkins, J., Muller, F., Godfrey, A., Gernaey, K. V., Gani, R., Woodley, J. M. (2012). A generic process template for continuous pharmaceutical production. Computer Aided Chemical Engineering, 31, 715-719.
  4. Singh, R., Boukouvala, F., Jayjock, E., Ramachandran, R. Ierapetritou, M., Muzzio, F. (2012). Flexible Multipurpose Continuous Processing: integration of process flow modeling for continuous processing of pharmaceutical solid dosage forms. PharmPro Magazine, Pharmaceutical Processing, 27(6), 22-25.
  5. Singh, R., Boukouvala, F., Jayjock, E., Ramachandran, R. Ierapetritou, M., Muzzio, F. (2012). Flexible Multipurpose Continuous Processing of Pharmaceutical Tablet Manufacturing Process. GMP news, European Compliance Academic (ECE), http://www.gmp-compliance.org/ecanl_503_0_news_3268_7248_n.html.

Years 2011-2008

  1. Singh, R., Gernaey, K. V., Gani, R. (2010). ICAS-PAT: A Software for Design, Analysis & Validation of PAT Systems. Computers & Chemical Engineering Journal, 34(7), 1108-1136.
  2. Singh, R., Gernaey, K. V., Gani, R. (2010). An ontological knowledge based system for selection of process monitoring and analysis tools. Computers & Chemical Engineering Journal, 34(7), 1137-1154.
  3. Singh, R., Gernaey, K. V., Gani, R. (2009). Model-based computer-aided framework for design of process monitoring and analysis systems. Computers & Chemical Engineering Journal, 33(1), 22-42.
  4. Samad, N. A. F. A., Singh, R., Sin, G., Gernaey, K. V., Gani, R. (2011). A generic multi-dimensional model-based system for batch cooling crystallization processes. Computers & Chemical Engineering Journal, 35(5), 828-843.
  5. Samad, N. A. F. A., Singh, R., Sin, G., Gernaey, K. V., Gani, R. (2011). Systematic Procedure for Generating Operational Policies to Achieve Target Crystal Size Distribution (CSD) in Batch Cooling Crystallization. IEEE, 1-6. Print ISBN: 978-1-4577-0003-3. DOI: 10.1109/ICMSAO.2011.5775588.
  6. Samad, N. A. F. A., Singh, R., Sin, G., Gernaey, K. V., Gani, R. (2011). Integration of Generic Multi-dimensional Model and Operational Policies for Batch Cooling Crystallization. Computer Aided Chemical Engineering, 29, 86-90.
  7. Samad, N. A. F. A., Singh, R., Sin, G., Gernaey, K. V., Gani, R. (2010). Control of process operation and monitoring of product qualities through generic model-based in batch cooling crystallization. Computer Aided Chemical Engineering, 28, 613-618.
  8. Singh, R., Rozada-Sanchez, R., Wrate, T., Muller, F., Gernaey, K. V., Gani, R., Woodley, J. M. (2010). A retrofit strategy to achieve â??Fast, Flexible, Future (F3)â? pharmaceutical production processes. Computer Aided Chemical Engineering, 29, 291-295.
  9. Singh, R., Gernaey, K. V., Gani, R. (2009). A software tool for design of process monitoring and analysis systems. Computer Aided Chemical Engineering, 26, 321-326.
  10. Singh, R., Gernaey, K. V., Gani, R. (2008). Off-line design of PAT systems for on-line applications. Computer Aided Chemical Engineering, 25, 423-428.

2. Book Chapters

  1. Singh, R., Figueroa, CV, Sahay, A., Karry, KM, Fernando Muzzio, F., Ierapetritou, M., Ramachandran, R. (2014). Chapter 7: Advanced Control of continuous pharmaceutical tablet manufacturing processes. Book title: Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture. Publisher: Humana Press, ISBN: 978-1-4939-2995-5, 191 â?? 223. 
  2. Ierapetritou, M., Escotet-Espinoza, M. S., Singh, R. (2016). Process Simulation and control for continuous pharmaceutical manufacturing of solid drug products. A chapter of book â??Continuous manufacturing of pharmaceuticalsâ? edited by Peter Kleinebudde, Johannes Khinast and Jukka Rantanen. Publisher: Wiley-VCH. Accepted.
  3. Oka, S, Escotet-Espinoza, M. S., Singh, R., Scicolone, J., Hausner, D., Ierapetritou, M., Muzzio, F. (2016). Design of an integrated continuous manufacturing system. A chapter of book â??Continuous manufacturing of pharmaceuticalsâ? edited by Peter Kleinebudde, Johannes Khinast and Jukka Rantanen. Publisher: Wiley-VCH. Accepted.
  4. A Book chapter in â??Product and Process Modelling: A case study approachâ?:
  • Singh, R. (2011). Fermentation process modeling. Chapter 12.2 of book â??Product and Process Modelling: A case study approachâ? edited by I Cameron & R. Gani. Publisher: Elsevier, pp 380-396.
  • Singh, R. (2011). Milling process model. Chapter 12.4 of book â??Product and Process Modelling: A case study approachâ? edited by I Cameron & R. Gani. Publisher: Elsevier, pp 407-413.  
  • Singh, R. (2011). Granulation process model. Chapter 12.5 of book â??Product and Process Modelling: A case study approachâ? edited by I Cameron & R. Gani. Publisher: Elsevier, pp 413-422.  
  • Singh, R. (2011). Pharmaceutical tablet pressing process model. Chapter 12.6 of book â??Product and Process Modelling: A case study approachâ? edited by I Cameron & R. Gani. Publisher: Elsevier, pp 422-430.  
  • Singh, R. (2011). Milk pasteurization process modeling. Chapter 12.3 of book â??Product and Process Modelling: A case study approachâ? edited by I Cameron & R. Gani. Publisher: Elsevier, pp 396-406.