(6hp) Applied Pharmaceutical Process System Engineering

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. Author’s main research area is applied 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, recently 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 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 eight projects funded by NSF, industries and regulator with total grants exceeding 10 million USD. I was involved in proposal writing of these projects and I am 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 DTU’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 “EFCE Excellence Award 2010”, 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 accreditations’. I have published several peer reviewed scientific international Journal articles, popular reputed magazine articles, book chapters and presented in more than 68 international conferences. I am actively serving as a conference session chair, guest editor of Journal, manuscripts reviewer and 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 design, optimization, monitoring and control of continuous tablet manufacturing plant.

Activities in AIChE 2015 conference

Session chair/co-chair

1. Chair of session, “10E07 Advances in Information Management and Integration”.
2. Co-chair of session, “10C06 Dynamic Simulation and Optimization”.

Presenter (Oral presentations)

1. Ravendra Singh, et al. (2015). Implementation of Advanced Multilayer Plant-Wide Control Architecture into a Direct Compaction Continuous Pharmaceutical Manufacturing Process. Session: 26002 Application of Quality By Design in Drug Product Formulation Design & Process Development.
2. Ravendra Singh, et al. (2015). Dynamic Modeling and Advanced Control of Tablet Press. Session: 26003 Model Based Integrated Design of Pharmaceutical Drug Substance and Drug Product Processes.
3. Ravendra Singh, et al. (2015). Sensor modeling. Session: 10B06 Process Monitoring and Fault Detection.
4. Ashish Shah, Rohit Ramachandran, Ravendra Singh* (2015). Moving Horizon Based Real Time Optimization and Advanced Hybrid Model Predictive Control of Continuous Pharmaceutical Manufacturing Process. Session: 10B04 Economics and Process Control.

Co-author (Oral presentations)

Four presentations in sessions 10E07, 26006, 26003.

Selected references

1. Singh, R., et al. (2015). PROCESSES Journal, 3, 339-356.
2. Singh, R., et al. (2015). Integrated moving horizon based real time optimization and hybrid MPC-PID control of a direct compaction continuous tablet manufacturing process. Journal of Pharmaceutical Innovation, DOI: 10.1007/s12247-015-9221-x. Accepted.
3. Simon, L. L., .. Singh, R., et al. (2015). Organic Process Research & Development, 19, 3-62.
4. Singh, R., et al. (2014). International Journal of Pharmaceutics, 473, 38–54.
5. Singh, R., et al. (2014). Computers & Chemical Engineering Journal, 66, 186-200.
6. Singh, R., et al. (2014). Journal of Pharmaceutical Innovation, 9, 16-37.
7. Sen, M., Barrasso, D., Singh, R., et al. (2014). Processes Journal, 2(1), 89-111.
8. Sen, M., Singh, R., et al. (2014). Journal of Pharmaceutical Innovation, 9, 65-81.
9. Sen, M., Singh, R., et al. (2014). PROCESSES Journal, 2, 392-418; doi:10.3390/pr2020392.
10. 10.  Sen, M., Chaudhury, A., Singh, R., et al. (2014). American Journal of Modern Chemical Engineering, 1, 13-29.
11. Singh, R., et al. (2013). European Journal of Pharmaceutics and Biopharmaceutics, 85(3), Part B, 1164-1182.
12. Singh, R., et al. (2013). Computers & Chemical Engineering Journal, 58, 344 - 368.
13. Sen, M., Dubey, A., Singh, R., et al. (2013). Journal of Powder Technology, http://dx.doi.org/10.1155/2013/843784.
14. Sen, M., Chaudhury, A., Singh, R., et al. (2013). International Journal of Pharmaceutics, 445 (1-2), 29-38.
15. Sen, M., Rogers, A., Singh, R., et al. (2013). Chemical Engineering Science, 102, 56 – 66.
16. Singh, R., et al. (2012). International Journal of Pharmaceutics, 438 (1-2), 307-326.
17. Sen, M., Singh, R., et al. (2012). Chemical Engineering Science, 18, 349-360.
18. Samad, N. A. F. A., Singh, R., et al. (2011). Computers & Chemical Engineering Journal, 35(5), 828-843.
19. Singh, R., et al. (2011). Process and Product Modelling: A case study approach. Book chapters 12.2-12.6, Publisher: Elsevier, pp 380-430. 
20. Singh, R., et al. (2010). Computers & Chemical Engineering Journal, 34(7), 1108-1136.
21. Singh, R., et al. (2010). Computers & Chemical Engineering Journal, 34(7), 1137-1154.
22. Singh, R., et al. (2009). Computers & Chemical Engineering Journal, 33(1), 22-42.
23. Singh, R., et al. (2014). Advanced Control of continuous pharmaceutical tablet manufacturing processes. Book chapter, Publisher: Humana Press, in press.    
24. Singh, R., et al. (2015). European Pharmaceutical Review 20(2), 76-80.
25. Sen, M., Singh, R., Ramachandran, R. (2015). The Medicine Maker, February, 05, 42-45.
26. Escotet-Espinoza, M. S., Singh, R., et al. (2015). Pharmaceutical Technology 39 (4), 34-42.
27. Singh, R., et al. (2015). Computer Aided Chemical Engineering, accepted.
28. Singh, R., et al. (2013). Computer Aided Chemical Engineering, 32, 757-762.
29. Muzzio, F., Singh, R., et al. (2013). Pharmaceutical Technology magazine, 37(6), 40-41, 77.
30. Singh, R., et al. (2013). BioPharma magazine Asia, 2(5), 18-25.
31. Singh, R., et al. (2012). Computer Aided Chemical Engineering, 31, 715-719.
32. Singh, R., et al. (2012). PharmPro Magazine, Pharmaceutical Processing, 27(6), 22-25.
33. Singh, R., et al. (2012). European Compliance Academic (ECE), http://www.gmp-compliance.org/ecanl_503_0_news_3268_7248_n.html.
34. Samad, N. A. F. A., Singh, R., Sin, G., Gernaey, K. V., Gani, R. (2011). IEEE, 1-6.      
35. Gani, R., Singh, R. (2011). GEN: Genetic Engineering & Biotechnology News, 31(6), 40-41.
36. Samad, N. A. F. A., Singh, R., et al. (2010). Computer Aided Chemical Engineering, 28, 613-618.
37. Singh, R., et al. (2010). Computer Aided Chemical Engineering, 29, 291-295.
38. Samad, N. A. F. A., Singh, R., et al. (2010). Computer Aided Chemical Engineering, 29, 86-90.
39. Singh, R., et al. (2009). Computer Aided Chemical Engineering, 26, 321-326.
40. Singh, R., et al. (2008). Computer Aided Chemical Engineering, 25, 423-428.

Contact: Email: ravendra.singh@rutgers.edu

NSF Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA