Journal of Pharmaceutical Innovation

, Volume 14, Issue 4, pp 316–331 | Cite as

Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process

  • Aparajith Bhaskar
  • Ravendra SinghEmail author
Original Article



During continuous manufacturing, there may be some out of specification tablets that need to be diverted in real time, in order to ensure the quality of the final product. Specifically, the content uniformity of each tablet must be guaranteed before it can be released to market. However, currently, no methods or tools are available that can assure the content uniformity and divert the non-confirming products in real time. The aim of this work is to develop and evaluate a strategy to divert the non-confirming tablets in real time and thereby assure drug concentration of final tablets.


This work has been conducted in silico using a combination of MATLAB and Simulink. A methodology to implement a residence time distribution (RTD)-based control system for drug concentration-based tablet diversion which uses the convolution integral was developed and implemented in MATLAB. Comparisons between the performance of “fixed window” and “RTD-based” approaches for diversion have also been presented and used to assess optimal usability.


In this work, two novel strategies namely, “fixed window approach” and “RTD-based approach” have been developed and evaluated for real-time diversion of non-confirming tablets. The RTD-based control system was designed, developed, and implemented in silico. A framework for its implementation in a real-time system has also been elaborated on. This methodology was compared to an alternative fixed window approach. The proposed control system is analyzed for various manufacturing scenarios, systems, and disturbances.


A comparison of the two proposed strategies suggests that the “RTD-based control system” is more efficient in every simulated scenario. The relative performance is best when the disturbances in the system are characterized by short pulse-like changes.


Residence time distribution RTD Control Continuous manufacturing Quality by design Continuous pharmaceutical manufacturing 


Funding Information

This work is supported by the Rutgers Research Council, through grant 202342 RC-17-Singh R; the US Food and Drug Administration (FDA), through grant 11695471; and the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through grant NSF-ECC 0540855.


  1. 1.
    Lee SL, O’Connor TF, Yang X, Cruz CN, Chatterjee S, Madurawe RD, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191–9.CrossRefGoogle Scholar
  2. 2.
    Plumb K. Continuous processing in the pharmaceutical industry: changing the mind set. Chem Eng Res Des. 2005;83(6):730–8.CrossRefGoogle Scholar
  3. 3.
    FDA. Guidance for industry PAT—a framework for innovative pharmaceutical development, manufacturing, and quality assurance.Google Scholar
  4. 4.
    Bhaskar A, Barros FN, Singh R. Development and implementation of an advanced model predictive control system into continuous pharmaceutical tablet compaction process. Int J Pharm. 2017;534(1–2):159–78.CrossRefGoogle Scholar
  5. 5.
    Nunes de Barros F, Bhaskar A, Singh R. A validated model for design and evaluation of control architectures for a continuous tablet compaction process. vol. 5, Processes. 2017Google Scholar
  6. 6.
    Su Q, Moreno M, Giridhar A, Reklaitis GV, Nagy ZK. A systematic framework for process control design and risk analysis in continuous pharmaceutical solid-dosage manufacturing. J Pharm Innov. 2017;12(4):327–46.CrossRefGoogle Scholar
  7. 7.
    Singh R, Muzzio JF, Ierapetritou M, Ramachandran R. A Combined feed-forward/feed-back control system for a QbD-based continuous tablet manufacturing process, vol. 3, Processes. 2015.Google Scholar
  8. 8.
    Singh R, Ierapetritou M, Ramachandran R. System-wide hybrid MPC–PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction. Eur J Pharm Biopharm. 2013;85(3, Part B):1164–82.CrossRefGoogle Scholar
  9. 9.
    Ramachandran R, Arjunan J, Chaudhury A, Ierapetritou MG. Model-based control-loop performance of a continuous direct compaction process. J Pharm Innov. 2011;6(4):249–63.CrossRefGoogle Scholar
  10. 10.
    Singh R, Ierapetritou M, Ramachandran R. An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction. Int J Pharm. 2012;438(1):307–26.CrossRefGoogle Scholar
  11. 11.
    Hsu S-H, Reklaitis GV, Venkatasubramanian V. Modeling and control of roller compaction for pharmaceutical manufacturing. Part I: process dynamics and control framework. J Pharm Innov. 2010;5(1):14–23.CrossRefGoogle Scholar
  12. 12.
    Mesbah A, Paulson JA, Lakerveld R, Braatz RD. Model predictive control of an integrated continuous pharmaceutical manufacturing pilot plant. Org Process Res Dev. 2017;21(6):844–54.CrossRefGoogle Scholar
  13. 13.
    Lakerveld R, Benyahia B, Heider PL, Zhang H, Wolfe A, Testa CJ, et al. The application of an automated control strategy for an integrated continuous pharmaceutical pilot plant. Org Process Res Dev. 2015;19(9):1088–100.CrossRefGoogle Scholar
  14. 14.
    Singh R, Muzzio FJ, Ierapetritou M, Ramachandran R. Integrated control and data management system for continuous pharmaceutical anufacturing process. Oral presentation at AIChE annual meeting, Minneapolis, MN, 29 October - 3 November. 2017.Google Scholar
  15. 15.
    Gao Y, Vanarase A, Muzzio F, Ierapetritou M. Characterizing continuous powder mixing using residence time distribution. Chem Eng Sci. 2011;66(3):417–25.CrossRefGoogle Scholar
  16. 16.
    Gao Y, Muzzio FJ, Ierapetritou MG. A review of the residence time distribution (RTD) applications in solid unit operations. Powder Technol. 2012;228:416–23.CrossRefGoogle Scholar
  17. 17.
    Abouzeid A-ZMA, Mika TS, Sastry KV, Fuerstenau DW. The influence of operating variables on the residence time distribution for material transport in a continuous rotary drum. Powder Technol. 1974;10(6):273–88.CrossRefGoogle Scholar
  18. 18.
    Mateo-Ortiz D, Méndez R. Relationship between residence time distribution and forces applied by paddles on powder attrition during the die filling process. Powder Technol. 2015;278:111–7.CrossRefGoogle Scholar
  19. 19.
    Engisch W, Muzzio F. Using residence time distributions (RTDs) to address the traceability of raw materials in continuous pharmaceutical manufacturing. J Pharm Innov. 2016 Nov 14;11:64–81.CrossRefGoogle Scholar
  20. 20.
    Fogler H. Elements of chemical reaction engineering. 2006.Google Scholar
  21. 21.
    Singh R, Sahay A, Karry KM, Muzzio F, Ierapetritou M, Ramachandran R. Implementation of an advanced hybrid MPC–PID control system using PAT tools into a direct compaction continuous pharmaceutical tablet manufacturing pilot plant. Int J Pharm. 2014;473(1):38–54.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Department of Chemical and Biochemical Engineering, RutgersThe State University of New JerseyPiscatawayUSA

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