Journal of Pharmaceutical Innovation

, Volume 9, Issue 1, pp 16–37 | Cite as

Closed-Loop Feedback Control of a Continuous Pharmaceutical Tablet Manufacturing Process via Wet Granulation

  • Ravendra Singh
  • Dana Barrasso
  • Anwesha Chaudhury
  • Maitraye Sen
  • Marianthi Ierapetritou
  • Rohit RamachandranEmail author
Research Article


The wet granulation route of tablet manufacturing in a pharmaceutical manufacturing process is very common due to its numerous processing advantages such as enhanced powder flow and decreased segregation. However, this route is still operated in batch mode with little (if any) usage of an automatic control system. Tablet manufacturing via wet granulation, integrated with online/inline real time sensors and coupled with an automatic feedback control system, is highly desired for the transition of the pharmaceutical industry toward quality by design as opposed to quality by testing. In this manuscript, an efficient, plant-wide control strategy for an integrated continuous pharmaceutical tablet manufacturing process via wet granulation has been designed in silico. An effective controller parameter tuning strategy involving an integral of time absolute error method coupled with an optimization strategy has been used. The designed control system has been implemented in a flowsheet model that was simulated in gPROMS (Process System Enterprise) to evaluate its performance. The ability of the control system to reject the unknown disturbances and track the set point has been analyzed. Advanced techniques such as anti-windup and scale-up factor have been used to improve controller performance. Results demonstrate enhanced achievement of critical quality attributes under closed-loop operation, thus illustrating the potential of closed-loop feedback control in improving pharmaceutical tablet manufacturing operations.


Process control Pharmaceutical Granulation Continuous processing Population balance model 



Surface area (in square meters)


API composition (–)


Mean particle size (in meters)


PBM density function particles


Height (in meters)


Mass (in kilograms)


Number (–)


Compaction pressure (in megapascals)


Radius (in meters)


Relative standard deviation (–)


Residence time (in seconds)


Porosity (–)


Powder bulk density (in kilograms per cubic meter)


Material stress (in megapascals)

Rate (in particles per second)


Feeder rotation rate (in revolutions per minute)


Breakage kernel


Stress-angle empirical parameter




Time constant







Particle size











Inlet stream


Outlet stream




Set point


Rotation rate



Feed frame disk




Feed frame






Tablet press



This work is supported by the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through grant NSF-ECC 0540855. The authors would also like to acknowledge Pieter Schmal (PSE) for useful discussions.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ravendra Singh
    • 1
  • Dana Barrasso
    • 1
  • Anwesha Chaudhury
    • 1
  • Maitraye Sen
    • 1
  • Marianthi Ierapetritou
    • 1
  • Rohit Ramachandran
    • 1
    Email author
  1. 1.Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS), Department of Chemical and Biochemical EngineeringRutgers, The State University of New JerseyPiscatawayUSA

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