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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 Ramachandran
Research Article

Abstract

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.

Keywords

Process control Pharmaceutical Granulation Continuous processing Population balance model 

Nomenclature

A

Surface area (in square meters)

CAPI

API composition (–)

d50

Mean particle size (in meters)

F

PBM density function particles

H

Height (in meters)

m

Mass (in kilograms)

n

Number (–)

P

Compaction pressure (in megapascals)

R

Radius (in meters)

RSD

Relative standard deviation (–)

RT

Residence time (in seconds)

ε

Porosity (–)

ρbulk

Powder bulk density (in kilograms per cubic meter)

σ

Material stress (in megapascals)

Rate (in particles per second)

ω

Feeder rotation rate (in revolutions per minute)

kbreak

Breakage kernel

Krc

Stress-angle empirical parameter

θ

Delay

τ

Time constant

Domain

g

Gas

n

Component

r

Particle size

s1

API

s2

Excipient

z1

Axial

z2

Radial

Subscript

in

Inlet stream

out

Outlet stream

P

Pressure

sp

Set point

ω

Rotation rate

Superscript

disc

Feed frame disk

f

Feeder

ff

Feed frame

m

Mixer

mil

Mill

tp

Tablet press

Notes

Acknowledgments

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
  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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