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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Funding

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.

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Authors and Affiliations

  1. Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Aparajith Bhaskar & Ravendra Singh

Authors
  1. Aparajith Bhaskar
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  2. Ravendra Singh
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Corresponding author

Correspondence to Ravendra Singh.

Appendix

Appendix

Nomenclature

Abbreviations

Variable

API

Active pharmaceutical ingredient

CSTR

Continuous stirred tank reactor

CQA

Critical quality attributes

NIR

Near infrared

PFR

Plugged flow reactor

PAT

Process analytical technology

RTRT

Real-time release testing

RTD

Residence time distribution

Symbol

Variable

Units

C

Concentration

g/m3

C(t)

Concentration at time t

(%)

E(t)

Residence time distribution function

s−1

F(t)

Cumulative distribution function

(−)

n

Number of tanks

(−)

t

Time

s

ε

Manufacturing efficiency

%

σ

Variance

s

τ

Mean residence time

s

Subscript

Variable

a

Accept

di

Initial delay

df

Final delay

exp

Experimental

f

Concentration after step change

in

Input stream

o

Off-specification

out

Output stream

s

Specification

r

Reject

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Bhaskar, A., Singh, R. Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process. J Pharm Innov 14, 316–331 (2019). https://doi.org/10.1007/s12247-018-9356-7

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  • DOI: https://doi.org/10.1007/s12247-018-9356-7

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