A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process

09 Jun 2023 | Contributor(s): Singh, Ravendra, Muzzio, Fernando J, Ierapetritou, Marianthi, Ramachandran, Rohit

Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic control of the end product quality as desired by QbD (quality by design)-based efficient manufacturing. The precise control of the quality of the pharmaceutical...

A comparative review of multi-rate moving horizon estimation schemes for bioprocess applications

09 Jun 2023 | Contributor(s): Elsheikh, Mohamed, Hille, Rubin Tatulea-Codrean, Alexandru, Kramer, Stefan

Advanced control and monitoring of bioprocesses are dependent on accurate state and parameter information. At the same time, bioprocesses are well known for their time-varying behavior and difficulty of obtaining online measurements of the important process states. The selection and the tuning of...

A Continuous Operation Concept for a Rotary Tablet Press Using Mass Flow Operating Points

09 Jun 2023 | Contributor(s): Martinetz, Michael Christian, Rehrl, Jakob Aigner, Isabella Sacher, Stephan, Khinast, Johannes

Abstract In a continuous pharmaceutical manufacturing line the rotary tablet press was viewed as the master of control concept and defined the mass flow through the entire process. According to a conventional control concept, missing mass flow from an upstream unit operation leads to a shutdown...

A fast moving horizon estimation algorithm based on nonlinear programming sensitivity

09 Jun 2023 | Contributor(s): Zavala, Victor M, Laird, Carl D, Biegler, Lorenz T

Moving horizon estimation (MHE) is an efficient optimization-based strategy for state estimation. Despite the attractiveness of this method, its application in industrial settings has been rather limited. This has been mainly due to the difficulty to solve, in real-time, the associated dynamic...

A Hybrid MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this work, a hybrid MPC (model predictive control)-PID (proportional-integral-derivative) control system has been designed for the continuous purification and processing framework of active pharmaceutical ingredients (APIs). The specific unit operations associated with the purification and...

A hybrid neural network-first principles approach to process modeling

09 Jun 2023 | Contributor(s): Psichogios, Dimitris C., Ungar, Lyle H.

A hybrid neural network‐first principles modeling scheme is developed and used to model a fedbatch bioreactor. The hybrid model combines a partial first principles model, which incorporates the available prior knowledge about the process being modeled, with a neural network which...

A hybrid NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations

09 Jun 2023 | Contributor(s): Cogoni, Giuseppe, Husain, Anas, Alam, Md Anik, Liu, Yang Angela, Kamyar, Reza

Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet...

A model-based framework for design and analysis of PAT systems

09 Jun 2023 | Workshop | Contributor(s): Gani, Rafiqul, Singh, Ravendra, Gernaey, Krist

A Moving Horizon Estimator for processes with multi-rate measurements: A Nonlinear Programming sensitivity approach

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Lopez-Negrete, Rodrigo, Biegler, Lorenz T.

Moving Horizon Estimation (MHE) provides a framework that allows one to incorporate both frequent and infrequent observations easily because it uses a window of past measurements, where the slower ones can be introduced as they become available. Also, MHE allows for the use of constraints on the...

A Moving Horizon-Based Approach for Least-Squares Estimation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Robertson, Douglas G., Lee, Jay H., Rawlings, James B.

A general formulation of the moving horizon estimator is presented. An algorithm with a fixed-size estimation window and constraints on states, disturbances, and measurement noise is developed, and a probabilistic interpretation is given. The moving horizon formulation requires only one more...

A multi-scale hybrid CFD-DEM-PBM description of a fluid-bed granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, Maitraye, Barrasso, Dana Singh, Ravendra, Ramachandran, Rohit

In this study, a hybrid multi-scale model has been developed for a continuous fluid bed wet granulation process by dynamically coupling computational fluid dynamics (CFD) with a discrete element model (DEM) and population balance model (PBM). In this process, the granules are formed by spraying...

A novel robust digital design of a network of industrial continuous cooling crystallizers of dextrose monohydrate: From laboratory experiments to industrial application

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Nagy, Zoltan K., Szilagyi, Botond Pal, Kanjakha, Tabar, Iman Beheshti ;

This paper presents the first-ever industrial application of the digital design of a complex, large-scale industrial continuous crystallization network. The aim of the work is to optimize a large-scale continuous crystallization network used for the purification of dextrose monohydrate, by...

A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Su, Qinglin, Ganesh, Sudarshan Moreno, Mariana Bommireddy, Yasasvi, Gonzalez, Marcial, Reklaitis, Gintaras V., Nagy, Zoltan K.

The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD...

A retrofit strategy to achieve “Fast, Flexible, Future (F3)” pharmaceutical production processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Rozada-Sanchez, Raquel Wrate, Tim Muller, Frans Gernaey, Krist V Gani, Rafiqul, Woodley, John M

n the work reported here, a substrates adoption methodology for a series of similar substrates has been developed as part of a retrofit strategy. The objective is to achieve “fast, flexible and future” pharmaceutical production processes by adapting a generic modular process-plant template....

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sohail Arshad, Muhammad, Zafar, Saman, Yousef, Bushra, Alyassin, Yasmine, Ali, Radeyah, AlAsiri, Ali, Chang, Ming-Wei, Ahmad, Zeeshan, Ali Elkordy, Amal, Faheem, Ahmed, Pitt, Kendal

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight...

A systematic computer aided framework for design and analysis of PAT systems

09 Jun 2023 | Workshop | Contributor(s): Gernaey, Krist, Singh, Ravendra, Gani, Rafiqul

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A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Sahay, Abhishek Muzzio, Fernando Ierapetritou, Marianthi, Ramachandran, Rohit

A novel manufacturing strategy based on continuous processing integrated with online/inline monitoring tools coupled with an advanced control system is highly desired for efficient Quality by Design (QbD)-based pharmaceutical manufacturing. A control system ensures the predefined end product...

A Systematic Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Su, Qinglin, Moreno, Mariana, Giridhar, Arun, Reklaitis, Gintaras, Nagy, Zoltan

The paradigm shift in the pharmaceutical industry to continuous manufacturing, which has recently progressed from conceptual demonstration to pilot production, has stimulated the development and application of process systems engineering (PSE) tools for implementing efficient and robust control...

A Systematic Framework for the Design and Implementation of Sensing and Control Architecture for a Continuous Pharmaceutical Manufacturing Plant

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Muzzio, Fernando J Ierapetritou, Marianthi, Ramachnadran, Rohit

The continuous pharmaceutical manufacture (CPM) plant and control architecture developed earlier is currently being widely implemented in industries [1,2]. CPM indeed provides an appropriate platform to implement suitable monitoring and control architecture, to improve product quality, and to...

A Systematic Framework for the Design and Implementation of Sensing and Control Architecture for a Continuous Pharmaceutical Manufacturing Plant

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Muzzio, Fernando J Ierapetritou, Marianthi, Ramachnadran, Rohit

The continuous pharmaceutical manufacture (CPM) plant and control architecture developed earlier is currently being widely implemented in industries [1,2]. CPM indeed provides an appropriate platform to implement suitable monitoring and control architecture, to improve product quality, and to...

A systematic framework to monitor mulling processes using Near Infrared spectroscopy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wu, Suyang, Panikar, Savitha S Singh, Ravendra Zhang, Jun Glasser, Benjamin, Ramachandran, Rohit

The optimal design of sensor location and setup is essential to ensure the accuracy and precision of in-line process monitoring of water/moisture content. This manuscript presents a systematic framework of using Near Infrared (NIR) spectroscopy to monitor moisture content in an alumina mulling...

A Validated Model for Design and Evaluation of Control Architectures for a Continuous Tablet Compaction Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Nunes de Barros, Fernando, Bhaskar, Aparajith, Singh, Ravendra

The systematic design of an advanced and efficient control strategy for controlling critical quality attributes of the tablet compaction operation is necessary to increase the robustness of a continuous pharmaceutical manufacturing process and for real time release. A process model plays a very...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Shen, Dongying E., Zhu, Xiaoxiang, Graham, Lauren R., Robinson, Jo A., Huggins, Seth, Allian, Ayman, Hart, Roger, Walker,Shawn D., Rolandi, Pablo, Braatz, Richard D.

This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic...

Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Zhang, P, Weeranoppanant, NThomas, DA, Tahara, K, Stelzer, T, Russell, MG, O'Mahony, M, Myerson, AS, Lin, HK, Kelly, LP, Jensen, KF, Jamison, TF, Dai, CH, Cui, YQ, Briggs, N, Beingessner, RL, Adamo, A

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on...

Advanced control of a continuous oscillatory flow crystalliser

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Tahir, F, Krzemieniewska-Nandwani, KMack, J, Lovett, D, Siddique, H, Mabbott, F, Raval, V, Houson, I, Florence, A

This paper presents the application and challenges of achieving Model Predictive Control (MPC) on two continuous oscillatory baffled crystallisation reactors, delivering precise product quality control in the face of raw material fluctuations. A key advantage of MPC is that it effectively deals...