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

09 Jun 2023 | 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 | 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 novel robust digital design of a network of industrial continuous cooling crystallizers of dextrose monohydrate: From laboratory experiments to industrial application

09 Jun 2023 | 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 | 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 review of emerging technologies enabling improved solid oral dosage form manufacturing and processing

09 Jun 2023 | 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 Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing

09 Jun 2023 | 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 | 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 Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation

09 Jun 2023 | 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 | 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 | 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...

An agile and robust in-line NIR potency deviation detection method for monitoring and control of a continuous direct compression process

09 Jun 2023 | Contributor(s): Alam, Md Anik, Liu, Yang Angela

Near Infrared (NIR) method for blend potency estimation has been commonly used as an essential tool for process monitoring and control in continuous manufacturing of solid oral dosage forms. Robustness has been the main challenge for successful application of an NIR method, which often results in...

An engineering study on the enhanced control and operation of continuous manufacturing of pharmaceutical tablets via roller compaction

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

A novel manufacturing strategy based on continuous processing integrated with online monitoring tools coupled with efficient automatic feedback control system is highly desired for efficient Quality by Design (QbD) based manufacturing ofthe next generation of pharmaceutical products with optimal...

Anti-fouling control of plug-flow crystallization via heating and cooling cycle

09 Jun 2023 | Contributor(s): Koswara, Andy, Nagy, Zoltan K.

Plug-flow crystallization (PFC) is a promising continuous pharmaceutical crystallization process but is prone to fouling due to uncontrolled crystallization on the reactor surface (encrustation). This results in operational issues such as (1) flow blockage, (2) increased thermal resistance, and...

Application of FT-NIR Analysis for In-line and Real-Time Monitoring of Pharmaceutical Hot Melt Extrusion: a Technical Note

09 Jun 2023 | Contributor(s): Vo, Anh Q., He, Herman, Zhang, Jiaxiang, Martin, Scott, Chen, Rui, Repka, Michael A.

Continuous manufacturing, a gaining interest paradigm in the pharmaceutical industry, requires in-process monitoring of critical process parameters to ensure product consistency. This study demonstrated the application of Fourier transform near-infrared (FT-NIR) spectroscopy in conjunction with...

Application of Model-Free and Model-Based Quality-by-Control (QbC) for the Efficient Design of Pharmaceutical Crystallization Processes

09 Jun 2023 | Contributor(s): Szilagyi, Botond, Eren, Ayse Quon, Justin L. Papageorgiou, Charles D., Nagy, Zoltan K.

The design of pharmaceutical crystallization processes is a challenging engineering problem because of the specific and versatile quality requirements of the end-product, amplified by the tight regulatory standards. The current industrial standard for crystallization process design is based on...

Application of process analytical technology-based feedback control for the crystallization of pharmaceuticals in porous media

09 Jun 2023 | Contributor(s): Acevedo, David A., Ling, Jing Chadwick, Keith, Nagy, Zoltak K. ;

The purpose of this work is to implement a feedback control approach during the cooling crystallization of paracetamol (PCM) in porous media to increase the amount of PCM in the alginate beads (i.e., drug loading) and minimize the heterogeneous nucleation occurring in the bulk system. Two types...

Approach to establishment of control strategy for oral solid dosage forms using continuous manufacturing

09 Jun 2023 | Contributor(s): Ishimoto, Hayato, Kano, Manabu, Sugiyama, Hirokazu, Takeuchi, Hirofumi, Terada, Katsuhide, Aoyama, Atsushi, Shoda, Takuji, Demizu, Yosuke, Shimamura, Jinen, Yokoyama, Reiji, Miyamoto, Yuji, Hasegawa, Koji, Serizawa, Masaru, Unosawa, Kazuomi, Osaki, Kazuo, Asai, Naochika, Matsuda, Yoshihiro

As a result of the Research Article activities of the Japan Agency for Medical Research Article and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology...

Characterization of Near-Infrared and Raman Spectroscopy for In-Line Monitoring of a Low-Drug Load Formulation in a Continuous Manufacturing Process

09 Jun 2023 | Contributor(s): Harms, Zachary, Shi, Zhenqi: Kulkarni, Rajesh, Myers, David P.

Reflectance spectroscopy is an excellent candidate for process analytical technology (PAT) applications in continuous manufacturing of pharmaceutical tablets. Spectroscopic methods provide a real-time, nondestructive measurement of the active pharmaceutical ingredient (API) concentration in order...

Comparative investigation of supersaturation and automated direct nucleation control of crystal size distributions using ATR-UV/vis spectroscopy and FBRM

09 Jun 2023 | Contributor(s): Saleemi, Ali N., Rielly, Chris D., Nagy, Zoltan K.

The paper presents a thorough evaluation of different control strategies used in cooling crystallization, namely, unseeded linear cooling, seeded linear cooling, supersaturation control, and automated direct nucleation control. The sensitivity and robustness of supersaturation and automated...

Comparative performance of concentration and temperature controlled batch crystallizations

09 Jun 2023 | Contributor(s): Nagy, Zoltan K., Chew, Jia W. Fujiwara, Mitsuko, Braatz, Richard D.

An increased interest has been directed towards the crystallization of pharmaceuticals and proteins in recent years, which have additional complications compared to the extensively studied inorganic batch and continuous crystallizations. Recent advances in process analytical technology have...