A modeling and control framework for extraction processes

05 Sep 2024 | Peer-reviewed journal | Contributor(s): Peter Neugebauer, Jakob Rehrl, Peter Poechlauer, Dirk Kirschneck, Martin Horn, Martin Steinberger, Stephan Sacher, Joscha Boehm, Daniel Moser

Many continuously operated pharmaceutical process routes have been presented recently. Most of these cover the synthesis of the active pharmaceutical ingredient (API) or solid dosage processing. However, the API purification is also gaining attraction. One widespread and waste-intensive unit...

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 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 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 Real-Time Process Analytics for Multistep Synthesis in Continuous Flow

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sagmeister, Peter, Lebl, René, Castillo, Ismael, Rehrl, Jakob, Kruisz, Julia, Sipek, Martin, Horn, Martin, Sacher, Stephan, Cantillo, David, Williams, Jason D, Kappe, Oliver

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and...

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

09 Jun 2023 | Peer-reviewed journal | 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 Ultra-Performance Liquid Chromatography as an Online Process Analytical Technology Tool in Pharmaceutical Crystallization

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Yang, Yang, Zhang, Chuntao Pal, Kanjakha Koswara, Andy, Quon, Justin, Mckeown, Rahn, Goss, Charles, Nagy, Zoltan K

Concentration is often an important process parameter in pharmaceutical crystallization processes. In this work, an ultra-performance liquid chromatography (UPLC) system designed for process monitoring (Waters PATROL UPLC) was applied online as a process analytical technology tool for real-time...

Assessment of blend uniformity in a continuous tablet manufacturing process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sierra-Vega, Nobel, Román-Ospino, Andrés, Scicolone, James, Muzzio, Fernando, Romañach, Rodolfo, Mendez, Rafael

Blend uniformity was monitored throughout a continuous manufacturing (CM) process by near infrared (NIR) spectroscopic measurements of flowing blends and compared to the drug concentration in the tablets. The NIR spectra were obtained through the chute after the blender and within the feed frame,...

Characterization of NIR interfaces for the feeding and in-line monitoring of a continuous granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Román-Ospino, Andrés D, Tamrakar, Ashutosh Igne, Benoît Dimaso, Elyse Towns Airiau, Christian Clancy, Donald J Pereira, Glinka Muzzio, Fernando J Singh, Ravendra, Ramachandran, Rohit

This work describes the characterization of three NIR interfaces intended to monitor a continuous granulation process. Two interfaces (i.e. a barrel interface and a rotating paddle interface) were evaluated to monitor the API concentration at the entrance of the granulator, and a third interface...

Closed-loop feedback control of a continuous pharmaceutical tablet manufacturing process via wet granulation

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

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...

Compact NMR Spectroscopy for Automated Continuous-Flow Production of Chemicals and Pharmaceuticals (On-Demand)

31 Jan 2024 | Seminars | Contributor(s): Klas Meyer

Chemical companies are under constant pressure to improve productivity while cutting costs. Flexible and modular chemical plants can produce high-quality products using multi-purpose equipment with short downtimes, reducing time to market for new products. Intensified continuous production...

Continuous Manufacturing in the Pharmaceutical Industry: Enhancing Drug Production

23 Jul 2024 | Website | Contributor(s): Timmerman, Siebe

A significant shift towards continuous manufacturing (CM) is currently underway in the pharmaceutical industry. Unlike the more commonly used batch processing, CM operates continuously. This method potentially offers increased efficiency, agility, and flexibility in the manufacturing of drug...

Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Ng, DZL, Nelson, AZWard, G, Lai, D, Doyle, PS, Khan, SA

Purpose Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients(APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the...

Control strategy and methods for continuous direct compression processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Suzuki, Yasuhiro, Sugiyama, Hirokazu, Kano, Manabu, Shimono, Ryutaro, Shimada, Gosuke, Furukawa, Ryoichi, Mano, Eichi, Motoyama, Keiichi, Koide, Tatsuo, Matsui, Yasuhiro, Kurasaki, Kazuki, Takayama, Issei, Hikage, Shunin, Katori, Noriko, Kikuchi, Masahiko, Sakai, Hiroshi, Matsuda, Yoshihiro

We presented a control strategy for tablet manufacturing processes based on continuous direct compression. The work was conducted by the experts of pharmaceutical companies, machine suppliers, academia, and regulatory authority in Japan. Among different items in the process, the component ratio...

Crystal shape and size control using a plug flow crystallization configuration

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sang-Il Kwon, Joseph, Nayhouse, Michael Orkoulas, Gerassimos

This work focuses on modeling and control of a continuous plug flow crystallizer (PFC) used to produce tetragonal hen-egg-white (HEW) lysozyme crystals and proposes an optimization-based control scheme to produce crystals with desired size and shape distributions in the presence of disturbances....

Determination of Residence Time Distribution in a Continuous Powder Mixing Process With Supervised and Unsupervised Modeling of In-line Near Infrared (NIR) Spectroscopic Data

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Pedersen, Troels, Karttunen, Anssi-Pekka, Korhonen, Ossi, Wu, Jian Xiong, Naelapää, Kaisa, Skibsted, Erik, Rantanen, Jukka

Successful implementation of continuous manufacturing processes requires robust methods to assess and control product quality in a real-time mode. In this study, the residence time distribution of a continuous powder mixing process was investigated via pulse tracer experiments using near infrared...

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGmaTM-25: Part 2 Granule Size

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Selma Celikovic, Johannes Poms, Johannes Khinast, Martin Horn, Jakob Rehrl

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of...

Development of a Controlled Continuous Low-Dose Feeding Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Fathollahi, Sara, Kruisz, Julia, Sacher, Stephan, Rehrl, Jakob, Escotet-Espinoza, M. Sebastian, DiNunzio, James, Glasser, Benjamin J., Khinast, Johannes G.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum...

Development of an In-Line Near-Infrared Method for Blend Content Uniformity Assessment in a Tablet Feed Frame

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Li, Yi, Anderson, Carl A, Drennen, James K, Airiau, Christian, Igne, Benoît

Process analytical technology (PAT) has shown great potential for in-line tableting process monitoring. The study focuses on the development and validation of an in-line near-infrared (NIR) spectroscopic method for the determination of content uniformity of blends in a tablet feed frame. An...

Development of Near Infrared Spectroscopy-based Process Monitoring Methodology for Pharmaceutical Continuous Manufacturing Using an Offline Calibration Approach

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Hetrick, Evan, Barnes, Lukas E, Garrett, Aaron W, Rupard, Robert G, Kramer, Timothy T, Cooper, Tony M, Myers, David P, Shi, Zhenqi, Castle, Bryan C

A near-infrared (NIR) calibration was developed using an efficient offline approach to enable a quantitative partial least-squares (PLS) chemometric model to measure and monitor the concentration of active pharmaceutical ingredients (API) in powder blends in the feed frame (FF) of a tablet press....

Direct compaction: An update of materials, trouble-shooting, and application

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Li, Z, Zhao, LJLin, X, Shen, L, Feng, Y

Direct compaction (DC) is the preferred choice for tablet manufacturing; however, only less than 20% of active pharmaceutical ingredients could be compacted via DC as its high requirement for functional properties of materials. Materials with improper functionalities could lead to serious...

Ensuring tablet quality via model-based control of a continuous direct compaction process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Kirchengast, M, Celikovic, SRehrl, J, Sacher, S, Kruisz, J, Khinast, J, Horn, M

Switching from batch to continuous pharmaceutical production offers several advantages, such as an increased productivity, a steady product quality, and decreased costs. This paper presents a control strategy for direct compaction on a continuous tablet production line consisting of two feeders,...

Exceptional Events Management Applied to Roller Compaction of Pharmaceutical Powders

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Hamdan, Intan Munirah, Reklaitis, Gintaras V., Venkatasubramanian, Venkat

Introduction This study focuses on the development and implementation of an Exceptional Events Management (EEM) framework that detects, diagnoses, and mitigates exceptional events inherent to particulate processes that are prevalent in the pharmaceutical industry. Methods The EEM framework...

Experimental determination of residence time distribution in continuous dry granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mangal, Haress, Kleinebudde, Peter

With increasing importance of continuous manufacturing, the interest in integrating dry granulation into a continuous manufacturing line is growing. Residence time distribution measurements are of importance as they provide information about duration of materials within the process. These data...

From powder to tablets: Investigation of residence time distributions in a continuous manufacturing process train as basis for continuous process verification

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Pauli, Victoria, Kleinebudde, Peter, Krumme, Markus

The essence of Continuous Manufacturing (CM) resides in the fact that continuous process units are directly connected to each other forming a continuous process train. The thorough understanding of material flow in this train based on suitable sensors, including on-line process analytical...