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 review of PAT strategies in secondary solid oral dosage manufacturing of small molecules

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Laske, Stephan, Paudel, Amrit, Scheibelhofer, Otto, Sacher, Stephan, Hoermann, Theresa, Khinast, Johannes, Kelly, Adrian, Rantannen, Jukka, Korhonen, Ossi, Stauffer, Fanny, De Leersnyder, Fien, De Beer, Thomas, Mantanus, Jerome, Chavez, Pierre-Francois, Thoorens, Benjamin, Ghiotti, Patrizia, Schubert, Martin, Tajarobi, Pirjo, Haeffler, Gunnar, Lakio, Satu, Fransson, Magnus, Sparen, Anders, Abrahmsen-Alami, Susanna, Folestad, Staffan, Funke, Adrian, Backx, Ivo, Kavsek, Barbara, Kjell, Francois, Michaelis, Marc, Page, Trevor, Palmer, John, Schaepman, Alexander, Sekulic, Sonja, Hammond, Steve, Braun, Birgit, Colegrove, Brenda

Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological and mathematical) methods for material (e.g. materials,...

A sampling system for flowing powders based on the theory of sampling

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Alvarado-Hernández, Bárbara B, Sierra-Vega, Nobel O, Martínez-Cartagena, Pedro, Hormaza, Manuel, Méndez, Rafael, Romañach, Rodolfo J.

An innovative chute and stream sampler system for flowing powders has been developed and tested. The system is designed for representative sampling based on the principles of the Theory of Sampling (TOS). The sampling system was used in combination with near infrared (NIR) spectroscopy to...

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...

An Innovative Sampling Interface for Monitoring Flowing Pharmaceutical Powder Mixtures

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Martínez-Cartagena, Pedro, Romañach, Rodolfo J., Sierra-Vega, Nobel O; Alvarado-Hernández, Bárbara B; Méndez, Rafael

A chute was designed following the principles of the Theory of Sampling to minimize the variations in powder flow and provide all particles in the flowing blends with the same opportunity of being selected as a sample. The design also reduces the thickness of the chute to allow the analysis of a...

Analysis of powder phenomena inside a Fette 3090 feed frame using in-line NIR spectroscopy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mateo-Ortiz Daniel, Colon, Yleana, Romañach, Rodolfo, Mendez, Rafael

New analytical methods are needed to understand and optimize the processes by which tablets are produced. Fette 3090 tablet presses are commonly used in the pharmaceutical industry. A near-infrared (NIR) probe was installed into a Fette 3090 feed frame to understand and monitor the die filling...

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,...

Assessment of Robustness for a Near-Infrared Concentration Model for Real-Time Release Testing in a Continuous Manufacturing Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Colon, Yleana, Vargas, Jenny, Sánchez, Eric, Navarro, Gilfredo, Romañach, Rodolfo

This study describes the robustness test of a transmission near-infrared spectroscopic (NIRS) model for prediction of drug concentration in core tablets as part of real-time release testing (RTRt) efforts for a continuous manufacturing process. Seven calibration blend samples were prepared...

Challenges, opportunities and recent advances in near infrared spectroscopy applications for monitoring blend uniformity in the continuous manufacturing of solid oral dosage forms

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Velez, Natasha L., Drennen, James K., Anderson, Carl A.

Near infrared (NIR) spectroscopy has been widely recognized as a powerful PAT tool for monitoring blend uniformity in continuous manufacturing (CM) processes. However, the dynamic nature of the powder stream and the fast rate at which it moves, compared to batch processes, introduces challenges...

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 | Peer-reviewed journal | 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...

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...

Cleaning of direct compression continuous manufacturing equipment through displacement of API residues by excipients

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Patel, Dhavalkumar S, Méndez, Rafael, Romañach, Rodolfo J

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning...

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...

Comparison Between Pure Component Modeling Approaches for Monitoring Pharmaceutical Powder Blends with Near‑Infrared Spectroscopy in Continuous Manufacturing Schemes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Rish, Adam J., Henson, Samuel R., Alam, Md. Anik, Liu, Yang, Drennen, James K., Anderson, Carl A.

Near-infrared (NIR) spectroscopy has become an important process analytical technology (PAT) for monitoring and implementing control in continuous manufacturing (CM) schemes. However, NIR requires complex multivariate models to properly extract the relevant information and the traditional model...

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...

Continuous quantitative monitoring of powder mixing dynamics by near-infrared spectroscopy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Koller, DM, Posch, A, Horl, G, Voura, C, Radl, S, Urbanetz, N, Fraser, SD, Tritthart, W, Reiter, F, Schlingmann, M, Khinast, JG

FT-NIR spectroscopy with a fiber optical reflection probe was applied as a process analytical technology tool for the continuous quantitative in-line monitoring of pharmaceutical powder mixing processes in a bladed mixer. Two powders, acetyl salicylic acid as an active pharmaceutical ingredient...

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 of three different continuous pharmaceutical manufacturing processes: Use of soft sensors

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Rehrl, J, Karttunen, APNicolai, N, Hormann, T, Horn, M, Korhonen, O, Nopens, I, De, Beer, T, Khinast, JG

One major advantage of continuous pharmaceutical manufacturing over traditional batch manufacturing is the possibility of enhanced in-process control, reducing out-of-specification and waste material by appropriate discharge strategies. The decision on material discharge can be based on 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...