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 PAT-based qualification of pharmaceutical excipients produced by batch or continuous processing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Hertrampf A., Müller H., Menezes J.C., Herdling T.

Pharmaceutical excipients have an influence on the main requirements for medicinal products (viz., quality, safety and efficacy) but also on their manufacturability. During product lifecycle it may become necessary to introduce minor changes (e.g., to continuously improve it) or major changes in...

A Perspective on Quality by Design: A Preclinical Opportunity

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

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 Shared Vision for Pharmaceutical Development and Manufacturing in the 21st Century: Contributions of the PAT Initiative

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

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

09 Jun 2023 | Peer-reviewed journal | 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 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...

An Overview of Pharmaceutical Manufacturing for Solid Dosage Forms

09 Jun 2023 | Chapter Book | Contributor(s): Sacher, Stephan, Khinast, Johannes G.

In this chapter, the main processing steps and manufacturing aspects of solid dosage forms are described and the relevant literature is reviewed. Starting with powder feeding, powder blending, granulation (dry and wet), and drying the most important unit operations to make compactable granules...

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 Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Zhang, Haitao, Lakerveld, Richard, Heider, Patrick, Tao, Mengying, Su, Min, Testa, Christopher, D’Antonio, Alyssa, Barton, Paul, Braatz, Richard, Trout, Bernhardt, Myerson, Allan, Jensen, Klavs, Evans, James

Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated continuous manufacturing (ICM) of pharmaceuticals. However, appropriate selection of PAT tools is challenging, and the design and operation of...

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 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 Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Simon, Levente L, Pataki, Hajnalka, Marosi, György, Meemken, Fabian, Hungerbühler, Konrad, Baiker, Alfons, Tummala, Srinivas, Glennon, Brian, Kuentz, Martin, Steele, Gerry, Kramer, Herman J. M, Rydzak, James W.

This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in...

At-line monitoring of salification process of the antiretroviral lamivudine-saccharinate salt using FT-MIR spectroscopy with multivariate curve resolution

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mazivila, SJ, Castro, RAELeitao, JMM, da;Silva, JCGE

This article presents a promising application of Fourier transform-mid infrared (FT-MIR) spectroscopy with multivariate curve resolution - alternating least-squares (MCR-ALS) as an at-line process analytical technology (PAT) to enhancing the understanding and continuous control of a...

Benchtop NIR method development for continuous manufacturing scale to enable efficient PAT application for solid oral dosage form

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Alam, MA, Liu, YADolph, S, Pawliczek, M, Peeters, E, Palm, A

A Near Infrared (NIR) method was developed using a small benchtop feed frame system to quantify Saccharin potency in a powder blend during continuous manufacturing process. A 15-point Design of Experiments (DoE) was created based on the NIR spectral response and compositions of the formulation to...

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...

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...

Combined feedforward/feedback control of an integrated continuous granulation process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Pereira, Glinka Cathy, Muddu, Shashank Venkat Román-Ospino, Andrés David Clancy, Don Igne, Benoit Airiau, Christian Muzzio, Fernando J Ierapetritou, Marianthi Ramachandran, Rohit, Singh, Ravendra

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical...