A framework of hybrid model development with identification of plant-model mismatch

09 Jun 2023 | Contributor(s): Chen, Yingjie, Ierapetritou, Marianthi

Abstract Hybrid modeling has attracted increasing attention in order to take advantage of the additional data to improve process understanding. Current practice often adopts mechanistic models to predict process behaviors. These mechanistic models are based on physical understandings and...

A hybrid model for multipoint real time potency observation in continuous direct compression manufacturing operations

09 Jun 2023 | Contributor(s): Gallo-Molina, Juan Pablo, Cogoni, Giuseppe, Peeters, Elisabeth, Rao Ambati, Seshagiri, Nopens, Ingmar

The ongoing transition from batch to continuous manufacturing offers both challenges and opportunities in the field of oral solid dosage form production. In turn, Process Analytical Technology (PAT) offers a path towards the successful deployment of continuous tablet manufacturing in rotary...

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 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 New Software Framework for Implementing Crystal Growth Models to Materials of Any Crystallographic Complexity

09 Jun 2023 | Contributor(s): Zhao, Yongsheng, Tilbury, Carl J. Landis, Steven Sun, Yuanyuan, Li, Jinjin, Zhu, Peng, Doherty, Michael F.

To continue the realization of new therapeutics, a more diverse range of solid forms is being considered. Synthetic modalities are broadening beyond simple organic molecules to more complicated structures, including organic salts, cocrystals, and solvates. As in all crystalline applications,...

A Novel Integrated Workflow for Isolation Solvent Selection Using Prediction and Modeling

09 Jun 2023 | Contributor(s): Ottoboni, S, Wareham, BVassileiou, A, Robertson, M, Brown, CJ, Johnston, B, Price, CJ

A predictive tool was developed to aid process design and to rationally select optimal solvents for isolation of active pharmaceutical ingredients. The objective was to minimize the experimental work required to design a purification process by (i) starting from a rationally selected...

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

09 Jun 2023 | 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 Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate

09 Jun 2023 | Peer-reviewed journal | Contributor(s): O'Mahony, M, Leung, AKFerguson, S, Trout, BL, Myerson, AS

A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at <= 106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so...

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 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 Stochastic Population Balance Equation Model for Nucleation and Growth of Crystals with Multiple Polymorphs

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Maggioni, Giovanni, Mazzotti, Marco

Understanding polymorph crystallization is important due to the different properties, such as bioavailability or crystal shape, exhibited by the different crystal forms. In this work, we present a model, based on population balance equations, describing the unseeded crystallization by cooling of...

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Urwin, SJ, Levilain, GMarziano, I, Merritt, JM, Houson, I, Ter;Horst, JH

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to...

A Systematic Framework for Data Management and Integration in a Continuous Pharmaceutical Manufacturing Processing Line

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cao, Huiyi, Mushnoori, Srinivas, Higgins, Barry, Kollipara, Chandrasekhar, Fermier, Adam, Hausner, Douglas, Jha, Shantenu, Singh, Ravendra, Ierapetritou, Marianthi, Ramachandran, Rohit

As the pharmaceutical industry seeks more efficient methods for the production of higher value therapeutics, the associated data analysis, data visualization, and predictive modeling require dependable data origination, management, transfer, and integration. As a result, the management and...

A systematic reactor design approach for the synthesis of active pharmaceutical ingredients

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Emenike, VN, Schenkendorf, R, Krewer, U

Today's highly competitive pharmaceutical industry is in dire need of an accelerated transition from the drug development phase to the drug production phase. At the heart of this transition are chemical reactors that facilitate the synthesis of active pharmaceutical ingredients (APIs) and whose...

A very boring 120 h: 15million tablets under a continuous state of control

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Holman, James, Tantuccio, Anthony, Palmera, Jhon, Doninck, Tom van, Meyer, Robert

The aimof this study is to showthe robustness of a commercial direct compression system running continuously under relevant process conditions for over 120 h. The study will apply a representative commercial control strategy including real time monitoring of process parameters, rejection of OOS...

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...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Byrn, Stephen, Futran, Maricio, Thomas, Hayden, Jayjock, Eric, Maron, Nicola, Meyer, Robert F., Myerson, Allan S., Thien, Michael P., Trout, Bernhardt L.

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to...

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20-21, 2014 Continuous Manufacturing Symposium

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Baxendale, IR, Braatz, RDHodnett, BK, Jensen, KF, Johnson, MD, Sharratt, P, Sherlock, JP, Florence, AJ

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for...

Active pharmaceutical ingredient (API) production involving continuous processes - A process systems engineering (PSE)-assisted design framework

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cervera-Padrell, AE, Skovby, TKiil, S, Gani, R, Gernaey, KV

A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and...