Using online mass spectrometry to predict the end point during drying of pharmaceutical products

09 Jun 2023 | Contributor(s): Dodda, Aditya G., Saranteas, Kostas, Henson, Michael A.

Drying of active pharmaceutical ingredients (APIs) is an energy-intensive process that is often a manufacturing bottleneck due to the relatively long processing times. A key objective is the ability to determine the drying end point, the time at which all solvent has been evaporated from the...

Towards a novel continuous HME-Tableting line: Process development and control concept

09 Jun 2023 | Contributor(s): Sacher, Stephan, Celikovic, Selma, Rehrl, Jakob, Poms, Johannes, Kirchengast, Martin, Kruisz, Julia, Sipek, Martin, Salar-Behzadi, Sharareh, Berger, Hannes, Stark, Gerald, Horn, Martin, Khinast, Johannes G.

The objective of this study was to develop a novel closed-loop controlled continuous tablet manufacturing line, which first uses hot melt extrusion (HME) to produce pellets based on API and a polymer matrix. Such systems can be used to make complex pharmaceutical formulations, e.g., amorphous...

The Changing Face of Process Development & Chemical Manufacturing - A View from the Regulators on Continuous Manufacturing

09 Jun 2023 | Contributor(s): Wiles, Charolotte

Industry wide there is a drive for resource efficiency and flexibility, to adapt quickly in what is increasingly becoming a volatile, changing marketplace. As the ‘patent cliff’ looms for many high-volume API’s, there is also a shift away from blockbusters towards lower volume, higher potency...

System-wide hybrid MPC–PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction

09 Jun 2023 | Contributor(s): Singh, Ravendra, Ierapetritou, Marianthi, Ramachandran, Rohit

The next generation of QbD based pharmaceutical products will be manufactured through continuous processing. This will allow the integration of online/inline monitoring tools, coupled with an efficient advanced model-based feedback control systems, to achieve precise control of process variables,...

Solvothermal Crystallization Kinetics and Control of Crystal Size Distribution of MOF-808 in a Continuous Flow Reactor

09 Jun 2023 | Contributor(s): Bagi, Sujay D., Myerson, Allan S. Román-Leshkov, Yuriy, Román-Leshkov, Yuriy

A fundamental understanding of the crystallization pathways for metal-organic frameworks (MOFs) allows for exploring the untapped combinatorial space of the organic and inorganic building units, creating possibilities to synthesize highly crystalline frameworks with desired physicochemical...

Selective crystallization of the metastable α-form of L-glutamic acid using concentration feedback control

09 Jun 2023 | Contributor(s): Kee, Nicholas C.S., Tan, Reginald B.H. Braatz, Richard D., Braatz, Richard D.

A systematic methodology is presented for the selective crystallization of the metastable form of a monotropic dimorph, L-glutamic acid, for batch cooling crystallization. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics was used to...

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and sustainable Fine-Chemical Manufacturing

09 Jun 2023 | Contributor(s): Morin, Mathieu, Zhang, Wenyao, Mallik, Debasis, Organ, Michael G

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through...

Robust nonlinear model predictive control of batch processes

09 Jun 2023 | Contributor(s): Nagy, Zoltan K., Braatz, Richard D.

NMPC explicitly addresses constraints and nonlinearities during the feedback control of batch processes. This NMPC algorithm also explicitly takes parameter uncertainty into account in the state estimation and state feedback controller designs. An extended Kalman filter estimates the process...

Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process

09 Jun 2023 | Contributor(s): Bhaskar, Aparajith, Singh, Ravendra

Real-Time Monitoring of Powder Mass Flowrates for Plant-Wide Control of a Continuous Direct Compaction Tablet Manufacturing Process

09 Jun 2023 | Contributor(s): Huang, Yan-Shu, Medina-González, Sergio Straiton, Benjamin Keller, Joshua, Marashdeh, Qussai, Gonzalez, Marcial, Nagy, Zoltan, Reklaitis, Gintaras V.

While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the...

Real-time process monitoring in a semi-continuous fluid-bed dryer - microwave resonance technology versus near-infrared spectroscopy

09 Jun 2023 | Contributor(s): Peters, Johanna, Teske, Andreas, Taute, Wolfgang, Döscher, Claas, Höft, Michael, Knöchel, Reinhard, Breitkreutz, Jörg

The trend towards continuous manufacturing in the pharmaceutical industry is associated with an increasing demand for advanced control strategies. It is a mandatory requirement to obtain reliable real-time information on critical quality attributes (CQA) during every process step as the decision...

Real time monitoring of powder blend bulk density for coupled feed-forward/feed-back control of a continuous direct compaction tablet manufacturing process

09 Jun 2023 | Contributor(s): Singh, Ravendra, Román-Ospino, Andrés D. Romañach, Rodolfo J. Ierapetritou, Marianthi, Ramachandran, Rohit

The pharmaceutical industry is strictly regulated, where precise and accurate control of the end product quality is necessary to ensure the effectiveness of the drug products. For such control, the process and raw materials variability ideally need to be fed-forward in real time into an automatic...

Real-time feasible model-based crystal size and shape control of crystallization processes

09 Jun 2023 | Contributor(s): Szilagyi, Botond, Nagy, Zoltan K.

The simultaneous control of crystal size and shape is particularly important in fine chemical and pharmaceutical crystallization. These two quantities influence the dissolution rate and bioavailability of final drug products, and also contribute to the manufacturability and efficiency of...

Process scheduling under uncertainty : Review and challenges

09 Jun 2023 | Contributor(s): Li, Zukui, Ierapetritou, Marianthi

Uncertainty is a very important concern in production scheduling since it can cause infeasibilities and production disturbances. Thus scheduling under uncertainty has received a lot of attention in the open literature in recent years from chemical engineering and operations research communities....

Process Control of Drug Product Continuous Manufacturing Operations - a Study in Operational Simplification and Continuous Improvement

09 Jun 2023 | Contributor(s): Medendorp, Joseph, Shapally, Sreendhar, Vrieze, Derek, Tolton, Kelly

Purpose The purpose of this manuscript is to demonstrate that implementation of gravimetric measurements provides the same assurance of product quality and process control as spectroscopic measurements (1) for control of drug content in a fixed-dose combination (FDC) tablet and (2) for...

Prediction and control of crystal shape distribution in the presence of crystal growth modifiers

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Majumder, Aniruddha, Nagy, Zoltan K

The crystal product quality, functionality and properties such as flow characteristics are greatly influenced by the crystal size and shape distributions. Hence, prediction and control of crystal size and shape distributions are important from the viewpoint of smooth operation and product...

Predictive Model-Based Process Start-Up in Pharmaceutical Continuous Granulation and Drying

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

Continuous manufacturing (CM) is a promising strategy to achieve various benefits in the context of quality, flexibility, safety and cost in pharmaceutical production. One of the main technical challenges of CM is that the process needs to handle transient conditions such as the start-up phase...

pH and Conductivity Control in an Integrated Biomanufacturing Plant

09 Jun 2023 | Workshop | Contributor(s): Lu, Amos E, Paulson, Joel A Braatz, Richard D, Fellow, Ieee

This paper designs pH and conductivity control systems for a biomanufacturing platform that specializes in the production of biologically derived medicines on demand. Dynamic models and control strategies are presented for a buffer mixing unit that must produce high quality buffers for use within...

PAT implementation for advanced process control in solid dosage manufacturing - A practical guide

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sacher, Stephan, Poms, Johannes, Rehrl, Jakob, Khinast, Johannes G.

The implementation of continuous pharmaceutical manufacturing requires advanced control strategies rather than traditional end product testing or an operation within a small range of controlled parameters. A high level of automation based on process models and hierarchical control concepts is...

Optimal Dynamic Continuous Manufacturing of Pharmaceuticals with Recycle

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Patrascu, Michael, Barton, Paul I.

Continuous manufacturing of pharmaceuticals is challenged by short campaigns due to the low volume of some products. This calls for optimization of the entire dynamic campaign to achieve the highest overall yields and productivity and to minimize waste. In this paper, we investigate how recycles...

ON-OFF Feedback Control of Plug-Flow Crystallization: A Case of Quality-by-Control in Continuous Manufacturing

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

Plug-flow crystallization (PFC) is a promising candidate to realizing the paradigm shift from batch-to-continuous pharmaceutical manufacturing. While PFC has been recently touted as the ideal continuous crystallizer due to its compact design, proper mixing, and flexible cooling and antisolvent...

Nucleation kinetics of paracetamolethanol solutions from metastable zone widths

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mitchell, Niall A., Frawley, Patrick J.

A study of the nucleation kinetics for a cooling crystallisation of paracetamolethanol solutions in a batch reactor is described in this paper. Metastable zone width (MSZW) experiments were conducted in order to estimate the nucleation kinetics of the system. Measured MSZWs can be affected by...

Nucleation kinetics of polymorphs: Induction period and interfacial energy measurements

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Teychené, S., Biscans, B.

Nucleation kinetics of eflucimibe polymorphs have been investigated in ethanol and n-heptane mixture. The two eflucimibe polymorphs, A and B, crystallize concomitantly for a wide range of operating conditions. The effects of supersaturation on the nucleation rates of the two existing polymorphs...

Nucleation Studies of Active Pharmaceutical Ingredients in an Air-Segmented Microfluidic Drop-Based Crystallizer

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Lu, Jennifer, Litster, James D., Nagy, Zoltan K.

In this work, an innovative experimental platform to study the nucleation behavior of an active pharmaceutical ingredient (API) using a gas-segmented flow produced by a microfluidic T-junction device with fine perfluoroalkoxy alkane (PFA) tubing is presented. In the experiments, a continuous...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and in Situ Control of Downstream Production

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Capellades, Gerard, Neurohr, Clemence Briggs, Naomi Rapp, Kersten, Hammersmith, Gregory, Brancazio, David, Derksen, Bridget, Myerson, Allan S.

Traditional pharmaceutical manufacturing operates around a supply chain that is subject to complex logistics and is vulnerable to spikes in demand and interruptions. In this context, continuous pharmaceutical manufacturing in portable, refrigerator-sized factories is a promising solution with...