Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis

09 Jun 2023 | Contributor(s): Madarasz, L, Kote, AGyurkes, M, Farkas, A, Hambalko, B, Pataki, H, Fulop, G, Marosi, G, Lengyel, L, Casian, T, Csorba, K, Nagy, ZK

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles...

Using a material property library to find surrogate materials for pharmaceutical process development

09 Jun 2023 | Contributor(s): Escotet-Espinoza, MS, Moghtadernejad, SScicolone, J, Wang, YF, Pereira, G, Schafer, E, Vigh, T, Klingeleers, D, Ierapetritou, M, Muzzio, FJ

Material properties are known to have a significant impact on pharmaceutical manufacturing performance, particularly for solid product processes. Evaluating the performance of a specific material, for example an active pharmaceutical ingredient or excipient, is critical during development stages...

Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review

09 Jun 2023 | Contributor(s): Bhalode, Pooja, Tian, Huayu Gupta, Shashwat Razavi, Sonia M Roman-Ospino, Andres Talebian, Shahrzad Singh, Ravendra Scicolone, James V Muzzio, Fernando J, Ierapetritou, Marianthi

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA’s support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber,...

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...

Simplified end-to-end continuous manufacturing by feeding API suspensions in twin-screw wet granulation

09 Jun 2023 | Contributor(s): Schmidt, A, de, Waard, HMoll, KP, Kleinebudde, P, Krumme, M

This study focussed on investigating the coupling of continuous manufacturing of drug substance and continuous manufacture of drug product. An important step in such an integrated end-to-end continuous manufacturing was envisioned by dosing the API as suspension into a twin-screw wet granulation...

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

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...

Quality Risk Assessment and Mitigation of Pharmaceutical Continuous Manufacturing Using Flowsheet Modeling Approach

09 Jun 2023 | Contributor(s): Tian, Geng;, Koolivand, Abdollah, Arden, Nilou S., Lee, Sau, O'Connor, Thomas F.

Integrated flowsheet modeling is an engineering approach that can provide a framework for understanding the impact of process dynamics on drug quality and associated risks during production, thereby facilitating the development of robust continuous processes. In this investigation, flowsheet...

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 modi fi ers

09 Jun 2023 | 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 quality...

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

09 Jun 2023 | 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...

Powder composition monitoring in continuous pharmaceutical solid-dosage form manufacturing using state estimation-Proof of concept

09 Jun 2023 | Contributor(s): Destro, Francesco, Munoz, Salvador Garcia, Bezzo, Fabrizio, Barolo, Massimiliano

In continuous solid-dosage form manufacturing, the powder feeding system is responsible for supplying downstream the correct formulation of the drug product ingredients. The composition of the powder delivered by the feeding system is inferred from the measurements of powder mass flow from the...

pH and Conductivity Control in an Integrated Biomanufacturing Plant

09 Jun 2023 | 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...