Critical review on the role of excipient properties in pharmaceutical powder-to-tablet continuous manufacturing

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bastiaan H. J. Dickhoff, Henderik W. Frijlink

The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of...

Process intensification of pharmaceutical powder blending at commercial throughputs by utilizing semi-continuous mini-blending

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Maarten Jaspers, Florian Tegel, Timo P. Roelofs, Fabian Starsich, Yunfei Li Song, Bernhard Meir, Richard Elkes, Bastiaan H.J. Dickhoff

Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often...

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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Engisch, William, Muzzio, Fernando

Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing,...

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

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

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Baumann, M, Baxendale, IR

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient...

The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): McAuliffe M.A.P., Omahony G.E., Blackshields C.A., Collins J.A., Egan D.P., Kiernan L., Oneill E., Lenihan S., Walker G.M., Crean A.M.

Real-time process monitoring using process analytical technology (PAT) tools can augment process understanding, enable improved process control, and hence facilitate the production of high-quality pharmaceutical products. While beneficial for batch processes, the availability of PAT tools to...

The scope of PAT in real-time advanced control of tablet quality

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

Continuous pharmaceutical manufacturing together with process analytical technology (PAT) provides a suitable platform for automatic feed-forward/feed-back (FF/FB) control of the end product quality as desired by quality by design (QbD)-based efficient manufacturing. The precise control of the...

Surrogate-based Optimization for Pharmaceutical Manufacturing Processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wang, Zilong, Escotet-Espinoza, M Sebastian Singh, Ravendra, Ierapetritou, Marianthi

The development of pharmaceutical manufacturing processes has been facilitated by recent advances in the process simulation area. However, since the simulations are usually complex and the analytical expressions of the model can be unknown, it is difficult to directly apply traditional...

Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cole, KP, Reizman, BJHess, M, Groh, JM, Laurila, ME, Cope, RF, Campbell, BM, Forst, MB, Burt, JL, Maloney, TD, Johnson, MD, Mitchell, D, Polster, CS, Mitra, AW, Boukerche, M, Conder, EW, Braden, TM, Miller, RD, Heller, MR, Phillips, JL, Howell, JR

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical...

Small-Volume Continuous Manufacturing of Merestinib. Part 2.Technology Transfer and cGMP Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Reizman, Brandon J., Hess, Molly, Burt, Justin L., Maloney, Todd D., Johnson, Martin D., Laurila, Michael E., Cope, Richard F., Luciani, Carla V., Buser, Jonas Y., Campbell, Bradley M., Forst, Mindy B., Mitchell, David, Braden, Timothy M., Lippelt, Christopher K., Boukerche, Moussa, Starkey, Derek R., Miller, Richard D., Chen, Jing, Sun, Baoquan, Kwok, Martin, Zhang, Xin, Tadayon, Sam, Huang, Ping

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations...

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

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

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry...

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry...

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

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bhaskar, Aparajith, Singh, Ravendra

Recent advances in integrated process analytical techniques, modeling, and control strategies to enable continuous biomanufacturing of monoclonal antibodies

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Chopda, Viki, Gyorgypal, Aron Yang, Ou Singh, Ravendra Ramachandran, Rohit Zhang, Haoran Tsilomelekis, George Chundawat, Shishir PS, Ierapetritou, Marianthi G

Continuous bioprocessing is significantly changing the biological drugs (or biologics) manufacturing landscape by potentially improving product quality, process stability, and overall profitability, as was similarly seen during the adoption of advanced manufacturing processes for small molecule...

Residence Time Distribution as a Traceability Method for Lot Changes in A Pharmaceutical Continuous Manufacturing System

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sánchez-Paternina, Adriluz, Martínez-Cartagena, Pedro Li, Jingzhe Scicolone, James Singh, Ravendra Lugo, Yleana C Romañach, Rodolfo J Muzzio, Fernando J, Román-Ospino, Andrés D

Residence time distribution (RTD) models were developed to track raw material lots and investigate batch transitions in a continuous manufacturing system. Two raw materials with similar physical properties (granular metformin and lactose) were identified via Principal Component Analysis (PCA)...

Residence time distribution modelling and in line monitoring of drug concentration in a tablet press feed frame containing dead zones

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Tanimura, Shinji, Singh, Ravendra Román-Ospino, Andrés D, Ierapetritou, Marianthi

The presence of a ‘significant dead zone’ in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet...

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

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

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

09 Jun 2023 | Peer-reviewed journal | 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 optimization for continuous extrusion wet granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Tan, L, Carella, AJ, Ren, YK, Lo, JB

Three granulating binders in high drug-load acetaminophen blends were evaluated using high shear granulation and extrusion granulation. A polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, whereas polyvinylpyrrolidone and hydroxypropyl...

Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products

09 Jun 2023 | Chapter Book | Contributor(s): Ierapetritou, Marianthi, Escotet-Espinoza, M Sebastian, Singh, Ravendra

This chapter focuses on the application and development of unit operation and process models of the major routes of continuous solid dose manufacturing. Process models developed in the chapter are very important tools for the design of control system. The chapter also focuses on the current...

Process dynamics and control of API manufacturing and purification processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, Maitraye, Singh, Ravendra, Ramachandran, Rohit

The pharmaceutical industries have started transitioning toward continuous mode of manufacturing recently. Due to many advantages of the continuous manufacturing over the traditional alternatives, the industries are putting huge effort to efficiently adapt the continuous processing mode. However,...