A Co-Processed API Approach for a Shear Sensitive Compound Affording Improved Chemical Stability and Streamlined Drug Product Processing

09 Jun 2023 | Contributor(s): Schenck, L, Neri, CJia, XJ, Schafer, W, Axnanda, S, Canfield, N, Li, F, Shah, V

The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular...

A Comparison Between Lab-Scale and Hot-Melt-Extruder-Based Anti-inflammatory Ointment Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Thakkar, R, Ashour, EAShukla, A, Wang, R, Chambliss, WG, Bandari, S, Murthy, N, Repka, MA

Hot-melt extrusion (HME) has been extensively investigated for continuous manufacturing of amorphous solid dispersions, to improve the solubility of poorly water-soluble drug substances, impart abuse deterrence to controlled substances, taste masking for pediatric and geriatric formulations and...

A comprehensive analysis and optimization of continuous twin-screw granulation processes via sequential experimentation strategy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Meng, Wei, Rao, Kallakuri Suparna, Snee, Ronald D., Ramachandran, Rohit., Muzzio, Fernando J

Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation...

A continuous manufacturing concept for a pharmaceutical oral suspension

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bostijn, N, Van, Renterghem, JDhondt, W, Vervaet, C, De;Beer, T

The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed...

A Continuous Operation Concept for a Rotary Tablet Press Using Mass Flow Operating Points

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Martinetz, Michael Christian, Rehrl, Jakob Aigner, Isabella Sacher, Stephan, Khinast, Johannes

Abstract In a continuous pharmaceutical manufacturing line the rotary tablet press was viewed as the master of control concept and defined the mass flow through the entire process. According to a conventional control concept, missing mass flow from an upstream unit operation leads to a shutdown...

A flowsheet model for the development of a continuous process for pharmaceutical tablets: An industrial perspective

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Garcia-Munoz, Salvador, Butterbaugh, Adam Leavesley, Ian Manley, Leo Francis, Slade, David, Bermingham, Sean

A dynamic model of a continuous direct compression process for pharmaceutical tablets is presented. The objective is to assess the impact of the variability from the feeder system on the concentration of drug in the powder in the feed frame of a tablet press. The model is based on principles of...

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

09 Jun 2023 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations

09 Jun 2023 | Peer-reviewed journal | 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 large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Matsunami, Kensaku, Nagato, Takuya, Hasegawa, Koji, Sugiyama, Hirokazu

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing...

A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bostijn, N, Dhondt, J, Ryckaert, A, Szabo, E, Dhondt, W, Van Snick, B, Vanhoorne, V, Vervaet, C, De Beer, T

In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the...

A NIR-Based Study of Desorption Kinetics during Continuous Spin Freeze-Drying

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Leys, Laurens, Nuytten, Gust, Lammens, Joris, Van Bockstal, Pieter-Jan, Corver, Jos, Vervaet, Chris, De Beer, Thomas

The pharmaceutical industry is progressing toward the development of more continuous manufacturing techniques. At the same time, the industry is striving toward more process understanding and improved process control, which requires the implementation of process analytical technology tools (PAT)....

A primary drying model-based comparison of conventional batch freeze-drying to continuous spin-freeze-drying for unit doses

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Leys, L., Vanbillemont, B., Van Bockstal, P. J., Lammens, J., Nuytten, G., Corver, J., Vervaet, C., De Beer, T.

An innovative continuous spin-freeze-drying technology for unit doses was recently developed. For this technology, a mechanistic primary drying model was developed allowing the calculation of the optimal dynamic drying trajectory for spin-frozen formulations. In this work, a model-based and...

A Study on In-Line Tablet Coating-the Influence of Compaction and Coating on Tablet Dimensional Changes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cahyadi, C., Tan, B. X., Chan, L. W., Heng, P. W. S.

Prior to coating, tablets are usually stored for a definite period to enable complete strain recovery and prevent subsequent volumetric expansion-related coating defects. In-line coating is defined as the coating of tablets immediately after compaction. In-line coating will be expected to improve...

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 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 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 systematic study of the impact of changes of roller compactor equipment on granule and tablet properties

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Haeffler, Gunnar, Schmidt, Leonard, Lakio, Satu, Reynolds, Gavin, Odman, Jonas, Tajarobi, Pirjo

Typical industrial development of roller compaction processes include changes in scale from laboratory to pilot and then further to production scale and also changes in equipment design due to equipment availability in different manufacturing facilities. Transfer and scale-up of roller compaction...

A Training on: Continuous Manufacturing (Direct Compaction) of Solid Dose Pharmaceutical Products

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Moghtadernejad, Sara, Escotet-Espinoza, M. Sebastian, Oka, Sarang, Singh, Ravendra, Liu, Zhanjie, Roman-Ospino, Andres D., Li, Tianyi, Razavi, Sonia, Panikar, Savitha, Scicolone, James, Callegari, Gerardo, Hausner, Douglas, Muzzio, Fernando

As the pharmaceutical industry increasingly adopts continuous manufacturing technology, significant attention must be paid to process analytical technology (PAT), process integration, and process control. Published information is no substitute for hands-on comprehensive training, which is...

A Validated Model for Design and Evaluation of Control Architectures for a Continuous Tablet Compaction Process

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

The systematic design of an advanced and efficient control strategy for controlling critical quality attributes of the tablet compaction operation is necessary to increase the robustness of a continuous pharmaceutical manufacturing process and for real time release. A process model plays a very...

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...

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...