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

09 Jun 2023 | 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 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 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 Systematic Framework for Data Management and Integration in a Continuous Pharmaceutical Manufacturing Processing Line

09 Jun 2023 | 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 | 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 | 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 | 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...

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

09 Jun 2023 | 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...

Advanced Model Predictive Feedforward/Feedback Control of a Tablet Press

09 Jun 2023 | Contributor(s): Haas, Nicholas Townsend, Ierapetritou, Marianthi, Singh, Ravendra

In continuous pharmaceutical manufacturing, real-time precise control of critical quality attributes (CQAs) is necessary for quality by design (QbD)-based manufacturing and real-time release (RTR) with minimum consumption of time, space, and resources. Pharmaceutical tablets can be produced...

Advances in Twin-Screw Granulation Processing

09 Jun 2023 | Contributor(s): Nandi, Uttom, Trivedi, Vivek, Ross, Steven A., Douroumis, Dennis

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process...

Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation

09 Jun 2023 | Contributor(s): Kim, Su-Hyeon, Hwang, Kyu-Min, Cho, Cheol-Hee, Nguyen, Thi-Tram, Seok, Su Hyun, Hwang, Kyu-Mok, Kim, Ju-Young, Park, Chun-Woong, Rhee, Yun-Seok, Park, Eun-Seok

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The...

Artificial neural network modelling of continuous wet granulation using a twin-screw extruder

09 Jun 2023 | Contributor(s): Shirazian, Saeed, Kuhs, Manuel, Darwish, Shaza, Croker, Denise., Walker, Gavin M

Computational modelling of twin-screw granulation was conducted by using an artificial neural network (ANN) approach. Various ANN configurations were considered with changing hidden layers, nodes and activation functions to determine the optimum model for the prediction of the process. The neural...

Asymmetric distribution in twin screw granulation

09 Jun 2023 | Contributor(s): Seem, Tim Chan, Rowson, Neil A., Gabbott, Ian, de Matas, Marcel, Reynolds, Gavin K., Ingram, Andy

Positron Emission Particle Tracking (PEPT) was successfully employed to validate measured transverse asymmetry in material distribution in the conveying zones of a Twin Screw Granulator (TSG). Flow asymmetry was established to be a property of the granulator geometry and dependent on fill level....

Biocatalytic Continuous Manufacturing of Diabetes Drug: Plantwide Process Modeling, Optimization, and Environmental and Economic Analysis

09 Jun 2023 | Contributor(s): Ho, CH, Yi, JR, Wang, XN

This work proposes a comprehensive framework of biocatalytic continuous manufacturing of sitagliptin, the active pharmaceutical ingredient of the leading dipeptidyl peptidase-4 inhibitor antidiabetic drug. Continuous manufacturing has the advantages of quality consistency, reduced waste...

Breakage and drying behaviour of granules in a continuous fluid bed dryer: Influence of process parameters and wet granule transfer

09 Jun 2023 | Contributor(s): De Leersnyder, F., Vanhoorne, V., Bekaert, H., Vercruysse, J., Ghijs, M., Bostijn, N., Verstraeten, M., Cappuyns, P., Van Assche, I., Vander Heyden, Y., Ziemons, E., Remon, J. P., Nopens, I., Vervaet, C., De Beer, T.

Although twin screw granulation has already been widely studied in recent years, only few studies addressed the subsequent continuous drying which is required after wet granulation and still suffers from a lack of detailed understanding. The latter is important for optimisation and control and,...

Characteristics of multi-component formulation granules formed using distributive mixing elements in twin screw granulation

09 Jun 2023 | Contributor(s): Pradhan, Shankali U., Sen, Maitraye, Li, Jiayu, Gabbott, Ian, Reynolds, Gavin, Litster, James D., Wassgren, Carl R.

This work examines the influence of pharmaceutical powder formulation characteristics on granule properties formed using distributive mixing elements (DMEs) in twin screw granulation. High and low drug dose formulations with three different active pharmaceutical ingredients (APIs) were...

Characterization of material properties

09 Jun 2023 | Contributor(s): Razavi, Sonia, Oka, Sarang, Escotet-Espinoza, M. Sebastian, Wang, Yifan, Li, Tianyi, Futran Mauricio., Muzzio, Fernando

This chapter describes the importance of deepening our understanding of material properties and their effect on process performance. There are many measurement techniques to describe the complex nature of powders, some of which are provided in this chapter. Strong knowledge of multivariate...

Combined feedforward/feedback control of an integrated continuous granulation process

09 Jun 2023 | Contributor(s): Pereira, Glinka Cathy, Muddu, Shashank Venkat Román-Ospino, Andrés David Clancy, Don Igne, Benoit Airiau, Christian Muzzio, Fernando J Ierapetritou, Marianthi Ramachandran, Rohit, Singh, Ravendra

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical...

Continuous integrated filtration, washing and drying of aspirin: digital design of a novel intensified unit

09 Jun 2023 | Contributor(s): Destro, F, Wang, VAbdi, M, Feng, X, Wood, E, Coleman, S, Firth, P, Barton, A, Barolo, M, Nagy, ZK

Within the recent modernization of pharmaceutical manufacturing, an important milestone consists in developing enabling technologies for end-to-end continuous production of drug products. Continuous filtration, washing and drying of active pharmaceutical ingredients from mother liquors in...

Continuous manufacture of polymeric cellular dosage forms

09 Jun 2023 | Contributor(s): Blaesi, Aron H, Saka, Nannaji

The most prevalent pharmaceutical dosage forms at present are granular solids in the form of oral tablets and capsules. While effective in releasing drug rapidly upon contact with gastrointestinal fluid, their manufacture, which relies on particulate processing, is fraught with difficulties...

Continuous Melt Granulation for Taste-Masking of Ibuprofen

09 Jun 2023 | Contributor(s): Forster, Seth P., Lebo, David B.

This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and...

Continuous Production of Five Active Pharmaceutical Ingredients in Flexible Plug-and-Play Modules: A Demonstration Campaign

09 Jun 2023 | Contributor(s): Rogers, L, Briggs, NAchermann, R, Adamo, A, Azad, M, Brancazio, D, Capellades, G, Hammersmith, G, Hart, T, Imbrogno, J, Kelly, LP, Liang, GH, Neurohr, C, Rapp, K, Russell, MG, Salz, C, Thomas, DA, Weimann, L, Jamison, TF, Myerson, AS, Jensen, KF

Traditional pharmaceutical manufacturing is based on a complex supply chain that is vulnerable to spikes in demand and interruptions. Continuous pharmaceutical production in compact modules is a potential solution that allows for drug manufacturing when and where it is needed with significantly...

Continuous twin screw granulation and fluid bed drying: A mechanistic scaling approach focusing optimal tablet properties

09 Jun 2023 | Contributor(s): Menth, Judith, Maus, Martin, Wagner, Karl G.

This study provides the results of investigation on scaling approaches for three differently-sized continuous granulation lines, each consisting of a twin screw wet granulation process and a continuous fluid bed drying process. To check the initial scaling approach with regard to granule and...

Continuous twin screw granulation: A complex interplay between formulation properties, process settings and screw design

09 Jun 2023 | Contributor(s): Portier, Christoph, Pandelaere, KDelaet, U, Vigh, T, Di, Pretoro, G, De, Beer, T, Vervaet, C, Vanhoorne, V

Due to the numerous advantages over batch manufacturing, continuous manufacturing techniques such as twin screw wet granulation are rapidly gaining importance in pharmaceutical production. Since a large knowledge gap on the importance of formulation variables exists, this study systematically...