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...

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...

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...

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 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...

Evaluation of a Combined MHE-NMPC Approach to Handle Plant-Model Mismatch in a Rotary Tablet Press

09 Jun 2023 | Contributor(s): Huang, Yan-Shu, Reklaitis, Gintaras V.

The transition from batch to continuous processes in the pharmaceutical industry has been driven by the potential improvement in process controllability, product quality homogeneity, and reduction of material inventory. A quality-by-control (QbC) approach has been implemented in a variety of...

Improving Feedability of Highly Adhesive Active Pharmaceutical Ingredients by Silication

09 Jun 2023 | Contributor(s): Escotet-Espinoza, M. Sebastian, Moghtadernejad, Sara, Sanchez, Eric, Cappuyns, Philippe, Van Assche, Ivo, Di Pretoro, Giustino, Ierapetritou, Marianthi, Scicolone, James V., Muzzio, Fernando J.

Purpose: Loss-in-weight feeders play a vital role in assuring blend and content uniformity as well as lot-to-lot powder traceability in continuous manufacturing. Irregular flow from the feeders propagates through the system, potentially resulting in out-of-specification product. Powder properties...

In-line particle size measurement based on image analysis in a fully continuous granule manufacturing line for rapid process understanding and development

09 Jun 2023 | Contributor(s): Madarász, Lajos, Köte, Ákos, Hambalkó, Bence, Csorba, Kristóf, Kovács, Viktor, Lengyel, László, Marosi, Györgya, Farkas, Attilaa, Nagy, Zsombor Kristóf, Domokos, András

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method...

Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets

09 Jun 2023 | Contributor(s): Fonteyne, Margot, Wickström, Henrika, Peeters, Elisabeth, Vercruysse, Jurgen, Ehlers, Henrik, Peters, Björn-Hendrik, Remon, Jean Paul, Vervaet, Chris, Ketolainen, Jarkko, Sandler, Niklas, Rantanen, Jukka., Naelapää, Kaisa

Continuous manufacturing gains more and more interest within the pharmaceutical industry. The International Conference of Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product...

Mapping key process parameters to the performance of a continuous dry powder blender in a continuous direct compression system

09 Jun 2023 | Contributor(s): Palmer, J, Reynolds, GK, Tahir, F, Yadav, IK, Meehan, E, Holman, J, Bajwa, G

This work aims to expand the typical raw material attributes that can successfully be processed on a continuous direct compression line with a particular focus on the continuous dry powder blender. Three grades of Acetaminophen were investigated as model active pharmaceutical ingredients and...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

09 Jun 2023 | Contributor(s): Armstrong, Cameron, Miyai, Yuma, Formosa, Anna, Thomas Dale, Chen, Esther, Hart, Travis, Schultz, Victor, Desai, Bimbisar, Cai, Angela, Almasy, Alexandra, Jensen, Klavs, Roper, Thomas

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with...

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

09 Jun 2023 | 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...

Optimized continuous pharmaceutical manufacturing via model-predictive control

09 Jun 2023 | Contributor(s): Rehrl, Jakob, Kruisz, Julia, Sacher, Stephan, Khinast, Johannes, Horn, Martin

This paper demonstrates the application of model-predictive control to a feeding blending unit used in continuous pharmaceutical manufacturing. The goal of this contribution is, on the one hand, to highlight the advantages of the proposed concept compared to conventional PI-controllers, and, on...

PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy

09 Jun 2023 | Contributor(s): Miyai, Yuma, Formosa, Anna, Armstrong, Cameron, Marquardt, Brian, Rogers, Luke, Roper, Thomas

The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufacturing process, PAT and its...