Methodology for a Variable Rate Control Strategy Development in Continuous Manufacturing Applied to Twin-screw Wet-Granulation and Continuous Fluid-bed Drying

09 Jun 2023 | Contributor(s): Pauli, Victoria, Elbaz, Frantz, Kleinebudde, Peter, Krumme, Markus

Purpose: Continuous manufacturing (CM) promises unrestricted scale up of production volume through runtime, together with lower product quality variability through stricter process control. However, unforeseen incidents that disrupt the process’ steady state or even force temporary shutdown of...

Micro reactor and flow chemistry for industrial applications in drug discovery and development

09 Jun 2023 | Contributor(s): Baraldi, PT, Hessel, V

In this review, case studies focused on syntheses of active pharmaceutical ingredients, intermediates and lead compounds are reported employing micro reactors and continuous flow technology in areas such as medicinal chemistry, chemical development and manufacturing. The advantages of flow...

Microfluidic droplet liquid reactors for active pharmaceutical ingredient crystallization by diffusion controlled solvent extraction

09 Jun 2023 | Contributor(s): Tona, RM, McDonald, TAOAkhavein, N, Larkin, JD, Lai, D

A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed for rapid and low-cost screening of crystal polymorphism (i. e. molecular crystallographic arrangement or internal structure) and habit (i.e. crystallographic...

Mixing Cell: a Device to Mimic Extent of Lubrication and Shear in Continuous Tubular Blenders

09 Jun 2023 | Contributor(s): Moghtadernejad, S, Escotet-Espinoz, AMS, Liu, ZJ, Schafer, E, Muzzio, F

Continuous manufacturing (CM) has clear potential for manufacturing solid oral dosages. It provides several advantages that may aid the manufacturing and quality of drug products. However, one of the main challenges of this technology is the relatively large amount of knowledge required and the...

Model Based Estimation of 2D Crystallization Kinetics From Concentration and CLD Measurements

09 Jun 2023 | Contributor(s): Szilagyi, Botond, Borsos, Akos Simone, Elena Nagy, Zoltan K., Espuña, Antonio, Graells, Moisès, Puigjaner, Luis

Due to the fact that crystal size and shape influence relevant macroscopic properties of solid particles, the understanding and control of these quantities have increasing importance in particulate science. Crystallization, the primary crystal formation and purification process, is usually...

Model development and prediction of particle size distribution, density and friability of a comilling operation in a continuous pharmaceutical manufacturing process

09 Jun 2023 | Contributor(s): Metta, Nirupaplava, Verstraeten, Maxim Ghijs, Michael Kumar, Ashish Schafer, Elisabeth Singh, Ravendra De Beer, Thomas Nopens, Ingmar Cappuyns, Philippe, Van Assche, Ivo

The comilling process plays an important role in solid oral dosage manufacturing. In this process, the granulated products are comminuted to the required size distribution through collisions created from a rotating impeller. In addition to predicting particle size distribution, there is a need to...

Model identification and control of solution crystallization processes: a review

09 Jun 2023 | Contributor(s): Rawlings, James B., Miller, Stephen M., Witkowski, Walter R.

The modeling of crystal quality (size, shape, and purity) is discussed. Numerical methods for the model solution are reviewed including collocation and Galerkin's method on finite elements. Measurement technologies for on-line crystal size distribution are presented. The difficulties with laser...

Model predictive control in pharmaceutical continuous manufacturing: A review from a user's perspective

09 Jun 2023 | Contributor(s): Jelsch, Morgane, Roggo, Yves, Kleinebudde, Peter, Krumme, Markus

Pharmaceutical continuous manufacturing is considered as an emerging technology by the regulatory agencies, which have defined a framework guided by an effective quality risk management. With the understanding of process dynamics and the appropriate control strategy, pharmaceutical continuous...

Model-based analysis of high shear wet granulation from batch to continuous processes in pharmaceutical production - A critical review

09 Jun 2023 | Contributor(s): Kumar, Ashish, Gernaey, Krist V., De Beer, Thomas, Nopens, Ingmar

The manufacturing of pharmaceutical dosage forms, which has traditionally been a batch-wise process, is now also transformed into a series of continuous operations. Some operations such as tabletting and milling are already performed in continuous mode, while the adaptation towards a complete...

Model-based approach to the design of pharmaceutical roller-compaction processes

09 Jun 2023 | Contributor(s): Toson, Peter, Lopes, Diogo G. Paus, Raphael Kumar, Ashish, Geens, Jeroen, Stibale, Sandy, Quodbach, Julian, Kleinebudde, Peter, Hsiao, Wen-Kai, Khinast, Johannes

This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an...

Model-based comparison of batch and flow syntheses of an active pharmaceutical ingredient using heterogeneous hydrogenation

09 Jun 2023 | Contributor(s): Kim, J, Yonekura, HWatanabe, T, Yoshikawa, S, Nakanishi, H, Badr, S, Sugiyama, H

This work presents a model-based comparison of the batch and flow syntheses for doripenem, which is an antibiotic active pharmaceutical ingredient. The targeted reaction is heterogeneous hydrogenation, the most widely used method for reduction reaction in drug syntheses. We developed rigorous...

Mechanistic investigation of a Ru-catalyzed direct asymmetric reductive amination reaction for a batch or continuous process scale-up: an industrial perspective

09 Jun 2023 | Contributor(s): Changi, SM, Yokozawa, TYamamoto, T, Nakajima, H, Embry, MC, Vaid, R, Luciani, CV, Wong, SW, Johnson, M, Moher, ED

A comprehensive assessment of a Ru-catalyzed direct asymmetric reductive amination (DARA) reaction for producing an intermediate for an active pharmaceutical ingredient (API) was carried out. Experiments were conducted to investigate the impact of process parameters (such as reaction temperature,...

Mechanistic modeling and parameter-adaptive nonlinear model predictive control of a microbioreactor

09 Jun 2023 | Contributor(s): Hong, Moo Sun, Braatz, Richard D.

Microbioreactors are a promising technology to accelerate biologic drug development. In aerobic cellular respiration, a potential limit to the productivity of such systems is the transport of oxygen from an external gas to the most oxygen-deficient cells, and the potential for excessive spatially...

Mechanistic modeling for systematic design and analysis of PAT systems

09 Jun 2023 | Contributor(s): Singh, Ravendra, Samad, Noor Asma Fazli Abdul Gernaey, Krist V Woodley, John M, Gani, Rafiqul

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Mechanistic modelling of industrial-scale roller compactor ‘Freund TF-MINI model’

09 Jun 2023 | Contributor(s): Sajjia, Mustafa, Shirazian, Saeed Egan, David Iqbal, Javed, Albadarin, Ahmad, Southern, Mark, Walker, Gavin

A pharmaceutical roller compaction process was modelled using the Johanson powder mechanics model, which may be employed to achieve desired process performance. Mathematical modelling of the compaction of microcrystalline cellulose (PH102) was used to determine optimal process conditions for an...

Mechanistic modelling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process

09 Jun 2023 | Contributor(s): Van Bockstal, Pieter-Jan, Mortier, Severine Therese F. C., De Meyer, Laurens, Corver, Jos, Vervaet, Chris, Nopens, Ingmar, De Beer, Thomas

Conventional pharmaceutical fieeze-drying is an inefficient and expensive batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply...

Mechanochemistry Can Reduce Life Cycle Environmental Impacts of Manufacturing Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Galant, O, Cerfeda, GMcCalmont, AS, James, SL, Porcheddu, A, Delogu, F, Crawford, DE, Colacino, E, Spatari, S

The scale-up of mechanochemical methods could play a transformative role in making manufacturing processes in the pharmaceutical industry greener by eliminating solvent use and recovery. Combined with energy-efficient continuous processing that consolidates reaction steps, mechanochemistry's...

Melt Extrusion

09 Jun 2023 | Contributor(s): Haser, A, DiNunzio, JCMartin, C, McGinity, JW, Zhang, F

Techniques to overcome poor aqueous solubility of active pharmaceutical ingredients (APIs) continue to gain interest with a reported 30% of marketed compounds classified as BCS II and 10% classified as BCS IV. Approximately 70% of new chemical entities under development may be classified as BCS...

Melt extrusion with poorly soluble drugs - An integrated review

09 Jun 2023 | Contributor(s): Repka, Michael A., Bandari, Suresh, Kallakunta, Venkata Raman, Vo, Anh Q., McFall, Haley, Pimparade, Manjeet B., Bhagurkar, Ajinkya M.

Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly...

Metabolic Engineering: The Ultimate Paradigm for Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Contributor(s): Yadav, VG, Stephanopoulos, G

Research Article and development (R&D) expenditures by pharmaceutical companies doubled over the past decade, yet candidate attrition rates and development times rose markedly during this period. Understandably, companies have begun downsizing their pipelines and diverting investments away from...

Metamorphosis of Twin Screw Extruder-Based Granulation Technology: Applications Focusing on Its Impact on Conventional Granulation Technology

09 Jun 2023 | Contributor(s): Rao, Rajat Radhakrishna, Pandey, Abhijeet, Hegde, Aswathi R., Kulkarni, Vijay Induvadan, Chincholi, Chetan, Rao, Vinay, Bhushan, Indu, Mutalik, Srinivas

In order to be at pace with the market requirements of solid dosage forms and regulatory standards, a transformation towards systematic processing using continuous manufacturing (CM) and automated model-based control is being thought through for its fundamental advantages over conventional batch...

Method Development and Validation of an Inline Process Analytical Technology Method for Blend Monitoring in the Tablet Feed Frame Using Raman Spectroscopy

09 Jun 2023 | Contributor(s): Li, Y, Anderson, CADrennen, JK, Airiau, C, Igne, B

Inline process analytical technology sensors are the key elements to enable continuous manufacturing. They facilitate real-time monitoring of critical quality attributes of both intermediate materials and finished products. The aim of this study was to demonstrate method development and...

Method for characterization of loss-in-weight feeder equipment

09 Jun 2023 | Contributor(s): William E. Engisch, Fernando J. Muzzio 

This paper presents a method for evaluating the steady state performance of loss-in-weight powder feeding equipment and then demonstrates the use of the method in evaluating the performance of a K-Tron KT35 loss-in-weight feeder for three pharmaceutical grade powders. The method describes in...

Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness

09 Jun 2023 | Contributor(s): Stauffer, F, Vanhoorne, VPilcer, G, Chavez, PF, Vervaet, C, De;Beer, T

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to...

Manipulation of ionic liquid anion-solute-antisolvent interactions for the purification of acetaminophen

09 Jun 2023 | Contributor(s): Weber, CC, Kunov-Kruse, AJRogers, RD, Myerson, AS

Hydrogen bond donating cosolvents have been shown to significantly reduce the solubility of acetaminophen (AAP) in ionic liquids containing the acetate anion. Reduced solubility arises from competition for solvation by the acetate anion and can be used for the design of advanced separation...