Digital design of an integrated purification system for continuous pharmaceutical manufacturing

Hur, Inyoung; Casas-Orozco, Daniel; Laky, Daniel J.; Destro, Francesco; Nagy, Zoltan K.

doi:10.1016/j.ces.2023.119534

Cited by 4 publications

(3 citation statements)

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“…Of course, consideration of dynamics in the superstructure-based process modeling would be required in such cases. Additionally, different types of optimization algorithms may be required when combined with antisolvent crystallization, cooling crystallization, continuous crystallization-filtration-drying carousels, and other processes for different types of biobased materials. This is also an important subject for future research.…”

Section: Resultsmentioning

confidence: 99%

Operational Strategy of Reconfigurable Multi-Effect Evaporation Processes for Bio-Based Amino Acid Production

Kim,

Park,

Park

et al. 2024

Ind. Eng. Chem. Res.

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The techno-economic impact of implementing a reconfigurable system in the integrated process was investigated, when L-threonine and L-valine were coproduced with a 5-effect preheater-integrated feed-forward evaporator, followed by singlestage evaporative crystallizers. A superstructure-based modeling and simulation framework was developed to consider all possible multieffect evaporator configurations. Evaporative capacity constrained by solubility limitations and fluid scaling was rigorously examined, providing the knowledge to select the most appropriate configuration and minimize steam consumption without compromising productivity. For L-threonine production, the 4−5−3− 2−1 sequence with a preheater showed the highest energy efficiency, with a maximum reduction of 8.4% in steam usage compared to the standard condition. For L-valine production, the 5−4−3−2−1 sequence without a preheater was most energyefficient, showing a maximum reduction of 7.3% in steam usage compared to the standard condition. These results clearly illustrate the agility of the reconfigurable multieffect evaporation system under various uncertain operational factors.

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Section: Resultsmentioning

confidence: 99%

Operational Strategy of Reconfigurable Multi-Effect Evaporation Processes for Bio-Based Amino Acid Production

Kim,

Park,

Park

et al. 2024

Ind. Eng. Chem. Res.

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“…Filtration is typically performed in order to gain solid isolation from the product. The evaluation of filtration performance is frequently determined by the recoverable mass (cake yield), the solvent retention of the filter cake, the filterability and purity of the crystals. , Continuous integrated filtering is an emerging field of research in the pharmaceutical sector in both mathematical modeling − and experimentation. ,,,− …”

Section: Introductionmentioning

confidence: 99%

“…Process intensification is achieved by a holistic application of (i) continuous manufacturing, (ii) process integration, (iii) intensified unit operation using oscillatory mixing, (iv) intensified process based on spherical agglomeration, (v) novel equipment design with automation, and (vi) application of integrated array of process analytical technology (PAT) tools. We have previously investigated various components of this overall process, such as continuous manufacturing, , utilizing novel equipment, ,, use of process analytical technology (PAT) tools in monitoring processes, ,− feedback controls and quality by control (QbC) methods, ,− digital models via model-based optimizations, ,,,,, and combination of various mechanism ,,,,,− (i.e., spherical agglomeration, milling, nucleation in porous media). PAT tools in conjunction with mathematical models have been used successfully for the mechanistic understanding of spherical crystallization and agglomeration. ,, Peña and Nagy (2015) were the first to report the continuous integration of crystallization and spherical agglomeration in a coupled two-stage stirred tank system.…”

Section: Introductionmentioning

confidence: 99%

Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

Parvaresh,

Nagy

2024

Org. Process Res. Dev.

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Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various technological steps into a coherent end-to-end continuous system, such as settling, clogging and breakage of particles during transfer, long filtration and drying times and large residence times needed to achieve desired product qualities. This study addresses these difficulties by creating and implementing an end-to-end continuous manufacturing process for atorvastatin calcium (ASC), a statin that is frequently used to treat hypercholesterolemia. The first end-toend integrated continuous, process involving reaction, crystallization, spherical agglomeration, filtration and drying is presented in this work. This approach uses a novel modular integrated continuous manufacturing system, which is developed to improve control over process parameters for the purpose of producing pharmaceutical compounds. Process intensification is achieved by a holistic integration of novel equipment design such as oscillatory flow crystallizers as well as innovative process development (spherical agglomeration). Both the product quality and the manufacturing efficiency are enhanced as a result. This study aims to ascertain the influence of crucial process parameters on the end product's quality through an extensive experimental investigation. Process variables, filtration and drying times, were changed, which offered information about how to best optimize the continuous manufacturing process for ASC with and without the spherical agglomeration step. This paper highlights the use of such methodologies in demonstrating the viability and benefits of a novel continuous end-to-end manufacturing process for ASC as it demonstrated significant improvements in cake yield, solvent retention, throughput and productivity and its potential for the future of intensified integrated continuous pharmaceutical manufacturing.

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Enhanced sustainability with crystallization in continuous flow

Neugebauer,

Soritz,

Khinast

et al. 2024

Current Opinion in Green and Sustainable Chemistry

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Digital design of an integrated purification system for continuous pharmaceutical manufacturing

Cited by 4 publications

References 50 publications

Operational Strategy of Reconfigurable Multi-Effect Evaporation Processes for Bio-Based Amino Acid Production

Operational Strategy of Reconfigurable Multi-Effect Evaporation Processes for Bio-Based Amino Acid Production

Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

Enhanced sustainability with crystallization in continuous flow

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