Use Of Continuous Process Research Articles

Proceedings of the 2023 Viral Clearance Symposium, Session 4: Continuous Processing.

The continuous processing session at the 2023 Viral Clearance Symposium (VCS) focused on understanding how to effectively design viral clearance operations for use in continuous processes and methods to perform viral clearance studies. In this session, an approach to directly address control considerations with operating continuous-flow reactors for low pH viral inactivation was presented. Continuous-flow low pH incubation chamber design and implications for residence time determination were discussed. Additionally, viral clearance capability between batch operation and connected operation were demonstrated to be comparable for a connected bind-elute chromatography and flow-through chromatography step. Overall, this session provided additional scientific knowledge to support viral clearance strategies when implementing a continuous manufacturing process.

A continuous photo-Fenton-like process using persulfate salts for the degradation of acetaminophen under solar irradiation at circumneutral pH

The demand for sustainable and feasible water treatment technologies (WTT) increases with the growing realization of the magnitude of the damage that our indiscriminate wastewater disposal strategy has caused the Environment. Considering the increasing costs of energy, the development of solar-driven processes is key to ensuring the economic feasibility of WTT for industries of all sizes. In this direction, this paper reports the development of a photo-Fenton-like system based on the persulfate ion and the use of solar irradiation as its coactivator for use in continuous processes. Using acetaminophen as model contaminant (C0 = 5 ppm), we showed that under optimal conditions and circumneutral pH (pH ∼5.6), a removal of 94% was achievable with a residence time of 3.3 min. Economically, this translates into a collector area per order of 11.4 m2/(m3 order), in line with the best numbers found in the literature. We showed that this was achieved due to the improved concentration of sulfate radicals, SO4•−, formed in the system, when compared to the same process carried out in a small-scale batch reactor. Our results, obtained under controlled conditions using a solar simulator, were validated under natural sunlight, confirming the feasibility of our proposed intensification strategy.

Scalable fabrication, compartmentalization and applications of living microtissues.

Living microtissues are used in a multitude of applications as they more closely resemble native tissue physiology, as compared to 2D cultures. Microtissues are typically composed of a combination of cells and materials in varying combinations, which are dictated by the applications’ design requirements. Their applications range wide, from fundamental biological research such as differentiation studies to industrial applications such as cruelty-free meat production. However, their translation to industrial and clinical settings has been hindered due to the lack of scalability of microtissue production techniques. Continuous microfluidic processes provide an opportunity to overcome this limitation as they offer higher throughput production rates as compared to traditional batch techniques, while maintaining reproducible control over microtissue composition and size. In this review, we provide a comprehensive overview of the current approaches to engineer microtissues with a focus on the advantages of, and need for, the use of continuous processes to produce microtissues in large quantities. Finally, an outlook is provided that outlines the required developments to enable large-scale microtissue fabrication using continuous processes.

Lipase Immobilization in Mesoporous Silica Nanoparticles for Biofuel Production

Lipases are ubiquitous enzymes whose physiological role is the hydrolysis of triacylglycerol into fatty acids. They are the most studied and industrially interesting enzymes, thanks to their versatility to promote a plethora of reactions on a wide range of substrates. In fact, depending on the reaction conditions, they can also catalyze synthesis reactions, such as esterification, acidolysis and transesterification. The latter is particularly important for biodiesel production. Biodiesel can be produced from animal fats or vegetable oils and is considered as a biodegradable, non-toxic and renewable energy source. The use of lipases as industrial catalysts is subordinated to their immobilization on insoluble supports, to allow multiple uses and use in continuous processes, but also to stabilize the enzyme, intrinsically prone to denaturation with consequent loss of activity. Among the materials that can be used for lipase immobilization, mesoporous silica nanoparticles represent a good choice due to the combination of thermal and mechanical stability with controlled textural characteristics. Moreover, the presence of abundant surface hydroxyl groups allows for easy chemical surface functionalization. This latter aspect has the main importance since lipases have a high affinity with hydrophobic supports. The objective of this work is to provide an overview of the recent progress of lipase immobilization in mesoporous silica nanoparticles with a focus on biodiesel production.

In-Line Monitoring and Control of Rheological Properties through Data-Driven Ultrasound Soft-Sensors.

The use of continuous processing is replacing batch modes because of their capabilities to address issues of agility, flexibility, cost, and robustness. Continuous processes can be operated at more extreme conditions, resulting in higher speed and efficiency. The issue when using a continuous process is to maintain the satisfaction of quality indices even in the presence of perturbations. For this reason, it is important to evaluate in-line key performance indicators. Rheology is a critical parameter when dealing with the production of complex fluids obtained by mixing and filling. In this work, a tomographic ultrasonic velocity meter is applied to obtain the rheological curve of a non-Newtonian fluid. Raw ultrasound signals are processed using a data-driven approach based on principal component analysis (PCA) and feedforward neural networks (FNN). The obtained sensor has been associated with a data-driven decision support system for conducting the process.

Selective synthesis of monolaurin catalyzed by layered zinc laurate

In the present study, zinc laurate (ZL) was synthesized by precipitation and characterized by X-ray diffraction, Fourier transform infrared spectroscopy and thermal analysis. ZL was applied for monolaurin synthesis by esterification of lauric acid with glycerol using a 23 factorial design to determine the best conditions for monolaurin production. Conversion of nearly to 70% was achieved by using a lauric acid:glycerol molar ratio of 1:1, 2 wt % of catalyst and 140 °C, reaching to 33% of monolaurin selectivity. Statistical analyses at a confidence level of 95% indicated that the decrease in lauric acid:glycerol molar ratio was significant to enhance the monolaurin production. Moreover, the solid was able to be reused, preserving its original structure and the catalytic activity, which indicated the potential use in continuous processes.

Polymer Supported Carbon for Safe and Effective Remediation of PFOA- and PFOS-Contaminated Water

Powdered activated carbon (PAC) is an economical sorbent for removing micropollutants from water, but it generates hazardous dust that is flammable and a respiration hazard. Additionally, the fine particles of PAC can cake and block filters and membranes, complicating its use in continuous processes. In this study, we present a sulfur polymer support for PAC that overcomes these problems. The blend of the sulfur polymer and PAC generates low dust and it does not block filters. The utility of the sorbent is demonstrated in the remediation of water contaminated with perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), persistent micropollutants that currently threaten water safety worldwide. Fundamental discoveries of PFOA self-assembly are also reported, as well as testing on a field sample of contaminated surface water.

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing.

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

Surface modification and immobilization in poly(acrylic acid) of Ag/ZnO for photocatalytic degradation of endocrine‐disrupting compounds

ABSTRACTSilver‐modified ZnO particles (Ag/ZnO) are effective catalysts for the photodegradation of water pollutants such as bisphenol‐A. However, until now, their use in continuous processes was back‐drawn because of difficulties associated with their recovery. To overcome this problem, the present work aimed at immobilizing Ag/ZnO in cross‐linked poly(acrylic acid) ‐PAA‐. Ag/ZnO was first silanized using (3‐glycidyloxypropyl)trimethoxysilane and thoroughly dispersed in a water‐acrylic acid solution. The suspension was then submitted to radical polymerization in presence of a cross‐linker (N,N′‐Methylenebisacrylamide). The resulting composites were characterized in terms of chemical structure, morphology, crystallinity, thermal properties, and photostability. Their analyses showed that the silanized particles were chemically anchored to PAA and homogeneously distributed in the matrix. UV‐assisted photocatalysis of bisphenol‐A aqueous solutions showed that immobilized Ag/ZnO can achieve photodegradation performances comparable to pure Ag/ZnO and allows its use in successive cycles and, consequently, in continuous processes. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43528.

Transposition of a triphosgene-based process for pharmaceutical development: from mg·h-1 to kg·h-1 of an unsymmetrical urea

A two reaction synthesis of a urea, using triphosgene, was studied. The objective was to transpose the process from laboratory scale to pre-industrial plant. The whole study was performed in a continuous process, adapting the characteristic dimensions and length of the reactor. In this paper, the development of the process is presented, and the choices about safety and operating conditions constraints are discussed. The final operation allows a 70% global yield in a 7 week study. Furthermore, the use of microreactors not only permits an exhaustive study of the process operating parameters, but also provides feedback on the developed chemistry itself. The results obtained are a demonstration of the use of continuous processes in small scale reactors for complex molecule development. The mg·h-1 to kg·h-1 is a key transposition in the pharmaceutical industries project development, as it can help to accelerate the first lot production used in toxicological or pre-clinic stages.

Towards a Greener Pharmacy by More Eco Design

This review proposes an overview of the main trends explored by the pharmaceutical industry in order to develop a greener and smarter pharmacy minimizing any negative impact to the environment, and using more sustainable processes and drugs. If many drugs have their origin in nature, many active ingredients are “toxic by design”. Some trials were carried out to design “green pills”, or greener active ingredients “benign by design”, avoiding the environmental pollution risk. More efforts were developed to reduce fine chemicals production footprints, and to decrease their E-factor. Biotechnology, and the use of enzymes for some transformation reactions is another good way of progress. Advanced galenics allows to reduce drug footprints on environment, since it can deliver the right dose of drug at the right time and at the right place, decrease the drug doses, and lower the wastes. Use of continuous processes is a strong trend in the area of primary and secondary pharmaceutical production. It is linked to the quality by design concept and to the in-process control by process analytical technology tools. Added to their diversification strategy, and despite their lower research productivity, and that more and more patented blockbusters become or will become generics soon, it will help the pharmaceutical companies to continue their development. At the same time, these efforts toward a greener pharmacy, and a social education of patients, will contribute to the health organization economies and to preserve the future of our planet.

Manufacture of a β-Hydroxyester via a Continuous Reformatsky Process

The use of continuous processing in a Reformatsky reaction has been investigated as a means to control the large heat of reaction and reduce the inventory of hazardous materials. A laboratory-scale continuous miniplant for manufacture of an aromatic β-hydroxyester has been designed and built for a production rate of about 100 mL/h. The plant operated at steady state for several hours and provided strong evidence that a larger-scale continuous plant could readily be designed. For this chemistry, the use of continuous processing is not only a safer and more efficient technology (as compared to the typical batch process) but also cleaner, giving fewer byproduct and at much lower concentration.

New composite materials as support for selective hydrogenation; egg-shell catalysts

It has been demonstrated that using low-cost materials and a relatively simple process, complex supports with a mixed inorganic–organic structure can be synthesized. These supports combine hydrophilic–hydrophobic dual properties and are especially suited for preparing egg-shell supported metal catalysts to be used in highly exothermal catalytic reactions or in systems of consecutive reactions where diffusive problems decrease the selectivity. The synthesized supports have an extremely thin active layer. They also proved to be more mechanically resistant than other commercial supports thus being amenable for use in continuous processes with long packed beds. Pd catalysts supported over the new composite materials were found to be highly active for the selective hydrogenation of styrene, a representative compound of pyrolisis gasolines. They also displayed smaller diffusive constraints than other Pd catalysts prepared from commercial supports.

Practical Use of Continuous Processing in Developing and Scaling Up Laboratory Processes

Continuous operations can be used for the efficient scale-up of many processes that cannot be carried out through batch operations. Rapid reactions with reactive intermediates and products can be scaled up in the laboratory using continuously stirred tank reactors (CSTR) and plug flow reactors (PFR). Continuous processing in small reactors allows for better control of exothermic processing, creating a larger margin of safety for scale-up. This review also discusses the advantages of continuous processing for thermochemical rearrangements, immobilized catalysts, and microwave, photochemical, electrochemical, and sonochemical processes. Many of these continuous operations can be performed using equipment readily available for the laboratory, and can be readily scaled up in the laboratory and pilot plant.

Oxidative phenol coupling catalyzed by polymer‐bound copper‐imidazole complexes

AbstractPolymer‐bound imidazole‐copper(II) complexes were investigated and applied as catalysts for oxidative coupling (polymerization) of 2,6‐dialkylphenols. These polymeric catalysts were also immobilized on silica particles through adsorption, quaternization and grafting. Especially, the grafted catalysts showed interesting catalytic properties, e.g. good specificity for C‐O coupling and very good stability during prolonged use in continuous processes. This stability furnished new information about the mechanism of the oxidative coupling polymerization. Finally, this reaction was optimized for the preparation of PPO‐type telechelics.