Traditional Batch Processes Research Articles

Tailoring the crystal size distribution of an active pharmaceutical ingredient by continuous antisolvent crystallization in a planar oscillatory flow crystallizer

An active pharmaceutical ingredient is currently produced in a traditional batch antisolvent crystallization process. Although well-established, this process lacks flexibility to control the crystal size distribution (CSD). Therefore, a new process was developed to enable the control of the CSD according to different specifications. This new process was implemented in continuous in a planar oscillatory flow crystallizer (planar-OFC). In this work, the main goal was to enable the production of small crystals to meet very specific formulation requirements and, simultaneously, promote the aggregation of these small particles to optimize the filtration operation. First, the operating conditions were optimized for continuous operation. Then, the planar-OFC was divided into two spatially independent sections, the nucleation zone (where nucleation is dominant) and the crystal growth zone (where crystal growth is dominant), so as to control the CSD as a function of the residence time in each zone. In particular, the formation of aggregates could be promoted by increasing the residence time in the nucleation zone. Ultimately, the planar-OFC was able to produce smaller particles with significantly narrower CSDs than the traditional batch process. This is particularly important when small particle sizes are required, thus reducing manufacturing time and operating costs.

Innovation in a Continuous System of Distillation by Steam to Obtain Essential Oil from Persian Lime Juice (Citrus latifolia Tanaka).

The citrus industry is one of the most important economic areas within the global agricultural sector. Persian lime is commonly used to produce lime juice and essential oil, which are usually obtained by batch distillation. The aim of this work was to validate a patented continuous steam distillation process and to both physically and chemically characterize the volatile fractions of essential Persian lime oil. Prior to distillation, lime juice was obtained by pressing the lime fruit. Afterwards, the juice was subjected to a continuous steam distillation process by varying the ratio of distillate flow to feed flow (0.2, 0.4, and 0.6). The distillate oil fractions were characterized by measuring their density, optical rotation, and refractive index. Gas chromatography GC-FID was used to analyze the chemical compositions of the oil fractions. The process of continuous steam distillation presented high oil recovery efficiencies (up to 90%) and lower steam consumption compared to traditional batch process distillation since steam consumption ranged from 32 to 60% for different steam levels. Moreover, a reduction in process time was observed (from 8 to 4 h). The oil fractions obtained via continuous steam distillation differed significantly in their composition from the parent compounds and the fractions.

Durable, magnetic-responsive melamine sponge composite for high efficiency, in situ oil–water separation

The development of durable and high-performance absorbents for in situ oil–water separation is of critical importance for addressing severe water pollution in daily life as well as for solving accidental large-scale oil spillages. Herein, we demonstrate a simple and scalable approach to fabricate magnetic-responsive superhydrophobic melamine sponges by in situ deposition of PDA coatings and Fe3O4 nanoparticles, followed by surface silanization with low surface energy 1H,1H,2H,2H-perfluorooctyltriethoxysilane (PTOS) layer. The prepared melamine sponge composite (PTOS-Fe3O4@PDA/MF) not only exhibits a very high water contact angle of 165 ± 1.5° and an excellent ability to uptake a variety of oils and organic solvents (e.g. up to 141.1 g/g for chloroform), but also shows robust durability and superior recyclability. The PTOS-Fe3O4@PDA/MF sponge can also efficiently separate oils (or organic solvents) and water, as demonstrated by different model systems including immiscible oil–water solution mixture and miscible water–oil (W/O) emulsion (stabilized by surfactants). Furthermore, the PTOS-Fe3O4@PDA/MF sponge is able to in situ recover organics from water using a peristaltic pump, which gives it significant advantages over other traditional batch processes for oil–water separation. We believe that the PTOS-Fe3O4@PDA/MF sponge provides a very promising material solution to address oil–water separation, especially for the large-scale problems that have been long-time challenges with conventional sorption methods.

Pilot-scale demonstration of an end-to-end integrated and continuous biomanufacturing process.

There has been increasing momentum recently in the biopharmaceutical industry to transition from traditional batch processes to next-generation integrated and continuous biomanufacturing. This transition from batch to continuous is expected to offer several advantages which, taken together, could significantly improve access to biologics drugs for patients. Despite this recent momentum, there has not been a commercial implementation of a continuous bioprocess reported in the literature. In this study, we describe a successful pilot-scale proof-of-concept demonstration of an end-to-end integrated and continuous bioprocess for the production of a monoclonal antibody (mAb). This process incorporated all of the key unit operations found in a typical mAb production process, including the final steps of virus removal filtration, ultrafiltration, diafiltration, and formulation. The end-to-end integrated process was operated for a total of 25 days and produced a total of 4.9 kg (200 g/day or 2 g/L BRX/day) of the drug substance from a 100-L perfusion bioreactor (BRX) with acceptable product quality and minimal operator intervention. This successful proof-of-concept demonstrates that end-to-end integrated continuous bioprocessing is achievable with current technologies and represents an important step toward the realization of a commercial integrated and continuous bioprocessing process.

Advantages of continuous Fenton reaction over the traditional batch process in wastewater treatment in a single and two-step mode

Advantages of continuous Fenton reaction over the traditional batch process in wastewater treatment in a single and two-step mode

Flow Synthesis of 2‐[Methyl(pyridin‐2‐yl)amino]ethanol: An Experimental and Computational Study

AbstractMicroreactor technology is increasingly applied in the chemical‐pharmaceutical industry for safer and more efficient drug production as compared to the traditional batch process. This technology is employed for the first time to study the production of 2‐[methyl(pyridin‐2‐yl)amino]ethanol, the first intermediate in rosiglitazone synthesis. Under the optimum operating conditions, a single microreactor chip at 160 °C allowed to produce the equivalent of more than five batch reactors at 120 °C. The kinetic study indicated that the reaction is second order. Thermodynamic parameters were determined by the Eyring equation and density functional theory (DFT) calculations with good agreement. DFT results suggested a concerted nucleophilic aromatic substitution reaction mechanism.

Kinetic behavior of soluble Pectinex Ultra SP-L converting sucrose into fructo-oligosaccharides in batch and continuous fashion

AbstractThe enzymatic conversion of sucrose to fructo-oligosaccharides (FOS) catalyzed by Pectinex Ultra SP-L, a commercial enzyme preparation from Aspergillus aculeatus, under free condition was studied. A mathematical analysis of the transfructosylation reactions was carried out to estimate the dynamic and steady-state performance of an enzyme membrane reactor (EMR) and to compare the continuous production scheme with the traditional batch process realized in stirred-tank reactor (STR). Kinetic parameters were identified simultaneously from a series of progress curves obtained from STR and EMR experimental runs. Model estimates appeared to fit well to experimental observations under the studied reaction conditions. Although conventional batch reactor outperforms EMR in terms of conversion, EMR compares favorably regarding productivity. The on-site industrial implementation of this technology might be attractive for food manufacturers aiming at utilizing a value-added sweetener mixture with prebiotic properties.

Why Is Batch Processing Still Dominating the Biologics Landscape? Towards an Integrated Continuous Bioprocessing Alternative

Continuous manufacturing of biologics (biopharmaceuticals) has been an area of active research and development for many reasons, ranging from the demand for operational streamlining to the requirement of achieving obvious economic benefits. At the same time, biopharma strives to develop systems and concepts that can operate at similar scales for clinical and commercial production—using flexible infrastructures, such as single-use flow paths and small surge vessels. These developments should simplify technology transfer, reduce footprint and capital investment, and will allow to react readily to changing market pressures while maintaining quality attributes. Despite a number of clearly identified benefits compared to traditional batch processes, continuous bioprocessing is still not widely adopted for commercial manufacturing. This paper details how industry-specific technological, organizational, economic, and regulatory barriers that exist in biopharmaceutical manufacturing are hindering the adoption of continuous production processes. Based on this understanding, the roles of process systems engineering (PSE), process analytical technologies, and process modeling and simulation are highlighted as key enabling tools in overcoming these multi-faceted barriers in today’s manufacturing environment. Of course, we do recognize that there is also a need for a clear set of regulations to guide a transition of biologics manufacturing towards continuous processing. Furthermore, the role played by the emerging fields of process integration and automation as well as digitalization is explored, as these are the tools of the future to facilitate this transition from batch to continuous production. Finally, an outlook focusing on technology, management, and regulatory aspects is presented to identify key concerted efforts required to drive the broad adaptation of continuous manufacturing in biopharmaceutical processes.

Spray Freeze-Drying as a Solution to Continuous Manufacturing of Pharmaceutical Products in Bulk

Pharmaceutical manufacturing is evolving from traditional batch processes to continuous ones. The new global competition focused on throughput and quality of drug products is certainly the driving force behind this transition which, thus, represents the new challenge of pharmaceutical manufacturing and hence of lyophilization as a downstream operation. In this direction, the present review deals with the most recent technologies, based on spray freeze-drying, that can achieve this objective. It provides a comprehensive overview of the physics behind this process and of the most recent equipment design.

Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing of Pharmaceuticals

Disadvantages of the traditional batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent-intensive, solvent recovery is necessary to achieve the goal of sustainable manufacturing. A simple vapor–liquid equilibrium (VLE) setup was designed, and its reliability was assessed, from which the VLE data for a two-solvent system were obtained and, accordingly, the distillation columns were designed. The recovered solvent purities were >99.9 wt % for the first solvent (Solvent 1) and >99.8 wt % for the second solvent (Solvent 2), and the recovery yields were 94.9% and 98.3%, respectively. From the E-factor analysis, approximately 30% less waste was generated in the ICM process compared with a corresponding batch process. After integration of the solvent recovery system, the E-factors for both the batch and ICM processes decreased significantly, from 1.63 to 0.29 and from 0.77 to 0.21, respectively.

Design space and robustness analysis of batch and counter-current frontal chromatography processes for the removal of antibody aggregates

Increasing molecular diversity and market competition requires biopharmaceutical manufacturers to intensify their processes. In this respect, frontal chromatography on cation exchange resins has shown its potential to effectively remove aggregates. However, yield losses during the wash step need to be accepted in order to ensure robust product quality. In this work, we present a novel counter-current frontal chromatography process called Flow2, which uses inline dilution during an interconnected wash phase to allow high monomer recovery without contaminating the product pool with impurities. Its model-based design spaces under purity and yield constraints are compared with those corresponding to traditional batch processes in terms of size and process attributes yield and productivity. The Flow2 process shows the largest extent of feasible operating points independent of feed conditions. Thereby, it allows the implementation of higher ionic strength wash, thus widening the range of operating conditions resulting in yields above 95% compared to batch processes. Productivities of batch and counter-current processes are the same at short regeneration times and equal residence time. However, long regeneration times, while influencing the size of the Flow2 design space, are not detrimental for its productivity resulting in twice as high values as obtained for the batch process. Furthermore, process robustness is evaluated by the ability of the process to maintain the required product quality when subjected to process parameter perturbations. It is found that the Flow2 process is able to retain a larger design space associated also with higher yields showing its ability to improve process attributes without sacrificing robustness at the same time.

Automated and Continuous Production of Polymeric Nanoparticles.

Polymeric nanoparticles (NPs) are increasingly used as therapeutics, diagnostics, and building blocks in (bio)materials science. Current barriers to translation are limited control over NP physicochemical properties and robust scale-up of their production. Flow-based devices have emerged for controlled production of polymeric NPs, both for rapid formulation screening (~μg min−1) and on-scale production (~mg min−1). While flow-based devices have improved NP production compared to traditional batch processes, automated processes are desired for robust NP production at scale. Therefore, we engineered an automated coaxial jet mixer (CJM), which controlled the mixing of an organic stream containing block copolymer and an aqueous stream, for the continuous nanoprecipitation of polymeric NPs. The CJM was operated stably under computer control for up to 24 h and automated control over the flow conditions tuned poly(ethylene glycol)-block-polylactide (PEG5K-b-PLA20K) NP size between ≈56 nm and ≈79 nm. In addition, the automated CJM enabled production of NPs of similar size (Dh ≈ 50 nm) from chemically diverse block copolymers, PEG5K-b-PLA20K, PEG-block-poly(lactide-co-glycolide) (PEG5K-b-PLGA20K), and PEG-block-polycaprolactone (PEG5K-b-PCL20K), by tuning the flow conditions for each block copolymer. Further, the automated CJM was used to produce model nanotherapeutics in a reproducible manner without user intervention. Finally, NPs produced with the automated CJM were used to scale the formation of injectable polymer–nanoparticle (PNP) hydrogels, without modifying the mechanical properties of the PNP gel. In conclusion, the automated CJM enabled stable, tunable, and continuous production of polymeric NPs, which are needed for the scale-up and translation of this important class of biomaterials.

High-Throughput Template-Free Continuous Flow Synthesis of Polyaniline Nanofibers

The large-scale and high-throughput synthesis of conjugated polymer based nanofibers always remain a challenge for the chemists due to the issues related to secondary nucleation in traditional batch processes. Typically polyaniline (PANI) nanofibers are synthesized under highly dilute conditions resulting in a very low throughput of few hundred milligrams per hour and a low space-time yield (STY) of 1–2 g·L–1·h–1. In this manuscript, we report the continuous flow synthesis of PANI nanofibers which results in high throughput (17–30 g·h–1) and high space-time yield (140–450 g·L–1·h–1). These polyaniline nanofibers show high surface area (42 m2·g–1), high specific capacitance (577 F·g–1), and high crystallinity. Finally, the present method is generic in nature and, in principle, can be extended for the synthesis of nanofibers of other conjugated polymers via oxidative polymerization.

A review on high throughput roll-to-roll manufacturing of chemical vapor deposition graphene

The interest in graphene has surged over the past few years due to its exceptional mechanical, thermal, electrical, and optical properties, as well as its potential for flexible electronic applications. The traditional batch process for graphene synthesis and transfer need to be replaced by a high throughput, low-cost manufacturing process in order to enable mass production of graphene-based devices. Roll-to-roll (R2R) manufacturing and its related enabling technologies have been employed for both graphene growth and transfer, the two essential steps in graphene fabrication. It has been demonstrated that large-scale graphene production is feasible and has the potential to achieve economic success in the near future. This review provides an analysis of the state-of-the-art R2R manufacturing techniques for large-scale graphene fabrication. Different growth and transfer methods are compared. The benefit, limitation, and future outlook of R2R graphene fabrication are discussed. It is expected that through this review a benchmark is established for future development in R2R large-scale graphene production.

Simulation and energy analysis of the ABE fermentation integrated with gas stripping

The production of acetone, n-butanol and ethanol (ABE) by fermentation has recently gained renewed attention to produce fuels and chemicals from renewable resources.The main problem associated with the ABE fermentation is the self-inhibition of the process due to butanol toxicity to the culture. The use of a separation method, which enables selective removal of toxic components from the fermentation broth, may contribute to improve the economics of such process.This work concerns the recovery of butanol from a batch fermenter, in which the ABE mixture is recovered from the broth by means of gas stripping. The aim of this work is to compare the performances of the integrated fermentation-gas stripping process with those of a conventional batch fermenter. For this purpose, both processes have been modeled and their energy requirements have been determined by means of an energy analysis. Results suggest that the continuous product removal from the fermenter allows to reduce the fermentation time by 50%. Therefore, the process productivity is almost double. At the same time, the total specific energy requirement for the integrated recovery process is almost three times greater than that of the traditional batch process. This is essentially due to the duty required at the condenser for products recovery from the gas stream, as a result of the low concentration of ABE in the recovered stream. Therefore, the application of an integrated recovery process allows to increase the process productivity, but at the expense of an increase in the whole process energy demand.

Image analysis framework with focus evaluation for in situ characterisation of particle size and shape attributes

Particle processing industries, such as pharmaceutical, food processing and consumer goods sectors, increasingly require strategies to control and engineer particle attributes. In both traditional batch and continuous processes, particle size and shape need to be effectively monitored through in-line measurements from Process Analytical Technologies. However, obtaining quantitative information from these measurements has proven to be challenging and in-line imaging techniques are primarily used for qualitative purposes. Two key challenges are: (1) the presence of out-of-focus objects and (2) images only represent 2D projections of three-dimensional objects. In this work, a novel framework to process frames from in-line imaging probes incorporates a focus evaluation step in order to extract meaningful quantitative shape and size information through rejection of out-of-focus particles. Furthermore, a model is proposed that simulates the 2D projection of three-dimensional particles onto the focal plane and computes the corresponding size and shape distributions. The framework is quantified and evaluated against standard particles of well-defined size and shape such as polystyrene microspheres and needle-like cuboid silicon particles.

Scalable manufacturing of carbon nanotubes on continuous carbon fibers surface from chemical vapor deposition

A novel process has been successfully developed to grow carbon nanotubes (CNTs) on continuously moving carbon fibers (CF) surface by a unique open-ended chemical vapor deposition (CVD) furnace. Systematic researches were carried out under various deposition temperatures, velocities of continuous carbon fibers and catalyst concentrations. The morphologies and structures of CNTs were investigated by field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopy (HRTEM), which indicated clearly that carbon fibers with uniformly distributed CNTs were achieved, with the optimum parameters of 650 °C deposition temperature and 6 cm min−1 velocity of continuous carbon fibers and 0.05 M catalyst concentration, respectively. By means of the single fiber push-out tests, the interfacial shear strength (IFSS) of carbon fibers growing CNTs was increased significantly by 84.4% compared to the desized carbon fibers. Furthermore, the results of single fiber tensile test verified that there is scarcely any degradation in the mechanical properties of carbon fibers after the growth of CNTs with the optimum parameters. This study provides a new and original vision for scalable manufacturing of CNTs on continuous moving substrate, when compared to the traditional batch process.

AUTOMATED SYSTEM FOR CONTINUOUS MICROALGAE CULTIVATION IN PHOTOBIOREACTORS

The objective of this work was to design a automate system for microalgae cultivation on a continuous modes in laboratory scale and allow its remote monitoring and control. For this, a sensor were developed is able to measure biomass concentration. The concentration sensor used the principle of light scattering, that is, by measuring the turbidity of the culture medium by the use of a set of phototransistor and green led. It presented an mean absolute percentage error of 8.46% during the experiment. A pH, temperature and light sensor were also installed. The control of all the sensors was accomplished by means of an microcontroller. For remote control and monitoring of the controller, a database was designed and implemented on a Raspberry Pi connected to the network. The graphics and data collected are available on an HTML page that allows changes in the control mode of the photobioreactor, for example by changing the dilution rates. The controller was able to operate the photobioreactor in batch mode, as well as to maintain the culture operating in continuous regime. The continuous production of microalgae biomass in a continuous regime showed productivity 74.5% higher than the traditional batch process and 28.2% higher than semicontinuous cultivation.

Organocatalytic α-trifluoromethylthiolation of silylenol ethers: Batch vs continuous flow reactions

This work describes the organocatalytic α-trifluoromethylthiolation of silylenol ethers using N-(trifluoromethylthio)saccharin as trifluoromethylthiolating reagent that is activated by the presence of catalytic amounts of a Lewis base. Tetrahydrothiophene was identified as the best organocatalyst and it was successfully employed to promote the synthesis of different α-trifluoromethylketones; the reaction has been performed under a traditional batch methodology and under continuous flow conditions. In general, yields obtained using the traditional batch process were higher than those observed when the reaction was performed under flow conditions. However, short reaction times, higher productivity and higher space time yields were observed when a flow system process was employed. Preliminary DFT calculations were also performed in order to elucidate the mechanism of the reaction.

Diagnosis of incipient fault conditions in batch processes using estimated data covariance structures

This paper revisits the monitoring of traditional batch processes and introduces a different concept to diagnose incipient fault conditions. Traditional data-driven methods utilize a 3D arrangement of recorded data from a number of reference batches and unfold this arrangement to construct conventional non-negative squared monitoring statistics. To address the presence of non-stationary and non-Gaussian distributed process variables, the proposed concept relies on the statistical local approach. Following from the central limit theorem, the statistics derived from the statistical local approach have an asymptotic multivariate normal distribution. Moreover, the moving window approach that underlies the statistical local approach is applied over the entire batch cycle. This, in turn, allows describing the typically nonstationary trends in temperature and pressure variables as well as concentrations within a batch cycle. Through an application to a simulated penicillin fermentation process, the paper shows that monitoring statistics derived from the statistical local approach are more sensitive than traditional multivariate statistical methods.