Traditional Batch Processes Research Articles

Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis.

Flow synthesis is becoming increasingly relevant as a sustainable and safe alternative to traditional batch processes, as reaction conditions that are not usually achievable in batch chemistry can be exploited (for example, higher temperatures and pressures). Telescoped continuous reactions have the potential to reduce waste by decreasing the number of separate unit operations (e.g., crystallization, filtration, washing, and drying), increase safety due to limiting operator interaction with potentially harmful materials that can be reacted in subsequent steps, minimize supply chain disruption, and reduce the need to store large inventories of intermediates as they can be synthesized on demand. Optimization of these flow processes leads to further efficiency when exploring new reactions, as with a higher yield comes higher purity, reduced waste, and a greener synthesis. This project explored a two-step process consisting of a three-phase heterogeneously catalyzed hydrogenation followed by a homogeneous amidation reaction. The steps were optimized individually and as a multistep telescoped process for yield using remote automated control via a Bayesian optimization algorithm and HPLC analysis to assess the performance of a reaction for a given set of experimental conditions. 2-MeTHF was selected as a green solvent throughout the process, and the heterogeneous step provided good atom economy due to the use of pure hydrogen gas as a reagent. This research highlights the benefits of using multistage automated optimization in the development of pharmaceutical syntheses. The combination of telescoping and optimization with automation allows for swift investigation of synthetic processes in a minimum number of experiments, leading to a reduction in the number of experiments performed and a large reduction in process mass intensity values.

Lignocellulose Treatment Using a Flow-Through Variant of OrganoCat Process.

This study adapts the biphasic OrganoCat system into a flow-through (FT) reactor, using a heated tubular setup where a mixture of oxalic acid and 2-methyltetrahydrofuran (2-MTHF) is pumped through beech wood biomass. This method minimizes solvent-biomass contact time, facilitating rapid product removal and reducing the risk of secondary reactions. A comparative analysis with traditional batch processes reveals that the FT system, especially under severe conditions, significantly enhances extraction efficiency, yielding higher amounts of lignin and sugars with reduced solid residue. Notably, the FT system shows partial hydrolysis of the cellulose, which increases with temperature while not producing significant amounts of furfural or 5-HMF, indicating more efficient depolymerization of polysaccharides without substantial sugar degradation. A statistical design of experiments (DOE) using a Box-Behnken design elucidates the influence of process variables (time, solvent flow rate, temperature) on the yield. Key findings highlight reactor temperature as the dominant factor affecting yields, with process time showing a significant but less pronounced impact. This study demonstrates the potential of the FT OrganoCat system for efficient lignocellulosic biomass fractionation and represents an advancement towards continuous lignocellulose processing, contributing to our knowledge of process optimization for improved biorefinery applications.

Covalent organic framework membrane reactor for boosting catalytic performance

Membrane reactors are known for their efficiency and superior operability compared to traditional batch processes, but their limited diversity poses challenges in meeting various reaction requirements. Herein, we leverage the molecular tunability of covalent organic frameworks (COFs) to broaden their applicability in membrane reactors. Our COF membrane demonstrates an exceptional ability to achieve complete conversion in just 0.63 s at room temperature—a benchmark in efficiency for Knoevenagel condensation. This performance significantly surpasses that of the corresponding homogeneous catalyst and COF powder by factors of 176 and 375 in turnover frequency, respectively. The enhanced concentration of reactants and the rapid removal of generated water within the membrane greatly accelerate the reaction, reducing the apparent activation energy. Consequently, this membrane reactor enables reactions that are unattainable using both COF powders and homogeneous catalysts. Considering the versatility, our findings highlight the substantial promise of COF-based membrane reactors in organic transformations.

Process intensification in flow chemistry using micro and millidevices: Numerical simulations of the syntheses of three different intermediate API compounds for diabetes mellitus drug production

Microreactor Technology (MRT) appears as an interesting alternative for process intensification, including the development of continuous synthesis of fine chemicals and Active Pharmaceutical Ingredients (API). The inherent proposal of MRT is to reduce the scale-up time by simply increasing the number of microreactors in parallel, the numbering-up concept using optimal designed micro or millidevices. Among the API, rosiglitazone and lobeglitazone are derivatives of thiazolidine-2,4-dione (TZD), which is used as a building block, for molecules with biological activity, sensitive to insulin and, thus, with its administration the body makes better use of the insulin it produces, being an important structural element in medicinal chemistry, especially for type 2 diabetes mellitus, one of the biggest concerns in the health area worldwide, affecting nowadays more than 180 million people. The numerical assessment of MRT for various API synthesis related to type 2 diabetes mellitus drugs indicates its comparable or superior performance compared to traditional batch process. Specifically, proposed micromixer designs facilitate successful scale-up to milliscale while maintaining microscale performance, with significantly lower pressure drops than commercial Asia microreactors. The proposed flow distributors offer good performance in ensuring uniform distribution across outlets due to their conical shape design and laminar flow regime, with low pressure drops. The flow distributor with eights outlet is preferred for higher flow rates due to its superior performance, minimizing the pressure drops. Efficient flow rate and molar concentration control at each reactor unit can be ensured by using one distributor for each reactant's feed stream. This approach guarantees accurate concentration, flow rate control and ideal residence time, ultimately facilitating higher total throughput for scale-up. The potential use of micromixer actuators lies in its ability to maintain or enhance performance while transitioning from micro to milli-scale, offering promising alternatives for process intensification and scale-up in pharmaceutical synthesis, particularly for medications targeting type 2 diabetes mellitus.

Biological Removal of Zinc (II) by Fusarium solani under Different Modes of Operational Strategies: A Comparative Study

The goal of the current batch biosorption experiment was to determine how well Fusarium solani (isolated from soil) resting cells could remove zinc (II) from aqueous solution. With an increase in pH (up to pH 5.0) and an increase in initial zinc (II) concentration of up to 500 mg/L, the specific zinc (II) removal increases. By increasing biomass content from 2.5 to 5.5 g/L, the specific zinc (II) removal remained nearly constant. The investigations also utilised resting cells from various growth stages and at an initial zinc (II) concentration of 500 mg/L, the maximum specific zinc (II) uptake (51.7 mg/g) was accomplished (36 h old). The comparison of the results revealed that cells in a growing state (63.9 mg/g) can achieve the highest selective uptake. Hence, the uptake of zinc(II) under various operational strategies was only done with growing cells. The biological uptake of zinc (II) was then done in a fed batch mode of operation using Fusarium solani growing cells. Increased volume pulse feeding (IVPF) and constant volume pulse feeding (CVPF) were used to study the fed batch process and the impacts of these operational methods on biological performance were contrasted with those of a traditional batch process. According to batch experiments, at pH 5.0 and an initial zinc (II) ion concentration of 500 mg/l, the maximum specific zinc (II) removal was 63.9 mg/g. The maximal specific zinc (II) removal in the IVPF process was determined to be 45.47 mg/g and 33.58 mg/g, but the values in the CVPF process were 33.12 mg/g and 22.59 mg/g respectively for the first and second pulse feedings in both cases. The zinc (II) uptake found in prior investigations carried out by the current authors employing the continuous mode of operation was then compared with these results. The process could be run for a longer period of time with a maximum specific zinc (II) removal of 52.8 mg/g when operating in a continuous mode which was shown to be the optimal operational strategy.

Evaluating end-to-end continuous antibody manufacture with column-free capture alternatives from economic, environmental, and robustness perspectives.

Process intensification efforts have renewed interest in the potential of end-to-end continuous manufacture with column-free capture alternatives. This article describes a decisional tool that encompasses mass balance and design equations, process economics, stochastic simulation and multi-criteria decision-making and enables the evaluation of different batch, and continuous flowsheets for monoclonal antibody (mAb) manufacture. The traditional batch process was compared with end-to-end continuous bioprocesses with either protein A capture or column-free capture employing aqueous two-phase extraction or precipitation from economic, environmental, and robustness perspectives. The cost of goods analysis predicted that continuous flowsheets could offer substantial cost savings (~20%-40%) over the batch process at low and medium annual commercial demands (100-500 kg); however, at tonnage demands they resulted in either comparable or higher costs. Comparing the continuous options, the continuous flowsheets with protein A or precipitation yielded similar COG/g values, while aqueous two-phase extraction presented higher costs. The analysis of overall process mass intensities accounting for water and consumables suggested that the continuous flowsheet with protein A would result in the lowest environmental burden. When the economic, environmental, and operational criteria were reconciled using multi-criteria decision-making analysis, the continuous protein A-based flowsheet was found to be the most favorable. A target analysis highlighted the need for process improvements in the following parameters to reduce the manufacturing costs of the continuous column-free capture options below that of protein A: the perfusion volumetric productivity, the harvested cell culture fluid percentage in column-free operations, the column-free step yields along with the implementation of buffer concentrates.

Artificial Neural Network Modelling Hydrodenticity for Optimal Design by Microfluidics of Polymer Nanoparticles to Apply in Magnetic Resonance Imaging.

The engineering of nanoparticles impacts the control of their nano-bio interactions at each level of the delivery pathway. Therefore, optimal nanoparticle physicochemical properties should be identified to favour on-target interactions and deliver efficiently active compounds to a specific target. To date, traditional batch processes do not guarantee the reproducibility of results and low polydispersity index of the nanostructures, while microfluidics has emerged as cost effectiveness, short-production time approach to control the nanoparticle size and size distribution. Several thermodynamic processes have been implemented in microfluidics, such as nanoprecipitation, ionotropic gelation, self-assembly, etc., to produce nanoparticles in a continuous mode and high throughput way. In this work, we show how the Artificial Neural Network (ANN) can be adopted to model the impact of microfluidic parameters(namely, flow rates and polymer concentrations) on the size of the nanoparticles. Promising results have been obtained, with the highest model accuracy reaching 98.9%, thus confirming the proposed approach's potential applicability for an ANN-guided biopolymer nanoparticle design for biomedical applications. Nanostructures with different degrees of complexity are analyzed, and a proof-of-concept machine learning approach is proposed to evaluateHydrodenticityin biopolymer matrices. STATEMENT OF SIGNIFICANCE: Size, shape and surface charge determine nano-bio interactions of nanoparticles and their ability to target diseases. The ideal nanoparticle design avoids off-target interactions and favours on-target interactions. So, tools enabling the identification of the optimal nanoparticle physicochemical properties for delivery to a specific target are required. In this work, we evaluate the use of Artificial Neural Network (ANN) to analyze the role of microfluidic parameters in predicting the optimal size of the different hydrogel nanoparticles and their ability to trigger Hydrodenticity.

Smart batch process: The evolution from 1D and 2D to new 3D perspectives in the era of Big Data

Big Data will revolutionize modern industry by improving process optimization, facilitating insight discovery, and improving decision-making. This big data revolution presents a multitude of possibilities and challenges in evolving from traditional batch processes to smart batch processes. This tremendous potential requires the ability to extract value from vast amounts of industrial process data. Using a new three-dimensional (3D) perspective of time, batch, and operational context, this paper explores smart batch processes with higher efficiency, greater profitability, and longer sustainability. First, we review the traditional one-dimensional (1D) perspective on batch processes and summarize the existing two-dimensional (2D) perspectives on batch processes, i.e., modeling, monitoring, control, and optimization methods. Based on those results, the spotlight will focus on how big data can be used to achieve smart batch processes using the 3D perspective. This will include detailed discussions of definitions and concepts, operational mechanisms, and the benefits and advantages of smart batch processes. For further implementation of the 3D perspective, we present several monitoring and control methodologies. Next, we analyze several challenges and issues in implementing smart batch processes in the era of Big Data. In conclusion, we provide both a novel viewpoint and encouragement for future research into batch process automation from the 3D perspective.

Integrated Continuous Wet Granulation and Drying: Process Evaluation and Comparison with Batch Processing.

The pharmaceutical industry is in the midst of a transition from traditional batch processes to continuous manufacturing. However, the challenges in making this transition vary depending on the selected manufacturing process. Compared with other oral solid dosage processes, wet granulation has been challenging to move towards continuous processing since traditional equipment has been predominantly strictly batch, instead of readily adapted to material flow such as dry granulation or tablet compression, and there have been few equipment options for continuous granule drying. Recently, pilot and commercial scale equipment combining a twin-screw wet granulator and a novel horizontal vibratory fluid-bed dryer have been developed. This study describes the process space of that equipment and compares the granules produced with batch high-shear and fluid-bed wet granulation processes. The results of this evaluation demonstrate that the equipment works across a range of formulations, effectively granulates and dries, and produces granules of similar or improved quality to batch wet granulation and drying.

The transition from batch to continuous manufacturing for tablet manufacturing performance comparison and control system review

The pharmaceutical industry is motivated to improve tablet productivity in order to adapt to the expanding drug market. One innovative way is the transition of the traditional batch tablet manufacturing process to a continuous process. This paper aims to review the performance of continuous tablet manufacturing processes. From the comparison of continuous to traditional batch processes, the continuous tablet manufacturing process demonstrates improvements in production flexibility, robustness, and ultimately process profitability. The continuous process is proven to mix drug particles with more evenly distributed size and less segregation resulting in tablets with better quality compared to the traditional batch process. The improvement on the continuous tablet manufacturing process requires robust control system for process automation to counteract process noise and disturbances in process feed. A well-tuned Proportional Integral Derivative (PID) control is sufficient for the process to produce a desirable product. Developing a new algorithm for model predictive control (MPC) and enhancing the control system with MPC-PID control can further improve the system performance. Overall, the transition from batch to continuous tablet manufacturing is supported by pharmaceutical companies as well as organizations like Food and Drug Administration (FDA).

Chitosan, Chitosan/IgG-Loaded, and N-Trimethyl Chitosan Chloride Nanoparticles as Potential Adjuvant and Carrier-Delivery Systems.

This work proposes a feasible, reproducible, and low-cost modified method to manufacture chitosan, chitosan/IgG-protein-loaded, and trimethylated chitosan nanoparticles, using microfluidics combined with the microemulsion technique, which differs from the traditional batch process of chitosan-based nanoparticles. The synthesis process consists of generating microreactors of chitosan-based polymer in a poly-dimethylsiloxane ψ-shaped microfluidic device and then crosslinking with sodium tripolyphosphate outside the cell. Transmission electron microscopy demonstrates an improvement in size control and distribution of the solid-shape chitosan nanoparticles (~80 nm) compared to the batch synthesis. Regarding chitosan/IgG-protein-loaded nanoparticles, these presented a core-shell morphology having a diameter of close to 15 nm. Raman and X-ray photoelectron spectroscopies confirmed the ionic crosslinking between the amino groups of chitosan and the phosphate groups of sodium tripolyphosphate in the fabricated samples and the total encapsulation of IgG protein during the fabrication of chitosan/IgG-loaded nanoparticles. Then, an ionic crosslinking and nucleation-diffusion process of chitosan-sodium tripolyphosphate was carried out during the nanoparticle formation, with and without IgG protein loading. The use of N-trimethyl chloride chitosan nanoparticles in vitro on human-keratinocyte-derived cell line HaCaT did not show side effects independently of its concentration from 1 to 10 μg/mL. Therefore, the proposed materials could be used as potential carrier-delivery systems.

Fundamental and Development of Microreaction Technology for the Application of Fine Chemicals Synthesis

The fine chemical process has many environmental and safety problems related to the unavoidable use of various organic reactions which are highly involved with exothermic reactions, explosive intermediates, corrosive reagents, toxic or reactive gases, flammable and pyrophoric compounds, and extreme conditions. Limited by the traditional batch process, the efficiency of these reactions should be manually lowered to keep the reaction from going out of control. Benefiting from its rapid transfer of reaction heat, efficient micro-mixing of ingredients, and minimal hold-up of hazardous reagents, continuous-flow microreaction synthesis has emerged as a new technology for producing fine chemicals efficiently and safely in the last two decades. Here, we will introduce some recent progress on the fundamentals and developments of efficient, green, and safe processes for fine chemical synthesis using microreaction technology mainly by our group, including rearrangement reaction, cycloaddition reaction, diazotization reaction, coupling reaction, alkylation reaction, and sulfonation reaction. Based on our research progress, the development of microreaction technology in fine chemical synthesis was discussed here, including applying online analysis and intelligent algorithms to improve the efficiency of the development of microreaction systems from lab scale to commercial production, extending the application of microreaction technology to solid or particle treatment, studying the behaviors of heterogeneous reactions, revealing principles for scaling up heterogeneous reactions in specialized microreactors, and decision toolbox considering both the characteristic of the microreaction system and the overall goal of the industry.

Continuous Flow Synthesis of Substituted 3,4-Propylenedioxythiophene Derivatives

We report a continuous flow method for the process intensification of commercially important propylenedioxythiophene (ProDOT) monomers. A new four-step synthetic route was designed to make the whole process more economical and continuous flow amenable. Apart from being safe and having a higher throughput via continuous flow, we could optimize each of the synthetic steps to quantitative conversion. GC–MS analysis was used to monitor each of the processes during optimization. The overall process could be completed in around 65 min, starting from the commercially available materials, as compared to the few days via the reported batch processes. Furthermore, we have shown that the most critical step of the Williamson etherification could be intensified via continuous flow to the space–time yield (STY) of 63 g/h/L as compared to 0.16 g/h/L via the traditional batch process. As all the synthetic steps in our continuous flow process were optimized to quantitative conversions, it opens up the possibility of telescoping of the whole process. We believe that our findings will be able to fill the existing gap in the process intensification for the synthesis of commercially important ProDOT-based monomers.

Alternate end-game strategies towards Nirmatrelvir synthesis: Defining a continuous flow process for the preparation of an anti-COVID drug

Scalable alternate end-game strategies for the synthesis of the anti-COVID drug molecule Nirmatrelvir (1, PF-07321332) have been described. The first involves a direct synthesis of 1 via amidation of the carboxylic acid 7 (suitably activated as a mixed anhydride with either pivaloyl chloride or T3P) with the amino-nitrile 10·HCl. T3P was found to be a more practical choice since the reagent promoted efficient and concomitant dehydration of the amide impurity 9 (derived from the amino-amide contaminant 8·HCl invariably present in 10·HCl) to 1. This observation allowed for the development of the second strategy, namely a continuous flow synthesis of 1 from 9 mediated by T3P. Under optimized conditions, this conversion could be achieved within 30 min in flow as opposed to 12–16 h in a traditional batch process. The final API had quality attributes comparable to those obtained in conventional flask processes.

Synthesis of insoluble sulfur and development of green technology based on Aspen Plus simulation

Abstract The continuous process for the production of insoluble sulfur (IS) has been developed to overcome the disadvantages associated with the traditional batch process, such as low automation, discontinuous production, and high consumption of sulfur and CS2. The consumption of CS2 in the continuous process is lower than that in the batch process. The recovery of solvent facilitates the recycling of CS2 and N2 in addition to the closed circulation of the entire system. The key process and recovery parameters of the IS synthesis were simulated using Aspen Plus. Sulfur was completely recovered after high-temperature pyrolysis, and the utilization ratio of sulfur atoms was increased from approximately 50% to more than 95%. Tail gas was comprehensively utilized through compression and cryogenic green treatment. Based on the developed green synthesis process and simulated process parameters, the continuous production of IS was evaluated on an industrial scale of 10,000 metric tonnes. Owing to the continuous characteristics of the production process, the air tightness of the production process was significantly improved, and the quality of the product was more stable than that of the product obtained by the current domestic batch process. The unconverted sulfur could be recycled after recovery, without low-grade sulfur as a by-product. The amount of sulfur used as raw material per unit product was reduced; the comprehensive conversion rate of sulfur to IS exceeded 95%, which significantly improved the utilization rate of sulfur atoms. Through the compression and condensation of the tail gas, the recovery efficiency of CS2 was considerably improved at the same temperature, and compressed N2 could be simultaneously obtained. The liquefaction rate of CS2 approached 91.78%, which was characterized by obvious greening.

Converting a mAb downstream process from batch to continuous using process modeling and process analytical technology.

The biopharmaceutical market is driving the revolution from traditional batch processes to continuous manufacturing for higher productivity and lower costs. In this work, a batch mAb downstream process has been converted into an integrated continuous process with the combination of multiple techniques. For process intensification, two batch mode unit operations (protein A capture chromatography, ultrafiltration/diafiltration) were converted into continuous ones; for continuity, surge tanks were used between adjacent steps, and level signals were used to trigger process start or stop, forming a holistic continuous process. For process automation, manual operations (e.g., pH and conductivity adjustment) were changed into automatic operation and load mass was controlled with process analytical technology (PAT). A model-based simulation was applied to estimate the loading conditions for the continuous capture process, resulting in 21% resin capacity utilization and 28% productivity improvement as compared to the batch process. Automatic load mass control of cation exchange chromatography (CEX) was achieved through a customized in-line protein quantity monitoring system, with a difference of less than 1.3% as compared to off-line analysis. Total process time was shortened from 4 days (batch process) to less than 24hours using the continuous downstream process with the overall productivity of 23.8g mAb per day for the bench-scale system. Comparable yield and quality data were obtained in three test runs, indicating a successful conversion from a batch process to a continuous process. The insight of this work could be a reference to other similar situations.

Highly efficient synthesis and application of aryl diazonium salts via femtosecond laser-tailored 3D flow microfluidic chips

The first example of the microfluidic chips (MFCs) consisting of centimeter-level 3D channels with high-density and large-volume fabricated by femtosecond laser micromachining were utilized to develop a time-saving, economical and hazardless flow synthesis process, and its advantages have been proved by in situ formation of aryldiazonium salts and subsequent borylation with bis(pinacolato)diboron. There are several important advantages in our 3D MFC-based flow synthesis technology, including the following: (1) the reaction temperature was altered from ice bath to room temperature; (2) the residence time was reduced by 10 times; (3) the yield was greatly improved, that is, several arylboronates were successfully obtained with higher yield compared to traditional batch process. Therefore, it can be envisioned that a novel, simplified flow synthetic protocol will be developed toward green organic synthesis via MFCs.

Batch-screening guided continuous flow synthesis of the metal-organic framework HKUST-1 in a millifluidic droplet reactor

Metal-organic frameworks (MOFs) are a class of crystalline and porous adsorbents, with wide-ranging applications in gas separations, membrane materials as well as sensors. Commonly used batch synthesis techniques for MOF production are limited by low productivity, high operating costs, and slow crystallization timescales, severely impeding the large-scale manufacturing of these materials. However, batch synthesis is a useful and easy technique to screen multiple reaction parameters to find an optimal chemistry. Therefore, in this study, we have used the batch process and screened a multidimensional reaction space consisting of 45 sample variations based on the crystallinity, yield, and instantaneous precipitation, which could lead to tube clogging under flow conditions. We have found one optimized reaction chemistry, that could be used in flow conditions, which in this study is a novel millifluidic droplet-based reactor for the continuous synthesis of HKUST-1 crystals. The biphasic flow in the millifluidic reactor consisted of droplets of the reactant solution, dispersed in a continuous phase of silicone oil. We investigate the differences in the quality and quantity of HKUST-1 synthesized via the continuous and batch techniques. Moreover, we have demonstrated that the HKUST-1 samples prepared via the continuous synthesis in a droplet based millifluidic reactor, at an ultra-low residence time exhibit excellent physical properties comparable to that obtained for the samples prepared by the traditional batch process. A clean, easy-to-install, and reusable millifluidic reactor presented in this work may pave the path for an economically viable, large-scale synthesis of HKUST-1.

Integrated Process Analytical Platform for Automated Monitoring of Monoclonal Antibody N-Linked Glycosylation.

The biopharmaceutical industry is transitioning toward the adoption of continuous biomanufacturing practices that are often more flexible and efficient than traditional batch processes. Federal regulatory agencies are further urging the use of advanced process analytical technology (PAT) to analyze the design space to increase the process knowledge and enable high-quality biologic production. Post-translational modifications of proteins, such as N-linked glycosylation, are often critical quality attributes that affect biologics' safety and efficacy, requiring close monitoring during manufacturing. Here, we developed an online sequential-injection-based PAT system, called N-GLYcanyzer, which can rapidly monitor mAb glycosylation during upstream biomanufacturing. The key innovation includes the design of an integrated mAb sampling and fully automated sample derivation system for antibody titer and glycoform analysis within 3 h. The N-GLYcanyzer process includes mAb capture, deglycosylation, released glycan labeling with fluorescent dyes, and labeled glycan enrichment for direct injection/analysis on an integrated high-performance liquid chromatography system. Different fluorescent tags and reductants were tested to maximize glycan labeling efficiency under aqueous conditions, while porous graphitized carbon (PGC) was used for optimizing glycan recovery and enrichment. We found that 2-aminobenzamide labeling of glycans with 2-picoline borane as a reducing agent, using the N-GLYcanyzer workflow, shows higher glycan labeling efficiency under aqueous conditions, leading upward to a 5-fold increase in fluorescent product intensity. Finally, we showcase how the N-GLYcanyzer platform can be implemented at-/online in an upstream bioreactor for automated and near-real-time glycosylation monitoring of a Trastuzumab biosimilar produced by Chinese hamster ovary cells.

Batch versus continuous blending of binary and ternary pharmaceutical powder mixtures

The material properties of excipients and active pharmaceutical ingredients (API's) are important parameters that affect blend uniformity of pharmaceutical powder formulations. With the current shift from batch to continuous manufacturing in the pharmaceutical industry, blending of excipients and API is converted to a continuous process. The relation between material properties and blend homogeneity, however, is generally based on batch-wise blending trials. Limited information is available on how material properties affect blending performance in a continuous process. Here, blending of API and excipients is studied in both a batch and a continuous process. Homogeneity of the resulting mixtures is analyzed, which reveals that the impact of material properties is very different in a continuous process. Where parameters such as particle size, density and flowability have significant impact on blending performance in a traditional batch process, continuous blending is more robust resulting in uniform blends for a large variety of blend compositions.