Conference abstracts
Day 1 – September 18
Keynote: Thomas Rehm, Fraunhofer Institute for Microengineering and Microsystems IMM
What do doughnuts have to do with a sustainable chemical industry?
We are currently facing major changes and inherent challenges due to a changed geopolitical situation, which has been particularly evident in recent years in our dependence on the supply of pharmaceutical products or energy sources. In light of the climate crisis and the urgent need for greater sustainability and environmental protection for future generations, it is imperative that we reconsider the traditional economic models and their underlying principles, which are now jeopardising the planet’s ability to sustain life and the social fabric of our society. This approach is analysed in the so-called Doughnut Economics, which was first formulated more than 10 years ago. The ideas described there align perfectly with the Sustainable Development Goals defined by the UN and roadmaps of research organisations worldwide. In this keynote, we will give an insight into the Doughnut Economics and their ideas for the chemical industry, the visions and the research needs as well as our own approaches for transforming chemistry into a sustainable key technology.
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Dainis Kaldre, F. Hoffmann-La Roche
Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib
This work outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence incorporates multiple telescoped unit continuous operations, including a Br/Mg exchange reaction leading to intramolecular cyclization of the magnesium species onto a neighboring nitrile group to form a five-membered ring in 5-exo-dig fashion. The product from the reaction mixture is obtained after continuous aqueous acidic hydrolysis, neutralization/extraction, water wash, and phase separation. Each of these unit operations took place in a cascade of continuous stirred tank reactors. The control strategy was refined via a series of continuous lab studies at 20 g/h using a Design of Experiments approach to define process parameter ranges and to help identify any criticality therein. The learnings from this laboratory study served as a basis for the construction of a suitable pilot-plant facility, where the control strategy was verified at a representative manufacturing scale of about 1.0 kg/h.
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Giuseppe Menin, COPA-DATA
How Modular Automation unlocks flexibility and digitalization in flow chemistry
The emergence of a new manufacturing paradigm in flow chemistry presents significant challenges for engineers grappling with automation and digitization. Flow chemistry processes involve specialized modules, each designed for specific functionalities and interconnected to produce targeted products. However, these modules often come from different suppliers, each automated by distinct control systems, leading to compatibility issues from a digital integration perspective.
Traditional automation systems, rooted in classical Distributed Control System (DCS) architectures, excel in large batch chemistry equipment but fall short in meeting the demands of high reconfigurability, modularity, and interoperability inherent in this novel production paradigm.
For some years now, the concept of ‘Modular Production’ has been gaining ground, whereby production processes are subdivided into intelligent modules capable of communicating with each other in a standardized manner. Those modules are combined with a software application on top capable of automatically recognizing the services every module is capable to offer and ‘Orchestrating’ their operation according to a user-defined sequence. We call it “Plug & Produce”.
To support this production concept, a standard called MTP – Module Type Package (VDI/VDE/NAMUR 2658) – has been developed and has proven its worth in recent years.
The contribute will introduce the advantages of this new approach based on MTP standard by giving concrete examples of the application of modular automation in the life sciences field, which will compose a concept paper that is currently being developed by ISPE Pharma 4.0 – Plug & Produce Working Group.
In particular, we will see how Merck Darmstadt in Germany is applying modular automation in the process development laboratories and pilot plants.
Furthermore, we will discuss how Modular Automation can address: Paperless operations, Tech Transfer and Flexibility.
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Jeff Derrick, Merck
Development of a Multi-Step Claisen Condensation in Flow
Flow chemistry is a powerful technology that enables transformations that would not be possible in batch. The fast and efficient mixing of reagents and precise control of process parameters allows for the formation of reactive intermediates and immediate consumption in following chemical steps. Towards this end, we have recently demonstrated the applicability of flow chemistry to enable the use of a Claisen condensation reaction to access a key 1,3-ketoester intermediate starting from readily available and inexpensive reagents. Claisen condensations to synthesize masked 1,2,3-tricarbonyl derivatives are rarely reported,6,7 and their implementation in an API manufacturing route is unprecedented. The inherent reactivity challenges of the substrates and intermediates required for such disconnections could explain their scarce synthetic use (Figure 1A). For example, the lack of enolizable protons in the 1,3-ketoester (1) prevents the formation of a stabilized enolate like compound 4 (Figure 1C). Moreover, this absence of enolizable protons creates the possibility of a retro-Claisen condensation since there is no clear thermodynamic sink. Conversely, electrophilic ester 3 can be enolized, potentially leading to the undesired crossed Claisen product and to two additional homo-Claisen products. Despite these challenges, the efficiency and cost-benefit offered by this Claisen disconnection prompted us to find creative solutions to solve these reactivity issues.
Content & Relevance: The proposed oral presentation will cover the early development and scale up of a Claisen condensation. Compared to other synthetic approaches, the Claisen sequence provides access to a key 1,3-ketoester intermeidate in excellent yield, starting from readily available and inexpensive reagents. The solutions to be discussed in this presentation to overcome reactivity challenges associated with this transformation include the design and selection of appropriate electrophile coupling partner, and the implementation of a three-step continuous flow cascade for the generation and immediate consumption of unstable reactive intermediates. The developed Claisen sequence we demonstrated on kilogram-scale highlighting its viability, efficiency, and robustness.
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Lana Borukhova, Sanofi
Innovating Pharmaceutical Manufacturing: The Transition to Hybrid Manufacturing for Small Molecule API Production
The pharmaceutical industry faces significant challenges, including rising development costs, stringent regulatory and environmental demands, and the need for rapid delivery of increasingly complex molecules. Traditional batch manufacturing, while foundational, presents limitations in scalability and efficiency, especially for demanding reactions. The presentation will explore the adoption of hybrid manufacturing in the production of small molecule Active Pharmaceutical Ingredients (APIs), combining the strengths of both batch and continuous manufacturing to enhance sustainability and operational efficiency. The hybrid manufacturing involves reducing reactor sizes, increasing automation levels, and employing modular technology platforms. This strategy aims to sustain operational continuity in batch processes, aligning with advancements in digitalization, automation, and standardization. The integration of continuous and batch processes into a hybrid model offers improved control, reduced cycle times, and enhanced product quality. Modular fabrication further supports rapid implementation and flexibility, enabling the pharmaceutical industry to respond more effectively to changing market demands. Hybrid manufacturing represents a significant leap towards more sustainable and efficient pharmaceutical production. By leveraging smaller, automated reactors and modular technology platforms, this approach promises to accelerate the introduction of new products, reduce environmental impact, and drive the industry towards a more sustainable future.
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Hendrik Held – Ehrfeld Mikrotechnik, Thomas Kretschmar – Hitec Zang
Process automation as key enabler for autonomous optimization in flow chemistry
Automation constitutes an essential component in the modern manufacturing industries and the precise control of chemical processes is no exception. To achieve the full potential of such concepts in the chemical industry it is important to have access to precise and abundant measurements of reaction conditions. At the same time flow chemistry in general and millireactor technology in particular provide exactly this precision with a great number of sensors placed as closely to the process as possible. Continuously operated reactors also provide highly reproducible reaction conditions, thus facilitating process automation. The implementation of automation is a crucial enabling factor for the execution of experimental plans without the involvement of human operators. When coupled with suitable online analytics, optimization algorithms and a suitable model, such systems can autonomously find optimal experimental conditions. This contribution presents two illustrative examples of reactor setups from Ehrfeld Mikrotechnik that have been automated with equipment and software from HiTec Zang. The applied models include surrogate models and physico-chemical reactor models, which are utilized for process optimization and automated kinetic parameter estimation. Target values were analyzed using UV-VIS and NIR techniques. The optimal process conditions or the estimated kinetic model can subsequently be employed for reactor scale-up with relative ease.
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Bernd Werner, Boehringer Ingelheim Pharma
Flow Chemistry at Boehringer Ingelheim – Learnings within a 4+1 Step Campaign
Boehringer Ingelheim (BI) is evaluating Flow Chemistry since more than two decades but only within the last decade also in pilot plant. Many trials did not perform due to e.g. clogging, of those successful outcomes most starved of project stops. Else, the synthetic routes nowadays are more and more designed to outsource just any critical chemistry reducing the chances for potential cases for Flow Chemistry – at least within the GMP part of the API syntheses at BI. Yet Flow Chemistry is still awaiting its breakthrough for BI.
Here we present the success story of a telescoped four-step flow process including a final extraction and a subsequent batch conversion of highly energetic structures, the results, the drawbacks and the learnings we experienced within two pilot plant campaigns.
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Lukas Grahl – Semodia, Sebastian Hartner – Merck Electronics
Using Ontologies for Description of Process Equipment and Process Capabilities
The chemical and pharmaceutical industry is currently facing four critical challenges: Time to Market, Quality, Costs, and Sustainability. In today’s competitive landscape, the speed at which a new product can be developed and brought to market is crucial, as delays can result in lost opportunities and reduced market share. Ensuring the highest quality of products is non-negotiable, especially in industries that directly impact human health, necessitating the consistent meeting of rigorous quality standards and regulations. Additionally, there is constant pressure to reduce costs while maintaining high standards of quality and efficiency. Companies must find ways to streamline processes and eliminate waste without compromising on performance. Furthermore, environmental sustainability is becoming increasingly important, as companies are under pressure to adopt green practices, reduce their carbon footprint, and contribute to a sustainable future.
In addition to these challenges, we are operating in a VUCA (Volatile, Uncertain, Complex, and Ambiguous) world, necessitating a transformation towards a resilient product life cycle ecosystem. At Merck, it was decided to implement MTP (Module Type Package) and POL (Process Orchestration Layer) technology to overcome these hurdles and prepare for the future. A surge in new technologies was observed and designed to address specific process needs, and the catalog of available technologies is expanding rapidly. Therefore, it is essential for Merck to access and integrate these technologies seamlessly into the plant environment.
Moreover, digitalization is evolving rapidly, and semantic data allows Merck to enhance their knowledge of process and asset capabilities. This advancement can be enabled by standardization and open, accessible data spaces, which provide the necessary answers to Merck queries. Ideally, this would lead to a one-stop shop for operators, streamlining operations and enhancing efficiency.
Building on the previous points, the Marketplace by Semodia presents itself as the ideal solution to address the challenges faced by the chemical and pharmaceutical industries such as Merck. The Marketplace connects plant engineers and operators with PEA (Process Equipment Assembly) manufacturers, enabling them to respond efficiently to dynamic market conditions. The platform serves as an interactive space that combines state-of-the-art automation with sophisticated information models that meet the high demands of the industry.
The backbone of this system is Semodia’s innovative information model manifested in an ontology. This ontology is based on open industry standards such as VDI 2776 (1) and the DEXPI Process Specification Model (2). This model allows a detailed and user-friendly visualization of plant components, encompassing both process engineering functions/capabilities and physical specifications. The ontology can be used for specifying PEAs functionalities in an early engineering phase already. Afterwards it is further enriched with additional and more detailed descriptions within detailed engineering.
The Marketplace then provides a structured catalog of all available PEAs, accompanied by the detailed specifications on process and physical properties. With a structured search, users can filter specifically for the PEAs they need, ensuring they find exactly those that perfectly fulfill their requirements.
By establishing the Marketplace, Merck and other industry leaders can seamlessly integrate new technologies into their environments, driving efficiency, and maintaining a competitive edge. This platform not only streamlines the process of finding and implementing new equipment but also fosters a more resilient and adaptable production ecosystem especially for continuous flow processes.
In this presentation Sebastian Härtner from Merck explains how important modular systems and the associated modular automation using MTP is and reports on the current challenges of PEA selection from the perspective of plant operators. Semodia highlights how the Marketplace and ontologies help addressing these key challenges. With help of an example of a PEA, the ontology and engineering workflow will be presented in more detail. The adaptability of such ontologies in combination with the use of open industry standards enable companies to efficiently integrate new technologies and respond swiftly to changing market conditions.
References
VDI 2776 Blatt 1-2, Verfahrenstechnische Anlagen – Modulare Anlagen, 2020-2021
DEXPI Process Specification release v1.0 DEXPI Process Specification 1.0 released – DEXPI, 15.12.2
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Di Sha, Ou Shisheng
Application of Continuous Flow Microreactors in Chemical Synthesis Processes
The traditional intermittent process is currently challenging to control accurately in terms of process parameters, product structure, and performance. This is mainly due to its macroscopic scale, which leads to poor product uniformity and significant safety risks during process. Therefore, both the scientific and industrial community are actively searching ways to achieve safe, controllable, and efficient chemical preparation. In this regard, microreactors have proved to be a promising solution due to their miniaturization, integration, high safety standards, and excellent mass and heat transfer efficiency. Consequently, microreactor technology has already been adopted in pharmaceutical and fine chemical industrial projects in Europe, showing great potential for chemical preparation. However, there are still many challenges to overcome. We have been focused on the application of microreactors in hazardous chemical synthesis processes, particularly for special reactions such as microreaction hydrogenation (nitroreduction, deprotection, pyridine derivative reduction, cyano reduction and double bond reduction) and microreaction synthesis (nitration reaction, low temperature reaction, high temperature reaction, and oxidation reaction). We also explored future research directions and emphasized the need for large-scale production, waste treatment, and the development of intelligent platforms in the field of microreactor technology.
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Simon Coleman, AWL
Modular Type Packages (MTP) & Continuous Rapid API Development Systems
DEC Group is a leading supplier of true end-to-end solutions. Alconbury Weston Ltd (AWL), part of the DEC Group, supplies continuous reaction, crystallization and filtration/drying equipment.
One of the key challenges in process development is the requirement for flexibility. Modular Type Packages (MTP) are becoming an increasingly popular approach within some of the major Pharma groups and other industries. AWL will demonstrate how Modular Type Packages can be used to allow for flexible and configurable connections of unit operation modules, and how this can deliver multi-modular systems for both development and production.
Case Studies will be presented describing the translation from lab to Production scale Systems. This includes some recent work on a process for production of silica developed by Technische Universität Berlin, involving a continuous reaction, solid/liquid extraction, filtration and drying processes.
The talk will also discuss Rapid API Development platforms. One of the major bottle necks in API development is the time and resource required to carry out multiple experiments as part of an extensive Design of Experiments. In some cases, this can require 3 months of lab work and analysis.
A Case Study carried out with one of the top ten pharma companies will be presented describing how AWL’s continuous processing technology can be used to significantly reduce the time in API development from months to days. The talk will show how the platform incorporates automated reaction, crystallisation, filtration, washing, drying, solids discharge and collection in bottles, as well as automatic data population of the results of each sub-batch. The system allows the process to already be validated at lab-scale for use in a continuous process at production scale.
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Fireside chat: Nima Yazdanpanah – Procegence, Howard Stamato – Stamato Solutions, Sebastian Hartner – Merck Electronics
Hacking the Digital World
The rate of change in the digital world is accelerating. How can you keep up? Open forum discussing the range of tools and applications in the pharmaceutical industry and how to gain support and acceptance of change in a challenging environment with regulatory oversight.
In this session we will discuss different applications of the digitalization methods and tools with a panel expert. The topics range will include mechanistic modeling and simulation, AI/ML, and data driven models in process and product development, process optimization, process control, technology transfer, CMC, and quality control.
DAY 2 – September 19
Keynote: Nima Yazdanpanah, Procegence
System Dynamic, RTD, and Control Strategy Development
The continuous manufacturing platforms include multiple unit operations with seamless connections, and continuous flow of material that goes through different transformations. The system is intrinsically dynamic, which is aimed to be kept under the state-of-control. The System Dynamic evaluation and such knowledge development is required to understand how to keep the system under the state-of-control, what would be the impact of disturbances on downstream steps and product quality, and develop control strategies. Also, the residence time distribution (RTD) for single unit operation, a cluster of equipment, and end-to-end will be required to track the deviation, dispersion, time-to-product, and magnitude-to-product. A combination of these tools and the developed knowledge will be essential for maintaining the process under the state-of-control, developing a control strategy, designing robust control systems, sizing surge tanks, locating deviation points, …. and ensuring consistent product quality.
In this presentation, an industrial scale continuous manufacturing platform of a drug substance with 2 PFRs, 1 CSTR, and 1 surge tank will be used to demonstrate system dynamics, sensitivity analysis, RTD, funnel plots, and control strategies for different disturbance scenarios. The complex chemistry steps include multiple reactions (and side reactions, which generate impurities), that are sensitive to the flow ratio of reagents and the temperature of reactors. Modeling and simulation tools that were utilized for developing the RTD, TTD, dispersion, process design and optimization, and process control protocols development will be discussed. The outcomes of this effort have been used for design space, risk analysis, control strategy, and other required regulatory filling information for the CMC package.
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Laurent Vanoye, Laboratoire CP2M Catalyse
Flow hydrogenation in milli-structured reactors : how to handle moderate or intensive
Hydrogenation is one of the most commonly used chemical reaction in the fine chemical industry and it is mostly conducted in batch. Batch hydrogenation has a number of issues related to the safe handling of powder catalysts which is often toxic, to the difficulty of building up the hydrogen pressure above 10 bar and to the safety concerns of having large volumes of hydrogen.
Continuous hydrogenation has several advantages versus batch, with a safer process, the opportunity to intensify the reaction at high temperature and pressure to make it very cost-effective and the ability to reach high selectivity.
This presentation will focus on continuous hydrogenation with fixed bed catalysts on a pilot reactor, which can be easily scaled-up to the full industrial scale. We will show that by using milli-structured heat exchange reactors, we are able to manage very demanding hydrogenation reactions: The first case will be on acetophenone hydrogenation and will show that it is possible to conduct a moderate hydrogenation with a high selectivity in a milli-structured pack bed reactor. The impact of the reactor configuration (serial parallel) will be discussed.
The second case study will be on Myrcene hydrogenation, a very fast and exothermic reaction and it will show that the high heat exchange capacities of this reactor allows to conduct safely this reaction.
The third case study will be on fatty acid hydrogenation with transition metal catalyst. The aim is to present an alternative to the use of precious metal catalyst for this widely used reaction and to show that by using high hydrogen pressure, it is possible to reach high conversion and very low metal leaching.
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Wen-Chun Zhang, Asymchem
Integration of Continuous Flow Technology with Enzymatic Biotransformation and Advanced Pharmaceutical Material Science
Asymchem is a comprehensive contract development and manufacturing organization (CDMO) with a complete continuum of support from preclinical to commercialization. Founded in 1997, Asymchem offers integrated solutions spanning the entire drug substance and drug product life cycle, backed by cutting-edge technology including flow chemistry and green manufacturing. With R&D and manufacturing operations in China, Europe, and the U.S. and a team of proven experts, we provide a full range of CDMO services for a global client base.
In this presentation, we will delve into how Asymchem leverages its multidisciplinary expertise to enhance enzyme immobilization with continuous flow technology. We will highlight our integration of cutting-edge synthetic biology, advanced pharmaceutical materials, and continuous flow technologies in advancing the field of immobilization enzymatic biotransformation.
We will demonstrate our successful implementation of immobilized enzymatic processes from gram to metric ton scales in cGMP manufacturing facilities with several case studies. These case studies underscore our capability to deliver innovative solutions that meet the stringent demands of modern manufacturing.
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Larry Yuanxian Wang, PharmaBlock
Leveraging Micropacked Bed Technology and Continuous Processes for Sustainable Pharmaceutical Manufacturing on Metric Ton scale
PharmaBlock has integrated micropacked bed technology with continuous chemical processes to significantly advance the manufacturing of pharmaceutical building blocks and intermediates. Our latest work includes two notable projects: Continuous Production of 3-Oxocyclobutane-1-carboxylic Acid on a Metric Ton Scale: Traditional batch methods for producing this intermediate, crucial for drugs like Abrocitinib and Ivosidenib, have been replaced by a novel continuous process. This method, integrating decarboxylation, extraction, and decolorization, has been demonstrated at a 2 metric ton scale to increase production efficiency by 20 times, reduce energy consumption by 68,000 kW, and eliminate 8 tons of hazardous waste.
Innovative Synthesis of tert-Butyl 3-Oxoazetidine-1-Carboxylate (2) and Its Derivative (3): Utilizing air oxidation and reductive amination reactions in a consecutive manner, this two-step process is highly atom-economic and enabled by immobilized ruthenium catalyst with a careful selection of greener reagents and solvents. A highly automated engineering design includes safety features such as monitoring the concentration of acetonitrile vapor and hydrogen, along with an automatic shut-off function. This new process has been successfully demonstrated on a metric ton scale for the oxidation step and 200 kg scale for the reductive amination step, with significant improvements in equipment volume efficiency, Process Mass Intensity, safety, environmental friendliness, and ultimately cost efficiency.
These initiatives exemplify our commitment to green chemistry, showcasing how innovative engineering and process design can drastically reduce the carbon footprint of pharmaceutical manufacturing, improve safety, and lower costs. The success of these projects has earned us two consecutive ACS CMO Excellence in Green Chemistry Awards and positions us at the forefront of sustainable pharmaceutical practices.
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Torsten Stelzer, MIT
Enabling Integrated Continuous Drug Substance Manufacturing
Continuous manufacturing has transformed the operation of modern industry because of processing enhancements. When applied to the production of active pharmaceutical ingredients (APIs), continuous manufacturing can be grouped into continuous synthesis (CS), using flow chemistry for the generation of API molecules and continuous crystallization (CC) for purification and solid formation of APIs suitable for drug product formulations (typical solid).1
While a vast number of publications report novel flow synthesis processes for APIs, e.g.,2,3 their integration with vital CC to produce crystalline APIs (90% of APIs) is elusive, to date.
To reap the benefits of CS developments, close collaborations between the organic chemists and industrial crystallization experts are needed to tackle this rarely reported challenge in endto-end continuous API manufacturing.1,4
In this study, we report the purification for an API obtained by flow synthesis via
continuous crystallization to deliver it as crystalline material ready for formulation. In addition, some challenges identified to hinder the CS-CC process integration will be highlighted, too, contributing to the overarching goal of enabling integrated continuous manufacturing.
References
- O’Mahony, M.; Ferguson, S.; Stelzer, T.; Myerson, A. Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals. In Science of Synthesis: Flow Chemistry in Organic Synthesis; Jamison, T. F., Koch, G., Eds.; Georg Thieme Verlag KG: Stuttgart, 2018; pp 51–102.
- Silva-Brenes, D. V; Emmanuel, N.; Lopez-Mejias, V.; Duconge Soler, J.; Vlaar, C.; Stelzer, T.; Monbaliu, J.-C. M. Out-Smarting Smart Drug Modafinil through Flow Chemistry. Green Chem. 2022, 24, 2094–2103.
- Silva-Brenes, D. V; Reyes-Vargas, S. K.; Duconge, J.; Vlaar, C.; Stelzer, T.; Monbaliu, J.-C. M. Continuous Flow Intensification for the Synthesis of High-Purity Warfarin. Org. Process Res. Dev. 2023.
- Monbaliu, J.-C. M.; Stelzer, T.; Revalor, E.; Weeranoppanant, N.; Jensen, K. F.; Myerson, A. S. Compact and Integrated Approach for Advanced End-to-End Production, Purification, and Aqueous Formulation of Lidocaine Hydrochloride. Org. Process Res. Dev. 2016, 20 (7), 1347–1353.
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Eric Trzeciak, Tacmina corporation
Introducing Smoothflow Pumps: Safely Ensuring Continuous, Precise Flow in Reactor Systems
Pumps are an essential part of continuous flow reactor systems. They must provide continuous, precise flows even under high pressure conditions and maintain stable performance for long periods of time. In addition, many reactors also handle dangerous chemicals, requiring pumps that can safely handle them. In our presentation, we will introduce o
