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Flow chemistry facilitates the reproducibility of chemical processes otherwise inefficient or problematic and allows not only the minimization and optimization of reaction time, but also safety improvement and easy scale up. For this reason, this widely explored technology is generally considered as green methodology. With its cost and energy efficiency, automation provided by flow chemistry is a step toward a much greater sustainability in chemistry. In addition, flow chemistry assists the progress of scalability: the optimization of reaction conditions is faster, and the scaling up of the processes is facilitated. Because of the above-mentioned characteristic, flow processes present clearly advantages over batch production. Nevertheless, not all reactions work when transferred to flow chemistry manufacturing because of solubility’s issue. An integration between batch and flow methodologies needs to be envisaged.

Finally, together with automation, digitalization is another important parameter for an efficient scale up and greener transition. The Digital Twin technology are virtual copies of the physical processes can in fact support the transition towards a more circular scale up and help companies reduce their resources and carbon footprint.

This literature review is therefore organised into two macro-areas:

1. A focus on Flow Chemistry. The first abstract presents a multistep continuous flow synthesis of an API, while in the second and third studies photo- and electro-chemistries are combined with flow chemistry to implement large scale synthesis. Finally, the last abstract presents a comparison between flow and batch production: for one selected compound, flow chemistry was successfully exploited to improve batch process limitations, while problems connected to the second compound showed that flow chemistry should not be considered a priori as a general successful approach for the synthesis of every drug.
2. A focus on Digital Twin: the first abstract provides a detailed definition of digital twin, explains its applications in the manufacturing supply chain and sustainability, and presents a sustainable digital twin implementation framework. The second one presents a novel digital twin ecosystem suitable for testing/process monitoring/remote management of an additive manufacturing machine in a simulated virtual environment. Lastly, in the final abstract digital twin applications in the bio-manufacturing industry are presented.

Liquid-liquid Extraction (LLE) is an often overlooked process step that can lead to different bottlenecks during scale up and production of a wide range of pharmaceuticals, fine chemicals and specialty chemicals in both batch and flow. Often, this slow process requires waiting for a biphasic system to gravity separate out, a method that can take hours to days to accomplish. Furthermore, this settling is often carried out in the same reactor in which the product is made. As a result, valuable reactor space is left unused during a reaction just to accommodate, later on, the extraction solvent. This results in a substantial reduction of plant’s productivity.

Through the use of technology, these hurdles (reduced reactor productivity, slow settling) can be overcome by taking the extraction out of the reactor and into a flow through extraction unit. By combining in-line mass transfer with continuous membrane separation, extractions can now be carried out in significantly less time, while doubling the capacity of the reactor. Here we discuss how this “hybrid” batch/continuous processing can be used to leverage existing batch assets and facilitate the transition to fully continuous processing.

CONGRESS ABSTRACTS
In the following pages you can find the Agenda and abstracts of the two days Congress on Flow chemistry which is organized during Achema at the Flow Chemistry Pavilion, Hall 9.1

The pharmaceutical and specialty chemical industry is slowly adopting a new paradigm of continuous processing with smart development and manufacturing. Process development tools in the context of Quality by Design (QbD) allow a holistic evaluation of chemical synthesis and unit operations. Including Process Analytical Technology (PAT) in the early-stage development provides a significant advantage in both process control and modelling. These concepts integrated with modular production plants, provide uniform processing and full process control. Interchangeability of plant modules will be possible with standards like Module Type Package (MPT) for vendor-independent integration. Future chemical plants will provide uniform processing according to the chemical requirements of a process, with intensified mass and heat transfer and each molecule experiencing the same processing conditions.

Flow Chemistry and Continuous Manufacture offer a wider set of chemical transformations for industrial manufacturing processes and in doing so allows intensification and simplification of synthetic routes to complex organic molecules. This technological approach alone does not address the emerging needs for supply of products like medicines; that of a sustainable and resilient supply base that can quickly supply patients. This requires the addition of new approaches to Automation, Digitalisation, Modularity and Modelling to the functionality of Flow Chemistry to achieve a transformation of the design processes and the supply chain for medicine manufacture.

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Catalytic static mixers (CSMs) have recently been developed as hydrogenation catalysts for continuous flow reactor systems. By basing the structure on a 3D-printed metal scaffold, CSMs can be designed to fit flow reactors of any dimensions. The catalytically-active surface can be applied by several different techniques, which provide complementary reactivity and compatibility. Their low catalyst loading, as well as high activity and stability, has already provided a convincing case for certain applications, particularly due to facile scalability. Here, we examine the technology, based on a number of examples from the literature. We aim to highlight the potential of CSMs as an alternative to packed bed reactors, specifically for application in fine chemical and pharmaceutical manufacturing.

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This is a special edition (Issue 4s) of Chimica Oggi – Chemistry Today journal,