The “Factory of Tomorrow” for Flow Processes and Microreactors

Dominic Roberge, B. Kimmerle, M. Gottsponer, C. Schnider and P. Elsner

Lonza AG, Continuous Flow Microreactor Technology, Switzerland Abstract The use of microreactors and mini plant systems enable the control of hazardous and demanding reactions. The concept is embedded in the design of the “Factory of Tomorrow”. The key concept behind the utilization of flow is to achieve extreme process intensification. This intensification enables inherently safer conditions that lead to the development of new processes, so-called “Flash Chemistry,” that could otherwise never be performed under batch conditions [1]. In a microreactor it is possible to perform highly energetic reactions, work with unstable intermediates, employ more reactive reagents, and use more active catalysts that enable new, out-of-the-box chemistry. Figure 1 shows a typical plate type microreactor called FlowPlate™ [2]. The individual plates are selected from the physico-chemical properties of the reaction. For example plates with a small channel depth are used at reaction start while the channel depth is increased when the reaction gets slower at longer residence time [3] (multi-scale approach). Figure 1. Lonza FlowPlate™ MicroReactor of the size A5 as individual plate and imbedded in a complete rack.

A microreactor will be at the heart of flow processes to control the “Flash Reaction” but will be implemented in parallel to other flow unit operations such as liquid-liquid extraction, distillation and crystallization (Figure 2). In addition, the workspaces can be designed for high temperature and high pressure reactions; a new domain for a typical organic chemist [4].The outcome will lead to highly intensified mini-plant approaches that will be the basis of the “Factory of tomorrow.” The ultimate results of the initiative are more sustainable, greener, and economical processes for producing a wide range of pharmaceuticals.

Figure 2. Example of a mini-plant system including a FlowPlate™ microreactor, a distillation unit, a cascade of 3 continuous stirrer tank reactors (CSTR), and a liquid-liquid counter-current extraction column. This mini-plant can have a very high productivity up to 40 kg of isolated product per day (400 L of reaction medium flowing IN and OUT). REFERENCES [1] J.-I. Yoshida, A. Nagaki, T. Yamada, Chem. Eur. J. 14 (2008), 7450-7459. [2] www.ehrfeld.com [3] D. M. Roberge, M. Gottsponer, M. Eyholzer, N. Kockmann, Chem. Today 27 (2009), 8-

11. [4] V. Hessel, B. Cortese, M. H. J. M. de Croon, Chem. Eng. Sci. 66 (2011) 1426-1448.

Sustainable Manufacture of Fine Chemicals by Flow Processes

Peter Poechlauer, DSM Innovative Synthesis B.V.

Abstract

Western manufacturers of fine chemicals find themselves in a squeeze to reliably provide high

quality products at competitive prices while having to stick to ever tighter environmental

legislation.

DSM’s aspirations in sustainability give clear directions for development of new products and

processes and define sustainability as business driver. This has earned us top positions in the

Dow Jones sustainability Index over the last 5 years.

As a consequence of this strategy DSM is developing and using flow processes in fine

chemicals manufacture at all scales. Designing new flow processes or translating known batch

recipes into flow processes is seen as one measure to fulfill requirements of both product

quality and process sustainability.

The presentation highlights our present priorities and goals in fine chemicals manufacture and

shows how flow processes can be used to fulfill them. Both in batch and in flow processes,

thorough process understanding is instrumental, and operating a process continuously allows

a more detailed understanding and better use of kinetics and thermodynamics of a given

reaction to improve its selectivity and yield.

Our considerations on sustainability of a process may start with defining the “most efficient”

route in a route scouting exercise. They are quickly expanded to “process scouting”, as we

investigate further parameters such as availability, storage and handling of starting materials,

amount and nature of waste, and size and energy demand of the respective plant. This

procedure yields both integrated costs and a clearer picture of the footprint of a process in

comparison to others.

This procedure is illustrated by recent examples of processes we have developed. We quantify

the effects by applying state-of-the art metrics such as process mass intensity (PMI).

Finally an outlook is given on directions of development in the field, and how they will affect

our ways of manufacturing fine chemicals.

Continuous Processes - Sustainable Manufacturing

Jörg Schrickel, CABB AG, Switzerland

Abstract In the early stages of a development of new compounds, lab chemists think of number of synthesis steps and a typical reaction in the flask is a batch reaction. They do not necessarily think of continuous processes for the syntheses of their molecules. During upscaling, the batch process from the lab is transferred into a larger industrial scale, but mainly remains a batch process. There are several aspects why a process can be run more efficiently in a continuous than a batch process - and these are often economical aspects. In the light of a sustainable production continuous processes show advantages regarding use of energy, creation of waste and waste water, and tend to consume less working hours and thus less exposure of staff to chemicals through automation. In addition, safety is also an important driver for continuous processes. CABB has a long experience in continuous processes in large commercial scale. CABB operates dedicated plants for the manufacture of reagents, intermediates and finished products. Based on this experience, CABB has converted other syntheses from batch into continuous processes. The improvement of processes is part of CABB's Quality Management System and thus leads to a continuous review of established processes. This presentation will cover different aspects regarding efficiency, economics and saftey of batch vs continuous processes. Case studies will show practical examples where batch processes were transferred into continuous processes with benefits in economics, reduction of materials used and an increase in safety.

Value Proposition for the Implementation of Continuous Manufacturing

James M B Evans, MIT, USA

Abstract

I will describe the motivation for and vision behind continuous manufacturing and reduction

to practice continuous manufacturing as the ultimate in lean manufacturing with quantified

and fully integrated processes. I will also present a cost analysis based on a basic case

study, and the potential impact on the supply chain from a pure cost perspective. I will also

discuss the challenges and how address them.

Developments in Continuous Processing Technology for Tablet Manufacture

Trevor Page, GEA, Pharma Systems, UK

Abstract Continuous processing for the secondary Pharmaceutical industry has recently taken some significant steps to move out of the laboratory and into the factory. Previously Continuous process was often considered as unsuitable for development activities and only suitable for large volume product. However new thinking has resulted in smaller and more agile systems which provide a practical bridge between development and manufacturing . This presentation looks at some of the technical and practical considerations involved in the design and operation of continuous tablet production systems.

From Substance to Product - An Industrial Perspective on Continuous Processing

Amy Robertson, Associate Principal Scientist Pharmaceutical Development, AstraZeneca, Macclesfield, UK

Abstract Within the pharmaceutical industry there is growing interest in continuous processing as an alternative to traditional batch processing. This spans manufacturing processes from drug substance to drug product, and includes unit operations such as chemical reactions, extractions, crystallization and wet granulation. For certain processes switching to continuous processes may offer cost savings, greater flexibility in scale-up and access to a wider range of reaction conditions than currently accessible in a batch process. By introducing continuous crystallization processes for the active pharmaceutical ingredient (API) there is a potential to remove batch to batch variations and to achieve greater control over the particle properties leading to the opportunity to remove subsequent unit operations such as milling or micronisation. The presentation will include examples of the application of continuous processes to both drug substance and drug product manufacture.

Insights from GSK's Experience in Developing Pharmaceutical Continuous Crystallization Processes - What have we learned and where are the gaps.

Chris Price, GlaxoSmithKline, UK

Abstract GSK have successfully developed and scaled up a number of continuous pharmaceutical crystallization processes to produce drug substance particles with very consistent physical attributes suitable for direct formulation. Along the way we have learned some important practical lessons, some of which are directed to pharmaceutical aspects others are more generally applicable. More importantly we have identified some priority areas for strategic research which has the potential to accelerate the application of continuous processing in the pharmaceutical industry. In this presentation we will use process development examples to illustrate our practical learning and share our suggestions for future strategic and enabling work.

Chemical Understanding: The Key to Continuous Processing

Mark Bratt, Intensichem, UK

Abstract Initial laboratory investigation of chemical reactions in flow tends to use specific reactors for a wide varieties of transformations. Whilst a valid approach for pure or custom synthesis, this approach is not always suitable when developing a complete commercial process. Through techniques such as process modelling, it is more appropriate for the equipment to be designed to the unit operation required. This enables chemistry to be carried out which is not possible in batch mode and can access a wider range of conditions. More importantly, specifying the technology to the process offers more versatility and ensures a higher likelihood of scalability and success in industrial production. Case studies exemplifying this strategy will be presented.

The Amazing Journey of a Molecule - Separating, Controlling and Intensifying

Chemical and Physical Changes

Antonio Quintieri and Denis Osullivan, P&G Company

Abstract The amazing journey of a molecule

How take full control of chemical and physical changes to invent and deliver the magic

behind great brands?

Break the barrier between formulation and process development going to very small scale

and learn fundamentals where molecules meet. See what happen when Process

Intensification meet Fast Moving Consumer Goods company.

Separating, Controlling and Intensifying Chemical and Physical Changes

Our processes involve multiple chemical and physical changes. When we make the product

in a beaker or a typical continuous process, many of these changes happen simultaneously.

It’s impossible to isolate the impact of individual parameters. With its rapid kinetics and high

intensities, microProcessing enables us to separate and control the changes, and be

confident that the profile undergone by each molecule is identical. This enables us to

optimise our process parameters in a “clean” environment, and then use these to design the

best possible continuous process.

From Laboratory to Production: a Seamless Scale-up

Alessandra Vizza, Corning Reactor Technologies. France

Abstract Flow reactors continuously and efficiently stream chemicals in a highly controlled manner. Given the high level of optimization, significant savings can be realized by bringing together fewer reagents to obtain the same amount of final product achieved by batch. Due to proven advantages such as efficient mixing, very intense heat and mass transfer and a narrow residence time distribution enabling greener, more economical and safer processes than the conventional approach, small-scale channel reactors have emerged as a new technology offering advantages over classical approaches. A large offer of micro devices exists, and they are useful especially in quick experimental studies and reducing a product’s development phase. However, despite their advantages, there is little information concerning successful industrial applications. This could be explained by the lack of sufficient throughput of many existing devices. But, this can be solved by numbering-up. Corning developed continuous reactors with hydraulic diameter in the range of millimeters that are easily scalable and can be customized to particular needs. These devices make possible the switch of chemical reactions from batch mode to continuous processing through more efficient, more economical and safer processes. In addition these reactors provide a platform for developing innovative chemistries that have never been considered industrially practical, either for hazardous or yield reasons. The reactors are composed of fluidic modules, which offer a great flexibility of design. These devices are as small as necessary, providing the throughput of conventional batch systems while keeping the advantages of micro-reactors. Fluidic modules have different footprints and internal dimensions leading to internal volumes from 0.5 to 250 ml and operating flow rates between 2 up to about 3000 g/min. The scale-up is performed efficiently, without degrading the characteristics of the device. Besides the increase of footprint and internal dimensions together with an internal flow splitting with recombination of the channels, Corning multiscale design strategy relies on a combination of passive distribution system at reactor bank level and active distribution system at reactor level. Implementing continuous technology requires a different approach compared to traditional batch processes. This presentation will describe how to fill the transition gap from traditional to continuous technologies and from feasibility tests to process optimization. The effective use of process intensification in order to overcome the limitation of traditional processes will be shown. Thus, a cost-effective solution for various reactions increasing yields and safety, while

decreasing energy consumption and waste generation will be illustrated.

1

Flow Reactor Technology: A Flexible Tool for Reaction Optimisation and Chemical

Production

Charlotte Wiles, Chemtrix BV, The Netherlands

Abstract

Background: Throughout the numerous stages of chemical process development there are many

associated risks, perhaps none as costly as the failure to scale a synthetic process to reach the

desired production capacity of a key intermediate or API (active pharmaceutical ingredient).

Whilst the emerging technique of micro reaction technology enables those working in research and

development to rapidly screen novel process windows such as high temperatures, high pressures and

short reaction times, the production volume of each reactor is inherently small – typically mg’s. It has

long been discussed that once optimised, productivity of micro reactor processes can be increased by

numbering-up or via continuous operation – significant quantities of devices would however be

required to achieve modest production volumes.

Looking at this from a commercial standpoint however, it becomes clear that this is not economically

feasible as production rates of tonnes annum-1 would require hundreds of thousands of micro

reactors. Consequently to address this, we have selected to increase the reactor volume (features up

to 3 mm2), whilst ensuring that the size change maintains the efficient heat transfer and mixing

associated with micro-scale flow reactors.

Results: With this in mind, we present new data which validates our up-scaling principle of taking

optimal reaction conditions from Labtrix® micro reactors (1 to 19.5 µl Volume) to KiloFlow® meso

reactors (0.8 to 13.0 ml Volume) without a loss of mixing performance. Examples are also provided

on end-user processes up to the tonne annum-1 scale using Plantrix® Industrial flow reactors made of

EKasic silicon carbide with system volumes ranging of a few ml to several litres.

Summary/Conclusions: Combining academic research and industrial case studies, Chemtrix BV

have commercialised flow reactor apparatus that facilitates the optimisation of processes using mg-

quantities of material and subsequent scale-up to kg quantities without the need for parameter re-

optimisation. Examples of 13,000 x scale-up from micro to meso reactors will be presented.

Intensified Pumps for Intensified Processes

Carsten Damerau, HNP Mikrosysteme GmbH, Germany

Abstract A short overview of functional principles of the most common pump types will be given. The relevant properties are outlined using the example of micro annular gear pumps. The focus of the presentation is set on materials, performance, precision and pulsation. In chemical processes, pumps are part of a complex setup of interacting components. As there is no one-size-fits-all pump special challenges result from selecting the most suitable pump type and its configuration. In consequence pump manufacturers need a deeper understanding of the customer's application and depend on complete information. The influence of liquid's composition, viscosities, pressure conditions and flow rates is demonstrated.

Innovations in Mass Flow Meters Boosting Process Efficiency in Batch & Continuous Operation

Sonal Gilani, Emerson Process Management, The Netherlands

Abstract Coriolis mass flow meters have revolutionized flow metering in process industry. By providing best in class accuracy on mass flow, the most vital parameter in stoichiometry of the chemical processes, it has enabled the users to achieve higher quality product, increased yield and process robustness. With 30+ years and 750,000 Coriolis flow meters installed globally, Micromotion has been leading the innovation in the field, offering unique advantages to its users in batching and continuous operation. The unique meter geometry that enables sensor operation at low frequency, combined with the patented DSP technology, allows consistent and reliable measurement of flow with gas or air entrainment and also during empty full empty batching. This has also eliminated the necessity of using weigh scales that causes bottlenecks and may increase HSE risks. The non-intrusive in-line meter diagnostics enables operator to check for any shift in meter performance ensuring that the continuous process is uninterrupted due to any unnecessary maintenance, proving or recalibration. The unparalleled value of virtually no maintenance combined with ease of installation ensures lowest operating cost and highest return on investment. The seminar will present informative content about these innovations that are unique to MicroMotion’s mass flow meters and how these innovations when applied to the real world has generated immense value for its users.