Industry goes with the Flow

Flowid looks at the implementation of continuous manufacturing in the speciality chemicals and pharmaceutical industries

Whilst continuous production, or flow, is a mainstream technology in the petrochemical industry, it has seen only limited implementation in speciality chemicals and pharmaceuticals. In discussions at conferences with industry partners, the reasons for this are generally agreed to be that:

R&D and product development are still mostly done in batch
Scale-up to pilot and production levels are also mostly done in batch
Suitable flow skids are not considered and/or not available

The focus on microfluidic systems in the past 20 years has resulted in the development of excellent lab equipment for continuous processing, which is available and in use. Scale-up to pilot and production scale, however, generally failed, as ‘numbering up’ reactors was not the solution.

One major reason why little has been said about successful use of flow in the speciality chemicals and pharmaceutical industries is IP-related. Industrial continuous pilot and production is seen as a competitive advantage and is part of the customers’ IP strategy.

The use of flow for production purposes is thus more abundant then one might assume. However, its implementation did take some decades, because R&D experience is limited compared to batch processes. There is hardly any know-how and expertise in flow.

SpinPro production skid for gas-liquid application

Presenting flow as the Holy Grail and the solution for everything is not right. Continuous manufacturing must make sense – chemically, safety-wise and financially. Clients’ drivers need to meet, and technology, knowledge and experience needs to be available and combined. The key drivers for going with flow are:

Excellent mass transfer, due to excellent mixing
Optimised heat transfer
Increased safety
A smaller footprint
Increased yield
Reduced energy use
Extension, replacement and depreciation of existing production plants

These drivers are very much customer-specific, and vary from case to case, but the main goal is always to reduce capital and operating costs (capex, opex). The chemistry must make sense. Suitable chemistry has to be developed, starting from a continuous process point of view.

It is often neither feasible nor advisable to transfer a batch process directly into a continuous process. To obtain the best solution, it is essential to go back to the drawing board in the lab and take into account the flow process opportunity with its advantages and disadvantages.

These processes also require suitable continuous downstream processing. Doing this right is another major opportunity for suppliers of equipment. Zaiput’s liquid/liquid separator is an excellent example. For a totally modular, fully integrated continuous plant, the ProcessNet-Dechema initiative in Germany shows great potential.

Last but not least, specialised companies offering suitable and scalable technology for continuous manufacturing are few and still relatively small. To get flow technology faster to the industry, cooperation is essential. We believe that progress can be made by presenting and sharing the opportunities for flow at events, as, for example, at the Flow Pavilion at Achema in 2018.

Modular set-up for mixture of phases in Flowid SpinPro R300 and separated by Zaiput SEP 3000

Flowid’s lessons learned

Flowid’s lessons learned in the past ten years have been very diverse. We started with implementations of microfluidic systems, but we ran into scale-up problems with our customers. Nor did it provide us enough income to keep going.

Changing the game, we decided to redefine our business model and see the scale-up problem as an opportunity. We changed our focus to production reactors with capacities of thousands of tonnes/year, pilot scale reactors (tens to hundreds of tonnes) and lab-scale reactors (hundreds of kg)

Simply offering these flow reactors in a box did not do the job either, however. Customers needed more. We started by redefining their processes to make them viable in flow, then developed both pilot- and production-scale flow skids as a ‘plug & produce’ system, by integrating suitable pumps, process controls and reactors – not necessary our own – with appropriate tie-ins at customers’ plants. These skids can be upon request certified for GMP, ATEX and/or food grade.

Flow in pharma & organometallics

The pharmaceutical industry has its own drivers for change. Typically research and scale-up are done in batch mode. At that point, regulations have been roadblocks, preventing any change to continuous processing.

However, the FDA directive to change from batch to continuous production to overcome quality fluctuation is now becoming a nice driver to cooperate with pharma companies and implement flow systems. Meanwhile, lab devices from Vapourtec, Uniqsis, Ehrfeld and others have provided the flow platform at an early R&D phase, facilitating some successful scale-ups to pilot and production.

From discussions with the pharma world, Flowid understands there is specific interest in toolbox technology as a means to make organometallic reactions safer and greener. To this end, Flowid teamed up with Albemarle, a major speciality chemicals company with a leading position in lithium-based chemistry,

Together, the two companies developed a next-phase technology, which gives easy and safe operation, combined with a higher yield production. This technology will be further developed in a dedicated production skid for the specific purpose of organometallic applications.

It has already been demonstrated for BuLi and HexLi chemistry that a continuous production method gives higher yields, with lower solvent volumes and at temperatures closer to ambient. The requirement for cryogenic conditions for these types of reactions performed in batch is circumvented, making it a cheaper and more sustainable process.

Flowid SpinPro Reactors

Flowid offers process development services to convert batch processes in to continuous processes, plus the engineering and construction of skids based on flow technology. These continuous solutions are offered on a laboratory-, pilot- and production scale. By performing chemistry in flow costs can be reduced significantly, mainly caused by:

* Lower safety investments

* Reduced footprint

* Simplified or reduced work up steps

* More efficient use of energy

* Easy and fast start-up, shut-down and cleaning; reducing turnaround time

* Reduction of operator handling

The SpinPro is a continuous flow reactor that controls fast, exothermic, multi-phase reactions between immiscible liquids or between liquids and gases, dynamically. It can also carry out precipitation and emulsification reactions.

The reactions they can carry out include organometallic reactions, halogenation, nitration and others. The larger SpinPro R300 is for production capacities of up to 1,000 L/hour throughput, while the smaller SpinPro R10 ranges from 70 L/hour down to ml/minute.

SpinPro R300 device

SpinPro R300 cross sectional view

Conclusion

Flow processing is a proven and scalable technology, from laboratory devices for screening purposes, up to high-capacity production devices. By combining chemistry and engineering knowledge, in combination with experience and cooperation, complete set-ups have been installed in pharmaceutical and fine chemical factories all over the world. The drives for using continuous flow processes vary, but these all result in reduced investment and operational costs.