Our Research Focus: Converting batch production to continuous processing

Nikolay Cherkasov explains how complex compounds for pharmaceuticals and agrochemicals can be produced continuously rather than batchwise

COMPLEX chemicals are mostly produced in batch while energy and other costs could be halved by moving to continuous production. This unique combination of unblocking the path towards net zero and improving economic competitiveness makes continuous processing a priority.

This priority is recognised by the government in our £1.3m (US$1.6m) project “Scalable continuous manufacturing for sustainable chemical production”, part-funded by the Industrial Energy Efficiency Accelerator (IEEA). The IEEA is funded by the Department for Energy Security and Net Zero as part of the Net Zero Innovation Portfolio (NZIP) and it is managed by the Carbon Trust with support from Jacobs and Innovate UK KTN.

In this project, we collaborate with Robinson Brothers and the Process Intensification Group of Newcastle University. The aims are to 

• Scale-up our scalable agitated baffle reactor (SABRe) technology from 1 up to 1,000 t/y chemical production;
• Prove that the technology reduces costs and energy consumption in the manufacturing of fragrances and speciality chemicals. 

Benefits of flow chemistry

Continuous (also called flow) chemical production is proven to reduce costs and energy wastage. For example, Novartis produced a pharmaceutical intermediate continuously.¹ Compared to batch production, the yield almost doubled (from 34% to 65%), waste was more than halved (from 105 to 45 gwaste/gproduct) – all while reducing the overall process costs by 35%. 

Continuous production brings other benefits. Processes difficult or impossible in batch could be performed safely in flow with much tighter process control and product quality.²  

These benefits originate from two fundamental improvements over the batch. Firstly, a continuous process provides efficient time-space utilisation – it performs useful work most of the time. A batch process, meanwhile, requires daily start-stops to load, clean, heat-up – steps that produce no useful product but incur substantial costs. A senior pharma executive said that a fully utilised production batch reactor produces chemicals at most 10% of time! Therefore, a continuous production could increase productivity 10-fold only by its continuous nature. 

Secondly, there is a myriad of technical advantages originating from smaller channel dimensions resulting in rapid heat transfer, exceptional mixing, and simpler automation. These translate to broader, safer process operation than in batch, increased product selectivity (and thus less waste), faster throughput, and higher product quality. 

State of the art: why do we use batch at all?

Depending on the area you work in, batch chemistry is either a surprise or an everyday reality. Of the 300 largest-tonnage chemicals (commodities, petrochemicals) all are produced continuously – without exception. For compounds produced below 10,000 t/y (complex compounds such as agrochemicals, specialities), batch synthesis dominates (~97% all processes).³

I believe that there are three main reasons batch is so prevalent:

• Not all processes benefit from a continuous production. The literature consensus is that unavoidably slow processes (>1 h intrinsic reaction time) are the least viable.⁴  In a 50 hour batch run, 8-hour start-stop cycles are not as bad as the same cycles repeated every 10 minutes. Some processes work well in batch.
• The legacy and convenience of batch. Batch processing is established with honed process conditions and operational know-how by many contract manufacturers. Batch is their first point of call.
• Higher capital costs for continuous processing. Continuous production is often established as a process-dedicated facility. Multipurpose batch plants could produce almost any compound and spread their capital costs over many processes. Batch capital requirements are lower. 

Microreactors and scale-up

Microreactors arrived in the 2000s as a possible answer to these problems. Microreactors rely on sub-millimetre dimensions to deliver mixing 10–1,000 times faster than batch mixing, 10–100 times faster mass transfer and 10–100 times faster heat transfer. Such microreactors already deliver commercial outputs in pharmaceutical and related fields.

For example, C Oliver Kappe, scientific director of the Center for Continuous Flow Synthesis and Processing at the University of Graz⁵, obtained hazardous reagents from benign compounds using microreactors as on-site generators. The generators enable safe handling of hazardous materials and open new synthetic pathways, even when the reagents are too hazardous to synthesise, store, and transport on any scale.  The small size of microreactors provides a manageable hazard up to about 100g-scale production.

This example shows both the promise and the weakness of microreactors. Their great performance comes from micro-dimensions. But if you want to produce kilogramme and tonne-quantities, the microreactors must be scaled-up.