FLOW CHEMISTRY the infrastructure needed varies greatly and depends on the available chemistry , cost of goods , volumes required and the hazard profile of a transformation . As a result , no single solution fits all scenarios . The modularity and flexibility of continuous flow set-ups enables the development of small , agile production plants that can be used for the manufacture of multiple products – with easy re-configuration allowing for rapid product change-over when needed . On this basis , it is no surprise that CDMOs are among the fastest to adopt flow chemistry at lab and production scale .
Case study
Ajinomoto Bio-Pharma Services has a long-standing track record in the performance of hazardous processes . It received a request to scale up a challenging multi-step process for a cyclopropanated product – initially to tens of kg and subsequently to a multitonne / week demand . The process combined three highly exothermic steps : a thermolabile intermediate , gaseous by-products and a potent product ( Occupational Exposure Band ( OEB ) 5 , 0.1-1 µ g / m 3 ). All of them posed significant safety concerns as the batch size requirement increased . Using its experience in the development of lab- and pilotscale continuous processes , the
A Plantrix MR555 flow reactor was used as part of by Ajinomoto Bio-Pharma Services ' continuous manufacturing plant . team was able to identify several areas for process improvement . These included a reduction in unit operations , increased process safety through thermal management and increased productivity by decreasing solvent usage . This resulted in the delivery of an initial 50 kg batch and later realising a 28-fold increase in productivity as the process moved to the plant . A multi-purpose , modular , automated flow system was designed and constructed , and Hazop was evaluated . A Plantrix MR555 flow reactor at the heart of the system ( pictured opposite ) was chosen for the most energetic reaction steps (~ 400 J / g ) as the brazefree silicon carbide modules provided the necessary combination of thermal control and chemical compatibility , replacing multiple slow batch additions over about eight hours . The high heat exchange obtained within the flow reactor allowed for a significant reduction in solvent use , which shortened the post-reaction time and increased productivity . The flow system also limited exposure risk to the OEB 5 material , because the process stream remains contained as it passes through the various reaction steps . To further optimise the process and reduce the cost of production , Ajinomoto Bio-Pharma Services developed an efficient extraction process that minimised losses of the OEB 5 material . This allowed telescoping of the work-up in the extraction column with the neutralisation and removal of acid traces from the product stream . Separation of the well-mixed phases was then achieved with an in-house designed glass settler . Significant efforts went into the recovery and recycle of raw materials , together with efficient treatment of the waste streams . This included the incorporation of thin-film evaporation and fractional distillation of the organic product stream , enabling a large part of the solvent to be recovered and re-used in the synthesis of the diazomethane precursor and its work-up .
With a focus on sustainable manufacturing , the team successfully implemented continuous flow within the lab , transferred it to a pilot scale ( 120 kg ) and subsequently into production , delivering 500 tonnes in the first year . The benefits resulting directly from the use of continuous manufacturing included :
• Achieving the target manufacturing price via process intensification
• A two-fold increase in productivity compared to the dedicated batch unit
• 20 % reduction in diazomethane precursor consumption & 50 % solvent reduction
• Enhanced process robustness through automation
• Reduced material inventory
• Facile containment and isolation of an OEB 5 compound
What ’ s next ?
The next steps involve improvements to the downstream batch processes to allow for a further increase in production capacity . In parallel , work is underway to replicate the production system on a second Ajinomoto Bio- Pharma Services site , with all three reaction steps being performed continuously . For the technology , going forwards we see further opportunities in the sector to increase the use of PATor model-based automation into modular and flexible continuous manufacturing units , allowing makers of complex formulated products such as pharmaceuticals , chemicals and personal healthcare products to not only increase productivity and overall process sustainability , but also deliver predictable product quality . •
Reference :
1 : https :// www . fda . gov / regulatory-information / search-fdaguidance-documents / quality-considerations-continuousmanufacturing ; FDA docket number 2019-D-0298
J j
Dr Charlotte Wiles
CEO
CHEMTRIX c . wiles @ chemtrix . com
www . chemtrix . com
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