Dr Olivier Dapremont , executive director - process technologies at Ampac Fine Chemicals , introduces a new concept in flow chemistry
FLOW CHEMISTRY
Flow process development : Crossing the cGMP barrier
Dr Olivier Dapremont , executive director - process technologies at Ampac Fine Chemicals , introduces a new concept in flow chemistry
Over a decade ago , various equipment manufacturers , often spin-offs from academia , started offering tools to help chemists develop continuous processes , with the promise of better mass and / or heat transfer . Batch reactors were going to become obsolete and be replaced by smaller , more efficient , well-automated pieces of high-tech hardware .
This prediction has not materialised yet . It is difficult to convince chemists to drop the versatile batch reactor and the well-understood rules of scale-up for the promise of a better process using complex technology and requiring a significant amount of data before being used at any scale . The perception that a batch reaction can be developed with minimum process knowledge and therefore be up and running in the chemist ’ s hood in a few days contrasts with the need for significant upfront work to understand the chemistry to get the flow process going .
In addition , this new technology had limited scale-up possibilities because larger-scale equipment did not exist . While benchtop equipment for flow is relatively easy to set up ( a few peristaltic , syringe or HPLC pumps , some tubing , valves and fittings , including a selection of analytical devices such as pH , UV and FTIR ), kilo-scale equipment will have to be designed for the optimised process conditions .
It would then take at least six to 12 months to build the equipment , install it in a batch plant and qualify it for production of cGMP material . This is too long to support clinical trials and therefore it is a significant hurdle . Developing a process using a new technology that cannot be scaled up immediately in any plant is pointless under the current timeline constraints .
Unless the chemistry was highly hazardous or the expected commercial volumes were enormous , the main driver to replace the batch process by a continuous process was not there . Figure 1 - Expansion of operating range using flow chemistry
Thus , the technology remained a ‘ great potential but not for this project ’ kind of solution .
In the past decade , major pharmaceutical companies started to evolve their views . New and existing manufacturing processes must be environmentally friendly and costeffective , and the APIs must reach the market earlier . Very aggressive carbon footprint targets , as well as time-tomarket timelines , were put forward .
This sparked a renewed interest in flow chemistry as continuous processes provide significant cost-optimisation and give access to chemistry routes otherwise inaccessible in simple batch reactors , allowing for a better process mass intensity ( PMI ). Most pharmaceutical companies created a division within their organisations dedicated to continuous flow development , with chemists , engineers , analytical chemists and automation engineers .
This significant shift in the approach to continuous process is essential to ensure better processes are developed . Unfortunately , the tools for scale-up are still lacking as the reactors for flow chemistry are often processspecific and require high automation and pertinent control strategy ( i . e . appropriate process analytical technology ( PAT ) and feedback loop automation ).
Consequently , there is a significant barrier of entry to get into cGMP kilo manufacturing because of the time and capital investment still required to perform the scale-up from the R & D process developed at the bench scale . A solution needed to be developed to break this barrier .
SEP / OCT 2023 SPECCHEMONLINE . COM
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