PEPTIDES & PROTEINS
Figure 4 - Percolation wash concept
References :
1 : A . Isidro-Llobet , M . N . Kenworthy , S . Mukherjee , M . E . Kopach , K . Wegner , F . Gallou , A . G . Smith & F . Roschangar , J . Org . Chem . 2019 , 84 ( 8 ), 4615-4628
2 : V . Martin , P . H . G . Egelund , H . Johansson , S . T . Le Quement , F . Wojcik & D . S . Pedersen , RSC Adv . 2020 , 10 ( 69 ), 42457- 42492
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6 : O . Ludemann-Hombourger , I . Martinuzzi , C . Bobier & E . Francomme , ‘ Automated synthesis reactor system with a recirculation loop ’, Patent No . WO2019 211531 A1 , 2018
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‣ approach is commonly applied on fixed bed reactors or chromatographic columns , but its implementation in a stirred batch SPPS reactor is more complex . 6 , 7 The concept of washing by percolation consists of applying a percolation washing ( i . e . as a plug flow reactor ) in a reactor that has the design of a STR rather than a column . When the reaction is completed , the stirrer is stopped , the resin is sedimented , and the inlet and outlet streams are adjusted to optimise percolation performance ( Figure 4 ). Implementing the percolation concept on a stirred batch SPPS reactor requires specific considerations to ensure both , the performance and the robustness of the process :
• Liquid level in the reactor : The amount should be sufficient to keep the bed wet , but it should be minimised above the resin to avoid dilution and back-mixing
• Percolation velocity : This should be optimised to allow a good diffusion in the resin , while minimising the time spent for washing
• Dispersion of inlet flow : The dispersion of the liquid should be able to ensure both a removal of the residues on the surface of the reactor and a homogeneous distribution on the resin
• Stirrer & reactor design : The geometry of the system is optimised to minimise the disturbance of the percolation to ensure a plug flow stream within the resin bed
Figure 5 - Reduction of residual piperidine concentration by percolation wash
Percolation washing was modelled , based on the parameters measured above . The percolation conditions were optimised with the numerical model before implementation on the SPPS reactor ( Figure 5 ), and the actual result showed a very good accuracy in the predicted performance . We compared percolation washing with batch washing with respect to washing volume to attain an endpoint defined as 100 ppm of residual piperidine in the discharged liquid phase . The experimental and numerical model illustrated a drastic impact on the solvent consumption in this application example , where the percolation wash reduced solvent consumption by 57 % compared to batch washing . Moreover , it had a positive impact on process productivity compared to batch .
The application of this improved practice of percolation on largescale GMP manufacturing units has generated a significant reduction of the solvent consumption and the concept design has shown an excellent robustness and reliability . Percolation is now routinely considered for production processes at PolyPeptide Group manufacturing sites to improve the sustainability and the performance of the SPPS processes . •
Renan Ravetti
INNOVATION SCIENTIST
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