TY - JOUR

T1 - Using PAT to accelerate the transition to continuous API manufacturing

AU - de Gouveia, Maria Francisca Dias Folque

AU - Rahbek, Jesper P.

AU - Mortensen, Asmus R.

AU - Pedersen, Mette T.

AU - Felizardo, Pedro M.

AU - Bro, Rasmus

AU - Mealy, Michael J.

PY - 2017

Y1 - 2017

N2 - Significant improvements can be realized by converting conventional batch processes into continuous ones. The main drivers include reduction of cost and waste, increased safety, and simpler scale-up and tech transfer activities. Re-designing the process layout offers the opportunity to incorporate a set of process analytical technologies (PAT) embraced in the Quality-by-Design (QbD) framework. These tools are used for process state estimation, providing enhanced understanding of the underlying variability in the process impacting quality and yield. This work describes a road map for identifying the best technology to speed-up the development of continuous processes while providing the basis for developing analytical methods for monitoring and controlling the continuous full-scale reaction. The suitability of in-line Raman, FT-infrared (FT-IR), and near-infrared (NIR) spectroscopy for real-time process monitoring was investigated in the production of 1-bromo-2-iodobenzene. The synthesis consists of three consecutive reaction steps including the formation of an unstable diazonium salt intermediate, which is critical to secure high yield and avoid formation of by-products. All spectroscopic methods were able to capture critical information related to the accumulation of the intermediate with very similar accuracy. NIR spectroscopy proved to be satisfactory in terms of performance, ease of installation, full-scale transferability, and stability to very adverse process conditions. As such, in-line NIR was selected to monitor the continuous full-scale production. The quantitative method was developed against theoretical concentration values of the intermediate since representative sampling for off-line reference analysis cannot be achieved. The rapid and reliable analytical system allowed the following: speeding up the design of the continuous process and a better understanding of the manufacturing requirements to ensure optimal yield and avoid unreacted raw materials and by-products in the continuous reactor effluent. Graphical Abstract Using PAT to accelerate the transition to continuous API manufacturing.

AB - Significant improvements can be realized by converting conventional batch processes into continuous ones. The main drivers include reduction of cost and waste, increased safety, and simpler scale-up and tech transfer activities. Re-designing the process layout offers the opportunity to incorporate a set of process analytical technologies (PAT) embraced in the Quality-by-Design (QbD) framework. These tools are used for process state estimation, providing enhanced understanding of the underlying variability in the process impacting quality and yield. This work describes a road map for identifying the best technology to speed-up the development of continuous processes while providing the basis for developing analytical methods for monitoring and controlling the continuous full-scale reaction. The suitability of in-line Raman, FT-infrared (FT-IR), and near-infrared (NIR) spectroscopy for real-time process monitoring was investigated in the production of 1-bromo-2-iodobenzene. The synthesis consists of three consecutive reaction steps including the formation of an unstable diazonium salt intermediate, which is critical to secure high yield and avoid formation of by-products. All spectroscopic methods were able to capture critical information related to the accumulation of the intermediate with very similar accuracy. NIR spectroscopy proved to be satisfactory in terms of performance, ease of installation, full-scale transferability, and stability to very adverse process conditions. As such, in-line NIR was selected to monitor the continuous full-scale production. The quantitative method was developed against theoretical concentration values of the intermediate since representative sampling for off-line reference analysis cannot be achieved. The rapid and reliable analytical system allowed the following: speeding up the design of the continuous process and a better understanding of the manufacturing requirements to ensure optimal yield and avoid unreacted raw materials and by-products in the continuous reactor effluent. Graphical Abstract Using PAT to accelerate the transition to continuous API manufacturing.

U2 - 10.1007/s00216-016-9834-z

DO - 10.1007/s00216-016-9834-z

M3 - Journal article

C2 - 27515798

VL - 409

SP - 821

EP - 832

JO - Analytical and Bioanalytical Chemistry

JF - Analytical and Bioanalytical Chemistry

SN - 1618-2642

IS - 3

ER -