Using PAT to accelerate the transition to continuous API manufacturing

• Published in: Analytical and bioanalytical chemistry Vol. 409; no. 3; pp. 821 - 832
• Main Authors: Gouveia, Francisca F., Rahbek, Jesper P., Mortensen, Asmus R., Pedersen, Mette T., Felizardo, Pedro M., Bro, Rasmus, Mealy, Michael J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2017; Springer; Springer Nature B.V
• Subjects: Analytical Chemistry; Batch processes; Biochemistry; By products; Byproducts; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Design analysis; Food Science; Formations; Laboratory Medicine; Manufacturing; Mathematical analysis; Monitoring; Monitoring methods; Monitoring/Environmental Analysis; Optimal yield; Pharmaceutical industry; Process Analytics in Science and Industry; Process controls; Production management; R&D; Raw materials; Research & development; Research Paper; Sampling; Spectroscopy; Synthesis (chemistry); Denmark; Process development; Spectroscopies; Continuous processes; In-line monitoring
• ISSN: 1618-2642; 1618-2650
• DOI: 10.1007/s00216-016-9834-z

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