A continuous synthesis line was developed integrating different common reaction stepsnamely nitration, substitution and hydrogenation. Mesalazine as model drug substancewas produced from 2-chlorobenzoic acid in continuous flow mode. A multi-instrument PATstrategy was implemented to equip the full line with in-line monitoring capability for crit-ical quality attributes (CQAs) at several points. While most applications of PAT in Research Articleand manufacturing of the drug substance are limited to in-process control of quality, in thisstudy real-time process information was generated to support automated process controlactions. Process models were developed for all steps of the synthesis route either mechanis-tic based on reaction kinetics, data driven based on process data or depicting the residencetime distribution (RTD). These models facilitated the development and implementation ofan automation concept. Feedback loops were established using model predictive controllersfor each unit operation, with the objective to maximize yield and minimize side products.The results indicate the high potential of an advanced control concept based on processmodels and real-time process data.

• Research Article Center Pharmaceutical Engineering GmbH
• Graz University of Technology
• Evonik Industries AG/Graz University of Technology

• PAT
• API synthesis

1. Advanced process control
2. API synthesis
3. continuous manufacturing
4. Control concept
5. Model predictive control
6. pat
7. PAT strategy
8. Research Article