(117e) Real Time Process Monitoring with PAT for Continuous Pharmaceutical Manufacturing: Toward Advanced Process Control and Real Time Optimization with Ciprofloxacin Synthesis

The manufacturing of medicines is most commonly conducted using batch processing with the active pharmaceutical ingredient (API) and drug product manufacturing often segregated and performed at different times and sites. The final drug product is typically shipped and/or stockpiled awaiting administration to a patient. The Pharmaceutical Engineering Lab at Virginia Commonwealth University (VCU) is working to develop more efficient processes with continuous manufacturing for the generic drugs that are on the list of essential medicines. The motivation lies in the potential for increased process efficiency and safety as well as reduced process time, waste, space requirements, and operational costs. This advancement in the pharmaceutical manufacturing of both drug substance and product lend itself to the utilizations of inline flow cells and in-situ probes for real time data collection. The needs for real time quality assurance and control of the pharmaceutical products led to the introduction of the process analytical technology (PAT) guidance by the Food and Drug Administration (FDA) in 2004

Here we report the implementation of PAT for the real time monitoring of continuous ciprofloxacin synthesis developed for the portable end-to-end continuous pharmaceutical manufacturing system, Pharmacy on Demand (PoD). This work will discuss the implementation of PAT at various stages of the API synthesis, specifically the use of FTIR and Raman spectroscopies for developing product concentration prediction models using chemometric analysis. Two locations in the five-step continuous synthesis were selected for understanding and controlling the critical process parameters (CPPs) to achieve the desired critical quality attributes (CQAs). These models were validated experimentally, and integrated into the PoD units’ PAT framework orchestrated by synTQ, a PAT management software. The PAT package was deployed during a 12-hour continuous ciprofloxacin synthesis in which its powerful real time process monitoring capability through product concentration predictions was demonstrated. The implementation of PAT in mobile manufacturing platform expands the capabilities for pharmaceutical manufacturing technologies by demonstrating its ability to produce a high-quality API with advanced quality assurance and control.