(467e) Development and Validation of Raman and Blaze Metrics As Process Analytical Technology (PAT) Tools to Monitor Continuous Synthesis and Crystallization of Carbamazepine

Pharmaceutical manufacturing is subjected to geographical and socio-economic barriers which has led to longer, more complex, and fragmented supply chain issues ultimately causing drug shortages. Continuous manufacturing (CM) is an advanced manufacturing technology which can have a positive impact in areas of public health, safety, quality, security, and sustainability by strengthening the medicine supply chain. As a result, the development and adoption of CM as well as the use of process analytical technologies (PATs) has been rising steadily in the pharmaceutical industry and is supported by regulators (e.g., ICH Q13). PAT tools can play a critical role during development, commercialization, and lifecycle of a continuous process by facilitating process understanding and control strategy. In this work, a continuous synthesis was designed and developed for a model drug carbamazepine (CBZ) using continuous stirred tank reactor (CSTR) EasyMax system. The synthesized product stream was telescoped into a mixed-suspension mixed-product crystallizer and a filtration unit to isolate the preliminary CBZ form I polymorph as solid product. Continuous cooling recrystallization was carried out in the end into another CSTR system to obtain the desired CBZ form III polymorph. An in-line Raman method using MarqMetrix probe was developed to monitor the starting material (iminostilbene or ISB) and product (CBZ) during the continuous synthesis. The in-line Raman method was developed by implementing least square regression of peaks and trapezoidal approximations using Python. The in-line Raman method was subsequently validated as per ICH Q2 (R1) for linearity (more than 0.99 for correlation coefficient, R²), accuracy (100 ± 5.1% for all three levels of quality control standards) and precision (< 2.1% RSD for all three levels of quality control standards) for the three days of method validation. During the final crystallization step, the polymorph transformation from CBZ form I to form III was monitored using a BlazeMetrics microscopy probe and the transformation was confirmed by powder XRD results. Overall, the continuous production of CBZ was achieved through three successive processes: continuous synthesis, continuous crystallization and polymorph transformation with integrated PAT tools to monitor the progress process dynamics.

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