Realizing continuous manufacturing and green manufacturing of an herbal product based on micro-devices and online monitoring

The pharmaceutical industry is gradually transitioning from batch production to continuous manufacturing. This study aims to continuously manufacture an herbal product of sinomenine hydrochloride crystals. A continuous manufacturing device was set up using a micro phase separator, T-shaped micromixers, and online spectrometers to achieve the continuous process of washing, phase separation, and acid crystallization. Continuous phase separation of anisole phase and aqueous phase was achieved by a homemade membrane phase separator. Near-infrared (NIR) spectrometer was used to collect data and establish quantitative models of the contents of sinomenine and water, with model R 2 values higher than 0.8. The residence time distribution of sinomenine in both partial and overall processes was measured by the pulse method. Based on two online monitoring devices, UV detector and NIR spectrometer, a series of process control strategies including online monitoring, real time release testing, disturbance management and diversion strategy were developed to ensure the state of control. The average purity of sinomenine hydrochloride crystals prepared with continuous manufacturing was about 90.8 %, which showed no significant difference compared with those prepared with batch manufacturing. The green degree of the continuous manufacturing process reached 104 points due to the improvements in production efficiency and the ability to use real-time analysis to prevent accidents. The process monitoring method and control strategy for continuous manufacturing processes can also be used for other herbal product manufacturing.