Use of PAT tools in the development, monitor and control of continuous manufacturing processes
Applying a Quality by Design concept in the development of a continuous process, allows process parameters to be more flexible while ensuring a quality product is obtained. Along with line and soft sensors, Process Analytical Technology (PAT) tools are critical to ensure the process stays under the “state of control” whereas tracking and diversion of non-conforming product based on Residence Time Distribution (RTD) are part of the automation system of the equipment and must be defined in the development stage. Moreover, these monitoring and control mechanisms opens the possibility for Real Time Release (testing), which implies the PAT location is critical, providing it can act on a representative sample. As an example, in a GEA Continuous Direct Compression system, the choice between a Light House Probe (LHP) and the DRLS installed in the feedframe to monitor blend potency, must take into consideration the intended overall control strategy. In this sense, whereas the LHP monitors the powder before the final mixing (which occurs in the feedframe) and therefore the RTD must be taken into consideration to initiate diversion (at the press level), the DRLS is more prone to sample presentation deviations (when powder properties slightly change during the batch).
For flexibility purposes, the development of chemometric models (calibration) can be initiated in the laboratory in a setup that mimics the original environment (PAT stack rig for LHP and feedframe simulators for DRLS). In the laboratory, PAT tools are also widely used in the determination of RTD, whereas method configuration of the PAT Management System can also be optimized and used to support the development activities. If needed in the control strategy or for development purposes only, and if proved feasible, tablet assay determination in transmittance by Near Infrared or Reflectance by Raman, can also be developed at this stage.