Process analytical technology as in-process control tool in semi-continuous manufacturing of PLGA/PEG-PLGA microspheres.

Nowadays, among 3rd generation drug delivery systems, biodegradable polymeric based long-acting injectable depot has achieved tremendous success in clinical application. So far, there have been two dozen of commercial products of Poly (lactic-co-glycolic acid) microspheres available in the market. Recently, continuous manufacturing concept has been successfully applied on oral solid formulation from buzzword to reality. However, the polymeric injectable microspheres are still stayed at batch manufacturing phase due to the lack of understanding of knowledge matrix. In this study, micro-mixer as a plug-and-play emulsification modules, Raman spectroscopy and focused beam reflectance measurement as real-time monitoring modules are integrated into a novel semi-continuous manufacturing streamline to provides more efficient upscaling flexibility in microspheres production. In this end to end semi-continuous manufacturing process, amphiphilic block polymer monomethoxy-poly (ethylene glycol) modified PLGA (mPEG-PLGA) was used for encapsulating Gallic acid. Additionally, with guarantee of good robustness, the correlation relationship between critical process parameters, critical material attributes and critical quality attributes were investigated. The time-space evolution process and mechanism for formation of PEG-PLGA microsphere with particular morphology were elaborated. Altogether, this study firstly established semi-continuous manufacturing streamline for PLGA/PEG-PLGA microspheres, which would not only lower the cost of production, narrow process variability and smaller equipment/environmental footprint but also applied in-process control (IPC) and QbD principle on complicated production process of microspheres. Therefore, this study build confidence in the industrial development of PLGA/PEG-PLGA microspheres and establish best practice standards, which might be a quantum leap for developing PLGA microspheres in the future.