A unique PAT tool for real-time inline size characterization in continuous manufacturing

Nanoparticle size is considered a critical quality attribute of nanotherapeutics. In order to have a better understanding and control of nanoparticle synthesis and formulation processes, process analytical technology (PAT) tools for inline size characterization during continuous manufacturing are highly desired. However, commonly used particle size measurement techniques require product sampling and sample preparation e.g., through dilution. Typically, such particle size analysis is performed offline, away from the manufacturing facility. This “off-line” mode of analysis can cause additional time delays, allows only limited process insights, and leads to higher development and manufacturing costs.
Here, we introduce the NanoFlowSizer, an in-line measuring device that can non-invasively determine the hydrodynamic size of nanoparticulate suspensions in flow. The NanoFlowSizer is based on Spatially Resolved Dynamic Light Scattering (SR-DLS), a technique that combines low coherence interferometry with traditional dynamic light scattering, providing sizing measurements every 3-10 seconds in flowing suspensions (up to ~250 L/h). SR-DLS confers the ability to differentiate between multiple and single scattered lights, making particle size determinations in highly turbid and/or concentrated nanoformulations possible. These features enable the NanoFlowSizer as a process analytical technology (PAT) tool for nanoparticle continuous manufacturing systems, such as high-pressure-based size reduction systems and solvent injection-based manufacturing systems. The inline size measurement can be used as a feedback mechanism to control the formation of nanoparticles according to predefined particle size and particle size dispersion requirements, thus providing a much-needed combined process and quality control.
Overall, the ability to measure the size of nanotherapeutics in flow allows for continuous improvements of products and processes. In our contribution, we will focus on the application of the NanoFlowSizer for in situ process control measurements of nanoparticles during continuous manufacturing.