Impact of critical process parameters and critical material attributes on the critical quality attributes of...

Liposomes were one of the earliest drug delivery vehicles used for anti-cancer therapeutics and similarly, lipid-based nanoparticles have been used for abundance of applications as gene therapies. The methods to produce these particles have remained relatively unchanged until the recent emergence of continuous manufacturing. Continuous processing enables accelerated development of nanoparticle formulations while providing a scalable manufacturing solution. For this work a continuous processing platform for the production of lipid and polymeric-based nanoparticle formulations has been developed at the University of Connecticut. This research focuses on the formation of liposomes encompassing multiple design of experiments (DoEs) to identify functional relationships between critical process parameters (CPPs), critical material attributes (CMAs), and critical quality attributes (CQAs) for liposomal formulations produced using this continuous processing platform. Liposomes of various sizes and of low polydispersity index (PDI) were produced with different material attributes under various processing conditions. In general, lower mole percentages of cholesterol produced larger particles whereas the mole percent of phosphatidylglycerol did not seem to have a s impact on the size of the liposomes that were produced. The results showed that similarly sized liposomes could be produced with different processing conditions allowing for the flexibility to operate in regions most suitable for formulation components that may be sensitive to certain processing conditions. For example, if the target size of a formulation is 100 nm but the active pharmaceutical ingredient is sensitive to temperature, then the formulation can be manufactured at high (55 °C) or low (30 °C) depending on its characteristics. Additionally, the relationships between CMAs and CPPs were different from conventional liposomal manufacturing methods, allowing for more flexibility when using a continuous processing system. Models that can effectively predict the hydrodynamic diameter of monodispersed liposomes produced using continuous processing were developed. The models developed from the DoEs in this study may be useful for accelerated development of new lipid formulations as well as facilitate the translation from traditional manufacturing methods to continuous manufacturing for products already on the market.