The past few decades have witnessed a rapid increase in the number of complex drug products (such as liposomes, polymeric nanocarriers, and nanosuspensions) reaching the market. These complex drug products have unique in vivo and in vitro characteristics that meet various therapeutic needs, and have greatly benefited human health. However, due to their complex formulation and processing methodologies, as well as the inherent issues associated with batch-type manufacturing (e.g. open system transfer of materials, batch-to- batch variation, scale-up procedures and supervised production) and the resultant high failure rate, their manufacturing cost is very high. Accordingly, robust and modern technology (e.g. end-to-end continuous manufacturing) with no interruptions in production is essential. In recent years a concerted effort has been made by the pharmaceutical industry to develop and implement continuous manufacturing for traditional drug products such as tablets. However, the development and implementation of continuous manufacturing for complex drug products has yet to be reported. In addition, the knowledge and experiential base that support FDA review and regulatory policies on continuous manufacturing are still lacking. Over the past two years, a prototype system that is capable of continuously producing liposomes with defined characteristics such as particle size and drug encapsulation, has been successfully designed and developed at the University of Connecticut (UConn). A mechanistic understanding of the impact of transforming batch-to-continuous processing on product quality of liposomes has been provided. Building on the knowledge and experience gained, it is now proposed to expand the current UConn prototype system to a continuous manufacturing platform with modular and portable components for a variety of complex dosage forms and drug candidates. Computational modeling (such as Molecular Dynamics, Computational Fluid Dynamics, and multi-scale) will be conducted to fully understand and simulate nanocarrier formation and drug entrapment during continuous manufacturing. In addition, a Graphical User Interface (GUI) based library will be created for quality based risk assessment and to provide a roadmap to solve continuous manufacturing challenges for complex dosage forms. A continuous manufacturing platform with modular components suitable for a cGMP facility will be built and tested using a variety of complex dosage forms. The proposed research will be extremely valuable to advance state-of-the-art manufacturing technology, and help bridge the gap between discoveries in academia and implementation by industry. Moreover, the knowledge that will be gained on continuous manufacturing of complex dosage forms will not only help the Agency with review function but also provide necessary information to guide policy development. Consequently, regulatory science will be advanced to facilitate the implementation and assessment of continuous manufacturing of complex dosage forms, which in turn will ensure a continuous supply of high quality and safe complex drug products to the public, at a reduced cost.
This proposal seeks to develop and build a continuous manufacturing platform with modular components for complex dosage forms, as well as to create a Graphical User Interface (GUI) based library to support quality based risk assessment and to provide a roadmap to solve continuous manufacturing challenges for complex dosage forms. This will facilitate the modernization of pharmaceutical manufacturing technology for complex dosage forms, as well as help the Agency with review function and provide necessary information to guide policy development. As a consequence of the proposed research, the FDA regulatory science will be advanced, and high quality cost-effective complex drug products (that require less extensive regulatory oversight) will be produced for the benefit of the public.