This Small Business Innovation Research (SBIR) Phase I project aims to develop a scale-up manufacturing process of nitric oxide-releasing silica nanoparticles. The main challenge is controlling the nanoparticle crystal size while maintaining high levels of nitric oxide storage. In this project, critical process parameters including reactant addition rate, reaction temperature and mixing rate will be studied. The Balanced-Nucleation and Growth (BNG) Model will be utilized to transform process data into predictors of controlled particle size.
The broader/commercial impact of this project will be the potential to provide large-volume nitric oxide-releasing silica nanoparticles for placement in products aimed at the prevention and treatment of infectious diseases. Availability of large-quantity nitric oxide-releasing silica nanoparticles is important to combat the rising number of nosocomial infections. However, the necessary scale-up technology to manufacture nitric oxide-releasing silica nanoparticles is not available. This project is expected to provide the processes to manufacture large quantities of nitric oxide-releasing silica nanoparticles for anti-infective product development.
Description of Project The goal of this Small Business Innovation Research Phase I project was to scale up the production of a new drug candidate that has the potential to provide a number of therapies for healthcare infections. Based on nitric oxide, a free radical gas naturally produced by the human body to help fight infections, Novan’s proprietary technology has broad spectrum antimicrobial activity including the ability to combat drug resistant bacteria without the potential for breeding resistance. To date, the challenges associated with the storage and controlled release of nitric oxide gas have hindered the development of nitric oxide based products. Novan’s technology overcomes both of these issues by storing large quantities of nitric oxide in a solid phase and "tuning" the nitric oxide release to last for long or short time periods. The main challenge for the Phase I study was controlling the manufacturing process while moving toward a reproducible production scale. The research effort optimized critical process parameters, increased production capacity, improved cost efficiency, and implemented more environmental friendly manufacturing techniques by reducing waste output. Significant Outcomes A "Design of Experiments" statistical model was used to identify which parameters, if any, could be optimized to improve the manufacturing process. The resulting analysis compared product yield and nitric oxide loading across a matrix of reactions. The model accounted for 99.99% of the variability in the responses, illustrating consistency with the process and confirming that no major unknown environmental variables were influential. Specific process improvements included a six-fold increase in batch yield, more than 100-fold increase in production capacity per liter, conditions for increased potency of the active pharmaceutical ingredient, and overall improvements in the quality of the product. A follow up study on this information led to an innovative sol-gel process that addressed the homogeneity problem in large scale silica particle production, representing significant additions to Novan’s intellectual property portfolio. Most importantly, the breakthroughs in process manufacturing led to the development of NVN1000, a new active pharmaceutical ingredient, based on the Company’s proprietary nitric oxide-releasing technology. Summary This period of short, but intense research has led to improvements in the manufacture of the Company’s nitric oxide-releasing technology. Further development efforts during Phase II research will increase knowledge on the process variables and provide new insights in controlling the quality of the final product. NVN1000 has been produced multiple times with consistent recovery and quality, increasing the Company’s confidence in achieving future goals for large-scale manufacturing. This achievement was partially due to the discovery of a simple method of controlling the process of nucleation and growth of silica particles. Further, the process improvements yielded NVN1000 with generally higher nitric oxide loading, which means a higher potency in subsequent anti-microbial testing. More process development work is necessary to produce pharmaceutical quantities necessary for clinical trials and to implement "Quality by Design" principles for manufacturing in accordance with current Good Manufacturing Practices. These two activities are the center piece of the proposed Phase II work. With the rapid advance of multi-drug resistant organisms and the reduced investment by major pharmaceutical companies in this therapeutic area, there is a growing need for solutions to infection. Novan’s nitric oxide-releasing technology presents a promising alternative to conventional antibiotics and has clear points of differentiation over other commercial offerings targeting this urgent, unmet medical need.
