(198a) Quality By Design in Nanomedicine: Application to a Microemulsion Delivery System

Nanomedicine is a concept which makes use of nano-scale carriers to provide therapeutic or diagnostic benefits in medicine. Despite promise of increased therapeutic efficacy, uncertainty of safety and translatability of nanomedicine platforms remain prevalent. Quality by design (QbD) is a practice used to heighten process safety and assure product quality. The methodology eases the development of pharmaceutical products by deliberate process that can lead to the procurement of high quality, effective nanoformulations while minimizing risk, time, and resources. QbD builds quality into a product by first establishing the overall objectives and defining ways in which to control the process. Although its use is strongly encouraged in the pharmaceutical industry, it is underutilized in the rapidly expanding field of nanomedicine. The presented work exemplifies a case study in which a QbD strategy is used in robust formulation development and highlights the benefits accrued as a result of applying QbD to nanomedicine, employing microemulsions as a model nanoformulation.

Microemulsions, a type of nanomedicine characterized by droplet diameter of 15-50 nm, are thermodynamically stable colloidal dispersions which are used to increase drug solubility and half-life. Microemulsions are safe, given that they can be developed with biodegradable, generally regarded as safe (GRAS) oils and surfactants. For these reasons, we chose microemulsions as our model nanoformulation. First, the quality target product profile (QTPP) of the microemulsion product was defined. After defining the associated critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs), we compiled a library of modes of failure during product manufacturing and ranked them using failure modes, effects, and criticality analysis (FMECA). We used the results of risk assessment to create a design of experiments (DOE) to which we fit multiple linear regression and logistic regression models to predict microemulsion properties and probability of meeting CQA specifications. We performed comprehensive quality control analyses to evaluate CQAs and overall were able to identify stable microemulsion formulations in a timely manner using a small number of experimental runs. Finally, we demonstrate the loading capability with multiple BCS class II drugs to demonstrate the versatility of this formulation and investigate the scale-up of the optimized microemulsion. Adapting this QbD methodology to other nanomedicine products is of value for time and resource minimization as well as smoothing the path to regulatory approval.