CERSI Collaborators: Taylor Woehl, Ph.D.

FDA Collaborators: Bin Qin, Ph.D.,, Yan Wang, Ph.D.,, Xiaoming Xu, Ph.D., CDER FDA., Kuo-Tang Liao, Ph.D.

Project Start Date: July 2020

Regulatory Science Challenge

Nanoparticle-based drugs are drugs where the active pharmaceutical ingredient (API) is formulated into tiny particles with sizes below 1000 nanometers (nano- means a “billionth part of”). Nanoparticles are over 1000 times smaller than the diameter of a strand of human hair. By reducing the size of the API, certain properties can be improved, such as how fast the API dissolves and where it distributes inside the body. However, it is challenging to create nanoparticles that are identical in size. Instead, nanoparticles typically come in a broad range of sizes and shapes, making it challenging to accurately measure their size.

Accurate particle size characterization is important because the size of nanoparticles in a drug product is a critical quality attribute, which may impact how they interact with biological tissue. This makes size an important attribute to be measured during drug product development, regulatory review and approval. Reliable and accurate measurement of particle size is also critical for generic drug developers, given that particle size is used frequently as a criteria to establish equivalence to the brand name drug. Conventional experimental techniques (i.e., the common way to make a measurement), such as light scattering, are not able to accurately measure the particle size distribution or the amount of drug in each nanoparticle. New experimental methods would be helpful to quantify the nanoparticle size and composition distribution more reliably in nanoparticle-based drugs.

Project Description and Goals

This project will develop a new analytical tool, hyperspectral interferometric scattering microscopy (h-IFS), to measure the size distribution (percentage of particles of certain size) and composition of particles in drug products that contain nanoparticles. This approach uses an optical microscope, which magnifies the nanoparticles using light and a complex lens assembly, to measure the size of nanoparticles based on how light scatters from the particles. Researchers at the University of Maryland will build a prototype instrument and will develop image analysis software to process h-IFS data. Researchers will use well-known model nanoparticle samples to validate the method and determine its limitations and strengths. Researchers will demonstrate application of this method on two FDA approved nanoparticle drug products for metastatic cancer, Abraxane® and Onivyde®. Given that particle size is a critical quality attribute of these drug products, this project will provide a useful new characterization tool for generic drug developers.

Research Outcomes/Results

The research project has had several outcomes, including:

1. a prototype h-IFS microscope
2. software algorithms for automated data processing,
3. demonstrating h-IFS on model nanoparticles, and
4. characterization of paclitaxel (chemotherapy medication) nanoparticles in Abraxane®.

The h-IFS was validated by measuring the range of particle sizes in colloidal suspensions of gold, silver, and silicon dioxide nanoparticles with well-known sizes. Results demonstrate that h-IFS can detect paclitaxel nanoparticles with a reported size of 130 nm from the drug Abraxane®. Results have shown that agglomerates, collections of several paclitaxel nanoparticles stuck together, scatter light differently than single particles, and that h-IFS can detect these agglomerates by measuring, on a single particle level, the effect of light wavelength on light scattering.

Research Impacts

The goals of this research align with several CERSI research impact metrics. First, this work will advance regulatory science by enhancing the resources, expertise, and capacity of the FDA to characterize drug products containing nanoparticles. h-IFS is not yet an established technique in the pharmaceutical industry or academia, and this work is expected to be a catalyst for future research into the development and use of h-IFS by drug developers. h-IFS is an optical technique, suggesting it could be implemented in a high throughput manner to be suitable for industry use. Finally, future implementation of h-IFS may enhance characterization of nanoparticles drug products by providing an orthogonal measurement to existing methods, such as light scattering, which is expected to better inform regulatory decisions based on more reliable measurements of the particle size distribution and nanoparticle composition.