In an installment of its “Regulatory Science in Action” series, FDA details how a newly developed nuclear magnetic resonance (NMR) spectroscopy method enabled researchers at the agency’s Center for Drug Evaluation and Research (CDER) to characterize—crucially, in a non-invasive way—microstructure properties in complex, oil-in-water nanoemulsion ophthalmic formulations (1).

Evaluating a drug to relieve ocular pain

The research centered around difluprednate, which has been approved as an orphan drug to treat post-operative ocular pain and inflammation (1). It is insoluble in water and, as such, was formulated as an oil-in-water nanoemulsion.

CDER researchers have been developing NMR spectroscopy to characterize such formulations since 2018, and, according to FDA, the researchers’ work culminated in correlated microstructure changes being observed for the first time in nanoemulsion formulations.

More spectroscopy applications

The July/August 2025 issue of Pharmaceutical Technology® also explores applications of spectroscopy, namely ultraviolet (UV) spectroscopy as a continuous, in-line method to monitor cleaning processes to confirm cleanliness of equipment surfaces through final rinse water analysis (2).

“Results showed that in-line monitoring capability of UV spectroscopy enables continuous monitoring of the entire cleaning cycle and applicability to quality by design, process analytical technology, process digitalization, and sustainability goals of a Pharma 4.0 manufacturing facility,” the authors wrote.

Read this peer-reviewed article in full right now at PharmTech.com.

Below are further implications of CDER’s work for formulation scientists, analytical chemists, and manufacturers of complex drug products.

A quality control tool

For formulation scientists, the ability to noninvasively monitor nanoemulsion dynamics could lead to more robust excipient selection, formulation optimization, and stability prediction. For manufacturers, intact NMR may offer a quality control tool that minimizes sample manipulation while enhancing sensitivity to early signs of instability.

The study also demonstrated that different NMR relaxation times and diffusion coefficients can serve as surrogate indicators for microstructural changes, suggesting possible future development of NMR-based specifications for complex generics and innovator products alike.

Relevance for complex generics, quality assessment

FDA's emphasis on intact NMR aligns with its broader goals to facilitate the development of complex generics, particularly those containing nano-sized active or excipient particles. By enabling more precise characterization of reference listed drugs and their generic counterparts, this approach may support bioequivalence determinations and post-approval change assessments.

Furthermore, FDA noted that the study aligns with quality by design principles, offering a means to better understand critical quality attributes of nanoemulsions without disrupting the formulation environment.

A step forward

The adoption of intact NMR as a regulatory science tool represents a meaningful step in enhancing FDA’s analytical capabilities for complex dosage forms. As nanotechnology-based drug products continue to enter the market, advanced tools like these will likely become essential in supporting both premarket evaluations and ongoing quality assurance.

“Based on data obtained in this study, intact NMR methods for characterization of nanoemulsion can now be recommended to generic drug sponsors,” FDA said in the blog post (1). “These sensitive and accurate analytical methods may save resources for [the] pharmaceutical industry, accelerate generic drug development, and enhance the quality assessment of these drugs, ultimately resulting in lower costs to [the] American public.”

References

1. FDA. Modern Intact NMR Approach Reveals Synchronized Microstructural Changes in Nanoemulsion Drug Formulations. FDA.gov, last updated Aug. 4, 2025 (accessed Aug. 5, 2025).
2. Schallom, J, et al. In-Line UV Spectrometry Monitoring in Cleaning Validation. Pharmaceutical Technology 2025 49 (6) 18–22.