Nearly half of all drug shortages in 2022 were caused by quality issues or manufacturing delays, according to the Center for Drug Evaluation and Research (CDER). Evaluating the critical quality attributes of high-concentration protein formulations in their actual commercial formulations and containers can help eliminate that situation while enhancing pharmacovigilance efforts.

Typical analysis technologies require diluting and transferring product from primary containers, thereby increasing the potential for aggregation and viscosity. A recent paper by scientists at Merck and the University of Maryland, however, shows that water proton nuclear magnetic resonance (wNMR) can non-invasively analyze high-concentration drug products—notably, monoclonal antibodies—under heat and freeze/thaw stress conditions even when they are in opaque, sealed, and labeled vials.

“As a measurement technology, wNMR enables data collection in places where no quantitative data can be collected using current technologies (e.g., sealed drug products),” co-author Bruce Yu, PhD, director of the Bio- & Nano-Technology Center at the University of Maryland, tells GEN. “New data may lead to new concepts and even paradigm shifts. When data are collected on every vial before release and then before injection, our understanding of drug quality and safety may very well change.”

The scientists assessed protein aggregation in a pre-filled syringe of dupilumab, comparing results from wNMR and traditional orthogonal biophysical analytical techniques. They found “wNMR successfully confirmed content uniformity, detected reversible aggregation upon dilution, irreversible aggregation upon prolonged stress at 50°C, and interesting recoverable molecular association upon freeze/thaw cycles.”

Benefits begin with simplicity

“wNMR involves no reagents or consumables. It’s a dry operation with no wet chemistry,” Yu says. Additional benefits include “simplicity, affordability, a small footprint, and the potential for point-of-care inspection by care providers.”

Prior research shows wNMR can detect protein aggregation in therapeutic mAbs at a concentration of 55 mg/mL, and also detect aggregation under flow conditions. Other research showed wNMR also can detect mAb oxidative degradation.

“Drug makers may use the flow mode of wNMR for process monitoring or the regular mode of wNMR for product inspection,” Yu says. “The biggest potential impact may be in real-time process monitoring and 100% quantitative pre-release product inspection.”

Overall, he continues, “wNMR may strengthen pharmaceutical quality control through enhanced process monitoring and product inspection. It also may help drug makers with their formulation work, such as excipient screening.”

wNMR also can enhance preventive pharmacovigilance. “This goes beyond preventing harm,” Yu points out. “It may also help alleviate public mistrust of drugs and vaccines, at least to some extent.”

Before adopting wNMR to evaluate high-concentration protein formulations, Yu advises drug manufacturers to compare this method against the analytic technologies they usually use. “A good starting point might be the fill-finish operations, using the flow-mode to monitor the filling operation, and using the regular mode to inspect every vial.”

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