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Leveraging Active Material Science Technologies to Mitigate Nitrosamine Risks in Pharmaceutical Products

Hammond B, Murph A, Comer I, Pratt J, Daou J.

RDD Asia 2024. Volume 1, 2024: 72-80.

Abstract:

The presence of N-nitrosamines in pharmaceutical products is currently an area of high regulatory and industry scrutiny, as nitrosamine impurity levels above acceptable regulatory limits have been observed in several products. This problem is not limited by drug delivery method and is a challenge that needs to be addressed in inhaled and nasal drug products, as well as oral dosage forms. The application of a novel 3-Phase Activ-Polymer™ technology, composed of a main polymer which provides the physical structure (extruded film, molded component, etc.), channeling agent to control kinetics, and active materials, to mitigate N-nitrosamine formation in drugs is described. When engineered as N-Sorb nitrosamine mitigation technology, the active materials can act as barriers to prevent or reduce the interaction of secondary or tertiary amines present in drugs with nitrosating agents by scavenging these species, thereby reducing the potential for N-nitrosamines formation. While N-Sorb technology can be deployed in multiple physical formats, for the purpose of this study, tests were conducted using N-Sorb composite films. Ranitidine, recognized for its susceptibility to nitrosamine formation, was selected as a model drug to demonstrate the efficacy of this approach. Nitrite and nitrosamine levels in ranitidine capsule samples stored in a blister format with, and without, N-Sorb films under various conditions were quantified. All mitigations showed some degree of hinderance of N-nitrosodimethylamine (NDMA) growth from the initial timepoint to three-month real time equivalent. The N-Sorb1 film reduced NDMA formation by 60%. A literature-based model predicted that the N-Sorb1 film could extend the US Food and Drug Administration (FDA) acceptable intake (AI) limit by 7.5 months. This active material science technologies approach offers a promising solution for all drugs susceptible to nitrosamine contamination.