https://www.sciencedirect.com/science/article/abs/pii/S1773224726010610
Abstract
Nitrosamine drug substance-related impurities (NDSRIs) can form in oral solid drug products when a nitrosatable API or API-related amine encounters a nitrosating species within a favourable local microenvironment. This critical review examines the formulation and manufacturing variables that govern that encounter, including excipient-derived nitrite, supplier and lot variability, microenvironmental pH, water activity, salt form, solid-state (dis)order, granulation, particle engineering, manufacturing atmosphere, and storage. Evidence is distinguished as direct NDSRI drug-product evidence, transferable evidence from other pharmaceutical nitrosamine systems, general pharmaceutical-science evidence, or mechanistic inference. A simple formulation-level nitrite mass balance is included as a prioritisation aid for identifying dominant excipient contributions; it is not proposed as a validated predictor of NDSRI concentration. Mitigation options are evaluated against both their expected effect on nitrosation risk and their potential consequences for dissolution, stability, manufacturability, and bioequivalence. Integrated atomoxetine and miglustat case studies illustrate reactive and proactive control strategies. Overall, the evidence supports treating NDSRI prevention as a product-development and lifecycle-control problem in oral solid dosage forms, while also showing where recommendations remain provisional because direct product data are limited.
