John McLaughlin1, Mark Parry1 & Miles Jeanneret1
1Intertek Melbourn, Saxon Way, Melbourn, Herts, SG8 6DN, UK
Summary
The global transition toward environmentally sustainable pressurized metered-dose inhalers (pMDIs) requires a thorough understanding of potential impurities introduced during reformulation, particularly nitrosamines, a class of potential human carcinogens that has seen significant development of legislation and understanding of risk in recent years. This study presents work developing analytical methods and investigating the risk of nitrosamine formation in marketed pMDI pharmaceutical products. Further studies will extend this work to look at the risks and control strategies when undergoing reformulation with next-generation low Global Warming Potential (GWP) propellants.
Two commercially available pMDIs, Symbicort, containing formoterol, and Ventolin, containing salbutamol, were assessed for the formation of their respective nitrosamine impurities, N-nitroso formoterol (NNF) and N-nitroso salbutamol (NNS). Sensitive LC-MS methods were developed for both, achieving limits of quantification well below established acceptable daily intake (ADI) thresholds. Linearity and accuracy were confirmed across relevant concentration ranges. Initial testing showed trace levels of NNF near the method’s limit of detection in Symbicort, while no NNS was detected in Ventolin. Following forced degradation at 60 °C for up to six weeks, Symbicort exhibited quantifiable levels of NNF, though still significantly below the ADI, while Ventolin remained nitrosamine-free throughout.
This proof-of-concept work demonstrates the utility of the analytical methods and supports their application in ongoing studies. Future work will evaluate nitrosamine formation following incorporation of low GWP propellants and examine interactions with device components (e.g., valves, seals, actuators) to identify potential sources of nitrosamine formation.
These findings will guide safe, compliant reformulation strategies, ensuring continued patient access to essential inhalation therapies with a lower environmental impact.