Switching from current pressurised metered dose inhaler (pMDI) propellants to new propellants with lower global warming potential (GWP) could help to reduce the carbon footprint of pMDI-delivered medicines significantly. When looking at the reformulation of an existing product, there is also a need to review the analytical methodology and overall chemistry, manufacturing and controls approach.
With changes being made to the formulation, a suitable validation gap analysis of methods will be required as these methods will underpin the generation of critical data supporting product characterisation, stability and in vitro bioequivalence work. This presents opportunities to address key analytical issues associated with contaminants such as nitrosamines or leachables which represent significant risks to patient safety.
Nitrosamine Formation in pMDIs
Since the EMA and FDA introduced guidelines in 2020 on controlling nitrosamine impurities in medicinal products, industry stakeholders have undertaken extensive risk assessments and testing. These efforts are time-consuming and costly, requiring the development of sensitive detection methods and comprehensive root cause analysis, potentially leading to significant reformulation to comply with new intake limits.
The transition to low GWP propellants in pMDIs provides a chance to proactively address nitrosamine formation early in formulation development. Utilising advanced analytical techniques, such as Liquid Chromatography Mass Spectrometry (LC-MS) and Gas Chromatography Mass Spectrometry (GC-MS) can help streamline efforts to meet regulatory requirements for nitrosamine levels. Tandem LC-MS/MS provides high sensitivity and specificity for detecting API specific nitrosamines, even in complex pMDI
matrices. GC-MS is effective for analysing volatile, non-API-specific nitrosamines and potential degradation products from propellants. Utilising both LC-MS and GCMS in early trials enables comprehensive screening, identifies nitrosamine sources and ensures regulatory compliance.
Nitrosamines primarily form through reactions between secondary or tertiary amines and nitrosating agents, like nitrous oxides or nitrites, under acidic conditions. In pMDIs, nitrosamine formation can result
from interactions among the propellant system, active pharmaceutical ingredients (APIs), excipients, and device materials. The introduction of low GWP propellants to pMDIs necessitates thorough analytical evaluation to minimise the risk of nitrosamine formation.
