In 2024, the European Medicines Agency updated its guidance on nitrosamine impurities. The update revised several Acceptable Intake values, expanded the list of N-nitrosamine drug-substance-related impurities, and introduced stricter expectations for risk assessment and control.
Although the changes appeared technical, they created significant operational and commercial consequences across the pharmaceutical industry. Many companies needed to repeat portfolio-level risk assessments, perform additional analytical testing, revalidate API processes, initiate retrospective CAPAs, and submit regulatory variations.
Moreover, the revised guidance affected both new and marketed products. Some companies delayed product launches, while others placed existing products on hold. In certain cases, management teams also had to decide whether the cost of reformulation or revalidation justified keeping older products in the portfolio.
Therefore, the main challenge did not involve compliance alone. Pharmaceutical companies also needed to manage analytical capacity, supply continuity, development timelines, regulatory submissions, and portfolio profitability.
This assessment outlines the main compliance GAPs created by EMA’s 2024 nitrosamine guidance. It also presents a structured remediation approach based on portfolio triage, confirmatory testing, CAPA planning, process redesign, and lifecycle control.
To address these challenges, our team assessed the regulatory, analytical, operational, and commercial impact of EMA’s updated nitrosamine requirements. We reviewed the main GAPs across product portfolios, legacy API routes, analytical methods, supplier information, regulatory submissions, and lifecycle controls. Moreover, our team structured a remediation approach that covered portfolio triage, confirmatory testing, root-cause analysis, CAPA planning, regulatory variations, process redesign, and long-term nitrosamine risk management.
We assist pharmaceutical teams in assessing and managing nitrosamines risks by aligning processes with ICH M7 requirements and current regulatory expectations.
A regulatory variation may become necessary when testing confirms a nitrosamine above the applicable Acceptable Intake or when remediation changes the approved process, specification, analytical method, or control strategy. The Marketing Authorization Holder should coordinate the variation with the investigation, CAPA plan, validation work, and supply strategy.
A previous assessment may have relied on an older Acceptable Intake value or may not have included a newly listed NDSRI. Therefore, the revised CPCA category can change the permitted daily exposure and alter the product’s risk classification. Companies should reassess affected APIs and drug products against the current values.
Companies should prioritize routes that use or historically used tertiary amines, DIPEA, NMP, nitrosation-prone reagents, or related intermediates. Limited supplier traceability, older pre-2018 routes, and the absence of a recent portfolio assessment also indicate a higher need for reassessment.
