The U.S. Food and Drug Administration (FDA) has released an updated version of its guidance titled “Control of Nitrosamine Impurities in Human Drugs”, outlining essential deadlines for manufacturers to assess and mitigate associated risks. Adherence to these timelines is crucial to maintain market authorization and ensure patient safety.
Key Updates:
- Introduction of Nitrosamine Drug Substance-Related Impurities (NDSRIs):
- The updated guidance now addresses NDSRIs, a class of nitrosamines structurally similar to active pharmaceutical ingredients (APIs). These impurities can form during manufacturing or storage. The FDA provides a framework for predicting their mutagenic and carcinogenic potential, along with recommended acceptable intake (AI) limits.
- Recommended Mitigation Strategies:
- The FDA suggests formulation design modifications to prevent NDSRI formation. For instance, incorporating antioxidants like ascorbic acid or alpha-tocopherol may inhibit nitrosamine formation. Additionally, adjusting the formulation’s pH to neutral or basic levels can reduce nitrosamine formation kinetics.
- Updated Acceptable Intake (AI) Limits:
- The guidance includes revised AI limits for specific nitrosamine impurities, based on predicted carcinogenic potency categorization. These updates aim to provide clearer safety thresholds for manufacturers.
- Enhanced Risk Assessment and Testing Recommendations:
- Manufacturers are encouraged to implement robust risk assessments and confirmatory testing protocols. The guidance outlines steps to detect and prevent unacceptable levels of nitrosamine impurities, emphasizing the importance of understanding potential root causes.
Due date for conclusion of NDSRI confirmatory testing of drug products and submission of required changes in drug applications is 1 August 2025.
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