Nitrosamine Impurity Risk Assessment Checklist

Scope and Risk Evaluation (Step 1)

Identify products and potential nitrosamine root causes.

• Are all marketed and pipeline products with vulnerable amine structures or nitrosating conditions included in the risk assessment scope? *
• Have all potential root causes been evaluated, including APIs, excipients, recovered solvents, catalysts, water, and packaging? *
• Is the potential for Nitrosamine Drug-Substance-Related Impurities (NDSRIs) formed from the API's own secondary or tertiary amine assessed? *
• Are supplier and contract manufacturer processes assessed for nitrite and secondary amine sources? *

Confirmatory Testing (Step 2)

• Where risk is identified, is confirmatory testing performed with a validated, suitably sensitive method (e.g., LC-MS/MS or GC-MS/MS)? *
• Is the method limit of quantitation at or below 10% of the acceptable intake limit? *
• Record the number of confirmatory batches tested.
• Are results reported to the health authority within the required reporting timeframe when a nitrosamine is detected? *

Acceptable Intake and Limits

• Is an acceptable intake (AI) limit established for each identified nitrosamine using the Carcinogenic Potency Categorization Approach (CPCA) or compound-specific data? *
• Is total daily nitrosamine exposure controlled when multiple nitrosamines are present? *
• Is the maximum daily dose used to convert AI (ng/day) into a concentration limit (ppm)? *

Control Strategy and Change Management

• Is a control strategy documented to prevent, reduce, or purge nitrosamines to below the AI limit? *
• Is the nitrosamine risk assessment reviewed and updated under change control when process, supplier, or specification changes occur? *
• Are risk assessment conclusions approved by the quality unit and documented? *