FDA guidance, “Control of Nitrosamine Impurities in Human Drugs,” revises the final guidance of the same name issued on February 24, 2021, by including information about nitrosamine drug substance related impurities (NDSRIs), recommending implementation of new nitrosamine control strategies, and providing an updated timeline for manufacturers and applicants to implement these recommendations.

Nitrosamine impurities are important to control because they are potential human carcinogens. Long-term exposure to these impurities at levels above acceptable limits can increase the risk of cancer. Nitrosamines can be found in various consumer products and the environment, and they have been detected in several pharmaceutical products since 2018, prompting recalls and regulatory actions. A lot of regulatory action. Nitrosamine impurities may be one of the biggest drivers of changes in the GMPs.

Current Regulatory View

Regulators, including the FDA, Health Canada, and the European Medicines Agency (EMA), have been actively working to address the presence of nitrosamine impurities in medications. The current regulatory view emphasizes:

• Risk Assessment and Control: Regulatory agencies have established acceptable intake (AI) limits for nitrosamines in drug products. These limits are designed to minimize the risk of cancer associated with long-term exposure to these impurities.
• Guidance and Frameworks: Agencies have issued guidance documents outlining frameworks for assessing and controlling nitrosamine impurities. For example, the FDA’s guidance includes recommendations for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) and provides AI limits based on carcinogenic potency categorization.
• International Collaboration: There is significant collaboration among global regulators to harmonize approaches and methodologies for controlling nitrosamine impurities. This includes the adoption of the Carcinogenic Potency Categorization Approach (CPCA) to determine AI limits.
• Industry Responsibility: Manufacturers are responsible for understanding their processes to prevent nitrosamine formation and for conducting risk assessments. They must implement control strategies and perform confirmatory testing to ensure that nitrosamine levels remain below the established AI limits.

Regulators are focused on ensuring the safety of pharmaceutical products by controlling nitrosamine impurities through comprehensive risk assessments, setting stringent AI limits, and fostering international cooperation. Companies need to make sure they are ahead of this matter.