FDA/HESI Collaborative Roadmap: Advancing Hazard and Risk Assessment of Nitrosamine Impurities in Pharmaceuticals

Disclaimer: The summary provided below mirrors my individual perspective as an attendee of the workshop and does not reflect the official position of the FDA/HESI.

FDA/HESI Research Roadmap Planning on Hazard and Risk Assessment of Nitrosamine Impurities in Drugs:

Over the past five years, a global discussion surrounding the safety of human-use medications has centered on the presence of N-nitrosamines. However, the landscape has evolved since 2021, as the focus has shifted from small nitrosamines to Nitrosamine Drug Substance Related Impurities (NDSRIs).

This paradigm shift necessitates our attention and action to ensure comprehensive risk characterization. Here are key future points that demand our attention and collective efforts:

Harmonized Guidelines for Acceptable Intake Levels (AIs): Developing consistent guidelines is imperative when determining AIs for NAs with limited data. This ensures a robust and standardized approach across regulatory frameworks, enhancing safety evaluation.

Triage System for NDSRIs: Implementing a triage system allows us to prioritize Cohorts of Concern (CoCs) over NAs with higher AIs, such as those within the Threshold of Toxicological Concern (TTC) of 1.5 μg/day. This targeted approach enables efficient risk management.

Weight of Evidence (WOE) Approach: Enhancing AI assessment by incorporating the WOE approach is crucial. Relying solely on animal data limits our understanding, but by considering multiple sources of information, we achieve a more comprehensive risk evaluation.

Transparency in AI Development: Promoting transparency in AI development is essential. Detailed monographs for both simple alkyl NAs and NDSRIs provide clear guidance and foster trust in the evaluation process.

Incorporating ICH M7 Principles: Adhering to the principles outlined in the ICH M7 guidelines is paramount. However, we must recognize that certain NAs may exhibit higher potency, requiring specific considerations during risk assessment.

Comprehensive Feature Assessment: Recognizing the importance of considering multiple features within NAs, particularly in complex NDSRIs, ensures a thorough risk assessment. Each element contributes to a holistic understanding of their potential impact.

Leveraging Carcinogenicity Data: Expanding our utilization of publicly available carcinogenicity data reduces reliance on surrogate analysis, enhancing the assessment of NAs. Robust data from various sources contributes to a more reliable evaluation.

Continuous Refinement: Continuous improvement is essential in refining features and weights with new testing data. Drawing parallels with the evolutionary nature of ICH M7 (Q)SAR models for other mutagenic impurities enhances our risk assessment capabilities.

Molar Basis Potency: Exploring NDSRI potency on a molar basis provides a comprehensive understanding of their risk profiles. This approach offers valuable insights into their potential impact.

Embracing Emerging Data: Integrating emerging data types and chemical/biological considerations, such as quantum mechanical descriptors and metabolic insights, empowers us with enhanced risk characterization tools. Staying abreast of advancements enriches our evaluation processes.

Distinct Chemical Space: Recognizing that the chemical space of NDSRIs differs significantly from that of small molecule nitrosamines is critical. Unique risk assessment approaches are required to fully comprehend their potential impact.

Addressing Data Gaps: Identifying and addressing data gaps are crucial steps to guide compound selection for NDSRI testing initiatives. Comprehensive coverage ensures a comprehensive understanding of potential risks.

Continuous Learning: Emphasizing the continuous acquisition of new data and knowledge is paramount. This iterative process progressively enhances our models’ performance, resulting in greater prediction accuracy and broader risk coverage.


@lucas10mauriz that’s a fantastic summary. I will be sharing our notes soon as well. Thank you…


Dear @Naiffer_Host , the workshop was fantastic! Unfortunately, I couldn’t be there in person to witness all the discussions. However, the ones I could remotely attend were incredibly enriching, which is why I’ve decided to provide a summary. I am eagerly awaiting the official summary of the event. I’m certain it will be a milestone in the discussion on NDSRI