5th Annual Genotoxic & Non-Genotoxic Impurities: Nitrosamines & Beyond Summit 2025

• Current situation - level of risk.

• Risk Assessment - what are the main areas of concern / risk.

• What we have learnt from scientific Collaboration control and analysis.

• Safety Science and Acceptable Intakes - strengths and limitations of CPCA and EAT.

• What next for Nitrosamines - What would success look like.

• Use of genetic toxicity data for assessing nitrosamines.

• Calculating BMD and AI using in vivo mutation data.

• Recent considerations from the ICH M7.

• Overview of toxicological risk assessment of nitrosamines.

• Comparison between agency- and literature-published acceptable intake values.

• Challenges with the current state of affairs and future perspectives.

• Weight-of-evidence approach in setting acceptable intake limits – NDBzA as a case study.

• Analytical challenges in Large Volume Parenterals.

• Method development at ppt range.

• Method validation in an international laboratory network.

Using holistic weight-of-evidence to set acceptable intake (AI) limits for NDSRIs

including:

• Anchor approach based on positive in vivo mutagenicity data.

• QM and CYP 450 binding to categorize potency.

• Avoidance of risk.

a. The drug substance; b. The drug product process; c. The drug product formulation

• Risk reduction (amelioration).

a. Process change; b. Low nitrite strategies; c. Scavengers - a last resort?

• The regulatory implications involved in risk reduction.

a. Stability; b. Bioavailability and biowaivers;

• Processes from initial risk identification through control strategy implementation.

• Product control vs. testing requirements.

• Mitigation techniques, when active change is needed.

• Regulatory expectation of very low default limit for NDSRIs.

• Nitrosamines and carcinogenic potency.

• CPCA / EAT / MutaMouse – main elements in nitrosamine limit setting.

• Predictivity of the EAT (Enhanced Ames test).

• Publication of the EFPIA / IQ DS and DP workflows within OPRD.

• An enhancement to the risk assessment process through the development of additional workflows for potential amine impurities for DS and DP.

• Focus areas for science – based on CMC wish list from external health authorities.

• Summary, Reflections and looking forward.

• Regulatory updates in the new ISO 10993-1 and impact on toxicological risk assessment.

• Practical challenges in applying ISO 10993-17:2023 for medical devices.

• Case studies.

• Overview of recent advances for non-mutagenic impurities.

• Potential impact of the EMA reflection paper on non-mutagenic impurities.

• Impact of global regulatory divergence and what it means in the real world.

• Possible alternative framework for non-mutagenic impurities.

• ICH Q6(R1) revision: opportunities for increased harmonisation and use of science and risk-based approaches.

• Current standard approaches in toxicological risk assessment of E&L.

• Route to route extrapolation and read across.

• Update on ICH guideline Q3E on the assessment and control of E&L.

• Overview of approaches for qualifying non-mutagenic impurities.

• Key considerations from the EMA Draft Reflection Paper on the Qualification of NMIs.

• Establishing acceptable limits based on safety data and exposure levels.

• Achieve confident decision making through pre-competitive data sharing initiatives, driven by industry collaboration.

• Automate the identification and calculation of elemental impurities with a high-quality database and user-friendly software.

• Transforming ICH Q3D risk assessments into streamlined in silico workflows.