**Last week US FDA has released Generic Drugs- Science & Research Priorities for year 2024. It has identified 8 priorities for this year.
Nitrosamines was mentioned as first in the list-
- Nitrosamines (The formulation and manufacturing mitigation strategies and their effects on absorption and/or bioavailability of APIs, Utilizations of simulation and modelling to assess the performance of generic product in the event of re-formulation, Developing analytical methods, and approaches using orthogonal methods, Consideration of tertiary amines beyond secondary amines or other factors that may improve the ability to predict formation of NDSRIs or small molecule nitrosamines, Estimating AI using toxicology studies and QSAR).
We may see more developments, guidance and dialogues with US FDA on these!
FY 2024- US FDA Generic Drugs Research Priorities.pdf (126.4 KB)
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FY 2024 GDUFA Science and Research Report
Summary of FY 2024 Activities
During FY 2024, FDA’s research related to N-nitrosamine impurities in drug products involved two external research Grants and several internal research projects. These works focused on assessing the risk of forming N-nitrosamines including nitrosamine drug substance-related impurities (NDSRIs), developing analytical methods for the quantitation of impurities, understanding toxicological risks of these impurities, exploring strategies to prevent or mitigate their formation by reformulating drug products potentially with suitable antioxidants or pH modifiers, and weighing the potential impacts of reformulations on the bioequivalence (BE) of generic products.
Active FDA Research
● Assessing the Occurrence and Extension of NDSRI Formed from the Nitrosation of API Related Substances (‘Fragment’ of API)
● Assessing the Prevalence of NDSRI Contamination in Pharmaceutical Products and Gaining Insights into the Contributing Factors for the Contamination: Analytical Method Development and NDSRIs Screening in Various Drug Products
● Developing Consensus Approach for Evaluating the Mutagenicity and Cancer Risk of Nitrosamine Drug Impurities and Nitrosated Drug-Substance Related Impurities (NDSRIs), Using In Vitro Mutagenicity Assays ● Endogenous Nitrosamine: Application of Tiny-TIM System as an In-Vitro Tool to Investigate the Nitrosamine Formation under Physiologically Relevant Conditions
● Establishment of an In Vivo Mutation Test Pipeline for Evaluating the Mutagenicity of N-Nitrosamines
● Evaluating the Strategy of Mitigating NDSRI Formation Through Manufacturing Process (Solid Dispersion) Using Selected Model Drug
● IC-MS Method Development to Improve Method Detectability of Nitrite/Nitrate in Drug Product
● In Vitro and In Silico Modeling Approaches for Supporting Biowaiver for Non Q1/Q2 BCS Class 3 Drug Products
● Mitigation Studies of Nitrosamine Formation in Metformin, Bumetanide, and Other Model Drug Products
● Mutagenicity of NDSRIs in Bacterial and Mammalian Cell Genotoxicity Assays Optimized for Evaluating the Mutagenicity of N-Nitrosamines
● Roles of Excipients in the Formation of NDMA in Metformin Drug Products
● Managing Bioequivalence Risks for Nitrosamine Impacted Drug Products Containing BCS IV Drug Substances
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