|  FDA | CDER | Small Business and Industry Assistance INDUSTRY NEWS | | Updates on Possible Mitigation Strategies to Reduce the Risk of Nitrosamine Drug Substance Related Impurities (NDSRIs) in Drug Products FDA is providing information to industry on possible mitigation strategies to reduce the risk of nitrosamine drug substance related impurities (NDSRIs) in drug products, including consideration of the role of formulation design for controlling nitrosamine levels in drug products. - In September 2020, FDA issued a guidance for industry, Control of Nitrosamine Impurities in Human Drugs to help ensure the safety of the U.S. drug supply by recommending steps manufacturers of active pharmaceutical ingredients (API) and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products. The guidance also described conditions that may introduce nitrosamine impurities and described a three-step mitigation strategy.
- In February 2021, FDA updated the guidance to specify timeframes for completion of nitrosamine mitigation activities by drug manufacturers. The strategy includes:
- Step 1: Risk assessment - Recommended completion date was March 31, 2021
- Step 2: Confirmatory testing if risks are identified - Recommended timeline for completion is October 1, 2023
- Step 3: Reporting changes implemented to prevent or reduce the presence of nitrosamine impurities in drug products in approved and pending new drug applications (NDAs) and abbreviated new drug applications (ANDAs) - Recommended timeline for completion is October 1, 2023
Recently, FDA received additional reports of certain types of nitrosamine impurities that formed in several drug products. These NDSRIs are a class of nitrosamines sharing structural similarity to the API. NDSRIs can be generated during manufacturing or during the shelf-life storage period of the drug product. In some cases, the root cause of NDSRI formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts. Nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs in certain drug products. FDA expects manufacturers to ascertain the presence of nitrosamines, including NDSRIs, using the three-step mitigation strategy. Manufacturers should now be engaged in the confirmatory testing and reporting changes stages of their mitigation activities (steps 2 and 3). If NDSRIs are detected in the drug product at objectionable levels, FDA encourages applicants to develop control strategies and/or design approaches to reduce NDSRIs to acceptable levels. See FDA's announcement for information on approaches to mitigate or prevent formation of NDSRIs, as well as meeting requests to discuss these mitigation strategies: | | | The Small Business and Industry Assistance (SBIA) program in the Center for Drug Evaluation and Research provides guidance, education and updates for regulated industry. | | | |
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