The U.S. Food and Drug Administration (FDA) announced the establishment of a docket requesting public comments on the identification, assessment, and control of N-nitrosamine drug substance-related impurities (NDSRIs) in drug product development and regulatory review.  The docket provides interested parties an opportunity to comment on NDSRI scientific and regulatory considerations.[i] For more information on nitrosamines and FDA’s regulatory review of potential nitrosamine contamination, please read our April 2023 post. Public comments are due by July 3, 2023.

Issues for Consideration and Request for Comments

The FDA has identified several areas that may benefit from collaborative efforts and requests comments on the following topics to provide further information on scientific and/or regulatory approaches to these types of impurities in drug products. The FDA is also interested in any challenges preventing industry from identifying, assessing, and controlling NDSRIs.

1. What additional topics related to the evaluation of nitrosamines should be a priority to address through guidance documents?

2. What factors should the FDA consider in prioritizing its evaluation of NDSRIs on a compound-specific basis?

3. What additional mitigation strategies should be considered for reducing NDSRI formation or eliminating these impurities (where feasible)?

4. What scientific and technical factors should the FDA consider in developing best practices for conducting testing for NDSRIs (e.g., Ames test, enhanced Ames test, follow up in vitro mutagenicity, in vivo transgenic gene mutation test) in support of establishing acceptable intake (AI) limits?

         a. Are there other tests recommended for assessing mutagenic potential of NDSRIs, and how supportable are these methods?

         b. Would “short-term” carcinogenicity testing (e.g., six-month transgenic mouse model) be informative to evaluate the risk associated with NDSRIs?

         c. If so, what are the advantages and disadvantages to such testing?

         d. Are there other types of studies that may further inform the FDA about the risk associated with NDSRI (e.g., in vitro/in vivo metabolism, DNA biomarkers, identification of reactive intermediates)?

5. The FDA recommended in the Nitrosamine Guidance that confirmatory testing of drug products and submission of required changes in drug applications be concluded on or before October 1, 2023. Would an extension of the recommended timeline for submission of changes in drug applications as described in the guidance to June 1, 2024, allow for additional assessment of NDSRIs and enable collaborative efforts among affected applicants? How can the FDA further support manufacturers’ efforts toward completion of confirmatory testing?

6. How can the FDA facilitate collaborative efforts to generate reliable compound-specific data on NDSRIs and reduce the need for additional and potentially duplicative testing?

7. Are there obstacles that the industry has encountered when engaging in collaborative efforts that could allow companies to share data to assess the safety of NDSRIs, particularly with the intent of reducing redundant testing and integrating the 3R principles? Such examples of collaboration may include enhancing (Q)SAR methods and models, conducting in vitro mutagenicity testing and/or in vivo transgenic gene mutation tests. If there are such obstacles, are there ways that the FDA could facilitate collaboration?

8. In implementing recommendations for controlling nitrosamines, including NDSRIs, have manufacturers or suppliers experienced difficulties with meeting recommended AI limits that has led to discontinuation of manufacturing or distribution?

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Nelson Mullins continues to closely monitor FDA regulatory developments as well as the litigation risks they create.

[i] Identification, Assessment, and Control of Nitrosamine Drug Substance-Related Impurities in Human Drug Products; Establishment of a Public Docket; Request for Comments, 88 Fed. Reg. 28557, 28557-28562 (May 4, 2023), available at https://www.federalregister.gov/documents/2023/05/04/2023-09526/identification-assessment-and-control-of-nitrosamine-drug-substance-related-impurities-in-human-drug.