// August 07, 2023

Pharmaceutical community eyeing FDA guidance on nitrosamines with great interest

person holding a pill between thier fingers

Nitrosamines are naturally occurring chemical compounds that people are regularly exposed to at low levels. Deli meats, vegetables, dairy products and even water can contain low levels of nitrosamines. However, some nitrosamines can increase the risk of developing cancer when people are regularly exposed to them over long periods of time.

In 2018, the U.S. Food and Drug Administration (FDA) detected nitrosamines in blood pressure medications that exceeded acceptable limits and sparked a series of recalls. At the time, one of the drugs affected by the recall was the ninth-most prescribed medicine in the United States. Since then, these and other forms of nitrosamines, including nitrosamine drug substance-related impurities (NDSRIs), have been found in other commonly used medicines.

This ongoing issue has led to inter-disciplinary cooperation and collaboration between stakeholders to reduce or eliminate the presence of nitrosamine impurities in the drug supply chain. Last week, U.S. FDA issued a new guidance on nitrosamines for immediate implementation, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs),” providing drug manufacturers and applicants with a recommended framework for a risk-based safety assessment of NDSRIs that could be present in approved and marketed drug products, as well as products under review by the FDA. Immediately after the FDA announcement, members of USP’s Nitrosamines Exchange began actively engaging in real-time conversations dissecting the guidance for implications for the pharmaceutical industry and comparison with recent recommendations made by the European Medicines Agency, Health Canada, and the Ministry of Health, Labour and Welfare in Japan. We will all surely learn more in the coming days as our scientists and regulatory colleagues sink their teeth further into the new update.

Earlier this summer, the FDA requested further stakeholder input on approaches for identifying and testing novel nitrosamines identified in drug products and active pharmaceutical ingredients (APIs) that were not addressed in FDA’s original guidance, which was published in September 2020, nor in the updated guidance from February 2021.

USP welcomed this opportunity to provide comments to FDA, having developed new reference standards, reference materials and testing methods for manufacturers to understand and control NDSRIs and help to safeguard medicine quality. USP submitted comments in response to the request, Docket No. FDA-FDA-2023-N-1585 for “Identification, Assessment, and Control of Nitrosamine Drug Substance-Related Impurities in Human Drug Products; Establishment of a Public Docket; Request for Comments,” earlier this month. Read the full comments here, and a summary of highlights from the submission are below.

Reconsidering standards to support control of nitrosamines

USP is considering how documentary standards can be updated or developed to support both manufacturers and regulators in addressing the array of challenges that accompany tackling NDSRIs. We welcome support and input from the FDA and other stakeholders on revisions to the existing General Chapter <1469> on nitrosamine impurities, development of new general chapters, or developing new or modifying existing monographs to address simple nitrosamines or NDSRIs.

Combining documentary and physical reference standards

Industry stakeholders have expressed a need for high-quality, reliable nitrosamine-related materials for analytical testing, as well as product-specific methods and limits for NDSRIs. USP’s official documentary standards along with physical reference standards and Pharmaceutical Analytical Impurities (PAIs) can help industry identify and mitigate harmful nitrosamines. USP has a number of highly characterized nitrosamine Reference Standards and a rapidly expanding list of both simple nitrosamine and NDSRI Pharmaceutical Analytical Impurities reference materials, which can be used in analytical testing, along with USP’s official documentary standards, to detect NDSRIs across the drug lifecycle. USP’s most recent releases of PAIs include materials related to antimicrobials and hypertension medications, classes of drugs that have been involved in recalls due to unacceptable levels of nitrosamines. PAI products are different from official USP Reference Standards. PAI products are not required for compendial compliance.

Continual engagement is needed to help address uncertainties and bolster coordinated efforts

Given the global nature of the pharmaceutical supply chain, collaboration among international regulators and global stakeholders, including pharmacopeias, is needed to encourage information sharing and alignment of tests and procedures.

Under the scope of the Pharmacopeial Discussion Group workplan, USP along with the European Pharmacopeia and the Japanese Pharmacopeia, may collaborate on harmonization of existing NDSRI standards and prospective development of new standards.

However, recognizing that there is a need for stakeholders to exchange information efficiently in a real-time, secure environment, USP has established the Nitrosamines Exchange and Nitrosamines Analytical Hub.

USP’s Nitrosamines Exchange is an open-access platform and online community where more than 3,700 members from 90+ countries around the world share updates, learnings, challenges and solutions. Also housed within the Nitrosamines Exchange is the Nitrosamines Analytical Hub, a public online repository containing non-official analytical procedures for the testing of nitrosamine impurities and related substances. These procedures are carefully curated by USP’s science staff, either through internal development and validation or by scientific review of donated materials. An example: USP is currently developing analytical procedures for determination of nitrates and nitrites in certain excipients to help manufacturers select excipients having low levels of nitrites as part of their risk mitigation strategies. USP plans to share the range of nitrate and nitrite results in the Analytical Hub.

Web-based forums like the Nitrosamines Exchange and Nitrosamines Analytical Hub are effective settings to reach a broad group of diverse stakeholders who can share and collaborate in a neutral venue from a trusted source. Expansion and improved awareness of virtual venues like these can play a critical role in identifying and incorporating new and innovative techniques for NDSRI quality control.

The importance of collaboration

USP is in full support of the FDA’s ongoing efforts aiming to minimize the public health risk of NDSRIs, and encourages interested stakeholders to join USP’s Nitrosamines Exchange online community, where experts are engaging in real-time discussions on challenges, solutions and regulatory developments.