Pharmaceutical industry wants FDA to extend deadline for testing novel nitrosamines

Industry stakeholders urged the US Food and Drug Administration (FDA) to postpone its October 2023 deadline for testing drug products for novel nitrosamines, saying there is still much scientific uncertainty on how to test these products and how to set daily acceptable limits in light of scarce toxicological data for these impurities. Until these issues are resolved, FDA should hold off establishing a deadline, industry groups said.

These comments were in response to the agency’s request for public input on how it should regulate novel nitrosamines, also called nitrosamine drug substance-related impurities (NDSRIs), to help inform safety assessments. The agency’s notice acknowledged the challenge of setting impurity levels for NDSRIs. (RELATED: FDA wants feedback on testing methods for new nitrosamines, Regulatory Focus 5 May 2023)

Most of the comments from the pharmaceutical industry, including lobbying groups such as the Pharmaceutical Research and Manufacturers of America (PhRMA), the Association for Accessible Medicines (AAM) and the Consumer Healthcare Products Association (CHPA), as well as several individual drugmakers, requested a testing reprieve for at least another six months.

AAM and PhRMA also want FDA to wait until the end of 2023, until the nonprofit Health and Environmental Sciences Institute’s Genetic Toxicology Technical Committee (HESI GTTC) completes its body of work related to setting acceptable limits for NDSRIs before setting a testing deadline.

Commenters also asked FDA to align its nitrosamine testing requirements with those of other regulators to provide a harmonized approach for identifying and testing novel nitrosamines in drugs products and active pharmaceutical ingredients (APIs).

FDA’s 2020 final guidance on nitrosamine testing recommended that manufacturers conduct testing on all their drug products and APIs to ensure they do not have unacceptable high levels of nitrosamines by 1 October 2023. The recent notice asked whether this deadline should be extended for novel nitrosamines.

Pharma seeks extended testing deadline

PhRMA, AAM, CHPA, Upsher-Smith and Catalent were among some of those groups requesting the delay.

“The number of outstanding scientific questions as well as the state of completion of the work across the industry to date suggest that it is unrealistic to establish a deadline less than a year away to complete all of the work to assess the hazards of nitrosamines in drug products and take appropriate remedial action,” AAM said.

AAM further noted that, “As FDA has recognized, the scope of the problem has expanded over time, and many more products may be affected than was first thought. Further, for generic drug manufacturers with larger product portfolios, the impact is much greater as compared to reference listed drug (“RLD”) manufacturers. Some large generic companies may have as many as 250 ANDAs that could be affected, each requiring significant time and resources to complete testing and remediation when necessary.”

The generics group noted that on May 31 and June 1, 2023, FDA and the Health and Environmental Sciences Institute (HESI) held a public meeting to discuss ways to improve nitrosamine risk assessments and develop a nitrosamine-research roadmap. The group said that “during the meeting, it was clear that fundamental scientific questions associated with assessing the risks of NDSRIs remain unresolved, and research must continue to resolve them.”

AAM recommended extending the deadline to 31 December 2033.

PhRMA also requested an extension. The group states that “such an extension would help ensure the continuity of drug supply and avoid drug shortages. It would also help better inform FDA’s regulatory decision making by allowing for the development of sufficiently robust data.”

PhRMA also wants FDA to wait until the work of HESI is completed before taking further action. “In considering the extension date, it is important to understand that it will take until the end of 2023 for the Health and Environmental Sciences Institute (HESI) to complete a body of work related to the Ames test, which is intended to inform the optimal Ames protocol for N-nitrosamine hazard identification. This is expected to be an important element of the risk assessment framework which will be used to set AIs [acceptable intakes] and prioritize NDSRIs for further in vivo testing.”

CHPA also said its members request an extension “beyond the current deadline of October 1, 2023.” The group notes that “several CHPA members are continuing to experience testing challenges due to capacity and analytical method constraints based on known complexities, availability of reference standards, specialized instrumentation and trained experts required to achieve accurate results with appropriately low levels of detection.” In addition, the group noted that “many members have submitted proposed AI for NDSRIs and are still waiting on FDA feedback.”

In the meantime, Upsher-Smith requested a three-year extension. During the interim, FDA should “consider publishing of interim limit and allowable period for NDSRIs while industries evaluate NDSRIs source and implementation of mitigatory strategy to keep NDSRIs within the AI limit. FDA could establish a confirmatory method (example Ames test or other mutagenic tests, surrogate studies etc.) that would be acceptable to the agency rather than having firms spend a lot of time in developing methods that may not be acceptable by the agency.”

Catalent also requested an extension. The firm writes that “in view of the complexities involved in reliably testing NDSRIs and industrywide capacity for testing, Catalent as a contract manufacturer supporting numerous products in various phases of development would welcome an extension of the recommended timeline for submission of changes in drug applications as described in the guidance to June 1, 2024.”

International alignment

In addition, PhRMA, AAM and CHPA urged FDA to align its testing approach with other regulators in setting testing limits for novel nitrosamines.

PhRMA “urges FDA to work with other regulatory authorities, as well as the pharmaceutical industry, to advance a globally aligned, transparent approach for the detection and control of nitrosamine impurities in pharmaceutical products. Collaboration between Industry and global regulators will be essential to establishing a shared understanding, addressing key scientific and policy gaps, and implementing globally-aligned solutions that help ensure patient safety and preserve supply chain stability.”

“We strongly encourage FDA to ensure alignment with other health authorities considering limits for NDSRIs,” AAM wrote.

CHPA also suggested FDA align its nitrosamine guidance with the European Medicines Agency (EMA).

Upsher-Smith asked that FDA collaborate with the United States Pharmacopoeia (USP), HESI, EMA and industry on testing limits proposed by these organizations. The company wrote that “industry would benefit from a repository of AI safety limits for different molecules. FDA’s current AI limit of 26.5 ng/day might not be applicable to all NDSRIs.”

IPEC: Food a far greater risk

For its part, the International Pharmaceutical Excipients Council (IPEC) said the FDA’s emphasis on nitrosamine testing of pharmaceuticals is misplaced and asserted that food poses a far greater nitrosamine risk.

IPEC states that “while U.S. FDA focuses on health exposures in products that can be controlled by regulatory limits, i.e., drug products, it is clear that foods are a far greater source of nitrosamine exposure for people. For example, intake of nitrosamines from raw cabbage (1 cup, 89 g, serving size) and raw broccoli (1/2 cup, 36 g, serving size) would expose the consumer to ~267 ng and ~23 ng natural nitrosamines, respectively. Most food sources (grains and grain products, vegetables, meat, dairy, oils, etc.) have been shown to contain ng/g levels of NDMA and other nitrosamines.”

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Pharmaceutical industry wants FDA to extend deadline for testing novel nitrosamines

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