FDA Releases Final Guidance on Recommended Acceptable Intake Limits for Nitrosamines

On August 4, 2023, the U.S. Food and Drug Administration (FDA or Agency) issued a final guidance for immediate implementation entitled Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (Guidance). NDSRIs are a subcategory of nitrosamine impurities that share structural similarity to the active pharmaceutical ingredient (API) in drug products and typically lack compound-specific mutagenicity and carcinogenicity data to inform safety assessments.

The Agency last issued guidance for industry on the control of nitrosamine impurities in human drugs in February 2021.^[1] That guidance provides recommended acceptable intake (AI) limits for six non-NDSRI nitrosamine impurities, a threshold of 26.5 ng/day for reporting any other nitrosamine impurity to FDA, and a deadline of October 1, 2023 for completion of confirmatory testing of drug products and submission of required changes in drug applications.

This Guidance focuses on recommendations for predicting the mutagenic and carcinogenic potential of NDSRIs, as well as AIs for NDSRIs. Notably, it endorses the Carcinogenic Potency Categorization Approach (CPCA) (a methodology for AI determination that uses structural features of NDSRIs), discusses two specific methods (specifically, the enhanced Ames test and the read-across analysis) for justifying a higher AI than the limit derived from the CPCA, acknowledges that marketed products containing levels of nitrosamines above the recommended AI may be granted an interim AI on a case-by-case basis, and provides a new deadline of August 1, 2025 for completion of confirmatory testing of drug products and submission of required changes in drug applications.

In connection with the Guidance, FDA also posted a new nitrosamine website with information on: (1) recommended AI limits for certain NDSRIs based on predicted carcinogenicity potency categorization listed by APIs that hypothetically could be at risk of forming such NDSRIs; (2) recommended AI limits for certain NDSRIs based on compound-specific data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain NDSRIs; (4) recommended testing methods for confirmatory testing of certain NDSRIs; and (5) recommended safety testing methods for NDSRIs. FDA’s website currently includes FDA-recommended AI limits for 251 NDSRIs ranging from 26.5 ng/day to 1,500 ng/day.

Scope of Guidance

The Guidance applies to prescription drug products and over-the-counter drug products on the market and in clinical development. It does not apply to NDSRIs that are detected in products indicated for use in patients with advanced cancers.

Carcinogenic Potency Categorization Approach

The CPCA is a methodology that uses predicted carcinogenic potency categorization to assign a recommended AI limit to an NDSRI based on the NDSRI’s activating and deactivating structural features. Like the European Medicines Agency and Health Canada, which issued updated nitrosamine guidance on July 7, 2023 and July 24, 2023, respectively, FDA’s Guidance endorses the CPCA for deriving AI limits.

The Guidance acknowledges that the CPCA “is a conservative approach that represents the best available science at this time and is expected to be further refined and expanded as new data become available” and that “the associated recommended AI limits generally represent the conservative lower limit for the range of potencies falling within each category.”

The CPCA should not be applied where FDA has already recommended an AI limit based on compound-specific assessments or read-across analysis from a surrogate. The Guidance also provides that “manufacturers and applicants can use an alternative approach [to establishing AIs] if it satisfies the requirements of the applicable statutes and regulations.”

Recommendations for Products with Multiple Nitrosamines

For products containing multiple nitrosamines, if the total level of nitrosamines exceeds the recommended AI limit for the most potent nitrosamine in the drug product based on the maximum daily dose, the Guidance instructs manufacturers to contact the Agency.

The Guidance also recognizes that basing the total nitrosamine limit on the most potent individual nitrosamine limit might not be practical, and encourages manufacturers to contact the Agency if they would like to propose a nitrosamine limit other than the recommended AI of the most potent nitrosamine impurity detected.

Considerations for Marketed Products with Nitrosamine Levels Above Recommended AI Limits

The Guidance notes that, generally, any drug product batch found to contain levels of an NDSRI above the FDA-recommended AI limit should not be released for distribution and may warrant removal from the market, because such drug products may be considered adulterated under section 501 of the FD&C Act. However, manufacturers may provide a scientifically justified rationale to pursue an AI limit different than the FDA-recommended limit.

If drug product batches already in distribution contain levels of NDSRIs above the FDA- recommended AI limit, and manufacturing changes or recalls are likely to lead to a disruption in the drug supply, then manufacturers and applicants should immediately contact the Center for Drug Evaluation and Research’s Drug Shortage Staff. FDA will evaluate each circumstance on a case-by-case basis and consider whether to recommend an interim AI limit for a temporary period.

Approaches to Justify a Higher AI Limit

As noted above, the Guidance directs manufacturers to submit a scientifically justified rationale to pursue an AI limit higher than the FDA-recommended limit.

Compound-specific data could be used to support a higher AI limit. FDA recommends in vitro mutagenicity testing, specifically, the enhanced Ames assay. A negative result in a valid enhanced Ames assay may be used to support a higher limit, although it does not automatically result in a limit of 1500 ng/day or higher as it does in the EU (or a limit of 1500 ng/day in Canada). Recommendations for the enhanced Ames assay test conditions are available on FDA’s nitrosamine website.

A read-across assessment based on a surrogate also could be used to support a higher AI limit. The surrogate should have robust carcinogenicity data, and if no suitable surrogate is available, manufacturers may consider NDMA, N-nitroso piperidine (NPIP), 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK), N-nitroso pyrrolidine (NPYR), and N-nitroso morpholine (NMOR) as surrogates for the read-across.

Approaches to justify or qualify a proposed alternative AI limit should be submitted to FDA in a supplement or amendment, as appropriate, before implementation.

Recommended Timeline for Marketed Drug Products

Manufacturers and applicants who have not considered NDSRIs in previous risk assessments should reevaluate the risk within 3 months of publication of the Guidance, with a recommended completion date by November 1, 2023.

The Guidance also recommends concluding NDSRI confirmatory testing of drug products and submitting required changes in drug applications by August 1, 2025. Manufacturers and applicants should ensure that any NDSRIs in their drug products meet the FDA-recommended AI limit by August 1, 2025. FDA recommends that manufacturers and applicants providing a scientifically justified rationale to pursue an AI limit different than the FDA-recommended limit should complete this process in time to submit any relevant changes to applications by August 1, 2025.

Recommended Timeline for Drug Products in Development and Under FDA Review

The Guidance recommends applicants conduct a risk assessment for NDSRIs and conduct confirmatory testing as appropriate prior to submission of an original application (or as quickly as possible in an amendment if the original application has already been submitted).

Applicants with pending applications should conduct the risk assessment expeditiously and inform FDA if confirmatory testing finds NDSRI levels above the AI limits recommended in the Guidance. If an NDSRI is detected above the recommended AI limit, the applicant should amend the application as appropriate, and the Agency will work with the applicant to resolve issues during the review cycle.

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