A Closer Look at FDA's Nitrosamine Impurity Regulations for NDSRIs

August 30, 2023

Lab technician injecting a beaker

FDA Provides Acceptable Intake Limits for Nitrosamines Drug-Substance Related Impurities (NDSRIs). Can You Comply?

The U.S. Food and Drug Administration (FDA) recently issued final guidance entitled; "Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)" that provides further clarity to manufacturers and Sponsors on establishing/applying acceptable intake (AI) limits for potential NDSRIs in their products. NDSRIs are defined as a class of nitrosamine impurities that have been identified in many drug products and could also share structural similarity to the active pharmaceutical ingredient (API).

This guidance is a follow-on document to the 2021 FDA guidance entitled, "Control of Nitrosamine Impurities in Human Drugs", which focused on specific known nitrosamines of concern at that time, and recommended steps manufacturers of active pharmaceutical ingredients and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in their products. The new guidance, based on additional data gathered by FDA over the last two years, now provides a framework for not only how to assess the presence of NSDRIs in their Drug Substance and Drug Products and the recommended confirmatory tests, but also provides recommended acceptable intake (AI) limits for those identified NSDRIs and the reporting structure to FDA. FDA also announced and recommended for Sponsors to review, their website that contains (and is periodically updated) listing of the recommended AIs of those known NDSRIs to date that could be present in Drug Products.

The NDSRI guidance applies to all drugs, including prescription and OTC that are approved, pending approval, grandfathered, or under clinical development. Biological products that contain chemically synthesized fragments that are in clinical development, approved or pending approval are also within scope of the guidance. It is important to note that this guidance does not extend to NDSRIs found in products intended for patients with advanced cancers.

Assessment of Carcinogenic Potency Categories

The guidance recommends a risk assessment for the safety of NDSRIs and uses structure-activity relationships (SAR) of N-Nitroso compounds to "assess and classify the mutagenic and carcinogenic risk" of the nitrosamines. The SAR considers the chemical structure of the nitrosamine and the surrounding atoms to calculate a quantitative carcinogenic or mutagenic risk, or "Potency Category" associated with the nitrosamine. The guidance also provides AI limits for each potency category as assigned below:

Table 1: The Five Predicted Carcinogenic Potency Categories and Associated Recommended AI Limits for NDSRIs
Recommended AI
1 26.5 The recommended AI limit of 26.5 ng/day is equal to the class-specific limit for nitrosamine impurities based on the most potent, robustly tested nitrosamine, N-nitrosodiethylamine (NDEA). NDSRIs assigned to Category 1 are predicted to have carcinogenic potency no higher than the class-specific limit for nitrosamine impurities.
2 100 The recommended AI limit of 100 ng/day is representative of two potent, robustly tested nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK), which have recommended AI limits of 96 ng/day and 100 ng/day, respectively. NDSRIs assigned to Category 2 are predicted to have carcinogenic potency no higher than NDMA and NNK.
3 400 Compared to Potency Category 2, NDSRIs in this category have lower carcinogenic potency due to, for example, the presence of a weakly deactivating structural feature. The recommended AI limit was set to reflect a 4-fold decrease in carcinogenic potency from Category 2.
4 1500 NDSRIs assigned to Category 4 may be metabolically activated through an alpha-hydroxylation pathway but are predicted to be of low carcinogenic potency, for example, because the pathway is disfavored due to steric or electronic influences, or because clearance pathways are favored. The recommended AI limit of 1500 ng/day is set at the TTC per ICH M7(R2).
5 1500 NDSRIs assigned to Category 5 are not predicted to be metabolically activated via an α-hydroxylation pathway due to steric hindrance or the absence of α-hydrogens, or are predicted to form unstable species that will not react with DNA. The recommended AI limit of 1500 ng/day is set at the TTC per ICH M7(R2).
AI = acceptable intake; ng = nanogram; NDSRI = nitrosamine drug substance-related impurities; TTC = threshold of toxicological concern.

Determining the Potency Score

The guidance outlines a framework for determining the potency score. It states, "for nitrosamine drug substance-related impurities (NDSRIs) not assigned to Potency Category 5, the Potency Score is calculated as the sum of the α-Hydrogen Score, Deactivating Feature Score, and Activating Feature Score based on selected structural features present in the NDSRI." A series of tables assist chemists in assessing the chemical structure of the active ingredient or excipient to ascertain individual and overall potency scores. For drug products that contain nitrosamines from multiple sources, the potency score of the most potent nitrosamine should be used to define the limit for nitrosamines in the product. FDA may recommend an AI limit based on compound-specific assessments and other information FDA has obtained, and this recommended AI limit should be utilized over the predicted carcinogenic potency categorization approach.

Alternate Acceptable Intake Limits

The FDA guidance outlines a pathway to justify or qualify an alternate AI limit if a product exceeds the limits proposed in the guidance. While a drug product manufacturer is requested to reduce or remove the NDSRI, the manufacturers could potentially justify the higher level through thorough mutagenicity assessments or "read-across assessments based on a surrogate."  The latter is permissible if the NDSRI has a "well-justified AI limit based on a surrogate that maintains a 1 in 100,000 cancer risk estimate and is higher than the AI limit associated with the predicted carcinogenic potency category for that NDSRI in certain cases." Currently, the guideline lists NDMA, N-nitroso piperidine (NPIP), 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK), N-nitroso pyrrolidine (NPYR), and N-nitroso morpholine (NMOR) as potential surrogates when the manufacturer can make an appropriate justification. Regardless, any approach to justify or qualify an alternate AI limit should be submitted to the FDA prior to implementation.

Market Implications

Marketed drug products containing NDSRIs above the FDA-recommended AI limit should not be released to distribution and may require removal from the market. The guidance encourages the manufacturer to contact the FDA if a recall will lead to a disruption in the drug supply. The FDA will evaluate the impact on drug supply on a case-by-case basis and may work with the manufacturer to consider or implement an interim AI limit for a temporary period.

Guidance Implementation

The FDA's implementation expectations for approved or marketed products include:

  1. NDSRIs not included in previous risk assessments should be re-evaluated per this guidance by November 1, 2023.
  2. Confirmatory testing of batches using validated, sensitive methods should start as soon as the presence of an NDSRI is suggested. Conclusion of the confirmatory testing, the test method, validation, and results should be submitted to the FDA by no later than August 1, 2025.
  3. "If a nitrosamine impurity is detected, manufacturers should investigate the root cause and implement changes in the manufacturing process or product formulation to eliminate, mitigate, or reduce nitrosamine impurities consistent with the recommendations in the Nitrosamine Guidance. Manufacturers must implement any changes in accordance with appropriate requirements. In addition, applicants must submit proposed formulation changes through supplements or amendments to their applications. Generally, the FDA considers reformulation of an approved drug product a major change requiring a prior approval supplement (PAS)".

For applications pending review with the Agency, the applicant should conduct risk assessments as soon as possible and inform the FDA if confirmatory testing finds NDSRIs above the AI limits in the guidance. The applicant may need to amend the application based on these findings.

In the pre-submission stage, the "FDA recommends that an applicant conduct a risk assessment for NDSRIs and conduct confirmatory testing as appropriate prior to submission of an original application." If the risk assessment or confirmation testing results are not available at the time of submission, they can be submitted via an amendment to the submission as quickly as possible "to minimize any potential adverse impact on the application assessment timeline."

Get Help from Regulatory Experts

ProPharma Regulatory Sciences can assist in performing and or evaluating the risk assessments per this new guidance and also in the FDA communication strategy and preparation for the required submission of the NDSRI confirmatory test methods and results to the FDA. We can also assist in the mitigation strategy, preparation of, and submission of manufacturing or formulation changes applied to minimize the NDSRIs in the Drug Substance and Drug Products. Contact us today to speak to one of our regulatory experts.


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