FDA revises final guidance on nitrosamine impurities

Editor’s note: This article was updated on 5 September to correct information related to daily acceptable intake (AI) limits for nitrosamines and on 6 September to add a reference to FDA's webpage for nitrosamine acceptable intake limits.
 
The US Food and Drug Administration (FDA) on Wednesday issued a revised final guidance to assist manufacturers in detecting and controlling nitrosamine impurities in pharmaceutical products.
 
The guidance revises a previous version issued in February 2021 and includes some major changes. These changes include the addition of a new section on nitrosamine drug substance-related impurities (NDSRIs), as these novel nitrosamines were not addressed in the earlier guidance, as well as expanded information on FDA’s August 2023 guidance establishing acceptable intake limits for NDSRIs. (RELATED: FDA sets acceptable intake limits for nitrosamines in drugs, Regulatory Focus 7 August 2023)
 
FDA said the revision offers details on “two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (nitrosamine impurities that do not share structural similarity to the [active pharmaceutical ingredient] API and are found in many different drug products) and NDSRIs that share structural similarity to the API and are generally unique to each API.”
 
The guidance also provides new recommendations on implementing nitrosamine impurity control strategies. In addition, FDA announced that “the guidance clarifies how manufacturers should assess test results to determine whether specifications for nitrosamine impurities are warranted, and provides recommendations for how to report revised specifications, when and how to contact the Agency, and recommended alternative approaches to establishing total nitrosamine impurity limits.”
 
The guidance applies to all chemically synthesized APIs, drug products containing chemically synthesized APIs or fragments (including biological products containing synthesized fragments), drug products at risk, and semisynthetic and fermentation products that are at risk due to their structures.
 
In the guidance, FDA recommends that an AI limit be determined through use of a Carcinogenic Potency Categorization Approach (CPCA) when “robust” carcinogenicity data and additional safety information are not available. It further specifies that other approaches for determining an AI limit for a specific nitrosamine “could be based on database and literature searches for available carcinogenicity and bacterial mutagenicity data or in vivo and/or in vitro testing using the specific compound.”
 
It also recommends that manufacturers consult a new web page that includes updated information on recommended acceptable intake limits for 270 hypothetical NDSRIs and other identified nitrosamine impurities (Table 1) and nine AI limits for certain nitrosamine impurities (Table 2).
 
The guidance also recommends methods for determining AI limits for nitrosamines that do not already have limits. The guidance states that “if the AI limit cannot be determined using the approaches described in this section [on Acceptable Intake Limits], FDA recommends that 26.5 ng/day be used as the new AI limit.”
 
The guidance’s Appendix B discusses the method for determining AI and Appendix C details an alternative flexible AI limit approach for products that contain multiple nitrosamines.
 
For NDSRIs, FDA recommends that manufacturers consult its web page that includes updated information on recommended AI limits for certain NDSRIs impurities based on their predicted CPCA. FDA also recommends that manufacturers consult its August 2023 guidance on NDSRIs.
 
The guidance recommends that API and drug product manufacturers take the following steps to mitigate small-molecule nitrosamine impurities as well as NDSRIs in their products:

• Assess the risk of nitrosamine impurities in APIs, marketed products, and products under approved and pending applications;
• Perform confirmatory testing when there is any risk for the presence of nitrosamine impurities; and,
• Report changes implemented to prevent or reduce nitrosamine impurities in APIs and drug products to FDA. This includes submission of any drug master file (DMF) amendments and changes to approved applications and pending applications.

For small molecule nitrosamine impurities, FDA recommended that these risk assessments for approved or marketed products be done by 31 March 2021, and that applicants conduct confirmatory testing of drug products and submit changes in drug applications by 1 October 2023.

For NDSRIs, FDA reiterated a point in the August 2023 guidance and recommended that manufacturers and applicants complete a risk assessment for NDSRIs by 1 November 2023, as part of overall risk management. The guidance also reiterates that manufacturers conduct NDSRI confirmatory testing of drug products and submit any changes in drug applications by 1 August 2025.

FDA is implementing this guidance without prior public comment as “prior public participation is not feasible or appropriate.”

Guidance