FDA Updates Guideline for Control of Nitrosamines

FDA has issued an Updated Guidance for Control of Nitrosamines in Human Drugs in September 2024. This guidance revises the final guidance of the same title issued on February 24, 2021.

Qvents presents in this post the salient changes and updates in the revised USFDA guideline for Control of Nitrosamines in Human Drugs.

• The revised guidance extend beyond the previously specified drug categories and include
  • Drug products containing chemically synthesized APIs or fragments (including biological products containing synthesized fragments) and
  • Semisynthetic and fermentation products that are at risk due to their structures
• This revision includes a new section that describes nitrosamine drug substance-related impurities (NDSRIs), potential root causes of NDSRIs, and mitigation strategies to prevent or reduce the presence of NDSRIs
• The guidance describes two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API), and NDSRIs, which share structural similarity to the API and are generally unique to each API
• The revised guidance emphasizes the inclusion of NDSRIs (Nitrosamine Drug Substance-Related Impurities) in the three-step mitigation strategy for nitrosamines
• The revised guidance recommends conclusion of confirmatory testing and submission of changes by August 1, 2025 for drug products that may have NDSRIs.
• The revised guidance recommends determination of Acceptable Intake (AI) limit for Nitrosamine impurities using the Predicted Carcinogenic Potency Categorisation Approach (PCPC) when robust data are not available on specific nitrosamine compounds. The guidance also recommends alternate flexible approach for AI limits when multiple nitrosamine impurities are present in drug products based on acceptable cancer risk as outlined in ICH M7(R2).
• Guidance is provided to manufacturers on how to determine whether specifications for nitrosamine impurities are warranted, how to report revised specifications and alternative approaches to establishing total nitrosamine impurity limits. Based on test results from confirmatory testing if nitrosamine levels in the drug product are not more than 10% of the recommended Acceptable Intake (AI) limit, then a formal specification limit is not needed. If nitrosamines exceed 10% but are still within the AI limit, specifications should be established in both the release and stability specifications and submit this information to the FDA through a Changes Being Effected in 30 Days (CBE-30) supplement. If confirmatory testing shows that nitrosamine levels exceed the AI limit manufacturers and applicants should implement such changes in formulation process, packaging etc that are demonstrated to ensure that nitrosamine levels remain within the recommended AI limit and information should be submitted to agency as a Prior Approval Supplement (PAS).
• The guidance recommends assessment of secondary packaging components during extractables and leachable studies for risk of nitrite and nitrosamine impurities.
• The guidance emphasizes awareness of the supply chain of API raw materials and supplier oversight for Vendor-Sourced Raw Materials for preventing nitrosamine impurities
• The guidance provides recommendations for mitigation strategies to reduce or eliminate or eliminate nitrosamine impurities.  The guidance recommend mitigation measures like screening excipients for potential sources of nitrosating agents or nitrosamine precursors, use of antioxidants in drug formulations to prevent nitrosamine formation, modify the microenvironment to neutral or basic pH in the drug product formulation when NDSRIs are detected in drug products.
• The revised guidance gives recommendations for stability data and bioequivalence studies to support approval of drug products reformulated for reducing or eliminating nitrosamine impurities.
• When submitting changes to drug product to reduce or eliminate nitrosamine impurities, three months accelerated and long term stability data for three batches should be provided.
• Reformulation of an approved product generally require an in vivo BA/BE study. However immediate-release (IR) solid oral and oral suspension products incorporating an API that is BCS I, II, or III and reformulated to include one of the antioxidants evaluated by FDA or a pH modifier flexibility is provided. BA or BE may be demonstrated without an in vivo study where a product reformulation is supported by appropriate chemistry data and comparative dissolution data. Products containing BCS IV APIs, will likely require an in vivo BA/BE study as the reformulation may affect drug performance. Applicants are encouraged to communicate with FDA to discuss approaches to establish BA or BE.
• FDA intend to provide information connected with this guidance in a web page. This will include recommended acceptable intake limits, analytical test methods for nitrosamine impurities and timelines for implementing mitigation recommendations.

USFDA Guidance Control of Nitrosamines in Human Drugs (September 2024)