Nitrosamine impurities guidance updated with more information related to root causes of formation, mitigation and implementation of recommended AI limits and setting of specification for the recommended acceptable intake in drug products.
Guidance has updated from February 2021 Revision 1 to September 2024 Revision 2 complete details provided below:
Changes:
- Incorporation of NDSRIs (Nitrosamine Drug Substance-Related Impurities):
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- The updated guidance includes new sections on two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (nitrosamine impurities that do not share structural similarity to the 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. NDSRIs, which are impurities structurally related to the active pharmaceutical ingredients (APIs). The root causes and strategies for mitigating NDSRIs are extensively discussed. With this revision, this guidance describes
- Addition of Reformulation Guidelines:
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- The updated guidance includes guidance on reformulating drug products to mitigate nitrosamine impurities, such as using antioxidants and pH modifiers. It emphasizes the need for bioequivalence (BE) studies when reformulating existing products.
- New Timelines for Risk Assessments:
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- The new guidance provides updated timelines for assessing and addressing nitrosamine impurities, including deadlines for evaluating NDSRIs by August 1, 2025.
- Emphasis on Bioequivalence Studies:
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- The new document adds more specific guidance on the need for bioequivalence studies when changes are made to reduce nitrosamines in drug formulations.
Key Information added in new guidance:
- Risk Mitigation Strategy: The document outlines a three-step process: conduct risk assessments, perform confirmatory testing, and report changes to the FDA.
- Control of Nitrosamines in APIs: Manufacturers are advised to develop strategies ensuring nitrosamine levels remain below acceptable limits, with additional batch testing for at-risk APIs.
- Acceptable Intake (AI) Limits: Manufacturers are instructed to adhere to AI limits, with recommendations for submitting information on changes that could affect nitrosamine levels.
- Regulatory Reporting: The document provides detailed requirements for reporting manufacturing changes, including when bioequivalence studies are required after reformulation.
Summary:
The new guidance provides updated guidance on controlling nitrosamine impurities in pharmaceuticals, particularly focusing on Nitrosamine Drug Substance-Related Impurities (NDSRIs). The document outlines key steps for manufacturers, including conducting
risk assessments, confirmatory testing, and reporting changes to the FDA. It emphasizes the importance of bioequivalence (BE) studies when reformulating drug products to reduce nitrosamine levels.
New timelines have been introduced, requiring manufacturers to evaluate NDSRIs by August 2025. Acceptable intake (AI) limits for various nitrosamine impurities, such as NDMA and NDEA, are outlined, with guidance on how to ensure compliance. The guidance also highlights specific strategies for mitigating these impurities, such as adjusting pH levels or using antioxidants during formulation.
Risk mitigation is categorized into three steps: assessment of API and drug product processes, performing testing when risks are identified, and reporting changes to regulatory bodies. Additionally, the document discusses potential contamination sources like recovered solvents, catalysts, and raw materials, advising manufacturers on how to optimize manufacturing processes and reduce nitrosamine formation risks. This guidance aims to safeguard drug safety while balancing necessary production adjustments.
For more details refer to control of nitrosamine final guidance.
https://www.fda.gov/media/141720/download
