https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
The update is as follows;
Table 2: FDA Recommended AI Limits for Certain Nitrosamine Impurities
| Nitrosamine Name |
Source |
Recommended AI Limit (ng/day) |
Surrogate |
Date Added to Table |
| N-nitroso-dimethylamine |
Multiple |
96 |
Compound specific |
9/4/2024 *** |
| N-nitroso-diethylamine |
Multiple |
26.5 |
Compound specific |
9/4/2024 *** |
| N-nitroso-piperazine (NPZ) |
Ciprofloxacin |
1300 |
N-nitroso-piperidine (NPIP) |
9/4/2024 |
| N-nitroso-methylphenidate |
Methylphenidate |
1300 |
N-nitroso-piperidine (NPIP) |
9/4/2024 |
| N-nitroso-vonoprazan |
Vonoprazan |
96 |
N-nitroso-dimethylamine (NDMA) |
9/4/2024 |
|
|
|
|
|
*** This limit was previously communicated on September 3, 2020 in the Nitrosamine Guidance
Revision Table
| Revision |
Nitrosamine Name |
Change |
Data posted |
| 6 |
N-nitroso-dimethylamine |
Added to Table 2 |
9/4/2024 |
| 6 |
N-nitroso-diethylamine |
Added to Table 2 |
9/4/2024 |
| 6 |
N-nitroso-N-methyl-4-aminobutyric acid |
Added to Table 1 |
9/4/2024 |
| 6 |
N-nitroso-isopropylethylamine |
Added to Table 1 |
9/4/2024 |
| 6 |
N-nitroso-diisopropylamine |
Added to Table 1 |
9/4/2024 |
| 6 |
1-methyl-4-nitrosopiperazine |
Added to Table 1 |
9/4/2024 |
| 6 |
1-cyclopentyl-4-nitrosopiperazine (or 1-Nitroso-4-cyclopentylpiperazine) |
Added to Table 1 |
9/4/2024 |
| 6 |
N-nitroso-methylphenylamine |
Added to Table 1 |
9/4/2024 |
| 6 |
N-nitroso-degarelix |
Deleted from Table 1 |
9/4/2024 |
| 6 |
N-nitroso-methylphenidate |
Added to Table 2 |
9/4/2024 |
| 6 |
N-nitroso-vonoprazan |
Added to Table 2 |
9/4/2024 |
| 6 |
N-nitroso-piperazine (NPZ) |
Added to Table 2 |
9/4/2024 |
NDMA to MeNP in the Revision Table were included in Nitrosamine guidance rev.1 and not in the AI list. These AI values (except for NDMA and NDEA) are updated by CPCA from those in previous guidance.
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Recommended Implementation Timelines and Other Emerging Scientific and Technical Issues are newly added to this page.
Recommended Implementation Timelines
FDA recommends different implementation timelines depending on the regulatory status of the drug product and the type of nitrosamine impurity at issue. When recommending implementation timelines, FDA may consider factors such as the potential risk to the public health, the state of scientific knowledge, the scope of the problem, the feasibility and complexity of implementing effective prevention or mitigation strategies, and the risk of drug shortages. For example, to address a new nitrosamine impurity, the most effective mitigation may be reformulation, which could require substantial time to complete, and thus FDA may recommend a longer implementation timeline. A different nitrosamine impurity may be best addressed through replacement of packaging, for which FDA may recommend a shorter implementation timeline. If the need for the change is urgent due to a significant public health concern posed by the nitrosamine impurity, immediate implementation may be recommended. In some cases, FDA may also consider international harmonization in establishing implementation timelines.
Table 4: Recommended Implementation Timelines
(Updated: 9/4/2024)
| Nitrosamine Impurity |
Performing Risk Assessment |
Confirmatory Testing |
Submission of Required Changes |
| Small Molecule Nitrosamines |
March 31, 2021 |
When a risk is identified |
October 1, 2023 |
| NDSRIs |
November 1, 2023 |
When a risk is identified |
August 1, 2025 |
Other Emerging Scientific and Technical Issues
As FDA becomes aware of new and emerging information on nitrosamine impurities, it may communicate new information on nitrosamine impurities and FDA’s understanding of the root cause of such impurities and their formations. It may also communicate recommendations for mitigation to address such nitrosamine impurities.
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