CDER Nitrosamine Impurity Acceptable Intake Limits
Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)
Guidance for Industry
Control of Nitrosamine Impurities in Human Drugs
Guidance for Industry
Recommended Acceptable Intake (AI) Limits, Implementation Timelines, Emerging Scientific and Technical Issues, and Testing Methods
On this page:
- Recommended AI Limits for Certain Nitrosamine Impurities based on the predicted Carcinogenic Potency Categorization Approach (CPCA), including certain recommended AI limits for drug products with a hypothetical risk of forming NDSRIs
- Recommended AI Limits for Certain Nitrosamine Impurities based on Compound-Specific Data or Read-Across Analysis from a Surrogate
- Recommended Interim AI Limits for Certain Nitrosamine Impurities
- Recommended Implementation Timelines
- Other Emerging Scientific and Technical Issues
- Recommended Analytical Methods for Confirmatory Testing of Nitrosamine Impurities
- Recommended Safety Testing Methods for Nitrosamine Impurities
- Revision Table
On 8/4/2023, FDA issued a final guidance on Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (August 2023) (RAIL Guidance) which provided recommendations for NDSRI AI limits based on predicted carcinogenic potency categorization. On 9/4/2024, FDA issued a final guidance on Control of Nitrosamine Impurities in Human Drugs (September 2024, Rev.2) (Nitrosamine Guidance). The Nitrosamine Guidance describes two classes of nitrosamines – small-molecule nitrosamines and NDSRIs; and also provides recommendations to industry on mitigation strategies to control nitrosamines and on implementation of these strategies. Manufacturers should reference these two guidances for information on determining AI limits and for recommendations on reducing or preventing nitrosamine impurities in their drug products. To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated information on this website in connection with these guidances.
Specifically, FDA intends to include on this website updated information on: (1) recommended AI limits for certain nitrosamine impurities, including NDSRIs, based on their predicted carcinogenic potency categorization; (2) recommended AI limits for certain nitrosamine impurities based on compound-specific data from carcinogenicity and mutagenicity data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain nitrosamine impurities; (4) recommended implementation timelines; (5) other emerging scientific and technical issues; (6) recommended analytical methods for confirmatory testing of certain nitrosamine impurities; and (7) recommended safety testing methods for nitrosamine impurities.
The RAIL Guidance and the Nitrosamine Guidance (including the information on this associated website) represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. They do not establish any rights for any person and are not binding on FDA or the public. Manufacturers are encouraged to adopt FDA recommended AI limits, where provided, for products marketed in the U.S. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
The public may comment on the information below by submitting a comment to the public docket established for the guidances Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) and Control of Nitrosamine Impurities in Human Drugs (Docket No. FDA-2020-D-1530). Comments may be submitted at any time for Agency consideration. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to www.regulations.gov. All comments should be identified with the docket number FDA-2020-D-1530 and complete title of the relevant guidance or guidances. For additional information, please refer to the Federal Register Notices of Availability for the Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance and the Control of Nitrosamine Impurities in Human Drugs Guidance, available at www.regulations.gov (search Docket FDA-2020-D-1530).
Recommended AI Limits for Certain Nitrosamine Impurities
Based on the predicted Carcinogenic Potency Categorization Approach (CPCA) for APIs at Hypothetical Risk of Forming NDSRIs and Other Identified Nitrosamine Impurities
Nitrosamine impurities can form by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions). There are 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 can form by nitrosation of APIs and API fragments that contain secondary amine or dimethyl tertiary amine centers. This can occur under conditions related to the formulation and manufacturing process for the drug product, such as by reaction with residual nitrites in excipients used to formulate the drug product.
Table 1, below, presents recommended acceptable intake (AI) limits for nitrosamine impurities (i.e., NDSRIs and other identified nitrosamine impurities) that were based on the predicted Carcinogenic Potency Categorization Approach (CPCA). Recommended AI limits for hypothetical NDSRIs based on the predicted CPCA are presented. These are nitrosamine impurities that are associated with specific APIs as identified in the Source column of the table. Table 1 also presents recommended AI limits for other identified nitrosamine impurities predicted by CPCA that are not NDSRIs. These other nitrosamine impurities are not generally associated with a single API or API fragment and are designated as “multiple” in the Source column of the table because they have been identified in multiple drug products and/or substances.
Another potential source of nitrosamine impurities that is not associated with a specific API is packaging. As described in the Nitrosamine Guidance, leachates from packaging may be a source of nitrosamine impurities or nitrites that can react to form nitrosamine impurities. Nitrosamine impurities that may be present due to leaching from certain packaging will be designated with the symbol “#” and identified as having multiple sources, (i.e., there is not a single API associated with the nitrosamine).
If a nitrosamine impurity (i.e., NDSRI or other identified nitrosamine impurity) currently listed in Table 1 is formed, the corresponding recommended AI limit in Table 1 applies. FDA may move a nitrosamine impurity to Table 2 if compound-specific data or read-across analysis from a surrogate becomes available and an updated recommended AI limit applies. Generally, the recommended AI limits based on the predicted CPCA should not be applied to nitrosamine impurities in circumstances in which FDA otherwise recommends an AI limit (e.g., based on compound-specific assessments or read-across analysis from a surrogate) in Table 2.
For APIs with more than one nitrosatable amine center, the predicted carcinogenic potency category for each unique nitrosamine formed by mono-nitrosation of the API is presented in Table 1, where each nitrosamine from the same API is differentiated by the suffix “-1,” “-2,” etc., in the Nitrosamine Name column. Chemical structure images* for nitrosamines in Table 1 can be accessed by clicking on the hyperlinked Nitrosamine Name. This table will be updated periodically based on new information.
This is not an all-inclusive list of APIs that have the potential to form nitrosamine impurities, including NDSRIs; there are other possible routes of formation. In addition, the recommended AI limits for the nitrosamine impurities on this website do not necessarily correspond to the observed level of any nitrosamine(s) found in any particular drug product. Furthermore, inclusion of an API on the list is not confirmation that a nitrosamine impurity is present in a drug product containing that drug substance. A recommended AI limit is based on a safety assessment that includes evaluation of the mutagenic and carcinogenic potential of the impurity and represents the level at or below which FDA has determined that the impurity or impurities would not pose a safety concern for patients taking the drug product.
* Chemical structure images provided by the National Institutes of Health/National Center for Advancing Translational Sciences.
Table 1: FDA Recommended AI Limits for Certain Hypothetical NDSRIs and Other Identified Nitrosamine Impurities
(Updated: 1/17/2025)
Based on the predicted Carcinogenic Potency Categorization Approach
* Source is the form of the drug substance in the free base or free acid form.
** See Table 3.
References
- (Q)SAR model reporting format (QMRF) for CPCA, described in Kruhlak NL, et al. Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA). Regul Toxicol Pharmacol. 2024 Jun; 150:105640.
Recommended AI Limits for Certain Nitrosamine Impurities
Based on Compound-Specific Carcinogenicity and Mutagenicity Data or Read-Across Analysis from a Surrogate
If data are available, a recommended AI limit can be based on a safety assessment that includes evaluation of the mutagenic and carcinogenic potential of the impurity; such a limit would represent the level at or below which FDA has determined that the impurity or impurities would not pose a safety concern for patients. A recommended compound-specific AI limit can be calculated based on rodent carcinogenic potency data such as TD50 values identified in the published scientific literature. When the mutagenic potential of a nitrosamine is not adequately characterized, FDA has used structure activity relationships to support the identification of a robustly-tested surrogate that is similar in structure and reactivity to the nitrosamine to generate an estimate of carcinogenic potency from which an AI limit can be scientifically determined. The rationale for the choice of surrogate (similar in structure and reactivity) is significant because test data from the identified surrogate are then used to generate an estimate, either quantitatively or qualitatively, for a compound that lacks robust mutagenicity and carcinogenicity data (commonly referred to as a read-across analysis).
Table 2 presents FDA recommended AI Limits for certain nitrosamines based on compound-specific data or read-across analysis from a surrogate. If a nitrosamine appears in Table 2, the recommended AI limit in Table 2 applies, rather than a limit based on the predicted carcinogenic potency categorization approach.
Table 2: FDA Recommended AI Limits for Certain Nitrosamine Impurities
(Updated: 1/17/2025)
Based on Compound-Specific Carcinogenicity and Mutagenicity Data or Read-Across Analysis from a Surrogate
| Nitrosamine Name | Source | Recommended AI Limit (ng/day) | Surrogate | Date Added to Table |
|---|---|---|---|---|
| N-nitroso-desmethyl-diltiazem | Diltiazem | 100 | 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) | 1/17/2025 |
| N-nitroso-duloxetine | Duloxetine | 100 | 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) | 8/4/2023 |
| N-nitroso-fluoxetine | Fluoxetine | 100 | 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) | 10/11/2023 |
| N-nitroso-atomoxetine | Atomoxetine | 100 | 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) | 12/1/2023 |
| N-nitroso-dimethylamine (NDMA) | Multiple | 96 | Compound specific | 9/4/2024 *** |
| N-nitroso-diethylamine (NDEA) | 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 |
**See Table 3.
*** This limit was previously communicated on September 3, 2020 in the Nitrosamine Guidance
Recommended Interim AI Limits for Certain Nitrosamine Impurities
If drug product batches already in distribution contain nitrosamine impurities at levels above the FDA recommended AI limit, and manufacturing changes or recalls are likely to lead to a disruption in the drug supply, then manufacturers and applicants should immediately contact CDER’s Drug Shortage Staff at drugshortages@fda.hhs.gov. When contacted about a potential disruption in the drug supply, FDA intends to evaluate each circumstance on a case-by-case basis. FDA may work directly with a specific manufacturer or applicant of the marketed drug and intends to consider whether it is appropriate to recommend an interim AI limit for a temporary period. If FDA recommends an interim AI limit, it generally does not intend to object, for example based on applicable underlying CGMP violations, to distribution of such drug product batches that contain nitrosamine impurity levels at or below the recommended interim AI limit during the specified period under certain circumstances which will be determined on a case-by-case basis. In certain cases where FDA does not intend to object to the distribution of drug products from multiple drug manufacturers that contain nitrosamine levels at or below the recommended interim AI limit, FDA intends to post such recommended interim AI limit on this website.
Table 3: Recommended Interim AI Limits* for Certain Nitrosamine Impurities** for Approved or Currently Marketed Products
(Updated: 12/31/2024)
| Nitrosamine Name | Source | Recommended Interim AI Limit (ng/day) | Recommended Interim Control Limit (ppm) | Estimated Duration*** |
|---|---|---|---|---|
| N-nitroso-ciprofloxacin | Ciprofloxacin (tablets) | 12,000 ng/day | 8 ppm | 3/31/2025 |
| 1-methyl-4-nitrosopiperazine (MNP) | Rifampin (injection) | 3,000 ng/day | 5 ppm | 8/1/2025 |
| N-nitroso-protriptyline | Protriptyline | 3,000 ng/day | 50 ppm | 8/1/2025 |
| N-nitroso-dorzolamide | Dorzolamide (single ingredient product only) | 500 ng/day | 139 ppm | 8/1/2025 |
| N-nitroso-sertraline | Sertraline | 600 ng/day | 3 ppm | 8/1/2025 |
*Note that an AI limit can be converted into a parts per million (ppm) control limit. The conversion varies by product and is calculated based on a drug’s maximum daily dose (MDD) as reflected in the drug labeling (ppm = AI (nanograms (ng))/MDD (milligrams)).
**A decision to release lots remains solely the firm’s responsibility. Firms are responsible for ensuring that their drugs are manufactured in compliance with all applicable requirements, including CGMP, and FDA expects them to vigilantly monitor and promptly report to FDA any adverse drug experiences or other findings that may affect product quality or safety.
***“Estimated Duration” is the date by which FDA intends to reassess the recommended interim control limit. As indicated in the RAIL guidance and Nitrosamine Guidance, while FDA recommends conclusion of NDSRI confirmatory testing of drug products and submission of required changes in drug applications by August 1, 2025 for approved or currently marketed products, FDA may recommend that firms complete an expedited risk assessment, confirmatory testing, or other regulatory action based on information available to the Agency. With respect to FDA-recommended interim control limits, FDA generally does not intend to object to the distribution by manufacturers and applicants of drug products that contain nitrosamine levels at or below the recommended interim control limit, until the date identified in the “Estimated Duration” column. However, if FDA becomes aware that the shortage risk has been alleviated, FDA may provide additional notification or may reconsider its recommended interim control limit.
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.
Recommended Analytical Testing Methods for Confirmatory Testing of Certain Nitrosamine Impurities
If manufacturers and applicants identify a risk of nitrosamine formation in a drug product, then confirmatory testing of batches should be conducted using sensitive and appropriately validated methods.
FDA is providing examples of FDA-generated analytical testing methods for industry to use in detecting nitrosamine impurities in specific drug substances and drug products. The methods must be validated by the user if the resulting data are used to support a required quality assessment of the drug substance or drug product, or if the results are used in a regulatory submission.
Table 5: Recommended Analytical Testing Methods
(Updated 10/1/2024)
*This method was previously available on the FDA website.
Recommended Safety Testing Methods for Nitrosamine Impurities
A manufacturer or applicant may submit a scientifically justified rationale to pursue an AI limit higher than the FDA recommended limit associated with the predicted carcinogenic potency category for that nitrosamine or otherwise recommended by FDA. Alternative approaches using safety data, such as obtaining compound-specific data or using read-across assessment to a suitable surrogate, could be used to support a higher limit. FDA may request additional information if a manufacturer pursues an alternative AI limit. FDA acknowledges that other drug regulatory agencies may recommend AI limits that differ from those recommended by FDA. Manufacturers and application holders for drug products approved or marketed in the United States should refer to AI limit recommendations published or otherwise communicated by FDA. In order to assist manufacturers and applicants in conducting safety testing, FDA is recommending that if in vitro mutagenicity testing is contemplated, an enhanced Ames assay be used to assess whether a nitrosamine poses a mutagenic risk. A negative result in a valid enhanced Ames assay may be used to support a higher limit for a nitrosamine; however, manufacturers and applicants should note that FDA may request additional safety data beyond the enhanced Ames assay to support alternative AI limits.
In addition to the enhanced Ames test, the Agency is currently requesting a second in vitro mammalian cell mutation assay and in vitro metabolism data (including human hepatocyte or microsome) to support an AI limit of 1500 ng/day. Negative results in the in vitro mutation tests along with metabolism data are considered supportive. Additional in vivo mutagenicity data may be requested to support AI limits above 1500 ng/day. Specifically, a negative result in an in vivo mutagenicity study may not be supportive of an AI limit equal to the qualification thresholds stated in ICH guidances for industry Q3A(R2) Impurities in New Drug Substances (June 2008) and Q3B(R2) Impurities in New Drug Products (August 2006). FDA acknowledges that these recommendations may differ from those of other drug regulatory agencies.
The following recommendations represent FDA’s current thinking; data gaps in the information available to support the safety of nitrosamines remain to be addressed with future research.
The Organisation for Economic Co-operation and Development (OECD)’s Test Guideline No. 471 “Bacterial Reverse Mutation Test” provides standard recommendations for the conduct of the bacterial reverse mutation test (also known as the Ames assay) to assess the mutagenic potential of a test compound. For nitrosamines, enhanced testing conditions for the Ames assay are recommended by FDA due to the reported reduced sensitivity of the assay under standard conditions for some nitrosamines such as N-nitroso-dimethylamine (NDMA). FDA specifically recommends use of an enhanced Ames assay for nitrosamines, because the sensitivity of the Ames assay to nitrosamines, especially NDSRIs, is currently an active area of research. Additionally, NDSRIs generally have a wider variety of functional groups present than typically found in low molecular weight nitrosamines (such as NDMA) historically studied, and the additional testing conditions described in the enhanced Ames assay have been shown to provide a more sensitive assessment of the mutagenic potential for nitrosamine impurities.
If a standard Ames assay is conducted on a nitrosamine and produces a positive result, FDA recommends there is no need to conduct an additional assay using enhanced testing conditions. The enhanced Ames assay test conditions presented below are informed by work conducted by FDA’s National Center for Toxicological Research (NCTR) (Li X et al., 2023), as well as other groups, and have been evaluated for a variety of nitrosamines, including NDSRIs. Evaluation of Ames assay test conditions for nitrosamines is ongoing with a goal to identify the most robust Ames testing conditions. The enhanced Ames assay test conditions recommended by FDA for nitrosamines and described below will be updated as warranted. Deviations from the recommended conditions should be scientifically justified.
Tester strains: S. typhimurium TA98, TA100, TA1535, TA1537, and E. coli WP2 uvrA (pKM101) tester strains should be included.
Type of assay and preincubation time: The pre-incubation method is recommended, and not plate incorporation. The recommended pre-incubation time is 30 minutes.
Species and concentration of S9: FDA recommends that Ames assays should be conducted in the absence of a post-mitochondrial fraction (S9), and also in the presence of 30% rat liver S9, as well as 30% hamster liver S9. FDA also recommends that the rat and hamster post-mitochondrial fractions (S9s) should be prepared from rodents treated with inducers of cytochrome P450 enzymes (e.g., a combination of phenobarbital and β-naphthoflavone).
Negative (solvent/vehicle) control: FDA recommends that solvents be compatible with the Ames assay as per the OECD 471 guideline. Solvents can include, but are not limited to:
- water
- organic solvents such as acetone, methanol and DMSO
When an organic solvent is used, the lowest possible volume should be included in the pre-incubation mixture with justification to indicate that the volume of solvent does not interfere with metabolic activation of the N-nitrosamine or NDSRI.
Positive controls: Concurrent strain-specific positive controls should be included per the OECD 471 guideline.
Two N-nitrosamines, including NDSRIs, that are known to be mutagenic in the presence of S9 should also be included as positive controls.
The choice of the N-nitrosamine positive controls needs to be justified based on the anticipated metabolism of the N-nitrosamine and the cytochrome P450 enzymes most likely involved. In addition, if an organic solvent is used to dissolve the test compound, FDA recommends that the volume of organic solvent employed to dissolve the N-nitrosamine positive controls results in a similar concentration as for the test compound in the pre-incubation mix, if possible.
N-Nitrosamine positive controls to consider include:
- NDMA (CAS # 62-75-9)
- 1-Cyclopentyl-4-nitrosopiperazine (CAS # 61379-66-6)
- An NDSRI
All other recommendations for the Ames assay should follow the OECD 471 guideline.
References
- OECD Test Guideline No. 471 “Bacterial Reverse Mutation Test” 2020.
- Li X, et al. Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays. Regul Toxicol Pharmacol. 2023 Jun; 141:105410.
Revision Table
Revision Table for Updated Information
| Revision | Nitrosamine Name | Change | Date Posted* |
|---|---|---|---|
| 0 | Original Webpage Posting | Initial posting of Updated Information/Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) | 8/4/2023** |
| 1 | N-nitroso-arformoterol | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-hydrochlorothiazide | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-quinapril | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-nortriptyline | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-desmethyl-imipramine | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-avacopan | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-belumosudil | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-benzonatate | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-deucravacitinib | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-exametazime | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-finerenone | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-leniolisib | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-desmethyl-maralixibat | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-maribavir | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-omidenepag isopropyl | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-pafolacianine | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-viloxazine | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-lorcaserin | Deleted from Table 1 | 10/11/2023 |
| 1 | N-nitroso-isoxsuprine | Deleted from Table 1 | 10/11/2023 |
| 1 | N-nitroso-desmethyl-azithromycin | Added to Table 1 | 10/11/2023 |
| 1 | N-nitroso-fluoxetine | Added to Table 2 | 10/11/2023 |
| 2 | N-nitroso-ciprofloxacin | Added to Table 1 | 12/1/2023 |
| 2 | N-nitroso-ciprofloxacin | Deleted from Table 2 | 12/1/2023 |
| 2 | N-nitroso-atomoxetine | Deleted from Table 1 | 12/1/2023 |
| 3 | N-nitroso-duloxetine | Added to Table 3 | 2/23/2024 |
| 3 | N-nitroso-bumetanide | Added Testing Method for the Determination of N-nitroso-bumetanide | 2/23/2024 |
| 3 | N-nitroso-propranolol | Added Testing Method for the Determination of N-nitroso-propranolol | 2/23/2024 |
| 3 | N-nitroso-varenicline | Added Testing Method for the Determination of N-nitroso-varenicline | 2/23/2024 |
| 4 | N-nitroso-varenicline | Deleted from Table 2 | 3/5/2024 |
| 4 | N-nitroso-varenicline | Added to Table 1 | 3/5/2024 |
| 5 | N-nitroso-ciprofloxacin | Added to Table 3 | 4/18/2024 |
| 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-methylphenidate | Added to Table 2 | 9/4/2024 |
| 6 | N-nitroso-vonoprazan | Added to Table 2 | 9/4/2024 |
| 6 | Added Section on Other Emerging Scientific and Technical Issues | 9/4/2024 | |
| 6 | Added Section on Recommended Implementation Timelines | 9/4/2024 | |
| 6 | N-nitroso-piperazine (NPZ) | Added to Table 2 | 9/4/2024 |
| 6 | N-nitroso-degarelix | Deleted from Table 1 | 9/4/2024 |
| 7 | N-nitroso-duloxetine | Updated estimated duration of interim limit in Table 3 from 10/1/2024 to 12/31/2024 | 9/27/2024 |
| 8 | Multiple | Added to Table 1 and Table 2 acronyms for certain nitrosamines: NIPEA/NEIPA, NDIPA, NMBA, MNP, CPNP, NMPA, NDMA, NDEA | 10/1/2024 |
| 8 | Multiple | Added to Table 5 previously available testing methods for detection of nitrosamines in angiotensin II receptor blocker (ARB)s valsartan, losartan, and irbesartan; bumetanide; metformin; propranolol; ranitidine; rifampin and rifapentine; and varenicline | 10/1/2024 |
| 8 | Added Table 5 for Recommended Analytical Testing Methods | 10/1/2024 | |
| 9 | 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (NTTP) | Added to Table 1 | 10/7/2024 |
| 9 | 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (NTTP) | Deleted from Table 2 recommended AI limit of 37 ng/day based on the surrogate N-nitroso-1,2,3,6-tetrahydropyridine (NTHP), previously communicated on August 9, 2022, and previously published in Table 2 on August 4, 2023 | 10/7/2024 |
| 10 | N-nitroso-dorzolamide | Added to Table 3 | 10/15/2024 |
| 11 | N-((2-isopropylthiazol-4-yl)methyl)-N-methylnitrous amide (NITMA) aka N-nitroso-2,4-thiazoleamine (NNTA) | Added to Table 1 | 10/28/2024 |
| 11 | N-((2-isopropylthiazol-4-yl)methyl)-N-methylnitrous amide (NITMA) aka N-nitroso-2,4-thiazoleamine (NNTA) | Information on Ritonavir added to Emerging Issues section | 10/28/2024 |
| 12 | N-nitroso-sertraline | Added to Table 3 | 10/31/2024 |
| 13 | N-nitroso-sertraline | Corrected duration in Table 3 | 11/1/2024 |
| 14 | N-nitroso-ribociclib-1 | Added to Table 1 | 11/20/2024 |
| 14 | N-nitroso-ribociclib-2 | Added to Table 1 | 11/20/2024 |
| 14 | Added (Q)SAR Model Reporting Format (QMRF) for the Carcinogenic Potency Categorization Approach (CPCA) | 11/20/2024 | |
| 15 | N-nitroso-ciprofloxacin | Corrected source in Table 3 to Ciprofloxacin tablets | 12/31/2024 |
| 15 | N-nitroso-protriptyline | Interim limit added to Table 3 | 12/31/2024 |
| 15 | N-nitroso-duloxetine | Interim limit deleted from Table 3 | 12/31/2024 |
| 15 | 1-methyl-4-nitrosopiperazine (MNP) | Interim limit added to Table 3 | 12/31/2024 |
| 16 | N-nitroso-desmethyl-diltiazem | Added to Table 2 | 1/17/2025 |
| 16 | N-nitroso-desmethyl-diltiazem | Deleted from Table 1 | 1/17/2025 |
*The revisions to the webpage associated with the FDA guidances for industry, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) and Control of Nitrosamine Impurities in Human Drugs are for immediate implementation as of the date of posting.
**The effective date of the FDA guidance for industry, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) is August 7, 2023 and the effective date of the FDA guidance for industry, Control of Nitrosamine Impurities in Human Drugs is September 5, 2024, when the Notices of Availability were published in the Federal Register.