Nitrosamine Related Guidance
Reynolds Cantave, PharmD
Sr. Regulatory Business Process Manager
Office of Quality Assurance, Office of Pharmaceutical Quality
CDER | US FDA
Generic Drug Forum – April 10, 2025
Learning Objectives
• Define Nitrosamines and describe the two structural classes of these
impurities.
• Describe purpose of predicted carcinogenic potency categorization
approach (CPCA) framework introduced with 2023 Guidance.
• Describe four key updates published in 2024 Guidance for Industry:
Control of Nitrosamine Impurities in Human Drugs.
• Describe control strategy recommendations described in 2024 Guidance
for Industry: Control of Nitrosamine Impurities in Human Drugs.
• List elements of the three-step mitigation strategy.
• Describe recommendations NDSRI mitigation strategies and
recommended supporting stability data for reformulation.
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Brief Historical Background
• June 2018, CDER Alerted to presence of NDMA in
Valsartan
• Prompted global regulatory response and
industry-wide action
• Subsequently, scope expands to include additional
drugs and new nitrosamines
• Ongoing investigations into other drug products
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What are Nitrosamines?
• N-nitroso compounds: formed by nitrosation of
susceptible amines
• Genotoxic, probable human carcinogens
• Commonly found in the environment, rubber,
foods (cured meats, beer, and cheese), and
pharmaceuticals
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“Small Molecule” vs. “NDSRI”
• Small molecule Nitrosamines • Nitrosamine drug substance
(not associated with API. e.g., related impurities – NDSRIs
NDMA, NDEA, NMPA, (associated with API)
NDIPA, NDBA, and NBMA
etc.)
N-Nitrosodimethylamine (NDMA) N-nitroso-phenylephrine
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Challenge Question #1
FDA’s recommended three-step mitigation
strategy include all of the following, except:
A. Perform Risk Assessment
B. Submission of Risk Assessment to FDA
C. Perform Confirmatory Testing
D. Report Changes to FDA, as appropriate
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Introduction to Nitrosamine
Guidance
• Challenges in Analytical Method Development,
Understanding root-cause of nitrosamine
contamination, and deriving Acceptable Intake
Limits
• Need to communicate Agency observations and
understandings
• Outline expectations and provide guidance
• Collaborate to address public health concern
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Evolution of FDA Guidance on
Nitrosamine Impurities
2020/2021 Control of Nitrosamine Impurities in Human Drugs
2023 Recommended Acceptable Intake Limits for Nitrosamine
Described root causes of nitrosamine
impurities 2024 Control of Nitrosamine Impurities
Focused on small molecule Provided a framework for predicting in Human Drugs Revision 2
nitrosamines acceptable intake (AI) limits
Provided API-focused Addressed nitrosamine drug
recommendations Broadened scope to both small
substance-related impurities molecule nitrosamines and NDSRIs
Introduced 3-step mitigation strategy (NDSRIs)
Added new recommendations for
• 1. Conduct risk assessments Introduced predicted carcinogenic nitrosamine impurity controls
• 2. Perform confirmatory testing potency categorization approach
(CPCA) Provided implementation
• 3. Report changes to prevent or recommendations
reduce nitrosamine impurities per
applicable requirements* Included reformulation as a mitigation
strategy with CMC and BE
recommendations
*For the applicable requirements regarding reporting changes, see 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12 regarding changes to approved
applications; 21 CFR 314.60 and 21 CFR 314.96 regarding amendments to pending applications; and 21 CFR 314.420(c) regarding changes to DMFs.
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New Recommendations for Nitrosamine
Controls: Multiple Nitrosamine Impurities
2020 Guidance Standard Approach
If multiple nitrosamine impurities are detected, total should not
exceed 26.5 ng/day (or the AI for the most potent nitrosamine)
2024 Guidance - Flexible Approach
Levels of the nitrosamine impurities when totaled should result in an
exposure level that does not exceed the acceptable cancer risk of
1:100,000 as outlined in ICH M7(R2).1
1. M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (July 2023).
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New Recommendations for Nitrosamine
Controls: Method Sensitivity – Limit of
Quantitation (LOQ)
Example: Drug X
2020 Guidance – Single Limit
MDD = 100 mg/day
AI 1500 ng/day
Control limit1 = 15 ppm LOQs should be at or below 0.03 ppm
LOQ = 0.03 ppm
LOQ = 1.5 ppm 2024 Guidance – Flexible Approach
Example: LOQ is 10% AI
Limits of Detection and Quantitation should follow ICH
Q2(R1) and be commensurate with the level at which the
1. AI (ng/day)/MDD (mg) = limit in ppm
impurities must be controlled.2
2. Q2(R1) Validation of Analytical Procedures: Text and Methodology (November 2005)
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Implementation of Control Strategies –
Assessing Test Results
Key
FDA or Manufacturer
Identifies a Risk
- Assess Risk
Nitrosamine does not Nitrosamine may form
Does a nitrosamine form?
form
- Test
Action:
Action: Perform confirmatory
No routine testing needed testing - Report Changes
Test results >AI
Test results <10% AI Test results >10% AI and ≤AI Action:
• Manufacturing changes are needed to mitigate
Action: Action: nitrosamine impurity
No specification needed Specification needed • Alternatively, submit supporting data for a different
proposed AI
Action for Approved Products: Action for Approved Products: Action for Approved Products:
Send info in Annual Report Submit a CBE-30 Submit a PAS
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Additional Reporting
Considerations
• Timely reporting of confirmed nitrosamine
findings above AI limits via Field Alert Reports
(FARs) for marketed products
• Action likely to lead to a disruption in drug
supply, Notify FDA’s Drug Shortage Staff
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Timelines and Updates
FDA recommend conclusion of NDSRI confirmatory testing of drug products and submission of changes
by August 1, 2025.
As FDA becomes aware of new and emerging information on nitrosamine impurities, it may
communicate information on the identification of new nitrosamine impurities and FDA’s understanding
of the root cause of such impurities and their formations.
FDA may communicate new recommended AI limits, recommendations for prevention or mitigation to
address such nitrosamine impurities, and recommended timelines for implementing the mitigation
recommendations.
Check the CDER Nitrosamine Impurity Acceptable Intake Limits webpage for updates.
• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
acceptable-intake-limits
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CDER Nitrosamine Impurity
Acceptable Intake Limits – Webpage
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
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NDSRI Mitigation Strategies
• Recommendations to mitigate nitrosamine
formation in drug products
– Screen excipients for nitrite impurities
– Add antioxidant
– Add pH modifier
– Other innovative strategies
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Stability Data to Support
Reformulated Products
• Three batches • FDA may request 6
mo. accelerated
• 3 mo. data at submission stability data with
– accelerated time points 0, potential upward
1, 2, and 3 mo.) trend.
– long-term (0 and 3 mo.) • Long-term stability
• For OTC monograph data of first three
products, manufacturers production batches,
should retain similar through shelf life,
supporting information at submitted to annual
the facility report.
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Alternative Bioequivalence (BE)
Approaches
• Challenges
– Such reformulation may need an in vivo BE study to support changes
• Alternative BE approaches
– Regulation:
• 21 CFR 320.24(b)(6): any other approach deemed adequate by FDA
– Science: three research projects
• Addition of antioxidants to formulations could significantly inhibit nitrosamine formation1
• Small amounts of four antioxidants (ascorbic acid, α-tocopherol, propyl gallate, or
cysteine) do not affect permeability of BCS III model drugs2
• Small amounts of antioxidants do not affect intestinal transporter activities3
1. Shakleya, et al. Journal of Pharmaceutical Sciences, 2023, 112 (12): 3075-87
2. Lu, et al. Journal of Pharmaceutical Sciences, 2024, 113 (9): 2708-14
3. Kulkarni et al. Pharmaceutics, 2024, 16: 647
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Challenge Question #2
Which of the following statements is NOT true?
A. FDA recommends that applicants perform confirmatory testing if a Risk Assessment
indicates an impurity is at a low risk of formation.
B. FDA recommends that applicants routinely control a nitrosamine if testing results
indicate that nitrosamine is found <10% of the Acceptable Intake Limit.
C. FDA recommends that applicants routinely control a nitrosamine if testing results
indicate that nitrosamine is found >10% and ≤ the Acceptable Intake Limit.
D. FDA recommends that if applicants find nitrosamine impurities in their product
exceeding recommended AI limits, they mitigate and report changes as a Prior
Approval Supplement (PAS). Alternatively, they may provide justification for a
different limit via PAS.
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Future Considerations
• Research into novel nitrosamine compounds
and formation pathways
• Development of advanced analytical
technologies for improved detection
• Ongoing evaluation of long-term health
impacts
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Industry Responsibilities
• Proactive risk assessment of product portfolio
• Implementation of robust control strategies
across facilities
• Timely communication with regulators on
findings and engagement on mitigation efforts
• Investment in research and technology for
nitrosamine control
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FDA's Expectations
• Observe current and future nitrosamine guidance
recommendations
• Transparency in reporting and addressing
nitrosamine issues
• Commitment to patient safety through rigorous
quality control
• Collaboration with FDA on improving nitrosamine
control measures
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Take-Away Messages
Added new
Defined Nitrosamines Described evolution of Provided the webpage
recommendations for
and described their two FDA Guidance on for nitrosamine
nitrosamine impurity
structural classes Nitrosamine Impurities acceptable intake limits
controls
Highlighted importance Emphasized a
Encouraged ongoing
of proactive risk collaborative approach
vigilance required from
assessment and remains essential for
industry and regulators
mitigation protecting public health
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Acknowledgements
• Colleagues
– Office of Pharmaceutical Quality
– Office of New Drugs
– Office of Generic Drugs
• Nitrosamine workgroups in FDA
• Susan Zuk and Dongmei Lu
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Questions?
Reynolds Cantave, PharmD
Sr. Regulatory Business Process Manager
Office of Quality Assurance, Office of Pharmaceutical Quality
CDER | US FDA
