FDA Guidance for Industry
Control of Nitrosamine Impurities
in Human Drugs
Dongmei Lu, Ph.D.
Office of Policy for Pharmaceutical Quality
Office of Pharmaceutical Quality
CDER/FDA
June 15, 2023
www.fda.gov 1
Disclaimer
This presentation reflects the views of the
author and should not be construed to
represent FDA's views or policies
2
Outline
• Background
• Root Causes of Nitrosamines (NSA)
• FDA Recommendations to Manufacturers
• Recent NDSRI Issues and FDA Recommendations for
Mitigation Strategies
• Reporting Changes to FDA
3
Background
• What are Nitrosamines (NSA)?
Secondary, tertiary, or quaternary amines
• Probable or possible human carcinogen; potent genotoxic agents;
“cohort of concern” compounds in the ICH M7(R1)
➢ Small molecule NSA (NDMA, NDEA..)
➢ Nitrosamine drug substance-related impurity (NDSRI) found in
drug products (DP) related to API (or API fragment)*
*See FDA’s announcement on Updates on possible mitigation strategies to reduce the risk of nitrosamine drug
substance-related impurities in drug products
4
Brief History of Nitrosamine Issues
Nitrosamine Guidance Published NDSRI Announcement
Initial nitrosamine findings in ARBs
led to recalls, withdrawals and drug
shortages (valsartan, losartan, 2021 NDSRI in Chantix (varenicline) was
irbesartan). Problem: NDMA & 2020 metformin voluntary recalls. reported to exceed the AI limit.
NDEA Problem: NDMA Problem: NDSRI.
Recall of ARBs Metformin Varenicline
2019 2020
2018 2020 2021 2022
Ranitidine Rifampin & Rifapentine Sitagliptin
2020 FDA became aware of nitrosamine 2022 FDA became aware of
2019 ranitidine recalls followed by impurities in TB medications of Rifampin
2020 removal from the market of nitrosamine impurity NTTP in
and Rifapentine. certain samples of sitagliptin
Zantac (all ranitidine products).
Problem: MNP and CPNP Problem: NDSRI
Problem: NDMA
FDA’s Efforts
• Information dissemination from FDA
➢ Public webpage for announcements
➢ Product-specific communications
➢ Industry meetings
➢ Workshops
• Various working groups within FDA and collaboration with international
regulators
• Guidance
➢ Guidance for immediate implementation because of importance of
providing timely information to API and DP manufacturers
➢ Revision 1- update on implementation dates (2/2021)
6
Contents of Guidance*
• Root causes
➢ in APIs
➢ in DP other than API sourced nitrosamines
• Recommendations
➢ Acceptable Intake Limits
➢ to API manufacturers
➢ to DP manufacturers
• Reporting Changes
Timeline for risk assessment, confirmatory testing and submission
➢ Approved/marketed drug products
➢ Pending applications
* Focused on small molecule nitrosamines 7
Root Causes
API
Drug
Product
8
Recommendations
Acceptable Intake Limits (AI)
AI Limits for Some Nitrosamines in DPs
Nitrosamine AI Limit (ng/day)1,2
NDMA 96
NDEA 26.5
NMBA 96
NMPA 26.5
NIPEA 26.5
NDIPA 26.5
MNP* 96
CPNP* 96
1
The AI limit is a daily exposure to a compound that approximates a 1:100,000 cancer risk after 70 years of exposure.
2 The conversion of AI limit into ppm varies by product and is calculated based on a drug’s maximum daily dose (MDD) as
reflected in the drug label (ppm = AI (ng)/MDD (mg)).
* These AI are not included in the current guidance but were published in FDA public webpage 9
Three Steps for Mitigation Strategy
1. Risk Assessment
2. Confirmatory Testing
(if any risk)
3. Reporting Changes
10
Recommendations to API Manufacturers
• API manufacturers: (corresponding to root causes)
➢ Optimize design of process in ROS: condition, avoid amine bases/ solvent,
control reaction sequence/ process conditions
➢ Audit/monitor supply chain
➢ Avoid cross-contamination
➢ Reprocess/rework batches
11
Recommendations to API Manufacturers
• Control of Nitrosamine Impurity in APIs
➢ LOQ< nitrosamine level ≤AI
▪ control strategy (including specifications)
➢ Nitrosamine level > AI
▪ The batches should not be released unless with FDA agreement to
prevent/mitigate drug shortages
12
Recommendations to DP Manufacturers
• DP manufacturers: (corresponding to root causes)
➢ Collaborate with API manufacturers:
▪ continuously test API lots until verified w/o unacceptable
levels of nitrosamines (NSAs)
➢ Evaluate all pathways (including degradation) during manufacture
and storage
➢ Remove precursor impurities (such as DMA) that may be carried-
over from API synthesis which can form nitrosamine in drug
products
13
Recommendations to DP Manufacturers
• Control of Nitrosamines in DPs
➢ LOQ<NSA level ≤AI:
▪ control strategy (specification);
▪ necessary if risk is inherent from API or DP
➢ NSA level > AI:
▪ Batches should not be released
▪ contact FDA regarding batches on the market
▪ FDA may exercise regulatory discretion when warranted to
prevent/mitigate drug shortages
14
Nitrosamine Drug Substance –
Related Impurities (NDSRIs)
• Recently, NDSRIs were identified in certain products, e.g., Varenicline,
Sitagliptin
• Sharing structural similarity to the API; unique to each API (containing API or
API fragment)
• Root causes:
➢ APIs (secondary or tertiary amines) are exposed to nitrosating compounds such as
nitrite impurities in excipients
➢ formed during drug product manufacture or shelf-life storage
15
NDSRI Mitigation Strategies
FDA public announcement 11/18/2021#
• Screen excipients for nitrite impurities
• Add Antioxidant
• Add pH modifier
• Other innovative strategies
# https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-
impurities 16
Reporting Changes to FDA
• Recommended timeline for three steps (risk assessment, confirmatory testing
and submission of changes)
➢ Approved/marketed DPs
▪ Risk assessment: within 7 months from guidance’s first publication (March 1 s t, 2021)
▪ Confirmatory testing: start once risk identified; ASAP for high-risk products
▪ Submission: last two steps within 3 years of guidance publication (October 1 s t, 2023); FDA is
seeking comments on extension of recommended timeline.*
➢ Pending applications
▪ Pre-submission: risk assessment, confirmatory testing. Changes may be submitted in
amendment if not included in original submission
▪ Pending with FDA:
❖ risk assessment, confirmatory testing if at risk
❖ report to FDA if NSA>AI
❖ If LOQ<NSA level ≤AI, amendment with control strategy
* See 88 FR 28557 https://www.federalregister.gov/documents/2023/05/04/2023-09526/identification-assessment-and-control-of-nitrosamine-drug-substance-
related-impurities-in-human-drug (5/4/2023) 17
