SBIA 2020
FDA’s Overview of
the Guidance for Industry:
Control of Nitrosamine Impurities in
Human Drugs
David Keire, Ph.D. and Dongmei Lu, Ph.D.
Office of Pharmaceutical Quality
CDER/U.S. FDA
October 2, 2020
1
Advancing
Pharmaceutical Quality:
Nitrosamines in Drugs
David Keire
Deputy Director
Office of Testing and Research
Office of Pharmaceutical Quality
US FDA Center for Drug Evaluation and Research
October 2, 2020
Pharmaceutical Quality
A quality product of any kind consistently
meets the expectations of the user.
www.fda.gov
3
Pharmaceutical Quality
A quality product of any kind consistently
meets the expectations of the user.
Drugs are no different.
www.fda.gov
4
Patients expect safe and effective
medicine with every dose they take.
www.fda.gov
5
Pharmaceutical quality is
assuring every dose is safe and
effective, free of contamination
and defects.
www.fda.gov
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It is what gives patients confidence
in their next dose of medicine.
www.fda.gov
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Nitrosamines are everywhere.
• NDMA and other nitrosamines are common contaminants in low
amounts (ppm) in foods, beverages, cosmetics, water, tobacco
products and consumer goods (1-4).
1. Gushgari AJ, Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere. 2018;210:1124-36.
2. Kocak D, Ozel MZ, Gogus F, Hamilton JF, Lewis AC. Determination of volatile nitrosamines in grilled lamb and vegetables using comprehensive gas
chromatography - nitrogen chemiluminescence detection. Food Chem. 2012;135(4):2215-20.
3. Park JE, Seo JE, Lee JY, Kwon H. Distribution of Seven N-Nitrosamines in Food. Toxicol Res. 2015;31(3):279-88.
4. Lim DS, Roh TH, Kim MK, Kwon YC, Choi SM, Kwack SJ, et al. Risk assessment of N-nitrosodiethylamine (NDEA) and N-nitrosodiethanolamine (NDELA) in
cosmetics. J Toxicol Environ Health A. 2018;81(12):465-80.
8
ICH M7(R1) Assessment and Control of DNA
Reactive (Mutagenic) Impurities in Pharmaceuticals
To Limit Potential Carcinogenic Risk
• Compounds from some structural classes of mutagens can
display extremely high carcinogenic potency (cohort of concern),
i.e., aflatoxin-like, N-nitroso-, and alkyl-azoxy structures. If these
compounds are found as impurities in pharmaceuticals,
acceptable intakes for these high-potency carcinogens would
likely be significantly lower than the acceptable intakes defined in
this guidance.
9
ICH M7 (2)
• Other Considerations for Marketed Products: Application of this
guidance to marketed products may be warranted if there is
specific cause for concern. The existence of impurity structural
alerts alone is considered insufficient to trigger follow-up
measures, unless it is a structure in the cohort of concern
(Section III (3)). However, a specific cause for concern would be
new relevant impurity hazard data (classified as Class 1 or 2,
Section 6) generated after the overall control strategy and
specifications for market authorization were established.
10
Timeline of US Drug Nitrosamine Issues
• June 2018 – FDA informed of the presence of NDMA from
a valsartan manufacturer
• July 2018 – voluntary recall of valsartan due to NDMA
• Sept 2018 – NDEA detected in a previously recalled
valsartan
• Oct 2018 – irbesartan recalled due to NDEA
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Timeline of US Drug Nitrosamine Issues (2)
• Nov 2018 – losartan recalled due to NDEA
• Dec 2018 – FDA posted interim limits for NDMA/NDEA in
ARBs
• Feb 2019 – FDA posted interim limit for NMBA in ARBs
• March 2019 – NMBA detected in losartan
– Temporary drug shortage mitigation: “FDA not objecting to
losartan with NMBA below 9.82 ppm remaining on the
market.”
12
Timeline of US Drug Nitrosamine Issues (3)
• June 2019 – FDA became aware of laboratory testing that
detected NDMA in ranitidine
• Aug 2019 – General Advice letter to ARB applicants and
DMF holders posted to FDA.gov
• Root causes for nitrosamines in ARBs discussed
• Sept 2019 – ranitidine recalled due to NDMA
13
Timeline of US Drug Nitrosamine Issues (4)
• Dec 2019 – NDMA detected in some metformin
products but recalls not warranted as the amounts were
below AI
• Dec 2019 – 1-methy-4-nitrosopiperazine (MNP) reported
in rifampin
• Jan 2020 – nizatidine recalled due to NDMA
• April 2020 – FDA requested withdrawal of all ranitidine
from the U.S. market
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Timeline of US Drug Nitrosamine Issues (5)
• May 2020 – metformin extended-release recalled due
to NDMA
• May 2020 – 1-cyclopentyl-4-nitrosopiperazine (CPNP)
reported in rifapentine
• Numerous information requests to industry from
FDA and responses from industry throughout this
entire time period
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International Regulators
• This included (under established confidentiality agreements):
– Scientific discussions about acceptable intake limits
– Sharing of laboratory methods and test results
– Coordination of joint inspections where appropriate
– Sharing of inspectional findings
• Essential to future global drug safety/quality investigations
www.fda.gov 16
Outcome:
Over the past 2 years, industry and
regulators have learned a lot about
what factors lead to the risk of
nitrosamine impurities in
pharmaceuticals
17
Root Causes of Nitrosamine Contamination
▪ Physicochemical ▪ Use of recovered or
properties of the Process Supply recycled materials or
starting materials, Related Chain other intermediates
intermediates or contaminated with
Drug Substance nitrosamines
Nitrosamines
▪ Specific process in the Drug ▪ Cross-contamination
conditions Substance
and/or Drug
in multi-purpose
▪ Impurities in or Product facilities
reactions with raw ➢ Quality Oversight
materials ▪ Stability: Drug Substance or Drug
➢ Development and Product
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Control Strategies Stability ▪ Excipient compatibility
➢Quality Oversight - 18 -
Potential Nitrosamine Impurities Generated
During the Synthesis of ARB Drug Substances
Br -
DMF TEA DIPEA TBAB NMP
NDMA NDEA NEIPA NDIPA
NMBA NDBA 19
Nitrosamine Risk Assessment
• Assess stages of API or Drug Product manufacturing
– Are there API or formulation steps that have the
potential to have reactive amines in the presence of
nitroso compounds?
– Are there reagents (e.g., catalysts, solvents) that may
have components that could form nitroso-compounds in
side reactions?
– What about intermediates or reagents sourced from
suppliers?
• Is there nitrosamine risk? 20
If nitrosamine risk is present
• Is the nitroso-compound a known mutagen as per ICH M7?
• Determine a drug-specific acceptable intake (AI) based
on the maximum daily dose (MDD) of the drug.
• Establish an analytical target based on the AI and MDD.
• Develop and validate an analytical procedure sensitive
enough to track and trace nitroso-compounds in the
manufacturing process.
– Conduct an assessment of the nitrosamine formation and
purge capacity of the synthetic route.
21
Stability
• Is the nitrosamine content stable over time in the
API?
• Does the nitrosamine content increase during
formulation?
• Is the nitrosamine amount stable under “real world”
conditions in the drug product?
Based on these data, an appropriate control
strategy can be proposed to regulators.
22
Challenges
• Root cause for nitrosamine impurities
– Investigation(s) ongoing
– Not one source (but some common factors)
• Where recalls were warranted,
– Is the drug medically necessary?
– Will a recall lead to a drug shortage?
– If a recall occurs, are there safe and effective alternatives that
patients can switch to?
• Ongoing communications with patients, healthcare providers, media,
industry and international regulators
• Rapid development of validated laboratory testing methods
www.fda.gov 23
FDA sampling and testing of the US Drug
Supply for Nitrosamines
• The US FDA analytical procedure development approach has
been to have two validated orthogonal tests (primary and
confirmatory) for each drug.
– Typically, developed and validated on one API and a single dosage form.
• However, the FDA is testing many different dosage forms
– The second orthogonal test (if the value measured is similar) provides
assurance that no matrix interference has occurred with the primary
measurement.
– Spike recovery checks are key steps across products
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FDA and USP Posted Testing Methods
• ARBs – 6 methods
– NDMA, NDEA, NMBA, NDBA, NDIPA, NEIPA Any method should be validated
by the user if the resulting data
• Ranitidine – 2 methods are used to support a required
– NDMA quality assessment of the API or
• Metformin – 2 methods drug product, or if the results are
used in a regulatory submission.
– NDMA
• Rifampin and Rifapentine – 1 shared method
– MNP, CPNP
• USP Chapter <1469> Nitrosamine Impurities went to PF (link below). Four
methods described. Out for Comment.
– 6 USP reference standards are available
https://online.usppf.com/usppf/document/GUID-C97F817C-A383-4693-8E0C-2F0A0A371977_10101_en-US
www.fda.gov 25
Suitable Analytical Measurements on Trace
Amounts (ppm to ppb) of Nitrosamines
• Key to detection of nitrosamines in each drug is the application
of appropriate measurement technology focused on detecting
amounts of nitrosamines in solvents, intermediates, APIs and
across finished dosage forms.
– LOQs should be appropriately below AI amounts (Guidance!)
• Many analytical procedures developed by regulatory labs have
been made publicly available to speed the risk-based screening
of manufacturing processes for nitrosamines (FDA.gov).
26
1. FDA/CDER. FDA Updates and Press Announcements on NDMA in
Metformin FDA.gov2020 [Available from:
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-
press-announcements-ndma-metformin.
2. FDA/CDER. FDA Updates and Press Announcements on Angiotensin II
Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) 2020
[Available from: https://www.fda.gov/drugs/drug-safety-and-
availability/fda-updates-and-press-announcements-angiotensin-ii-
receptor-blocker-arb-recalls-valsartan-losartan.
3. FDA/CDER. FDA Updates and Press Announcements on NDMA in Zantac
(ranitidine) 2020 [Available from: https://www.fda.gov/drugs/drug-safety-
and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine.
4. CDER/FDA. Laboratory Tests | Metformin 2020 [Available from:
https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-
metformin.
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FDA Expectations of Industry
“Manufacturers are responsible for understanding their
processes, which includes preventing the presence of
unacceptable impurities. Manufacturers are also
responsible for developing and using suitable methods
to detect and limit unacceptable impurities, including
any new impurities that may arise when they make
changes to their manufacturing processes.”
https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-
impurities-medications
What industry should know about nitrosamine impurities.
www.fda.gov 28
Drug Quality & the U.S. Market
“The FDA is committed to ensuring that the medicines
Americans take are safe and effective. When we identify drug
quality lapses that pose potential risks for patients, we make
every effort to understand the issues and provide our best
recommendation to the public as quickly and accurately as
possible. We will continue to investigate and work to ensure
these types of impurities do not exceed acceptable limits so
that patients can continue taking their medicines without
concern.”
https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-
impurities-medications
Can we trust FDA and its approvals and drug surveillance? 29
www.fda.gov
FDA Guidance
Control of Nitrosamine Impurities
in Human Drugs
FDA Recommendations
Dongmei Lu, Ph.D.
Office of Policy for Pharmaceutical Quality
Office of Pharmaceutical Quality │CDER │U.S. FDA
October 2, 2020
30
FDA Guidance
Control of Nitrosamine Impurities
in Human Drugs
FDA Recommendations
Dongmei Lu, Ph.D.
Office of Policy for Pharmaceutical Quality
Office of Pharmaceutical Quality │CDER │U.S. FDA
October 2, 2020
31
Guidance was published on Sept 1st, 2020
Guidance link: https://www.fda.gov/media/141720/download
Comment submission (Docket ID: FDA-2020-D-1530):
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/control-nitrosamine-impurities-human-drugs
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Outline
• Background
• Root Causes of Nitrosamines
• FDA Recommendations to Manufacturers
• Reporting Changes to FDA
www.fda.gov 33
What are Nitrosamines?
• What are Nitrosamines?
Secondary, tertiary,
or quaternary amines
• Nitrosamines are
➢ Probable or possible human carcinogens
➢ Potent genotoxic agents
➢ “Cohort of concern” compounds in the ICH M7(R1)
ICH M7 (R1) Guidance: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To
Limit Potential Carcinogenic Risk (March 2018)
www.fda.gov https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 34
Nitrosamines Detected
• 7 possible nitrosamines could form (NDMA, NDEA, NMBA, NMPA, NIPEA,
NDIPA, NDBA) and 5 actually have been found in APIs and drug products
• More are under investigation…
www.fda.gov 35
Impacts
• Drug Shortages:
➢ valsartan, olmesartan, eprosartan, nizatidine
• Withdrawals/recalls:
➢ ranitidine (all products)- withdrawal
➢ sartans (certain product lots)
➢ metformin (certain extended-release product lots)
https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-
losartan-and.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin
www.fda.gov 36
Industry Needs
• Urgent Need: for API and drug product
manufacturers
➢Assess potential nitrosamines in any pharmaceutical
product at risk for their presence
➢Develop a prevention strategy
www.fda.gov 37
FDA Efforts
• FDA:
➢investigated intensively
➢communicated with public via announcements
➢worked with industry to remove affected products
from market
➢coordinated with international regulators
➢developed guidance/instructions to industry
www.fda.gov 38
What is Covered in Guidance
• Root causes
➢ In APIs
➢ In drug products other than API contamination
• Recommendations
➢ Acceptable Intake Limits
➢ To API manufacturers
➢ To drug product manufacturers
• Three- step Mitigation Strategy
• Reporting Changes
Timeline for three-step actions
39
Root Causes of Nitrosamine Impurities in APIs
and Drug Products
▪ Physicochemical ▪ Use of recovered or
properties of the Process Supply recycled materials or
starting materials, Chain other intermediates
Related
intermediates or contaminated with
Drug Substance nitrosamines
▪ Specific process Nitrosamines ▪ Cross-contamination
conditions in the Drug in multi-purpose
▪ Impurities in or Substance
and/or Drug facilities
reactions with raw Product ➢ Quality Oversight
materials
➢ Development and
Control Strategies ▪ Stability of the Drug Substance or Drug
40
Product
Stability ▪ Excipient compatibility
➢Quality Oversight - 40 -
Guidance Recommendations
41
Nitrosamine Intake Limits
• Acceptable Intake Limits (AI)
Table 1. AI Limits for Nitrosamines in Drug Products
Nitrosamine AI Limit (ng/day)1,2
NDMA 96
NDEA 26.5
NMBA 96
NMPA 26.5
NIPEA 26.5
NDIPA 26.5
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 the 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)).
42
Implementation of AI
• AI is only applicable if a single nitrosamine is found - Table 1
• If >1 nitrosamines:
➢ Total quantity ≤ AI of the most potent one (26.5 ng/day) based on MDD
➢ otherwise contact FDA*
• Analytical methods:
➢LOQ ≤ 0.03 ppm
➢If MDD is high (e.g., > 1g), LOQ and LOD as low as reasonably practical
• API manufacturers should control nitrosamine level to ensure
Drug Product meets these criteria
* FDA Contact: CDER-OPQ-Inquiries@fda.hhs.gov
43
Three Steps for Mitigation Strategy
1. Risk Assessment
2. Confirmatory Testing
(if any risk)
3. Reporting Changes
44
Three Steps for Mitigation Strategy
• APIs, marketed products, and
1. Risk Assessment products under approved/ pending
applications.
• Conduct in a timely manner based
on the prioritization of drugs:
➢ MDD
➢ treatment duration
➢ therapeutic indication
➢ number of patients treated
• FDA may recommend certain drug
products as higher priority based on
understanding
• If no risk, no further action.
45
Three Steps for Mitigation Strategy
1. Risk Assessment
Analytical methods need to have
2. Confirmatory Testing specificity, excellent
(if any risk) chromatographic separation, and
highly sensitive detection capability.
46
Three Steps for Mitigation Strategy
1. Risk Assessment
2. Confirmatory Testing
(if any risk)
Report changes implemented to prevent
or reduce nitrosamines. This includes
3. Reporting Changes DMF amendments and changes to
approved/pending applications.
All risk assessment reports stay at manufacture site, available upon request 47
Recommendations to API Manufacturers
• Optimize design of process in ROS
➢ Related reaction conditions
➢ Amine bases
➢ Amide solvents – use caution
➢ Replace nitrites with other quenching agents for azide
decomposition processes
➢ Control reaction sequence/conditions
• Audit/monitor supply chain
• Avoid cross-contamination
48
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
49
Recommendations to Drug Product Manufacturers
• Collaborate with API manufacturers
➢If risk is detected, continuously test API lots until
verified to be without unacceptable levels of
nitrosamines
• Evaluate all pathways (including degradation) during
manufacture and storage
50
Recommendations to Drug Product Manufacturers
• Control of nitrosamines in drug products
➢ LOQ< nitrosamine level ≤AI:
▪ control strategy (specification); also necessary if risk is inherent from
API or drug product
➢ nitrosamine 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.
51
Timeline: Three-Step Implementation
• Approved/marketed drug products
1. Risk assessment
6 months from guidance publication (March 1st, 2021)
2. Confirmatory testing
Start once risk is identified; Immediately for high risk products
3. Submission of changes to FDA
Last two steps concluded within 3 years of guidance publication
(September 1st, 2023)
Determine Report
Test
Risk Changes
52
Implementation for Pending Applications
• Pending applications
➢Pre-submission:
▪ Risk assessment, confirmatory testing if at risk
▪ Changes may be submitted in amendment if not included in the
original submission
➢Pending with FDA:
▪ Risk assessment, confirmatory testing if at risk
▪ Report to FDA if nitrosamine level >AI
▪ If LOQ< nitrosamine level ≤AI, amendment with control strategy
(including specifications)
53
Summary
This guidance describes
• Potential root causes of nitrosamine impurities in APIs and
drug products
• Established AI limits
• Recommendations on the steps to take for prevention or
mitigation of this issue
• Timeline for the implementation
• Expectations in DMFs/applications at various stages
54
Harmonization
• Harmonization with other international regulators
➢Systemic approaches of three-step mitigation strategy
➢Timeline for implementation of three-step strategy
(EMA)
➢Acceptable Intake Limits
➢Analytical methods and criteria
• Benefits - APIs/drug product manufacturers and
applicants can evaluate and address risks in consistent
approaches globally
55
Acknowledgements
• Colleagues from OPQ (7 sub-offices)
• Colleagues from OND, OGD, ORA
• OPQ Nitrosamine Workgroup
• CDER Task Force Workgroup
• EMA/EDQM/OMCL
• HSA/TGA/HC
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Thank You!
