SBIA 2020

FDA’s Overview ofthe Guidance for Industry:
Control of Nitrosamine Impurities inHuman Drugs
David Keire, Ph.D. and Dongmei Lu, Ph.D.
Office of Pharmaceutical Quality
CDER/U.S. FDA
October 2, 20201

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.gov3

Pharmaceutical Quality
A quality product of any kind consistently
meets the expectations of the user.

Drugs are no different.
www.fda.gov

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Patients expect safe and effective
medicine with every dose they take.

www.fda.gov

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Pharmaceutical quality is
assuring every dose is safe andeffective, free of contaminationand 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.
2.
3.
4.

Gushgari AJ, Halden RU. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere. 2018;210:1124-36.
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.
Park JE, Seo JE, Lee JY, Kwon H. Distribution of Seven N-Nitrosamines in Food. Toxicol Res. 2015;31(3):279-88.
Lim DS, Roh TH, Kim MK, Kwon YC, Choi SM, Kwack SJ, et al. Risk assessment of N-nitrosodiethylamine (NDEA) and N-nitrosodiethanolamine (NDELA) incosmetics. 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 candisplay extremely high carcinogenic potency (cohort of concern),i.e., aflatoxin-like, N-nitroso-, and alkyl-azoxy structures. If thesecompounds are found as impurities in pharmaceuticals,
acceptable intakes for these high-potency carcinogens would
likely be significantly lower than the acceptable intakes defined inthis guidance.
9

ICH M7 (2)• Other Considerations for Marketed Products: Application of thisguidance 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 andspecifications for market authorization were established.

10Timeline of US Drug Nitrosamine Issues• June 2018 – FDA informed of the presence of NDMA froma valsartan manufacturer• July 2018 – voluntary recall of valsartan due to NDMA
• Sept 2018 – NDEA detected in a previously recalledvalsartan• 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 inARBs• Feb 2019 – FDA posted interim limit for NMBA in ARBs
• March 2019 – NMBA detected in losartan– Temporary drug shortage mitigation: “FDA not objecting tolosartan with NMBA below 9.82 ppm remaining on themarket.”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 andDMF holders posted to FDA.gov• Root causes for nitrosamines in ARBs discussed• Sept 2019 – ranitidine recalled due to NDMA

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Timeline of US Drug Nitrosamine Issues (4)• Dec 2019 – NDMA detected in some metformin
products but recalls not warranted as the amounts werebelow AI• Dec 2019 – 1-methy-4-nitrosopiperazine (MNP) reportedin rifampin• Jan 2020 – nizatidine recalled due to NDMA
• April 2020 – FDA requested withdrawal of all ranitidinefrom the U.S. market
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Timeline of US Drug Nitrosamine Issues (5)• May 2020 – metformin extended-release recalled dueto NDMA
• May 2020 – 1-cyclopentyl-4-nitrosopiperazine (CPNP)
reported in rifapentine• Numerous information requests to industry from
FDA and responses from industry throughout thisentire time period
15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.gov16

Outcome:
Over the past 2 years, industry andregulators have learned a lot about
what factors lead to the risk ofnitrosamine impurities inpharmaceuticals
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Root Causes of Nitrosamine Contamination▪ Physicochemical
properties of thestarting materials,
intermediates orDrug Substance▪ Specific process
conditions▪ Impurities in orreactions with raw
materials➢ Development andControl Strategies

SupplyChainProcess
RelatedNitrosaminesin the Drug
Substance
and/or Drug
Product▪ Stability: Drug Substance or Drug
Product▪ Excipient compatibility➢Quality Oversight - 18 18

Stability▪ Use of recovered or
recycled materials orother intermediates
contaminated withnitrosamines▪ Cross-contaminationin multi-purpose
facilities➢ Quality OversightPotential Nitrosamine Impurities Generated
During the Synthesis of ARB Drug Substances
Br DMF

TEA

DIPEA

TBAB

NMP+NDMA

NDEA

NEIPA

NDIPA

NMBA

NDBA

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Nitrosamine Risk Assessment• Assess stages of API or Drug Product manufacturing– Are there API or formulation steps that have thepotential to have reactive amines in the presence ofnitroso compounds?
– Are there reagents (e.g., catalysts, solvents) that may
have components that could form nitroso-compounds inside reactions?
– What about intermediates or reagents sourced fromsuppliers?
• Is there nitrosamine risk?

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If nitrosamine risk is present• Is the nitroso-compound a known mutagen as per ICH M7?
• Determine a drug-specific acceptable intake (AI) basedon 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 themanufacturing process.
– Conduct an assessment of the nitrosamine formation andpurge capacity of the synthetic route.
21Stability• Is the nitrosamine content stable over time in theAPI?
• 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 thatpatients can switch to?
• Ongoing communications with patients, healthcare providers, media,industry and international regulators• Rapid development of validated laboratory testing methods
www.fda.gov

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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 andconfirmatory) 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 primarymeasurement.
– 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• Ranitidine – 2 methods– NDMA• Metformin – 2 methods– NDMAAny method should be validated
by the user if the resulting data
are used to support a required
quality assessment of the API ordrug product, or if the results areused in a regulatory submission.

• Rifampin and Rifapentine – 1 shared method– MNP, CPNP

• USP Chapter <1469> Nitrosamine Impurities went to PF (link below). Fourmethods 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

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Suitable Analytical Measurements on Trace
Amounts (ppm to ppb) of Nitrosamines• Key to detection of nitrosamines in each drug is the applicationof appropriate measurement technology focused on detecting
amounts of nitrosamines in solvents, intermediates, APIs andacross finished dosage forms.
– LOQs should be appropriately below AI amounts (Guidance!)• Many analytical procedures developed by regulatory labs havebeen made publicly available to speed the risk-based screeningof manufacturing processes for nitrosamines (FDA.gov).
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1. FDA/CDER. FDA Updates and Press Announcements on NDMA inMetformin FDA.gov2020 [Available from:https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-andpress-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-andavailability/fda-updates-and-press-announcements-angiotensin-iireceptor-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-safetyand-availability/fda-updates-and-press-announcements-ndma-zantacranitidine.
4. CDER/FDA. Laboratory Tests | Metformin 2020 [Available from:https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-testsmetformin.

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FDA Expectations of Industry“Manufacturers are responsible for understanding theirprocesses, which includes preventing the presence ofunacceptable 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 makechanges to their manufacturing processes.”
https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamineimpurities-medications
What industry should know about nitrosamine impurities.
www.fda.gov

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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 makeevery 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 sothat patients can continue taking their medicines withoutconcern.”

www.fda.gov

https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamineimpurities-medications
Can we trust FDA and its approvals and drug surveillance?

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FDA GuidanceControl 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 GuidanceControl 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, 202031

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-guidancedocuments/control-nitrosamine-impurities-human-drugs
32Outline• Background• Root Causes of Nitrosamines• FDA Recommendations to Manufacturers• Reporting Changes to FDA

www.fda.gov

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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)

www.fda.gov

ICH M7 (R1) Guidance: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To
Limit Potential Carcinogenic Risk (March 2018)https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

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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

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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-valsartanlosartan-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-metforminwww.fda.gov

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Industry Needs• Urgent Need: for API and drug productmanufacturers➢Assess potential nitrosamines in any pharmaceuticalproduct at risk for their presence➢Develop a prevention strategy

www.fda.gov

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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

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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
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Root Causes of Nitrosamine Impurities in APIs
and Drug Products▪ Physicochemical
properties of thestarting materials,intermediates or
Drug Substance▪ Specific process
conditions▪ Impurities in orreactions with raw
materials➢ Development andControl Strategies

SupplyChainProcess
RelatedNitrosaminesin the Drug
Substance
and/or DrugProduct▪ Stability of the Drug Substance or DrugProduct▪ Excipient compatibility- 40 ➢Quality Oversight
40Stability▪ Use of recovered or
recycled materials orother intermediates
contaminated withnitrosamines▪ Cross-contaminationin multi-purpose
facilities➢ Quality OversightGuidance Recommendations

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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 ofexposure.
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)).
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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
1. Risk Assessment• APIs, marketed products, andproducts under approved/ pending
applications.
• Conduct in a timely manner basedon the prioritization of drugs:➢ MDD➢ treatment duration➢ therapeutic indication➢ number of patients treated• FDA may recommend certain drug
products as higher priority based onunderstanding• If no risk, no further action.
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Three Steps for Mitigation Strategy
1. Risk Assessment

2. Confirmatory Testing(if any risk)

Analytical methods need to havespecificity, excellent
chromatographic separation, andhighly sensitive detection capability.

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Three Steps for Mitigation Strategy
1. Risk Assessment

2. Confirmatory Testing(if any risk)

3. Reporting Changes

Report changes implemented to preventor reduce nitrosamines. This includes
DMF amendments and changes toapproved/pending applications.

All risk assessment reports stay at manufacture site, available upon request

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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-contamination48

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

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Recommendations to Drug Product Manufacturers• Collaborate with API manufacturers➢If risk is detected, continuously test API lots until
verified to be without unacceptable levels ofnitrosamines• Evaluate all pathways (including degradation) during
manufacture and storage

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Recommendations to Drug Product Manufacturers• Control of nitrosamines in drug products➢ LOQ< nitrosamine level ≤AI:
▪ control strategy (specification); also necessary if risk is inherent fromAPI 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 toprevent/mitigate drug shortages.

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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)
DetermineRisk

Test

ReportChanges
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 theoriginal 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

SummaryThis guidance describes• Potential root causes of nitrosamine impurities in APIs anddrug 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
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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 andapplicants can evaluate and address risks in consistent
approaches globally55

Acknowledgements• Colleagues from OPQ (7 sub-offices)• Colleagues from OND, OGD, ORA• OPQ Nitrosamine Workgroup• CDER Task Force Workgroup• EMA/EDQM/OMCL• HSA/TGA/HC56

Thank You!