This document discusses nitrosamine impurities in human drugs. It begins by classifying impurities into organic, inorganic, and residual solvent categories. It then provides background on nitrosamines, explaining that they are probable carcinogens that can form during manufacturing through nitrosation reactions between amines and nitrous acid. The document identifies seven common nitrosamine impurities and discusses acceptable intake limits. It provides guidance for manufacturers on controlling nitrosamine impurities, including risk assessment, testing, validation methods, and specification limits.

1. NITROSAMINE IMPURITIES
IN HUMAN DRUGS
U.S. Department of Health and Human Services
Food and Drug Administration (FDA)
Center for Drug Evaluation & Research(CDER)
MD TUHIN REZA
SENIOR DEPUTY MANAGER, R&DA
RENATA LIMITED

2. Impurities can be classified into 3 categories
❑Organic impurities (process and drug-related)
Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be
identified or unidentified, volatile or non-volatile. Nitrosamines are organic impurity.
❑Inorganic impurities
Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:
Reagents, ligands and catalysts, Heavy metals or other residual metals, Inorganic salts & other materials
❑Residual solvents
Overview of Drug Impurities

3. Background of Nitrosamines in Drugs
❑ In 1956, two British scientist proved Nitrosamines are carcinogenic.
❑ Ingesting high levels of NDMA may lead to stomach and colorectal cancer. Animals that ate NDMA
developed liver, lung, kidney, and testicular cancers.
❑ In 2018, several drug products including ARBs (angiotensin II receptor blockers), Ranitidine,
Nizatidine, and Metformin have been found to contain unacceptable levels of nitrosamines(NDMA).
❑ In September 2019, FDA learned that some common heartburn product (Ranitidine) contained
unacceptable levels of NDMA.
❑ On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.
❑ Manufacturers should prioritize evaluation of APIs and drug products based on factors such as
maximum daily dose, duration of treatment, therapeutic indication, and number of patients treated.

4. What is Nitrosamines ?
The term
Nitrosamine
describes a class of
compounds having
the chemical
structure of a
nitroso group
bonded to an
amine .

5. The compounds can form by a nitrosating reaction between amines (secondary, tertiary,
or quaternary amines) and nitrous acid (nitrite salts under acidic conditions).
These nitrosamines are probable or possible human carcinogens.
How are Nitrosamines formed ?

6. FDA has identified seven nitrosamine impurities that theoretically could be
present in drug products. Five of them have actually been detected in drug
substances or drug products.
1. N-nitrosodimethykamine (NDMA)
2. N-nitrosodiethylamine (NDEA)
3. N-nitroso-N-methyl-4-aminobutanoic acid (NMBA)
4. N-nitrosoisopropylethyl amine (NIPEA)
5. N-nitrosodiisopropylamine (NDIPA)
6. Nnitrosodibutylamine (NDBA) and
7. N-nitrosomethylphenylamine (NMPA)
NAME OF NITROSAMINE IMPURITIES

7. Structure of Nitrosamines

8. General Root Causes for the Presence of NI in APIs & Drug Products
APIs
❑General Conditions That Lead to Nitrosamine Formation
❑Sources of Secondary, Tertiary, and Quaternary Amines That Can Form Nitrosamines
❑Contamination in Vendor-Sourced Raw Materials
❑Recovered Solvents, Catalysts, and Reagents as Sources of Contamination
❑Quenching Process as a Source of Nitrosamine Contamination
❑Lack of Process Optimization and Control
Drug Products
❑Nitrites are common nitrosating impurities that have been reported in many excipients at
ppm levels.
❑Nitrosamine impurities (NI) may be present in potable water.
❑Some drug products may undergo degradation pathways that form nitrosamine impurities;
this could potentially occur during drug product storage.

9. ❑Approximates a 1:100,000 cancer risk after 70 years of exposure.
❑These limits are applicable only if a drug product contains a single
nitrosamine.
Acceptable Intake Limit per Day

10. Calculation of Nitrosamine & Co-relation with ppm/ppb
Where AI= Acceptable Intake & MDD=Maximum Daily Doses
Example of NDEA for any drug product where AI=26.5 ng
& MDD= 880 mg/day
PPM=AI/MDD
=26.5/880
=0.03
PPM (ng/mg) =
AI per day (ng)
MDD (mg)
PPB (ng/gm) =
AI per day (ng)
MDD (gm)

11. A recommended limit
for total nitrosamines
of 0.03 ppm is not
more than 26.5
ng/day .
For drug products with an
MDD of less than 880 mg/day
For drug products with an
MDD of above 880 mg/day
The limit for total
nitrosamines should
be adjusted so as not
to exceed the
recommended limit of
26.5 ng/day
.
MDD & Limit

12. If more than one of the nitrosamine impurities is detected

13. If more than one is detected
and the total quantity of
nitrosamine impurities
exceeds 26.5 ng/day based on
the MDD, the manufacturer
should contact the Agency for
evaluation.
If more than one of the
nitrosamine impurities is
detected

14. If there is no AI limit

15. Contact with
agency
CDER-OPQ-Inquiries@fda.hhs.gov
If there is no AI limit
If nitrosamines without published AI limits are found
in drug products, manufacturers should use the
approach outlined in ICH M7(R1) &

16. LOD, LOQ & Validation
❑ As sensitive methods with LOQ in the parts-per-billion (ppb) range are needed to meet the low AI.
❑ Manufacturers of APIs and drug products should use methods with LOQs at or below 0.03 ppm.
❑ If more than one nitrosamine is detected, then the analytical method should be validated for LOQs
below 0.03 ppm.
❑ Manufacturers should establish methods for which the LOQ and LOD are as low as reasonably
practical for products for which the MDD is high (e.g., greater than 1 g). For example, if the MDD
is 1200 mg, the LOQ should be below 0.02 ppm.
FDA-recommended analytical methods for detecting nitrosamine impurities can be found at
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-
zantacranitidine, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-
announcements-ndmametformin, and in the 12/12/2018 update at
https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm

17. Control of Nitrosamine Impurities in APIs
❑ Manufacturers should develop an appropriate control strategy, which should include
specification limits, to ensure that the nitrosamine level reliably remains well below the AI
limit in the API.
❑ If a nitrosamine impurity is detected above the LOQ, the API manufacturer should develop a
strategy to ensure that the nitrosamine level remains within the AI limit.
❑ Given existing uncertainties regarding nitrosamine impurities and their presence in drugs, for
APIs with an impurity detected above the LOQ or at-risk APIs, testing of each batch on
release should be conducted.
❑ Any API batch found to contain levels of nitrosamine impurities above the recommended AI
should not be released by the API manufacturer for distribution unless, with prior FDA
agreement.

18. ❑Drug product manufacturers should conduct risk assessment collaborating with API
manufacturer to determine the potential nitrosamine impurities in drug products .
❑Excipients assessments.
❑The risk assessment should also include evaluation of any pathway (including
degradation) that may introduce nitrosamines during drug product manufacture or
storage.
❑If the risk assessment determines that there is no potential for nitrosamine impurities,
there is no need to take further action.
Continue….
Control of Nitrosamine Impurities in Drug Products

19. ❑ If a risk of nitrosamines in a drug product is identified, confirmatory testing of batches
should be conducted using sensitive and appropriately validated method.
❑ If a nitrosamine impurity is detected, manufacturers should investigate the root cause
and implement changes in the manufacturing process to mitigate or reduce nitrosamine
impurities
❑ If a nitrosamine impurity is detected above the LOQ, the manufacturer should develop
a strategy to ensure that the nitrosamine level remains within the AI limit.®
❑ The control strategy should include specification limits for the identified nitrosamine.

20. ❑ This guidance has been prepared by the Office of Pharmaceutical Quality (OPQ) in the Center for
Drug Evaluation and Research (CDER) at the Food and Drug Administration. You may submit
comments on this guidance at any time. Submit comments to Docket No. FDA-2020-D-1530
(available at https:/regulations.gov/docket/FDA-2020-D-1530)
FDA has been collaborating with
❑ European Medicines Agency (EMA),
❑ European Directorate for the Quality of Medicines and Healthcare (EDQM),
❑ Health Canada (HC),
❑ Therapeutic Goods Administration (TGA, Australia),
❑ Pharmaceuticals and Medical Devices Agency (PMDA, Japan),
❑ Health Sciences Authority, Singapore (HSA, Singapore), and
❑ Swissmedic (Switzerland).
Collaboration

21. THANK YOU