Dr.

Vishwanath Karad MITWPU School of Pharmacy

NAME ; POORNIMA JADHAV

ROLL NO: ; 07
SPECIALIZATION ; M.PHARMACY IN QUALITY ASSURANCE
SUPERVISED BY : Dr. SWATI JAGDALE

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 NITROSAMINE
IMPURITIES
IN
PHARMACEUTICAL
INDUSTRY.
Content
• Abstract
• Introduction
• Health risk
• Drugs containing nitrosamine impurity
• Root causes of nitrosamine impurity
• Drug recall process
• Case study
• Regulatory guidelines
• Analytical technique
• Regulatory approach
• Future outlook
• Bibliography
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ABSTRACT:
• Nitrofurans When more than one nitrosamine impurity is found, the overall amount of
impurities surpasses 26.5 ng/day, which is the maximum daily dosage (MDD) that is considered
safe for the most potent nitrosamines. When determining the carcinogenic risk to people,
pharmaceutical product management of possibly mutagenic contaminants is crucial. Interest in
nitrosamine impurities' potential to cause cancer and mutagenesis has surged when they were
shown to be present in several commercially available medicinal products. The chemical class
that is regarded as belonging to a "cohort of concern" means that certain basic control
procedures, including using the threshold of toxicological concern (TTC), cannot be used. Drugs
like ranitidine and nizatidine are Spartans. These impurities developed in drug products as a
result of the utilization of raw materials, catalysts, and solvents in the production process. The
press has been released by the various regulatory
• Keywords : AI , food and drug administration

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 INTRODUCTION
• Class of chemical substances known to cause cancer is
called nitrosamines. Pharmaceuticals are one of the many
goods that include them. The industry and regulatory bodies
are quite concerned about the occurrence of nitrosamines in
medications.

• Nitrosamine is categorized as a class 1 impurity in ICH M7

[R1].

• These contaminants may result from the use of reagents,

catalysts, solvents, or raw materials during manufacture..
 Why are they considered carcinogenic ?

potential Health Risks

Nitrosamines are known to be carcinogenic and have been linked to an increased risk
of certain types of cancer, such as bladder cancer and colorectal cancer. As such, it is
important for pharmaceutical companies to take steps to minimize nitrosamine
formation in their products.

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Drugs containing nitrosamine impurity

Rifampicin Ranitidine Sartans Metformin

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ROOT CAUSES
OF
NITROSAMINE
IMPURITIES .
 PROCESS SUPPLY
• Properties of the • Use of recovered or
RELATED CHAIN
starting materials, recycled materials or
intermediates or other intermediates
drug substance contaminated with
• Specific process nitrosamines
conditions ▪ Cross-contamination
• Impurities in or NITROSAMINE in multi-purpose
reactions with IN DRUG facilities
raw materials
SUBSTANCE.

• Stability of drug substance or drug

STABILITY product
▪ Excipient compatibility
Drug recall process:

Potentially carcinogenic
API
/PRODUCT
MANUFACTU
RING
PROCESS
Detection of Product
Drug NITROSAMINE Nitrosamine RECALL from
R-N(-R)-N=O
product impurities The market

DEGRADATION
DURING
STORAGE
E.g. NDMA ,NDEA,
NMBA
FDA RECALL:
April 27, 2020
July 5, 2018
METGLUCO Tablets 250 mg, 500 mg
VALSARTAN Tablets 20 mg, 40 mg, 80 mg,
METFORMIN HYDROCHLORIDE Tablets 500
160 mg “AA” mg MT “JG
- Containing valsartan API manufactured by - NDMA levels above the recommended AI limit
Zhejiang Huahai Pharmaceuticals Co., Ltd.

September 16, 2020

METFORMIN HYDROCHLORIDE Tablets 500 mg

February 7, 2019
MT
“NICHIIKO”
AMVALO Combination Tablets “Pfizer” - NDMA levels above the recommended AI limit
NDEA levels above the recommended AI limit
and the detection of NDMA
April 26, 2021

METFORMIN HYDROCHLORIDE Tablets 500 mg MT

September 26, 2019
“JG”
RANITIDINE Tablets 75 mg, 150 mg (9 companies) - NDMA levels above the recommended AI limit or
RANITIDINE Injection 50 mg, 100 mg (3 possibility of the presence of NDMA
companies
The detection or possibility of the presence of
NDMA
Regulatory approach [risk and control]
Risk Assessment
• Risk assessment is a
crucial step in identifying
and mitigating the
potential risk of
nitrosamine
contamination in
pharmaceutical products.
Quality Control
Mitigation Strategies
Measures
• common mitigation • Effective quality control
strategies include measures are necessary to
reducing the use of ensure that nitrosamine
nitrosamine-containing: contamination is detected
• raw materials and addressed in a timely
• implementing robust manner.
analytical methods for • This may include regular
detection and testing of raw materials
quantification of and finished products, as
nitrosamines. well as monitoring of
• regular testing of raw manufacturing processes
materials and finished and equipment.
products to detect the
presence of nitrosamines.
Regulatory Guidelines:
FDA Guidelines: AI LIMIT IN DRUG PRODUCT : Fig :1

NITROSAMINE AI Limit (ng/day)1

The FDA has set limits for
nitrosamine impurities in
pharmaceuticals, including a
limit of 96 ng/day for ranitidine
and 0.03 ppm for N-nitroso NDMA 96
dimethylamine (NDMA) in
NDEA 26.5
sartan drug products.
NMBA 96
NMPA 26.5
NDIPA 26.5
EMA Guidelines :

The EMA has also issued abbreviation :

guidelines for nitrosamine NDMA :N-Nitrosodimethylamin
impurities in NDEA : N-Nitrosodimethylamin
pharmaceuticals, including a NMBA : N-Nitrosomethylethylamine
NMPA : N- Nitroso-di-n-propyl amine
limit of 30 ng/day for
NDIPA : N-Nitrosoethylisppropylamine
ranitidine and 0.18 ppm for
NDMA in sartan drug
products.
Analytical Techniques for Nitrosamine Detection
Source :

• High Performance Liquid • Gas Chromatography- • HPTLC-Tandem mass

Chromatography (HPLC) Mass Spectrometry (GC- spectrometry
MS)
 Future Outlook
• Increased Regulatory Scrutiny
• Advanced Analytical Techniques
• Emerging Nitrosamine Contaminants
• Improved Risk Assessment and Mitigation Strategies
 CONCLUSION
• Nitrosamine pollution causes cancer. So, the amount of pollution that needs has a
limit. In order to be regulated by other means, the European Medical Agency and
the Food and Drug Administration are also taking aggressive action against these
toxins.

• These pollutants are produced when catalyst sources, solvents, and raw materials
react with nitrosating agents. Avoid using catalysts and solvents.

• First, there is nitrosamine contamination in the Sartan medication.

• There are restrictions on the acceptance of nitrosamine contamination in the daily

diet.

• Technologies including gas chromatography, mass spectrometry, and liquid

chromatography are used to find nitrosamine contamination.

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Bibliography
1. Shaikh T, Gosar A, Sayyed H. Nitrosamine impurities in drug substances and drug products.
Journal of Advances in Pharmacy Practices [Internet]. 2020 Jan 1; Available from:
https://www.academia.edu/41962442/Nitrosamine_Impurities_in_Drug_Substances_and_Dr
ug_Products
2. Control of Nitrosamine Impurities in Human Drugs, Food and Drug Administration
https://www.fda.gov/media/141720/download#:~:text=Because%20nitrosamines%20are%20pr
obable%20or,their%20APIs%20and%20drug%20products
.
3. Dattatraya JP, Arun SN, Deshmukh VK, Ghawate VG, Pund AR. A review on nitrosamine
impurities present in drugs. Pharm. Reson.. 2022;4(2):44-8.
4. ICH M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals
to Limit Potential Carcinogenic Risk. (2017). International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use
https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf {access on 18 oct ‘2023)

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