Nitrosamine Impurities in APIs and Drug products

In Pharmaceuticals the manufacturers of APIs and Drug products have findings of nitrosamine impurities which may be likely because the human carcinogens in the drugs were of great concern. Detection of nitrosamine impurities was found in some of the commonly prescribed medicine used for treating diabetes, antacids, and others.

Nitrosamine impurities and their presence and investigation in some of the drug products have been carried out by FDA since 2018, as several drug products have been found to contain nitrosamine at unacceptable levels in drugs like ranitidine, nizatidine, and metformin.

The regulatory agencies studied the details regarding the presence of nitrosamine in some of the APIs and drug products. Some of the drugs including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and Metformin have been recalled because of nitrosamine impurities, making it clear the risk and presence of potential nitrosamine in any of the pharmaceutical products. Nitrosamine formation can take place in different ways but the manufacturers should ensure through proper drug quality checks, evaluation, and investigation if any potential risks avoid any product recall. 

Control of Nitrosamine impurities in Human Drugs

The FDA has guidance for the Industry on “Control of Nitrosamine impurities in Human Drugs”, the recommendation is about nitrosamine formation and its root cause in APIs and drug products and also for the manufacturers to conduct the risk assessment on the marketed or approved products. Also, the preventive action to reduce or prevent the formation of nitrosamine in drug products and APIs and also this guidance is applicable for APIs synthesized chemically.

FDA recently became aware of nitrosamine impurity in certain samples of Sitagliptin as Nitroso-STG-19 (known as NTTP), a medicine used to control high blood pressure in patients with type 2 diabetes mellitus. FDA continues its ongoing review, compliance, surveillance, and pharmaceutical quality efforts over every product area and will continue to work with drug manufacturers to secure safe and effective, and high-quality drugs.

What are the nitrosamine impurities of API?

Nitrosamines or more correctly N-nitrosamines refers to any molecule containing the nitroso functional group. Seven Nitrosamine impurities have been identified by FDA and may be present in drug products. Chemical structures of seven nitrosamine potential impurities in APIs and Drug products as represented below.

Further, based on the above nitrosamine impurities, FDA has given acceptable interim limits for these impurities and also recommended to the manufacturers control the nitrosamine levels by reducing or removing the impurities if it is above the temporary limit.

European Medicines Agency (EMA) continues to monitor the presence of nitrosamine impurities in medicines in cooperation with regulators from outside the European Union (EU) and to work with marketing authorization holders to find rapid solutions to address any adverse findings. EMA evaluated the risk of nitrosamine presence or formation during the manufacturing of human medicines and issued guidance to the marketing authorization holders (MAH) to avoid the presence of nitrosamine impurities.

Recently European Medicines Agency (EMA) updated the guidance and recommendation for preventing the presence of nitrosamine and also in the context of applicants/MAHs of human medicinal products to work with active pharmaceutical ingredients (APIs) and finished products (FPs) manufacturers to control the presence of nitrosamine or below the limit.

European Medicines Agency recently published on 21st December 2022 questions and answers for marketing authorization holders/applicants on the CHMP opinion for article 5(3) of Regulation (EC) no 726/2004 referral on nitrosamine impurities in human medicinal products. There are updations like what the regulatory steps taken by the authorities following the identification of an N-nitrosamine exceeding the AI, the approach to control the presence of nitrosamines until a substance-specific AI is established, the approach to control the presence of N-nitrosamine exceeding the AI during CAPA implementation.   

The manufacturing process should have a control strategy in regard to N-nitrosamines, further including the prospective and current measures to mitigate the risk of generation or contamination with nitrosamine ( like change in the manufacturing process, raw material quality change, development of methods, appropriate specifications and also to evaluate the equipment and premise like its environmental monitoring and cleaning procedure).

The API and drug product manufacturers should take the appropriate action to check the levels of nitrosamine impurities in their products. Further, the API manufacturers should design the ROS (route of synthesis) for API development in such a way as to prevent the formation of nitrosamine impurities or to minimize its formation to the given limits.

Several nitrosamine impurities have been isolated and purified by chemical synthetic method and analytical techniques and are reported in pharmacopeia and also available at Veeprho:

LIST OF NITROSAMINE IMPURITIES:


(1-Nitrosopiperidin-4-yl)diphenylmethanol)

 CAS NO: 1038-06-8
IUPAC: 1-Nitrosopiperidin-4-yl)diphenylmethanol

(Bupropion Nitroso Impurity)

 CAS NO: NA
IUPAC: N-(Tert-butyl)-N-(1-(3-chlorophenyl)-1-oxopropan-2-yl)
nitrous amide

(Irbesartan Nitroso Impurity 1)

 CAS NO: N/A
IUPAC: 2-butyl-3-((2′-(1-nitroso-1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

(Irbesartan Nitroso Spiro Impurity)

 CAS NO: N/A
IUPAC : 2-butyl-3-nitroso-1,3-diazaspiro[4.4]non-1-en-4-one

(Lansoprazole Nitroso Impurity)
 
CAS NO: N/A
IUPAC: 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)sulfinyl)-1-nitroso-1H-benzo[d]imidazole

(Nitroso Abacavir Impurity)
  
CAS NO: N/A
IUPAC: N-(2-amino-9-((1S,4R)-4-(hydroxymethyl)cyclopent-2-en-1-yl)-9H-purin-6-yl)-N-cyclopropylnitrous amide

(Nitroso Valsartan Benzyl ester)
 
CAS NO: N/A
IUPAC: benzyl 2-(((2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(nitroso)amino)-3-methylbutanoate

(N-Nitroso Olmesartan)
 
CAS NO: N/A
IUPAC: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(2-hydroxypropan
-2-yl)-1-((2′-(2-nitroso-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylate

(N-Nitroso Valsartan Impurity)
 
CAS NO: N/A
IUPAC: 2-(((2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(nitroso)amino)-3-methylbutanoic acid

(N-Nitroso Valsartan Methyl Ester Impurity)
 
CAS NO: N/A
IUPAC: (S)-methyl 2-(((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(nitroso)amino)-3-methylbutanoate

(N-Nitrosodiisopropylamine (NDIPA))
 
CAS NO: 601-77-4
IUPAC: N-(1-Methylethyl)-N-nitroso-2-propanamine

(N-nitrosoethylisopropylamine (NEIPA))
 
CAS NO: 16339-04-1
IUPAC: N-ethyl-N-isopropylnitrous amide

(Nitroso-4-Hydroxy Carbazole)
 
CAS NO: N/A
IUPAC: 9-nitroso-9H-carbazol-4-ol

(Diethylamine Nitroso Impurity)
 
CAS NO: 23834-30-2
IUPAC: N-(2-(dimethylamino)ethyl)-N-methylnitrous amide

(Diethylamine Dinitroso Impurity)
 
CAS NO:  13256-12-7
IUPAC: N,N’-(ethane-1,2-diyl)bis(N-methylnitrous amide

FAQ’s

How many nitrosamine impurities have been identified by the FDA that may be theoretically present in drug products? 

Nitrosamines or more correctly N-nitrosamines refers to any molecule containing the nitroso functional group. Seven Nitrosamine impurities have been identified by FDA and may be present in drug products as N-nitrosodiethylamine (NDEA), NDMA, N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoisopropylethyl amine (NIPEA). N-nitrosomethylphenylamine(NMPA) and N-nitrosodibutylamine (NDBA). Actually, five of them have been detected in drug products and drug substances (NMPA, NIPEA, NMBA, NDEA, and NDMA).

What are the measures to control the presence of nitrosamine?

The manufacturing process should have a control strategy in regard to N-nitrosamines, further including the prospective and current measures to mitigate the risk of generation or contamination with nitrosamine ( like change in the manufacturing process, raw material quality change, development of methods, appropriate specifications and also to evaluate the equipment and premise like its environmental monitoring and cleaning procedure).

What are the new guidelines for nitrosamine impurities?

The guidance recommends control of any known mutagenic carcinogen such as nitroso compounds at or below a level such that there would be negligible human cancer risk associated with the exposure to potentially mutagenic impurities.

What is the limit of nitrosamine in drug products?

The acceptable limit of nitrosamine impurities in drug products varies depending on the specific nitrosamine and the type of drug product. Nitrosamines are considered to be potential carcinogens, and their presence in drug products is a serious concern for patient safety.
 
In recent years, regulatory agencies such as the US FDA and the European Medicines Agency (EMA) have issued guidelines for the acceptable levels of nitrosamine impurities in drug products. For example, the FDA has set a limit of 96 ng/day for nitrosamine impurities in certain angiotensin II receptor blocker (ARB) drug products, while the EMA has set a limit of 30 ng/day for nitrosamine impurities in sartan drug products.

References:

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