Nitrosamine Impurities in APIs and Drug products

The pharmaceutical manufacturers of APIs and the drug product have findings of nitrosamine impurities which may be likely because the human carcinogens in the drugs were of great concern. The detection of nitrosamine impurities was found in some of the commonly prescribed medicine used for the treatment of diabetes, antacids, and others. Some of the drugs including angiotensin II receptor blockers (ARBs), Ranitidine, Nizatidine, and  Metformin have been recalled because of nitrosamine impurities and this made it clear the risk and presence of potential nitrosamine in any of the pharmaceutical products. Nitrosamine formation can occur in different ways but the manufacturers should ensure through proper drug quality checks, and evaluations, and investigate any potential risks to avoid any product recall. 

Nitrosamine impurity’s presence and investigation in some of the drug products is carried out by FDA since 2018, as several drug products have been found to contain nitrosamine at unacceptable levels like ranitidine, nizatidine, and metformin. The regulatory agencies studied the details regarding the presence of nitrosamine in some of the APIs and drug products. The FDA has the guidance for the Industry on “Control of Nitrosamine impurities in Human Drugs”, the guidance is about the nitrosamine formation and its root cause in APIs and drug product and also for the manufacturers to conduct the risk assessment on the marketed or approved products and also the preventive action to reduce or prevent the formation of nitrosamine in drug products and APIs, also this guidance is applicable for the APIs synthesized chemically.

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

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

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 interim limit. 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.    

What are the measures to control the presence of nitrosamine?

The manufacturing process should have the control strategy in regard to N-nitrosamines, and further include 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, and appropriate specifications and also to evaluate the equipment and premises like its environmental monitoring and cleaning procedure). Marketing Authorization holder MAHs also should control the levels of nitrosamine in line with the limits as defined in Q10 and also may impact the risk of any future changes like as example change of packing, change of supplier, and change in the manufacturing process, also the MAH should ensure that the excipients and the active substances which are used in their FPs manufactured in good manufacturing practice and as per the compliance. Further N-nitrosamine presence in the FP should be lesser as much as possible or the limit as defined in the Q10.          

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.

The recommended guidance for API manufacturers is ICH Q7 Good manufacturing practice guidance for active pharmaceutical ingredients and Q11 development and manufacture of the drug substances. 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 labs:

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

The pharmaceutical manufacturers of APIs and the drug product have recent findings of nitrosamine impurities which may be likely because the human carcinogens in the drugs were of great concern. The detection of nitrosamine impurities was found in some of the commonly prescribed medicine used for the treatment of diabetes, antacids, and others.

Nitrosamine formation can occur in different ways but the manufacturers should ensure through proper drug quality checks, and evaluations, and investigate any potential risks to avoid any product recall. FDA, EMA, TGA, and Health Canada regulatory authorities published several notices to guide the manufacturer to control and limit nitrosamine impurities to acceptable levels. The authorities have also issued guidance for marketing authorities to assess the Nitrosamine impurities in human medicinal products.

References:

  • Control of Nitrosamine Impurities in Human Drugs Guidance for Industry. | www.fda.gov/media/141720/download.