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Nitrosamines in Pharmaceuticals | USFDA Perspective

Nitrosamines are a class of chemical compounds (probable human carcinogens) that have been found to be present in certain drug products. Since FDA has been investigating the presence of nitrosamine impurities in various drug products, including angiotensin II receptor blockers, and revealed that these drugs contain unacceptable levels of nitrosamines, posing a potential risk to patients. In response to this, the FDA has provided industry guidance for Control of Nitrosamine Impurities in Human Drugs in Feb 2021.


Measures taken to address Nitrosamines in Pharmaceuticals (API and Drug product): 

I) Risk Assessment:

a) Identify potential sources of contamination and take measures to prevent their introduction. 

b) Development and implementation of analytical methods for the detection and quantification of nitrosamines. 

c) Verification of the manufacturing process should be carried out to ensure that the final product is free of nitrosamines. 

d) Educating and training employees on best practices and potential risks associated with nitrosamine contamination.

e) Compliance with the limits set by USFDA.

f) Factors such as maximum daily dose, duration of treatment, therapeutic indication, and number of patients treated should be considered for drug product.

II) Confirmatory Testing:

If a risk was identified in Risk assessment, confirmatory testing on the products should be performed and the confirmed presence of nitrosamines above the acceptable levels reported as soon as possible.

a) Analytical method with LOD and LOQ for nitrosamine impurities

b) List of Contract Laboratories for the testing of nitrosamines

c) Evaluation of suitable approaches when either a single new (unknown) nitrosamine is identified, or more than one nitrosamine is identified.

Interpretation of the results of confirmatory testing with reference to the LOQ of the method and the acceptable limit for the nitrosamine impurity.

III) Update of Marketing Authorization:

Submission of DMF amendments in accordance with 21 CFR 314.420(c) (Drug Substance).

IV) Update of Approved Application as PAS with control strategy, classification of changes involved, updated API/FP and FP manufacturing process in 21 CFR 314.70 and 314.97 and pending applications under 21 CFR 314.60 and 314.96 (Drug Product)

Please note that - If the N-nitrosamine presence is confirmed to be intrinsic to the API, e.g. is a structural feature or a metabolic formation, and/or if additional root causes for the presence of nitrosamines are reported and require further extensive assessment, DSI can assist with FDA Type B- or C-meetings.

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Resource Person: Bharathi Kodal

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