In February 2021, the FDA released a guidance document “Control of Nitrosamine Impurities in Human Drugs” with a stated goal of emphasizing the importance of reducing and mitigating nitrosamine impurities in APIs and drug products. The guidance discusses nitrosamine formation and the “vulnerable” processes and materials that may produce nitrosamine impurities. This guidance applies to all chemically synthesized APIs and drug products containing chemically synthesized APIs.
Why release this guidance with such urgency?
The timeliness of the document comes after recent and somewhat startling findings of these carcinogenic compounds in a number of drugs. In June 2018, the FDA brought attention to the presence of N-nitrosodimethylamine (NDMA) in valsartan and subsequently a handful of other similar blood pressure medications from several manufacturers. In 2019, batches of heartburn medications such as ranitidine and batches of metformin diabetes medication were also recalled due to unacceptable levels of NDMA.
What are nitrosamines?
Nitrosamines are compounds with a nitroso group and amine bonded together [denoted (R1N(-R2)-N=O)]. They form as a reaction between amines and nitrous acid (nitrite salts in acidic conditions). In general, any process that uses nitrites in the presence of secondary, tertiary, or quaternary amines is at risk of generating nitrosamine impurities. These amines may even be degradation or impurity products of amide solvents such as N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, or N,N-diethylacetamide.
There are seven nitrosamine impurities that the FDA has identified as theoretically present in drug products.
Figure 1. Nitrosamines
Nitrosamine compounds are potently genotoxic and are probable human carcinogens. The ICH refers to these compounds as “cohorts of concern”. The FDA has established acceptable intake limits for six of the compounds.
Table 1. FDA Limits for NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA in Drug Products
| Nitrosamine | Acceptable Intake Limits (ng/day) |
|---|---|
| N-Nitrosodimethylamine (NDMA) | 96 |
| N-Nitrosodiethylamine (NDEA) | 26.5 |
| N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) | 96 |
| N-Nitrosomethylphenylamine (NMPA) | 26.5 |
| N-Nitrosoisopropylethylamine (NIPEA) | 26.5 |
| N-Nitrosodiisopropylamine (NDIPA) | 26.5 |
| Total nitrosamine quantity | 26.5 |
With these limits, methods requiring limits of quantitation (LOQs) in the parts-per-billion (ppb) range are necessary, specifically targeting LOQs at or below 0.03 ppm.
Testing for Nitrosamines
The majority of APIs are low risk for nitrosamine formation and, with a proper risk assessment documented, may not need confirmatory batch testing. This FDA guidance contains specific guidelines for these risk assessments and recommendations for designing manufacturing processes to minimize or prevent the formation of nitrosamine impurities. While the recommended competition date for risk assessments was March 31, 2021, for any product where a nitrosamine risk was identified the confirmatory testing should be completed on or before October 1, 2023.
Impurities Testing at EKG Labs
EKG Labs provides impurity testing services to the pharmaceutical and medical device industries. We can perform impurity identification in accordance with FDA and ICH guidelines for impurities. Using our state-of-the-art instrumentation, EKG Labs has the experience to isolate, analyze, and identify impurities. We have experience demonstrating precise recovery even in most challenging matrices and can extract your unique sample as necessary. EKG Labs can also develop and validate a risk-based, product-specific method in order to monitor one or more targeted compounds. At EKG Labs we work with you to provide a customized solution to your impurity identification and analysis needs.
If you are experiencing a challenge with impurities, nitrosamines or otherwise, or need analytical services to support your product development, please contact us at info@ekglabs.com, at 810-354-5229, or via our website.
About EKG Labs
EKG Labs is an analytical service provider for the pharmaceutical and medical device industries. Our wide variety of analytical services support product development, regulatory filings, and analytical chemistry investigations. Specialty analytical services include: extractables, leachables, chemical characterization, impurity identification, method development, method validation, and other investigational activities.
