FDA Releases Guidance on the Agency’s Understanding of Nitrosamine Impurities
On September 1, 2020, the U.S. Food and Drug Administration (“FDA”) released a new guidance document, Guidance for Industry: Control of Nitrosamine Impurities in Human Drugs,[i] following a series of recalls of several prescription and over-the-counter drugs due to nitrosamine contamination.[ii] The guidance is written broadly and applies to all drugs with chemically synthesized active pharmaceutical ingredients (“APIs”) and chemically synthesized APIs. In the guidance, FDA discusses possible root causes of the presence of nitrosamines in drugs and provides recommendations for manufacturers of drug products and APIs.
FDA considers many nitrosamines to be either “probable” or “possible” human carcinogens.[iii] The Agency has established acceptable intake limits for different nitrosamines based on a theoretical conservative estimate of a 1:100,000 cancer risk after 70 years of daily exposure. According to the FDA, “a person taking a drug that contains nitrosamines at-or-below the acceptable daily intake limits every day for 70 years is not expected to have an increased risk of cancer.”[iv] Apart from the acceptable limits, the guidance recommends manufacturers implement measures to reduce nitrosamine contamination in their products when possible.
Possible Root Causes of Nitrosamine Contamination
FDA has identified seven nitrosamine impurities that theoretically could be present in drug products: nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA). Five of these impurities have actually been detected in drug substances or drug products.
The guidance outlines several possible root causes for the formation of nitrosamines in drug products, including: (1) chemicals introduced during the manufacturing process; (2) contamination during production or transport of raw materials; (3) reuse of solvents, catalysts, and reagents; (4) addition of nitrous acid; (5) lack of process optimization and control; and (6) possible degradation of the products. FDA recommends that manufacturers consider these potential causes of nitrosamine formation and evaluate the risk for nitrosamine contamination in their APIs and drug products.
Recommendations for Assessing Risk of Nitrosamines
Drug product and API manufacturers should assess the risk that their products contain nitrosamines. FDA recommends that drug product manufacturers:
- Prioritize their products to be evaluated for nitrosamines based on an assessment of various factors, including maximum daily dose, duration of treatment, therapeutic indication, and numbers of patients treated;
- Refer to ICH Guidance Q9 Quality Risk Management from 2006[v] for more information on how to implement risk assessments;
- Work with their API manufacturer to identify at-risk conditions for nitrosamines; and
- Include an “evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage” within the risk assessment.
If risk assessments do not identify any potential for nitrosamine impurities, there is no need to take further action. The FDA is not currently requiring manufacturers to submit these risk assessments to the Agency, but it reserves the right to request them at a later time.
Recommendations for Testing and mitigating Nitrosamines
FDA recommends conducting confirmatory testing when there is “any risk” for the presence of nitrosamine impurities. The guidance states that testing must have “specificity, excellent chromatographic separation, and highly sensitive detection capability.” Testing may be conducted by the API manufacturer or by a qualified laboratory.
FDA lists a series of recommendations that API and drug manufacturers should consider in order to mitigate the risk of nitrosamine contamination of their products. These recommendations include audits of suppliers, performance of chemical analyses, as well as adoption of manufacturing processes that minimize the likelihood of nitrosamine formation. Manufacturers should also test representative samples of all incoming components and evaluate whether nitrosamines could form during product formulation or during the product’s shelf-life.
If a nitrosamine impurity is detected, FDA recommends testing each batch on release and developing a control strategy with specification limits. FDA notes that alternative testing approaches may be appropriate but should be supported by evidence and submitted to FDA in a supplement prior to implementation.
FDA provides acceptable intake limits for specific nitrosamines but clarifies that these limits only apply if a drug product contains a single nitrosamine. If a product contains multiple nitrosamines, the manufacturer should consult the FDA.
Recommendations for APIs and Drugs with Nitrosamines ABOVE RECOMMENDED LIMITS
FDA advises that APIs with nitrosamine impurities at or above recommended levels should not be distributed unless prior FDA approval is obtained to help prevent or mitigate a shortage of a drug. In addition, FDA provides that batches of drug product with nitrosamine impurities at or above recommended levels should not be released. However, FDA advises manufacturers to contact the Agency to see if FDA can help mitigate the risk of nitrosamine impurities while avoiding an interruption in the drug supply.
how we can help
King and Spalding represents a major pharmaceutical company in litigation relating to alleged nitrosamine contamination of pharmaceutical products and is at the forefront of the scientific and regulatory developments relating to nitrosamine impurities in pharmaceuticals. We expect the newly-issued FDA Guidance to draw even more attention to the issue of nitrosamine contamination and create additional litigation risk. Our FDA and Life Sciences team can provide detailed risk-mitigation and best-practices assessments in light of the FDA Guidance, as well as the regulatory history and scientific evidence relating to nitrosamine impurities in pharmaceutical products. Additionally, our Pharmaceutical & Medical Device litigation practice combines our industry knowledge with a deep bench of first-chair trial attorneys, allowing us to handle any aspect of litigation related to nitrosamine contamination.
[i] U.S. Food & Drug Admin., Control of Nitrosamine Impurities in Human Drugs (Sept. 2020), https://www.fda.gov/media/141720/download.
[ii] As of the date of this alert, recalls have been issued with respect to angiotensin II receptor blockers (ARBs), ranitidine, nizatidine, and some metformin drug products.
[iii] See U.S. Food & Drug Admin., M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk (Mar. 2020), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential.
[iv] U.S. Food & Drug Admin., Information about Nitrosamine Impurities in Medications (Sept. 1, 2020), available at https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications#:~:text=Nitrosamine%20impurities%20may%20increase%20the,an%20increased%20risk%20of%20cancer.
[v] ICH Guidance Q9 Quality Risk Management offers a systematic approach to quality risk management of drug products through the product’s lifecycle. U.S. Food & Drug Admin., Q9 Quality Risk Management (June 2006), https://www.fda.gov/media/71543/download.