N-Nitrosamine impurities: FDA issues detection, prevention guidance

Regulatory NewsRegulatory News | 01 September 2020 |  By 

An immediately effective guidance from the US Food and Drug Administration (FDA) details steps to be taken to detect and prevent the introduction of potentially carcinogenic nitrosamine impurities into finished drug products and active pharmaceutical ingredients.
“The recent unexpected finding of nitrosamine impurities, many of which are probable or possible human carcinogens, in drugs such as angiotensin II receptor blockers, ranitidine, nizatidine, metformin, rifampin and rifapentine has made clear the need for a risk management strategy to identify and minimize nitrosamines in any pharmaceutical product at risk for their presence,” said FDA in announcing the guidance.
The nitrosamine that has been most commonly found at elevated levels in pharmaceutical products is N-nitrosodimethylamine (NDMA), which was first found in valsartan, an angiotensin II receptor blocker, in mid-2018. Elevated levels of NDMA and other nitrosamines have since been found in the drugs and drug classes mentioned by FDA both in the US and globally.  (RELATED: FDA addresses nitrosamines in TB drugs, Regulatory Focus 20 August 2020; FDA recalls some ER metformin for NDMA impurity, Regulatory Focus 29 May 2020)
“The FDA and the international scientific community do not expect NDMA to cause harm when ingested at low levels,” said FDA Commissioner Stephen M. Hahn, MD, and Patrizia Cavazzoni, MD, acting director, Center for Drug Evaluation and Research, in a press release announcing the availability of the guidance. “However, given the risk that genotoxic substances such as NDMA may increase the risk of cancer if people are exposed to them above certain levels and over long periods of time, manufacturers have recalled drugs with NDMA levels higher than the FDA's recommended acceptable intake levels.”
FDA is working with global regulatory authorities on scientific information-sharing and a coordinated inspection effort, “to develop rapid solutions to ensure the safety and quality of the drug supply,” according to the guidance. (RELATED: EMA addresses risk evaluation, mitigation for nitrosamines, Regulatory Focus 06 August 2020)
The guidance lays out the steps to be taken by drugmakers and those manufacturing active pharmaceutical ingredients (APIs) to detect and prevent “objectionable levels” of nitrosamine impurities.
Circumstances that can lead to the introduction of nitrosamine impurities are also described in the guidance, which uses “the agency’s current understanding of the chemistry” of which drugmaking practices can result in elevated nitrosamine levels in finished products.
As the pharmaceutical industry and regulators have worked to track down the source of nitrosamine impurities, amines and nitrite salts formed under acidic reaction conditions have emerged as one potential generator of nitrosamines. The guidance points to the potential roles of tertiary and quaternary amines used as reagents, as well as amide solvents that can be a source of secondary amines.
However, the guidance also points to potential nitrite and amine impurities from vendor-sourced materials, a circumstance that highlights the importance of awareness of the entire raw material supply chain. Recovering solvents, especially when a quenching step is used, can also result in nitrosamine formation. The guidance details additional circumstances where recovered solvents, catalysts and reagents may be a contamination source.
Excipients may harbor nitrite and nitrosamine impurities that may vary widely from lot to lot or increase during storage. “Drug product manufacturers should also be aware that nitrite and nitrosamine impurities may be present in potable water,” according to the guidance.
FDA specifies in the guidance the acceptable intake limits for all nitrosamine impurities which have been detected in drug products in APIs; none exceed 96 ng/day.
The guidance recommends a comprehensive risk assessment program for APIs, marketed products and products under approved and pending applications. The risk assessment should be retained by industry but need not be submitted to FDA.
When risk is detected, drugmakers should conduct confirmatory testing via methods that take into account the low levels of acceptable intake and nitrosamines’ physical and chemical properties. Any changes made should be reported to FDA, with appropriate submission of drug master file amendments or changes to approved or pending applications. Reporting recommendations and timelines are detailed in the guidance.
With knowledge in hand about manufacturing conditions that may raise the risk of introducing nitrosamine impurities, FDA also directs API manufacturers to take specific steps to reduce the use of amines and amide solvents and replacing nitrites with other quenching agents when possible. API manufacturers should also look back at their supply chain with a comprehensive audit for risk and take care to avoid cross-contamination from recovered materials.
The guidance also directs drug product manufacturers to conduct risk assessments in collaboration with API manufacturers. The guidance contains step-by-step instructions for drug manufacturers who do detect nitrosamine impurities in finished drug products. The agency should be contacted in this instance so that it can determine regulatory action; any recalls or manufacturing changes that may result in a drug supply disruption should be reported to drugshortages@fda.hhs.gov as well.
The guidance was made immediately effective as a matter of public safety, but FDA is still receiving public commentary under the provisions of 21 CFR 10.115, the agency’s good guidance practices (GGP) regulation.


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