FDA suggests alternative approaches for nitrosamine risk assessments

Regulatory NewsRegulatory News
| 23 November 2021 | By Joanne S. Eglovitch 

The US Food and Drug Administration (FDA) has suggested that manufacturers consider using certain antioxidants or excipients, such as sodium carbonate, to their drug products to inhibit the formation of nitrosamine impurities.
These approaches were outlined in recent update on possible mitigation strategies to reduce the risk of nitrosamine impurities in drug products. The update was prompted by reports of certain types of nitrosamine impurities that formed in “several drug products.”
FDA said that “nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs [nitrosamine drug-substance-related impurities] in certain drug products.”
The update is meant to complement FDA’s guidance in September 2020 on controlling the risk of nitrosamine in drug products. (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus 1 September 2020)
“NDSRIs can be generated during manufacturing or during the shelf-life storage period of the drug product,” according to the update, which noted that NDSRIs are similar in their structure to the active pharmaceutical ingredient (API) that they contaminate. “In some cases, the root cause of NDSRI formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts.”
One mitigation strategy outlined in the 2020 guidance calls for a supplier qualification program to assess potential impurities across excipient suppliers and excipient lots. FDA said that “this is only one strategy, and other approaches may be equally or more effective in controlling nitrosamine levels.”
“The first of these possible mitigation strategies is derived from literature reports showing that commonly used antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) inhibit the formation of nitrosamines based upon data from human gastric fluid in vitro studies,” wrote FDA in its update.
The inhibitory effect that ascorbic acid has on nitrosamine formation was noted as far back as 1976, when investigators proposed that the finished dose form of “easily and rapidly nitrosatable drugs” should include ascorbic acid.
A more recent in-press study, also cited in FDA’s nitrosamine update, examined the effectiveness of antioxidants and amino acids as inhibitors of nitrosamine formation in oral solid dosage forms (OSDs).  
Kausik K. Nanda, of Merck’s Discovery Pharmaceutical Sciences, and coauthors tested a variety of inhibitors including ascorbic acid, sodium ascorbate, a-tocopherol, caffeic acid, and ferulic acid against 4-pheylpiperidine hydrochloride (4-PPHCl), finding nitrosamine reduction of more than 80% with use of these five inhibitors. The study, wrote Nanda and coauthors, “has preliminarily demonstrated that the addition of antioxidants to formulations may significantly inhibit the formation of NDSRIs in drug products.”
The study, published online in the Journal of Pharmaceutical Sciences, also found that the amino acids glycine, lysine, and histidine effectively inhibited nitrosamine formation in solution.
The abstract says the study “demonstrates for the first time, that the inhibition of nitrosamine formation in oral solid dosage forms is indeed feasible with suitable inhibitors.”
Still another approach proposed by FDA calls for using certain excipients such as sodium carbonate to “modify the micro-environment to neutral or basic pH.” This principle, wrote the agency, “should in principle inhibit the formation of NDSRIs.”
Regardless of the approach taken, FDA said that “each manufacturer should determine the potential benefit from and demonstrate the suitability of any reformulation approach.”
If applicants are intending to reformulate their products, they may submit supplements or amendments without scheduling a meeting with FDA. The agency said that any formulation changes may be made as long as they are aligned with current good manufacturing practices.
The nitrosamine impurity issue has emerged as the center of worldwide regulatory attention since elevated levels of N-nitrosodimethylamine (NDMA) were found in APIs for certain blood pressure medicines in June 2018.
FDA update on nitrosamine risk assessments


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Tags: FDA, nitrosamines

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