Nitrosamine Drug Substance-related Impurities: FDA Recommendations for Minimising Risks through Formulation Design Changes

Analogous to the procedure in Europe, manufacturers of APIs and medicinal products authorised in the USA must demonstrate that their products comply with the requirements for nitrosamine impurities in a three-step process. The FDA Guidance for Industry Control of Nitrosamine Impurities in Human Drugs provides detailed instructions on this:

1. Risk assessments for APIs and authorised medicinal products or medicinal products in the authorisation procedure. The risk assessments are to be prioritised in time; they do not have to be submitted to the authority, but must be provided upon request. The deadline for completion of the risk assessments was 31 March 2021.

2. Confirmatory testing after a risk has been identified by the medicinal product manufacturer, the API manufacturer or by a qualified contract laboratory. Deadline: 1 October 2023

3. Change notifications for measures to reduce the risk of nitrosamine contamination. Deadline: 1 October 2023.

Drug Substance-related Nitrosamines and FDA recommendations

In a communication entitled "Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products" dated 18 November 2021, the FDA provides information on the risks of the formation of nitrosamine species that are directly derived from the API in question. Under certain conditions (temperature, pH, etc.), nitrosyl cations are formed in the presence of nitrous acid in an acidic environment. These cations react directly with the amino group of the API and thus form so-called Drug Substance-related Nitrosamine Impurities (NDSRIs). Nitrite anions or the corresponding salts, especially sodium nitrite, which are in equilibrium with nitrous acid, can occur as impurities in a number of common excipients and even in water used for the manufacturing process.
Drug Substance-related nitrosamines are not identical to the commonly detected 6 nitrosamine species listed in Table 1 of the Guidance, for which binding limits are also given.

In its communication, the FDA requests manufacturers of APIs and medicinal products to take a fresh look at the formulations of their products from this aspect. Based on a literature search on the topic of suppression of nitrosamine formation by antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E), the agency recommends examining the addition of these substances to the formulation of medicinal products, especially if the risk assessment does not exclude a possible formation of this type of nitrosamines.

Literature on the formation or prevention of nitrosamines

The literature references given at the end of the FDA communication are very interesting for a deeper understanding of the problem of nitrosamine formation, as they lead to a large number of further technical articles on this topic.

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