Update on N-Nitrosamines Impurities from World Health Organization (WHO) [18Sep23]
Applicants are reminded of the latest N-nitrosamines assessment policies for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs):
- https://extranet.who.int/pqweb/sites/default/files/documents/NitrosamineContaminationPolicy_FPP-Applications-Dec2022%20.pdf
- https://extranet.who.int/pqweb/sites/default/files/documents/Guidance_Nitrosamine_Contamination_Policy_APIs_Rev1.pdf
New approaches to define acceptable intakes (AIs) for N-nitrosamine impurities in medicines
New approaches have been developed by medicines regulatory authorities collaborating under the Nitrosamines International Technical Working Group (NITWG) and Nitrosamines International Strategic Group (NISG).
The Carcinogenic Potency Categorization Approach (CPCA) for N-nitrosamines categorizes N-nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), into predefined predicted carcinogenic potency categories, each with a corresponding acceptable intake (AI) limit. This categorization is based on an assessment of activating or deactivating structural features present in the molecule. The EMA questions and answers document on N-nitrosamines provides more information on the CPCA and related clarifications: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf
In addition, The Enhanced Ames Test Conditions for N-nitrosamines, provides an approach for supporting a higher AI value if levels of a given nitrosamine in a product are found to be above a limit established based on the CPCA. The above-mentioned EMA Q&A document can be consulted for more information.
These approaches may be used to propose AIs for newly identified N-nitrosamines or for the N-nitrosamines whose current AIs were established based on SAR analysis. Note that the CPCA is not applicable for N-nitrosamines for which AIs have been established based on toxicological data such as NDMA and NDBA.
Rifampicin products
Previous notes regarding rifampicin products can be found at:
PQT/MED continues to accept interim limits for 1-methyl-4-nitrosopiperazine (MeNP) impurity at or below 5ppm while manufacturers continue to work on corrective actions that should be applied to decrease the impurity content to lifetime acceptable levels.
All rifampicin API and FPP manufacturers have been requested to introduce the implementation of corrective actions such that the AI or further reduced interim limits are achieved by end of this year (2023).
Applicants should note that the AI for MeNP has been revised to 400ng/day based on the CPCA. PQT/MED will keep monitoring the responses related to rifampicin products and the ongoing work by manufacturers to decrease the impurity up to the revised limit.
Rifapentine products
Previous notes regarding rifapentine products can be found at:
PQT/MED continues to accept interim release limits for 1-cyclopentyl-4-nitrosopiperazine (CPNP) at or below 20 ppm while manufacturers continue to work on corrective actions that should be applied to decrease the impurity content to AI levels. The CPCA may be employed to revisit the acceptable intake for CPNP.
Other products
Information available to PQT/MED and international regulators indicate the presence of nitrites (usually at trace levels) in common use excipients. Consequently, the potential presence of N-nitrosamines (including Nitrosamine Drug Substance Relate Impurities - NDSRIs) in FPPs that contain a secondary or tertiary amine API cannot be ruled out without additional risk assessment considerations or confirmatory testing.
Therefore, all manufacturers of FPPs containing APIs with secondary or tertiary amine groups are requested to update the risk assessment exercises completed for these products to consider the potential presence of N-nitrosamines, including NDSRIs, and where needed undertake confirmatory testing. To this end, the CPCA mentioned above should help categorize the carcinogenic potency of the suspected nitrosamine impurity and therefore prioritization for confirmatory testing (for example suspected nitrosamines assigned to potency categories 1, 2 or 3, based on CPCA, should be prioritized for confirmatory testing unless the potential formation of the suspected nitrosamine is demonstrated to be unlikely as part of the risk assessment exercise).
For further information please contact: Dr Matthias Stahl at stahlm@who.int