In September 2023, PQT/MED issued a call to manufacturers to revisit and update their risk assessments for Finished Pharmaceutical Products (FPP) containing APIs with vulnerable amine groups. This update aimed to address the potential presence of N-nitrosamines, including nitrosamine drug substance-related impurities (NDSRIs), and to request confirmatory testing where necessary:
https://extranet.who.int/prequal/news/update-n-nitrosamine-impurities
Following this call, PQT/MED has continued to work closely with FPP manufacturers to ensure timely completion of confirmatory testing and the implementation of appropriate control strategies or corrective actions for the affected products. A significant number of potentially affected FPPs have now been tested, and results have been submitted to PQT/MED. Efforts are on-going to complete testing for the remaining products.
Findings from Confirmatory Testing
To-date, confirmatory test results have revealed that certain FPPs formulated with mifepristone, moxifloxacin or ritonavir do contain nitrosamines at levels exceeding acceptable intake limits established according to the Carcinogenic Potency Categorization Approach (CPCA), adopted by regulatory agencies collaborating under the Nitrosamines International Technical Working Group (NITWG).
Interim Measures
Based on benefit-risk considerations, PQT/MED has determined that affected FPP batches may continue to be released under interim acceptable limits, since the risk to the patient associated with interruption of treatment far outweighs any potential future cancer risk associated with nitrosamines present in the products at these levels. These interim limits will remain in place while manufacturers pursue corrective actions or conduct toxicological studies (e.g., enhanced AMES assay tests or other) that may support a higher acceptable intake/limit. PQT/MED will keep monitoring this ongoing work by manufacturers.
Rifampicin and Rifapentine Products
Most manufacturers of rifampicin API have implemented corrective actions significantly reducing the levels of 1-methyl-4-nitrosopiperazine (MeNP) in both APIs and FPPs. PQT/MED will continue to work to ensure that all rifampicin API and FPP manufacturers move from the interim limits approach to adopting the regular acceptable limit set based on the CPCA. Until then, the interim limits remain applicable.
Similarly, manufacturers of rifapentine FPPs have taken steps to reduce levels of 1-cyclopentyl-4-nitrosopiperazine (CPNP). While improvements have been observed, further work is needed to meet CPCA-based acceptable intake levels or to generate toxicological data that could justify a higher acceptable intake. PQT/MED remains actively engaged with manufacturers to support these efforts, and interim limits continue to apply in the meantime.