The regulation of Nitrosamine impurities in pharmaceutical products is frequently debated in Europe and the United States.
In 2018, certain nitrosamines (N-nitrosodiethylamine and N-nitrosodimethylamine) were detected in a number of APIs used in hypertension medications and related drugs. N-nitrosamines are known carcinogens, and the pharmaceutical industry needed a way to deal with them. Several factors are thought to be responsible for the presence of these substances in APIs, including the manufacturing conditions of the API itself, accidental contamination from the manufacturing environment, solvent recovery procedures, and decomposition of the substance.
In 2019, the European Commission adopted a legally binding decision on N-nitrosamine impurities in bulk sartans with tetrazole rings (valsartan, candesartan, irbesartan, losartan, and olmesartan), which were initially at issue. To address the issue, the European Medicines Agency (EMA) issued the first edition of a Q&A document on nitrosamine contamination in 2020, which was revised frequently, perhaps due to the urgency of the issue, and the 16th edition* was issued in July 2023.。
*EMA's recently updated Q&A document on nitrosamine impurities : “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”
According to this latest Q&A document, all manufacturers/applicants of pharmaceutical products should mitigate the presence of nitrosamine impurities in the drug product as much as possible, control these "cohorts of concern" below acceptable intake(AI), keep them as low as possible and take appropriate risk mitigation measures based on ICH M7 principles. Since various molecular species of nitrosamines are generated from various pathways and uniform standardization is difficult, the relevant European regulation required manufacturers themselves to take three steps, Step 1: Risk assessment, Step 2: Testing for confirmation, and Step 3: Reduction measures. Although the project seemed to have achieved some success, the major problem remained how to determine the AI of nitrosamines for which no toxicity data were available or for which new nitrosamines had emerged.
* Cohort of Concern: refers to highly active genotoxic carcinogens such as aflatoxin-like compounds, N-nitroso compounds, and azoxy compounds.
Question 10 of this Q&A document, "Which limits apply for nitrosamines in medicinal products?" describes how to set the AI for nitrosamines in two scenarios, as shown below, and detailed application examples are presented in new Appendices 2 and 3. Anyone interested is encouraged to read them.
１．For nitrosamines for which sufficient toxicity data are available, calculate the TD50* value according to ICH M7(R2) and calculate the AI.
*TD50 (Toxic Dose 50): The dose at which a substance, when administered to animals, causes toxicity in 50% of the animals used in the study.
２．For nitrosamines for which there is insufficient data basis, the Carcinogenic Potency Categorization Approach (CPCA*) is used to determine the acceptable intake.
*CPCA is an approach that utilizes structure-activity relationships, focusing on the fact that hydroxylation of hydrogen on the α-carbon of a nitrosoamino group is involved in carcinogenicity. The evaluation method is based on the number of hydrogen atoms on the α-carbons adjacent to the N-nitroso group and the structural characteristics of the molecule. If the CPCA presented by the EMA is introduced, it is expected that the limit values for nitrosamines can be set mechanically, enabling rapid risk assessment and reducing the burden on companies.
The EDQM (European Directorate for the Quality of Medicines & HealthCare) also announced in its newsroom measures for CEP* holders.
*CEP(Suitability to the monographs of the European Pharmacopoeia): A "Certificate of Conformity with the Quality Standards for Active Pharmaceutical Ingredients" linked to the European Pharmacopoeia issued by the EDQM
If an N-nitrosamine in an application is newly classified, the CEP holder may update the CEP application according to the new assessment criteria and submit a minor revision request to the EDQM. Similarly, for revisions related to nitrosamine impurities currently under assessment, holders are encouraged to update their CEP applications according to the newly established AI and submit the relevant data to EDQM.
For new N-nitrosamines and N-nitrosamines not listed in the appendix of this revised Q&A collection, the AI should be determined using the Carcinogenic Category Classification Approach (CPCA).
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