// November 27, 2023

Revisiting the Landscape of Potential Nitrosamines in Pharmaceuticals using CPCA framework: Q&A with Naiffer Romero

Researcher holding pharmaceuticals in lab

USP’s Naiffer Romero has teamed up with researchers at LHASA Limited, AstraZeneca, Sai Life Sciences and Merck for collaborative research on nitrosamines impurities that was published this month in the Journal of Pharmaceutical Sciences. Quality Matters recently sat down with Romero, who leads USP’s Nitrosamines Exchange, to learn more about the new research and what it means for the field.

Q: The new research is a collaborative effort between USP and others working on nitrosamines detection and control. How did the project originate?

A: Last year, USP collaborated with a group of scientists from diverse industry and non-profit entities, to conduct an in-silico analysis of more than 12,000 active pharmaceutical ingredients (APIs) and API-related impurities and degradants from the Global Substance Registration System (GSRS). The GSRS is a database hosted by the U.S. FDA and created in partnership with FDA’s Health Informatics team, National Institute of Health's National Center for Advancing Translational Sciences (NCATS), and the European Medicines Agency (EMA) to enable the efficient and accurate exchange of information on what substances are in regulated products.

Our group looked at the ~12,000 substances from the GSRS and analyzed their chemical structures for characteristics that make them vulnerable to forming nitrosamines under certain relevant conditions.

We wanted to get a sense as to how potentially widespread the problem of nitrosamine impurities in medications could be. Our analysis found that 40% of the APIs and 30% of API impurities are potential nitrosamine precursors. These were higher-than expected percentages, which suggested that the potential problem of nitrosamine impurities in medications is even larger than we initially thought. Last year’s research originated as a discussion in our Nitrosamines Exchange community, and we were pleased to see it come to life. It’s such a great example of the way the online community is enabling the exchange of information to accelerate progress, as well as the positive and very real impact that kind of collaboration can result in. We are very proud of the community and how it is contributing to global efforts to control nitrosamines impurities in medicines.

Q: What was the opportunity to expand upon the initial research?

A: This summer, a wave of regulatory activity on nitrosamines took place around the world, with numerous agencies publishing new or revised guidances. Official updates came out of Europe, Canada, and Japan. In early August, the FDA published its own highly anticipated new guidance, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs).”

The updates from the regulatory agencies have a key element in common: the introduction of a framework for risk-based assessment of NDSRIs. The first to come out was from the European Medicines Agency (EMA). In July, EMA’s guidance on NDSRI detection and mitigation introduced a new Carcinogenic Potency Categorization Approach (CPCA).

The CPCA is a framework for determining the acceptable intake (AI) level of a given NDSRI and aiding in risk assessment for various APIs. The methodology can be used to assess the mutagenic potential and carcinogenic potency of NDSRIs – a new approach that is made possible by advancements in the science and understanding of the structure-activity relationships of the compounds. Within the CPCA, nitrosamines are categorized into one of five potency categories according to their carcinogenicity (1=most potent; 5=least potent). In the new EMA guidance, AI limits are set for each category, so manufacturers are no longer required to meet a default AI limit, and there is more flexibility – as well as increased limits – for those substances that are deemed to be less carcinogenic and therefore pose less risk.

Prior to the CPCA framework, manufacturers lacking carcinogenicity study data for a specific compound were required to comply with the most restrictive nitrosamine limits (18 ng/day for EMA and 26.5 ng/day for FDA). 

Q: How is the new research related to CPCA?

A: As I mentioned, in the original analysis of more than 12,000 small molecule drugs and impurities from the GSRS, 40% of the APIs and 29.6% of the impurities were at risk of nitrosamine formation. 

In this new study, we wanted to take a look at those APIs and impurities considered at risk and apply the new CPCA framework to determine what categories these at-risk substances would fall into. The small molecule drugs and API impurities identified were analyzed using EMA’s CPCA.

Q: What did the new research find?

A: The APIs and API impurities that were analyzed in this study can be divided into two groups based on their chemical structures: secondary amines and tertiary amines. For the secondary amines, most of the potential nitrosamines fall in potency categories 4 and 5 (less dangerous). For the tertiary amines, the nitrosamines that could form were distributed more evenly across the five categories in the CPCA.

It is important to note that many of the potential nitrosamines identified may not form under conditions of API synthesis, drug product manufacturing, or drug product storage. 

Within the APIs, impurities, and degradants of the top 200 drugs by sales, only one nitrosamine – N-nitroso-vonoprazan – was identified as a category 1 nitrosamine. This is welcome news, as it’s the most restrictive category in the CPCA.

Read Part Two of this Q&A with Naiffer Romero to learn more about the new research, the new CPCA framework, and what is on the horizon.