// December 08, 2023

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

different kinds of pills on a table

Quality Matters recently sat down with USP Principal Scientist Naiffer Romero, who has teamed up with researchers at LHASA Limited, AstraZeneca, Sai Life Sciences and Merck for collaborative research on nitrosamine impurities. In Part One of this series, we discussed the new research. Here’s Part Two.

Q: We talked about the new research and how it is related to the Carcinogenic Potency Categorization Approach (CPCA) framework issued earlier this year. How has the CPCA been received?

A: CPCA is a major step forward, but it’s not a silver bullet. There are unresolved issues that still need to be addressed.

For example, while CPCA is an important tool for evaluating the level of risk posed by NDSRIs, it’s not all-inclusive. Other factors must also be considered, including unknown impurities, chemical structures, reaction mechanisms and treatment benefits.

Technical limitations also exist. In some cases, the analytical methods used to quantitate NDSRIs may not be sufficiently sensitive to quantify the impurities at limits defined as acceptable for CPCA categories 1 through 3. The availability of robust and trustworthy reference standards could potentially help with some of the analytical challenges. 

Product recalls are also a real risk. Some potential NDSRIs that are assigned categories 1 and 2 may result in products being removed from the market if acceptable limits cannot be achieved. That scenario could potentially be avoided if limits close to their true safety risk can be derived from alternative approaches, such as metabolism studies, comet assays, and duplex sequencing.

The introduction of the CPCA has given scientists a new framework with which to tackle the problem of these impurities, and members of the Nitrosamines Exchange have embraced the opportunity to dive deeper into what the CPCA means for industry. There is near-constant discussion taking place in the Exchange as the result of this year’s exciting regulatory developments.

Q: What is next for research in this area?

As we continue to understand the implications of new regulatory developments – we have seen additional regulatory agencies issue new or revised guidances on nitrosamines as recently as early November – those working on the issue of nitrosamines in pharmaceuticals will continue to look to the new frameworks and work through their implications for industry.

There is great focus on quality testing. Detecting and controlling the presence of NDSRIs may require analytical testing and animal toxicological studies such as in vitro and in vivo mutagenicity assays. These activities require high-quality reference materials and robust testing methods. Leveraging decades of expertise in developing reference standards, USP now provides reference materials specifically for nitrosamines testing to ensure reliable analytical results. USP is also dedicating laboratory resources to develop robust and dependable analytical methods for impurities.

To learn more about USP’s work on nitrosamines, and to access the analytical methods being posted in its Analytical Hub, visit the Nitrosamines Exchange.