As a standard-setting organization, the United States Pharmacopeia (USP) has guided pharmaceutical safety for close to 200 years. Now, in the face of rising nitrosamine contamination in pharmaceuticals, the organization is spearheading modern initiatives to confront and manage this critical challenge.
Central to these efforts is Naiffer Romero, Principal Scientist at USP, leading scientific and technical engagement on compendial priority topics. Part of the scientific affairs team, Romero drives several nitrosamine-focused initiatives. His journey began with the detection of NDMA in valsartan in 2018—a moment he describes as lucky or cursed, depending on one’s viewpoint. Since then, he has been deeply involved in tracking and shaping the response to the evolving nitrosamine landscape.
In a recent discussion with Separation Science, Romero highlighted USP's comprehensive approach to nitrosamine contamination, including the collaborative creation of General Chapter <1469> and the dynamic Nitrosamines Exchange platform. These initiatives, alongside predictive tools and SAR models, underscore USP's proactive role in addressing current and future risks in pharmaceutical safety.
Nitrosamines have become a real issue of concern. Can you highlight the USP chapters that tackle this issue and share any recent updates?
USP published General Chapter <1469> on nitrosamine impurities in September 2020. This chapter outlines a general approach and specific considerations for managing nitrosamine challenges. It also introduces a range of analytical methods and a full suite of reference standard materials specifically developed to support analytical testing for these impurities.
Additionally, it's important to note that this chapter was the result of close collaboration between our expert volunteers in the nitrosamine joint subcommittee and FDA government liaisons, who are also vital to our standard-setting activities at USP.
With the new 2023 FDA guidelines on acceptable intake limits for nitrosamines and the surge in drug recalls, how is USP guiding companies through these enhanced regulatory standards?
In terms of compendial standards, we are constantly evaluating the impact of recent revisions. We're working to understand how these standards fit into the new regulatory landscape. As we gain more insights and have ongoing internal discussions, we'll continue sharing information with the community.
In addition, we're constantly developing tools and resources to support our stakeholders in better understanding and navigating the challenges posed by nitrosamines, as we've been doing since the beginning. One key initiative is the Nitrosamines Exchange, an online community hosted by USP. It has over 4,000 members from 60 countries, actively engaging, discussing, and sharing best practices related to nitrosamines.
How crucial are initiatives such as pre-competitive data sharing in addressing the challenges of nitrosamines? And can you give us a little background about why USP created the Nitrosamines Exchange and the related Analytical Hub?
I would say it's not just about data sharing; knowledge sharing is also crucial for tackling the issue of nitrosamine impurities. That critical sharing has proven to help accelerate and deepen understanding of the science around nitrosamines.
When the Nitrosamines Exchange was first introduced, we had two motivations in mind. The first one was the democratization of knowledge. We wanted to create a space where everyone affected by nitrosamines could see all the research, learning, and discussion related to nitrosamine impurities. That continues to this day.
The second motivation was to create a networking space. It was important for us to provide a place where scientists, chemists, and staff working on nitrosamines could gather and connect. They could share their experiences with nitrosamines and discuss the challenges they face in different organizations or areas of the pharmaceutical production process.
Following the Nitrosamines Exchange, we introduced the Analytical Hub, which was developed based on feedback specifically from the analytical chemistry community. They needed a centralized location to find and access analytical methods for jumpstarting their lab work. The hub has become a repository of non-compendial analytical methods, or 'analytical notes,' which include not just method details, but also a comprehensive package of information crucial for lab development.
In support of these methods, USP has accelerated the development of a wide range of nitrosamine impurity materials, part of our Pharmaceutical Analytical Impurities (PAI) program. These are materials that we make available to support the testing of various nitrosamines and include impurities listed in USP monographs but not available as USP Reference Standards as well as critical degradants and process impurities.
Having the Analytical Hub within the Nitrosamines Exchange has brought an interesting dynamic to the community. The vibrancy of the Nitrosamines Exchange is encouraging analytical chemists to collaborate and troubleshoot methods together. This community of chemists is not only helping each other with methods but also sharing best practices identified or developed in their labs. It's really fascinating to see this free exchange of best practices and tips within the analytical work.
Predictive tools and SAR models are pivotal in impurity control. Could you elaborate on how USP is utilizing these technologies, particularly in light of recent findings that up to 40% of APIs might be at risk for nitrosamine contamination?
Let me start with how we got to the 40% number. You're probably familiar with API-related nitrosamines, or NDSRIs, and how the regulatory guidance defined this impurity class when they first emerged in 2021. It seemed like every month, almost every week, we saw reports of a new impurity somewhere in the world.
We started wondering about the real magnitude of this problem regarding complex nitrosamines. Until then, we were dealing with simple chemistry and nitrosamines with simple structures. But now, we're dealing with complex nitrosamines—almost as complex as the API itself—forming on the API molecule.
To tackle this, we reached out to community members to see if they were interested in analyzing this problem at a high level. Some were keen, especially on looking at it from a risk perspective. So, we gathered a group of scientists interested in these issues to conduct this risk assessment.
We looked into the USP structural database, which has about 12,000 structures. We asked a simple question: how many of these structures, APIs, and impurities, have chemical groups that could become precursors to nitrosamine?
Through this, we found that out of all the APIs in the USP database, 40% of them, close to 4,000 structures, could carry the risk of forming nitrosamines.
We went further in that study and looked not only at the number of structures that could form this impurity but also at their reactivity—how easily these impurities could form. We couldn't assess 12,000 structures in the lab, so we relied on in silico tools for this. In our publication, we also examined the potential carcinogenicity or mutagenicity of these structures using these in silico models. These tools are becoming increasingly important for assessing the risk of potential impurities in molecule portfolios or families.
Looking forward, how can pharmaceutical companies stay ahead of impurity-related risks?
Overall, I believe that nitrosamines have really opened our eyes. There's much greater awareness now in the industry and among regulators about the threat that nitrosamines pose. And it’s not just about nitrosamines anymore. The bigger conversation is shifting towards genotoxic impurities. Are we looking into genotoxic impurities as thoroughly as we should? That's the next big question.
Understanding the sources of these nitrosamines, unique to each manufacturer, product, and formulation, is crucial. As organizations work through their risk assessments and understand the details of their processes, they'll gain solid knowledge in this area.
When it comes to mitigation, the industry is keen on resolving this issue. I see a new research area emerging around scavenger agents, which are added to formulations to prevent nitrosamine formation. There's a lot of research happening, even from the FDA.
On the safety side, the discussion is ongoing. More and more data is emerging on different safety evaluations of nitrosamines. It's about understanding the true mutagenic potency of these impurities. Also, the use of in silico tools or novel in vitro testing could help predict or measure the potential of these structures in any pharmaceutical product.
My advice to the industry is to stay attuned to the evolution of this topic. The regulations, processes, and standards, including our approach at USP, are all evolving. Here at USP, our nitrosamine team will keep working on programs, resources, tools, and standards to support all our stakeholders in the industry and regulatory bodies that rely on us for these controls.
This article is featured in our May 2024 publication, Pharmaceutical Purity and Precision. Find out what’s happening in the world of pharmaceutical impurity analysis and learn about the latest topics and techniques.
