In April, the World Health Organization (WHO) became the latest health authority to release a draft guidance on Current Good Manufacturing Practices (CGMP) considerations for the prevention and management of nitrosamine contamination in pharmaceutical products. The new draft guidance is applicable to all manufacturers of excipients, active pharmaceutical ingredients, and more than 130 finished pharmaceutical products. The last year has seen a whirlwind of updates from other regulatory agencies as well. In light of these developments, Quality Matters sat down with Mrunal Jaywant, who leads USP’s global work on nitrosamines, to talk about where the industry currently stands in regard to overcoming the challenges posed by these impurities.
Q: Since the discovery of nitrosamines in medicines in 2018, regulatory agencies and industry members around the world have taken swift action to prevent unacceptable levels of nitrosamine impurities from forming in pharmaceuticals. How have you seen the approach to handling nitrosamines transform over the last six years?
A: Following the discovery of nitrosamines in 2018, USP, U.S. and international regulators, policymakers and industry members have spent significant time and resources gathering information to understand the seriousness of nitrosamine impurities in medicines. This process has included determining how to identify acceptable intake (AI) limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) and establishing appropriate analytical procedures and reference materials to ensure AI limits are not exceeded. Because the recommended AIs depend on the regulatory agency providing guidance, USP has made additional efforts to help manufacturers understand the varied guidance and limits used globally.
In recent years, it has become increasingly apparent that both industry members and regulatory bodies need to figure out how to reduce the risks of nitrosamines to keep quality products in the market without disruption. Though the discovery of nitrosamine impurities in medicine is recent, we must adjust and/or modify processes to address impurities now while simultaneously taking steps to reduce concerns in the future.
A key component of decreasing nitrosamine impurities is raising awareness. Nitrosamines are not specific to a particular region or country; this is a global problem that requires continuous collaboration and information sharing. However, countries around the globe are at various stages of development for their regulatory policies. At USP, we are facilitating collaborative discussions and educational sessions through trainings, domestic and international workshops, and the creation of our Nitrosamines Exchange, a knowledge-based community designed to allow representatives from international regulatory and health agencies, along with industry members globally, to share and discuss recent updates and information related to nitrosamines. USP is dedicated to managing and mitigating pharmaceutical impurities, including nitrosamines in medicines, so we have developed new approaches to help industry understand and address this issue.
Q: What is the latest guidance on AI limits from the different regulatory agencies that have issued recommendations?
A: Around the globe, various regulatory agencies have provided AI limits based on the predicted carcinogenic potency categorization approach. They have also recommended interim AI limits for certain NDSRIs. We have been monitoring the guidance published by different regulators with great interest -- here’s an overview of the latest updates, as of May 2024:
- U.S. FDA: The FDA provided recommended AIs for over 260 NDSRIs based on predicted carcinogenic potency categorization and four NDSRIs based on compound-specific data or read-across analysis from a surrogate and recommended interim AI limits for two NDSRIs, N-nitroso-duloxetine (600 ng/day) and N-nitroso-ciprofloxacin (12,000 ng/day).
- European Medicines Agency (EMA): EMA provided AIs for over 130 N-Nitrosamines based on robust scientific knowledge about carcinogenic potency and a Carcinogenic Potency Categorisation Approach (CPCA) was proposed.
- Health Canada: Health Canada provided AIs for nearly 130 N-Nitrosamines based on several approaches including compound-specific data, structure-activity relationship (SAR) assessments, read-across from a surrogate with sufficient compound-specific data and the CPCA.
- Therapeutic Goods Administration (TGA)-Australia: TGA provided AIs for over 130 Nitrosamines in medicines. TGA's approach in setting AI limits for N-Nitrosamines has been to align, where possible, with international regulators like U.S. FDA, EMA and Health Canada.
- Pharmaceuticals and Medical Devices Agency (PMDA)-Japan: PMDA provided AIs for nine N-Nitrosamines and follows U.S. FDA, EMA guidance.
- World Health Organization (WHO): In April, WHO issued an updated draft guidance indicating that the Enhanced Ames Test (EAT) conditions and the CPCA should be considered when setting appropriate AI limits.
Q: How do you expect the current AI limits for nitrosamines in medicines to evolve as the strategy for handling the impurities shifts?
A: When nitrosamines were initially discovered in medicines, the pharmaceutical industry struggled to understand the magnitude of the issue. As we have learned more about nitrosamines, these impurities have proven to be a serious safety issue for patients. The AI limits of nitrosamines – or “safe” levels of nitrosamines that patients can consume over time – are generally understood to be very low.
The current AI limits for many of the nitrosamine impurities as published by regulators recently have been calculated through CPCA scoring. This framework assesses the structure of an impurity, which then helps regulators determine how to define the appropriate limits of NDSRIs. The scoring is determined and published by the U.S. FDA and other global regulatory agencies to determine the AIs.
AI limits will continue to evolve as new information becomes available on nitrosamine impurities. In the future, we hope to see greater harmonization of AIs across regulatory agencies around the world. With harmonized limits in place, manufacturers would only need to meet one requirement, preserving valuable resources and time for companies across the pharmaceutical industry, and ensuring a safe medicines supply for all patients around the globe.
Q: Knowing that medium to smaller-size companies are still working to grasp revisions/updated procedures for testing for these impurities, what actions has USP taken to help manufacturers by building up global capability to mitigate the potential presence of nitrosamines in medicines?
A: Traditionally, USP’s role is to develop standards and lead education courses for manufacturers who use them. In the case of nitrosamines, most large organizations have the internal capabilities to determine the risk of nitrosamine formation in their processes and modify them as necessary to mitigate this risk. Unfortunately, many small and medium-sized companies lack the infrastructure to modify their existing processes and reformulate medicines to mitigate the risk of the formation of high levels of nitrosamines. That’s where USP comes in.
It can be overwhelming to know where to start to address nitrosamine impurities in drug products. This is exactly why we’re committed to providing education through platforms that are accessible to all, including roadshows, regulator workshops, in-person classroom trainings and laboratory demonstration sessions, international conferences, and consistent updates from USP and other members of the Nitrosamines Exchange. We are constantly evaluating our capabilities and determining how we can best support manufacturers and regulators.
Q: While it is clear the industry is actively working to mitigate nitrosamines in medicines, what is USP doing now to address risk assessment challenges?
A: USP is seeking input from stakeholders to understand if a need for risk assessment guidance still exists since manufacturers will need to reevaluate risk any time they change certain manufacturing practices, and when new threats enter the market. Based on industry input, USP may consider collaborating with its Expert Committee members and Nitrosamine Exchange community members to develop simple guidance on risk assessment.
Q: What tools or processes do you hope to see implemented to help solve future issues related to impurities or contaminants in medicines?
A: Today, USP offers a General Chapter, associated USP Reference Standards and an education course on nitrosamine impurities. In addition, USP offers:
- Nitrosamine Pharmaceutical Analytical Impurities (PAIs) reference materials
- Access to the Nitrosamines Exchange: a virtual knowledge-based community
- The Analytical Hub: an online repository of analytical methods
- Publications in reputable journals
- Stakeholder engagement programs
As a member of the Pharmacopeial Discussion Group (PDG), USP has formed, along with pharmacopeias from Europe, Japan and India, a sub team focused on nitrosamines approaches and challenges to identify the scope of collaboration for the future. USP is also considering collaboration with individual PDG members to align on approaches. Additionally, USP may continue to develop further documentary standards to address nitrites in excipients and introduce more PAIs based on industry needs. We are focused on developing tools and resources that help companies navigate this issue and enhancing our knowledge of how regulators are enforcing current AI limits.
In the future, USP will also prioritize the development of standards, using predictive tools, to help prevent nitrosamine impurities at the start of the drug development process by using a proactive approach.
Before the COVID pandemic, industry issues like this were often dealt with in a silo. Each company had to figure out how to avoid these kinds of problems within the walls of their own organizations. The pandemic proved to be an eye-opener that forced industry members to collaborate with each other and regulators to identify solutions.
We have seen this with the evolution of knowledge sharing within the Nitrosamines Exchange community. When we first launched the online community, we expected to see some initial hesitation around sharing information and solutions, but we have been pleased to see that discussions, questions and anecdotal experiences have been shared more and more frequently.
Q: Are there any final thoughts you’d like to share?
A: Nitrosamine impurities are not going to go away in the near future. The industry needs – and has already begun – to change its approach to dealing with nitrosamines and treating them as special impurities. One of the most important lessons learned through our experiences with nitrosamines is that industry must be ready to predict and address the potential presence of any mutagenic impurity in drug substances and drug products in the future.
