A recently completed pilot project in Vietnam to validate and implement monitoring procedures for nitrosamine impurities in medicines is an inspiring example of how international collaboration and cooperation can help ensure medicines quality across geographies and strengthen the supply chain.
The U.S. Pharmacopeia (USP) embarked on the pilot project in November 2021 with Vietnam’s National Institute of Drug Quality Control (NIDQC) to validate procedures for monitoring nitrosamine impurities in selected sartan drug products. The pilot testing and validation overcame previously identified shortcomings in analysis sensitivity due to matrix effects in nitrosamine monitoring to help ensure the quality of medicines.
Addressing nitrosamine challenges head on
Nitrosamine impurities are probable carcinogens that can potentially form in a variety of ways during the manufacture and shelf-life of a drug. Although our understanding of nitrosamines in pharmaceuticals is continuing to evolve, we do know that some nitrosamines may increase the risk of cancer if people are exposed to them above certain levels and over long periods of time. Starting in 2018, nitrosamine impurities were reported above the safe limits in sartans, a class of drugs used for high blood pressure and heart failure, and they were subsequently found in additional drug products, leading to multiple recalls in recent years. The complexity of the threat stems in part from the fact that pharmaceutical impurities can potentially form in a variety of ways during the drug product lifecycle, including drug development, manufacture, distribution, and storage.
As the situation has grown increasingly complicated, with new discoveries prompting even more new questions, access to knowledge has become crucial. USP has developed compendial standards and solutions for manufacturers and other stakeholders to mitigate risks effectively. We have seen global engagement by pharmacopoeias, quality control labs, industry and more, embracing the spirit of collaboration needed to tackle this challenge. Regulators around the globe have worked together to share related scientific knowledge and current thinking on technical safety and quality topics, developing guidance and issuing related public health alerts.
Vietnam: A case study
In Vietnam, recognizing an increased number of alerts and reports on the presence of nitrosamine impurities in various drug products, the NIDQC initiated a post-market surveillance monitoring program with the goal of analyzing nitrosamine levels in high-risk drugs. The monitoring program was an opportunity to work with USP’s Preferential Access for Regulators, or PAR, Program.
Since 2012, USP’s PAR program has provided low- to middle-income countries’ national medicines regulatory authorities with complimentary or discounted access to documentary standards, physical Reference Standards, and related professional education courses to increase their abilities to test the quality of medicines for their citizens. Participating regulators in the USP PAR program have reported that access to quality standards have increased their ability to verify the quality of critical medicines, from antibiotics to antihypertensives.
In Vietnam, while the necessary standards were obtained through USP’s PAR program and the lab purchased the instrumentation, USP experts offered technical assistance and scientific support to train scientists from NIDQC to verify and validate procedures included in USP General Chapter <1469> Nitrosamine Impurities. General Chapter <1469> is an informational chapter, published in December 2020 (official since June 1, 2021), which provides manufacturers with important information, tools, and approaches for evaluating and controlling nitrosamines.
The pilot project that began in November 2021 aimed to provide technical and scientific assistance and to train NIDQC scientists in verifying LC-MS and GC-MS procedures, troubleshooting technical issues during analysis, and validating analytical procedures, with the ultimate goal of increasing the safety and quality of sartans in Vietnam.
To implement the pilot project, we had the opportunity to work closely with Dr. Le Quang Thao, Deputy Director, NIDQC, and his team in Vietnam, who played a crucial role in facilitating coordination and providing ongoing regulatory support. We were pleased at the pilot’s outcome:
- It effectively addressed and overcame common analytical challenges related to poor sensitivity due to strong matrix effects.
- It successfully implemented and validated procedures for sartan drug products, leading to improved lab strengthening.
- The project provided valuable training to personnel on the ground, contributing to capacity building efforts in Vietnam.
Phase two of the pilot project has officially begun. Plans include continued post-market surveillance with sampling of sartans drug products and applying the validated procedures to ensure supplies of quality-assured medicines in the country.
We are proud of this collaboration in Vietnam and of the information sharing that USP is facilitating through our Nitrosamines Exchange, where scientists and other stakeholders from more than 80 countries can ask questions, share insights about what has worked for them, refer to publications, and more. The Exchange also features the Analytical Hub, a repository of downloadable analytical procedures to test for nitrosamine impurities and related substances in pharmaceuticals.
This collaboration stands as a signature example of how USP is participating in essential, laboratory-strengthening activities around the world, advancing our collective understanding of nitrosamines and available solutions and demonstrating the power of international collaboration to bolster medicines supply chain resilience. Today more than ever, it is vital to recognize the importance of multi-national collaboration to address challenges like nitrosamines that transcend international borders, and to facilitate health equity and trust in quality medicines around the world.