// May 25, 2023

Impurities in the medicines supply chain: Global cooperation essential to safeguarding patients

Asia-Pacific Economic Cooperation (APEC) forum’s Medical Product Supply Chain Dialogue

Continued global cooperation to strengthen supply chain resilience and assure medicines quality was a recurring theme at the Asia-Pacific Economic Cooperation (APEC) forum’s Medical Product Supply Chain Dialogue April 25-26, co-hosted by the U.S. FDA and USP in Rockville, Maryland. It was further underscored during a panel session at the event titled “Safeguarding Patients from Impurities in the Drug Supply Chain.”

The risk of pharmaceutical impurities that can have serious negative health consequences for patients has become a significant challenge for industry, regulators, pharmacopoeias, and other stakeholders in recent years. Establishing effective strategies to control and limit impurities in pharmaceutical products can help maximize manufacturing efficiency, manage costs, and reduce risks to end-users. Assessing and controlling for impurities throughout the entire drug product lifecycle is critical to ensure pharmaceutical product quality and safety, panelists generally agreed.

Nitrosamine impurities challenges

Much of the APEC panel discussion on impurities focused on nitrosamines in particular. Nitrosamine impurities can potentially form in a variety of ways during the manufacture and shelf-life of a drug and pose cancer risks if people are exposed to them above certain levels. Starting in 2018, the presence of nitrosamine impurities was identified in some angiotensin II receptor blockers used to treat high blood pressure and heart failure, and they were subsequently found in additional drug products. More recently, the U.S. recall of two lots of the hypertension medications quinapril and hydrochlorothiazide put the issue of nitrosamine impurities back in the spotlight. To address the issue, the FDA has collaborated with international regulators since 2018, sharing related scientific knowledge and current thinking on technical safety and quality topics, developing guidance, and issuing related public health alerts.

Panelist Jason Bunting, Pharm.D., FDA science policy advisor at the Center for Drug Evaluation and Research (CDER), addressed the topic of nitrosamine impurities from a regulatory perspective. “FDA has taken and continues to take these issues very seriously and they are the highest priority for patient safety and continued access to medically necessary drug products,” Bunting said.

FDA guidance issued in September 2020 provides a series of steps that manufacturers should take to prevent unacceptable levels of nitrosamines, and international regulators have taken a similar approach. While until mid-2021 stakeholders were dealing with what are called simple structure nitrosamines, or simple nitrosamines, at the end of that year a new type of nitrosamines emerged, defined as NDSRIs or nitrosamine drug substance-related impurities. As NDSRIs pose unique challenges, FDA subsequently issued updates on “possible mitigation strategies” to address them.

Bunting noted that FDA’s approach to emerging impurity issues has included establishment of the CDER Emerging Impurities and Contaminants Committee, which is dedicated to strategic, cross-cutting management of nitrosamines as well as other novel or complex impurity and contaminant issues. More broadly, Bunting indicated the agency is engaging in ongoing meetings with stakeholders to explore ways to mitigate drug impurities, inviting APEC meeting participants to join.

Quality standards

USP standards and solutions help regulators, manufacturers and other stakeholders better understand nitrosamine impurities, how to control them and how to mitigate the risks. USP’s latest such tool – the Nitrosamines Analytical Hub housed within USP’s Nitrosamines Exchange online community for sharing knowledge and solutions – is a public, web-based repository of downloadable analytical procedures to test for nitrosamine impurities in pharmaceuticals.

During the panel discussion, USP emphasized two critical priorities for keeping the global supply of medicines safe from harmful levels of impurities like nitrosamines. These include continued cooperation among global regulators, industry, and other stakeholders. This is especially true since there remain many uncertainties on what may be needed to fully address the problem. Also needed is greater proficiency with risk-based assessments in manufacturing. Thorough characterization of the composition of raw materials, including any impurities in those materials, and the chemical reactions that can occur during manufacturing or further along the supply chain that may lead to impurity formation, is needed to identify related risks. Where risks are identified, it is necessary that manufacturers investigate and establish appropriate controls. USP’s presentation during the panel discussion reminded attendees that while drug product recalls due to impurity risks have the potential to disrupt the supply chain or even create near-term shortages, such actions also represent reassuring evidence of the regulatory process working to protect patients.

Nitrosamine impurities risk mitigation

The risk of nitrosamine impurities in medicines is “not going away any time soon,” agreed Health Canada’s Gary Condran, manager, Quality Risk Management and Operations Division, Bureau of Pharmaceutical Sciences, Pharmaceutical Drugs Directorate, Health Products and Food Branch. Providing an international perspective on the panel, Condran gave an overview of Canada’s regulatory response as stepwise and in-line with the approach of other regulatory agencies, with risk assessments followed by confirmatory testing and mitigative actions. He emphasized that the risks of nitrosamine impurities can impact medicines regardless of whether they are brand-name or generic, prescription or over the counter, or pre- or post- regulatory approval.

Meanwhile, the impact of nitrosamine impurities has been felt across the entire spectrum of drug substances and products regulated by APEC meeting participants and beyond. As a result, significant work has been done among international regulatory partners on nitrosamines, initially including the sharing of information on communications and recalls, and later evolving to focus on technical issues. This has included contributions from international groups including the Nitrosamines International Strategic Group (NISG) and Nitrosamines International Technical Working Group (NITWG). Both organizations detailed their experiences with root causes, risk factors and risk mitigation measures for nitrosamine impurities formation in pharmaceuticals in a recent publication in the Journal of Pharmaceutical Sciences. The groups have also discussed approaches and are working towards alignment on acceptable nitrosamine intake levels, which will be added to Health Canada’s guidance on nitrosamines, Condran said.

Expanding on the nature of related risk assessments, risk factors, root causes, and risk mitigation, Condran observed a “checklist style” and “silo” approach to risk assessments, stressing the need for a more robust, comprehensive approach that thoroughly and clearly addresses potential risk factors with data-driven justifications and confirmatory testing to support conclusions. He also emphasized the importance of designing products and processes at the outset to avoid the formation or introduction of nitrosamine impurities. First understanding the cause(s) or source(s) of nitrosamine impurities establishes a scientific foundation for developing effective mitigation strategies and tactics, he suggested.

While much progress has been made in understanding and controlling nitrosamine impurities in medicines, and related analytical testing methods are continuing to improve, much work remains to be done, Bunting said. It also remains likely that evidence of nitrosamines in drugs will continue to be found, Bunting predicted. That makes the need for global cooperation all the more essential.