The presence of objectionable levels of chemical impurities in pharmaceuticals can have serious public health impacts. Not only do they pose a risk of harm to patients, but the discovery of unacceptable levels of impurities in trusted medicines can also undermine public confidence in the quality of drug products. Due to the potentially serious risk to public health, impurities in pharmaceuticals are strictly regulated.

The effects of the public health crisis due to unacceptable levels of nitrosamine impurities in commonly used medicines that were first discovered in 2018 are still being felt. Manufacturers and regulators both play a role in ensuring that impurity levels remain within acceptable limits. The complexity of the global pharmaceutical supply chain means manufacturers must be more diligent than ever to protect patient safety.  What happened and – more importantly – what’s preventing it from happening again?

Nitrosamines in everyday products

Nitrosamines are organic chemical compounds that may be present in low levels in a wide variety of products that people are exposed to every day. Air, water, and consumer products such as processed meats, alcoholic beverages, cosmetics, and cigarette smoke all contain nitrosamines. When they are metabolized, nitrosamines are converted to alkylating agents that can damage DNA and have been linked to cancer.

Where do nitrosamine impurities in medicines come from? The following are just some of the possible sources. They can be introduced when drug products are made via raw materials or solvents. Nitrosamines can form through chemical reactions that occur during drug manufacturing processes. They can result from product degradation. With multiple possible sources of nitrosamine impurities, it is critical that manufacturers evaluate their products for potential risks.  In cases where there is a risk of nitrosamines being present, analytical testing is used to detect and measure nitrosamine levels in medicines.

Nitrosamine impurities health crisis

Nitrosamines began making headlines when unacceptable levels of the nitrosamine, NDMA, were discovered in some batches of valsartan, an angiotensin II receptor blocker (ARB), commonly used to treat hypertension.  So many people around the world depend on valsartan to control their high blood pressure, that it is included on the World Health Organization’s list of essential medicines. In 2018, nearly 7.7 million prescriptions for valsartan were written in the U.S. alone. With so many people potentially exposed to unacceptable levels of nitrosamine impurities in their medicines, the U.S. Food and Drug Administration (FDA) and regulatory agencies worked with manufacturers around the world to recall affected batches of valsartan, as well as to publish health alerts to inform the public.

But the problem didn’t end with valsartan. Unacceptable levels of nitrosamines were subsequently detected in losartan and irbesartan, other drugs in the ARB family, resulting in additional recalls. Fortunately, some ARB products didn’t contain unacceptable nitrosamine levels.  This was welcomed news for some patients whose healthcare providers were able to prescribe alternative medications that treated the same condition but were not affected by the recalls.

A broader problem

The scope of the crisis became more alarming when further investigation revealed that other medicines besides ARBs also contained objectionable levels of nitrosamines. Ranitidine, one of the most widely used treatments for ulcers and acid indigestion, was also pulled from the market due to nitrosamine impurities.  Other drugs added to the list of recalls included nizatidine (a treatment for stomach and intestinal ulcers), metformin (used to treat high blood sugar) and, rifampin and rifapentine (antibiotics used to treat tuberculosis).

Having been found in several very different types of drug products suggested that careful monitoring and control of nitrosamine impurities is required to protect patients from exposure to unacceptable levels of these potentially carcinogenic substances.

Controlling nitrosamine impurities

Harmful impurities in medicines must be detected and controlled due to the potentially serious risk to public health. Operationally, impurities in drug ingredients or finished drug products can delay product approvals and trigger product recalls, introducing challenges including disruption of business operations, regulatory investigations and remediation.

The nitrosamine impurities crisis prompted regulators around the world to increase their scrutiny of drug manufacturing processes even further. In the future, this greater scrutiny may lead to the discovery of nitrosamine impurities in other medicines. For this reason, manufacturers need to understand which medicines are likely to form nitrosamines, how and at what levels nitrosamine impurities are forming, and how to control nitrosamines so that they aren’t present at levels that could be harmful to patients.

For over 200 years, the U.S. Pharmacopeia (USP) has been building trust where it matters most: in the world’s medicines, dietary supplements, and foods. Pharmaceutical manufacturers and regulators in more than 150 countries trust and rely on our rigorous public quality standards to help ensure the identity, strength, purity, and performance of medicines, to protect the patients who depend on them.

USP responded to the nitrosamine impurities crisis with a proposed general chapter on nitrosamine impurities that provides methods for detecting and measuring nitrosamine impurities, along with physical reference standards against which manufacturers can compare their test results. USP training resources, technical webinars, and technical service experts are available to help support manufacturers as they take proactive measures to prevent exposing patients to harmful levels of nitrosamine impurities.

The complexity and global nature of the pharmaceutical supply chain demands greater diligence, transparency and collaboration between manufacturers and regulatory agencies around the world to protect patient safety. Collaborative efforts between these and other stakeholders, along with effective tools to detect and control impurity levels, will help safeguard patients’ continued access to safe medicines that deliver the intended therapeutic benefit.  To find out more about the ways that USP standards and other resources can be used to help establish effective controls for nitrosamine impurities in quality medicines, please visit usp.org/nitrosamines.