// October 11, 2023

Standards on the Frontlines: Responding to public health crises and strengthening supply chains


Vulnerabilities or disruptions to the global medicine supply chain (including drug shortages) continue to make headlines. For more than 200 years, governments, manufacturers and health professionals have relied on USP quality standards as a foundational tool supporting a strong supply chain so that medical products are reliable, safe and work as they should for the many patients who depend on them.

More than 6,000 science-based standards set the bar for development, manufacture, distribution and administration of medicines and other health products. Governments and manufacturers rely on them to increase the availability of safe, quality medicines and to build patient and health provider trust in the global supply of medicine. USP standards are used on a daily basis to prevent supply chain disruptions that result from quality issues. They are also critical response tools when public health emergencies arise. The following examples demonstrate how our standards have been used to respond to public health crises, including addressing adverse effects from heparin, detecting and controlling for impurities such as nitrosamines and, responding to a hand sanitizer shortage, among many others.

Heparin: Stopping a deadly fake

In 2007 and 2008, nearly 150 patients died and hundreds more suffered serious adverse reactions after being treated with the blood-thinning drug heparin. The culprit—over-sulfated chondroitin sulfate (OSCS)—was discovered to have been substituted for some actual heparin. OSCS costs far less and was able to deceive existing quality tests by mimicking heparin’s blood thinning characteristics. The FDA, USP and its expert volunteers, and heparin manufacturers quickly converged to update the existing standard to include a new OSCS detection test.

Given the widespread sourcing, manufacture, and use of heparin worldwide, input from industry scientists in different countries and regions was critical for updating the standard to address the crisis. USP also developed physical reference standards for manufacturers to verify that their heparin ingredients met new test requirements. This work yielded much more than a checklist for manufacturers to ensure regulatory compliance. To better ensure that bad actors could not easily mimic heparin again in the future, a more stringent verification test of true heparin was implemented through the USP standard. However, FDA and USP recognized that it would take time for all heparin manufacturers to be able to meet the new requirements as newer technology was required. Thus, a phased approach was used to deploy and enforce more rigorous testing requirements to avoid unintended heparin shortages. The result—improved quality overall in the world’s global supply of this critical medicine. USP, FDA and the pharmaceutical industry continue to strengthen the quality of medicines like heparin through ongoing, collaborative development of robust scientific standards.

Nitrosamines: Controlling harmful impurities

Nitrosamines are naturally occurring chemical compounds that people are regularly exposed to at low levels in foods and other substances, and some nitrosamines can increase the risk of developing cancer when people are regularly exposed to them over long periods of time.

In 2018, the U.S. Food and Drug Administration (FDA) detected nitrosamines in blood pressure medications that exceeded acceptable limits and sparked a series of recalls. At the time, one of the drugs affected by the recall was the ninth-most prescribed medicine in the United States. Since then, these and other forms of nitrosamines, including nitrosamine drug substance-related impurities (NDSRIs), have been found in other commonly used medicines.

In response, USP consulted with its own scientific experts as well as experts from industry, regulatory agencies, and academia to examine and evaluate challenges manufacturers face regarding nitrosamine impurities, and, working with our expert volunteers, developed new standards, technical training, and other resources to help support effective mitigation plans for controlling nitrosamine impurities. USP published a general chapter in USP-NF, General Chapter <1469> Nitrosamine Impurities, which identifies possible sources in drug products, their components and their manufacturing process, along with the risks associated with each source. The chapter provides recommendations on risk assessment and the development of detection and control strategies and provides manufacturers with a range of different test methods for the detection and quantitation of nitrosamines in their products, to help ensure they remain below harmful levels.

As the science has continued to evolve, USP offers a growing portfolio of more than 200 Pharmaceutical Analytical Impurities to help manufacturers identify, measure and refine strategies to control impurities across their R&D and manufacturing processes and is developing new nitrosamine reference materials that are not part of General Chapter <1469> and will continue to expand the list.

In 2021, USP launched the Nitrosamines Exchange -- and within it, the Analytical Hub -- an online community platform that offers members the chance to quickly share real-time updates, learnings, challenges and solutions with one another. The Exchange currently has nearly 4,000 members from 90 countries around the globe helping each other stay up-to-date with the latest science and regulatory developments in efforts to control nitrosamines. The community currently supports 22 languages and is quickly growing. Membership is free.

Diethylene glycol (DEG) and ethylene glycol (EG): Quality control and testing

DEG are contaminants that can lead to acute kidney failure or death. These substances can find their way into the supply chain in several ways, through mislabeled products, human error, or through intentional adulteration by manufacturers or suppliers to achieve higher profits, the cause of most recent DEG contamination cases.

In 1937, more than a hundred people, many of them children, died in the United States after ingesting DEG-tainted cough syrup. This led to federal law (Federal Food, Drug and Cosmetic Act), requiring drug manufacturers to prove the safety of their products before they can be marketed in the U.S. Congress also added the requirement that drugs must generally meet standards for identity, strength, quality and purity found in the United States Pharmacopoeia–National Formulary published by USP.

Then, between 1992 – 2007 in Panama, China, Haiti, Bangladesh, Argentina, Nigeria, and India, there were mass poisonings when toxic DEG was used instead of the more expensive non-toxic glycerin in cough syrups and other medicines. In response, the USP standard for propylene glycol was modified specifically to include testing for the presence of the impurity diethylene glycol.

Unfortunately, the tragedies associated with DEG and EG contamination continue. The World Health Organization (WHO) urged a Call to Action earlier this year after substandard medicines identified in The Gambia, Indonesia and Uzbekistan were found to potentially contain unsafe amounts of DEG and EG as contaminants, resulting in the deaths of more than 300 children. In response, the USP developed a toolkit for manufacturers, regulators, and country pharmacopeias to address DEG and EG contamination associated with allergy, cold and cough medicines.

Ingredient testing by manufacturers can be used to successfully detect the presence of DEG, EG, and other poisons. Such testing is required by law for certain products marketed in the U.S. However, not all countries have the same quality assurance requirements and resources, particularly low- to middle-income countries (LMICs). In addition to the toolkit, USP continues to work with FDA, manufacturers and regulators around the world to build capabilities and bolster supply chain resilience.

Hand Sanitizer: Addressing shortages and safety during COVID-19

In early 2020, the rapidly evolving COVID-19 pandemic caused an expected shortage of alcohol-based hand sanitizers. Pandemic-related supply chain pressures created global shortages that led to new manufacturers, materials, and production pathways to meet demand.

These fast-paced changes caused an emergence of quality incidents both regionally and globally. When dangerous hand-sanitizer products entered the markets, USP quickly responded to update the alcohol standards to detect the toxic substance, methanol. Since USP standards are referenced in the laws of over 50 countries, and used in over 100 more, this update helped improve the quality of alcohol throughout the entire global supply chain and protected consumers around the world.

To support the manufacturers and protect the public, USP worked closely with FDA to provide three new formulations for hand sanitizer using different forms of alcohol and new test methods to detect dangerous impurities, including methanol. Additionally, USP developed an online toolkit with guidelines from major public health organizations on compounding alcohol-based hand sanitizers and the preparation of hand sanitizers by manufacturers, pharmacies, and other facilities. The toolkit was developed to help organizations meet the demand for these products, in light of ongoing shortages of commercially manufactured sanitizers.