A Mission Focused on Quality and Safety

Diethylene glycol (DEG) and ethylene glycol (EG) are toxic when ingested above acceptable limits. They can make their way into drug products as process impurities during the manufacture of four sugar alcohols (for example, sorbitol and maltitol solutions) and excipients manufactured with ethylene oxide as a starting material (for example, polyethylene glycol). Process-related impurities, such as EG, DEG (a dimer of EG), and triethylene glycol (TEG; a trimer of EG), may arise from the hydrogenation process of sugar alcohols or the reaction of ethylene oxide with water.

DEG and EG can also appear in drug products through economically motivated adulteration of high-risk excipients, such as glycerin and propylene glycol, which have a similar taste and appearance but are less expensive. Excipients can comprise up to 90 percent of a drug formulation, but their quality is often overlooked.

DEG and EG can find their way into the supply chain of any country. For products entering the US, testing of raw materials, active pharmaceutical ingredients, and inactive ingredients by the drug manufacturer is a cGMP requirement. However, low-to-middle-income countries may not have the same quality assurance requirements and/or resources to be able to identify deadly contaminants in medicines. 

Key factors contributing to the contamination of final drug products with DEG or EG include inadequate supplier qualification (lack of origin), lack of appropriate identity testing, and a complex supply chain (chain of custody). More about this is written on USP’s website: “Ensuring Product Safety: U.S. FDA Guidance on Testing High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol.”

DEG and EG adulteration and contamination have always been a serious public health concern, with deaths and adverse health outcomes caused by DEG and EG contamination occurring as early as 1937. The deaths of children have also been reported in many geographies over the last several decades. In 2022 and 2023, more than 300 deaths were reported because of people consuming liquid drug products contaminated with DEG and EG, including cough syrups and analgesics. Indeed, the seriousness of the issue has gained international attention in the past two years because of reports from multiple countries of patient deaths and illnesses, including young children.

Cough syrup and cold medicines are particularly vulnerable to adulteration because of cost pressure and commoditization. In many of the cases of DEG and EG contaminations seen with cough syrups, one of the main ingredients, glycerin, was replaced by DEG, which is cheaper. The physical properties of DEG and EG as colorless and sweet liquids make them difficult for patients, caregivers, or physicians to detect without laboratory testing, making these formulations more susceptible to contamination.

We have also seen an increase in the number of US FDA warning letters sent to manufacturers regarding DEG and EG testing over the past year. For context, there have been more than 40 warning letters from the US FDA on this topic since 2019 – but 33 of those have been issued since the start of 2023. These letters were sent to manufacturers that did not test or inadequately tested drug components for the presence of DEG or EG.

Testing requirements
 

US regulations require testing for impurities and adulterants in all raw materials used in medicines. Because of the high risk involved in DEG and EG contaminations, the US FDA Center for Drug Evaluation and Research issued additional guidance for industry members in May 2023 titled “Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol.”

If a manufacturer fails to follow this guidance, it can result in an FDA warning letter, import alert, and product recall, which is not only expensive, but also tarnishes the recipient organization’s reputation.

The latest FDA guidance is an update to the 2007 guidance on DEG. It identifies not only DEG but also EG as potential contaminants in high-risk components, including those listed in the title. It requires compliance with the identity standards for a drug, including drug components, with a name recognized in the USP-NF. The USP has several standards, including monographs, documentary standards, and reference standards, for several of the high-risk drug components – and has also organized multiple training workshops for manufacturers to increase their understanding of the use of standards for the quality assurance of excipients.

The guidance also states the incidents in liquid drug products before 2020 resulted because drug product manufacturers:

• Did not perform full identity testing on the glycerin raw material, including tests to quantify the amount of DEG present and to verify the purity of glycerin.
• Relied on the certificates of analysis provided by the supplier of the glycerin.
• Had limited information on the entire supply chain and chain of custody of the glycerin raw material, as it was not noted on the certificates of analysis. 

Pharmacopeial standards are science-based, data-driven, validated, and characterized, and they exist to confirm the identity, purity, strength, and quality of various drug components in drug development and manufacturing. These standards are used by manufacturers to prevent quality issues. The FDA requires that the identity of each component in a drug is verified, and that each component be tested for conformity with all appropriate written specifications for purity, strength, and quality. In place of such testing by the manufacturer, an analysis report may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such components by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.

The new FDA guidance from 2023 reinforces the requirement of identity testing and outlines recommendations for drug product manufacturers, repackers, preparers, and distributors of high-risk drug components, and for pharmacies. The following recommendations have been underscored: 

1. Drug product manufacturers must perform identity tests on samples from all containers of all lots of high-risk drug components.
2. For high-risk drug components, where the DEG and EG tests are not included in the identification test of the USP-NF monograph, a manufacturer uses a suitable and equivalent procedure that includes a test to detect and quantify DEG and EG, with a recommended safety limit of no more than 0.10 percent*.
3. Repackers, preparers, and distributors of high-risk components for use in drug products must test the high-risk components that are used, sold for use, or intended for use in drug products, providing the details of the original manufacturer in the certificates of analysis of each lot.

To prevent DEG and EG contaminations, manufacturers must test each incoming shipment (ideally each container of each shipment) of the high-risk excipient to ensure that levels of DEG and EG meet the limit set in the applicable pharmacopeia or regulatory guidance, have full transparency of the supply chain of the excipient, and purchase from a supplier – qualified by the manufacturer – that follows cGMP. In the absence of a pharmacopeial specification or regulatory guidance, they must verify that an excipient is safe in the amount it will be used.

Excipient manufacturers also make the same chemicals for use in non-pharmaceutical products in much larger volumes due to demand for that type of use. It is crucial that drug companies ensure that the excipients they receive have been manufactured according to applicable cGMP and are suitable for use in medicines.

Ensuring safety
 

At the USP, our mission is to ensure access to quality medicines and improve global health through public standards. Incidents such as contamination from DEG and EG reinforce the need for standards and the importance of investments in continuing to advocate for regulations that prioritize testing the quality of raw materials and industry practices that ensure patient safety.

Given the events surrounding substandard and falsified medicines that occurred in 2022 and 2023, it is clear that stakeholders must think differently about excipient quality. Monitoring, controlling, and testing the quality of all excipients in the medicines supply chain is necessary to protect patient safety.

As part of our work, we want to support all those involved in the global medicine manufacturing supply chain, which is why we have developed documentary standards that provide validated test procedures to establish the identity, purity, and quality of excipients through the USP–National Formulary (USP-NF); USP Reference Standards for excipients that have been tested and approved as suitable for use as comparison standards in USP-NF tests and assays; Ingredient Verification programs to test products, check documentation, and audit API, excipient, and dietary ingredients manufacturers; and on-demand learning opportunities through USP Education.

USP has also developed a free toolkit for DEG and EG in response to the World Health Organization issuing a call to action about substandard medicines containing unsafe amounts of these contaminants. The toolkit is designed to be used by manufacturers, regulators, and country pharmacopeias as a solution to address contaminations associated with allergy, cold, and cough medicines. It includes all relevant chapters, monographs, and other resources needed to advocate for excipient quality throughout the medicine supply chain – especially with high-risk components. Visit USP.org to download the toolkit.

It is important for industry members to identify all their high-risk components and have a proactive risk mitigation plan in place. To increase awareness on mitigating issues with raw materials, there was a session at the 2023 Asia-Pacific Economic Cooperation (APEC) forum’s Medical Product Supply Chain Dialogue titled “Mitigating and Managing Risks in Excipient Quality.” The forum panel emphasized the importance of implementing crucial measures, such as excipient testing, supplier qualification, and risk management through harmonized standards and regulations. As part of the USP’s APEC Center of Excellence status, we host the APEC Supply Chain Security Toolkit, which serves as a global resource to establish effective training programs, best practices, and processes for securing the global supply chain of medical products.

The FDA is also taking action to mitigate DEG and EG contaminations. Its May 2023 guidance requires compliance with the identity standards for a drug with a name recognized with the USP-NF, including drug components. Regulatory agencies in different countries can use this guidance, in addition to the World Health Organization (WHO) draft of a working document on cGMP for excipients used in pharmaceutical manufacturing, among other resources from regulatory agencies. USP is also working closely with FDA on the update of the documentary standard for polyethylene glycol (PEG). USP plans to revise the existing PEG monograph shortly and potentially propose several available DEG and EG testing methods through another avenue.

To ensure the safety of excipients, pharmaceutical manufacturers can work to increase transparency surrounding the origin of excipients, incorporate more testing throughout the supply chain, and verify the supplier’s certificate of analysis by conducting their own testing of incoming excipients. Users can find more information from USP Chapter <1080> Bulk Pharmaceutical Excipients—Certificate of Analysis in our toolkit.

Increasing education efforts can also ensure the safety of excipients. Sometimes there is a lack of awareness about needing a special grade for pharmaceutical use, which can result in the excipient manufacturer using the wrong grade excipient in a drug product. This single mistake can affect a drug product’s manufacturing or performance and can also possibly endanger patients who use the product. 

Unfortunately, DEG and EG adulteration and contaminations are not the only examples of how poor-quality excipients can lead to patient harm. By following pharmacopeial standards and testing every drug component before use, manufacturers can help protect public health by preventing contaminated and/or ineffective medicines from entering the supply chain. Excipient quality is critical to the integrity and functionality of a medicine and it cannot be an afterthought. 

* The USP-NF monograph on Polyethylene glycol (PEG) has a test for DEG and EG in the impurities section. The US FDA sent USP a letter requesting that the DEG and EG test be included in the Identification section of the PEG monograph for PEG above molecular weight of 1000.The USP Excipients Expert Committee is revisiting these two methods to determine if they are still relevant and if a test for molecular weights over 1000 should be developed based on newer technology. We are in the process of discussing with the FDA to get clarification for monographs that may have different specifications. Since the FDA did not submit a request to the USP to change the acceptance criteria, at this point, the compendial specifications for PEG are still what is listed in the monograph "NMT 0.25% of the sum of ethylene glycol and diethylene glycol" or "The absorbance of the Sample solution does not exceed that of the Standard solution, corresponding to NMT 0.25% of combined ethylene glycol and diethylene glycol" depending on the molecular weight.