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Jun 19, 2023

FDA Guidance Outlines Expectations to Mitigate the Risk of Diethylene Glycol and Ethylene Glycol Contamination of Drug Products

Throughout 2022 and 2023, various countries reported confirmed or suspected cases of diethylene glycol (DEG) and ethylene glycol (EG) contamination in drug products that resulted in over 300

Throughout 2022 and 2023, various countries reported confirmed or suspected cases of diethylene glycol (DEG) and ethylene glycol (EG) contamination in drug products that resulted in over 300 fatalities, drawing several similarities to the 1937 case of DEG poisoning in the United States that led to the enactment of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in 1938. The World Health Organization also reported, on April 30, 2023, and June 16, 2023, that the risks associated with toxic EG and DEG–containing cough syrup are still present in multiple countries. On July 28, Bloomberg news published an extensive article related to such contamination found in market samples in some jurisdictions.

These recent incidents of DEG and EG contamination due to high-risk drug components, such as glycerin and propylene glycol, have prompted the U.S. Food and Drug Administration (FDA) to issue new guidance for pharmaceutical manufacturers, compounders, repackers, and suppliers. Specifically, in May 2023, the FDA published, for immediate implementation, its guidance for industry, Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol.

FDA’s guidance identifies certain practices that have allowed DEG- and EG-contaminated drug components to enter the pharmaceutical supply chain, including

FDA’s guidance highlights existing regulations and requirements drug manufacturers should follow to mitigate the risks of DEG and EG contamination of drug products. These include

FDA’s guidance goes further and provides additional recommendations that may exceed the scope of the existing requirements, which speaks to the agency’s focus and attention on preventing further incidents of such contamination. For example, FDA’s guidance recommends the following:

FDA has also recently issued warning letters to various drug manufacturers that make products containing high-risk components and that have failed to comply with identity testing requirements or establish reliability of the test analyses of a component’s supplier. Notable examples of warning letters issued in 2023 include these:

FDA’s guidance and recent warning letters make clear the agency’s compliance and enforcement focus on DEG and EG contamination controls and oversight. We expect FDA’s continued focus on this issue, and we expect FDA inspections to delve deeply into a drug manufacturing facility’s compliance with FDA’s guidance document. Accordingly, it will be critical for drug manufacturers to, among other things, proactively ensure compliance with the expectations detailed in FDA’s guidance, including maintaining current knowledge of their supply chain for high-risk drug components (i.e., the identity of the original manufacturer of the component and any subsequent repackers or distributors), evaluating specifications to ensure they align with FDA’s guidance, and ensuring a testing regimen that includes sampling from each container of each lot.

Our recent experiences indicate that FDA is using various tools such as records requests under 704(a)(4) to request specific information related to the firm’s controls of such high-risk components prior to release for manufacturing. FDA is also detaining suspected products and requesting information related to DEG and EG levels in the specific lots of high-risk components used in the manufacture of the detained lots and, if applicable, finished product testing.

Thank you to Ava Romanelli, intern for Sidley's Food, Drug and Medical Device practice group, for her significant contribution to this Update.

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