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  • Writer's pictureVika Yadav

FDA new guidelines, For Testing of DEG and Ethylene Glycol in Drug Component at Risk

  • PharmaVector Content Desk

Over the years the FDA has received numerous reports of high risk contaminants such as diethylene glycol (DEG) or ethylene glycol (EG) in Glycerin and other highly used medication components. A DEG poisoning incident in 1937 in the United States resulted from people ingesting elixir of sulfanilamide containing DEG as a solvent. The event caused several deaths that included many children. It led to the enactment of the Federal Food, Drug, and Cosmetic Act (FD&C Act or Act), which authorized FDA to oversee safety of Food, Drugs and Medical Devices including but not limited to establishing Drug Approval Process. The recent DEG poisoning incidents from the liquid dosage form indicated for children caused more than 300 deaths in the year 2022 and 2023 across 7 countries..

FDA has announced the availability of revised 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; Guidance for Industry”. This guidance replaces the 2007 guidance and provides advice on how industry can comply with applicable regulatory requirements and outlines recommendations to help pharmaceutical manufacturers and other suppliers of high-risk drug components prevent the use of drug components contaminated with diethylene glycol (DEG) and ethylene glycol (EG).

FDA observed that these mishaps has the following similarities:

• The manufacturers of the liquid drug products that contained contaminated glycerin did not perform full identity testing on the glycerin raw material, including tests to quantification of 2DEG present and the purity of the glycerin received.

• The manufacturers of the liquid drug products containing contaminated glycerin relied on the certificate of analysis (COA) provided by the supplier of the glycerin.

• The origin of the glycerin was not readily apparent from the CoA. The COA available at DP manufacturer was often a copy of a COA on the letterhead of the distributor of the glycerin, and not the original manufacturer. The chain of custody or distribution history of the glycerin was also not readily known, as it was sold multiple times before use in manufacturing of liquid products.

With this amended recommendation, which can be found here, the FDA has outlined general requirements of cGMP, Testing required along the supply chain and responsibility of QC Units. In addition to cGMP and Regulatory requirements, the agency has provided following additional recommendations-

  1. Ensure the specific identity analysis for each lot, which includes a limit test for DEG and EG, incorporates testing of samples from all containers of all lots of a high-risk drug component before the high-risk drug component is used in the manufacture or preparation of drug products.

  2. For high-risk drug components* where the DEG and EG tests are not included in the identification test of the USP-NF monograph for the component, a manufacturer uses a suitable and equivalent procedure that includes a test to detect and quantify DEG and EG, with safety limit for DEG and EG of NMT 0.10%.

  3. Drug product manufacturers maintain 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).

  4. All personnel in pharmaceutical manufacturing facilities (especially QC units) be made aware of the importance of proper DEG and EG contamination testing

  5. Repackers/distributors of high-risk components for use in drug products, test the high-risk components that are used, sold for use, or intended for use in drug products. Accurate and complete COAs that identify the original manufacturer of the components should be issued for each component lot shipment.

  6. Pharmacies that compound drug products and that use high-risk components in compounding either test each lot of each high-risk component for DEG and EG content, or ensure that such testing was properly done by a reliable supplier.

* Though FDA has only mentioned few components, such as Glycerin, Propylene glycol, Sorbitol etc, but it also recommends that all drug component which is at high-risk, with examples, such as, including but not limited to, PEG (<1000 MW), Diehtylene Glycol Sterate, Polysorbates, Polyoxyl 35 castor oil, be tested for DEG/EG.

The agency also expects that if the manufacturer has identified any of the drug component lots, with DEG/EG limits above the safety limits, used in drug product batches under distribution, appropriate Office of Product Quality be contacted for further action,such as voluntary recall.

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