Ethylene Glycol and Diethylene Glycol Contamination Risks and FDA’s New Guidance on Testing in High-Risk Drug Components
The FDA has recently issued new guidance for the pharmaceutical industry regarding the testing of ethylene glycol (EG) and diethylene glycol (DEG) in high-risk drug components in response to recent reports of fatal poisoning from DEG- or EG-contaminated oral liquid drug products1. In early 2023, the World Health Organization (WHO) issued worldwide health alerts regarding EG and DEG-contaminated medications in Indonesia, Gambia, and Uzbekistan, which were associated with over 300 fatalities, primarily in young children.2
While Ethylene Glycol and Diethylene Glycol have similar physical properties and a slightly sweet taste similar to other polyols, they are actually toxic. Ethylene Glycol and Diethylene Glycol are commonly used in antifreeze formulations like windshield wipers and engine coolants. Unfortunately, these substances have been found as contaminants in some commonly used excipients, including glycerin, propylene glycol, maltitol solution, sorbitol solution, and hydrogenated starch hydrolysate. These excipients are extensively used in various oral liquid formulations, such as cough syrups, antihistamines, analgesics, and antiemetics. Contamination can occur during the manufacturing process or through intentional adulteration. DEG and EG-contaminated drugs can cause serious harm or even death. EG and DEG are metabolized by alcohol dehydrogenase in the body, producing toxic metabolites that initially affect the central nervous system (CNS), then progress to impact the heart and eventually cause kidney damage. The accumulation of EG’s toxic metabolites leads to the deposition of calcium oxalate crystals in the kidneys, while DEG’s toxic metabolite, diglycolic acid, results in renal dysfunction.3,4 Kidney failure is the primary cause of death resulting from EG and DEG toxicity.
The FDA has primarily identified glycerin and certain sugar polyol solutions as high-risk drug components that have historically been found to be contaminated with EG and DEG. However, there are other drug excipients that are also susceptible to EG and DEG contamination. Generally, drug components synthesized from EG and DEG or manufactured in a similar synthetic scheme would be considered high-risk. For example, widely used sugar polyols such as maltitol, sorbitol, and hydrogenated starch hydrolysate are typically manufactured from their corresponding monosaccharides through catalytic hydrogenation. During this process, the sugar polyols can further undergo hydrogenolysis to form EG and DEG.5 Glycerin and propylene glycol, commonly used in the pharmaceutical industry, can also yield shorter polyhydric alcohols like ethylene glycol and diethylene glycol during their manufacturing process.6 As a result, EG and DEG can be present as process impurities in most sugar polyols. Additionally, EG and DEG have similar physical properties and natural sweetness like glycerin, propylene glycol, and other sugar alcohols, making them susceptible to intentional adulteration. Also, commonly used polyethylene glycol-based pharmaceutical surfactants, emulsifying agents, and solubilizers (such as polyethylene glycols, polyoxyethylene, and polysorbates) are commercially manufactured from ethylene glycol or ethylene oxide involving ethylene glycol as process intermediate. DEG is a by-product of the ethylene glycol conversion process and forms via partial hydrolysis of ethylene oxide. Therefore, EG and DEG can be present as process impurities in most synthetic surfactants. Surfactants are typically used in small amounts in liquid formulations but may be used to a greater extent in liquid emulsion-based formulations.
It is crucial for drug product manufacturers to implement sufficient measures to minimize the risk of EG and DEG contamination. FDA recommends that DEG and EG levels are controlled to no more than 0.10% in high-risk drug components, in line with the recommendations of the USP monographs for Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, and Sorbitol Solution. The FDA recommends testing DEG and EG as per the United States Pharmacopeia-National Formulary (USP-NF) compendia, where applicable, and implementing a suitable and equivalent procedure that includes a test to detect and quantify DEG and EG when the DEG and EG tests are not included in the USP-NF monograph. The following is a list of excipients that might be considered high-risk based on the likelihood of the presence of EG and DEG. However, please note that this list is not comprehensive, and the individual risk category should be based on specific applications such as formulation, concentration, and route of administration.
Table 1: List of High-Risk Excipients that Should be Tested for Ethylene Glycol and Polyethylene Glycol
|High-Risk Excipients||Recommended Testing|
|Propylene Glycol||USP-NF Monograph|
|Maltitol and Maltitol Solution||USP-NF Monograph|
|Sorbitol and Sorbitol Solution||USP-NF Monograph|
|Hydrogenated Starch Hydrolysate||USP-NF Monograph|
|Other sugar polyols synthesized via catalytic hydrogenation||Suitable Test Method|
|Polyethylene Glycol (MW <1000)||USP-NF monograph|
|Diethylene Glycol Stearates||USP-NF monograph|
|Polyethylene Glycol Monomethyl Ether 350/550 (MW <600)||USP-NF monograph|
|Polyoxyl 35 Castor Oil||USP-NF monograph|
|Polyoxyl 40 Hydrogenated Castor Oil||USP-NF monograph|
|Polysorbate 20/40/60/80||USP <469>|
|Polyoxyl 15 Hydroxystearate||USP <469>|
|Polyoxyl 20 Cetostearyl Ether||USP <469>|
|Polyoxyl 8 Stearate||USP <469>|
|Octoxynol 9||USP <469>|
|Nonoxynol 9||USP <469>|
|Surfactants, emulsifying and solubilizing agents manufactured from Ethylene Glycol||Suitable Test Method|
If DEG or EG levels exceed the USP-NF limit in any drug component, manufacturers should report it to FDA. If any batches of drug products containing components with DEG or EG levels surpassing 0.10% are already distributed, manufacturers should contact the appropriate Division of Pharmaceutical Quality Operations to determine the appropriate course of action, including product recall.
- Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other HighRisk Drug Components for Diethylene Glycol and Ethylene Glycol | FDA. (n.d.). Retrieved June 1, 2023, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol
- WHO urges action to protect children from contaminated medicines. (n.d.). Retrieved May 28, 2023, from https://www.who.int/news/item/23-01-2023-who-urges-action-to-protect-children-from-contaminated-medicines
- Fowles, J., Banton, M., Klapacz, J., & Shen, H. (2017). A toxicological review of the ethylene glycol series: Commonalities and differences in toxicity and modes of action. Toxicology Letters, 278, 66–83. https://doi.org/10.1016/J.TOXLET.2017.06.009
- Marraffa, J. M. (2022). Diethylene glycol. Reference Module in Biomedical Sciences. https://doi.org/10.1016/B978-0-12-824315-2.00154-8
- Ooms, R., Dusselier, M., Geboers, J. A., op de Beeck, B., Verhaeven, R., Gobechiya, E., Martens, J. A., Redl, A., & Sels, B. F. (2014). Conversion of sugars to ethylene glycol with nickel tungsten carbide in a fed-batch reactor: high productivity and reaction network elucidation. Green Chemistry, 16(2), 695–707. https://doi.org/10.1039/C3GC41431K
- Lahr, D. G., & Shanks, B. H. (2003). Kinetic Analysis of the Hydrogenolysis of Lower Polyhydric Alcohols: Glycerol to Glycols. Industrial and Engineering Chemistry Research, 42(22), 5467–5472. https://doi.org/10.1021/IE030468L
Omar Sharif, Associate, Regulatory Affairs – CMC