FDA Goes Back to Basics with Multiple Observations for Diethylene Glycol and Ethylene Glycol

In 2022, there were six Warning Letters and five 483 observations for issues relating to Diethylene Glycol (DEG) and Ethylene Glycol (EG). In 2023, there were thirty-six Warning Letters and nineteen 483 observations for DEG and EG concerns. So far this year (mid-February 2024), there have already been three Warning Letters containing observations for DEG and EG.

Why is the FDA concerned about this topic?

DEG and EG are poisonous contaminants that have resulted in fatalities by consumers of liquid drugs. In fact, these chemicals were an impetus in the passage of the Federal Food, Drug, and Cosmetic Act (FFDCA) in 1938 in response to DEG contamination of elixir of sulfanilamide that took the lives of 107 people, many of them children, in 1937. There have been repeated incidents of DEG contamination of liquid drug products resulting in deaths worldwide in subsequent years. As recently as 2022 and 2023, incidents of poisoning with DEG and EG in liquid drug products were reported in numerous countries.

What is the cause of poisonings with DEG and EG in drug products?

In most recent poisonings, it has been found that the Certificate of Analysis (COA) from the supplier was not reliable and the receiving pharmaceutical manufacturer did not test the incoming material for DEG and EG.

How can you avoid getting a 483 or Warning Letter observation for DEG or EG?

Drug products, drug substances, and drug components intended as excipients of a drug product must be controlled, per the Food and Drug Act. Identity testing must be conducted for each component of a drug product, which may include a limit test as part of identity testing of excipients with a high risk of containing DEG or EG.

The FDA has recently issued a revised Guidance to clarify that incoming identity testing must be performed for materials that are at high risk for containing DEG or EG. The materials listed in the FDA guidance encompass some, but not all, of the components that have a high risk of containing DEG or EG. USP-NF monographs for the high-risk components often include DEG and EG limit testing. It is expected that all containers received and intended for use in finished pharmaceuticals are tested. If there isn’t a monograph test, it is expected that the drug manufacturer develops an appropriate test for high-risk materials.

The FDA Guidance: Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol can be found here. If you or your firm are unclear on the FDA’s expectations with respect to DEG/EG testing, Lachman can help! Please reach out to us at LCS@LachmanConsultants.com for a consultation.