By Al Lorman, AAHP Counsel
The Food and Drug Administration (FDA) has begun another campaign to protect consumers from products that contain glycerin potentially contaminated with diethylene glycol (DEG) or ethylene glycol (EG). Last month, FDA issued an immediately-effective final guidance document, “Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol [DEG] and Ethylene Glycol [EG].” It essentially requires testing to assure that the ingredients named in the guidance contain no more than 0.10% of DEG and EG. This limit was adopted from USP monographs for a number of drugs. Ingredients containing quantities above that level are considered adulterated. FDA considers failure to test incoming glycerin and the other named ingredients a violation of the CGMP requirements. It is important to note that the Homeopathic Pharmacopeia of the United States provides that glycerin used in homeopathic products must meet the requirements of the USP, including the impurity test. The time to review your handling of incoming glycerin is now.
The new guidance updates and broadens a guidance document issued in 2007, which applied only to glycerin. Ironically, it was a 1937 outbreak of poisonings by DEG contained as a solvent in elixir of sulfanilamide which killed 107 persons and led to the enactment of the Federal Food, Drug, and Cosmetic Act of 1938.
In announcing the new guidance, FDA stated that:
In 2022 and 2023, numerous countries reported incidents of oral liquid drug products, primarily indicated for children, with confirmed or suspected contamination with high levels of DEG and EG. The cases of contamination, spanning at least seven different countries, were associated with more than 300 fatalities — mostly in children under the age of 5. At this time, FDA has no indication that any contaminated products connected to these recent international incidents have entered the U.S. drug supply chain.
In the last five years, FDA has issued 47 Warning Letters for failure to test for glycerin impurities; ten of those letters were issued this year. A homeopathic drug manufacturer in India received one of these Warning Letters after an FDA review of records supplied in response to a records request showed that because the company “did not perform the identity testing on each shipment of each glycerin lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of glycerin used in the manufacture of drug products.” FDA also noted that:
Additionally, in response to our record request, you tested retain samples of some finished product batches that had been shipped to or distributed in the United States for the presence of DEG and EG impurities using the 2018 Indian Pharmacopeia (IP) monograph for glycerin. However, you did not demonstrate that the 2018 IP method used for glycerin testing is suitable to identify the levels of DEG or EG in the finished drug product. Furthermore, you did not test every lot of drug product shipped to or distributed nor provide any evidence that would substantiate the results of the analytical testing (e.g., quantitative worksheets and chromatograms for impurities for each batch that was tested).
The company’s drugs were added to the automatic detention list. The Warning Letter is available here.
In a letter to the manufacturer’s U.S. distributor, FDA pointed out that the alleged violations are “particularly concerning from a public health perspective because of these CGMP violations and because [the drugs] are directed for use in infants and young children.” (Emphasis added.) This letter is available here.
AAHP has learned that at least one overseas manufacturer of homeopathic products has received an FDA records request asking if the company “manufacture[s] finished drug products or components (e.g., ingredients, processing aids) containing high-risk components such as propylene glycol, glycerin, polyethylene glycol, sorbitol solution, maltitol solution, and/or hydrogenated starch hydrolysate?” A positive response to this question leads to a number of highly specific questions concerning the products containing the “high risk” ingredients, including the identity of the finished products containing “high risk” ingredients, the testing associated with those ingredients, who conducts the testing, and copies of test worksheets. It is likely that all AAHP member companies will receive a similar document request if they have not already received one.
Although this guidance document is immediately in effect, it remains subject to comment in accordance with FDA's Good Guidance Practice regulation.