Testing for ethylene glycol, diethylene glycol and methanol – a hot topic during FDA inspections

The testing of starting materials and excipients used in the manufacture of medicinal products and active pharmaceutical ingredients is a basic GMP requirement. Compliance with this requirement is a hot topic during FDA inspections. Since 2023, the frequency of deficiencies in the testing of starting materials described in FDA warning letters has risen significantly. The regulatory requirements for this inspection are described in the Code of Federal Regulations 21 CFR 211.84.

What is the reason for this sudden increase in violations of Section 211.84?

Background

In May 2023, the FDA published the Guidance for Industry "Testing of Glycerin, Propylene Glycol, Malitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol' in response to incidents involving contaminated medicines – mainly paediatric medicines – which resulted in numerous deaths. These incidents were described in early January 2023 in a WHO communication entitled ‘WHO urges action to protect children from contaminated medicines’ about cases of poisoning in Gambia, Indonesia and Uzbekistan.

Ethylene glycol (EG) and diethylene glycol (DEG) are industrial chemicals used as antifreeze agents and are highly toxic to humans. They have a similarly sweet taste to glycerine, which is used in children's medicines such as cough syrup. Here, glycerine was obviously deliberately replaced with these glycol compounds in order to save costs – with fatal consequences.

The tragedy of this problem is particularly evident in the already far too long history of poisoning cases: in 1937, almost 90 years ago (!), 107 people, including many children, died in the United States from a medicine contaminated with DEG (sulfanilamide elixir). This disaster led to the enactment of the Federal Food, Drug, and Cosmetic Act and the establishment of the FDA as a regulatory authority. Further incidents occurred in 1995 and 1996 (Haiti), between 1990 and 1998 (Argentina, Bangladesh, India, Nigeria) and in 2006 (Panama).

What are the reasons why such contaminated preparations keep appearing on the market?

Main causes of contamination with DEG/EG

The Guidance for Industry lists three recurring errors in the control of supplied glycerine

• A complete identity test and a quantitative purity test are missing.
• The pharmaceutical manufacturer relies blindly on the supplier certificate for glycerine.
• The original manufacturer of the glycerine is not indicated on the certificate, i.e. the information on the certificate was copied onto the supplier's letterhead and does not correspond to that on the original certificate.

This is precisely what is reflected in the warning letters issued over the last three fiscal years – proof that violations of the obligation to adequately test raw materials are still commonplace, which ultimately led to the creation and publication of this guidance. A review of the warning letters issued during the 2023–25 financial years reveals another interesting point: Many of the companies that do not adequately test their raw materials manufacture topical products and hygiene items such as disinfectant wipes and hand sanitiser. In the latter case, the FDA criticises inadequate testing of ethanol for methanol, referring to the Guidance for Industry ‘Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol’, also published in 2023. The high number of these companies among the recipients of warning letters is a consequence of the coronavirus pandemic, during which numerous companies added hand sanitiser to their product portfolios – some of them, unfortunately, without adequately testing the main ingredient, ethanol.

The two guidelines on testing ethanol and testing glycerine and other high-risk components cannot be overestimated in terms of their relevance for the immediate protection of end consumers and represent an important addition to the already quite detailed requirements of Section 211.84.