Contamination of Drug Components and Products with Ethylene Glycol and Diethylene Glycol

9 June 2023

At the start of May 2023, the FDA published a new Guidance for Industry 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). My own research on this subject has been very limited, however, three things are clear. The final products affected such as cough syrups have meant that sadly, mainly children have been affected and 100’s have died from kidney failure as a result, and also much of the concern has focused on Glycerin raw material contaminated with DEG and EG.

This most recent FDA publication on the topic has been made to further alert manufacturers of a duty of care to consider the possible contamination of pharmaceutical materials with ethylene glycol and diethylene glycol. This story is not new, and in fact, can be traced back to 1937 when the deliberate addition of DEG as a solvent to the elixir of sulphanilamide. In the US, this led to the deaths of 107 individuals, mainly children, due to kidney failure. This resulted in the first US act requiring the safety demonstration of drugs before marketing. During the 1990s contaminated glycerol was responsible for many 100’s of deaths, again mainly children, in less developed regions such as Africa, South America, and Asia. The World Health Organisation (WHO) has had a major role in the dissemination of relevant information on a number of occasions and again at the end of January 2023 published guidance to help protect children from contaminated medicines. This stated that in 2022 and early 2023, and across seven different developing countries, over 300 children died as a direct result of the contamination of oral liquid drug products, as recently highlighted in an article on the Pharmaceutical Technology website, b my colleague John Welch. On perhaps the only positive note, there is no evidence that contaminated products have entered either the US or UK supply chains. I have focussed on the FDA responses to these problems but would point out that the MHRA has mirrored the FDA and issued much information and guidance to the UK pharmaceutical industry.

I accept that as yet, the UK has not been affected, however, one question I would pose is that while the FDA has highlighted the contamination problem as having a possible effect on Sorbitol Solution, with the USP monograph including a specific test for EG and DEG, why has no such test been adopted by the corresponding PhEur monographs for Sorbitol Liquids? The same is true for Maltitol Solution.

At Butterworth Laboratories I can confirm that we routinely perform the determination of EG and DEG on Glycerin and Propylene Glycol. We have also tested for EG and DEG in Maltitol Solution. We have also tested Nonchristallizing Sorbitol Solution for EG and DEG. We also recently validated methods for the analysis of EG and DEG in Polysorbate 20 and Polysorbate 80 based on the USP General Chapter <469>.

I can understand why DEG and EG could be found and is indeed often found at low levels in Glycerin and Propylene Glycol, however, I would ask another question of the reader of the present article. Why are DEG and EG found in Maltitol Solution, Hydrogenated Starch Hydrolysate, and Sorbitol Solution? Is this due to degradation or by-products of manufacture?

Frank Judge – Consultant Chemist Chromatography