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Why was this new Guidance for Industry developed?
In May of 2023, the FDA published a Guidance for Industry intended for immediate implementation. The 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: Guidance for Industry, is intended to address the potential public health hazard of diethylene glycol or ethylene glycol contamination in pharmaceutical products.1 Diethylene glycol and ethylene glycol (commonly known as anti-freeze) are toxic organic solvents that can cause significant adverse effects when ingested, including kidney failure and even death.2,3 In 2022 and 2023, cases of diethylene glycol and ethylene glycol toxicity as a result of contamination of liquid drug products resulted in more than 300 fatalities, primarily in pediatric patients.1 In January of 2023, the World Health Organization (WHO) published a statement calling for urgent action to prevent future poisonings and deaths as a result of diethylene glycol and ethylene glycol contamination in pharmaceutical products. At the time of publication of the above-mentioned Guidance FDA stated that it was not aware of contaminated products in the US supply chain. To maintain the safety of liquid drug products, FDA released this Guidance outlining specific procedures for testing and documentation of high-risk drug components for diethylene glycol and ethylene glycol.
How does contamination occur?
Diethylene glycol has chemical and physical properties similar to glycerin and propylene glycol. Diethylene glycol is synthesized from the reaction of ethylene oxide with ethylene glycol, so in addition to its own toxicity profile, diethylene glycol may also contain ethylene glycol as a toxic impurity. Given the similar properties and lower associated cost, contamination of common pharmaceutical excipients such as glycerin or propylene glycol has been hypothesized to occur as a cost cutting measure.4,5 In 2009, in response to FDA Guidance for Industry titled “Testing of Glycerin for Diethylene Gycol,”6, the United States Pharmacopeia (USP) updated the Monograph for glycerin to include diethylene glycol and ethylene glycol testing.7 The Monograph for propylene glycol was later updated in 2010 to add a limit of diethylene glycol and ethylene glycol to the identification.8
Which excipients are affected by this Guidance for Industry?
The Guidance specifically references glycerin, propylene glycol, maltitol solution, hydrogenated starch hydrolysate, and sorbitol solution as well as “other high risk drug components”.9 Fagron will be performing this testing on incoming lots of glycerin, polysorbate 20, polysorbate 80, PEG 300, PEG 400, diethylene glycol monoethyl ether (ethoxy diglycol), propylene glycol, and sorbitol solution consistent with the Guidance and the potentially high-risk drug components that are currently offered by the Company.
What are the newly required tests?
For a complete list of required testing, please see the FDA Guidance linked below. Though diethylene glycol and ethylene glycol testing has been a requirement for some of these high-risk drug components previously per USP, the FDA has expanded and updated this guidance and included information on recommended procedures and required limits. Some of the new requirements and recommendations include:
1. All high-risk drug components must be tested for diethylene glycol and ethylene glycol and ensure that no more than 0.1% of either contaminate is present in the product. The FDA recommends that this testing be performed on all containers of all lots of product prior to the use of the material as a drug component.10
2. Repackers who distribute and prepare high-risk components for use in drug products must perform the above testing on products intended for use in drug products. Repackers and distributors must also provide accurate and complete certificates of analysis (CoAs) that identify the original manufacturer and issue this CoA with each shipment.11
3. Pharmacies that compound drug products using these high-risk components either test each lot of high-risk components for diethylene glycol and ethylene glycol or ensure that the testing was done by a reliable supplier.12
What is Fagron currently doing to remain in compliance?
Fagron has historically ensured that all USP/NF grade products met standards put forth by USP and FDA, including any Monograph signifying diethylene glycol and ethylene glycol testing. Moving forward, Fagron will perform testing for diethylene glycol and ethylene glycol on all containers of all lots of incoming shipments of glycerin, polysorbate 20, polysorbate 80, PEG 300, PEG 400, diethylene glycol monoethyl ether (ethoxy diglycol), propylene glycol, and sorbitol solution. Additionally, as new batches are released Fagron will ensure that these high-risk excipients have Certificates of Analysis (CoAs) listing the original manufacturer of the product.
What does this mean for your practice?
Compounding pharmacies must ensure their potentially high-risk products come from a reliable supplier and that the above testing has been completed on their received product. It is essential for compounders to review every CoA for every active ingredient and excipient prior to its use in compounding. As new lots are received and repackaged by Fagron, we will ensure CoAs provided to customers note the relevant performed testing. For further questions regarding this new guidance or the steps Fagron is taking to stay in compliance, feel free to reach out to us at facts.support@fagronacademy.us.
You may review FDA’s Guidance for Industry in its entirety here: Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol | FDA
References:
1. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol.
2. Ghanem, H., Alkhayat A., & Almardini, A. (2012). Detection of diethylene glycol in glycerin and propylene glycol by using high performance thin layer chromatography HPTLC. IOSR Journal of Pharmacy(1), 29-34. http://www.iosrphr.org/papers/v1i1/D011029034.pdf.
3. Tanasescu, A., Macovei R.A, Tudosie, M.S. (2014). Outcome of patients in acute poisoning with ethylene glycol-factors which may have influence on evolution. Journal of Medicine and Life.; 7(3), 81-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391407/.
4. Ghanem, H., Alkhayat A., & Almardini, A. (2012). Detection of diethylene glycol in glycerin and propylene glycol by using high performance thin layer chromatography HPTLC
5. Centers for Disease Control. (2009). Fatal Poisoning Among Young Children from Diethylene Glycol-Contaminated Acetaminophen --- Nigeria, 2008—2009.. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5848a2.htm.
6. Federal Food and Drug Administration. (2007). Testing of Glycerin for Diethylene Glycol: Guidance for Industry. https://www.regulations.gov/document/FDA-2012-N-0143-0016
6. United States Pharmacopeia. (2009). Glycerin Monograph. https://www.uspnf.com/official-text/accelerated-revision-process/accelerated-revision-history/glycerin-monograph.
7. Elder D. (2022). The lingering menace of diethylene glycol/ethylene glycol adulteration. European Pharmaceutical Review (6). https://www.europeanpharmaceuticalreview.com/article/177370/diethylene-glycol-ethylene-glycol-adulteration/.
8. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol.
9. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry.
10. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry.
11. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry.
12. Federal Food and Drug Administration. (2023). Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol: Guidance for Industry.
