(M1430-02-13) Diethylene Glycol and Ethylene Glycol Challenges: Compendial Approach and Emerging Standards

Purpose: Since 1937, poisoning cases caused by contaminated or adulterated diethylene glycol (DEG) and ethylene glycol (EG) in medicines have been reported worldwide. See Table 1. (1-11) In response, the US Food and Drug Administration (FDA) and USP have been collaborating to address these serious public health issues. From 2007 to 2013, USP updated seven high-risk excipients, including Glycerin, Propylene Glycol, three Sorbitol solutions, Maltitol Solution and Hydrogenated Starch Hydrolysate, by adding the EG/DEG test to the Identification (ID) section of these monographs, consistent with the requests from the FDA. Additionally, a general chapter < 469 > ETHYLENE GLYCOL, DIETHYLENE GLYCOL, AND TRIETHYLENE GLYCOL IN ETHOXYLATED SUBSTANCES was developed in 2013-2014. >Tragically, between 2022 and 2023, over 300 fatalities—primarily children—occurred again in several countries due to EG/DEG contamination or adulteration of these high-risk excipients. Therefore, the World Health Organization (WHO) issued several alerts (1, 4–11), and the US FDA released a guidance in May 2023 for immediate implementation of industry to test high-risk excipients for EG and DEG (12). USP is currently employing multiple approaches, including both compendial and iterative approaches – emerging standards, to address the FDA’s February 2023 letter concerning the revision of the Polyethylene Glycol (PEG) monograph (13) and another FDA request to publish a validated EG/DEG testing method for liquid oral dosage forms. This poster will detail the proposed methods outlined in Chapter < 470 > Determination of Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Polyethylene Glycol and the EG/DEG testing methods for dosage forms that are intended to be published as emerging standards. Representative chromatograms will also be included to illustrate the methods.

Methods: In response to the FDA’s 2023 letter regarding PEG, USP issued several General Announcements and conducted a stakeholder survey between 2023 and 2024. These efforts aimed to gather feedback, collect batch data across various PEG grades, and obtain available EG/DEG testing methods from industry. As a result, the PEG monograph revision proposal was published in PF 50(3) [May – Jun. 2024] to include the EG/DEG test in the ID section with appropriate specification limits. (14) Since the existing EG/DEG testing method in Chapter < 469 > is not ideal for frequent ID testing because of high column temperature and long run time, a new standalone general chapter < 470 > was developed, as part of an iterative approach.(15) The new chapter < 470 > was published in PF 50(5) [Sep.-Oct. 2024] to propose several EG/DEG testing procedures for stakeholders to evaluate the equivalency and interchangeability of these methods and use them as alternative methods as necessary. USP also published an EG/DEG toolkit that is free for all interested stakeholders (16). In addition to testing high-risk excipients for EG and DEG, the US FDA laboratory has developed and validated a gas chromatography–mass spectrometry (GC-MS) method for detecting EG/DEG in liquid cough, cold, and allergy products containing glycerin. In collaboration with the FDA, USP plans to publish this method as an emerging standard. USP recently received several additional EG/DEG testing methods for oral drug dosage forms, including GC with flame ionization detection (GC-FID), GC-MS, and high-performance thin-layer chromatography (HPTLC). USP also plans to publish these methods using the emerging standards approach.

Results: Five EG/DEG testing procedures for PEG have been proposed in the new Chapter < 470 >. The highlights of these methods have been summarized in Table 2. As shown in Table 2, different column temperature and run time of each method affect the column lifetime and its suitability for frequent ID testing. Additionally, each method is only suitable for a certain range of PEG molecular weight. Four EG/DEG testing methods for oral liquid dosage forms are summarized in Table 3 and will be published as emerging standards on the USP website. To showcase the above methods, representative chromatograms will be displayed on the poster.

Conclusion: USP is taking multiple approaches to support stakeholders in addressing the significant public health risks posed by EG/DEG contamination/adulteration. By leveraging compendial standards and emerging standards, USP offers tools that enable stakeholders to implement effective quality control testing of EG/DEG for high-risk excipients and drug dosage forms. The approaches include: Compendial standards: 1) Update the high-risk excipient monographs by adding the EG/DEG test to the ID section that stakeholders must implement to comply with the current Good Manufacturing Practice (cGMP) requirements according to US Food, Drug & Cosmetics Act. 2) Create a standalone chapter < 470 > to provide analytical methodologies for stakeholders to evaluate and select based on their intended use. The methods are not mandatory if the chapter is not cross-referenced in monographs. Emerging Standards: Publish methodologies for EG/DEG testing in drug dosage forms through an emerging standards approach. While not mandatory, these emerging standards serve as early-stage tools to engage stakeholders and explore potential pathways toward the development of official compendial standards.

References: 1) “WHO urges action to protect children from contaminated medicines” published on January 23, 2023, https://www.who.int/news/item/23-01-2023-who-urges-action-to-protect-children-from-contaminated-medicines
2) Schep LJ et al. (2009) Clin. Toxicol., 47, 525-535.
3) Sheehan C et al. (2010) J. Excipients and Food Chem. 1 (2), 33-39
4) https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicines;
5) https://www.who.int/news/item/02-11-2022-medical-product-alert-n-7-2022-substandard-(contaminated)-paediatric-liquid-dosage-medicines; https://www.reuters.com/business/healthcare-pharmaceuticals/deadly-indonesian-cough-syrup-was-almost-pure-toxin-court-papers-show-2023-10-13/
6) https://www.who.int/news/item/11-01-2023-medical-product-alert-n-1-2023-substandard-(contaminated)-liquid-dosage-medicines;
7) https://www.livemint.com/news/india/uzbekistan-cough-syrup-deaths-centre-alerts-pharma-companies-against-maya-chemtech-s-propylene-11678807916498.html
8) Medical Product Alert N°4/2023: Substandard (contaminated) syrup medicines, https://www.who.int/news/item/25-04-2023-medical-product-alert-n-4-2023--substandard-(contaminated)-syrup-medicines.
9) https://www.who.int/news/item/15-04-2024-medical-product-alert-n-1-2024--falsified-(contaminated)-usp-ep-propylene-glycol#:~:text=Alert%20Summary,/EP)%20for%20medicinal%20use.
10) NAFDAC: https://nafdac.gov.ng/public-alert-no-013-2024-alert-on-recall-of-benylin-paediatrics-syrup-in-nigeria/
11) Kenvue (spin off from J&J) recalls in Nigeria: https://www.telegraph.co.uk/global-health/science-and-disease/rwanda-nigeria-kenya-south-africa-toxic-benylin-cough-syrup/
12) 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, May 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-propylene-glycol-maltitol-solution-hydrogenated-starch-hydrolysate-sorbitol
13) Letter from FDA (July 30, 2020) https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/fda-letter-alcohols-nitr-att.pdf
14) USP-NF Polyethylene Glycol, PF 50(3) [May-Jun. 2024]
15) USP-NF 〈470〉 Determination of Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Polyethylene Glycol, PF 50(5) [Sep.-Oct. 2024].
16) Diethylene Glycol (DEG) Resources, https://www.usp.org/excipients/diethylene-glycol-resources

Acknowledgements: This poster was based on the work of the USP 2020-2025 Complex Excipients Expert Committee. The views expressed in this poster are those of the authors and do not reflect official views and policies of the USP, USP Council of Experts, or the authors' institutions.

Table 1. Diethylene Glycol Incidents and Deaths

Table 2. Summary of EG/DEG Methods for Polyethylene Glycol in Chapter <470>

Table 3. Summary of EG/DEG Methods for Liquid Drug Dosage Forms