Ethylene Glycol and Diethylene Glycol contamination in liquid formulations pose significant safety risks. In recent years, multiple fatalities have been reported due to the presence of these contaminants in drug products. This article covers testing high-risk drug components for Diethylene Glycol and Ethylene Glycol.
An Overview of Ethylene Glycol and Diethylene Glycol
Ethylene Glycol is an organic compound and the simplest member of the glycol family. It is an odorless, colorless, and flammable liquid with a sweet taste. It is primarily used in the industry to manufacture polyesters and antifreeze formulations. Despite its industrial utility, Ethylene Glycol is toxic at high concentrations.
Diethylene Glycol is a four-carbon dimer of Ethylene Glycol and shares similar properties. It is also a colorless and odorless liquid with a sweet taste, widely used as a solvent and ingredient in various consumer products. However, like Ethylene Glycol, Diethylene Glycol is highly toxic when ingested.
Historical Context and Misuses
Historically, Diethylene Glycol has been misused as a viscosity modifier in oral and topical pharmaceutical solutions and personal care products. Its sweet taste has led to its misuse in sweetening wine and beer, resulting in numerous poisoning epidemics in the early 20th century.
One of the most notable incidents occurred in 1937 in the United States, where Diethylene Glycol was used as a solvent in an antibiotic preparation, resulting in over 100 deaths, a third of which were children. This tragedy led to the enactment of the Federal Food, Drug, and Cosmetic Act in 1938.
Similar incidents have occurred worldwide, including in Haiti (1995- 1996), where Diethylene Glycol-contaminated glycerin used in acetaminophen syrup caused over 80 fatalities, primarily children. Other countries like Argentina, Bangladesh, India, Nigeria, and Central America have also reported fatalities due to Diethylene Glycol contamination.
Health Safety Risks
Both Ethylene Glycol and Diethylene Glycol are rapidly absorbed when ingested, leading to severe consequences such as coma, seizures, metabolic acidosis, kidney failure, and death. The predominant route of exposure is ingestion, making the contamination of pharmaceutical products particularly dangerous.
Recent Incidents and Regulatory Response
Since 2022, the World Health Organization (WHO) has issued six global medical alerts for over-the-counter medicines contaminated with Diethylene Glycol and Ethylene Glycol. These incidents have been reported in at least seven countries and are associated with more than 300 fatalities, primarily affecting children under five.
In response, the FDA has extensively interacted with the WHO and other regulatory bodies to prevent contaminated medicines from reaching the U.S. Unlike previous incidents, the recent 2022-2023 incidents are related to substituting Propylene Glycol with Diethylene Glycol.
In May 2023, the FDA published new guidance for testing high-risk drug components for Diethylene Glycol and Ethylene Glycol. This new FDA guidance replaces the 2007 guidelines on testing Glycerin for Diethylene Glycol contamination, underscoring the critical need for pharmaceutical companies and suppliers to recognize the risks associated with glycerin and other high-risk drug components.
These components can potentially be contaminated with Diethylene Glycol and Ethylene Glycol, posing significant health hazards. The updated guidance aims to prevent such contaminated components from entering the drug supply chain, safeguarding public health. Following its release, the FDA issued warning letters in August 2023 to companies that failed to document testing for Diethylene Glycol and Ethylene Glycol in high-risk components.
Examples include a South Korean firm that did not test each shipment and a lot of Glycerin and Propylene Glycol, as well as several U.S. firms that similarly should have performed full identification tests on Glycerin as mandated.
Key Points of FDA Guidance
The FDA’s guidance emphasizes the following:
- Compliance with current good manufacturing practices (cGMP) regulations (21 CFR parts 210 and 211).
- Treating bulk or repackaged high-risk drug components as actual drugs.
- Testing the identity of each component using specific identity tests on each shipment and lot before manufacturing drug products.
- Ensuring a quality unit is responsible for approving or rejecting incoming lots for manufacturing operations.
- Adhering to compendial identification standards for drug components.
- Performing specific tests for Diethylene Glycol and Ethylene Glycol as detailed in the USP monograph, with an acceptable limit of not more than 0.10%.
Recommendations for Manufacturers
Manufacturers are recommended to perform specific identification tests on all samples from all containers of all lots for high-risk drug components. If these tests are not included in the USP monograph, they should develop suitable procedures to detect and quantify Diethylene Glycol and Ethylene Glycol.
It is also crucial for manufacturers to maintain current knowledge of the supply chain for high-risk drug components. Additionally, they should train personnel on the importance of testing for these contaminants and the potential hazards if such testing is not performed.
Manufacturers must ensure that repackers and distributors test for these contaminants and provide accurate Certificates of Analysis. Compounding pharmacies should either test each lot of high-risk components themselves or ensure that reliable suppliers conduct the necessary testing.
Analytical Procedures for Testing
The USP details the limit tests for Diethylene Glycol and Ethylene Glycol using gas chromatography with a flame ionization detector. The test procedures are outlined in specific monographs and Identification or Impurities test and/or in USP 469.
Example for Gas Chromatography Parameters (as detailed in USP Glycerin Monograph)
- Detector temperature: 250°C
- Injector temperature: 220°C
- Carrier gas: Helium at a flow rate of 4.5 mL/min
- Injection volume: 1 µL
- Split ratio: 10:1
- Oven temperature: As detailed in a specific procedure
Preparation of Solutions
Standard and sample solutions are prepared using USP Reference and internal standards. System suitability requirements detail relative retention times and resolution requirements to ensure the system is ready for testing.
Thin Layer Chromatography as a Screening of non-compliance Test
In October 2023, the WHO published additional guidance for testing Diethylene Glycol and Ethylene Glycol in liquid preparations for oral use. This includes a screening test using thin-layer chromatography, intended for National Quality Control Laboratories (NQCLs) without access to GC technique.
TLC Procedure
- Diluent: Methanol
- Standard solutions: Prepared at different concentrations (0.2% to 20%)
- Absorbent: Silica gel plate
- Application volume: 2 µL
- Development solvent system: Toluene, acetone, ammonia mixture
- Visualization solution: Potassium permanganate, sodium carbonate, and sodium hydroxide in water mixture
The TLC test is a semi-quantitative method with lower sensitivity (0.2% detection), higher uncertainty, and less specificity than GC. The TLC test requires fewer resources making it a quick and cost-effective screening tool.
Conclusion
Diethylene Glycol and Ethylene Glycol contaminants pose significant health risks when ingested above acceptable limits. Recent contamination incidents have prompted regulatory actions by the FDA and WHO to protect public health. The FDA and WHO have provided comprehensive guidance to help pharmaceutical manufacturers, compounders, re-packers, and suppliers identify and mitigate these risks through stringent testing and adherence to cGMP regulations.
Stakeholders must follow these guidelines to ensure the safety of drug components and protect end-users from the dangers of contaminated pharmaceuticals.
For more information and to stay updated on testing procedures, manufacturers must consult the latest FDA and WHO guidance documents and maintain robust quality control systems.
Nelson Labs
Nelson Labs performs comprehensive testing for Ethylene Glycol and Diethylene Glycol, along with other analytical tests, ensuring high quality and safety standards in pharmaceutical manufacturing.
For further questions or clarifications, please refer to the full FDA guidance document or contact Nelson Labs directly.
Author Details
Shiri Hechter, Nelson Labs- SHechter@nelsonlabs.com
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 5July/Aug 2024Pages: 44-45
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