Ethylene and Diethylene Testing - Warning Letter and Regulatory Activities

The issue of the analysis of glycerine for ethylene glycol and diethylene glycol as an ingredient used in the manufacture of pharmaceuticals continues.

The US Food and Drug Administration (FDA) inspected Higley Industries' drug manufacturing facility in September last year. As a result, the FDA has now issued a Warning Letter for significant violations of the applicable Good Manufacturing Practices (CGMP) in accordance with 21^CFR 210 and 211.

Based on the fact that the company's methods, facilities, or controls for manufacturing, processing, packaging, or holding do not meet CGMP requirements, its drug products are considered adulterated under Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

Objection to specific violations

Specific violations were observed during the inspection, including failure to test samples of each component for identity and compliance with all appropriate written specifications for purity, strength, and quality. In addition, the reliability of the component suppliers' test analyses was not validated and established at appropriate intervals. The following components were not adequately controlled:

• Ethanol: In particular, for ethanol used as an active ingredient, the company failed to test for methanol. The use of ethanol contaminated with methanol has led to several fatal cases of human poisoning worldwide.
• Glycerin: Glycerin, which has a high risk of contamination with diethylene glycol (DEG) or ethylene glycol (EG), was also not properly tested for identity prior to use in the manufacture of the drug products.
• Water: The company uses water from its own water system as a component for the manufacture of drug products without demonstrating that the water is suitable for use and complies with the USP monographs for water.

Now the company must demonstrate how it will test each component batch for compliance with all appropriate specifications for identity, strength, quality and purity. This includes clarifying how the reliability of supplier certification results will be ensured through initial and regular validation. In addition, a commitment is required to perform at least one specific identity test for each batch of components, especially for glycerine, propylene glycol and other high-risk components.

The company shall also outline the quality control specifications for chemical testing of each batch, conduct a comprehensive review of the material system to ensure qualification of all suppliers and adequacy of controls for incoming materials. A summary of the results from testing of all components is required to evaluate the reliability of the COA, as well as a description of the programme for qualification and monitoring of contract facilities.

A further commitment concerns the provision of test results for DEG and EC for all high-risk components and a full risk assessment for products containing ingredients at risk of DEG or EC contamination, including measures to ensure the safety and purity of the products.

Finally, a detailed description of the procedures for monitoring the water system, including routine microbial testing and the establishment of limits for total microbial counts and undesirable organisms, and a procedure to ensure continuous control, maintenance and monitoring of the water system to ensure its compliance with the USP monograph specifications is required.

The Regulatory Activities

The ethylene and diethylene issue in particular is of increasing concern to the authorities and pharmacopeias. A large number of Warning Letters have been published since 2022, but various regulatory activities have also taken place. In addition to the existing chapter of <USP469> Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances, these include the Guidance for Industry "Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol" and the USP initiative on "<470> Determination of Diethylene Glycol and Ethylene Glycol in Polyethylene Glycol". The Complex Excipients Expert Committee (CE EC) is thus planning to propose a revision of the USP monograph for polyethylene glycol (PEG) in response to a request from the FDA dated 10 February 2023.

This revision is to include a limit test for ethylene glycol and diethylene glycol (EG/DEG) in the Identification Domain (ID) to address the risks of contamination with these substances in PEG, especially in liquid and semi-solid forms. For liquid and semi-solid PEGs (polyethylene glycols) with a molecular weight of 1000 or less, the current USP General Chapter <469> describes a validated gas chromatographic test method for impurity analysis of EG/DEG. This chapter serves as a stand-alone resource that can be used by stakeholders before methods are incorporated into official monographs. Based on a similar approach, the USP is developing a new General Chapter <470> for EG/DEG testing in various PEGs. On 29 September 2023, the USP published a general announcement and conducted a survey on the determination of EG/DEG in PEGs, in which several stakeholders provided the USP with internally validated test methods for EG/DEG in PEGs that can be included in the new General Chapter <470> under development.

The revised and expanded ECA Academy webinar "Ethylene and Diethylene Glycol Testing" also deals specifically with this topic, including with a representative of USP.