FDA Implements Guidance on Testing of High-Risk Drug Components for Diethylene Glycol (DEG) and Ethylene Glycol (EG)

FDA Implements Guidance on Testing of High-Risk Drug Components for Diethylene Glycol (DEG) and Ethylene Glycol (EG)

May 18, 2023, Covington Alert

In connection with recent poisonings that have been linked to the contamination of drug products with the industrial chemicals diethylene glycol (“DEG”) and ethylene glycol (“EG”), FDA has issued a guidance for immediate implementation, entitled 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”). This Guidance, which was issued without prior public comment and took effect immediately upon publication, replaces FDA’s 2007 guidance on similar subject matter, “Testing of Glycerin for Diethylene Glycol.” The Guidance is an important reminder to pharmaceutical manufacturers and suppliers about the risks of using glycerin and other “high-risk drug components” that could be contaminated with DEG and EG, and is intended to help prevent the introduction of DEG- or EG-contaminated glycerin and other high-risk drug components into the drug supply chain, to detect such events when they occur, and to facilitate reporting and control through notice to public health officials.

At a high level, the Guidance outlines the statutory and regulatory provisions that require compliance with current good manufacturing practices (CGMP) that FDA considers “critical to ensuring the detection of DEG- and EG-contaminated drug components and avoiding additional poisoning incidents.” In addition to these requirements, the Guidance provides specific recommendations for additional measures to be taken by manufacturers and others using high-risk drug components to manufacture or prepare drug products to prevent DEG and EG contamination. The Guidance does not clarify how the requirements and expectations discussed therein will be assessed on inspections, but recent trends in FDA inspection observations and warning letters indicate that FDA will continue to pay close attention to this issue and take action to address deficiencies in this space.

Below is a summary of the Guidance. 

Why was the Guidance issued?

FDA is concerned about DEG and EG contamination of certain drug components because DEG and EG poisoning outbreaks have occurred on numerous occasions worldwide, resulting in hundreds of deaths. In the most recent series of contaminations, since the beginning of 2022, multiple countries outside of the United States have reported oral liquid drug products, primarily indicated for children, contaminated (or suspected of being contaminated) with high levels of DEG or EG. These incidents, spanning at least seven different countries, have resulted in over 300 fatalities, mostly in children under the age of 5.

The Guidance indicates that the past and current DEG/EG contamination events reflect similar lapses in the supply chain wherein manufacturers of oral liquid drug products relied upon supplier certificates of analysis (COAs) but the chain of custody or distribution history of the high-risk drug component was also not readily known or apparent from the COA. As a result of lax controls and failures to conduct required testing, DEG- and EG-contaminated components, such as propylene glycol, entered the pharmaceutical raw material supply chain and made their way into finished drugs. While FDA notes that at the time of issuance it is unaware of any such contaminations in the U.S. supply chain, FDA issued this Guidance for immediate implementation in light of the current outbreak to highlight key CGMP activities critical to detecting and preventing DEG and EG contamination events.

What is the Scope of the Guidance?

The Guidance is intended for pharmaceutical manufacturers, compounders, repackers, and suppliers of “high-risk drug components.”

For purposes of the Guidance, “high-risk drug components” are components of drug products that, through historical experience, have been found to be at higher risk of DEG or EG contamination compared to other drug components. “High-risk drug components” include all of the components listed in the title of the guidance—glycerin, propylene glycol, maltitol solution, hydrogenated starch hydrolysate, and sorbitol solution—as well as any others that are a higher risk for contamination with DEG or EG.[1]

Although DEG and EG contamination of drug products in oral liquid dosage forms prompted its issuance, the Guidance applies to all dosage forms because, among other things, the relevant CGMP requirements such as identity testing apply regardless of the route of administration or dosage form of the finished drug product.

What CGMP requirements are highlighted?

The Guidance highlights a number of key CGMP requirements that relate to prevention, detection, and controlling for the presence of DEG and EG contamination. These CGMP requirements include but are not limited to the following:

• Identity testing must be conducted to verify each drug component of every drug product, including specific identity tests if they exist.
• Such identity testing must be performed on representative samples of each shipment of each lot of each drug component before the component is used in a drug product, irrespective of the route of administration or dosage form of the finished drug product.
• Manufacturers must have a quality unit responsible for approving or rejecting incoming lots of materials used in manufacturing operations (including drug components). The quality unit, in turn, must have and follow written procedures for carrying out its responsibilities, and must reject any lot of component that does not meet appropriate written specifications.
• Drugs and drug components with names recognized in the U.S. Pharmacopeia-National Formulary (USP-NF) must comply with compendial identity standards, including any DEG and EG limits specified. Drug components without a DEG or EG test or lacking a DEG or EG limit in the USP-NF must “conform to appropriate acceptance criteria.”
  • Potential variability in the composition of products labeled as glycerin may necessitate modifications to the method for identity testing; FDA would likely accept method modifications for other drug components that present similar concerns.

Other Relevant Regulatory Requirements

Although they are not CGMP requirements, the Guidance also points to requirements related to DEG/EG testing and control that pertain to compounding pharmacies, as well as postmarket safety reporting requirements that apply to holders of New Drug Applications and Abbreviated New Drug Applications. Specifically:

• Compounding pharmacies operating under 21 U.S.C. § 353a (“503A compounding pharmacies”) are not subject to CGMP. However, 503A compounding pharmacies must compound drug products using bulk drug substances that comply with the standards of an applicable USP or NF monograph, if one exists, and must compound drug products using ingredients (other than bulk drug substances) that comply with the standards of an applicable USP or NF monograph, if one exists.
• Submission of drug product post-market safety and quality reports is not a CGMP requirement, and is instead a requirement that attaches to applicants who hold New Drug Applications and Abbreviated New Drug Applications. However, the Guidance asserts that a Field Alert Report (FAR) must be submitted to FDA if any test reveals that a distributed drug product contains DEG or EG levels in excess of the applicable safety limit.

What are the Agency’s additional recommendations?

The Guidance additionally recommends that those using high-risk drug components for manufacturing or preparing drug products take the following additional steps to prevent the use of DEG- and EG-contaminated components:

• Perform specific identity analysis on samples from all containers of all lots of high-risk drug component. The Guidance further specifies that the specific identity analysis should be conducted before the drug component is used to manufacture or prepare a drug product, and should include a limit test for DEG and EG.
• If DEG and EG tests are not included in the identification test of the USP-NF monograph of a high-risk drug component, employ a suitable and equivalent procedure to detect and quantify DEG and EG using a safety limit of NMT 0.10%.
• Maintain current knowledge of the supply chain for high-risk drug components (i.e. the identity of the original manufacturer of the component and any subsequent repackers or distributors).
• Make all personnel in pharmaceutical manufacturing facilities, but especially those directly responsible for receipt, testing, and release of components, aware of the importance of DEG and EG contamination testing, and the potential hazards if such testing is not done.
• For repackers and others who distribute high-risk components for use in drug products, test the high-risk drug components that are used, sold for use, or intended for use in drug products. Accurate and complete COAs identifying the original manufacturer of the components should be issued for each shipment of each component.
• For 503A compounding pharmacies that use high-risk components in compounding drug products, either test each lot of each high-risk drug component for DEG and EG content, or ensure that such testing was properly done by a reliable supplier.

The Guidance also recommends that taking the same precautions for determining supplier and lot acceptability of other components (e.g., polyethylene glycol 40 castor oil) that may be at risk for DEG or EG contamination, even if those components are not specifically mentioned in the Guidance.

Finally, the Guidance instructs stakeholders to notify FDA if any testing of any drug component identifies DEG or EG levels at or above the USP-NF monograph limit, or if any drug product batches are made with components whose testing identifies DEG or EG levels at or above the USP-NF monograph limit.

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Although the guidance was issued and immediately effective, stakeholders may submit comments at any time.

If you have any questions about this Guidance or related topics, please contact the members of our Food, Drugs, and Devices practice.