Amid DEG/EG contamination concerns, FDA issues guidance on testing high-risk drug components

The US Food and Drug Administration (FDA) on Tuesday issued an immediately effective guidance instructing pharmaceutical manufacturers, compounders, repackers and suppliers on how to identify diethylene glycol (DEG) or ethylene glycol (EG) contamination in high-risk drug components.

The risk of DEG poisoning is well known to the agency. FDA referenced a 1937 DEG poisoning event as a catalyst for the creation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In subsequent decades, including in the 1990s, DEG poisonings occurred in Argentina, Bangladesh, Haiti, India and Nigeria. A series of recent DEG poisoning incidents from drug products in liquid dosage form in 2022 and 2023 across seven countries led to up to 300 fatalities, the agency said.

FDA noted there’s no evidence contaminated products have reached the US supply chain, but the agency is releasing the final guidance “to alert the industry to the potential public health hazard of DEG and EG contamination for certain drug components in excess of the safety limit for drug products.”

“It is critical for safeguarding the quality and safety of medicines that all manufacturers, and others using high-risk drug components to manufacture or prepare drug products, are aware of the importance of detecting and preventing the use of DEG- and EG-contaminated components,” the agency said.

Francis Godwin, director of the FDA’s Office of Manufacturing Quality, recently told attendees at the Excipient World conference that DEG and EG contaminated products are a growing problem and among the “scariest things” his office encounters. He noted DEG and EG contamination “are words that raise the hair on the back of peoples’ necks” and “is why people at FDA don’t sleep.” (RELATED: FDA official cites concerns with benzene and DEG contamination, Regulatory Focus 8 May 2023)

Manufacturer compliance

The high-risk ingredients covered by the final guidance include glycerin, propylene glycol, maltitol solution, hydrogenated starch hydrolysate, sorbitol solution and other components. One of the most common reasons these incidents occur is because manufacturers increasingly rely on the certificate of analysis (COA) from the supplier of the high-risk products where the origin of the product is unclear, the agency said.

In the case of the 2022-2023 incidents, the COA the manufacturer received for liquid drug products “was often a copy of a COA on the letterhead of the distributor from whom they had purchased the glycerin and not the COA provided by the original manufacturer of the glycerin,” FDA said. “The chain of custody or distribution history of the glycerin was also not readily known, often because the glycerin might have been sold multiple times between its manufacture and its use in manufacturing the finished drug product.”

In the final guidance, FDA reminded manufacturers that they are required to comply with regulatory requirements and current good manufacturing practice (CGMP) measures, which include “oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.”

“Testing bulk or repackaged high-risk components for DEG and EG content is consistent with the CGMP requirement under section 501(a)(2)(B) of the FD&C Act,” they said.

Identity testing for finished drug products to verify drug product components is also required under CGMP regulations, the agency explained.

“To comply with CGMP regulations, representative samples of each shipment of each lot of a component must undergo appropriate identity testing before use in drug product manufacturing. These requirements apply irrespective of the route of administration or dosage form of the finished drug product,” FDA wrote.

Additionally, a Field Alert report is required if manufacturer testing identifies DEG or EG levels above the applicable safety limit.

Recommendations

The agency provided the following recommendations for manufacturers when taking measures to prevent DEG and EG contamination:

• Conduct a specific identity analysis for each lot that incorporates a DEG and EG limit test, includes samples from all containers in all lots prior to drug product preparation or manufacture;
• Use a “suitable and equivalent procedure” in situations where a high-risk drug component does not have a DEG or EG test in the identification test;
• Maintain knowledge of high-risk drug component supply chain;
• Educate appropriate pharmaceutical manufacturing facility personnel on the importance of proper DEG and EG contamination testing;
• Have repackers and other distributors of high-risk components for drug products test for DEG and EG contamination, and issue COAs with the original manufacturer of the components in each lot shipment; and
• In pharmacies that compound drug products, ensure testing was performed for high-risk components in compounding drug products by either lot testing or verifying the testing was performed by a reliable supplier.

The manufacturer should notify CDER when drug components have DEG or EG levels that meet or exceed appropriate limits and contact the respective Division of Pharmaceutical Quality Operations to coordinate any next steps and if a voluntary recall is necessary.

Guidance