FDA ramps up monitoring in high-risk areas following DEG-contamination deaths overseas

The US Food and Drug Administration (FDA) is ramping up its monitoring of firms in areas of the world considered high risk for manufacturing products susceptible to diethylene glycol (DEG) and ethylene glycol (EG) substitution, or those using high-risk excipients vulnerable to contamination.

The move follows deaths attributed to drugs tainted with these chemicals, Matthew Dionne, an FDA compliance officer, said at the Pharmaceutical Quality Symposium sponsored by the Small Business and Industry Assistance (SBIA) program on 1 November 2023. He pointed out that DEG and EG contaminated products have not affected the US supply chain.

Another worrisome trend is lax testing of component materials for DEG and EG. The agency sending out a growing number of warning letters in this area, Dionne explained. Of the 94 GMP warning letters FDA issued in FY 2023, 34% cited inadequate screening of drugs as a source of concern. In 2022, that just 5% of the warning letters noted this concern and in FY 2021 it was one percent.

History of contamination

Dionne, who works for the Office of Manufacturing Quality (OMQ) in the Center for Drug Evaluation and Research (CDER) noted that DEG and EG contamination in excipients has a long history, dating back to 1937 when DEG was used as an excipient in sulfanilamide and resulted in the death of more than 100 people, prompting the passage of the Food, Drug and Cosmetic Act in 1938.

Dionne said history is repeating itself with the recent DEG poisoning incidents involving contaminated products made in India, Indonesia, and Cambodia. These incidents affected 20 different products across seven countries and 12 manufacturers.

These poisonings were linked to 300 deaths in three countries in 2022, with most of the fatalities occurring in children. The incidents prompted the World Health Organization (WHO) to update its guidance on excipient GMPs (RELATED: WHO proposes updated excipient GMPs in wake of contaminated cough syrups, RAPS Focus 10 April 2023).

Supply chain monitoring, guidance

Following these deaths, Dionne said, FDA has been interacting “extensively” with health organizations, health regulators and industry, and has “ramped up monitoring” in this area.

As a result of this “heightened supply chain monitoring,” FDA is closely scrutinizing liquid formulations and has sent out 174 requests for records to drug product manufacturers located in “geographies of concern” and to those companies using high-risk excipients that may be affected by DEG and EG to ensure companies are adequately testing ingredients.

FDA has also updated its DEG and EG testing guidance, issued in 2007, instructing pharmaceutical manufacturers, compounders, repackers and suppliers on how to identify DEG or EG contamination in high-risk drug components (RELATED: Amid DEG/EG contamination concerns, FDA issues guidance on testing high-risk drug components, Regulatory Focus 10 May 2023).

Dionne pointed out that the recent contamination events are different than in other years when these substances were found in glycerin. The more recent cases appear to be related to substituting DEG and EG in propylene glycol. “Unscrupulous manufacturers and suppliers have used DEG and EG in excipients, or as an excipient, in lieu of costlier ingredients for economic gain,” he said.

He added that a “lack of GMP controls at the finished dosage form sites allowed for the contamination to enter drug products.”

He pointed out that DEG and EG contaminated products have not yet affected the US supply chain.

Manufacturers must test their products

For their part, Dionne said manufacturers must test their components even if they have been tested by a supplier.

Under the GMP regulations at 21 CFR 211.84, manufacturers are required to test or reject components and closures, until they are “deemed appropriate” for release. A drug product manufacturer cannot rely solely on a supplier’s certificate of analysis (COA), but must also verify the identity of the excipient, according to the regulation.

“A COA can be accepted, provided that at least one specific identity test is conducted by the manufacturer,” Dionne said.

CDER SBIA meeting

FDA ramps up monitoring in high-risk areas following DEG-contamination deaths overseas

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