FDA official cites concerns with benzene and DEG contamination

National Harbor, MD – Francis Godwin, director of the US Food and Drug Administration’s Office of Manufacturing Quality said benzene contamination is a “hot topic” that is causing “a lot of issues” in the quality space. He also said he is concerned about the growing number of contaminated products containing diethylene glycol (DEG) or ethylene glycol (EG), which are some of the “scariest things” his office is seeing.

Godwin spoke on 3 May at the Excipient World conference in National Harbor, MD. He highlighted some of the compliance issues affecting the excipient industry and discussed warning letter trends for fiscal year 2022.

Godwin further noted that a growing number of warning letters will result from onsite inspections as FDA starts to build up its onsite presence, reversing a pandemic-era trend of enforcement actions triggered by the use of alternative tools.

He said that excipients are viewed as drugs under the Federal Food, Drug and Cosmetic Act. The law defines a drug as used to diagnose, cure, mitigate, treat or prevent diseases and does not differentiate between finished drugs, active pharmaceutical ingredients (APIs) and excipients. “To make a long story short, excipients, even if an inactive ingredient, [are] considered a drug,” he said.

Benzene contamination a source of concern

An issue of concern is the growing number of recalls and warning letters tied to drug products that contain benzene, which he said is a “known carcinogen.” This chemical is typically used as an industrial solvent and is “not a friendly chemical.” He noted that “its use as a solvent for pharmaceutical use is restricted.”

Last year, FDA issued a warning letter issued to Mirfeel in South Korea for contaminated hand sanitizers containing benzenes. This year, FDA issued a warning letter to Voyant Beauty, a division of Accra-Pac, which makes over-the-counter (OTC) topical drug products. After inspecting the firm’s site in Elkhart, IN, inspectors said the firm failed to investigate products for benzene contamination.

These mounting concerns led FDA to issue a statement in December 2022 alerting manufacturers to the risk of benzene contamination in certain drugs, which was issued two days before Christmas. The FDA said in the statement that any drug containing more than 2 parts per million (ppm) benzene is adulterated and should be recalled.

DEG contamination the ‘scariest’ trend

Godwin said the “scariest” trend, however, are the poisonings related to diethylene glycol (DEG) and ethylene glycol (EG) contamination in excipients. Godwin said that “these are words that raise the hair on the back of peoples’ necks, this is why people at FDA don’t sleep because they’re worried about this.”

“DEG is an industrial chemical, it is not a drug, it is antifreeze, you put this in your car when it gets cold … it is poison,” he told the audience. “If you drink it, you will hurt and you are going to die. FDA has a long history with diethylene glycol.”

In 1937, DEG was used an excipient in sulfanilamide, and resulted in the death of more than 100 people. This tragedy prompted the passage of the Food, Drug, and Cosmetic Act in 1938. The reason it is used is because its cheaper than other chemicals and cannot be easily detected.

Godwin said that “sadly history is repeating itself,” with more DEG poisoning occurring in 2007 with DEG-tainted toothpaste from China, and more recently, DEG substitution for glycerin in Central America in the late 2000s.

More recently, there have been a number of reports of DEG contamination in children’s cough syrups found in several countries, which have resulted in the death of 300 children, he said. These concerns prompted the World Health Organization (WHO) to issue guidance to assist pharmaceutical manufacturers in assessing the quality of excipients to prevent poisoning. (RELATED: WHO proposes updated excipient GMPs in wake of contaminated cough syrup, Regulatory Focus 10 April 2023)

These contaminated products have not yet impacted US supply chains. Yet Godwin pointed out that “the supply chain is incredibly international, and incredibly complex. When something happens overseas it may impact things here sooner or later, so you have to be very mindful of that.” He added that “this is one of the things that keep me up at night.”

In response to these poisonings, FDA has heightened its supply chain monitoring to ensure these products do not infiltrate the Us supply chain. The agency reviewed its drug manufacturing inventory and issued 150 requests for records to manufacturers in “geographies of concern” who use excipients that may be affected by DEG and EG. Of those, nine firms have been placed on an import alert, he said that more import alerts “are likely.”

Averting contamination

To avert ingredient contamination, Godwin told suppliers to ensure their ingredients are tested for benzene, DEG and EG. He also stressed the importance of knowing the sourcing of ingredients.

Under the GMP regulations at CFR 21 Section 211.84, manufacturers have to perform identify testing of their raw materials, which include active ingredients and inactive ingredients. He added that “you should do this [testing] for good reason.”

More warning letters to follow onsite inspections

In other compliance areas, Godwin said that in FY 2022, FDA issued 72 warning letters, a slight decrease from 82 issued in FY 2021, and 81 issued in FY 2021. Yet a major difference is the agency is reverting to onsite inspections as an enforcement tool.

During the pandmeic, the agency had to “shift gears,” and rely more on sampling and records request in lieu of onsite inspections. “FDA is embarking and going back out and doing onsite inspections” for high-risk facilities, he said. He said that “I do anticipate that the numbers of warning letters” based on onsite inspections will increase and will continue to increase.”

In FY 2022, 50 or 69% of the warning letters stemmed from onsite inspection, while in FY 2021, 21 or 25.6% of warnings letters were promoted by onsite inspections.

Excipient World

FDA official cites concerns with benzene and DEG contamination

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