In August, Redica Systems had an unusual opportunity to show off the power of its Quality and Regulatory Intelligence at the 27th annual GMP by the Sea meeting in Cambridge, MD. After an FDA official presented the agency’s response to recent excipient contamination, Redica Systems corroborated — with charts — within hours, at the company’s own presentation.

“When the FDA took the big stage,” said Redica Systems CEO Michael de la Torre, “they were talking about materials receipt and handling, about how people are really getting in trouble because they’re not testing incoming components, which is a real problem.”

We actually see spiking in [483] observations

Redica Systems CEO Michael de la Torre

In late 2022, the FDA discovered a dangerous substitution of diethylene glycol/ethylene glycol (DEG/EG) for propylene glycol in children’s drug products overseas, said Francis Godwin, director of the FDA’s CDER Office of Manufacturing Quality.

Speaking before lunch on the second day of GMP by the Sea 2023, Godwin said the agency had ramped up supply-chain monitoring, including “increasing sampling, inspections, and other activities in this space.” In compliance actions, “thus far, over 20 firms have been placed on import alert, and multiple Warning Letters were recently issued.”

After lunch, de la Torre showed Redica Systems charts consistent with the FDA’s intense interest in incoming components, especially in Q2 of 2023. “We actually see spiking in [483] observations,” said de la Torre. “We were able to corroborate what the FDA said — so I slapped that together and put it into the presentation.”

As you can see in the figures below, Redica Systems Quality and Regulatory Intelligence shows a clear, rapid increase in 483 observations related to testing of incoming components. (Note: it’s possible that other events may have also contributed to FDA’s uptick in monitoring.

GMP Figure 1
Figure 1 | Both figures show trends in 483 observations. At left, the bar chart of Primary Issues shows a rise in issues related to Materials (orange) between Q1 and Q2 of 2023. In the figure on the right, the bar chart displays subcategories of Materials issues — including a large jump in (green) Material Receipt and Handling for that Q1 – Q2 period.

This substitution episode prompted the FDA to require identity testing of high-risk ingredients such as propylene glycol (pdf), although the agency has tangled with many similar substitutions over the years, including two recent events.

In 2006, the FDA warned manufacturers to use limit and identity tests for glycerin in accordance with cGMP regulations when DEG-contaminated glycerin was detected in Panamanian cough syrup, ultimately killing at least 100 people. In 2007, Chinese toothpaste makers also used glycerin contaminated with DEG, prompting the FDA to impose an import ban. No deaths were attributed to the toothpastes.

The FDA’s increased monitoring for DEG/EG substitutions results partly from this history and the existence of an economic motive, since DEG and EG are cheaper than propylene glycol (and glycerin).

Wherever such histories and motives exist, the FDA is likely to exert its oversight, particularly when high-risk substitutions are possible. For example, as Godwin mentioned, for over-sulfated chondroitin sulfate (OSCS) in heparin and methanol in alcohol, the agency also requires similarly specific identity testing.

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