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The FDA has sent another letter -- this time a -- to a company that it previously flagged for marketing amniotic fluid eye drops.

In a letter to Carl Harrell, MD, CEO of Regenerative Processing Plant in Palm Harbor, Florida, the agency said the company's Regener-Eyes Pro and Regener-Eyes Lite products were unapproved new drugs because they make claims about treating dry eyes.

FDA also said the facility violated several current good manufacturing practices (CGMPs), including not validating its aseptic practices and not having adequate environmental monitoring in aseptic areas.

Two years ago, Harrell received an over a version of its Regener-Eyes product that contained amniotic fluid. The agency sent a subsequent safety communication about other eye drops -- including StimulEyes -- that were made with amniotic fluid.

In its latest warning letter, FDA raised concern that the company was still producing eye drops with amniotic fluid, even though it said it stopped producing the drops in June 2021. "FDA has serious safety concerns about the use of amniotic fluid in eyedrops," the agency wrote in its letter.

Paul Knoepfler, PhD, a stem cell expert at the University of California Davis, that the story "reflects a broader, relatively slow and incremental FDA oversight approach to unapproved biological drugs."

Knoepfler said the pattern typically involves FDA sending an untitled letter, and then "a few years go by." Then, the agency sends a warning letter -- a step that's possibly repeated -- until ultimately "the firm becomes compliant or switches products, or continues under a new name and maybe a new location."

"There have even been cases where firms got multiple warning letters over a few years, extending periods of potential risks to consumers without definitive action or resolution," Knoepfler wrote. "I don't know that such slowness is workable in a fast-moving area like regenerative biologics."

Sandra Brown, MD, of Cabarrus Eye Center in Concord, North Carolina, who is a board member of the Dry Eye Foundation, said if the company is indeed selling eye drops with amniotic fluid, that could be a danger to the public.

"Because it is illegal to manufacture and sell amniotic fluid eye drops, there are no established quality controls on the supply chain of amniotic fluid and no standards for rendering it sterile," Brown said. "The fluid could be contaminated with bacteria or viruses, including organisms that cause sexually transmitted diseases."

On top of that, proteins in amniotic fluid "break down and become totally non-functional after a few hours of storage at room temperature," she said.

The warning letter follows an FDA inspection conducted over 10 days starting on June 20, 2023. FDA found three major issues: that the eye drops were unapproved new drugs, that they were misbranded, and that there were several CGMP violations at the facility.

FDA said Regener-Eyes Pro and Lite were unapproved new drugs because the company listed sodium chloride as an inactive ingredient but advertised that it improved tear hyperosmolarity, thereby making it an active ingredient from a regulatory perspective. Sodium chloride is not an allowed active ingredient in over-the-counter lubricant eye drops, and improving tear hyperosmolarity is not an allowed over-the-counter product claim. In addition, the products aren't labeled with the warnings that are required for over-the-counter lubricant eye drops.

The agency also noted that the products are misbranded, calling their labeling "misleading for several reasons," including the fact that sodium chloride is listed as an inactive ingredient, even though its marketing shows that the ingredient "is intended to furnish pharmacological activity for the treatment of a disease or condition."

The eye drops also purport to be "in full compliance with the FDA" when they are not, the agency wrote in its letter.

Additional CGMP violations included not validating processes for cleaning and disinfecting manufacturing areas, and failing to have a written testing program designed to assess the stability of its products.

In a section titled "additional concerns," the agency said Regener-Eyes Pro and Lite products were "packed in multi-dose vials that do not have a mechanism for backflow prevention and are labeled preservative-free," which means that they don't have a "substance to inhibit the growth of organisms" and the "container type did not provide adequate protection and minimize the hazard of injury from contamination during use."

"Multi-dose ophthalmic drug products should contain one or more suitable substances that will preserve a product and minimize the hazard of injury resulting from incidental contamination during use," the agency stated.

In this section, the FDA also said its inspectors found the company continued to receive shipments of amniotic fluid, and "many of the distributed amniotic fluid unit donor IDs identically matched lot codes" of the Pro and Lite products made after June 2021, when the company said it stopped making eye drops with amniotic fluid.

If the eye drops contained amniotic fluid, they would need an approved biologics license application, the agency added.

The FDA has had problematic eye drops in its crosshairs in recent years, beginning in February 2023 when the agency and CDC identified an outbreak of Pseudomonas aeruginosa linked to EzriCare Artificial Tears and a related product made by India-based Global Pharma. After a of those products, a from other companies were recalled due to bacterial or fungal contamination.

The FDA also about a long list of eye care products sold at major retailers, including CVS, Rite Aid, Target, and Walmart, and also sent a over several eye care products sold on its website.

Brown noted that bacteria and fungus "prefer a liquid environment for growth. Eye drops also contain ingredients that bacteria and fungus can use for food."

She added that a key problem is that manufacturers "ignore the requirements of current good manufacturing practices. The FDA inspection reports on foreign and U.S. manufacturers are surprisingly similar. Consumers should not assume that a U.S.-manufactured eye drop is safer."

Correction: This story has been updated to clarify why FDA considers RegenerEyes products unapproved new drugs.

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