Early last month, the FDA issued a warning letter to Regenerative Processing Plant, LLC (RPP), manufacturer of the Regener-Eyes ophthalmic products, following an inspection of its facility in June 2023.
The gist of its contents: Significant violations of the agency’s Current Good Manufacturing Practice (cGMP) regulations for its pharmaceuticals.
Wait just a minute … didn’t the FDA already report violations?
Good memory! Yes, back in December 2023. Those violations were also related to the June 2023 inspection (notably not previous inspections conducted in 2015, 2017, and 2020).
- Also take note: Though all four inspections were conducted at the Palm Harbor, Florida-located plant, those previous inspections were actually tissue processing inspections—not drug manufacturing inspections, as was the case of the June 2023 inspection.
Those details: The agency posted a summary of its findings—which ultimately led to the worst overall outcome rating of “Official Action Indicated (OAI)”—that included 15 regulatory violations.
And how did the company respond to these?
An RPP representative told Glance in December 2023 that, following the June 2023 inspection: “RPP spent the next 4 months completing the actions necessary to address the observations,” and, to date, had addressed all of the agency’s observations.
If that’s the case, then why a new warning letter?
That’s what we wondered as well (side note: see this rundown on what exactly a warning letter is).
So here’s what we know: On Aug. 16, the agency sent a warning letter addressed to Carl R. Harrell, MD, owner, chairman, CEO, and medical director of RPP, in regards to that 10-day June 2023 inspection.
- The products of interest in this letter:
- Regener-Eyes Professional (PRO) Ophthalmic Solution
- Regener-Eyes LITE Ophthalmic Solution
- Regener-Eyes ophthalmic drug product containing amniotic fluid
What issues were found with these products?
The letter stated that both Regener-Eyes PRO and LITE products are in violation of the Federal Food Drug & Cosmetic (FD&C) Act by being “unapproved new drugs introduced or delivered for introduction into interstate commerce (which is prohibited).”
Plus: Both products were also noted as being misbranded (false or misleading) under the FD&C Act.
We’ll explain below.
Let’s go into details on those violations.
Based on the product labeling for Regener-Eyes PRO and LITE—which indicate they “relieve dryness of the eye,” among other claims—the products are marketed as being intended for use as “ophthalmic demulcent (lubricant) drug products,” the agency stated.
The problem with this: The FDA determined that these products are actually “unapproved new drugs” and their marketing is in violation of two sections within the FD&C Act.
- Note: The term “new drug” applies to a product that is “not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling”—with a few exceptions, which the agency noted were not applicable in this case.
With this in mind: A supposed new drug is not permitted to be introduced or delivered for introduction into interstate commerce without an approved FDA application.
And in the case of these products?
According to the agency, there’s currently no FDA-approved applications for either of these Regener-Eyes products.
Yikes. Go on …
The FDA further wrote that certain nonprescription drugs marketed without an FDA approved application (referred to as “over-the-counter [OTC] monograph drugs”) are able to be legally marketed if they meet certain monograph requirements.
In this case: Per the agency, the Regener-Eyes products failed to meet monograph conditions and be deemed GRASE due to the use of unpermitted active ingredients, inaccurate portrayal of active vs inactive ingredients; and the exclusion of certain required labeling statements.
- As such: Regener-Eyes PRO and LITE were determined to be unapproved new drugs.
Time out on this for a moment. Didn't Regener-Eyes file an OTC Monograph Final?
Yes, but that was for Regener-Eyes’s flagship product: Regener-Eyes Ophthalmic Solution.
The details: The company previously noted to Glance that the FDA approved an OTC Monograph Final back in August 2022 for that solution.
- Regener-Eyes filed an OTC Monograph Final with the indication to relieve dryness of the eye for the Regener-Eyes Ophthalmic Solution.
- Even further: The OTC Monograph was reportedly the subject of a final administrative order by the FDA—meaning that the non-prescription drug is “generally (GRASE) for its intended use."
To note: Both Regener-Eyes PRO and LITE products include, among other ingredients, the flagship product formulation.
Interesting … are those all the violations?
Unfortunately, no. The letter also called out the Regener-Eyes PRO and LITE products as being misbranded under the FD&C Act due to their labeling because “false or misleading for several reasons.”
Included among those reasons:
- Incorrectly identifying an inactive ingredient (tonicity solution sodium chloride)
- Representing the products as being “in full compliance with the FDA”
- Inaccurately portraying OTC drug registration or listing as akin to prescription drug approval
- Misbranding products (due to their nonprescription nature)
Go on ..
There were also eight cGMP violations noted, viewable here.
A few of those included failure to:
- Establish / follow appropriate written procedures for preventing microbiological contamination of drug products
- Implement an adequate system for monitoring environmental conditions in order to prevent contamination or mixups
- Conduct at least one test to verify the identity of each component within a drug product
So these were all based on the June 2023 inspection, correct?
Indeed they were.
And it’s important to know: The agency noted that the company had responded to its initial Form 483 following that inspection on six separate occasions between July 2023 and February 2024.
- See our December 2023 coverage on that, which included 15 regulatory violations.
Did the company correct those violations?
The FDA acknowledged four specific actions the company took to address the violations within those six correspondences. Among those noted were:
- Voluntarily suspending manufacturing operations/distribution of any Regener-Eyes products filled post-inspection until after completing the corrective actions
- Hiring a qualified consultant to assist in meeting cGMP requirements and resuming drug manufacturing operations for the U.S. market
However: Some of those corrective actions “are not adequate to address the above-referenced violations,” the agency wrote.
Wait, why not?
Per the agency, this was “because they lack supporting documentation” and that Regener-Eyes’ responses “do not address [their] specific plans for disposition of the inventory of your ophthalmic products at your facility.”
Further: In reference to the company’s “previously distributed product,” the FDA said Regener-Eyes didn’t elaborate on the specific actions they took—or plan to take—in order to address those aforementioned violations on its distributed Regener-Eyes PRO and LITE products.
- Note: These products, the agency emphasized, were manufactured under its violation-targeted conditions and labeled with a 2-year shelf life.
- Six instances of additional inadequacies were also mentioned.
That’s quite a few issues … any other concerns?
You had to ask—and yes: three major areas:
- Contamination risks
- Products potentially containing amniotic fluid
- Records
Break them down for me.
We’ll start with contamination.
The FDA wrote that the Regener-Eyes PRO and LITE products:
- Are packed in multi-dose vials that do not have a mechanism for backup flow prevention and are preservative-free (see below for why this is an issue)
- Do not contain a substance that prevents organism growth
- Container type didn’t provide adequate protection or minimize the hazard of injury (ie: a condition or circumstance that could lead to injury, illness, or property damage) from contamination during use
And the concern?
According to the agency: Multi-dose ophthalmic drug products should have at least one suitable substance that preserves a product and “minimize the hazard of injury resulting from incidental contamination during use.”
- Even further: The FDA stipulated that any ophthalmic drug product lacking “adequate preservative properties” when exposed to this in-use contamination is particularly vulnerable to a rapid increase in microbes—which “can pose severe harm to consumers.”
And given the topical administration of Regener-Eyes products into the eyes, the company’s “significant cGMP violations” pose a “heightened risk of harm to users,” as the products bypass some of the body’s natural defenses.
Now this potential amniotic fluid.
The FDA stated that a October 2022 letter issued to Regener-Eyes, LLC notified the subsidiary that its flagship product (Regener-Eyes Ophthalmic Solution) appeared to be a drug and biological product that—in order to be lawfully marketed—required a valid biologics license.
During the June 2023 inspection: The agency noted that the company claimed it had discontinued manufacturing of that amniotic fluid-containing solution in June 2021 (approximately).
- Additionally: The company also reportedly stated that any remaining amniotic fluid at its facility was only used for research purposes.
And the issue with this?
Despite the company’s insistence, the FDA reported, investigators had documented that Regener-Eyes was continuing to receive shipments of amniotic fluids.
- Even more: These were matched with “RPP inventory and Regener-Eyes PRO and Regener-Eyes LITE manufacturing batch records for products manufactured after June 2021.”
The agency added that this finding plus its previously-stated violations—including failing to test sodium chloride for identity and to document the use of sodium chloride in its batch records—led it to question if the company’s products (manufactured post-June 2021) may actually still contain amniotic fluid.
Why the cause for concern with amniotic fluid eye drops?
Let’s talk about them: Amniotic fluid eye drops are regulated as drugs or biological products under the FDA’s protocols.
- In order to be FDA-approved for testing, mitigating, or curing disease, the drops need to have an investigational new drug application (IND)
- To be marketed, they would require a Biologics License Application (BLA).
And according to the FDA?
There are currently no amniotic fluid eye drops that have been approved for testing, mitigating, or curing diseases, the agency reported.
- See here for details on Regener-Eyes’ previous run-in with the agency (and its response) following a public safety notification issued in April 2023.
Gotcha. And along those lines …
Also of significant concern for the agency was that its investigators were “unable to obtain records pertaining to the manufacture and distribution of [their] Regener-Eyes ophthalmic solution product containing amniotic fluid” that was requested during their inspection.
Tell me that’s the last of these violations.
Unfortunately, no. Two other areas the FDA called out were:
- In-use stability studies
- Notably, the agency stated that “stability studies are needed to support” the company’s website claim indiating Regener-Eyes PRO and LITE products can be stored at room temperature and used within 90 days after opening.
- Glycerin-containing products
- The company’s glycerin-containing products require a limit test in the United States Pharmacopeia (USP) to ensure they meet the relevant safety limits.
That’s … a lot. Has the company responded to this yet?
Indeed it has. In response to Glance’s request for comment, the Regener-Eyes Corporate Team stated:
“It's important to note that this warning letter references an inspection conducted 15 months ago, June 2023, with some additional concerns regarding Regener-Eyes marketing claims and further updated concerns for RPP manufacturing.”
The team further noted that they have already engaged with the FDA to address these concerns, including already “eliminating the misbranding concerns” the agency noted as well as revising “our marketing practices and claims to align with OTC Monograph Drug standards.”
And in terms of those cGMP violations?
The Regener-Eyes team said its commitment to adhering to cGMP standards is “unwavering,” and that they “prioritize both patient safety and regulatory compliance.”
That being said …
“Our manufacturer (RPP) has already answered the FDA and has, since the audit in 2023, proactively implemented substantial improvements to strengthen our processes and enhance our procedures in response to FDA feedback concerning common Good Manufacturing Practices (cGMP),” the team told Glance.
They emphasized: “There have been no contaminations and no recalls of the Regener-Eyes products.”
And further noted: “RPP has also addressed concerns about Regener-Eyes product ingredients to ensure complete alignment with OTC Monograph Drug standards.”
Did they provide any specific update to their practices?
Just one: The team stated that they’re now using “new preservative free bottles” for their Regener-Eyes products, “which we believe will further enhance the safety and trust in the product.”
*Disclaimer: The information provided in this article does not and is not intended to constitute legal advice; instead, all information, content, materials available herein are for general information purposes only.
Editor's note: This article was updated on Sept. 17, 2024, to include the term "backup flow prevention" under the "Break it down for me" section as well as o clarify verbiage in a header indicating Regener-Eyes "filed" for an OTC Monograph Final instead of being "approved for" an OTC Monograph Final.