Regenerative Processing Plant FDA Warning Letter: The Non-Geek Translation
Written by DrB
I love reading the Code of Federal Regulations, the United States Code, Form 483 inspection reports, and FDA Warning Letters. I’ve read a lot of Warning Letters.
The FDA Warning Letter to Regenerative Processing Plant LLC (hereinafter, RPP) dated 8/16/2024 lays out in FDA-speak a typical litany of violations of the Federal Food, Drug & Cosmetic Act: manufacturing, marketing and selling an unapproved new prescription drug; misbranding; and adulteration.
And then there are the amazing extras under Additional Concerns.
I’m going to organize my non-geek translation in order of shock / entertainment value, not in the order that the information appears in the Warning Letter. Read on.
Adulterated
Adulteration: A violation of the Federal Food, Drug & Cosmetic Act which includes products that are defective, unsafe, not shown to be safe, filthy, or produced under insanitary conditions.
I would summarize FDA’s inspection report on RPP’s manufacturing facility in Palm Harbor as follows:
Your factory is a shack;
You don’t check your raw ingredients, they could be anything;
Your sterile manufacturing is anything but*;
It's just amazing to us how every record related to your amniotic fluid eye drops has vanished, along with all the reserve bottles you were supposed to keep for 1 year past the expiration date (which, do the math, would be until 2025).
The Warning Letter adds some FDA howlers:
You don’t actually put Tonicity Solution™ in your eye drops, as far as we can tell from your own manufacturing records;
You market a 2-year shelf life based on exactly zero data;
Ditto the 90-day open bottle time.
That is some serious adulteration.
Of course I had to look up FDA’s definition of ‘filth’ or ‘filthy.’ I couldn’t find something specific to drugs, but on the Food side I found this: "Examples of filth may include any objectionable matter contributed by animal contamination such as rodent, insect or bird matter; or any other objectionable matter contributed by insanitary conditions.”
Objectionable matter contributed by insanitary conditions in the manufacturing facility = bacteria, fungi, yeast, Acanthamoeba...
Now go throw out all your bottles.
* A media fill is a critical validation which establishes that a manufacturing process is sterile, every step of the way. Special moments from Form 483: “No investigations were conducted to determine the source of the contamination...You did not attempt to identify the species of microorganisms identified within all contaminated bottles.”
When (b)(4) = Recall
A Warning Letter to a manufacturer is the culmination of months of back-and-forth correspondence between FDA and the company. FDA received seven letters from RPP between July 2023 and February 2024. A Warning Letter happens when FDA is fed up.
Something I have never read in a Warning Letter until now: A manufacturer refusing to recall product that was manufactured under insanitary conditions (ie, adulterated) and asserting that there is no need to do so because nobody has complained.
“Although your firm committed to (b)(4) Regener-Eyes® products manufactured prior to implementing corrective actions on (b)(4) to address failing (b)(4) results, the response states that your firm believes no market action is required for bottles manufactured prior to this date (before corrective actions were implemented)….In the impact assessment, your firm concludes the Regener-Eyes® products are safe and stable based on a review of customer complaints.”
FDA uses (b)(4) whenever it redacts something we’d really like to know, such as a date or the number of bottles affected.
I’ve filled in the (b)(4) redactions below with my educated guesses [in brackets]:
FDA to RPP:
“Although your firm committed to [recalling] Regener-Eyes products manufactured prior to implementing corrective actions on [a date] to address failing [media fill] results, the response states that your firm believes no market action is required for bottles manufactured prior to this date (before corrective actions were implemented)....In the impact assessment, your firm concludes the Regener-Eyes products are safe and stable based on a review of customer complaints.”
Does this read to you like RPP said it would recall all the suspect lots, but then changed its mind and tried to wriggle out of it? That’s how it reads to me.
EzriCare artificial tears was the #9 selling eye drop on Amazon in its time, with thousands of ratings and an average of 4.5 stars. The EzriCare tragedy ended in blindness and death. An eye drop manufactured in a shack, by people who cut corners, ignore their own data when they don’t like it, and misplace paperwork, is safe until it isn’t.
And What About That Bottle
Finally, finally FDA got up close and personal about the lack of a multi-dose preservative free dropper.
Although RPP had to stop the ‘biologic’ advertising, it has prominently maintained its preservative-free advertising all the while using a cheap 3 mL bottle with an ordinary screw cap.
It is critically important that you remember that a MDPF bottle will not protect you from eye drops that were contaminated during the manufacturing process.
Unapproved New Drug
This gets a little more geeky but lets me brag about Mermaid Tears™.
Drugs fall into two categories: Prescription, and over-the-counter (OTC). OTC drugs are listed with FDA, not approved or registered. Prescription drugs are approved by FDA. Facilities that manufacture drugs are registered with FDA.
An FDA recipe book called OTC Monograph M018 stipulates the allowed active ingredients and allowed therapeutic claims for OTC eye drops. You can’t advertise that an OTC eye drop treats glaucoma, for example. The Monograph also specifies what additional information must be on the drug label (practically speaking, the official drug label equals the Drug Facts printed on the box). Interestingly, it says nothing about allowed in-active ingredients.
Listing an OTC drug involves electronic paperwork on CDER Direct, FDA’s self-service OTC drug listing portal. FDA does not review the listing and neither does FDA’s AI, if it has one. As long as you include all the required drug label sections (such as Uses, Storage, Warnings and Precautions) and an allowed active ingredient, you can make up any crazy eye drop you want, get it listed, and have it show up on DailyMed with a National Drug Code (NDC) number.
The Dry Eye Foundation’s very own crazy eye drop – Mermaid Tears™ – was outed to FDA by Bloomberg News, provoking FDA to de-activate our access to CDER Direct even before the Bloomberg article was published. The Mermaid Tears™ listing was subsequently removed from DailyMed. You can still read the archived drug label here.
Point being, for several glorious months, Mermaid Tears™ had the same prima facie legitimacy as any Big Pharma OTC eye drop: It’s on DailyMed, it must be okay.
Back to RPP…Regener-Eyes Pro and Regener-Eyes Lite both have Tonicity Solution™ listed as an inactive ingredient. However, RPP makes claims about the therapeutic benefits of Tonicity Solution, which automatically classifies it as an active ingredient. Nice try though.
Since Tonicity Solution is not an allowed active ingredient for OTC eye drops, by default Regener-Eyes eye drops are prescription drugs. Square peg round hole. Since neither product has FDA approval, both are unapproved new drugs.
Got it?
Unless a rule-breaking OTC eye drop is brought* to FDA’s attention, it can float along for years with a legit-seeming DailyMed listing and an NDC number. Since < 0.0001% of all consumers and doctors know that FDA doesn’t approve OTC drug listings or even review them, the typical patient believes that their OTC eye drop has the same proven safety and efficacy as their prescription drops and drugs.
*By, for example, a tiny non-profit dry eye patient advocacy organization.
Misbranding
Misbranding in FDA-speak means that the manufacturer or distributor (or both) are making false claims about the product, either straight-out or by implication. Examples for Regener-Eyes include:
Marketing the products as OTC when they are required to be prescription (ie, FDA approved);
Listing Tonicity Solution* as an inactive ingredient but making therapeutic claims about it;
Describing the products as “FDA registered as an OTC drug” (OTC drugs are listed, not registered);
Implying that registering a drug with FDA as an OTC drug means that it is automatically legal to market it as an OTC drug (see above unapproved new drug).
Although making false and misleading statements about unapproved prescription eye drops might seem like a (much) lesser sin compared with selling them OTC in the first place, it carries separate penalties [21 USC 331(a) for you Code lovers].
*If a manufacturer misbrands a product by making active ingredient claims for an ingredient listed as inactive, but the ingredient isn’t really in the product at all, does this cancel out the misbranding?
What’s Next?
FDA can place imported eye drops on an import alert so that no more drops get unloaded at the port. Product that is already in the US is typically dealt with through a manufacturer and/or distributor voluntary recall. There have been plenty of those in the past 2 years. FDA will monitor the company’s recall strategy to ensure that it is effective.
If a manufacturer agrees to a voluntary recall but is tardy about notifying the public through a Company Announcement on FDA.gov, FDA can post its own Public Notification.
What can FDA do if a manufacturer is refusing to do a voluntary recall? It can issue a forced recall, but this requires a court order. Ultimately FDA can request from a court the authority to seize the products. A look at FDA’s Seizures & Injunctions web page suggests this doesn’t happen much, probably because most US manufacturers and distributors aren’t stupid enough to go that far. Think of those legal fees.
I don’t know what FDA’s next move will be, but I suspect they will have to make one. RPP seems committed to cranking out Regener-Eyes until someone chains the factory shut.