The FDA issued warning letters to four manufacturers and distributors of ophthalmic formulations earlier this month, citing significant violations of federal regulations, misbranding, and contamination issues.
First things first: which companies?
- Amman Pharmaceutical Industries
- Delsam Pharma LLC
- EzriCare LLC
- LightEyez Limited
And what exactly does a warning letter signify?
Manufacturers may receive an FDA warning letter when, following an internal investigation, the agency has found the manufacturer has significantly violated FDA regulations.
These can include:
- Poor manufacturing practices
- Inaccuracies with claims of a product’s indication
- Incorrect direction for use
The letter will also mandate for companies to correct the issue, with an agency-set timeframe and directions provided for the company to notify the FDA of its plans moving forward.
See here for details on the different types of warning letters.
So what did these letters say?
We’ll break it down by company, starting with Amman, Jordan-based Amman Pharmaceutical Industries, a contract manufacturer of over-the-counter (OTC) and homeopathic products produced via aseptic processing.
Following a facility inspection from Aug. 7-15, 2023, the agency noted significant violation of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. As a result, its drug products were deemed to be adulterated (corrupt).
And the violations?
There were a handful:
- Failure to perform operations within areas of adequate size and separate or defined areas to prevent contamination or mix-ups in aseptic processing areas.
- Inadequate design of facility and equipment
- Inadequate monitoring of aseptic processing
- Unidirectional airflow
- Airflow in critical areas was insufficient to evaluate aseptic processing line suitability
- Failure to establish and follow written procedures designed to prevent microbiological contamination of drug products claiming to be sterile
- Includes validating all aseptic and sterilization processes
- Inadequate process simulation
- Poor aseptic technique and cleanroom behavior
- Lack of sterilization of all equipment in contact with sterile product components (ie: primary containers and closures)
- Includes validating all aseptic and sterilization processes
- Failure to include complete data in laboratory records from all tests needed for compliance with established specifications and standards
- Failure to establish adequate quality control unit for approving / rejecting all components of drug product materials
Has the company taken any steps to resolve these issues?
Per the FDA, Amman responded to its Form FDA 483 (issued following the inspection) on Sept. 6, 2023.
However, the agency stated that Amman’s proposed plan to remedy such issues to be “inadequate.”
Yikes. Now Delsam Pharma’s letter.
The letter stipulated that on March 6-24, 2023, an inspection of its manufacturing facility (operated by Global Pharma Healthcare Private Limited and located in Bronx, New York) revealed significant violations of CGMP regulations.
The result: drug products such as Delsam Pharma’s Artificial Tears and Artificial Eye Ointment were considered adulterated (corrupt).
Meaning: these products may have been contaminated due to unsanitary conditions observed in the facility, with the potential to be “injurious to health,” according to the FDA.
The agency also stated that both named products were misbranded, and that the company has yet to respond with its next steps to address the violations.
Weren’t these products part of the Pseudomonas (P.) aeruginosa outbreak last year?
Indeed they were.
In fact, Global Pharma issued a voluntary recall for two of its products in February 2023 following a health alert issued by the Centers for Disease Control and Prevention (CDC) linking them to potential bacteria contamination from P. aeruginosa.
This initial recall included EzriCare Artificial Tears (also manufactured by Global Pharma).
And the result: 81 patient cases across 18 states, 14 reports of vision loss, four reports of inoculations, and four deaths.
While we’re on the topic of EzriCare…
Similar to Amman and Delsam Pharma, the FDA noted in the warning letter from a March 8-21, 2023, that the manufacturing facility (located in Lakewood, New Jersey) inspection revealed “violative conditions” and significant violations of CGMP regulations.
Its products were deemed to be corrupt, as they were prepared, packed, or held under unsanitary conditions and could be contaminated or “injurious to health.”
Which products were manufactured at this location?
Most notably: EzriCare Artificial Tears (yes… the very same tied to a whopping 85% of P. aeruginosa patient cases last year, according to the CDC).
Among other violations, the FDA stated that the artificial tears product is misbranded in its intended use for diagnosing, curing, mitigating, treating, or preventing a specific disease.
After sample testing, the agency determined the product to be:
- Not sterile
- Contaminated with microorganisms (including P. aeruginosa)
- Potentially leading to minor or serious ocular infections
Gotcha. And now the LightEyez letter.
Following sample testing of LightEyez’s methylsulfonylmethane (MSM) Eye Repair Drops, the FDA stated it found the OTC product to be adulterated (corrupted) and, as a result, in violation of the agency’s Federal Food Drug & Cosmetic (FD&C) Act.
The reasoning: in part, because the drops consist “in whole or in part of any filthy, putrid, or decomposed substance.”
Other observations included the LightEyez manufacturing facility being deemed to not conform to the CGMP regulations.
So just one product was called out?
Not exactly.
The agency also noted that other variations of the MSM eye drop product (listed on the LightEyez website) for sale in the U.S. are actually “unapproved new drugs,” and, as such, violate federal rules.
Now, didn’t the FDA already issue a warning against the drops?
Good memory! In August 2023, the FDA warned consumers to not purchase and immediately stop using two MSM drops—one of which included the LightEyez MSM Eye Drops.
See here for those details, including the agency and company’s correspondence.
What else did they find?
Zeroing in specifically on that August 2023 warning, the agency’s sample testing identified “gross microbial contamination” and growth, including the following bacteria (which poses a high risk for patients):
- Pseudomonas species (spp.)
- Similar to EzriCare and Delsam Pharma products
- Mycobacterium spp.
- Mycolicibacterium spp.
- Methylorubrum spp.
To note: the agency reported that, although the company’s legal reps agreed to recall the MSM eye drops, after last corresponding on Aug. 28, 2023, LightEyez has ceased communication and has yet to initiate a recall for this product through the FDA.
The agency also stated that its on-site investigation of the company’s Sarasota, Florida-located manufacturing facility planned for Sept. 15, 2023, resulted in neither LightEyez nor its U.S. manufacturing being present (potentially due to moving locations with no notification).
The result: the FDA was unable to conduct an investigation.
Wow, that’s… a lot. So what’s the next step for these companies?
The FDA has requested that each company responds within 15 days of receiving their respective letters with how they plan to correct the violations.
And if they don’t?
For LightEyez, the FDA may withhold approval of new applications or supplements that list the respective companies as a drug manufacturer until “any violations are completely addressed and we confirm your compliance with CGMP.”
The FDA noted that it may also re-inspect (or technically in the case of LightEyez, inspect) to verify that the companies have completed corrective actions to any violations.
Additionally, failing to address the violations could result in “regulatory or legal action without further notice including, without limitation, seizure and injunction.”
Lastly… what if my patient has a reaction to one of these products?
Either a patient or healthcare provider (HCP) can report any adverse reactions to these drugs to the FDA’s MedWatch program.
*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.