FDA issues more warning letters to firms making contaminated eye drops

The US Food and Drug Administration (FDA) recently issued two warning letters to manufacturers that sold microbially contaminated ophthalmic drug products linked to an ongoing investigation into a deadly multistate outbreak. A third firm was also warned for making contaminated eye drops, though the company’s eye drops were not linked to the outbreak.

Two of the companies, EzriCare LLc and Delsam Pharma, were warned for shirking their responsibilities for ensuring the GMP compliance for contractors they use to manufacture their products.

In the meantime, a contract manufacturer of OTC and homeopathic drugs in Amman, Jordan, was warned for its lax approach to aseptic processing, as well as problems related to data manipulation.

The warning letters follow a recent announcement from FDA’s Jill Furman, director of the Office of Compliance (OC) at the Center for Drug Evaluation and Research (CDER), that the agency is paying heightened attention to ophthalmic products and diethylene glycol (DEG) contamination after recent safety issues. (RELATED: FDA compliance chiefs detail FY 2023 trends, plans for FY2024, Regulatory Focus 7 December 2023)

EzriCare

FDA found “violative conditions” at eye drop manufacturer EzriCare LLC located in Lakewood, New Jersey during an inspection in mid-March. FDA said the warning letter follows a similar warning letter to EzriCare’s contract manufacturer Global Pharma in October 2023. (RELATED: FDA: Global Pharma’s eye drops contaminated with ‘filth’ while Amazon made unapproved claims for eye drops, Regulatory Focus 17 November 2023)

FDA explained that the warning letter was tied to its collaboration with the US Centers for Disease Control and Prevention (CDC) in December 2022 to investigate a multistate outbreak of antibiotic-resistant Pseudomonas aeruginosa infections that affected over 80 patients, leading to four deaths and 14 cases of vision loss.

As part of this investigation, FDA collected finished product samples of Artificial Tears batches that were manufactured for EzriCare LLC by Global Pharma Healthcare Private Limited for testing.

FDA’s analysis of unopened units found that 14 batches of EzriCare LLC’s Artificial Tears were non-sterile and were “intrinsically contaminated with microorganisms.” The investigation further found that Pseudomonas aeruginosa isolates from three different batches of samples were close genetic matches to more than 85 clinical isolates associated with this outbreak.

“These test results demonstrate that these batches are adulterated under section 501(a)(1) of the FD&C Act, in that they consist in whole or in part of a filthy, putrid, or decomposed substance.”

FDA further reminded the company that, as a manufacturer, they are ultimately responsible for the drugs that are made in their name. The warning letter stated that “you are responsible for ensuring that the drugs you distribute are not adulterated and are manufactured in accordance with CGMP requirements.”

The company has ceased distributing the product.

Delsam

Delsam Pharma was also warned on 13 February following a mid-March 2023 inspection of its facility in the Bronx, New York. Like in the EzriCare warning letter, FDA said the warning letter follows its earlier warning to contract manufacturer Global Pharma in October 2023.

As part of this investigation, FDA collected finished product samples of Artificial Tears and Artificial Eye Ointment batches that were manufactured for Delsam Pharma LLC by Global Pharma Healthcare Private Limited and sent the samples for sterility testing at FDA laboratories. “Our analysis of intact (unopened) units found that four batches of Delsam Pharma’s Artificial Tears were non-sterile,” FDA wrote.

FDA also sampled a batch of the company’s Artificial Eye Ointment product, which was found to be non-sterile. “The testing of these intact units revealed that your ophthalmic drug products were intrinsically contaminated with microorganisms. These test results demonstrate that these batches are adulterated under section 501(a)(1) of the FD&C Act, in that they consist in whole or in part of a filthy, putrid, or decomposed substance.”

The warning letter also stresses that as the manufacturer, Delsam is ultimately responsible for the drugs manufactured by a CMO.

FDA reminded the company that “you are responsible for ensuring that the drugs you distribute are not adulterated and are manufactured in accordance with CGMP requirements.”

The agency also found the company lacked written procedures describing the handling of all written and oral complaints and failed to document and investigate complaints. “As a distributor, it is imperative that you communicate complaints to your CMO in a timely manner for appropriate follow-up,” said FDA.

Delsam has since inactivated its labeler code and discontinued drug listing submissions to FDA.

LightEyez

In a related development, FDA laboratory testing also revealed “gross microbial contamination” following the testing of ten samples of MSM Eye Repair Drops, according to a 15 February warning letter sent to Dr. Charles Carmichel, CEO of LightEyeZ Limited in London; the letter was posted to FDA’s website on 27 February.

Further, said FDA, “These test results demonstrate that this ophthalmic drug product is adulterated under section 501(a)(1) of the FD&C Act, in that it consists in whole or in part of a filthy, putrid, or decomposed substance.”

These contaminants included Pseudomonas spp., Mycobacterium spp., Mycolicibacterium spp., and Methylorubrum spp. FDA said “the presence of microorganisms in conjunction with the route of administration poses a high risk to patients. Using contaminated eye drops could result in a range of ocular infections, from minor to serious vision-threatening infections which could progress in some cases to a life-threatening infection.”

In August 2023, FDA issued a drug safety alert warning consumers not to purchase or use certain methylsulfonylmethane (MSM) eye drops, including MSM’s Eye Repair Drops, due to bacterial contamination.

The company’s US manufacturer, located in Sarasota, Florida, confirmed to FDA that drug components used in its MSM Eye Repair Drops were imported from LightEyez in the UK, and that the drug components imported included MSM used as an active ingredient. The company also said that a malfunctioning water system resulted in the use of unfiltered municipal water in its ophthalmic drug product.

FDA said since the last communication with the company in late August, and that neither the company nor the manufacturer have communicated with FDA or have initiated a recall. By 12 September though the company did issue a “service alert” or a recall on its website but only for one product.

Amman cited for poor aseptic practices, data manipulation

Separately, FDA issued a warning letter to Amman Pharmaceutical Industries in Amman, Jordan for poor aseptic processes and data integrity violations, following an inspection in mid-August 2023. The firm is a contract manufacturer of sterile over-the-counter (OTC) and homeopathic drug products produced by aseptic processing.

Investigators found “fundamental design flaws” in its aseptic processing operations, including “excessive and high-risk” manual interventions during batch manufacture. These interventions posed “unacceptable risks to product sterility.” One batch made in July 2023 required “several hundred manual interventions.”

Personnel also did not observe standard aseptic processing procedures. An operator “placed their foot into the ISO 5 enclosure when transferring the sterile hopper to the aseptic processing line.”

Investigators also observed operators repeatedly “exhibiting poor aseptic practices during filling operations, including using forearms to directly contact and move apparatus on the filling line; not wearing goggles, exposing facial skin in aseptic areas, crawling on hands and knees below aseptic processing line equipment, touching uncovered eye areas and personal cellular devices, exposing facial skin and touching direct product contact hosing over open product vessels, and not frequently sanitizing gloved hands.”

In addition, analytical chemists “were able to manipulate chromatographic integration parameters to erroneously obtain results meeting the established specifications” for the drug products. The letter stated that “it was only when our investigator requested that you follow your established integration procedures and recalculate the potency for the active ingredient, that you documented an out-of-specification test result, and subsequently opened an investigation.”

The firm has decided to recall all products and suspect production of all dugs for the US market and FDA placed the company on Import Alert in April 2023.

Delsam, EzriCare, LightEyez, Amman

FDA issues more warning letters to firms making contaminated eye drops

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