The eye-drop maker linked to a deadly outbreak of highly drug-resistant infections in the US had a slew of manufacturing violations — from brown slime on filling equipment to a lack of basic measures and systems to ensure sterility — according to a declassified inspection report by the U.S. Food and Drug Administration (PDF).
In February, the regulator warned consumers to immediately stop using eye drops and eye ointments made by Global Pharma, whose products were sold in the U.S. under the brand names EzriCare and Delsam Pharma and available through Amazon, Walmart, eBay and other retailers. Global Pharma later voluntarily recalled the products.
Health researchers had linked the drops to cases of a highly resistant drug Pseudomonas aeruginosa kind never before seen in the US. The strain is identified as VIM-GES-CRPA, which represents a carbapenem-resistant P. aeruginosa (CRPA) with Verona integron-mediated metallo-β-lactamase (VIM) and Guiana extended-spectrum β-lactamase (GES). Although affected people reported using multiple brands of eye drops, EzriCare was the most common. In addition, tests by the Centers for Disease Control and Prevention and independent researchers have identified the outbreak strain in opened bottles of EzriCare artificial tears.
As of March 14, 68 people in 16 states have been infected with the strain, the Centers for Disease Control and Prevention reports. Three people have died from the infection, eight have lost their sight and four have had their eyeballs surgically removed.
In February, the FDA noted that Global Pharma had several manufacturing violations, but the inspection report spells out the extent of the deficiencies. The 14-page report comes from a 10-day inspection of Global Pharma’s manufacturing facility in Thiruporur, India (just south of Chennai in the state of Tamil Nadu) that took place between February 20 and March 3.
The inspection report outlines eleven “observations” of malfunctions, with specifics. The first is that Global Pharma didn’t seem to bother verifying that its eye drops, which the company claimed were sterile, were actually sterile. There is “not enough validation data to show” that the company’s filtration system can “reliably sterilize” the eye drops, according to the FDA inspection report.
Deadly flaws
The facility, it seemed, was primed to produce contaminated products. FDA inspectors noted that Global Pharma failed to verify that components of the solutions purchased from suppliers were initially sterile. And the parts of the facility where the solution had to be made aseptically – free from contamination – were not suitable for producing sterile products. That is, the walls, ceilings, and floors were not smooth, hard surfaces that could be easily sterilized as they should be. Instead, there were cracks, protruding nails and holes in the wall. But even if the area was cleanable, the company’s cleaning protocols were also inadequate, the report said.
FDA inspectors found problems with machine cleaning and maintenance, which could have resulted in cross-contamination with other products manufactured at the facility. On the second day of inspection, an inspector also noted “black, brown-colored greasy deposits” on parts of the filling machine, and the facility’s equipment log noted that it had not been cleaned in nearly a month. A few days later, a manager told the inspector that there was “no procedure to clean the filling machine”.
Environmental monitoring for contamination at the facility was also lacking, the report found. And the sterility of primary packaging, including bottle caps, was not verified before use. Once the eye drops were bottled, the formula contained no preservative to prevent microbial contamination, and batches were released to the US without going through the quality control unit.
A CDC official previously told Ars she feared the VIM-GES-CRPA outbreak in the US will lead to more infections and drug resistance. “To date, largely drug resistant Pseudomonas with genes that rapidly spread resistance, such as VIM and GES, are rare in this country,” said Marissa Grossman, a CDC epidemic intelligence officer. organisms are not more common,” she said.
In March, the FDA issued recall notices for two other types of eye drops — from Pharmedica and Apotex — due to non-sterility concerns. The products, both listed as manufactured in North America, have not been associated with the VIM-GES-CRPA outbreak.
