The US Food and Drug Administration has found a series of violations in the manufacturing process and sterilisation methods adopted by Global Pharma, the Indian manufacturer of an eye drop that has been linked to 68 cases of eye infection in America, including eight cases of vision loss and three deaths.
The company recalled its product, EzriCare Artificial Tears Eye Drop, early in February. The over-the-counter product has been linked to a highly drug-resistant and rare bacterial infection.
From February 20 till March 3, a team of the US FDA inspected the Alathur plant of Global Pharma in Tamil Nadu.
The report, accessed by Scroll, lists several lapses at the plant that indicate that the eye drops might have been contaminated during the manufacturing stage.
The US drug inspectors found that the Indian manufacturer skipped vital tests to check for microbial growth in the drug, did not test active pharmaceutical ingredients and packaging material to ensure sterility, and failed to maintain an aseptic, pathogen-free environment in its plant.
“The US FDA takes its responsibility seriously to ensure the medical products the American public relies on meet our rigorous standards for quality, safety and effectiveness,” Jeremy Kahn, FDA press officer, told Scroll. “This issue continues to be an ongoing compliance matter.”
Scroll sent an email to Global Pharma, seeking its response to the report. This story will be updated if the company responds.
‘No lapses’, says Tamil Nadu
The report gains importance in the light of an alert issued by the Centers for Disease Control and Prevention in the US, linking the outbreak of a highly drug-resistant bacteria, Pseudomonas aeruginosa, to the EzriCare eye drop.
The bacteria is resistant to at least 12 antibiotics and drugs.
The pathogen “spread from person to person in a Connecticut long-term care center, [prompting] concerns that the strain could gain a foothold in U.S. health care settings, according to the Centers for Disease Control and Prevention”, The New York Times reported.
Earlier, the Centers for Disease Control and Prevention had tested blood and urine samples from patients who had fallen ill after using the eye drop. It concluded that the contamination had either occurred at the time of manufacturing or during the use of the eye drops.
The Tamil Nadu drug authorities said they are yet to complete their investigation.
State food and drug administration commissioner PV Vijayalakshmi said they “had drawn samples from the batches that were exported to the US and the raw material used in it”.
“All samples were reported to be of standard quality,” she said. “We will continue our inquiry. But we can confirm that the unopened containers were of standard quality.”
Vijayalakshmi said she is yet to receive the inspection report from the US drug inspectors.
In February, the Tamil Nadu authorities suspended manufacturing of all ophthalmic medicines at Global Pharma.
Violations in testing
Among the major violations, US drug inspectors flagged the inadequate testing methods used by Global Pharma in its production process.
The company lacked sterility assurance for drugs produced for the US market, the report said. “You have not established that the sterilisation process is effective across different manufacturing conditions,” the report noted.
DR Gahane, joint commissioner (drugs) in Maharashtra food and drug administration, said when a sterile product such as an eye drop is manufactured, it requires testing and validation at several points.
Once the bulk product is manufactured and tested for sterility, it is filled into tiny bottles by a filling machine. Before that, a dummy run is carried out to ensure that the machine is not contaminated. The drug is passed through the machine and tested for microbial growth. This test is called the media fill, Gahane said.
The US FDA report said that Global Pharma did not carry out the test.
It also skipped a test – the media growth promotion test – which is meant to check for microbial growth in the drug before it is finally filled into bottles.
Global Pharma also did not test some of the active pharmaceutical ingredients, or APIs, it purchased from vendors for purity and strength before using them.
Active pharmaceutical ingredients are the main substances in a drug that make it effective.
The company instead directly used the ingredients in its production process “based solely on certificates of analysis from suppliers without establishing the reliability of the supplier’s analysis”, the inspection report observed.
The report also found that Global Pharma purchased its packaging material, including bottles and caps, through a vendor but did not test them for sterility. It could not find sterility test reports for shipments meant for the US market in 2019, 2020, 2021 and 2022.
Lack of aseptic methods
The US FDA inspectors found that Global Pharma had not hired qualified operators in the clean room – a dust-free working area with strict temperature and humidity control – to ensure the fills were aseptic, and no written procedures were available regarding aseptic techniques used in the plant.
Aseptic refers to a microorganism-free environment. “The firm’s management stated verbal instructions were given to operators,” the report said.
Global Pharma also reused the clean room garbs, or protective gear used by manufacturing staff, by washing them. The inspection found the company did not track how many times the garb was reused. “Discoloured overalls, discoloured and worn-out booties were observed being used in the clean rooms,” the team noted.
To maintain an aseptic area, filtered air must also circulate freely.
The report found that the manufacturing unit’s air-flow filtration system was deficient in ensuring sterile air. This runs the risk of encouraging microbial growth, especially in parts of the manufacturing room where air flow is poor.
Operators and employees working in an aseptic area also need to follow a protocol and wear protective gear. The report noted that the staff said no such procedure was given to them in writing.
Omprakash Sadhwani, an independent drug consultant who retired as joint commissioner in the Maharashtra food and drug administration, said a manufacturer must follow a protocol to prevent all possible contamination of the product.
“If the US FDA inspection finds that the protocol is not strictly adhered to, that means there is a possibility of contamination,” Sadhwani said.
He said the use of “discoloured worn-out booties” are not violations as such, but they may indicate sources of contamination. “It is difficult to say how much these lapses can ultimately affect the production quality,” Sadhwani said.
The US FDA also noted that no equipment was set aside for drugs being made for the US market.
Neither did the inspectors find records on the cleaning process of the manufacturing unit, filtration tanks, and filling machines.
While the company’s quality assurance manager did provide details of cleaning methods, the inspection report claimed they were not adequate to prevent cross-contamination. The report also stated that machines used to fill eye drops or ointment into bottles were not wrapped or covered when not in use. This led to a risk of contamination.
The US Food and Drug Administration has issued a notice through Form 483 to Global Pharma’s chief executive officer AR Venkatesh on March 2.
“As a general matter, inspectional observations are listed on an FDA Form 483 when, in an FDA investigator’s judgment, the observed conditions or practices indicate that an FDA-regulated product may be in violation of FDA’s requirements,” Kahn said over email.
Cloud over Indian drugs
Since October last year, this is the third Indian pharmaceutical company linked with mass casualties or adverse events in other countries.
In October, 2022, the World Health Organisation had linked the deaths of 70 children in Gambia to four cough syrups exported by an Indian manufacturer, Maiden Pharmaceuticals.
Both the Gambia government’s parliamentary inquiry report and the World Health Organisation’s investigation showed the presence of diethylene glycol and ethylene glycol – known to be potentially fatal for children – in the four cough syrups manufactured by Maiden.
In contrast, the Drug Controller General of India has stated that the drugs and control batch samples from Maiden’s Sonepat unit tested at the Kolkata laboratory were found to be of standard quality.
In a separate case from 2013, a Sonepat court in February convicted the director and executive director of Maiden to two-and-a-half years of imprisonment for supplying substandard drugs to Vietnam. In 2022, four of Maiden’s drugs were found substandard in Kerala labs.
In December 2022, the Uzbekistan health ministry said that 18 children in the country had died because of the side-effects of cough syrup Dok-1 Max produced by another Indian pharmaceutical firm – Marion Biotech.
In March this year, the company’s licence for the Noida plant was cancelled by the Uttar Pradesh government.
The Indian government announced a drive to inspect drug manufacturing units in December in light of the Gambia and Uzbekistan incidents. The Central Drugs Standard Control Organisation also tested 1,375 drugs and syrups and found that at least 5% of them were of substandard quality.
In March, the government released information on inspections carried across 20 states in 203 drug manufacturing units. In the first phase, state drug regulators took action against 76 units, including cancelling the licences of 18 units. In at least three companies, product license permission was cancelled.
This reporting was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.