Antibiotic-Resistant Bacteria in Patients Is a Genetic Match to Product Contaminant

FDA has discovered a direct, causal link between a multi-state outbreak of antibiotic-resistant bacteria in 2022 and specific contaminated eyedrop products. The agency’s labs determined a “close genetic match” of isolates taken from eyecare product samples to clinical isolates from patients who used the eyedrops and suffered infections.

Samples of an antibiotic-resistant strain of the pathogenic bacteria Pseudomonas aeruginosa isolated from three different batches of eyedrop product samples collected by FDA were found to be close genetic matches to more than 85 clinical isolates that affected more than 80 patients. Fourteen of the patients suffered permanent vision loss, four had to have their eyeballs surgically removed, and four died.

The eyedrop product sampled, EzriCare Artificial Tears, was marketed by Lakewood NJ-based EzriCare, LLC. However, the eyecare product was manufactured by a contract manufacturing organization (CMO), Global Pharma Healthcare, located in Mumbai, India. FDA conducted inspections of both EzriCare and Global Pharma Healthcare facilities.

In February 2023, FDA warned consumers not to purchase or use EzriCare Artificial Tears due to potential contamination and recommended that Global Pharma recall Delsam Pharma’s Artificial Eye Ointment. The firm agreed to initiate a recall.

Inspection findings listed in the March 2023 Form 483 presented to the marketing firm EzriCare maintain that:

• The company had no quality unit, as required by FDA regulations,
• Responsibilities and procedures applicable to the quality control unit are not in writing, and
• The company has no procedures in place to ensure the quality of its drug products or to address complaints.

Findings at the eyedrop manufacturer acting as a CMO for EzriCare, Global Pharma Healthcare, focused on good manufacturing practice (GMP) shortcomings, as documented in the FDA form 483 issued on March 21, 2023. A warning letter resulting from the inspection was issued on October 20, 2023, documenting the egregious CGMP violations.

In the warning letter to EzriCare, FDA referenced the agency inspection of its CMO Global Pharma Healthcare and significant inspection findings:

“An inspection of Global Pharma Healthcare Private Limited revealed multiple CGMP violations, including but not limited to, the use of filling equipment that was inadequate for its intended use; the failure to validate the sterilization processes used to render ophthalmic drug products sterile; the lack of container closure integrity for multidose ophthalmic drugs that purport to be sterile; and the manufacture of multidose, over-the-counter (OTC) ophthalmic drugs that lack antimicrobial properties to preserve the formulation.”

The letter also emphasized EzriCare’s responsibilities regarding use of a contract manufacturer:

“You failed to have adequate procedures to ensure the ophthalmic drug products produced for your firm met appropriate quality attributes and were free of microbial contamination. For example, you failed to have adequate supplier qualification procedures to ensure that the drug products received from Global Pharma Healthcare Private Limited were manufactured in compliance with CGMPs prior to being distributed in the United States. Additionally, you were unable to provide any written agreements or procedures that demonstrated you required your CMOs to meet CGMP requirements or make suitable release decisions of drug products for distribution into the U.S. supply chain.”

Inspection Findings at Manufacturer Show Shortcomings

At the 48th annual International GMP Conference held in early March 2024 at the University of Georgia in Athens, Georgia, Parexel Vice President, Technical-Strategic Compliance Consulting, and former FDA Drug National Expert Investigator Ileana Barreto-Pettit analyzed the drug manufacturing deficiencies that FDA investigators observed on inspection and were recorded on the Form 483 that was issued to a manufacturer linked to the eyecare product outbreak. She did not identify the company as Global Pharma Healthcare, however, the observations she discussed match that form 483.

“Obviously, eye drops need to be sterile, because the eye bypasses some of the natural immune systems of your body,” she explained. “So, they must be sterile. And because these obviously were not sterile, patients died.”

Barreto-Pettit summarized the inspection findings around sterile filter validation, media fills, and airflow patterns in the aseptic manufacturing areas and commented on them based on her years of experience at FDA and her understanding of the requirements (see Figure 1, FDA Form 483 Observations).

 

Figure 1 | FDA Form 483 Observations

 

She emphasized the criticality of validating sterile filters. “This company had not validated the filters. When you have a sterilizing filter, you must validate it. They had not.” In addition, the investigators “tried to do an inventory of the type of filters they were using, because they had multiple different filters. The records did not match. So, they were not sure whether the correct filters were used to sterilize these products.”

Integrity testing is required for sterile filters, and the company records for that testing were incomplete or inaccurate. A lack of complete records is a data integrity issue.

Although the company did have a method for sterilizing its liquid products, it also produced ointment products. “Just because that process sterilizes liquid does not mean it will also sterilize the ointment,” the former FDA expert investigator maintained.

Aseptic process simulations, known in the industry as media fills – fundamental requirements for validating and monitoring aseptic processing – were not conducted. “Everybody knows what aseptic process simulations are if you are in the sterile industry. They did not even do the basic three consecutive batches for validating the sterilization.”

Reflecting on her FDA experience, Barreto-Pettit commented, “Up until last year, when I retired from the FDA, I was still citing companies for these same things, over and over – no growth promotion of media and not all integral units incubated. This was a manually intensive line with minimal barrier protection.”

Another major deficiency noted in the 483 was regarding airflow patterns.

“These are the famous ‘smoke studies.’ They were not performed under dynamic conditions. They did not have the operators in the filling line performing the activities when they were doing the smoke studies. It was just an empty room.”

In addition, the firm did not incorporate the interventions and other routine activities that occurred during the aseptic fill into its process simulations. “This is all extremely basic, 101, smoke studies,” Barreto Pettit stressed. “Companies must keep track of all the interventions that occur and incorporate them into subsequent media fills, which should be performed every six months.”

“When FDA investigators go into aseptic facilities, they watch those operations for hours. They are looking for those interventions. They are timing those interventions. And then they are going to look at your smoke studies, and then they are going to look at your media fills. And you better have those. If not, it is an observation.”

Other observations Barreto-Pettit chose to comment on from the 483 include the following:

• Container closure integrity
  • “They did not have evidence that the containers were even sterile. It doesn’t matter if you sterilize the liquid or the ointment if you then fill it into a container that has not been shown to be sterile.”
  • There was no evidence of container/closer integrity. “They had complaints of leaking bottles. If you have leaking, then you have the potential for cross contamination.”
• Facilities maintenance issues
  • In the aseptic processing area, the investigators found cracks and scratches on the Class A RABS enclosure. “What is the problem with that?” she asked? “Cleaning. If it is not smooth, it is not cleanable. You do not want to see scratches everywhere, because those little, tiny organisms can stay there, and contaminate your product.”
  • Smooth wall panel joints, cracked ceiling, nails in the Class B area. “When I see these things, I am going to ask you, as industry, or as QA, ‘Do you go into your facility and look for this? Do you look for cracked ceilings? Do you look for scratches on the RABS? Who does that? Does anybody do that?’ There should be some sort of monitoring program.”
• Inadequate equipment cleaning practices
• Inadequate gowning practices
• No antimicrobial effectiveness studies of a product that is formulated to be multi-use
• Environmental monitoring system
  • Some examples: No risk assessment. Alert and action limits were not based on historical data. No studies to show that residual disinfectants would not interfere with swab samples.  No non-viable particle air sampling during active filling. No growth promotion testing on plates used for personnel sampling. “They have everything that you can think of to indicate an inadequate environmental monitoring system.”

“What always bothers me is how did these products make it into the US market? I don’t care where it is manufactured, whether it is here, or whether it is in another country. A company that is this out of control should never be able to release product to the market.”

Eyedrop Sterility Concerns Continue

Fast forward seven months from the Global Pharma Healthcare inspection, and contaminated eyecare products resurfaced, at a different company.

Only days after a week-long FDA inspection of Navo Mumbai, India-based Kilitch Healthcare that ended on October 20, 2023, and resulted in a 19-page form 483, FDA again warned consumers about other specific brands of eyecare products.

In late October 2023 the agency warned consumers not to purchase and to immediately stop using 26 over-the-counter eye drop products due to the potential risk of eye infections that could result in partial vision loss or blindness. The 26 products are marketed under the following brands:

• CVS Health
• Leader (Cardinal Health)
• Rugby (Cardinal Health)
• Rite Aid
• Target Up & Up
• Velocity Pharma

FDA explained that it had not received any adverse event reports of eye infection associated with these products at that time. However, it recommended the manufacturer of the products recall all lots on October 25, 2023, after agency investigators found insanitary conditions in the manufacturing facility and positive bacterial test results from environmental sampling of critical drug production areas in the facility. Kilitch recalled all affected lots on November 15, 2023.

Barefoot Sterile Manufacturing

The October inspection of Kilitch was performed by two FDA investigators – Anastasia Shields and Justin Boyd. Boyd is a high-profile investigator whom Redica Systems calculates has a 74.5% 483 issuance rate and a 16.6% rate of 483s that he issues being escalated to a warning letter.

The form 483 issued on October 20, 2023, did indeed result in a warning letter dated March 28, 2024. It included the following language:

“FDA investigators observed your facility to be in a state of disrepair, poorly cleaned and maintained as evidenced by:

• (redacted) residue on the (redacted) adjacent to the HEPA filters in the ISO 5 area.
• Multiple barefoot employees in an ISO 8 area, without required gowning, including gloves, while handling materials being transferred into the ISO 7 manufacturing area.
• Operators used visibly dirty restricted access barrier system (RABS) (redacted) for interventions on the filling line.”

It is noted on the October 2023 form 483 that, “The deputy manager of production confirmed that [working barefoot and without gloves] is their standard practice.”

A December 2023 inspection of Farmingdale, New York-based Velocity Pharma resulted in a four-item 483, with observations questioning practices governing selection of CMOs, product storage, distribution, and recall practices and procedures.

The late 2023 FDA announcement including updates may be found here.

Lessons Learned

During 2022, a rash of infections caused by Pseudomonas aeruginosa was investigated by several state and federal authorities in cooperation with one another. Their months of detective work successfully identified the source of the widespread infections as coming from a specific eye care product, EzriCare Artificial Tears. Although it was marketed by Lakewood NJ-based EzriCare, LLC, FDA determined that the eyecare product was manufactured by contract manufacturing organization Global Pharma Healthcare located in Mumbai, India.

That determination prompted inspections of EzriCare and Global Pharma Healthcare. Each received an FDA warning letter. Those inspections revealed serious issues with EzriCare’s oversight of its CMO and egregious violations of GMPs by Global Pharma Healthcare in its manufacture of the products, which are supposed to be sterile but were not. An import alert preventing more violative products from entering the US and recalls of the products on the market prevented further adverse health consequences.

What are the lessons learned here?

• The reactive systems for assessing public health problems and taking action to limit the damage done worked. However, this tragedy re-emphasizes the fact that no health regulator, including the FDA, has the capability to proactively monitor the safety of every product making it to market.
• Prevention of consumer/patient harm is thus largely the responsibility of the marketing license holder. EzriCare did not live up to that responsibility, and some of its customers were seriously injured and died. It received a formal warning from the FDA.

Companies have at their disposal a number of tools to perform due diligence with for potential CMOs and other GMP partners to help prevent this kind of crisis, for example:

• Performing in-person physical inspections of CMOs is a critical part of the decision on whether to work with them. Egregious violations such as those at Global Pharma Healthcare would have been detected.
• Redica Systems has one of the largest databases of regulatory agency inspections and related data that can be used to find the data companies need to assess potential CMOs and other GMP partners. This includes the detailed inspection reports for the companies highlighted in this article.

Regarding the recent warnings from FDA regarding eye care products from other companies, it shows the agency’s proactive stance, warning consumers based on manufacturing inspection results before the products have caused any harm. The previous widespread patient harm provided lessons that have been learned.