EzriCare LLC

The U.S. Food and Drug Administration (FDA) inspected your facility, EzriCare LLC, FEI 3022210898, located at 1525 Prospect Street, Suite 204, Lakewood, New Jersey, from March 8 to March 21, 2023, after an FDA inspection revealed violative conditions at Global Pharma Healthcare Private Limited, a contract manufacturing organization (CMO) used to manufacture ophthalmic drugs for EzriCare LLC. The FDA inspection of this foreign facility revealed significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR Parts 210 and 211), causing these drug products to be adulterated, including within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).1 Because these products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, these drug products are also adulterated within the meaning of section 501(a)(2)(A) of the FD&C Act, 21 U.S.C. 351(a)(2)(A).

The inspection of your facility revealed that you operate as a distributor of EzriCare’s Artificial Tears. Your receipt in interstate commerce of adulterated drugs, and the delivery or proffered delivery thereof, is a violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c), and your distribution of adulterated drugs violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

In addition, EZRICARE Artificial Tears is misbranded under section 502(j) of the FD&C Act, 21 U.S.C. 352(j). Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.

We reviewed your April 10, 2023 response to our Form FDA 483 in detail.

In December 2022, FDA began collaborating with the Center for Disease Control and Prevention (CDC) on an investigation into the multistate outbreak of antibiotic-resistant Pseudomonas aeruginosa infections that ultimately affected more than 80 patients and led to 4 patient deaths and at least 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, and we sent the samples for sterility testing at FDA laboratories. Our analysis of intact (unopened) units found that 14 batches of EzriCare LLC’s Artificial Tears were non-sterile. The testing of these intact units revealed that your ophthalmic drug products were intrinsically contaminated with microorganisms. Microbiological isolates from the non-sterile samples were further characterized using whole genome sequencing and compared to isolates in a national database.2 Pseudomonas aeruginosa isolates from three different batches of intact Artificial Tears samples collected by FDA were found to be 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.

Significantly, the contamination of the drug products manufactured at Global Pharma Healthcare Private Limited, as indicated by FDA sample results, also demonstrates that the drugs made for you at Global Pharma Healthcare Private Limited are adulterated under 501(a)(2)(A) of the FD&C Act as they have been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health.

In addition, two intact samples of EzriCare’s Artificial Tears from different batches were found to contain visible, foreign particles.

An inspection of Global Pharma Healthcare Private Limited, conducted from February 20 to March 2, 2023, 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. Global Pharma Healthcare Private Limited was placed on Import Alert 66-40 on January 3, 2023, and received a Warning Letter (WL# 320-24-03), dated October 20, 2023, documenting the egregious CGMP violations. FDA sent you a copy of the warning letter issued to Global Pharma Healthcare Private Limited.

Our inspection of your firm and review of import records indicated that three shipments of EzriCare’s Artificial Tears were imported by a third-party, (b)(4), from the CMO, Global Pharma Healthcare Private Limited, FEI 3012323885, received by EzriCare LLC, and further distributed to customers.

During our inspection of your facility, you confirmed that you utilized CMOs to manufacture and import your ophthalmic drug product; however, 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. You stated in your response that your supplier, (b)(4), was responsible for the “formulation, packaging, and labeling” of the drug products that you distribute, however, your multidose ophthalmic drug product, labeled as EzriCare Artificial Tears, did not include a preservative, which in part rendered it injurious to health. You also stated that (b)(4) denied you direct contact “on multiple occasions” with your own CMO, yet you continued to distribute these drug products.

Additionally, FDA is concerned about your handling of product complaints. For example, you received multiple complaints regarding Artificial Tears distributed under your EzriCare label; however, you lacked written procedures describing the handling of all written and oral complaints for your drug products and failed to document and investigate complaints that were received. As a distributor, it is imperative that you communicate complaints to your CMO in a timely manner for appropriate follow-up.

You are responsible for ensuring that the drugs you distribute are not adulterated and are manufactured in accordance with CGMP requirements.

Provide a detailed plan to ensure you do not receive or deliver adulterated drugs in interstate commerce, in violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c). Items in your plan should include a full evaluation of your supplier and contract manufacturer qualification program, including a plan to conduct periodic audits of your suppliers, and a full evaluation of your handling of complaints. Also provide your evaluation of your current suppliers and contract manufacturers.

EZRICARE Artificial Tears is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, EZRICARE Artificial Tears is intended for use as ophthalmic demulcents.

Examples of claims from your product labeling that provide evidence of the intended uses (as defined by 21 CFR 201.128) of your product as a drug include, but may not be limited to, the following: EZRICARE Artificial Tears “Drug Facts . . . Uses . . . ■ for use as a protectant against further irritation or to relieve dryness of the eye ■ for the temporary relief of discomfort due to minor irritations of the eye, or to exposure to wind or sun” [from your product’s label]

EZRICARE Artificial Tears is misbranded under section 502(j) of the FD&C Act, 21 U.S.C. 352(j), because it is not sterile. 21 CFR 200.50 states that all preparations offered or intended for ophthalmic use should be sterile, and if not are deemed misbranded under section 502(j) of the FD&C Act.3 However, FDA analysis of samples of EZRICARE Artificial Tears determined that these products were contaminated with microorganisms. For example, microorganisms in your EZRICARE Artificial Tears product included but were not limited to Pseudomonas species. There is a reasonable probability that instillation of a bacterially contaminated eye product into the eye may cause a range of ocular infections, from minor to serious, vision-threatening infections which could progress in some cases to life-threatening systemic bacterial infection. Therefore, EZRICARE Artificial Tears is misbranded under section 502(j) of the FD&C Act, 21 U.S.C. 352(j).

The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

On February 2, 2023, a voluntary recall was initiated by Global Pharma Healthcare Private Limited for Artificial Tears, including those distributed by EzriCare LLC, based on bacterial contamination and CGMP concerns. Global Pharma Healthcare Private Limited’s recall announcement was posted to the FDA website: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/global-pharma-healthcare-issues-voluntary-nationwide-recall-artificial-tears-lubricant-eye-drops-due.

We acknowledge your commitment to cease distribution of all drugs. We note that your labeler code remains active with FDA. In response to this letter, clarify whether you intend to resume distributing any drugs in the future.

If you plan to resume any drug operations regulated under the FD&C Act, notify this office before resumption. You are responsible for resolving all deficiencies and systemic flaws applicable to your drug operations. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all corrective action and preventive action (CAPA).

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of your drugs regardless of agreements in place with your contract facility. You are required to ensure that the drugs you distribute are not adulterated. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts. We may re-inspect to verify that you have completed your corrective actions.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to orapharm1_responses@fda.hhs.gov. Your notification should refer to Warning Letter CMS # 658390 and reference FEI 3022210898.

If you have questions, please contact Compliance Officer CAPT Liatte Closs at Liatte.Closs@fda.hhs.gov.