Pharma Lab International Limited

[Leontina Heidgerken]

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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 and Artificial Eye Ointment batches that were manufactured by your facility, and we sent the samples for sterility testing at FDA laboratories. Our analysis of intact (unopened) units found that 18 batches of Artificial Tears were non-sterile. In addition, we also sampled a batch of your Artificial Eye Ointment product, and this batch was also found to be 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 lots are adulterated under section 501(a)(1) of the FD&C Act, in that they have been contaminated with filth, and rendered injurious to health.

Significantly, the pervasive contamination of your drug products, as indicated by FDA sample results, also demonstrates that all drugs made at your facility are adulterated under section 501(a)(2)(A) of the FD&C Act as they have been manufactured under insanitary conditions.

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

A. You lacked adequate scientific evidence that the aseptic filling machine used for manufacture of Artificial Tears was suitable for its intended use. Your qualification report was inadequate, including a lack of data on any batches filled as part of the qualification study. Further, all batches of Artificial Tears distributed to the U.S. market were manufactured using filling machine parameters that were outside the design specifications of the equipment.

C. You lacked meaningful airflow pattern studies for your aseptic processing lines. The studies were not performed under dynamic conditions and lacked simulation of interventions and other routine activities that occur during aseptic manufacturing operations.

You lacked evidence of reliable container closure integrity for your multi-use ophthalmic products that purport to be sterile. While visual inspections revealed leakers during batch manufacture, there was no assurance that your visual inspection procedure was adequate.

All sterile drugs must be packaged using a container-closure system that protects product integrity for the duration of its shelf-life. Maintenance of product integrity throughout stresses of its manufacture, storage, distribution, and consumer use is critical to product quality and safety. Loss of container-closure integrity is a direct cause of non-sterility of medicines.

In your response, you state you will perform container-closure integrity testing using a dye ingress method for your Artificial Tears product and a comprehensive sterility assessment. Your response is inadequate because your container-closure integrity testing protocol does not extend to Artificial Eye Ointment. In addition, you do not sufficiently address the sensitivity of your dye ingress method. The sensitivity of the method to be employed for your study is unclear, and you do not indicate whether it is capable of correlating with detection of bacteria comparable in size to Pseudomonas aeruginosa. Furthermore, your response does not include details on the comprehensive sterility assessment.

You manufactured multi-dose, over-the-counter (OTC) ophthalmic drug products for the product owners, EzriCare LLC, and Delsam Pharma LLC. These products lacked antimicrobial properties to preserve the formulation. Significantly, your firm also marketed this multi-dose product without performing antimicrobial effectiveness studies. It is essential that multi-dose ophthalmic drug products contain one or more suitable substances that will preserve the product and minimize the hazard of injury resulting from incidental contamination during use.

In your response, you state that antimicrobial effectiveness testing (AET) will be initiated for your Artificial Tears product, and you will use these studies to determine if a suitable preservative will be added to the formulation. Your response is inadequate because you do not explain why you failed to perform AET studies prior to launch of your drug product, and how you will correct such fundamental flaws in your product development program. You also make no commitment to conduct AET for the Artificial Eye Ointment formulation. In addition, although your protocol indicates that you follow the United States Pharmacopeia (USP), the acceptance criteria in the Artificial Tears protocol is less stringent and not in alignment with USP Antimicrobial Effectiveness Testing.

B. Cleanroom garments were not suitable for their intended use. For example, garments indicated to be clean were observed to be stained, worn out, and stored improperly. In addition, your firm re-used cleanroom garments for an unspecified number of times without tracking or validation.

C. You lacked written procedures and a training program on proper aseptic behavior and gowning for cleanroom operators. You also lacked evidence that all cleanroom operators are qualified through participation in a media fill, and the microbiological limit set in your gowning validation procedure is unsuitable for aseptic operations.

D. You lacked written procedures and a training program on proper aseptic behavior and gowning for cleanroom operators. You also lacked evidence that all cleanroom operators were qualified through participation in a media fill and justification for the microbiological limits used in your aseptic processing operator gowning qualification procedure (i.e., no more than (NMT) (b)(4) colony forming units (cfu) for each gowning location). You also lacked a commitment to systematically review staff qualifications and competencies throughout your operation, including but not limited to, ensuring an effective CGMP training program.

A drug product produced by aseptic processing can become contaminated not only by unacceptable practices in the manufacturing operation, but also due to the use of one or more defective components, containers, or closures.

B. You failed to adequately clean the equipment used to aseptically produce Artificial Tears. Significantly, our investigators observed visible grease-like residue on product contact surfaces of your filling machine after they had been cleaned.

Your environmental monitoring (EM) program (including personnel monitoring (PM)) was inadequate for classified areas used to produce sterile ophthalmic drug products. For example, non-viable air samples were not collected inside the Grade A filling zone or the Grade B surrounding areas during active filling, you lacked studies to demonstrate that residual disinfectant would not interfere with the swabs used for viable surface monitoring, and you lacked identification data on isolates recovered from EM and PM sampling.

Vigilant and responsive environmental and personnel monitoring programs should be designed to provide meaningful information on the state of control of your aseptic processing environment. Operations that include highly manually intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to, heightened emphasis on well-timed sampling to appropriately monitor batch manufacturing conditions.

Method suitability testing ensures the method can reliably determine the presence of microbial growth in the product. Method validation and verification is necessary to support reliable determinations of identity, strength, quality, purity, and potency of drugs. Without evaluating the validity of methods, you lack the basic assurance that the data provided to customers was an accurate reflection of pharmaceutical product quality and safety.

In your response, you make commitments to review your sterility testing and other analytical method validations, initiate sterility method verification, and revise your media preparation procedures. Your response is inadequate because you fail to provide revised procedures and you do not address your failure to perform adequate sterility testing on your distributed finished drug products.

In response to this letter, provide the following:

B. Your quality system does not adequately ensure the accuracy and integrity of data to support the quality of the drugs you manufacture. For example, your firm permitted the unacceptable practice of using pre-filled batch release documents.

Also describe how top management supports quality assurance and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

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