Stokes Healthcare Inc. dba Epicur Pharma — FDA Warning Letter Findings

In your response, you provided an executed potency test method validation protocol for your Tacrolimus AQ human drug products; however, this test method remains unvalidated because the validation study: a. Lacked scientific rationale to justify establishing some of the relative standard deviations limits at (b)(4) ; b. Documented significant intra-batch potency variability; c. Did not record chromatography column temperature information for specificity, limit of quantification, limit of detection, linearity, accuracy, precision, intermediate precision, and stability testing; d. Concluded that the analytical results meet all acceptance criteria, although some sample results failed to meet specifications. Additionally, you did not consider the impact of these test method changes on the accuracy of the potency results for all previously distributed batches within expiry.

Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).

Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Your firm failed to conduct (b)(4) testing on (b)(4) used to sterilize the human drug product Fluorouracil PF. Therefore, you do not have assurance that the (b)(4) was integral throughout use.

In your response, you commit to completing new media fill studies; however, the provided media fill protocol does not include simulating the high-risk step of (b)(4) drug product suspension.

Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Some of your facility’s drug products, such as various strengths of Tacrolimus (Aqueous) Ophthalmic Suspensions did not include the following information on the label: The quantity or proportion of each inactive ingredient. Additionally, some of your facility’s drug products, such as Tacrolimus (AQ) 0.5% Ophthalmic Suspension 10mL and Fluorouracil (AQ) PF 50mg/mL Injection Solution 50ms, did not include the following information on the container: Information to facilitate adverse event reporting: www.fda.gov/medwatch and 1-800-FDA-1088.

In your response, you stated that your firm’s media fill studies, smoke studies, and environmental monitoring program are supporting indicators that your HEPA filter airflow velocities are adequate; however, the current FDA inspection found deficiencies in each of these areas. As such, you have not provided scientific evidence to demonstrate that the wide ranges of airflow velocities generated by your HEPA filters do not adversely impact the airflow patterns inside your ISO 5 classified critical areas.

Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 classified critical area, in that you did not include production steps that may impede airflow such as mixing drug lots in (b)(4) vessels. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.

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)).

In your response, you commit to performing (b)(4) testing; however, your firm did not provide evidence that you have purchased the referenced (b)(4) Tester, or revised your standard operating procedures and master batch records. Additionally, while you stated you would perform additional sterility testing, the sterility test in itself is not indicative that the batch is sterile, because when contamination is present, it is not uniformly distributed throughout the batch. Therefore, aseptic processing controls, such as (b)(4) testing, are critical for ensuring the sterility of the finished drug products.

Your firm failed to establish written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)).

Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Concerning the release of non-conforming human drug products, you did not commit to improving Quality Unit training and oversight to prevent recurrence. Additionally, your response did not consider the unsuitability of: a. Modifying the potency test method to obtain passing potency results without scientific justification and revalidation, and without assessing the impact of these changes on the accuracy of the potency results for all previously distributed batches within expiry; b. Invalidating original potency results based on resampling results without scientific justification.

In your response, you commit to improving the timely closing of your investigations; however, you did not provide the referenced revised standard operating procedures and the Interim Status Report form.

Regarding process validation for your human drug products, you stated that you would execute the necessary validations; however, you did not perform a risk assessment to determine the impact of failing to perform process validations on the quality of the drug products that you previously and continue to distribute. Additionally, you did not provide validation plans or executed validation studies for FDA’s evaluation.

We acknowledge that you commit to performing a disinfection efficacy study; however, you did not provide information about the study goals and the protocol details. Furthermore, our review of data collected during the inspection revealed that your firm detected an adverse trend of Mucor circinelloides fungal contamination between November 3, 2022, and July 10, 2023, in your ISO 8 classified cleanrooms C715, C711, and C735. The (b)(4) located in cleanroom C715 is used to…

In your response, you stated that you provided a smoke study capturing the missing production activities cited in the FDA observation. However, our review of this new smoke study finds it to be inadequate because it does not include simulating the higher risk production steps of diluting and mixing the drug components using large volume vessels.

In your response regarding your Quality Unit failing to prevent numerous significant deficiencies, you did not assess the need and develop plans to strengthen quality oversight to ensure deficiencies do not reoccur.

Your firm failed to ensure an adequate contact time for your sporicidal agent used to disinfect your aseptic processing areas. According to the (b)(4) label, the required dwell time for (b)(4) is (b)(4) , but your firm's SOP only requires a (b)(4) dwell time. Further, the investigators observed that a (b)(4) dwell time is not always achieved during cleaning and disinfection. FDA investigators also noted CGMP violations at your facility, that caused your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…

You did not provide a response regarding your investigations failing to include root cause analysis and extension to other lots that may have been associated. Additionally, we are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation…

Your firm’s quality control unit failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

Your facility did not submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations). 3 For example, your documented Standard Operating Procedures (SOPs) for reporting adverse events do not state that a follow-up report is to be submitted to FDA within 15 calendar days of receipt of new information or as…

Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)). Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA…

Regarding your environmental monitoring program response, you indicated in your response that historical data will be used to justify sampling locations; however, you have not performed a risk assessment to determine if historical sampling sites meaningfully represent high risk operating conditions. Further, you did not provide the referenced change control CC-23-021 or details about your proposed risk assessment.

Your media fills were not performed under the most challenging or stressful conditions. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility. Specifically, your firm did not include higher risk production steps in your media fills, such as (b)(4) mixing of drug components in large vessels and (b)(4) to the finished drug product suspension. Additionally, sealed (b)(4) were used during media fills to protect media bottles during transfer from the (b)(4) to the ISO 5 classified critical areas, but these (b)(4) were not used during human drug production.