Central Admixture Pharmacy Services, Inc. — FDA Warning Letter Findings

Your firm 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).

You did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was recovered within the ISO 5 aseptic processing area. FDA investigators noted CGMP violations at your facility, that caused your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example…

Your response states the implementation of (b)(4) sterility testing in addition to the initial, (b)(4) sterility testing to now be performed for (b)(4) products and (b)(4) stability programs per Change Control CCR-4000317. However, you have not provided completed (b)(4) stability studies, to include sterility, for products with (b)(4) that were previously established using (b)(4) studies in lieu of (b)(4) sterility testing.

Regarding your firm’s electronic documentation management system, you have acknowledged that previously system access and permissions allowed for unauthorized personnel to make changes. However, you have not provided a completed investigation determining if any data or documents were modified or deleted due to the unauthorized access.

Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

In your responses, you acknowledge the need to further evaluate your rapid sterility method. As you continue to distribute products, you have not stated that in the interim you will use a compendial method or another validated method for drug product release. Therefore, there is no assurance that your rapid sterility test method is able to provide valid results prior to release of each drug product lot. In addition to the issues discussed above, you should note that CGMP…

Specifically, regarding the stability data for your oxytocin drug products, your firm’s responses did not address the following: a. You do not address the practice of rounding and averaging individual out of specification results and then ultimately reporting as a passing final result. b. You do not address the necessary significant figures needed for raw data before rounding and calculating the final reported result.

Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. The FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. The FDA intends to…

In your response regarding unknown peaks for the UPLC amino acid analysis, in part you state that you have revised your cleaning procedures for laboratory glassware, however, you did not provide a cleaning validation report demonstrating the effectiveness of the new cleaning procedure.

Your response states initiating Corrective and Preventive Actions (CAPAs) and Notice of Quality Events (NQEs) to address the underlying issues. However, your firm did not provide copies of all completed and retroactive investigation reports for, including but not limited to the following: accuracy of data and records for production and analytical testing; environmental monitoring excursions and events; invalid tests and out of specification results; non-conformance events; and releasing drug products before all testing is completed.

In your response, you note the initiation of Change Control CCR-4000314 to refurbish and passivate the ISO 5 workstations, with a change control completion date of September 29, 2023. However, you have not provided supporting documentation regarding the completion of refurbishing and passivating workstations (ISO 5).

Production areas and equipment were visibly dirty.

In your response, you note your firm has cleaned the stains caused by the cleaning agents and buffed all floors, however, you did not provide supporting documentation for remediation of the floor stains in Rooms E and F (ISO 7).

Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).