US Specialty Formulations, LLC — FDA Warning Letter Findings

Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

Your firm failed to establish 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)). 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…

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)).

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. 3 Specifically, your facility’s procedures for reporting adverse events are inadequate. For example, your documented procedures for reporting adverse events (1) do not include a definition of what constitutes a “serious” and “unexpected” adverse event; (2) do…

We acknowledge that you have some of the elements required to validate (b)(4) ; however, you have not provided documentation of a comprehensive validation study for your parametric release process, including, but not limited to: 1) process understanding, 2) process control, and 3) parametric release documentation (as described in the Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes ).

Concerning the July 2021 sitewide power failure investigation, we acknowledge that you have updated SOPs; however, you did not provide documentation to confirm total particulate count, temp, humidity, and pressure differential readings were within specification and verified as such prior to recommencing manufacturing.

An operator rested their fingertips on the work surface of the hood during aseptic production. These practices may introduce contamination into the ISO 5 work area. For example: a. Your filling technician did not re-sanitize their sterile gloves between resting fingertips on the ISO 5 work surface during pauses in filling operations and rotating trays of finished drug product vials during filling operations.

Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 area. 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 did not disinfect materials during transfer from the ISO 7 cleanroom into the ISO 5 hood. For example: a. Your filling technician working within your ISO 5 aseptic processing area received vials and stoppers in the ISO 7 buffer room from a support technician who wore non-sterile exam gloves and performed a wipe down of those same components with non-sterile wipes.

Concerning foreign material found on caps used to seal vials: neither a root cause nor an evaluation was made to identify the foreign material, determine if it originated at the vendor or at (b)(4) , examine other lots of caps from the same vendor or other products in which this implicated lot may have been used, and generate controls/CAPA to prevent recurrence.

Concerning the Sarracenia Purpurea 0.17 g/mL for injection drug product, you have neither identified nor provided evidence of the active pharmaceutical ingredient’s strength by a method that is highly specific and uses a reference standard. Furthermore, without being able to identify or establish the strength of the drug product, you cannot incorporate stability-indicating test methods that are reliable, meaningful, and specific that support its 18-month expiration date. In…

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 also 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 firm failed to follow required laboratory control mechanisms (21 CFR 211.160(a)).

Regarding the white fibers in vials failure investigation, we acknowledge that you affirmed the white fibers came from your vial supplier who purportedly investigated this nonconformance; however, details regarding the investigation and/or the findings of the investigation were not provided. Furthermore, no preventative actions were provided. Some of your corrective actions appear deficient…

We acknowledge that you have updated your Environmental Monitoring Program SOP to adjust the action limits; however, you did not provide updated EM/PM SOP training documentation. Furthermore, an updated QA-0003 non-conformance procedure that prevents a batch from being released with an open nonconformance was not provided.

We acknowledge your commitment to (b)(4) supplies that are used in the BSC to ensure the (b)(4) is opened just outside the BSC. Nevertheless, we have not received a commitment from you requiring sterile glove use within the ISO 7 cleanroom. It is possible that contaminants can be introduced into the ISO 5 environment from the handling of equipment and supplies with non-sterile exam gloves. Furthermore, you did not provide a sterility validation report from (b)(4) for the specific lot number of (b)(4) in question. Neither the certificate of quality, nor the technical specification sheet confirms the wipe lot’s sterility. Without a validation report or another document that affirms sterility, the question of whether the wipes are sterile remains unanswered.

We acknowledge the receipt of your assay method for medroxyprogesterone; however, you have not provided evidence to show that your (b)(4) method is equivalent or better than the compendial method established in the current USP.

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

Your facility’s drug products, for example B-Complex plus Chromic Chloride 30 mL, did not include the following information on the label: the dosage form as required by section 503B(a)(10)(A)(iii) of the FDCA. Furthermore, your facility’s drug products, for example Sarracenia Purpurea 0.17 g/mL, did not include the following information on the label: a list of active and inactive ingredients identified by established name and the quantity or proportion of each ingredient as required by section 503B(a)(10)(A)(iii)(X) of the FDCA.

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 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 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)).

An operator blocked first air by placing their gloved hands directly over open sterile containers.

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)).

The technique your technician displayed in the FDA 483 response smoke study video is inadequate. The filling movement over open vials is from (b)(4) as stated in your response, however, instead of leading with the filling nozzle, your technician leads with their hand, blocking the first-pass air above multiple open vials in the process. Furthermore, you did not address in your FDA 483 response the filling technician potentially contaminating their sterile gloves by touching the BSC work surface. There is potential for product impact, especially when the technician’s hands and fingers contact the ISO 5 work surface and later block first pass air during filling operations.

Your firm failed to conduct laboratory testing to determine whether each batch of drug product purporting to be sterile and pyrogen-free conforms to such requirements (21 CFR 211.167(a)).

We acknowledge that your (b)(4) performance verification appears to address concerns regarding the (b)(4) and sufficient (b)(4) to the (b)(4) prepared for vial filling operations; however, it does not address the interior drug product contact surface of filling tubing sets used for (b)(4) aseptic filling drug products. Your (b)(4) were placed outside the loop of coiled tubing, instead of inside the tubing.

Your firm failed to have buildings used in the manufacture, processing, packing, or holding of drug products of a suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations (21 CFR 211.42(a)).

Your firm used non-sterile wipes within the ISO 5 aseptic processing area. For example: a. Prior to production, non-sterile wipes were used to sanitize surfaces within the ISO 5 aseptic processing area. b. In preparation for production while removing air from the filling tubing, non-sterile wipes were used to wipe discarded drug product from the (b)(4) . c. During production, the filling tubing and barbed fitting (used as a filling nozzle) were placed on non-sterile wipes.