1Material and supplier control
Your firm provided several updated written procedures with your responses; however, they appear to be in draft form as the approval signature manifests are incomplete. Therefore, the effective date of these revised procedures cannot be verified. In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug…
2Aseptic processing and sterility assurance
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)).
3Aseptic processing and sterility assurance
Your media fills were not performed under the most challenging or stressful conditions. In addition, your firm continued to produce and distribute drug products intended to be sterile despite positive growth being identified in 10% of filled units during your January 2024 media fill. Your firm failed to investigate the positive growth and discarded all units that showed signs of microbial contamination. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.
4Aseptic processing and sterility assurance
Regarding your media fills, we acknowledge your commitments going forward and the revised procedures provided in your responses. However, we remain concerned with your firm’s failure to investigate the positive growth observed during your January 2024 media fill simulation. Any contaminated unit should be considered objectionable and investigated. The investigation should survey the possible causes of contamination and should assess the impact of products produced since the last successful media fill. In addition, your responses do not include data to adequately demonstrate a consistent ability to maintain aseptic operating conditions. During your latest media fill simulation, conducted in July 2024, you did not incubate all (b)(4) units, but instead only incubated (b)(4) randomly selected units. Your firm has provided no evidence that you have successfully performed additional media fill runs to ensure your aseptic processing operation is validated and your firm continues to produce via aseptic processing and distribute drug products intended to be sterile.
5Computer system validation
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. 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…
6Deviation, CAPA, and investigation
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).
7Documentation and records
Regarding your firm’s failure to provide our investigators with your 2023 media fill records due to technical issues, you provided a new procedure, SOP-0261 Retention of Records, which details document retention requirements; however, this procedure does not specify how and where documents will be retained or how these retained documents will be controlled. We acknowledge your statement that you have purchased a dedicated secure server system and that you have hired a validation consult to complete installation, operational, and performance qualification; however, you have not provided details on how you are currently retaining and securing documents while waiting for the server to be qualified. Complete and accurate records are necessary to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to reliably conduct batch record review, adequately investigate deviations and batch failures, and to ensure a continued state of validation processes.
8Equipment and facility
Your facility failed to submit a report to FDA in June 2024 identifying the drug products that you compounded during the previous 6-month period, including Heparin 4 units/mL in 0.9% Sodium Chloride (b)(4) IV bag, Phenylephrine 100 mcg/ml in 0.9% Sodium Chloride Solution 10ml syringe, and Phenylephrine HCl 25 mg in 0.9% Sodium Chloride 250 mL Bag.
9Aseptic processing and sterility assurance
Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
10Aseptic processing and sterility assurance
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. 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…
11Equipment and facility
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 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…
