Fagron BV — FDA Warning Letter Findings

You failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58). 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 has…

Regarding your failure to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile: a. We acknowledge your response to the failure to ensure that operators’ behavior in the ISO 5 aseptic processing area does not block or otherwise compromise “first-air” to critical surfaces such as vials. We note your contention that vial reconstitution is not an aseptic practice, as well as your…

You failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile (21 CFR 211.113(b)).

Regarding your failure to establish an adequate system for cleaning and disinfecting the room to produce aseptic conditions: We acknowledge your response regarding the brown, rust-like residue found on the wheelbases of the laminar flow hoods and tables in your ISO 7 areas. We note your plan to update procedures to enhance inspection and cleaning of these surfaces as necessary. However, your response did not include evidence—such as photographs or other documentation—demonstrating that remedial actions (e.g., cleaning) have been completed. Without this documentation, we are unable to evaluate the adequacy of your corrective action at this time.

You 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. Specifically, airflow visualization studies (i.e., smoke studies) do not accurately reflect the actual quantity and positioning of equipment, materials, and other components used during production. Consequently, it cannot be determined whether adequate, uninterrupted, unidirectional airflow is maintained throughout the aseptic drug production process. The 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…

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

You failed to thoroughly investigate any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed (21 CFR 211.192).

Regarding your failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed: We acknowledge the actions your firm has planned in response to its failure to adequately investigate and respond to an adverse trend involving defects associated with your intravenous fluid bags. We note the following action items: Assess bag storage and shipping…

Regarding your firm’s failure 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 processes: a. We acknowledge your interim and long-term corrective action plans to address deficiencies in your current (b)(4) process for intravenous fluid bags. We note your intention to (b)(4) and, if necessary, (b)(4) —are implemented and…

Regarding your failure to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair, including paint chipping on air returns and a door, and a divot in the floor, all in ISO 7 areas: We acknowledge your plans to repair and refinish the affected air returns and doors, as well as to repair the floor. However, you failed to provide evidence, such as photos or executed work orders, demonstrating that the repairs have been completed. Consequently, we cannot evaluate the adequacy of your corrective action at this time. Some of your corrective actions appear deficient…

Regarding your Quality Unit’s failure to exercise its responsibility to ensure drug products produced are in compliance with CGMP, and meet established specifications for identity, strength, quality and purity: We acknowledge the actions your firm has planned in response to its failure to adequately manage an adverse trend involving defects associated with your intravenous fluid bags. We note the following action items: Assess Fresenius Kabi vendor status based on review of…

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

You exposed sterile drugs and materials to lower than ISO-5 quality air. Specifically, operators' arms blocked the first air to sterile vancomycin vials during reconstitution. Additionally, operators vigorously shook the vials during this process. This rapid movement likely disrupts the unidirectional airflow within the ISO 5 aseptic processing area, creating a contamination risk.

Regarding your failure to establish an adequate system for monitoring environmental conditions in aseptic processing areas: We acknowledge your response regarding the failure to adequately perform active and passive air sampling within the ISO 5 area during aseptic operations, including your plan to initiate active air monitoring during filling operations. We recognize the importance of conducting effective environmental monitoring while minimizing the risk of contamination…

You 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)).