Poor Hygiene and Environmental Conditions - FDA Warning Letter

From October 9 to November 5, 2025, the FDA inspected the facility operated by Fagron Sterile Services (Fresenius Kabi Compounding, Canton, MA), which is registered as an outsourcing facility and manufactures sterile drugs. The inspection revealed serious deficiencies in the manufacture of sterile products that call into question sterility assurance and pose a risk to patients. On February 5, 2026, Fagron initiated a voluntary recall of various lots that were still within their shelf life.

Key Deficiencies
1. Unsanitary Conditions and Inadequate Sterility Assurance

Exposure of sterile products to air of less than ISO 5 quality
During the reconstitution of sterile vancomycin vials, operators’ arms obstructed the first-air area. In addition, the vials were shaken vigorously and rapidly. These rapid movements disrupt the unidirectional airflow in the ISO 5 area and increase the risk of contamination.

Inadequate smoke studies under dynamic conditions
The airflow visualization studies did not reflect the number or positioning of equipment, materials, and components under actual production conditions. Consequently, they did not demonstrate that uninterrupted, unidirectional airflow was maintained at all critical locations during aseptic manufacturing.

2. CGMP Violations

The FDA identified several systemic violations of 21 CFR Parts 210 and 211, including the following:

Quality Unit
The Quality Unit (QU) did not effectively fulfill its responsibility to ensure compliance with cGMP requirements and adherence to all specifications relating to the identity, strength, quality, and purity of the products, as required by 21 CFR 211.22.

Specifically, serious trends involving defects in the container-closure system of IV bags - including defects in injection and infusion ports - were not adequately controlled. Although the supplier acknowledged the defects, no robust root cause analysis had been conducted. Fagron continued to rely primarily on visual inspection of the finished products instead of fundamentally addressing the state of control of the process, for example by stopping production, changing the packaging material, or conducting a more extensive root cause investigation.

The inspectors also noted that the strong focus on port defects could impair the detection of other critical defects, such as particulate matter.

Inadequate investigations of deviations and adverse trends
Adverse trends involving defects in infusion-port seals across multiple supplier lots and bag configurations were documented as an “issue,” but did not result in appropriate measures, such as stopping production or distribution.
No comprehensive risk assessment was performed, and no scientifically sound investigation into the root cause was conducted despite repeated communications with the bag manufacturer. Potentially defective packaging components were not excluded from production.
The continued use of potentially defective bags for sterile products represents a significant contamination and patient risk and constitutes a violation of 21 CFR 211.192.

Deficient aseptic procedures and validation
In some cases, there were no appropriate written procedures to prevent microbial contamination of sterile products, as required by 21 CFR 211.113(b). Where procedures did exist, they were frequently not followed.

Examples include:

• The reconstitution of sterile vials and pooling of the bulk solution were sometimes performed outside a qualified ISO 5 area or were not treated as aseptic processes, even though puncturing the closure exposes sterile products to the surrounding environment.
• The argument that subsequent sterile filtration could compensate for inadequate aseptic conditions was clearly rejected by the FDA.
• Planned measures such as “(b)(4)” of the laminar-flow hood after shaking the vials did not address the fundamental problem of air turbulence, in the FDA’s view.

Inadequate environmental monitoring in aseptic areas
There was no adequate system for monitoring environmental conditions in aseptic areas.
Active and passive air sampling in the ISO 5 area was not performed sufficiently during all critical aseptic operations.
The placement of settle plates in the ISO 5 area was not clearly defined in the SOPs. The existing requirements referred only to ISO 7, ISO 8, and ISO 9 rooms.

Inadequate cleaning and disinfection and deficient facility conditions
There was no adequate cleaning and disinfection system to ensure aseptic conditions. Among other deficiencies identified in the ISO 7 areas were brown, rust-like residues on the bases of laminar-flow hoods and tables, chipped paint on air outlets and doors, and a hole in the floor.

3. Assessment of Corrective Actions

The FDA reviewed Fagron’s responses but was unable to make a final assessment of key corrective actions because supporting evidence - such as detailed documentation, photographs, and qualified studies - was missing.

In particular:

• Planned improvements to the bag-related process and new dynamic airflow qualification studies had not yet been completed or were not supported by data.
• Evidence of actual cleaning and repair activities in the ISO 7 areas was not provided.
• Fundamental weaknesses in the management of supplier and container-closure risks- including root cause analysis, risk assessment, escalation, and escalation measures - were not adequately addressed.

The FDA therefore identified a combination of inadequate sterility assurance measures - including first-air blockage, turbulent movements, insufficient smoke studies, and aseptic steps performed outside ISO 5 areas - along with incomplete environmental monitoring, structural and hygienic deficiencies, and serious shortcomings in the quality management system, including trend evaluation, deviation and OOS investigations, supplier oversight, and Quality Unit supervision.

Further details are available directly in the FDA’s Warning Letter.