Deficiencies in Staffing, Monitoring and Aseptic Techniques – Warning Letter to a European Company

A Warning Letter issued to Fareva Amboise and published in July is based on an FDA inspection conducted in September 2025. It describes significant CGMP violations in the sterile manufacturing of veterinary and human medicinal products. From the agency’s perspective, the main issues concern personnel hygiene and cleanroom behavior, aseptic technique, and significant weaknesses in cleaning, disinfection, and the technical condition of the equipment. In addition, the FDA criticized inadequate smoke studies, incomplete and insufficiently realistic media fills, as well as serious deficiencies in the handling of computerized systems and data integrity.

1. Personnel Hygiene, Cleanroom Behavior, and Aseptic Technique

The FDA identified fundamental problems with personnel behavior in Grade A/Grade B areas and with the practical implementation of aseptic working practices. During setup and filling operations, both material flows and movement patterns were observed that represented an immediate contamination risk to sterile product-contact surfaces.

The following issues were particularly highlighted:

Improper handling of materials and components

• Empty bottles were manually transferred from Grade A to Grade B and later returned to the critical area without being disinfected again.
• A bag containing product was introduced into Grade A without disinfection. During this process, the operator repeatedly reached over unprotected sterile parts to establish tubing connections.
• Protective covers were removed in Grade B before the parts were installed in Grade A

.Uncontrolled movements and reaching into critical zones

• Movements were not slow and controlled, particularly when handling the (b)(4) connections.
• Arms and hands were moved over open containers, sterilized contact surfaces, and sterile components.
• Repeated reaching into and across critical areas created an immediate contamination potential.

The company subsequently announced retraining, a reassessment of aseptic practices, and internal self-inspections. However, the FDA criticized the company for not providing a robust retrospective risk assessment systematically examining how these behavioral deficiencies may have affected the sterility of batches already manufactured and distributed. The planned self-inspections were also considered insufficiently specific with regard to frequency, scope, and binding requirements.

2. Monitoring and Assessment of Personnel in the Grade A Environment

Another key focus concerned the way personnel working directly in the Grade A area are microbiologically monitored and assessed.

The FDA criticized the fact that employees whose hands and forearms regularly enter Grade A areas were assessed only against Grade B limits. One particularly critical case involved the filling of a batch intended for the US market. A significant number of CFUs of Corynebacterium tuberculostearicum were detected on the forearm of an operator, even though the operator had been working directly in the Grade A environment.

Despite this significant finding, the company’s internal deviation assessment concluded that both aseptic practices and environmental conditions had been “compliant.”

The FDA criticized the following points:

• The monitoring limits are not based on the actual Grade A exposure and the associated real-world risk, but rather on formal area classifications.
• A thorough root-cause investigation into the contamination is lacking, as is a systematic assessment of whether the affected batch or other batches in which the employee participated may present an increased sterility risk.
• The company did not provide convincing evidence of implemented corrective actions, such as revised monitoring specifications, enhanced monitoring, or interim measures.

3. Cleaning, Disinfection, and Equipment Condition in the Aseptic Area

With regard to cleaning, disinfection, and the technical condition of the equipment, the FDA identified fundamental deficiencies in both aseptic design and the practical implementation of the hygiene strategy.

The key points included the following:

Critical equipment design: stopper bowl
Product-contact parts of the stopper-feeding system are permanently installed and cannot be disassembled. As a result, fully validated cleaning and sterilization of all contact surfaces cannot be assured.

Inadequate transport and disinfection strategy for parts
Equipment is disinfected in Grade C, transported through Grade B, and subsequently installed in Grade A without a final, timely disinfection immediately before introduction into the critical area.
There is no clear documentation of exactly when disinfection was performed or how long the disinfection remains valid. Validated post-disinfection hold times have not been established.

Insufficient sporicidal treatment and lack of efficacy evidence
Surfaces in the Grade A filling area are not routinely treated with a sporicidal agent.
Fully validated disinfection efficacy studies for all relevant surface materials—particularly (b)(4) components—are not available.

Visible equipment wear and weak preventive maintenance program
Inspectors found visible scratches, (b)(4), and wear on important components of the aseptic filling and closing lines.
These deficiencies had not been detected or addressed through the preventive maintenance program, indicating insufficient “technical vigilance” and an ineffective preventive maintenance system.
The company committed to developing a new, disassemblable stopper-bowl component, strengthening decontamination measures, establishing sporicidal treatments, conducting external validation activities, and revising its SOPs.

However, the FDA criticized the company because:

• Robust evidence of implementation—such as validated protocols, revised procedures, and documentation demonstrating execution—was lacking.
• No comprehensive risk assessment had been provided to determine whether sterile products already manufactured for the US market could be affected by these deficiencies.
• The proposed frequency of sporicidal applications was not supported by a scientifically credible rationale.
• The preventive maintenance concept did not convincingly explain how obvious damage would be detected and corrected at an early stage in the future.

4. Cleaning of Non-Dedicated Equipment and Cross-Contamination

In addition to the aseptic equipment, the Warning Letter describes significant weaknesses in the cleaning of non-dedicated equipment used to manufacture various human medicinal products.

For example, the FDA found residues on seals and inside the equipment. Analytical testing confirmed residues from previous manufacturing operations.

Although the company later argued that the residue was an excipient used in several products, the FDA generally regarded this finding as evidence of insufficiently effective and reproducible cleaning, and therefore as an indication of a materially increased risk of cross-contamination—including with other active ingredients that had not been explicitly tested.

The agency particularly criticized the following:

• No comprehensive assessment had been provided of all marketed batches manufactured on this multi-purpose equipment within their shelf life.
• There were no data demonstrating that the cleaning procedures are capable of reliably removing APIs and excipients to validated limits.
• A structured CAPA plan for the cleaning program, based on a lifecycle approach, was lacking.

The FDA therefore requested, among other measures:

• Testing of retention samples from affected batches, including the respective active ingredients processed;
• A comprehensive assessment of the cleaning processes; and
• A detailed CAPA plan with specific improvements and implementation timelines.

5. Additional Deficiencies

The smoke studies were also criticized. For example, the airflow visualizations at the Grade A filling line did not demonstrate clean unidirectional airflow. Instead, they showed stagnant zones, upward-directed airflow, and turbulent areas, particularly in the intervention and stopper-transport areas.

The media-fill programs also failed to realistically reflect actual operating conditions, particularly the frequency and nature of critical interventions.

Finally, deficiencies relating to computerized systems under 21 CFR 211.68 were identified. These included overwritten data and, consequently, a lack of data integrity.

Further details can be found directly in the FDA Warning Letter: