Fareva Amboise(FDA Ref. No.: 26-HFD-45-03-03)

Issuing Office:

Center for Veterinary Medicine

United States

Center for Drug Evaluation and Research (CDER)

United States

April 10, 2026

CMS Case: 723502

WARNING LETTER

Dear Mr. Rapy:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Fareva Amboise, FEI 3000234005, at Zone Industrielle 29, route des Industries 37 530 Pocé-sur-Cisse, France from September 8 to 16, 2025.

This warning letter summarizes significant violations of FDA’s Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21, Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your October 7, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondences dated December 11, 2025, December 23, 2025, and February 6, 2026.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. 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)).

Inadequate Smoke Studies

Airflow visualization studies performed for your Grade A (b)(4) aseptic filling line, which is used to fill animal drug products for the U.S. market, did not demonstrate unidirectional air flow and revealed multiple deficiencies in airflow patterns and aseptic practices. For example:

• During (b)(4) installation, air flowed from the operator (positioned in the Grade B area while leaning into the barrier) toward the (b)(4) intervention site where uncovered (b)(4) on the (b)(4) were exposed.
  • Air flowed upward towards the Grade B area when (b)(4) was (b)(4), leading to the (b)(4) and on top of (b)(4), rather than maintaining unidirectional flow away from critical surfaces.
  • Laminar flow patterns during interventions performed around the filling area showed a tendency to stagnate and flow upward in the area between (b)(4) where operators make tubing connections.
  • Airflow was turbulent with an (b)(4) flow while stoppers were transferred from the stopper bowl to the stoppering machine and over the conveyor moving open bottle.

Furthermore, your firm has not conducted dynamic airflow studies during filling and stoppering operations. The airflow studies reviewed during the inspection do not include airflow patterns during filling of (b)(4) containers (b)(4) filled on the (b)(4) production line, demonstrating incomplete qualification of your aseptic processing conditions.

Your response acknowledges inadequacies in the airflow studies reviewed during the inspection and references previous smoke studies (not provided during inspection) that purportedly confirm adequate airflow. However, you committed to conduct new dynamic smoke studies on the (b)(4) aseptic filling line under external consultant supervision and provided an "Evaluation of Smoke Studies" (December 8-19, 2025) in one of your response updates. The evaluation recognizes that (b)(4) has outdated equipment and environmental design causing non-conformities, including non-laminar flow issues that cannot be corrected through practice improvements alone, and proposes line improvements and procedural changes to mitigate the identified risks.

Your response is inadequate. While your December 2025 smoke studies evaluation identifies critical non-conformities requiring correction, you provide no specific timelines or deadlines for implementing the recommended corrections. The reference to change control AMB-CC-2025-227 is insufficient without committed completion dates. Also of note, the document you identified as the "Risk assessment on smoke studies" does not appear to correspond to the document referenced in your response attachments. Without a risk assessment, there is no information regarding the impact of the identified deficiencies on sterile drug products manufactured in your aseptic processing areas.

Poor Aseptic Technique and Cleanroom Behavior

Poor aseptic practices occurred during set up and filling operations of (b)(4) batches (b)(4) including the following:

• Inadequate handling of materials, sterile components and equipment:
  o An operator removed empty bottles from the Grade A area by hand into the Grade B area. Additionally, the operator later returned the bottles to the critical area for filling without disinfecting them.
  o An operator introduced a (b)(4) bag containing (b)(4) into the Grade A area without disinfection, then repeatedly reached over the unprotected sterile parts ((b)(4)) to make tubing connections.
  o An operator removed protective (b)(4) from sanitized equipment parts in the Grade B area, then transferred it into Grade A for installation.

• Inadequate personnel practices
  o Failure to consistently use slow and controlled movements during aseptic operations and while performing (b)(4) connections.
  o Reaching over sterilized equipment and positioning of arms directly above sterile contact surfaces.
  o Reaching into and over sterile components and equipment, creating direct contamination potential for sterile product contact surfaces.

In your response you committed to conducting a re-assessment of all aseptic practices. You proposed the implementation of specific actions to reduce risk during interventions to the Grade A area and periodic self-inspections by the production and QA managers. Additionally, you provided evidence of personnel re-training on aseptic behavior.

Your response is inadequate because it did not investigate the impact of these poor aseptic practices on the sterile drugs you manufactured. Further, the response does not provide sufficient details regarding the frequency and scope of the proposed self- inspections to be implemented to address the lack of oversight of aseptic behavior of the operators.

Inadequate Process Simulation (Media Fills)

Your media fills do not adequately simulate commercial operations. For example, FDA investigators observed significantly more (b)(4) interventions during aseptic filling operations on September 8, 2025, and in their review of the aseptic filling of (b)(4) batch (b)(4) than those that were documented in the corresponding media fill records, which indicates your media fills do not simulate worst-case conditions.

Additionally, complete information regarding the type, frequency, and timing of interventions was not consistently documented in the media fill or batch production records. For example, you performed numerous interventions during the filling of (b)(4) batch (b)(4) which you did not document in the batch record.

Furthermore, you do not have written procedures for vial rejection (e.g., rejecting vials during interventions or after (b)(4).) You reject vials after (b)(4) during media fills, but your lack of written procedures means there is no basis to conclude this is representative of routine production. You also fail to keep records of such rejections during commercial batches, which prevents any meaningful comparison with your media fill.

In response to this deficiency, you committed to establishing a (b)(4) process for interventions, add reminders for complete intervention documentation in batch records, analyze data to develop new media fill protocols, implement intervention batch documentation forms verified against video recordings, and establish new SOPs with operator training for vial removal activities.

Your response is inadequate because it fails to address the potential impact of the observed deficiencies or propose interim measures to mitigate risk to product quality. Furthermore, your response does not address overall aseptic processing deficiencies, including but not limited to inadequate airflow studies, personnel behavior issues, and inadequate process simulations. When a media fill program fails to adequately account for contamination risk factors or accurately replicate actual drug product exposure conditions, it becomes difficult to properly evaluate the state of process control or provide adequate sterility assurance.

Inadequate Monitoring of Personnel In Aseptic Areas

Your firm failed to ensure adequate monitoring of personnel operating within the critical area. For example, personnel whose hands and forearms extend into the Grade A area — where open vials, exposed sterile stoppers, and sterile equipment surfaces are present — were held to Grade B requirements ((b)(4) alert, (b)(4) CFU action limits) when their hands were monitored upon exit. For example, on April 17, 2025, during aseptic filling of (b)(4), batch (b)(4)(US batch), (b)(4) CFU’s of Corynebacterium tuberculostearicum, were recovered on the right forearm of Personnel ID:(b)(6), who participated in the filling activities.

You initiated a deviation to review (b)(4) batch (b)(4) and concluded that aseptic practices and environmental controls were compliant, despite the recovery of (b)(4) CFUs on an operator's forearm who had direct contact with the Grade A environment. You committed to implementing the use of (b)(4) to prevent (b)(4) under laminar flow, controlling (b)(4) and forearms to Grade A specifications, and improving the stopper bowl design to reduce interventions.

Your response is inadequate because you failed to acknowledge that personnel monitoring requirements should be based on actual Grade A exposure and contamination risk rather than arbitrary area designations. You concluded that your practices were "compliant" despite clear evidence that an operator with (b)(4) CFUs on their forearm had direct contact with the Grade A environment during aseptic operations. You failed to provide an investigation into the contamination source or potential product impact to determine if batch (b)(4) or other batches processed by contaminated personnel pose sterility risks to distributed products. Additionally, you failed to provide documentation evidencing implementation of the proposed corrections such as revised personnel monitoring procedures and to establish interim controls or enhanced supervision.

In response to this letter, provide the following:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
   All human interactions within the ISO 5 area
   Equipment placement and ergonomics
   Air quality in the ISO 5 area and surrounding room
   Facility layout
   Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

• Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit (QU) oversight (e.g., audit) during aseptic processing and its support-operations.

• A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.

• Smoke studies under dynamic conditions, with thorough and complete evaluations of aseptic interventions and operator positioning within the critical filling areas. After you remediate your aseptic operation, provide smoke studies that visualize airflow and critically evaluate unidirectional airflow. Include a video of your dynamic smoke studies.

• A comprehensive summary of your remediated media fill program that ensures appropriate simulations of worst-case conditions in commercial manufacturing.

2. Your firm failed to establish adequate control systems to prevent contamination during aseptic processing 211.42(c)(10)(v)

Inadequate systems for cleaning and disinfection

Your aseptic processing operation is inadequately designed to prevent contamination of sterile drug products. For example, the stopper bowl equipment, which directly contacts (b)(4) container closure components, has parts that are permanently fixed to the machine and cannot be disassembled. This design prevents adequate cleaning and sterilization of critical contact surfaces.1

Our investigators observed that equipment (b)(4) were disinfected and stored in a Grade C area, then transported through a Grade B area and installed in the Grade A area without re-disinfection. Additionally, your firm failed to maintain records of when equipment disinfection occurred2 and you lack cleaning validation data to support time limits for holding disinfected equipment prior to installation in the Grade A area.

Your facility does not routinely use a sporicidal agent on equipment surfaces within the Grade A filling barrier. Further, your firm has not conducted or provided validated disinfection efficacy studies to demonstrate the effectiveness of disinfection procedures for all surfaces in the Grade A filling area. This includes filling machine (b)(4) constructed from (b)(4).3

Moreover, during our inspection, apparent (b)(4), scratch marks and signs of wear were observed on the (b)(4) for the aseptic filling and capping lines. While you had performed the preventive maintenance (PM) on these equipment pieces, the preventive maintenance activities did not identify the damage on the equipment parts and corrective actions were not implemented until the deficiencies were noted during the inspection.

You acknowledged a design flaw in your equipment and committed to creating a new stopper bowl part that your operators can sterilize and install, with plans to incorporate this intervention into upcoming smoke studies. You also committed to revising assembly procedures for the stopper bowl, training your operators on these updates, and implementing reinforced decontamination activities that include (b)(4) sporicidal (b)(4) treatments followed by surface monitoring to verify effectiveness. To address inadequate transport of (b)(4) from Grade C to Grade A areas, you committed to updating procedures that will require your personnel to sterilize or disinfect (b)(4) before entering Grade A environments, with particular emphasis on parts that contact products directly, and you committed to validate these disinfection procedures. You proposed implementing (b)(4) sporicidal decontamination in Grade A areas while revising procedures that define methodology and frequency. Regarding disinfection efficacy studies for all Grade A surface materials, you referenced an ongoing validation that your provider is conducting and will generate comprehensive validation data. Finally, you presented a (b)(4) during the inspection and committed to assessing all your aseptic process equipment for degradation risks, verifying your preventive maintenance program, and implementing equipment defect verification and correction during (b)(4).

Your response to these observations is inadequate. While your response addresses the identified deficiencies, you failed to provide documentation evidencing the implementation of the proposed corrections or interim control measures such as validation protocols, revised procedures, or service provider contracts. You did not conduct an adequate risk assessment to determine if the drug products manufactured by your facility for the U.S. market are compromised for sterility. Additionally, we are concerned that your preventive maintenance program did not identify the improper equipment conditions, including scratches, cracks, and (b)(4), until these deficiencies were pointed out during our inspection. Your response lacks scientific justification for the proposed (b)(4) sporicidal treatment frequency and fails to adequately explain why routine sporicidal treatment was not previously considered necessary for aseptic operations. Furthermore, your preventive maintenance response does not provide sufficient scientific rationale for the proposed maintenance intervals and inadequately addresses how your previous maintenance program failed to detect obvious equipment defects that were readily apparent to our investigators. The absence of supporting documentation, combined with the failure to assess potential impact on distributed products and the systemic oversight failures in your maintenance program, demonstrates insufficient corrective action to ensure ongoing compliance with current good manufacturing practice requirements.

In response to this letter, provide the following:

• Your corrective action and preventive action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

3. 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, and you do not maintain a backup file of data. 21 CFR 211.68(b)

Your systems do not have the appropriate controls to prevent data deletion and record modifications.

For example, your firm uses (b)(4) particle counters to perform particle monitoring in classified areas. During the inspection on September 10, 2025, our investigator observed that operators could modify system dates, adjust alarm limits, and access settings without restriction. The equipment displayed that network user authentication was not enforced, and management confirmed that no controls were in place to ensure the integrity of printed data records.

Review of electronic data stored on your particle counters revealed multiple instances where Grade A action limits for particle counts were exceeded. However, your firm could not produce original printed documentation of these failing results despite extensive searches of batch records and data storage locations. Initial failing particle count results in Grade A areas were not recorded in batch records. Instead, retests were performed, and only conforming retest results were retained and included in production documentation. There was no evidence in batch records of the original failing results or required corrective actions such as notifying operators or cleaning the area.

Additionally, you lack adequate data backup and retention procedures. For example, your firm's vendor performed a calibration activity which deleted all electronic data prior to the calibration. You did not have backups of this data.

You acknowledged the data integrity failures with your (b)(4) particle counters and proposed several corrective actions. You opened a deviation to document the incident and committed to retraining all personnel on data retention obligations. You purchased new (b)(4) equipment with electronic data collection capabilities that will be connected to a server, proposed to conduct a system-wide review of other in-process control equipment for similar upgrades, and to investigate the root cause of particulate contamination at the (b)(4) machine laminar airflow. You also committed to developing an investment plan for upgrading older equipment and eliminating reliance on paper-based data collection systems.

Your response is inadequate because it fails to address the immediate and ongoing data integrity risks during the implementation timeline. Your response lacks sufficient interim controls to prevent data manipulation, provides no enhanced Quality Unit oversight of current (b)(4) operations, and offers only "retraining" as an immediate remedy for what appears to be data suppression. You did not commit to assessing the impact on already-released batches or implementing enhanced supervision during the interim period.

In response to this letter, provide the following:

• A comprehensive, independent assessment of computer system performance and security. Provide a report that identifies vulnerabilities in design and controls, and a thorough corrective action and preventive action (CAPA) plan for each of your laboratory or production computer systems, which contains the following elements:
  o A list of all hardware (both standalone and networked) and software used.
  o Identification and evaluation of vulnerabilities in performance and security of all of these computer systems, including but not limited to their configurations, administrative rights, password controls, audit trails capabilities and state of implementation for each system, qualification/validation status, deviation history, backup capabilities, network requirements, completeness of data records, suitability of current hardware/software for its intended use(s), change management, and management oversight.
  o An Assessment of each system to determine if unique usernames and passwords are used.
  o An evaluation of your policies and procedures regarding computers and data governance with special emphasis on audit trails, prohibiting data deletion, and appropriate modifications of results. Specify how your firm prevents data deletion and undocumented/inappropriate modifications of data. Also describe how you ensure original data and information are always preserved. Provide your procedures for audit trail review. Provide requirements for data retention and backup for all laboratory and production systems.

• A summary of your interim controls to assure reliable performance and security while your CAPA plan is being implemented.

4. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

You manufacture prescription (b)(4) dosage form human drug products used to treat various conditions including (b)(4). Your cleaning procedures for your (b)(4), non-dedicated manufacturing equipment was inadequate. For example,

• (b)(4) residues were observed on the gasket of the (b)(4) equipment.

• (b)(4) residues were observed inside the (b)(4) equipment.

During the inspection you collected and analyzed samples of the residue. The active pharmaceutical ingredient (b)(4) was detected.

In your response, you state that additional testing had been performed and confirmed the presence of (b)(4), an inactive ingredient which is found in multiple drug products. You then stated that there was no impact on the batches manufactured and distributed, as it was part of the formulation of multiple drug products.

Your response is inadequate. The presence of (b)(4) from previous batches detected indicates the potential for active ingredients from previous batches to cross contaminate other drug products you manufactured. You failed to assess the impact of your inadequate cleaning processes on products that are currently on the market and within expiry. Furthermore, you failed to provide supporting data to demonstrate that your cleaning practices are sufficient to remove contaminants from surfaces of your drug product manufacturing equipment.

It is essential that your facility and equipment are cleaned, and sanitary conditions are maintained, to ensure ongoing suitability for drug manufacturing, and to protect drug products from contamination.

In response to this letter, provide:

• A summary of results from testing retains samples of all drug product batches within expiry manufactured on non-dedicated (b)(4) equipment. You should test all other active ingredients processed in your (b)(4) equipment. Additionally, provide your scientific rationale for any specification related to cross contamination levels. If testing yields an out-of-specification (OOS) result, indicate the corrective actions you will take, including notifying customers and initiating recalls.

• A comprehensive assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product.

• A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

Additional Guidance on Aseptic Processing

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice at https://www.fda.gov/media/71026/download).4

Quality Systems

Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances: Q9 Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

You must correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA refusing admission of drugs manufactured at Fareva Amboise Zone Industrielle 29, route des industries 37530 Pocé-sur-Cisse - France under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Drugs that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CVM-483-Responses@fda.hhs.gov. Refer to the CMS Case number 723502 FEI 3000234005 and ATTN: Dayna I. Martínez when replying.

Sincerely,
/S/

Dillard Woody
Acting Director
Division of Drug Compliance
Office Surveillance and Compliance
Center for Veterinary Medicine

/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

______________

1 See also, 21 CFR 211.63 (equipment design).

2 See also, 21 CFR 211.182 (equipment cleaning records).

3 See also, 21 CFR 211.67 (equipment cleaning and maintenance).

4 While this document does not specifically reference the Center for Veterinary Medicine, its contents may be helpful as sterile animal drugs and human drugs produced by aseptic processing are subject to the same CGMP requirements.