FDA 就 Melrose Park 工厂 CGMP 违规向 Fresenius Kabi USA 发出警告信

Delivery Method:

VIA ELECTRONIC MAIL READ/DELIVERY RECEIPT REQUESTED

Reference #:

320-26-129

Product:

Drugs

Recipient:

Recipient Name

Mr. Pierluigi Antonelli

Recipient Title

Chief Executive Officer

Fresenius Kabi USA LLC

61346 Bad Homburg
Germany

(b)(4)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

September 22, 2026

WARNING LETTER
Reference number: 320-26-129

To Mr. Antonelli:

This warning letter advises you of significant violations observed during a U.S. Food and Drug Administration (FDA) inspection of your facility. Promptly address the violations described herein without delay, including ensuring that appropriate resources are allocated to fully address the violations and prevent their recurrence. This is not intended to be an all-inclusive list of the violations that exist at your facility. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations. Failure to adequately address violations may result in regulatory or legal action without further notice including, without limitation, seizure and injunction.

FDA Inspection

Violations were observed and documented during an inspection of your drug manufacturing facility, Fresenius Kabi USA LLC, FDA Establishment Identifier (FEI) 1450022, at 2085 N Hawthorne Ave, Melrose Park, IL from January 27 to February 18, 2026. This inspection was conducted under FDA’s statutory authority and public health responsibilities to protect the public from unsafe, ineffective, and poor quality drugs.

This warning letter summarizes significant violations of 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 March 11, 2026, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

Violations of the Federal Food, Drug, and Cosmetic Act

The following are violations identified during our inspection and review. As a reminder, this is not an all-inclusive list of violations at your facility.

1. 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).

Your firm is a manufacturer of sterile injectable drug products produced primarily through aseptic processing, including but not limited to, products for intravenous (b)(4) use. You failed to adequately investigate drug product failures and discrepancies.

Your investigations lacked data-supported root causes, formal documentation, expansion to all potentially affected products, and corrective action effectiveness checks. In multiple investigations, you inappropriately concluded there was no product impact based on overreliance on passing finished drug product test results (e.g., sterility, endotoxin, and environmental monitoring). The following examples illustrate these failures:

Endotoxin Test Failures

In 2025 and 2026, your firm received reports of patients experiencing adverse drug events, including apparent pyrogenic reactions, following administration of famotidine for injection. Notably, famotidine injection manufacturing had experienced multiple (b)(4) bioburden action limit failures. However, your firm failed to sufficiently investigate this critical deviation and permitted batch release following passing finished drug product test results (i.e., sterility, endotoxin).

Subsequent testing of finished product retains, as part of the investigation into the adverse event complaints, revealed an endotoxin failure. Your firm ultimately recalled three famotidine injection batches.

Your response acknowledges that (b)(4) bioburden samples showed gram-negative confluent growth. You state that, at the time of disposition of the affected batches, your firm did not consider the excessive bioburden to constitute an elevated endotoxin risk. You commit to revising procedures to ensure enhanced endotoxin sampling and testing whenever action-level gram-negative bacteria are identified during (b)(4) bioburden testing.

Your response is inadequate. You do not commit to comprehensive review and CAPA of your complaint system to increase vigilance, or to extensive CAPA effectiveness checks.

In order to prevent parenteral drug contamination with pyrogenic substances, including endotoxins, it is critical that your firm build quality into manufacturing operations and maintain ongoing robust upstream control. It should be noted that endotoxins are not retained by (b)(4). Any batch testing that reveals atypical bioburden levels is a signal that necessitates prompt attention. Pyrogen contamination in parenteral drug products can lead to significant adverse events such as fever, hypotension, inflammatory reactions, anaphylactic shock or death.

For more information about pyrogen and endotoxin testing, see FDA’s Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers https://www.fda.gov/media/83477/download.

Media Fill Failures

Your firm experienced media fill failures on your aseptic manufacturing Line (b)(4) with limited barrier protection in September and October 2024. Media fill failures also occurred on (b)(4) Restricted Access Barrier System manufacturing Line (b)(4) in April and October 2025. In each case, you determined the most probable contributing factors for each failure were deficient aseptic techniques by your operators. Your investigations did not consider how the poor aseptic practices went undetected by your firm’s aseptic observer program during commercial operations.

Your response includes your ongoing effort to improve aseptic practices, especially on your aseptic processing lines with limited barrier protection. You commit to an aseptic operations program assessment, updating procedures, and training operators.

Your response is inadequate because it does not provide clear timelines for addressing the fundamental design flaws of your aseptic processing lines with limited barrier protection which are inherently vulnerable to excessive contamination risk. Following your media fill failures, you placed (b)(4) commercial batches on hold, however, you did not act similarly for liquid products produced on your (b)(4) aseptic manufacturing lines with limited barrier protection. Notably, those processing lines shared operators from the processing lines associated with deficient aseptic techniques and media fill failures.

Extrinsic Biological Contamination (e.g., hair)

Beginning in May 2022, you documented at least nine incidences of extrinsic contamination (e.g., hair) during your visible particulate inspection. This contamination was described as free-floating and in direct contact with the drug product. Drug products contaminated with hair can have microbial contamination and are generally considered adulterated. You did not initiate timely investigations in response to this contamination.

Your response acknowledges the significance of issues involving extrinsic biological particulates and recognizes a procedural gap in how you classified critical defects such as extrinsic biological contamination. You commit to continuous improvement of your investigations program. Additionally, you commit to revising your particulate management system, conducting targeted supplier audits, and discontinuing tailgate samples for incoming stopper lots.

Your response is inadequate. You did not address why your quality unit (QU), your Corporate Expert Circle, and your Corporate Emergency Committee did not reject commercial batches associated with the extrinsic biological contamination and instead released them for distribution to your customers. Also, you did not provide details of your heightened incoming quality control of stoppers. Additionally, your response does not indicate that you examined retains of your distributed drug products for the presence of hair.

In response to this letter, provide:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, out-of-limit results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, the following:
  o Significant improvements in investigation competencies
  o Root cause evaluation and scope determination
  o Corrective action and preventive action (CAPA) effectiveness
  o Quality assurance unit oversight, and written procedures
  o Address how your firm will ensure all phases of investigations are appropriately conducted.
• A comprehensive review of root cause investigations for deviations related to biological particulate matter found in your products, including incoming inspection activities and subsequent CAPA activities. Provide supporting documents, including data generated and effectiveness evaluations.
• An independent, retrospective review of all critical investigations (including each in-process, release, and stability test specification failure) for the last three years as of the date of this letter. Evaluate the adequacy of each investigation, including but not limited to, the following:
  o Determine whether a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history) was conducted.
  o Assess sufficiency of review of related data and investigations to identify if there are potential systemic linkages.
  o Evaluate adequacy of scope, rigor, staff competencies, scientific/analytical foundation, root cause determinations, and CAPA.
  o Summary of findings of the assessment for each of the above elements.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program whenever needed, ensures final quality assurance unit decision authority, and is fully supported by executive management.
• A comprehensive evaluation of your program to prevent endotoxin contamination risks and associated CAPA, including but not limited to:
  o Containers and Closures ((b)(4) packaging components)
  o Ingredients
  o (b)(4) systems
  o Process and procedural controls
  o Design and control of your equipment, including preventive maintenance and repairs
  o Manufacturing environment
• An independent, comprehensive review of your environmental monitoring (EM) program to ensure vigilant, timely detection and response to potential product contamination hazards in your manufacturing environment. This assessment should include, but not be limited to, the following:
  o Establishing appropriate limits
  o Sampling methods
  o Sampling locations and frequencies
  o Trend analysis
  o Appropriate investigation of deviations and adverse trends
  o Comprehensive CAPA plan based on the findings of the assessment
• A comprehensive, independent review of your process simulation (e.g., media fill) program to ensure accurate simulations of commercial aseptic manufacturing operations, including but not limited to appropriate incorporation of worst-case conditions.
• An independent assessment of vials rejected for hair contamination, and an update that summarizes all analyses performed on suspected foreign matter identified as part of batch production (within expiration date) or after testing retains related to complaints.
• The most updated status on your supplier quality investigations for stoppers and any remediation efforts. Include the following:
  o Incoming component inspection results
  o Defect trends and Acceptable Quality Limit performance
  o Whether biological particulates have been identified in any incoming (b)(4) packaging components in the last three years

2. 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 Aseptic Process Simulations (Media Fills)

Your media fills failed to accurately simulate aseptic manufacturing operations.

At the time of the inspection, your firm used a sampling approach to determine a representative number of each intervention necessary to simulate your aseptic processes. A review showed that your media fill simulations did not adequately represent your maximum aseptic intervention counts (e.g., clearing stoppers in the (b)(4)/track, (b)(4) application, (b)(4) adjustment, removing vials from the (b)(4)). Additionally, inherent interventions (e.g., stopper additions, vial loading) are not documented in your batch records, which has the consequence of inadequate assessment of the risks these interventions present during actual aseptic production. Also, data indicated that the number of units in your media fills was insufficient.

Inadequate documentation of interventions was the subject of findings from FDA’s 2022 inspection.

In your response, you acknowledge some interventions did not simulate the maximum risk to your aseptic processes. You commit to implement an intervention docking and tracking system and enhanced oversight of related data. You state that you will ensure thorough review of batch intervention data in the future to support simulation of inherent and corrective interventions using an appropriate worst-case approach.

Your response is inadequate. We acknowledge your commitment to conduct appropriate media fill simulations for your aseptic processing lines. However, you do not address the need for sufficient media fill batch sizes and your response lacks sufficient detail on how you will document and track interventions.

When the potential for contamination is higher, as it is with your (b)(4) processing lines surrounded by barrier (b)(4), the number of units in a media fill should be the same as, or approach, the maximum production batch size. If a media fill program fails to incorporate contamination risk factors and closely simulate actual drug product exposure, the state of process control and assurance of sterility cannot be accurately assessed. Furthermore, your (b)(4) aseptic processing lines require an inordinate number of interventions and there is a need for fundamental design remediations. Notably, media fills cannot justify unsuitable manufacturing lines and processing conditions.

Aseptic Technique and Poor Cleanroom Behavior

We observed poor aseptic practices and inadequate oversight. These deviations included, but were not limited to, the following:

• Operators opening and closing (b)(4) doors with sharp movements while performing (b)(4) aseptic loading of (b)(4).
• Operators repeatedly contacted the (b)(4) barrier (b)(4) with their head and upper torso, including during (b)(4) installation and (b)(4) set up.
• Operators (b)(4) clamps over the (b)(4) sterile end of tubing (which conveys the sterile formulation) during setup activities.

In your response, you discuss your ongoing efforts to improve your aseptic operations, and you commit to engaging a third-party consultant to assess your aseptic operation oversight. Also, you commit to implementing a standardized interview template when investigations involving personnel activities or interventions relate to human error. Additionally, you commit to improving classified area material handling.

Your response fails to sufficiently acknowledge design flaws including, but not limited to, inadequate processing line layout, ergonomic deficiencies, excessive need for (b)(4) manipulations, insufficient barrier protection to provide adequate separation from surrounding areas, and other fundamental issues.

The ISO 5 (Grade A) area is critical because sterile products are exposed during aseptic production and therefore vulnerable to contamination if operations are not well designed and diligently controlled. Your aseptic processes should be designed, and operations executed, to prevent contamination hazards to your sterile product. Flaws in the design of cleanrooms and aseptic processing lines, or improper execution of operations, can promote an influx of contamination into the critical processing area.

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

In response to this letter, provide:

• A comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to, the following:
  o All human interactions within the ISO 5 area (e.g., risk reduction or elimination of (b)(4) interventions wherever possible)
  o Equipment suitability (e.g., reliability, capability, ergonomics, placement) and sufficient cleanroom space
  o Air quality in the ISO 5 area and surrounding room including, but not limited to, air volume and flow
  o Facility layout
  o Personnel flow and material flow (movement throughout all rooms used to conduct and support sterile operations and all material transfers)
  o Disinfection practices and procedures
  o Specific CAPA recommendations that will comprehensively address the design and control hazards identified in the risk assessment
  o A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible, comprehensive improvements to be made to aseptic processing operation design and control of your (b)(4) processing lines surrounded by barrier (b)(4) and explain how this CAPA plan will thoroughly and robustly remediate your deficient (b)(4) aseptic processing lines.
• Your systematic plan to assure adherence to appropriate aseptic practices, cleanroom behavior, and written procedures, including but not limited to, an independent assessment of the following with accompanying CAPA:
  o Suitability of actual practices based on extensive retrospective review and prospective observation of aseptic processing operations
  o Deficiencies in production management oversight, and identification of specific improvements to ensure effective and routine supervisory oversight for all batches
  o Frequency and depth of quality unit oversight (e.g., audit, ad hoc, daily interactions) of aseptic processing and its support operations
  o Adequacy of written procedures and operational ergonomics
  The assessment should also evaluate how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
• In an easily searchable tabular format, your updated plan to expedite the transfer of manufacturing from your Building (b)(4) aseptic filling lines to your Building (b)(4) lines without creating drug shortages. Include a list of backup contract manufacturing organizations that would be utilized in the event you are unable to ensure supply chain continuity.

3. Your firm failed to establish adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.110(a) and 21 CFR 211.42(c)(10)).

Inadequate Visual Inspection Program

Your visual inspection program is inadequate to ensure your sterile injectable drug products are essentially free of visible particulates and defects. For example:

• You categorized all non-glass particulate, regardless of material type (i.e., hair) as major, which means more severe particulates of biological origin are not considered critical.
• (b)(4) visible particulate inspection systems often exhibited low detectability and high variability regardless of particle type (e.g., glass, white particulate, black particulate) and size.
• Your probability of detection (POD) of particulates using (b)(4) visual inspection was inadequate. Your methods often exhibit PODs significantly less than (b)(4)% for particulate matter defects. In addition, glass particulates in the visible range were not consistently detected.
• You lacked defect limits for specific types of non-glass particulate matter in the visual inspection program.

In your response, you recognize that studies did not generate sufficient data across increasing particulate sizes to adequately qualify your visual inspection program and that comparison reports were not completed. Additionally, you indicated that all extrinsic particulates are now classified as critical defects and acknowledge the potential loss of sterility often associated with such particulates.

Your response is inadequate. Although you commit to evaluating the visual inspection program with the assistance of an independent third-party consultant, your response lacks a sufficient assessment of products currently on the market.

Visual detection of particulates is a probabilistic process that depends on, among other things, ensuring that visible particulates can be reproducibly detected by highly capable systems including, but not limited to, trained personnel with appropriate visual acuity. At a minimum, your visual inspection systems should reliably be capable of detecting particulates of 150 microns or greater at a 70% probability of detection. Furthermore, written procedures governing 100% inspections for visual particulates should clearly define the number of times re-inspection may be performed. You should limit and justify re-inspections. Generally, FDA does not recommend more than one re-inspection in an attempt to release a batch with atypical defect levels¹.

Inadequate Design of Facility and Equipment

We observed your (b)(4) processing lines (b)(4) surrounded by barrier (b)(4) under ceiling-fed high efficiency particulate air (HEPA) systems. These processing lines required frequent (b)(4) activities during equipment setup and throughout routine production and did not provide appropriate separation and protection of the ISO 5 areas. For example, we observed the following regarding these aseptic processing lines:

• The use of (b)(4) tubing, (b)(4) clamps, and hand tools when making critical aseptic connections within the ISO 5 area that risk interruption of first-pass air and introduce contamination hazards
• The use of barrier (b)(4) of varying lengths across each line, which provided inadequate protection of the ISO 5 processing line
• Frequent high-risk corrective interventions

In your response, you emphasize that your firm has been focused on your plan to transition production from your current aseptic manufacturing lines (b)(4) to your (b)(4) lines rather than updating the sterility assurance controls on your original lines. You further commit to re-evaluating and improving your aseptic processing lines with the assistance of a third-party.

Your response is inadequate. Your response lacks sufficient detail and corrective actions for sterility assurance improvements while you continue to use your (b)(4) processing lines with their inherent design flaws.

In response to this letter, provide:

• A comprehensive, independent assessment and remediation plan for your visual inspection program to ensure compliance with CGMP. The assessment and remediation should include, but not be limited to, the following:
  o Implementing enhancements to your 100% visible inspection program, including defining critical, major, and minor defects and the individual defect limits for drug products.
  o Ensuring adequate methods, equipment, and personnel qualifications to reproducibly detect visible particulates, including particulates which historically have been identified in your operation.
  o Conducting rigorous qualification studies to ensure your (b)(4) visible particulate inspection systems consistently and reproducibly detects the variety of visible particulates encountered in your drug products.
  o For drug products that are difficult to inspect (e.g., (b)(4) containers), implementing destructive testing or other advanced technologies (e.g., (b)(4)) as appropriate, with statistically significant sample sizes to test for defects.
  o Incorporating product-specific knowledge, process experience, deviation investigation analysis, recall/complaint data, and quality risk management to improve the visual inspection program.
• Your associated remediations to your visual inspection program, including any newly established written procedures, equipment, and methods. Include a summary of the review and recommendations made by your independent consultant.

Visible Particulate Contamination

We encourage the use of suitable (b)(4) visual inspection for particulates to augment the (b)(4) visual inspection program. (b)(4) methods should be rigorously studied, and qualified, to assess their capability and robustness under various conditions, machine settings, container-closure sizes, defect types, product characteristic, and other variables. In addition, any use of (b)(4) particulate inspection as an adjunct method does not supplant the need for (b)(4) visual inspection for various other attributes (e.g., cracks; myriad defects of container or closure; (b)(4) issues, volume, atypical, (b)(4), or other appearance defects).

Quality Systems

Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA guidance documents: Q8(R2) Pharmaceutical Development at https://www.fda.gov/media/71535/download,
Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download, and Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download.

CGMP Consultant

Based upon the nature of the violations we identified at your firm and because you failed to correct repeat violations, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Recall Discussion

On July 9, 2026, FDA held a teleconference with your firm to discuss voluntary recall. During this call, FDA informed you that our inspection revealed that drug products produced at Fresenius Kabi USA LLC contain particulate of biological origin, do not meet CGMP requirements, and are considered adulterated. Your firm initially released these adulterated batches for distribution based on your assertion that product testing results were adequate. Following the recall discussion with FDA, your firm committed to recalling six batches of drug products. As a result, on July 16, 2026, recalls were initiated for:

• Glycopyrrolate Injection, USP
• Lidocaine HCl Injection, USP
• Ropivacaine Hydrocholoride Injection, USP
• Lidocaine HCl Injection, USP

Request for a Meeting with FDA

After you submit your response to this warning letter, we recommend you reach out to this office to arrange for a teleconference to discuss your corrective and preventive actions in detail. Please direct your request to Christina Reyes at [email protected] and cc: [email protected].

Conclusion

You are responsible for investigating and determining the root causes of any violations and implementing corrective and preventative measures to ensure future and sustained compliance so that these violations and any others do not occur.

Unresolved violations may prevent other Federal agencies from awarding contracts. Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356c(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Send your written response to [email protected] within fifteen (15) business days of receipt of this letter². Identify your written response with FEI 1450022 and ATTN: Carrie A. Hughes in the subject line of the email.

If you have information that you believe demonstrates that your products are not in violation of the FD&C Act and FDA regulations, include that information for our consideration.

Please note FDA posts warning letters on www.FDA.gov.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

cc: Mr. Steven R. Nowicki
Plant Manager, Fresenius Kabi USA LLC
Melrose Park, IL
(b)(4)

_________________

1 See FDA’s draft guidance document Inspection of Injectable Products for Visible Particulates to help you meet the CGMP requirements pertaining to visible particulate inspections of sterile injectable drug products at https://www.fda.gov/media/154868/download.

2 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.