Par Health USA, LLC & Endo USA, Inc. MARCS-CMS 722121 — April 15, 2026

WARNING LETTER

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• Delivery Method: VIA UPS
• Reference #: 320-26-68
• Product: Drugs

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• Recipient: Mr. John Caldwell; VP Manufacturing Operations; Par Health USA, LLC & Endo USA, Inc.; 870 Parkdale Road; Rochester, MI 48307-1740; United States

• Issuing Office: Center for Drug Evaluation and Research (CDER); United States

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Warning Letter 320-26-68

April 15, 2026

Dear Mr. Caldwell:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, ENDO USA, Inc., FEI 1818977, at 870 Parkdale Road, Rochester, from October 6 to 20, 2025.

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 November 10, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. 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 211.42(c)(10)).

Inadequate Design of Facility and Equipment

Your firm is a contract manufacturer of sterile injectable drug products produced primarily through aseptic processing including, but not limited to, products for (b)(4) use. (b)(4) of your aseptic processing lines are described as “(b)(4) restricted access barrier systems.” However, (b)(4) of these processing lines (b)(4) are not restricted access barrier systems (RABS). They lacked fundamental RABS design elements, such as (b)(4), that are essential for reducing or eliminating direct gowned personnel intervention into the critical (ISO 5) area during batch manufacturing.

(b)(4) are (b)(4) foundational elements of RABS design and control, minimizing contamination risk from the surrounding cleanroom environment. Without these basic features, your processing lines (b)(4) cannot be categorized as RABS.

Additionally, your processing lines (b)(4) were designed as traditional aseptic filling lines surrounded by barrier (b)(4) under (b)(4) high efficiency particulate air (HEPA) systems. These processing lines required manually intensive operations 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:

• Excessive and high-risk manual interventions required during operations on your aseptic processing lines created unacceptable hazards to product sterility. For instance, barrier (b)(4) lines (b)(4) required hundreds of interventions, including numerous lubrications of (b)(4) and conveyor belts with (b)(4), during the production of a batch.
• Product contact equipment on multiple lines was poorly protected or otherwise exposed to contamination hazards. For example:
  o Barrier (b)(4) on opposite sides of processing line (b)(4) remained (b)(4) to the surrounding environment for almost (b)(4) during installation of the stopper bowl assembly.
  o (b)(4) manifold set up on line (b)(4) required personnel to break first pass air to the critical areas of the production line with their arms, head, and upper body, and lasted nearly (b)(4).
  o The design of the stopper bowl component required personnel to break first pass air with (b)(4) and forearms during installation on production lines (b)(4).
  o Product tubing extended above and over open vials and filling operations of line (b)(4).

Your aseptic processing cleanroom layout, filling equipment design, protection of ISO 5 areas, and the number and complexity of personnel interventions during setup and filling operations are deficient. These basic design deficiencies and manually intensive interventions affect multiple processing lines and compromise your ability to maintain aseptic conditions.

Inadequate Environmental Monitoring

You also failed to ensure adequate environmental monitoring (EM) of classified areas used for aseptic production of sterile injectable drug products. For example:

• EM of critical filling equipment (b)(4) did not ensure each of the (b)(4) were periodically assessed for microbiological quality.
• Your EM program for ISO 5 non-viable particulate monitoring was deficient. You failed to demonstrate that your sample collection apparatus (using tubing (b)(4) long with (b)(4) bends) provides meaningful and representative samples.

Inadequate Unidirectional Airflow

The qualification of airflow in critical areas demonstrated further inadequacies in the suitability and design of aseptic processing lines (b)(4). Dynamic airflow studies demonstrated that airflow patterns failed to adequately protect the aseptic processing line, including exposed sterile product and product contact equipment, from significant contamination hazards.

Your dynamic smoke studies did not demonstrate unidirectional airflow protection of the production line while barrier (b)(4) were (b)(4). The study showed air moving at a sharp angle toward (b)(4) vents, leaving critical areas of your aseptic processing line potentially unprotected.

Furthermore, design flaws in production equipment led to poor aseptic practices and ergonomics that compromised unidirectional airflow. For example:

• The (b)(4) assembly design required personnel to grip the (b)(4) with (b)(4), touching the critical portions of the (b)(4) through which the (b)(4) during assembly.
• Personnel blocked first pass air to (b)(4) with their forearms and (b)(4) during installation of the (b)(4) assembly.

Your response emphasizes aseptic processing controls measured by environmental and personnel monitoring recovery rates, numbers of media filled units produced, and sterility tests performed. Furthermore, in your response you also commit to reconfiguring line (b)(4), tightening EM specifications for ISO 5 non-viable particulate monitoring to account for tubing length, eliminating the need for (b)(4) lubrication, and ensuring all (b)(4) are monitored. You also acknowledge the high-risk aseptic line setup activities and have implemented improvements including maintaining (b)(4) protection of equipment for a longer period, changing sequence of setup activities, and improving operator ergonomics.

Your response is inadequate as the retrospective review does not overcome fundamental design flaws. Rather than implementing more extensive changes to the aseptic processing operation, you are attempting to partially mitigate significant aseptic processing line hazards. Overall, your response fails to address how you will ensure adequate aseptic processing operations and collect meaningful data to support your aseptic processes.

We acknowledge that you also have temporarily suspended manufacture and release of aseptically filled product from all (b)(4) production lines pending a third-party consultant review.

Your aseptic manufacturing 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 aseptic operations, can promote influx of contamination into the critical processing area.

Your firm’s response also includes evaluation of retrospective sterility testing data. It should be noted that a sterility test, while a critical quality control for aseptically processed products that purport to be sterile, cannot be solely relied upon as justification to release drug product batches. The test is only the last in a series of design provisions and controls intended to protect the consumer from distribution of an unsafe batch.

In response to this letter, provide:

• Comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to:
  o All human interactions within the ISO 5 area (e.g., risk reduction or elimination of manual interventions wherever possible)
  o Equipment suitability (e.g., reliability, capability, placement, ergonomics)
  o Air quality in the ISO 5 area and surrounding room
  o Facility layout
  o Material transfers
  o Personnel and material/process flow 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, comprehensive improvements to be made to aseptic processing operation design (e.g., separation, automation) and control, and explain how this corrective action and preventive action (CAPA) plan will systematically remediate your aseptic processing operation.

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 Process Simulation

Your media fills failed to accurately simulate aseptic manufacturing operations.

Your data reported maximum aseptic intervention counts per batch of over (b)(4) for line (b)(4) and nearing (b)(4) for line (b)(4). Approximately 30% of these interventions involved lubricating productions lines with (b)(4) due to persistent challenges with the proper functioning and movement of vials during processing. However, the number of worst-case interventions performed during routine batch manufacturing was significantly reduced in your media fill simulations. Additionally, you made the total number of units in your media fill simulations substantially smaller than some of your aseptically produced batch sizes.

In your response, you commit to including the maximum number of interventions during a media fill and to addressing the need for lubricating production lines. However, you fail to address media fill batch sizes. Given the manually intensive nature of your processes and fundamental design flaws, your media fills should reflect the worst-case number and type of interventions. When the potential for contamination is higher, as it is with the use of (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 aseptic processing lines require an inordinate number of interventions and necessitate fundamental design remediations. Notably, media fills cannot justify unsuitable manufacturing lines and processing conditions.

Poor Aseptic Technique and Cleanroom Behavior

We observed poor aseptic practices that were due, in part, to inadequate line design. In addition, our investigators observed operators failing to follow your written procedures during production operations on aseptic processing lines (b)(4). These deviations included, but were not limited to:

• Reaching over the (b)(4) processing line, open vials, and (b)(4) equipment with (b)(4), sleeves, head, and shoulders to perform line interventions.
• Inappropriate transfer of (b)(4) stoppers to the production line. For example:
  o Failure to follow procedures to disinfect the stopper bag during transfer to the production room.
  o Cutting open the stopper bag and exposing stoppers to the ISO 7 environment prior to emptying the contents into the ISO 5 production line.

Your response includes changes to procedures with applicable training for aseptic processing operators. However, your response fails to sufficiently acknowledge design flaws (e.g., equipment ergonomic flaws that affect operator performance), excessive need for manual manipulations, insufficiency of barrier protection to provide adequate separation from surrounding areas, and other fundamental issues.

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:

• Your systematic plan to assure adherence to appropriate aseptic practices, cleanroom behavior, and written procedures including, not but 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
  o evaluation of how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
• A comprehensive independent review of your process simulation (e.g., media fill) program to ensure appropriate simulations of worst-case conditions in commercial manufacturing.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your visual inspection program was inadequate to ensure your sterile injectable drug products were essentially free of visible particulates. For example,

Inadequate Personnel Capabilities

Your probability of detection of particulates using (b)(4) visual inspection was inadequate. You conducted Knapp studies for (b)(4)-mL and (b)(4)-mL vials and demonstrated that personnel were often not able to achieve a probability of detection of 70% for certain critical particulates larger than 150 microns (e.g., dark fibers, light fibers, glass, and (b)(4)).

Inadequate Procedures and Particle Characterization

• You incorrectly categorized critical defects as major and subsequently approved products that passed acceptable quality limits (AQL) testing. After completion of our inspection, you submitted Field Alert Reports for (b)(4) different products manufactured on (b)(4) different product lines where major particulates were recategorized as critical with subsequent AQL failures.
• Your written procedures allowed multiple re-inspections for visual particulates, and you acknowledged that up to (b)(4) re-inspections may be performed in support of batch release.

Furthermore, since 2023 you failed to conduct thorough investigations of trends in product quality glass defects that adequately remediate your visual inspection program and include adequate support for your product quality impact conclusions.

Your response included further details pertaining to a September 2023 deviation for adhered glass defect from a specific vial vendor. Your clarification further acknowledges that your visual inspection program did not adequately assess this defect type.

Although you stopped using the glass supplier and determined the defect had no impact on your batches, your investigation failed to assess the full scope, including the number of vials procured and used, and the impact on your entire product portfolio.

Additionally, adhered glass defects represent a recurring problem inadequately detected by your visual inspection program and not properly addressed through CAPA. For example, you produced (b)(4) batches of (b)(4) in July and August 2024. Your quality unit approved them for release, but later you identified internal adhered glass defects in these batches.

Further, you initiated CAPA 11768 following our inspection to assess 28 AQL failures related to visual inspection. You identified six as needing CAPA improvement.

Your response acknowledges serious deficiencies in your visual inspection program, as you have halted all visual inspection activities and hired a third-party consultant to completely remediate your process. You also commit to retrospective evaluation of all deviations for the previous three years, re-inspection of all retained samples for batches associated with adhered glass AQL failures, procedural changes to particle characterization/classification including performing retrospective trending and review, enhanced personnel training, and limiting the number of re-inspections to (b)(4) prior to batch disposition. Your response omits an assessment of products currently in commerce. You continue to lack assurance that distributed products are essentially free of visible particulate matter.

Visual detection of particulates is a probabilistic process that depends on, among other things, ensuring that visible particulates can be reproducibly detected by trained personnel with appropriate visual acuity. At a minimum, personnel 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.

In response to this letter, provide:

• A comprehensive assessment and remediation plan for your visual inspection program to ensure compliance with CGMP. The remediation plan should incorporate:
  o Implementing enhancements to your 100% visible inspection program
  o Ensuring adequate methods and personnel qualifications to reproducibly detect visible particulates including particulates which historically have been identified in your operation.
  o For drug products that are difficult to inspect (e.g., (b)(4), suspension products, (b)(4) containers), implementing destructive testing or other advanced technologies (e.g., (b)(4)) as appropriate, with statistically significant sample sizes to test for critical 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 and methods. Include a summary of the review and recommendations made by your independent consultant.
• Provide an assessment of changes implemented to your component supplier qualification program, visual inspection qualification practices, and CAPA to prevent visible particulates (e.g., glass) from contaminating your injectable drug products.
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, action level results (out of limits), and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

Visible Particulate Contamination

We encourage the use of suitable automated visual inspection for particulates to augment the (b)(4) visual inspection program. Automated 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 automated 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).

Ineffective Quality System

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production operations, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

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.

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 drugshortages@fda.hhs.gov, 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.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also 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.

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 days². 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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1818977 and ATTN: Matthew R. Dionne, Pharm.D., Compliance Officer.

Sincerely,
/S/

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

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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.