Pharmathen International S.A.(320-26-80)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-26-80

May 27, 2026

Dear Mr. Nason:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Pharmathen International S.A., FEI 3009961173, at Industrial Park, Sapes Rodopi Prefecture, Block No 5 Rodopi, Evrou, Greece, from November 10 to 21, 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 December 15, 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 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)).

The airflow visualization studies (i.e., smoke studies) you performed for the (b)(4) aseptic vial filling line you use to fill sterile powder drug products for the U.S. market did not demonstrate unidirectional airflow. This processing line is housed in an (b)(4) Restricted Access Barrier System ((b)(4)RABS).

For example, during the simulation of the (b)(4) installation, the (b)(4) remained (b)(4) for an extended time. The airflow was observed exiting the filling line area, bouncing off the operator’s chest, and reentering the filling line.

This problematic airflow pattern in your (b)(4)RABS creates significant potential for microbial contamination.

Notably, our investigators also observed multiples instances of inappropriate aseptic behavior. For example, when removing empty fallen vials, the operator blocked first air, and exposed vials were not discarded. In addition, your smoke studies failed to sufficiently evaluate removal of fallen vials as well as other critical aseptic manipulations.

Our inspection also found multiple instances of gram-negative microbes in ISO 5 air samples. It is highly atypical to find gram-negative microbes in an aseptic processing room environment. In one such instance, you attributed the probable cause of gram-negative microbial contamination to room disinfection practices and (b)(4) contamination. It is essential that you thoroughly investigate the recurring identification of gram-negative microbes in your aseptic processing environment to determine the root causes and fully remediate with appropriate actions.

Your firm also does not document non-routine interventions in the batch record, nor does it document whether vials are removed due to an intervention.

The ISO 5 (Grade A) area is critical because sterile products are exposed during aseptic production and therefore are 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 influx of contamination into the critical processing area in which sterile drugs are exposed.

In your response, you acknowledge the systematic deficiencies we identified through our inspection including deficient airflow visualization and operator interventions. Your risk assessment for the affected products includes recommendations to implement additional training, update procedures, and perform a gap assessment related to aseptic manufacturing processes.

Your response is inadequate. Your response does not sufficiently address the inadequate oversight of operators, nor the scope and extent of the poor aseptic practices. It also does not determine their root cause and potential impact on sterile drug products. Your risk assessment does not sufficiently evaluate the inspectional deficiencies and support the needed remediation of the overall aseptic processing operation including, but not limited to, the smoke study program. Smoke studies will be essential to substantively assess whether your remediated operation enables robust unidirectional airflow in the ISO 5 (Grade A) area and is capable of maintaining continuous protection of sterile drug products.

In response to this letter, provide the following:

• A review of past smoke studies by qualified independent consultants with a thorough and comprehensive review of deficiencies in the air flow visualization program and your aseptic processing operations. After you remediate your aseptic operation, provide a summary of updated smoke studies that visualize airflow and critically evaluate unidirectional airflow.

• A 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 Suitable cleanroom classifications, appropriate differential pressure limits, and alarm limits, Equipment placement and suitability including ergonomics for each human interaction 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 Reduction or elimination of aseptic manipulations
  o Facility layout
  o Personnel flow and material flow throughout all rooms used to conduct and support sterile operations
  o Cleaning and disinfection (e.g., use of sterile agents) program
  o Specific corrective action and preventive action (CAPA) recommendations that will comprehensively address the design and control hazards identified in the risk assessment

• 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 at your facility and explain how this CAPA plan will robustly remediate your deficient sterile manufacturing operations. Include comprehensive changes to the design of your aseptic processing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations.

• A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient including, but not limited to, completeness of batch record entries. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous (ALCOA) records throughout your operation.

2. 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 did not adequately investigate out-of-specification (OOS) and out-of-limit (OOL) results. Your investigations of sterility failures and significant environmental monitoring excursions lacked adequate scientific rationale to support root causes and implementation of effective CAPA.

Your firm did not implement effective CAPA to reduce recurrence of severe contamination hazards including, but not limited to, operator error that had contributed significantly to recurring sterility and media-fill failures over the past five years.

For example, your investigation did not include in-depth analysis of the conditions that create the circumstances for human error. It is imperative that you conduct in-depth, root-cause analysis to identify effective CAPA including design remediations.

Your firm also failed to investigate failures to meet in-process acceptance criteria for visible particulates. You lacked an adequate investigation for the failure of your (b)(4) injection sterile drug product to meet your visible particulate rejection limit of (b)(4)% of vials. Also, our inspection found a very high visual inspection rejection rate for multiple batches. For example, you rejected approximately (b)(4)% of vials during visual inspection of (b)(4) batch (b)(4).

In your response, you acknowledge the importance of conducting robust sterility failure investigations that include comprehensive root cause analyses and effective CAPA implementation. In particular, you indicate that investigations have not sufficiently addressed the underlying factors contributing to human error in manufacturing operations. However, your proposed CAPAs lack sufficient detail and a description of how effectiveness of these actions will be evaluated.

Your response also acknowledges the importance of maintaining a robust visual inspection program that includes routine particle identification and thorough deviation investigations to ensure effective CAPA. You commit to comprehensively evaluating your visual inspection program, assessing the manufacturing process, and identification of particles. You also plan to implement alternative methods to enhance visual inspection of (b)(4) Injection. Your response is inadequate. You did not provide sufficient detail on how your remediation plans will prevent foreign particle contamination.

It is important that visible particulate contamination is appropriately evaluated. When categorizing visible particles, extrinsic or foreign matter should receive special attention, as it may indicate possible insanitary or microbial contamination. Sterile manufacturing operations should be designed to prevent foreign contaminants, and such contamination should trigger a thorough investigation and appropriate CAPA.

For more information about handling out-of-specification and failing results, and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigating-out-specification-oos-test-results-pharmaceutical-production-level-2-revision. While this guidance addresses chemistry laboratory analyses, many of its principles are also relevant to investigating out-of-specification microbiological results and out-of-trend results.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure that your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
  o A determination of whether procedures used by your firm are robust and appropriate
  o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
  o A complete and final review of each batch and its related information before the QU disposition decision
  o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results, for U.S. products for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each OOS:
  o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
  o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
  o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include 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). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

• A comprehensive review and remediation plan for your OOS-result investigation system with a CAPA plan that includes, but is not limited to:
  o QU oversight of laboratory investigations
  o Identification of adverse laboratory control trends
  o Resolution of causes of laboratory variation
  o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
  o Adequate scoping of each investigation and its CAPA
  o Revised OOS investigation procedures with these and other remediations

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system that includes, but is not limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure that all phases of investigations are appropriately conducted.

• 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 investigation trends, improves the CAPA program wherever needed, ensures final QU decision authority, and is fully supported by executive management.

• An independent third-party review of the adequacy of your CAPA in response to each of your sterility failures, media-fill failures, and microbial deviation investigations over the last five years. Address the need for sterile facility and process redesign, wherever needed.

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

3. 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)).

Your aseptic processing operation was inadequately designed to prevent contamination of your sterile (b)(4) drug products. Significantly, your room pressurization and facility monitoring systems were fundamentally flawed. As a consequence, your aseptic processing operation was inadequately designed to prevent contamination of your sterile (b)(4) drug products.

Our inspection found the pressure differentials in the aseptic manufacturing rooms were inadequate. For example, the aseptic filling rooms had lower pressure than the adjacent rooms. This can result in contaminants readily migrating from lower-classified areas into the higher-classified areas where critical manufacturing operations occur.

Furthermore, you failed to routinely record basic facility monitoring data, including differential pressure, temperature, and humidity. Your monitoring devices displayed real-time data only and lack data storage capability. As a result, parameter excursions that occur when operators are not actively monitoring pressures went undocumented. You also had no alarm history or recorded data.

Reliable aseptic processes are designed to minimize exposure of sterile articles to potential contamination hazards including, but not limited to, variation in environmental conditions. A suitable facility monitoring system, with appropriate alarms and data retention, is critical to maintain appropriate environmental control throughout all your cleanrooms. You should appropriately investigate all deviations from established limits to rapidly detect atypical changes that can compromise the facility’s environment. Prompt detection of an emerging problem is essential to preventing contamination in your aseptic production operations. For example, differential pressure is a critical facility monitoring parameter. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness.

We acknowledge that you suspended manufacturing in November 2025.

In your response, you acknowledge that your legacy facility design and control strategy allowed an inappropriate (b)(4) to persist. You also acknowledge that this was compounded by your outdated monitoring systems that lack continuous data capture, alarm retention, and trending. You commit to establishing facility (b)(4) from areas of higher air cleanliness to lower areas. Also, you acknowledged that your aseptic manufacturing facility should have a system in place to continuously monitor, store, report, and trend historical pressure differential, temperature and humidity data, including alarm events.

Your response is inadequate. You do not provide CAPA details on how you plan to implement appropriate cleanroom facility (b)(4) from areas of higher air cleanliness to those of lower classification. Also, you did not perform a timely risk assessment to evaluate the impact of inadequate pressure differentials in your classified manufacturing areas.

In response to this letter, provide:

• Your CAPA plan and timeline to establish appropriate facility (b)(4) between cleanrooms. In addition, discuss whether you intend to install a new air handling system or you are modifying the existing system, and address how you will ensure its suitability for aseptic manufacturing.

• Your CAPA plan for the installation and validation of a compliant Facility Monitoring System.

• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment with assistance from an independent qualified consultant. 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.

4. Your firm failed to document at the time of performance required laboratory control mechanisms and to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).

Your control over microbiological laboratory records was inadequate. Our investigators found that microbial plates (for sterility, environmental monitoring, and water samples) in incubators lacked appropriate documentation. For example, you did not have raw data and information related to sample preparation and the batch/sample identification number available for review. You also did not document the associated data and information contemporaneously.

We also noticed that critical CGMP documentation forms used to document test results printed from your IQVIA software (e.g., sterility test report) are not adequately controlled.

Proper document control and data management is foundational to CGMP to ensure the availability and integrity of data. Data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA) to ensure complete and accurate records.

In your response, you acknowledge that raw data was not documented contemporaneously and the need to improve your documentation practices based on a thorough root cause analysis and CAPA plan. You indicate that you reviewed all in-process microbiological worksheets for missing sterility testing documentation and identified 14 additional batches with missing sterility documentation. Based on these findings, you have invalidated the sterility tests of all 16 batches. You also commit to engaging an independent third-party consultant to review the integrity of data by conducting a complete review of all batch release records and a sample of other CGMP records using statistical methods.

Your response is inadequate. Your response is limited to discarding sterility tests you conducted during our inspection and that were found to have inadequate CGMP documentation. You did not holistically assess microbiological laboratory practices to determine the full scope of the impact on microbiological test reliability. Additionally, your proposal for a third-party data integrity review using a statistical sampling method is inadequate, as the degree of retrospective review is not sufficient given the significance of the questionable practices documented during the inspection.

In response to this letter, provide:

• A comprehensive independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Include an assessment of all test methods and procedures used by your firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

• A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain contemporaneous, attributable, legible, complete, original, and accurate (ALCOA) records throughout your operation.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP: Questions and Answers for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers.

We acknowledge that you are using an independent third-party consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
  o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
  o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
  o An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
  o A comprehensive retrospective evaluation of the nature of testing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

• A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
  o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
  o A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
  o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
  o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
  o A commitment to have a qualified consultant conduct extensive annual audits for at least two years to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.
  o Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting data integrity concerns and with the authority to ensure any potential breach is promptly investigated by an independent quality assurance function, along with expertise from outside entities whenever needed.
  o A status report for any of the above activities already underway or completed.

Drug Recall

On (b)(4), FDA held a teleconference with you recommending you consider removing any batches of (b)(4) injection and (b)(4) suspension currently in distribution from the U.S. market and address the quality issues with the sponsors of these drugs.

On (b)(4), you communicated your commitment to cease manufacturing and distribution of all drugs for U.S. market for indefinite time until all CAPAs are completed and assessed by an external consultant. You also informed the agency that you had recommended the sponsors initiate voluntary recalls of (b)(4) injection and (b)(4) suspension in current distribution in U.S. market.

On (b)(4), your drugs sponsors, (b)(4), issued voluntary recalls of (b)(4) injection and (b)(4) suspension respectively due to lack of assurance of sterility. You also commit to not distributing batches that remain within your control.

Drug Production Suspended

We acknowledge your commitment to suspend production of all U.S. products at this facility, including (b)(4) injection,(b)(4) suspension, (b)(4) injection, (b)(4) injection (b)(4) capsule drugs. In response to this letter, clarify whether you intend to resume manufacturing any drugs for the U.S. market at this facility in the future.

If you plan to resume any sterile manufacturing operations regulated under the FD&C Act, notify this office before resuming those manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

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.

FDA placed all drugs and drug products offered for import into the United States from your firm on Import Alert 66-40 on April 23, 2026.

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 continuing to refuse admission of articles manufactured at Pharmathen International S.A., FEI 3009961173, at Industrial Park, Sapes Rodopi Prefecture, Block No 5 Rodopi, Evrou, Greece, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority 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 days1. 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.

After you receive this letter, respond to this office in writing within 15 working days. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices, and/or submit a request to schedule an FDA inspection.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3009961173 and ATTN: Rafael E. Arroyo.

Sincerely,
/S/

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

1 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.