Medline Inc(320-26-82)

Warning Letter 320-26-82

May 28, 2026

Dear Mr. Boyle:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Medline Industries, LP, FEI 3003983334, at 1710 South Lakeside Drive, Waukegan, Illinois, from October 6 to 14, 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 4, 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 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 manufactures (b)(4) for (b)(4) is also specifically labeled for (b)(4). Your manufacturing process includes (b)(4), and sealed into the respective finished drug product packaging.

Between June 2, 2023 and August 27, 2025, your firm isolated objectionable microorganisms (e.g., Bacillus cereus (B. cereus)) from (b)(4) finished drug product samples on approximately nine occasions. You also recovered B. cereus in at least five samples taken from your manufacturing environment since January 2025. You failed to adequately investigate and implement corrective actions and preventive actions (CAPA) to determine root causes and prevent recurrence of these repeated contamination incidents. This issue was cited on the previous Form FDA 483 issued to your firm in January 2025 and subsequently discussed during the most recent regulatory meeting held with your firm in May 2025.

Further, your investigations into contaminated drug product samples identified B. cereus in your manufacturing environment, including (b)(4) at your facility, as well as on (b)(4) at another Medline facility (Hartland), which supplies your bulk (b)(4). Multiple investigations since 2023 have determined that (b)(4) are a root cause for the B. cereus contamination in your drug products.

In your response, you acknowledge “that the FDA inspection identified gaps in adherence to the corrective actions and cGMP’s.” You suspended (b)(4) drug product production in October 2025. You also committed to verifying corrective actions and their effectiveness before notifying FDA of your intent to resume production. You also refer to several previously initiated CAPA in response to the microbiological contamination incidents, including management controls, deviation investigations, and facility and process improvements.

Your response is inadequate because you have not explained why your previous CAPA attempts were not successful. Additionally, your investigations failed to adequately identify the root causes of contamination in your drug products and the source of B. cereus contamination within your manufacturing environment, including from your bulk (b)(4). Your response also states that you have not released any drug product batches with failing microbiological test results. However, finished product microbiological testing cannot be relied upon as sole justification to release drug product batches, as contamination is not uniformly distributed in a system and any given sample may not be representative of the type or level of contamination.

Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that may pose a patient safety hazard. Your manufacturing processes and cleanroom environments are inadequately designed to assure an ongoing state of control. It is your responsibility to design and control operations to prevent contamination of your (b)(4).

Microbial contamination of (b)(4) drugs used for (b)(4) poses a significant risk of patient harm and adverse (b)(4) outcomes, (b)(4). Thus, the use of manufacturing processes that render these drugs sterile is an integral part of ensuring safety of patients due to the vulnerability to (b)(4) infection.

In response to this letter, provide:

• A comprehensive, independent risk assessment of all contamination hazards with respect to your manufacturing processes, equipment, and facilities, including, but not limited to:
  o All human interactions within the cleanroom areas (e.g., risk reduction or elimination of manual interventions wherever possible)
  o Equipment suitability (e.g., reliability, capability, ergonomics, placement) and sufficient cleanroom space
  o Air quality in the cleanroom 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 manufacturing operations, and all material transfers).

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe comprehensive improvements to be made to manufacturing operation design and control at your facility and explain how this CAPA plan will robustly remediate your deficient manufacturing operations. Include comprehensive changes to the design of both your manufacturing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations.

• An independent assessment by qualified experts of the various sterilization options that can be implemented for your (b)(4) products. Based on this assessment, provide a comprehensive plan and timeline to transition your (b)(4) drugs to terminal sterilization, or implement aseptic processing of these products. In the event that you are considering continued use of processes that are inherently vulnerable to contamination issues, provide a detailed rationale justifying your scientific and public health basis, with particular attention to the unacceptable patient risks posed by your historical contamination problems.

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, 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.

• 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:
  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 past related investigations (deviations, failures) to identify potential associated causes or linkages
  o Evaluate adequacy of scope, rigor, staff competencies, scientific/analytical foundation, 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 unit decisions, and is fully supported by executive management.

2. Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups; failed to perform operations within specifically defined areas of adequate size; and failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.42(c) and 21 CFR 211.67(b)).

Your firm isolated significant opportunistic pathogens, including B. cereus, in numerous samples of your (b)(4) finished drug products and the manufacturing environment.

You failed to establish appropriate design and control of your manufacturing operation to assure your (b)(4) drug products (b)(4) were suitable for their intended use. This issue was cited on the previous Form FDA 483 issued to your firm in January 2025 and subsequently discussed during the most recent regulatory meeting conducted with your firm in May 2025.

Deficient Manufacturing Practices

Your manufacturing operators engaged in practices that pose significant contamination risk to (b)(4) drug products, such as using cleaning tools without suitable gloves and then repeatedly touching the (b)(4). Investigations by your firm identified objectionable aseptic behaviors as a root cause of B. cereus contamination in your products.

Your manufacturing process involves (b)(4) manipulations including the (b)(4) drug components, equipment, and scrap materials. These activities are particularly worrisome if your operations are not conducted and maintained in an aseptic manner (e.g., donning sterile gowning), or the drug product is not sterilized in its final packaging. It is essential that manufacturers establish robust manufacturing design and process control measures to prevent contamination throughout production operations. In addition to appropriate manufacturing facilities and processes, raw materials (e.g., components, containers, and closures) must also be suitable for their intended use.

In your response, you acknowledge “that the FDA inspection identified gaps in adherence to the corrective actions and cGMP’s.” As noted above, you also state that you suspended production of the (b)(4) drug product in October 2025. You commit to verifying your corrective actions as effective prior to notifying FDA of your intent to resume production. You also refer to several previously initiated CAPA in response to the microbiological contamination incidents, including corrections to cleanroom behaviors, cleaning and maintenance procedures, contamination controls, and retraining.

Inadequate Cleaning and Disinfection

Your manufacturing operators have routinely deviated from procedures for cleaning and disinfection of your drug manufacturing equipment, including (b)(4) for (b)(4) drug products. For example, numerous deviation investigations have noted operator failures to properly clean and disinfect your (b)(4) and valves with (b)(4). Notably, (b)(4) have been identified as a root cause for B. cereus contamination in your drug products since 2023.

Establishing and following appropriate procedures for cleaning, disinfection, and whenever appropriate, sterilization is essential to ensuring product safety.

Your response is inadequate. Your proposed corrections are insufficient to remediate flawed facility and process design. You have unsuccessfully attempted similar corrective actions in the past.

In response to this letter, provide:

• An independent assessment and associated CAPA plan, following a thorough retrospective review of your cleaning, disinfection, and sterilization program, that includes appropriate remediations and timelines for completion. Provide a detailed summary of vulnerabilities in your processes and procedures relating to equipment cleaning, disinfection, and sterilization. Describe improvements to your program, including enhancements to cleaning and disinfection types and practices; addition or improvement of sterilization methods; and all other needed remediations.

• Your systematic plan to assure adherence to appropriate aseptic practices, cleanroom behavior, and written procedures, including but not limited to a thorough independent assessment of the following with accompanying CAPA:
  o Suitability of actual practices based on a retrospective review and prospective observation of cleanroom 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 behaviors and its support operations
  o Adequacy of written procedures
  o The risk assessment should also evaluate how poor aseptic technique and cleanroom behavior may have affected the quality of your drugs.

Repeat Observations at Multiple Sites

FDA cited similar CGMP observations at other facilities in your company’s network, including inadequate investigations into OOS results at your Hartland, Wisconsin site. These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected 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/media/158416/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.

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 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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3003983334 and ATTN: Philip Kreiter.

Sincerely,
/S/

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