International Medication Systems Limited MARCS-CMS 727560 — July 02, 2026

WARNING LETTER

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• Delivery Method: VIA Electronic Mail
• Reference #: 320-26-99
• Product: Drugs

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• Recipient: Dr. Jack Y. Zhang; Chief Executive Officer ; International Medication Systems Limited; 1886 Santa Anita Avenue; South El Monte, CA 91733; United States

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

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Warning Letter 320-26-99

July 2, 2026

Dear Dr. Zhang:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, International Medication System Limited, FEI 2016148, at 1886 Santa Anita Avenue, South El Monte, from December 9 to 19, 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 January 15, 2026, response to our Form FDA 483 in detail.

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 active pharmaceutical ingredients and sterile injectable drug products. The sterile injectable products include aseptically filled (b)(4).

Your firm failed to conduct adequate investigations. For example, you inadequately investigated multiple too-numerous-to-count (TNTC) microbial findings during the manufacture of epinephrine injection, lot EA038A5. Specifically, a viable air environmental monitoring plate, located next to the (b)(4) in your ISO 5 aseptic filling area, yielded a too-numerous-to-count result with confluent bacterial growth and numerous insect larvae. On the same day, personnel monitoring plates for an individual in the adjacent ISO 7 (b)(4) also yielded TNTC results and contained insect larvae.

Your investigation failed to identify a scientifically-supported root cause, instead attributing these exceedingly high environmental monitoring findings to an unsubstantiated hypothesis involving insect infiltration of sealed monitoring plates. Notably, written procedures require inspection of plates before use to ensure they are not contaminated or defective, and also require very strict handling measures following sampling (e.g., (b)(4) bags, sterile tape). The microbiological growth media batch also passed negative control testing. Although your deviation report lacked evidence of defects or sampling error, you assessed the contamination risk as “low” based on overreliance on passing sterility test results, and the quality unit approved the release of epinephrine injection, lot EA038A5.

The presence of insect larvae and gross microbial contamination in your aseptic processing area demonstrates a critical failure of your contamination control program. The decision to release a lot manufactured under these conditions also demonstrates that your quality unit failed to exercise its responsibility to ensure drug products are manufactured under appropriate conditions and to reject any lot produced under conditions that compromise its quality.

In your response, you reiterate that your investigation concluded the contamination was “post-exposure adventitious contamination external to the filling suite,” based on mostly acceptable environmental monitoring data in other locations that day. Using this rationale, you determined the two environmental contamination events were isolated incidents and the risk to the product was low. You also determined that no corrective actions were needed.

Your response is inadequate. Your investigation outcome based on a “post-exposure” hypothesis remains poorly supported by data. The occurrence of two severe contamination events on the same day in adjacent rooms indicates a significant breakdown in contamination control. Additionally, your failure to implement corrective actions reflects a critical deficiency in your investigation and indicates inadequate oversight of the state of control of the aseptic processing operation.

We also note that, between March 2021 and March 2026, your firm filed three field alert reports for contamination issues with sterile (b)(4) drug products. Since December 2023, you received over 90 customer complaints, many related to container-closure deficiencies such as glass breakage/vial cracking, (b)(4). Many of your investigations were closed without identifying a root cause.

In response to this letter, provide:

• A comprehensive, third-party assessment of your overall system for investigating deviations, discrepancies, complaints, OOS 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, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action (CAPA) effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A third-party 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 when needed, implements final quality unit decisions, and is fully supported by executive management.
• A comprehensive, independent review and update of all field alert reports and customer complaints for drug products within expiry, including scientifically sound root cause analyses, corrective actions implemented, and timelines for completion of the investigations. This review should include, where applicable, re-investigation of all complaints involving potential contamination and container-closure deficiencies. Include documentation of all investigative steps taken, potential root causes considered and those systematically ruled out, and any interim controls or preventive measures implemented. Include your corrective action plan based on this in-depth review and trend analysis.
• A comprehensive, third-party assessment and remediation plan for your pest control program. The assessment should include, but not be limited to, a review of facility design and maintenance, effectiveness of monitoring program, investigation procedures, historical findings, and personnel training.

2. 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. Your firm also 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 211.42(c)(10) and 21 CFR 211.113(b)).

Your firm’s aseptic processing lines and operations were inadequately designed, controlled, and monitored to prevent microbiological contamination.

Your firm refers to your aseptic processing lines as restricted access barrier systems (RABS). However, your equipment lacks fundamental design elements of a RABS, including (b)(4). Without this basic feature, as well as other design provisions, your processing lines cannot be categorized as RABS.

In addition to (b)(4), RABS include various design elements that are essential for minimizing or eliminating direct gowned personnel interventions ((b)(4) interactions) into the critical (ISO 5) area during batch manufacturing.

Your current process requires an operator to stand within a (b)(4) ISO 5 area. The operator manually cuts open numerous (e.g., approximately (b)(4)) stopper bags per batch and transfers stoppers using a (b)(4) scoop. These manually-intensive interventions pose a significant and repeated risk of microbial contamination. Despite the critical nature of this activity, your firm failed to conduct environmental monitoring in this area to evaluate its impact on the aseptic environment. This represents a serious gap in environmental control oversight.

Your firm also failed to adequately evaluate unidirectional airflow in the critical area, as the smoke studies conducted were fundamentally flawed. The placement and movement of the wand as well as other factors precluded meaningful assessment of airflow directionality.

The design of your aseptic filling line presents inherent contamination risks that are exacerbated by inadequate controls. These conditions are insufficient to ensure robust aseptic production of sterile drug products.

In your response, you state that you added a new environmental monitoring location in the (b)(4) area and conducted airflow studies in the ISO 5 (b)(4) area. You claim that operator movement has “no impact to 1st air, maintaining unidirectional airflow and minimal turbulence.” You also propose a long-term plan to upgrade the facility within two years, including upgrading the adjacent (b)(4) to ISO 5.

Your response is inadequate. Your proposal does not address the fundamental design flaws of your aseptic processing lines, as the primary contamination risks stem from extensive manual interventions within the ISO 5 processing area itself. Additionally, a long-term plan to upgrade the facility in two years is inadequate because it does not address how you will mitigate the immediate and ongoing risk to product quality posed by your current operations.

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/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice.

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:
  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, 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
• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe 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 both your aseptic processing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations.
• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. Your plan should also ensure that appropriate actions are taken throughout the company network.
• A retrospective review and risk assessment for drug product batches within expiry that were manufactured in the affected aseptic processing area. Provide a formal risk assessment evaluating the potential for non-sterility hazards for each batch, along with a report detailing your subsequent actions, such as customer notifications or product recalls.
• Perform a critical evaluation of airflow unidirectionality in your aseptic process with the assistance of a qualified consultant. Ensure smoke studies are conducted under dynamic conditions with thorough and complete evaluations of aseptic processing line airflow unidirectionality, including the impact of dynamic interactions and aseptic interventions. These thorough smoke studies should be performed after you remediate your aseptic operation and conducted using proper practices (e.g., neutrally buoyant media) to appropriately visualize airflow.

3. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).

Your (b)(4) system was inadequately designed, monitored, and maintained.

You use (b)(4) for cleaning drug manufacturing equipment, and the same system feeds your (b)(4) system. During the inspection, we observed gross contamination in the (b)(4) storage tank feeding the (b)(4) system with interior surfaces coated in dark-colored plaques. Further compounding these concerns, investigators observed that (b)(4) had been repaired with (b)(4) sealant material, and that threaded connections with seal tape were used in place of sanitary fittings. These systems failed to adhere to appropriate (b)(4) system design and maintenance standards.

In your response, you identify the observed dark-colored plaques in your (b)(4), non-sterile (b)(4) tank as (b)(4) biofilm, characterizing the contamination as “predictable and environmentally normal.” You add that the (b)(4) tank was (b)(4) allowed transmission of ambient light, which enabled photosynthesis and extensive (b)(4) growth on the tank walls. You assert that there was no impact on the quality of the downstream (b)(4), relying on passing test results to support this claim. The primary corrective action you reported was cleaning the affected tank.

Your response is inadequate. Your proposed corrective action of simply cleaning the storage tank is insufficient because it fails to address the fundamental design and maintenance flaws that allowed unchecked (b)(4) growth and gross contamination. A source (b)(4) tank should be designed and maintained to prevent it from becoming a reservoir for biological contamination as the resulting bioburden can potentially overwhelm downstream (b)(4) steps. Furthermore, your rationale of using passing downstream test results to justify the use of a grossly contaminated source tank is not in accord with basic system design and control standards. It is your responsibility to ensure that all equipment used in the manufacture of your drug products is appropriately designed, maintained, and controlled.

In response to this letter, provide:

• A comprehensive third-party assessment of your (b)(4) system design, control, and maintenance.
• A comprehensive remediation plan for the design, control, and maintenance of the (b)(4) system, including:
  o A comprehensive evaluation of vulnerabilities of (b)(4) system design and control and summarize all deficiencies found in the system. The summary should, at minimum, describe various system characteristics that were assessed for adequacy (system (b)(4), materials of construction, slope, any identified dead-legs, any stagnant locations, any unsanitary fittings, flow velocity, etc.)
  o Your interim plans for assuring the quality of your (b)(4) during your remediation.
  o A validation report for the (b)(4) system obtained after an appropriately designed system has been installed. Include the system validation protocol (installation qualification, operational qualification, and performance qualification), complete test results, and the final validation report.

Drug Recall

On March 26, 2026, FDA held a teleconference with you recommending you recall epinephrine injection USP 0.1 mg/mL lot EA038A5 from the U.S. market. On April 1, 2026, you initiated a voluntary recall of epinephrine injection USP 0.1 mg/mL, lot EA038A5, due to lack of sterility assurance. The recall was posted to the FDA’s Enforcement Report website at:
https://www.accessdata.fda.gov/scripts/ires/index.cfm?Product=219475

Quality Unit Authority

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.

Assurance of Sterility – Aseptic Processing

It should be noted that a sterility test, while a critical final quality control for all aseptically processed products that purport to be sterile, cannot be solely relied upon as justification to release each drug product batch. The sterility test is only the last in a series of design and control provisions intended to protect the consumer from distribution of an unsafe batch. Finished product testing alone does not establish sterility of all units because contamination is typically episodic and not uniformly distributed. Product contamination may go undetected for substantial periods if your firm is placing too much reliance on the final quality control test for sterility to become aware of a problem in aseptic manufacturing. It should also be noted that any positive sterility test result represents a serious CGMP issue that requires a comprehensive investigation into the cause and extent of the problem and a prompt review of the qualification status of your aseptic process.

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. The qualified consultant should also perform a comprehensive six-system audit¹ 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.

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.

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 days.² 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 2016148 and ATTN: Emily Wu.

Sincerely,
/S/

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

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1 i.e. Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.

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.