Sato Pharmaceutical Co., Ltd.

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sato Pharmaceutical Co., Ltd., FEI 3004055563, located at 1468 Hazama-Machi, Hachioji, Tokyo, Japan, from November 13 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 12, 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 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 processes (21 CFR 211.113(b)).

Your ISO 5 area used for aseptic filling of (b)(4) over-the-counter (OTC) (b)(4) drug products is fundamentally unsuitable for its intended use. The design and capability of your aseptic filling line (b)(4) Line) were not sufficient to establish and maintain a state of control.

Between November 2022 and February 2025, your attempts to validate your aseptic filling line resulted in at least six media fill failures. Notably, significant microbiological and foreign particulate contamination has been found in this line. The corrective actions you implemented appear insufficient to correct fundamental factors in aseptic process design that are essential to ensure reproducibility and ongoing contamination prevention. This line is used to manufacture (b)(4) drug products intended for the U.S. market, including (b)(4) and (b)(4).

Your design of the ISO 5 area does not ensure unidirectional airflow protection of the aseptic processing line in the event of (b)(4) interventions. The air intake vents for the Grade A laminar airflow ((b)(4) RABS) are located (b)(4) the RABS (b)(4) near the (b)(4) level on your (b)(4) Filling Line. When a (b)(4), air is drawn upward from the aseptic processing line. This fundamentally flawed design resulted in first-pass air not reaching the filling line, leaving the critical ISO 5 zone unprotected while sterile drug products were exposed.

The airflow visualization studies you performed on the (b)(4) Filling Line failed to adequately demonstrate unidirectional airflow and were deficient in the following respects:

• Your airflow visualization videos showed rapid manual movement of the smoke source.

• The position of the smoke source prevented evaluation of airflow through the entire height of the operational area. At times, the technician obscured visibility of airflow with their body.

Your response is inadequate. While you indicate plans to update the line prior to conducting media fills in October 2026 and resume commercial production after achieving (b)(4) successful media fills, your corrective actions are insufficient to address the fundamental design deficiencies in your aseptic processing operations.

While you commit to replacing the bottle holders with (b)(4) holders and to revise your smoke study procedures, you do not address the broader systemic failures in aseptic process design, environmental control, and contamination prevention.

These systemic issues pose an unacceptable risk to patients using your (b)(4) products.

In response to this letter, provide the following:

• 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 areao Gowning in the aseptic processing room and ancillary clean areas o Equipment placement and ergonomicso Air quality in the ISO 5 area and surrounding room o Facility layout o Personnel flows and material flows (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 improvements to be made to aseptic processing operation design and control at your facility and explain how this corrective action and preventive action (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.

2. Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms. Your firm also failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.165(b) and 21 CFR 211.166(a)).

Your firm did not have an adequate stability program to demonstrate that the chemical and microbiological properties of your drug products met established specifications and that they remain acceptable throughout their labeled shelf-life.

Your firm has not established stability-indicating methods for the OTC products you distribute to the U.S. market. During our review of stability data for multiple drug products, it was observed that your firm’s high performance liquid chromatographic (HPLC) analyses did not monitor or evaluate impurity peaks detected during testing. These impurity peaks were visible in the chromatograms but were not identified or adequately evaluated against established acceptance criteria. For example:

• Twelve-month and 24-month stability data for (b)(4), Lot #(b)(4), showed an early eluting peak before the (b)(4) peak. This peak was not present during release testing. According to your firm, this peak is a degradation impurity but is not currently monitored or reported during stability studies. • Twelve-month stability data for (b)(4), Lot #(b)(4), showed early eluting peaks before the (b)(4) peak. These peaks were not present during release testing. Your firm has not identified these degradation impurities.

The appearance of extraneous peaks during stability studies that were not present at release indicates potential product degradation, container-closure system interactions, or other impurities that could affect drug product safety and efficacy. The failure to monitor, identify, and control impurities throughout the drug product shelf life compromises your ability to ensure drug products maintain acceptable safety, identity, strength, purity, and quality throughout their expiration period.

Your stability testing programs did not include complete test parameters necessary to adequately assess product stability characteristics. Review of stability protocols and testing records revealed that you omit critical quality attributes from routine stability testing. For example:

• Your stability study program for (b)(4) (b)(4) expiry) does not include testing for viscosity, degradation products, (b)(4) content, and dose uniformity.

• Your stability study program for (b)(4) (b)(4) expiry) does not include testing for (b)(4) content ((b)(4) testing ), degradation products, particulate matter, and weight loss, which are essential parameters for a (b)(4) formulation.

Your response is inadequate. You indicate you are conducting a retrospective investigation of stability chromatograms and will establish new procedures requiring integration and monitoring of all chromatographic peaks. However, you have not provided stability-indicating methods for your OTC products, comprehensive identification of degradation products, or health hazard evaluations for products currently on the U.S. market that were released without adequate stability-indicating methods.

In response to this letter, provide the following:

• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should address the above deficiencies and include, but not be limited to:o Stability indicating methodso Stability studies for each drug product in its marketed container-closure system before distribution is permittedo An ongoing program in which representative batches of each product are added each year to the program to determine whether the shelf-life claim remains valido Detailed definition of the specific attributes to be tested at each station (timepoint) o All procedures that describe these and other elements of your remediated stability program

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 your (b)(4) OTC drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

(b)(4) produces (b)(4) OTC drug products for the U.S. market, such as (b)(4), that contain (b)(4) as an inactive ingredient. Your firm manufactured and released several OTC products to the U.S. market without conducting required microbiological testing, including testing for Burkholderia cepacia complex. These products include, but may not be limited to:

(b)(4)

Burkholderia cepacia complex organisms are opportunistic pathogens of particular concern for patients with compromised immune systems or chronic lung conditions.

Your response is inadequate. While you indicate you will conduct Burkholderia cepacia complex testing on reference samples and revise applicable procedures, you have not provided reserve sample testing results, health hazard evaluations for batches that were released without required microbiological testing, assessment of patient risk, or evaluation of the potential need for market action. You also have not provided evidence these products have passed (b)(4) testing at release and on stability to demonstrate the adequacy of your (b)(4) systems. In addition, you did not provide evidence that the (b)(4) used in your drug products meets the requirements for (b)(4).

In response to this letter, provide the following:

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision. o An action plan and timelines for conducting full chemical and microbiological testing (including impurities) of reserve samples to determine the quality of all batches of drug products distributed to the United States that are within expiry as of the date of this letter. o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

• For your (b)(4) OTC drug products that contain (b)(4):o Test data and results showing whether each of the drug products has passed the requirements in (b)(4) Test with the lowest (b)(4) level allowed for release or stability, whichever is lower. o Results of testing for (b)(4) content at release and on the product stability program.

We acknowledge that you halted production for the United States until corrective actions are made, and successful media fills completed. Given the fundamental flaws documented in your sterile production line, commit to not resuming production until corrective actions are made and you have discussed your CAPA plan with this office. Alternatively, if you no longer plan to make sterile drug products for the US market, provide a commitment to that effect in writing in response to this letter.

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 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.

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. 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 refusing admission of articles manufactured at Sato Pharmaceutical Co., Ltd., located at 1468, Hazama-Machi Hachioji, Tokyo, Japan, 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 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 3004055563 and ATTN: Brian Nicholson.