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Warning Letter 320-25-100

August 11, 2025

Dear Mr. Li:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Anhui Hanbon Daily Chemical Co., Ltd., FEI 3017153258, at No. 55 Chuangye Avenue, Xinqiao International Industrial Park, Huainan, Anhui, 232221, from February 24 to 28, 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 product is 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 March 11, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your firm failed to test samples of each component for specific identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and 211.84(d)(2)).

Your firm manufactures over-the-counter (OTC) drug products, such as (b)(4). You failed to perform adequate identity testing on each incoming component lot used in the manufacture of your drug products, including for (b)(4) and the active ingredient (b)(4).

(b)(4)

Your firm’s incoming component testing for (b)(4) consists of evaluating appearance and microbiological attributes but does not include adequate identity tests, such as spectroscopic identification, limits for (b)(4), and chromatographic comparison to the retention time of a standard. You did not test the incoming component, (b)(4), for the presence of (b)(4) contamination prior to using in your drug products. Additionally, based on documentation you provided during the inspection, your firm accepted and used several lots of an incorrect excipient, (b)(4), instead of the specified (b)(4) as described in your formulation, and subsequently used these (b)(4) lots in the manufacture of your drug products. Adequate incoming material controls should have identified the incorrect excipient, so that your quality unit could have prevented its use in the drug products.

The use of ingredients contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination at (b)(4).

(b)(4)

The United States Pharmacopeia (USP) monograph describes (b)(4) as a (b)(4). You received and used (b)(4) that contained greater than (b)(4) based on the supplier’s certificate of analysis (COA) and your own internal specification for the manufacture of your drug product. This material does not conform with the USP monograph.

In response to this letter, provide:

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
• A commitment to provide (b)(4) test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of (b)(4).
• A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4)). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4), including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective actions and preventive actions (CAPAs) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.

2. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

You failed to establish the adequacy of release testing procedures, and you released batches of drug products for distribution without conducting adequate testing to confirm critical quality attributes. For example, you did not use USP chemical and microbiological methods to test incoming drug substance or to test and release finished drug product, nor did you show equivalency or superiority for your alternate in-house methods.

Your response is inadequate. You committed to validate your analytical methods and retest affected batches. However, you did not provide sufficient evidence to demonstrate in-house methods are equivalent or superior to the USP methods. Therefore, your commitment to retest affected batches may not yield reliable and valid results.

Test methods must be validated to show they are suitable for their intended use, and equivalent or better than applicable USP compendial methods. The reproducibility of your test methods is essential to determine if your drug products meet established specifications for assay and microbial attributes.

In response to this letter, provide:

• 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.
• A list of chemical and microbial test methods and specifications used to analyze each batch of your drug product before making a batch disposition decision, and the associated written procedures.

3. Your firm failed to establish and follow a 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 211.166(a)).

Your firm failed to establish an adequate stability program, which includes data from long-term or accelerated storage conditions to demonstrate that your product remains acceptable throughout its labeled expiry period. Without appropriate stability studies, there is no scientific evidence to support that your drug product retains its quality attributes throughout the labeled (b)(4) expiry period.

In your response, you state that you will begin stability studies. Your response is inadequate because it lacks sufficient detail describing your stability program procedures and protocols, or equipment for these studies.

For products without appropriate stability studies, there is insufficient scientific evidence to support that drug products will meet established specifications and retain their quality attributes through their labeled expiry.

In response to this letter, provide:

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

4. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm failed to adequately validate the manufacturing process for your drug product. You do not have assurance that you are capable of consistently manufacturing your drug product with defined quality attributes. Your firm lacks process qualification and data to support fundamental process parameters.

In your response, you commit to completing process validation studies. However, your response is inadequate because you did not provide details on completing process performance qualification (PPQ) studies for your drug product, including but not limited to, a PPQ protocol and timeline. Likewise, you did not provide product impact assessments for distributed drug products and ongoing manufacturing.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. Without adequate process qualification, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA's Guidance for Industry, Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In response to this letter, provide:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for PPQ and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing PPQ for each of your marketed drug products.
• Process performance protocol(s), and written procedures for qualification of equipment and facilities.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

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 audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs 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.

See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/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. 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 No.55 Chuangye Avenue, Xinqiao International Industrial Park, Huainan, Anhui, 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 3017153258 and ATTN: Christina Capacci-Daniel.

Sincerely,
/S/

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

cc: U.S. Agent
Mr. Mark M. Yesil, CEO
Delta Brands Inc.
mark@deltabrands.com