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Warning Letter 320-25-107

September 9, 2025

Dear Ms. Bian:

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our February 10, 2025, request, and subsequent correspondence, for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Yangzhou Yulou Paper Products Co., Ltd., FEI 3032025702, at No.888 Jinbao West Road, Baoying County, Yangzhou, Jiangsu.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, parts 210 and 211 (21 CFR, parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding of drugs as described in your response to our 704(a)(4) request 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)).

Following review of records and other information provided pursuant to section 704(a)(4) of the FD&C Act, significant violations were observed 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 and sterilization processes. Your firm also failed to establish laboratory controls that include scientifically sound and appropriate specifications designed to ensure conformance with appropriate standards of identity, strength, quality, and purity. (21 CFR 211.113(b) and 211.160(b))

Your firm manufactures OTC drug products, including (b)(4) that are labeled as sterile and indicated for use (b)(4). Based on records and information you provided, you did not demonstrate that your (b)(4) are rendered sterile by an appropriate manufacturing process. Your production records do not indicate that you use aseptic processing or (b)(4) sterilization to render your (b)(4) sterile.

Furthermore, you did not provide evidence that you performed sterility testing using a validated method and provided microbiological test results with specification of “total number of bacterial colonies ≤ (b)(4) CFU/g.” Sterile products introduced to the U.S. market must meet United States Pharmacopeia (USP) <71> Sterility Tests. Microbiological contamination of products labeled as sterile could pose a serious hazard to patients.

In response to this letter, provide:

• A comprehensive assessment of your manufacturing processes which evaluates how you achieve sterility in your drug products.
• A list of chemical and microbiological 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 of retain samples to determine the quality of all batches of drug products distributed to the U.S. 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 recalling product.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. (21 CFR 211.84(d)(1))

Based on the records and information you provided, you did not demonstrate that you tested the identity of incoming components including (b)(4) used to manufacture your OTC drug products. For example, your February 26, 2025, response states that you do not perform identity testing for your components before use in manufacturing.

You also did not provide evidence that the (b)(4) you use to manufacture your drug products meets USP limits for (b)(4). See FDA’s guidance document (b)(4).

Without adequate testing, you do not have scientific evidence that your components conform to appropriate specifications prior to use in the manufacture of your drug products.

In response to this letter, provide the following for all components used in drug products imported to the United States prior to and after our 704(a)(4) request:

• 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component 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 establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. We note that identity testing is required for every lot of components regardless of supplier test result validation.

3. Your firm failed to establish and follow a written testing program designed to assess the stability characteristics of drug products. (21 CFR 211.166(a))

The records and information you provided did not demonstrate that the chemical and microbiological properties of your drug products remain acceptable throughout the labeled expiry period. For example, your February 26, 2025, response states that there was no stability data to support the (b)(4) shelf life for (b)(4) shipped to the United States.

Without stability studies, you do not have scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.

In response to this letter, provide the following for all drug products imported to the United States:

• A comprehensive, independent assessment and corrective and preventive action plan to ensure the adequacy of your stability program. Your remediation program should include, but not be limited to:
  o Stability indicating methods, including both analytical and microbiological tests
  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))

Lack of Process Validation

In your response to our 704(a)(4) request, you stated that no validation activities have been performed for your drug products, including (b)(4).

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.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.

Inadequate (b)(4) system

In your response to our 704(a)(4) request, you stated that you qualified your (b)(4) system in 2024, but you did not provide the summary report to support this statement, as requested. Your responses also suggested that you do not perform routine chemical or microbiological analysis to determine suitability of or monitor the (b)(4) generated for use in drug manufacturing.

(b)(4) is an ingredient in your drug products. (b)(4) must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. See FDA’s (b)(4).

In response to this letter, provide:

• A timeline for performing appropriate process performance qualification for each of your marketed drug products. Also include an explanation how you will ensure proper satisfactory process performance qualification studies are performed prior to future distribution of any drug products.
• Your process performance protocol(s) and written procedures for qualification of equipment and facilities.
• A (b)(4) system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produce (b)(4) that meets (b)(4) USP monograph specifications and appropriate microbiological limits. Include action/alert limits for total counts and objectionable organisms used for your (b)(4) system.
• A procedure for your (b)(4) system monitoring that specifies routine chemical and microbiological testing of (b)(4) to ensure its acceptability for use in each batch of drug products produced by your firm. Ensure that the total microbiological count limits for your (b)(4) are appropriately stringent in view of the intended use of each of the products produced by your firm.

5. Your firm failed to establish written responsibilities and procedures applicable to the quality control unit and to follow such written procedures. (21 CFR 211.22(d))

The records and information you provided demonstrate that you failed to implement written procedures to establish a quality unit (QU) with the CGMP responsibilities and authority to oversee the manufacture of your OTC drug products. For example, your response indicated there were no QU procedures for change control, customer complaints, annual product review, batch review, batch release or rejection, reprocessing and reworking, returns and salvaging, specifications, deviations, or corrective action and preventive action.

Based on FDA’s review of records and information provided in response to our request, your firm’s quality systems are inadequate. Please see FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for helpful information regarding 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/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your 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

Drug Recall

On (b)(4), FDA held a call with your firm to recommend market action for your sterile (b)(4) based on the sterility concerns. On (b)(4), you agreed to recall all (b)(4) from the U.S. market that are labeled as sterile and within expiry.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive 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.

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.

FDA placed all drugs and drug products offered for import into the United States from your firm on Import Alert 66-40 on August 26, 2025.

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 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 Yangzhou Yulou Paper Products Co., Ltd. at No.888 Jinbao West Road, Baoying County, Yangzhou, Jiangsu, 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 3032025702 and ATTN: Christopher Keating.

Sincerely,
/S/

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

Cc: Solomon Chen
U.S. Agent
Email: regmed.connect@gmail.com