Yahon Enterprise Co., Ltd. - 675592 - 06/05/2024

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Warning Letter 320-24-40

June 5, 2024

Dear Mr. Hsu Ke Fu:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Yahon Enterprise Co. Ltd., FEI 3017151342 at An Chu Hamlet, Tay Lac Village, Bac Son Commune, Trang Bom District, from December 15 to 21, 2023.

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 response to our Form FDA 483, received January 11, 2024, in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because you failed to provide supportive documentation for evaluation or adequate evidence of corrective actions taken to bring your operations into compliance with CGMP.

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

1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

You released over-the-counter (OTC) (b)(4) drug products without adequate quality control testing, including but not limited to the identity and strength of each active ingredient. For example, identity and potency testing was not performed for the active ingredient in your ethyl alcohol antiseptic wipes distributed in the U.S. market.

Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use, including both chemical and microbiological specifications. Because you lacked testing of each batch of your drug products, you do not know whether they conform to finished product specifications and are suitable for release to consumers.

In your response, you provide your test method and procedure used to perform identity and potency testing for the active ingredient in your drug products.

Your response is inadequate. Your response lacks sufficient justification for the testing you perform, which does not establish comparability to United States Pharmacopeia (USP) standards.

In response to this letter, provide a list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision, and the associated written procedures.

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

You failed to perform adequate identity testing on each lot of ethyl alcohol and benzylkonium chloride used to manufacture your OTC drug products. Because you did not perform adequate identity testing on each shipment of each lot, you failed to assure the acceptability of these components for use in the manufacture of your drug products.

In your response, you commit to testing ethyl alcohol and benzylkonium chloride ingredients by a third party (b)(4).

Your response is inadequate. Your response lacks specificity regarding your plans to test each lot of each shipment of incoming components.

Products Contain Ethanol (Methanol Risk)

You manufacture drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol at https://www.fda.gov/media/173005/download.

In response to this letter, provide:

• 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 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 Certificates of Analysis (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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

3. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

Your firm assigned a three-year expiry period to ethyl alcohol antiseptic wipes without scientific rationale to support the labeled expiry. At the time of inspection, you lacked stability data to substantiate the three-year expiry period and there was no assurance that your drug products will remain acceptable throughout their labeled expiry period without an ongoing stability program.

In your response, you explain that your three-year expiry date is based on accelerated stability and “quality confirmation” after inventory has been stored for 3 years.

Your response is inadequate. You fail to provide data to demonstrate that chemical and microbiological properties of your drug products will remain within specification throughout their labeled expiry period.

In response to this letter, provide:

• A comprehensive, independent assessment and corrective action and preventive action (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
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)
o All procedures that describe these and other elements of your remediated stability program.

4. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) lacked adequate control over your OTC drug manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to ensure:

• Adequate validation of manufacturing processes for ethyl alcohol antiseptic wipes (21 CFR 211.100(a)).
• Adequate cleaning validation for equipment used in the manufacture of ethyl alcohol antiseptic wipes (21 CFR 211.67(b)).
• Adequate storage and retention of CGMP records (21 CFR 211.180(a)).
• Adequate collection and storage of reserve samples (21 CFR 211.170(a)).

In your response, you acknowledge these deficiencies and provide your plan for implementing procedures and training.

Your response is insufficient because you fail to provide documentation confirming the implementation and adherence to these processes and procedures.

Your firm’s quality systems are inadequate. 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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070337.pdf.

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

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of process variability, and assures that manufacturing operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• A comprehensive, assessment of your reserve sample system. This assessment should include, but not be limited to, your procedure(s) to ensure reserve samples are appropriately identified, stored, and maintained. Your reserve sample program should also include provisions for verifying sample integrity and adherence to retention time requirements.

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 assist your firm in meeting CGMP requirements. 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 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 Yahon Enterprise Co. Ltd., An Chu Hamlet, Tay Lac Village, Bac Son Commune, Trang Bom District, Vietnam, 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 3017151342 and ATTN: Joseph Lambert, Pharm.D.

Sincerely,
/S/

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