Yangzhou Sion Commodity Co., Ltd. - 699183 - 03/12/2025

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Warning Letter 320-25-53

March 12, 2025

Dear Mr. Xu:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Yangzhou Sion Commodity Co., Ltd., FEI 3011346498, at No. 168 Longwang Road, Hangji Industrial Park, Yangzhou, Jiangsu, from September 23 to 27, 2024.

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 October 18, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

CGMP Violations

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

1. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).

You manufacture over-the-counter (OTC) drug products including (b)(4). Your firm failed to test incoming components used in manufacturing your finished OTC drug products to determine identity, purity, strength, and quality, and your firm did not establish a vendor qualification program for your raw material suppliers.

Your firm used results from your suppliers’ certificates of analysis (COAs) without establishing the reliability of your suppliers’ analyses through appropriate validation and without conducting at least one specific identity test on each incoming lot of components. You may not rely on your suppliers’ COA to verify the identity of your components.

In previous correspondence on September 28, 2023, associated with an FDA records request under section 704(a)(4) of the act, your firm committed to performing independent testing, to include identity testing for each shipment of high-risk component, as required by 21 CFR 211.84 (d)(1) & (2), using equivalent or better methods to those in the United States Pharmacopeia (USP).

However during the inspection, and contrary to previous commitments, your firm failed to demonstrate that you adequately tested each shipment of each lot of the incoming components at high-risk of (b)(4) contamination. These include, but are not limited to, testing of (b)(4) solution you used in manufacturing drug products to determine their appropriate identity. Identity testing for these and certain other high-risk drug components¹ include a limit test in the USP to ensure that the component meets the relevant safety limits for levels of (b)(4). Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your 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).

Additionally, you failed to perform identity testing on the component (b)(4) and lacked adequate impurities testing on (b)(4) before being used in manufacturing. Furthermore, (b)(4) was not adequately monitored for (b)(4).

In your response on October 18, 2024, you indicate that you have updated your procedures to mandate the testing of identity and purity of active ingredients and the testing of identity of nonactive ingredients. Your response is inadequate because you did not address your plans for qualification of your component suppliers, did not address your previous commitments to perform identity testing on high-risk components, and failed to clarify whether your firm tested all lots of drug products that you distributed to the United States for risk of (b)(4). You also failed to adequately address quality attributes of your components.

In response to this letter, provide:

• 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 action and preventive action (CAPA) 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.
• 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 revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of (b)(4) and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
• The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
• 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 procedure governing your program for ongoing control, maintenance, and monitoring that ensures your (b)(4) system consistently produces (b)(4) that meets (b)(4) USP monograph specifications and appropriate microbial limits.

2. 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 QU did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to:

• Perform assay testing for the strength of the active ingredient in (b)(4) drug products (21 CFR 211.165(b)).
• Ensure an adequate stability program (including assessment of product potency over the shelf life) to support your claimed (b)(4) expiry for (b)(4) drug products (21 CFR 211.166).
• Ensure that personnel had adequate training and experience for the production and analysis of (b)(4) drug products (21 CFR 211.25(a)).

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

You did not ensure that your QU implemented its basic functions. Your management should immediately and comprehensively assess your company’s manufacturing operations to ensure that your systems, processes, and products meet CGMP.

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.

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.
  o Performing a retrospective analysis of all batches shipped to the United States for the past 3 years to ensure product in U.S. commerce meets specifications for potency and purity. Your action plan to address any product quality or patient safety risks for batches of (b)(4) drug products in U.S. distribution, including potential customer notifications and recalls or market withdrawals.
  o A copy of the quality agreement with the contract testing laboratories used for finished product testing. Indicate where in this agreement specifies potency testing and provide documentation supporting that potency testing occurs before release of your (b)(4) drug product.
  o Justification for the potency discrepancy noted in your response pertaining to product retained testing. Your response demonstrated a (b)(4) potency specification (≤ (b)(4)%) for retained (b)(4) drug products as opposed to your label claim of (b)(4)% (b)(4).

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your laboratory records lacked complete and original data to support the analyses performed. For example:

• Your laboratory records included missing data. Furthermore, there were discrepancies between the original and re-written versions of testing records and COAs pertaining to active and non-active ingredients used in the manufacture of OTC drug products.
• Your firm did not retain original data to support testing of components used to manufacture OTC drug products for the U.S. market. During our inspection, you confirmed that original data, including balance printout slips, (b)(4) times, (b)(4), sample preparations, and equipment logs were not maintained.
• The use of correction fluid (white-out) was also observed to make corrections on paper records documenting microbial analyses of finished products and raw materials. These documentation practices raise concerns about the integrity, authenticity, and reliability of all your data, and quality of your drug products. Document control is essential to maintaining an adequate quality system.

In your response, you acknowledge that “QA management did not have a sound understanding of CGMP requirements.” You also commit to performing retrospective testing of “materials,” and state that you have updated procedures and re-trained personnel. Your response is inadequate, as you fail to fully consider comprehensive data integrity (DI) remediation to address the gaps and uncertainties caused by a significant adverse pattern of data that was discarded, lost, or not recorded contemporaneously. Additionally, your response did not consider plans to assess your manufacturing operation’s documentation system to determine where they are insufficient.

Reliability of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results, or conditions associated with all tests. Furthermore, the lack of reliable data compromises the quality unit’s (QU) ability to exercise its function of ensuring compliance to applicable standards.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant DI practices at https://www.fda.gov/media/119267/download.

We acknowledge that you are using an independent third-party consultant to perform DI training. However, we strongly recommend that you retain an independent third-party qualified consultant to audit your operation and assist in your DI remediation to meet FDA requirements. In response to this letter, provide:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
  o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
  o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
  o An assessment of the extent of DI deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered DI lapses.
  o A comprehensive retrospective evaluation of the nature of the testing and manufacturing DI deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all DI lapses.
• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of DI and analyses of the risks posed by ongoing operations.
• A management strategy for your firm that includes the details of your global CAPA plan. Your strategy should include:
  o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
  o A comprehensive description of the root causes of your DI lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for DI lapses remain able to influence CGMP-related or drug application data at your firm.
  o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
  o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
  o A commitment to have a qualified consultant conduct extensive annual audits, for at least 2 years, to assist in evaluating CAPA effectiveness after you have executed your DI remediation protocol.
  o Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting DI concerns and with the authority to ensure any potential breach is promptly investigated (by independent quality assurance function, along with expertise from outside entities whenever needed).
  o A status report for any of the above activities already underway or completed.

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 products offered for import into the United States from your firm on Import Alert 66-40 on January 31, 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 re-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 Sion Commodity Co., Ltd., No. 168 Longwang Road, Hangji Industrial Park, Yangzhou, Jiangsu 225111, China, 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 [or misbranded] 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 3011346498 and ATTN: Samina Khan, Compliance Officer.

Sincerely,
/S/

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

cc. US Agent
Charles Shen
Manton Business and Technology Services
37 Winding Ridge, Oakland, NJ, 07436
Email: cyshen@aol.com

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1 Components with higher risk of (b)(4) contamination compared to other drug components.