- Delivery Method:
- VIA UPS
Recipient NameMr. Wenxuan Han
Recipient TitleGeneral Manager/Owner
- NingBo Huize Commodity Co., Ltd.
14 Lizhou Road Yuyao, Zhejiang
Zhejiang Sheng, 315402
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Warning Letter 320-19-31
Return Receipt Requested
August 2, 2019
Mr. Wenxuan Han
NingBo Huize Commodity Co., Ltd.
14 Lizhou Road
Yuyao, Zhejiang, 315402
Dear Mr. Han:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, NingBo Huize Commodity Co., Ltd., at 14 Lizhou Road, Yuyao, Zhejiang, from March 18 to 22, 2019.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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).
Your firm manufactures “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL that are misbranded drug products. Specifically, “SPF 30 SUNSCREEN LOTION” 30mL is misbranded under sections 502(f)(1) and (f)(2) of the FD&C Act, 21 U.S.C. 352(f)(1) and (f)(2). Additionally, “SPF 30 SUNSCREEN LOTION” 60mL is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1). Introduction of such products into interstate commerce is prohibited under sections 301(a) of the FD&C Act, 21 U.S.C. 331(a).
We reviewed your April 10, 2019, response in detail and acknowledge subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22 (a)).
During our inspection of your facility, your quality staff provided multiple quality documents to our investigator. Based on concerns with the documents provided, our investigator questioned your Quality Manager regarding the validity of these documents. Your General Manager and Quality Manager, then stated that multiple documents provided were in fact falsified “for the purpose of this inspection.”
Falsified documents include cleaning validation reports, batch records for multiple drug products, and annual product reviews. Furthermore, you also stated that you could not provide basic records to support the CGMP requirements for the manufacture of drugs, including, but not limited to, the following:
- equipment qualification (21 CFR 211.63);
- raw material qualification and active pharmaceutical ingredient testing (21 CFR 211.84);
- finished product and raw material testing qualification (21 CFR 211.165);
- drug product stability program (21 CFR 211.166);
- batch records (21 CFR 211.188); and
- process validation (21 CFR 211.100).
In your response, you provided some CGMP documents in writing. However, considering you falsified documents in the past, FDA is concerned regarding their validity.
Your response is inadequate because you failed to fully review the scope of your deficiencies, and provide evidence that you have comprehensively remediated your systems, and to implement procedures and programs that ensure ongoing control over your drug manufacturing operation.
In your response to this letter, provide:
- A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
- a determination of whether procedures used by your firm are robust and appropriate;
- provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices;
- a complete and final review of each batch and its related information before the QU disposition decision; and
- oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Include a detailed corrective action and preventive action (CAPA) plan to remediate this system. Your CAPA plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, quality unit oversight, and written procedures. It should also address how you will ensure all phases of investigations were appropriately conducted and the CAPA is effective.
- 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 complete, independent 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 full summary of data integrity assessments performed by your third-party consultant. Include a copy of your protocols, which should include a detailed description of all aspects of your operation that were subject to independent evaluation, and the depth and extent of the assessments. See the Data Integrity Remediation heading below for the full remediation request.
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 that the consultant evaluates 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 consultant should provide certification that your remediated quality systems are satisfactory, and that all documents submitted to the FDA are valid.
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 .
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 data integrity practices at .
We strongly recommend that you retain a qualified consultant to assist in your remediation.
In response to this letter, provide the following:
- A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
- 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.
- 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.
- An assessment of the extent of data integrity 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 data integrity lapses.
- A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity 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 data integrity and analyses of the risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
- 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.
- A comprehensive description of the root causes of your data integrity 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 data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
- 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.
- 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.
- A status report for any of the above activities already underway or completed.
Misbranded Drugs Violations
“SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL
“SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL, are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL are intended for use as sunscreens.
Examples of claims observed on the product labels for “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL that establish the intended uses, as defined in 21 CFR 201.128, of the products include, but may not be limited to, the following:
“SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL product labels:
“SPF 30 Sunscreen”
The labeling for such drugs, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR). However, your products do not meet these requirements for the reasons described below.
“SPF 30 SUNSCREEN LOTION” 30mL is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), because the product label does not include any directions for use required under 21 CFR 201.327(e). “SPF 30 SUNSCREEN LOTION” 30mL is further misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2), because the product label does not include all of the required warnings described under 21 CFR 201.327(d). For example, the warnings section for SPF 30 SUNSCREEN LOTION” 30mL does not include “Do not use [bullet] on damaged or broken skin,” “When using this product [bullet] keep out of eyes. Rinse with water to remove,” and “Stop use and ask a doctor if [bullet] rash occurs” as required under 21 CFR 201.327(d)(1).
Furthermore, “SPF 30 SUNSCREEN LOTION” 60mL is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), because the product label does not include all of the applicable directions for use as required under 21 CFR 201.327(e). For example, the directions for use section for “SPF 30 SUNSCREEN LOTION” 60mL does not include “[bullet] apply liberally 15 minutes before sun exposure” as required by 21 CFR 201.327(e)(1)(ii) or “[bullet] reapply at least every 2 hours [bullet] use a water resistant sunscreen if swimming or sweating” as required by 21 CFR 201.327 (e)(4).
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of “SPF 30 SUNSCREEN LOTION” 30mL and “SPF 30 SUNSCREEN LOTION” 60mL violate this provision of the FD&C Act.
Recall of Drug Products
We acknowledge that, based on the FDA inspectional findings, you agreed to recall drug products distributed to the U.S. market within expiry.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
FDA placed your firm on Import Alert 66-40 on June 13, 2019.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at NingBo Huize Commodity Co., Ltd., 14 Lizhou Road, Yuyao, Zhejiang into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of 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).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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 or mail your reply to:
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3012941723.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research