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Via UPS  

Warning Letter 320-19-25

Return Receipt Requested

 

June 10, 2019

           

Mr. Yuhui Guo

Chairman

Xi’an Livingbond Nonwoven Products Corp., Ltd.

46, Jeyakgongdan 2-gil, Hyangnam-eup

No. 3 Standardized Plant, Xingyuan Road, Fengjing Ind Park,

Hu District, Xian Shaanxi 710300

China

 

Dear Mr. Guo:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Xi’an Livingbond Nonwoven Products Corp., Ltd., at 46, Jeyakgongdan 2-gil, Hyangnam-eup, No. 3 Standardized Plant, Xingyuan Road, Fengjing Ind Park, Hu District, Xian Shaanxi from January 7 to 10, 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 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).

Based on our review, your firm’s products, Antibacterial Wet Wipes (in four separate package configurations) are also misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x). Introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

We reviewed your January 25, 2019, response in detail.

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. Your firm also failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(a) and (b)).

Your firm manufactures and distributes (b)(4) for the United States market. Our inspection found that you did not test your over-the-counter (OTC) finished drug products to determine whether each batch meets identity and strength specifications before releasing those products to the U.S. market.

In addition, your firm lacked reliable testing for microbial attributes. For example, you did not have an adequate program for growth promotion testing of media used for microbial testing.

Complete testing of each batch is essential to determine if the drug products you manufacture meet appropriate specifications for chemical and microbial attributes.

In your response, you stated that you will send each finished product batch to a third party to test for active ingredient identity and strength prior to release.  You also stated that you plan to purchase a chromatographic analyzer.  

We acknowledge your commitment to perform growth promotion test on each batch of media to assure the reliability of the microbiological results.

Your response is inadequate because it did not commit to take any corrective action for products already in the market, include information about your third-party testing laboratory, or provide procedures to be used for additional testing. You must ensure each batch of your drug products meets all chemical and microbiological specifications before release.

In response to this letter, provide the following:

• A list of all chemical and microbial test methods and specifications used to analyze each batch of your drug products before making the batch disposition decision, and associated written procedures.
• A summary of test results obtained from retrospective testing of retain samples of all drug product batches currently in distribution in the United States. Include test results for identity and strength of active ingredients, and all other appropriate chemical and microbial quality attributes. If you released any batch that was out of specification, indicate the corrective action you will take, such as customer notifications and product recalls.
• A comprehensive and independent review of your laboratory practices, procedures, methods, equipment and analyst competencies. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to fully remediate your laboratory system. Your plan should also include the procedures you will use to evaluate the effectiveness of the implemented CAPA.
• Provide your procedure to assure that any test methods performed by a contract testing laboratory on your behalf are properly transferred and validated before use.

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

 

You failed to test incoming active pharmaceutical ingredients (API) and other components you use to manufacture your drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied solely on the component supplier’s analysis report without establishing the reliability of your suppliers’ analyses through appropriate validation.

 

In your response, you stated that you will purchase API from an appropriate company. You also committed to require your API supplier to provide an analysis report with detailed test data. In addition, you committed to conduct a comprehensive analysis of packaging and other materials purchased in the future to determine if they conform with written specifications.

 

Your response is inadequate because you failed to commit to test each lot of raw material (i.e., in all cases, for identity, and also for any attribute for which the COA has not been validated) before you use it in the manufacture of your drug products. In addition, you did not specify how you will establish the reliability of your suppliers’ analyses. Also, you did not take any action for products already in the market.

 

In response to this letter, provide the following:

• The chemical and microbiological quality control specifications you use to determine disposition of each incoming lot of components before 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 testing results on your supplier’s certificates of analysis (COA) in lieu of testing each component lot for purity, strength, and quality, specify how you will first establish the reliability and consistency of your supplier’s test results for these attributes through initial validation (followed by periodic re-validation). In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• A summary of test results obtained from full testing of all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure that describes this COA validation program.
• A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and have incoming material controls adequate to prevent use of unsuitable containers, closures, and components.

3.  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 lacks an ongoing program for monitoring process control to ensure stable manufacturing operations. You have not demonstrated that your manufacturing process is capable of consistently producing drugs of uniform character and quality.

Inadequate Control of Manufacturing Processes

You have not validated the processes used to manufacture your finished OTC drug products. You did not define or identify critical process parameters for your (b)(4). In addition, you do not have a program for monitoring process controls to ensure stable manufacturing operations and consistent drug quality.

In your response, you stated that you will validate your manufacturing process for (b)(4).

Your response is inadequate because you failed to provide a detailed process performance qualification protocol and an overall program to assure that you maintain a validated process throughout the product lifecycle. In addition, you failed to conduct a risk assessment for drugs already distributed to the U.S. market.

 

In response to this letter, provide your validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing process performance qualification for your drug products.

Inadequate Control of (b)(4) System

The (b)(4) used to manufacture your drug product and to clean manufacturing equipment comes from a system that you have not validated. You lack assurance that your (b)(4) system will consistently produce (b)(4) suitable for pharmaceutical use that conforms to the USP monograph for (b)(4) and appropriate microbial standards.

In your response, you stated that you will implement changes to improve your (b)(4) system.

Your response is inadequate because you failed to provide a comprehensive design review and a validation plan of your (b)(4) system.

In response to this letter, provide the following:

• A comprehensive, independent assessment of your (b)(4) system design, control, and maintenance.
• A comprehensive CAPA plan for remediating design, control, and maintenance of the (b)(4) system.
• Your (b)(4) system validation report. Also, summarize your improvements made to system design, as well as to the program for ongoing control and maintenance.
• Appropriate total count limits to ensure this system produces (b)(4) suitable for the intended uses of each of your products. Note that total count limits tighter than your action and alert limits may be generally appropriate for your (b)(4) products.

4.  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)).

Your firm lacked an adequate quality unit (QU). For example, your quality unit failed to establish written procedures for multiple responsibilities, such as CGMP training, annual product review (APR), and stability program.

In your response, you stated that you will improve your laboratory control procedures and have completed employee training in CGMP requirements.

Your response is inadequate because you failed to provide the procedures that will be implemented, including stability and APR.

In response to this letter, provide the following:

• New and updated procedures describing the roles and responsibilities of your QU and evidence that these procedures have been appropriately implemented.
• Your plan, with timelines, to develop and implement a complete drug stability program. This plan should also include an assessment of the stability of drug product currently on the U.S. market.
• A comprehensive assessment with corrective action and preventive actions (CAPA) to ensure your QU is given the needed authority and resources to effectively discharge its 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;
• complete and final review of each batch and its related information prior to the QU disposition decision; and
• oversight and approval of investigations, and discharging of all other QU duties to assure identity, strength, quality, and purity of all products.

Quality Systems

 

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

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.

Misbranded Drugs Violations

Antibacterial Wet Wipes

Xi'an Livingbond Nonwoven Products Corp., Ltd. manufactures OTC antibacterial wet wipes in four separate package configurations. The package configurations include a single use package with the name Antibacterial Wet Wipes on the principal display panel (PDP), a single use package with the name Antibacterial Hand Sanitizing Wipes on the PDP, a multiuse pouch that is citrus scented, and a multiuse pack with a flip top dispenser. These four package configurations are collectively referred to as Antibacterial Wet Wipes.

Antibacterial Wet Wipes 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 as defined 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, these products are intended as consumer antiseptic rubs.   

Examples of claims observed on the product labels for Antibacterial Wet Wipes that establish the intended uses of the products as defined in 21 CFR 201.128 include, but may not be limited to, the following:

“Uses: For hand washing to decrease bacteria on the skin.”

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, Antibacterial Wet Wipes do not meet these requirements for the reasons described below.

Antibacterial Wet Wipes are misbranded under section 502(x) of the FD&C Act 21 U.S.C. 352(x) because the products’ label fails to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. Please note that section 201(k) of the FD&C Act defines the term "label" as "...a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of this Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such…also appears on the outside container…”

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).

Conclusion

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 April 12, 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 Xi’an Livingbond Nonwoven Products Corp., Ltd., at 46, Jeyakgongdan 2-gil, Hyangnam-eup, No. 3 Standardized Plant, Xingyuan Road, Fengjing Ind Park, Hu District, Xian Shaanxi 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:

Chhaya Shetty

Interdisciplinary Scientist

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

 

Please identify your response with FEI 3013558030.

 

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research