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  5. Hangzhou Linkeweier Daily Chemicals Co., Ltd. - 595492 - 03/13/2020
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Hangzhou Linkeweier Daily Chemicals Co., Ltd. MARCS-CMS 595492 —

Delivery Method:
Reference #:

Recipient Name
Mr. Zhang Wenbing
Recipient Title
General Manager
Hangzhou Linkeweier Daily Chemicals Co., Ltd.

568 Dongfang Road, Yiqiao Town
Xiaoshan Qu
Hangzhou Shi
Zhejiang Sheng, 311256

Issuing Office:
Center for Drug Evaluation and Research | CDER

10903 New Hampshire Avenue
Silver Spring, MD 20993
United States

Warning Letter 320-20-30


March 13, 2020


Dear Mr. Wenbing

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hangzhou Linkweier Daily Chemicals Co. Ltd., FEI 3014324616, at 568 Dongfang Road, Yiqiao Town, Xiao Shan District, Hangzhou, Zhejiang, from September 11 to 17, 2019.

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 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).

We reviewed your September 24, 2019, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

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

1.  Your firm 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(b)).

Your firm contract manufactures over-the-counter (OTC) (b)(4) drug products. Your firm released these products without ensuring that they are free of objectionable microorganisms.

Moreover, your finished product is formulated with (b)(4) which you also fail to adequately monitor for microbial contamination. Poorly controlled (b)(4) systems may harbor objectionable microorganisms, which may contribute to the contamination of your finished product. 

Microbial testing of each batch is the last in a series of essential CGMP controls that ensure a drug product is free of objectionable microorganisms and suitable for release.

In your response, you stated that you will establish specifications for your OTC drug products. However, your response is inadequate because you did not provide sufficient rationale that your established specifications are appropriate. Additionally, you did not perform a retrospective review and risk evaluation of OTC drug products currently in the U.S. market within expiry.

In response to this letter, provide the following:

• A comprehensive independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards, not limited to your (b)(4) system.

• A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.

• All chemical and microbial test methods used to analyze each of your drug products.

• Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.

• A summary of results from testing reserve samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an out-of-specification result, indicate the corrective actions you will take, including notifying customers and initiating recalls.

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces (b)(4) that meets (b)(4) USP monograph specifications and appropriate microbial limits.

• A tabular summary of chemical and microbial monitoring results that you have collected from testing your (b)(4) system for the past two years. Within the table, also include the following:

    o Specification for tested attribute
    o Date of sampling
    o Point of use from which the sample was collected

2. 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 (2)).

Your firm failed to adequately test your incoming components, including the active ingredient, for identity, strength, purity, and other appropriate quality attributes. Instead, your firm relied on certificates of analyses (COA) from unqualified suppliers. Identity testing for each component lot used in drug product manufacturing is required, and you can only rely on COA for other component attributes by appropriately validating the suppliers’ test results at appropriate intervals. In addition, the COA for the incoming active ingredient lacks appropriate microbial testing.

Your response states you will ensure your suppliers send a “report of the percentage of each ingredient.” Your response is inadequate because it lacks specificity regarding your supplier validation program or plans to test each lot of each shipment of incoming components. Additionally, your response did not address retrospective assessment of the OTC drug products distributed in the U.S. market with components that have not been adequately tested to ensure conformance to established specifications.

In response to this letter, provide the following:

• 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 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.

• 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.

• A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

3. Your firm failed to establish adequate 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 failed to validate the processes used to manufacture your drug product. You have not performed process qualification studies, nor do you have a rigorous ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

In your response you stated that you will draft an “operational guide for the process to control variability in the characteristics.” Your response is inadequate because you did not provide sufficient details of the validation program for the process to ensure a robust and consistent
process. You also did not discuss a plan to review previously manufactured products to ensure they were manufactured with appropriate process controls.

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 ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies can result in product quality attribute failures. Process qualification studies determine whether an initial state of control has been established. Before commercial distribution, successful process qualification studies are necessary. 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 http://www.fda.gov/media/71021/download.

In response to this letter, provide the following:

• A detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

• 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 variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.

• Timelines for completed process performance qualification for marketed drug products for which a state of control has not been adequately/fully established.

4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your firm does not have an adequate stability testing program to demonstrate that the chemical and microbiological properties of your drug product remain acceptable throughout the claimed expiry period of (b)(4). Without appropriate stability data, you cannot ensure your drug 
products meet established specifications and all pre-determined quality criteria throughout the drug product’s assigned shelf-life.

In your response, you stated you will draft a “Product Stability Specification” and you will place a specific number of batches already distributed on stability. Your response is inadequate because you did not provide sufficient details, such as stability protocols that ensure all relevant quality criteria are incorporated in your new stability program. Furthermore, you did not indicate any actions to ensure or demonstrate that the chemical and microbiological properties of your drug product distributed in the United States remained stable throughout its 24-month expiry period.

In response to this letter, provide the following:

• 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 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.

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/media/71023/download.

CGMP Consultant Recommended

If your firm intends to resume manufacturing drugs for the U.S. market, 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 performs a comprehensive audit of your entire operation for CGMP compliance and 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.

Responsibilities as a Contractor

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You and your customer (b)(4) have a quality agreement regarding the drugs you manufacture on their behalf. You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with (b)(4) You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.


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 these violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on March 09, 2020.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Hangzhou Linkeweier Daily Chemicals Co., Ltd., at 568 Dongfang Road, Yiqiao Town, Xiao Shan District, Hangzhou, Zhejiang 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 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:

Deyaa Shaheen
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993

Please identify your response with FEI: 3014324616

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

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