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  5. Ningbo BST Clean and Care Products Co., Ltd - 587788 - 11/27/2019
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Ningbo BST Clean and Care Products Co., Ltd MARCS-CMS 587788 —

Delivery Method:

Recipient Name
Mr. Jack Wang
Recipient Title
Ningbo BST Clean and Care Products Co., Ltd

Xining Road, Xiwu Economic Development Zone
Fenghua Shi
Ningbo Shi
Zhejiang Sheng, 315100

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States

November 27, 2019


Warning Letter 320-20-08

Dear Mr. Wang:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Ningbo BST Clean and Care Products Co., Ltd., FEI 3008350682, at Xining Road, Xiwu Economic Development Zone, Fenghua, Ningbo Zhejiang, from June 10 to 14, 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 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 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 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-counter (OTC) drug products without adequately testing for the identity and strength of the active ingredient. During the inspection your personnel acknowledged that your firm does not test each batch of your (b)(4) drug products for active ingredient content.

Your personnel explained that drug samples are collected and sent to the Quality Control (QC) laboratory for testing. However, the records available indicate that the last lot tested for (b)(4) content and analytical testing was manufactured in 2011. You were unable to provide records of laboratory testing for drug product produced after 2011.

It is essential that you test each drug product batch to ensure it meets all established specifications. In addition to testing for chemical attributes including but not limited to identity and potency, each batch should also meet microbial specifications that are appropriate for the intended uses of your drug products.

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.
• An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States within expiry.
• A summary of all results obtained from testing reserve samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

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 firm lacks an adequate quality unit (QU). For example, you lacked written procedures for numerous functions of the QU, including but not limited to quality unit operations, batch release, change control, complaint handling, recalls, and annual product review. Additionally, your firm lacked procedures for equipment qualification, deviations/investigations, equipment cleaning, and many other procedures necessary to maintain a CGMP compliant drug manufacturing operation.

In addition, your QU does not ensure the issuance of production batch records for each batch of drug products manufactured for the U.S. market. Lastly, you lacked a stability program to ensure that the chemical and (b)(4) properties for your (b)(4) products will remain acceptable throughout their shelf-life.

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 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)

• 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 Updated standard operating procedures (SOPs) implemented that ensure your quality unit is fulfilling all responsibilities required

• 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.

3. Your firm failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58).

Our investigator observed multiple dirty and cracked floors and walls throughout your facility, including inside the production suite. The walls in the warehouse used for storage of raw materials and components were stained with what appeared to be a black mold-like substance. Most notably, our investigator observed pest infestation in your QC laboratory as evidenced by a hole in the wall with a bird nest inside, bird droppings on floors, and bird's nests on the laboratory counter.

It is essential that your facility is in a good state of repair and sanitary conditions are maintained.

In response to this letter, provide your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

4. Your firm failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

Your firm has not established an equipment cleaning program. Your personnel stated that he did not record the cleaning of the manufacturing equipment and that he had no knowledge of cleaning validation.

Your firm also failed to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, maintained and stored so that it is accurate and fit for use.

In response to this letter, provide the following:

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

• 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 SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

• A description of your manufacturing site design and list of all products, including any non-drug items. Also describe your design and controls at your facilities to ensure your segregation of facilities that make drugs and industrial products, in order to preclude any risks of cross-contamination and mix-ups.

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.

Your use of a consultant does not relieve your firm 's obligation to comply with CGMP. Your firm's executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.


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 November 26, 2019.

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 continuum to refuse admission of articles manufactured at Ningbo BST Clean and Care Products Co., Ltd., Xining Road, Fenghua, Ningbo 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:

Ernest Bizjak
Acting Team Lead
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 3008350682.

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

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