Warning Letter 320-20-02
October 3, 2019
Dear Mr. Yu:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Bingbing Pharmaceutical (Hubei) Co. Ltd., FEI 3014538973, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, from May 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 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 May 31, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)).
You manufactured drugs at your Wuhan facility at Building (b)(4), No. 5, Kangda Street, Longyang Avenue, Hanyang District, Wuhan, and then transferred drug production to your Hubei facility and closed the Wuhan facility. Your firm failed to maintain manufacturing records, raw material and finished product testing records, retain samples, stability samples, and other CGMP records for your over-the-counter (OTC) (b)(4) drug products manufactured at your Wuhan facility. During the inspection at the Hubei facility, you stated that you lost CGMP manufacturing documentation and drug product samples during the transfer of your manufacturing facility from Wuhan to Hubei in May 2018.
In your response, you stated that you initiated an investigation to assess the scope of impacted product, will attempt to collect samples from the market to evaluate and take “all mandatory and necessary measures,” and will conduct a quality system evaluation using a third-party consultant. Your response is inadequate because you failed to appropriately address the impact of missing records and samples on drug products already on the market. Maintaining all manufacturing and testing records, as well as representative product samples, is critical to establish that your products meet their required quality attributes.
In response to this letter, provide:
· A complete, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (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 detailed risk assessment of drug products on the market without any manufacturing documentation and without retains or stability samples to support investigations and expiration dating. Specify actions, with timelines, that you will take in response to the risk assessment, such as customer notifications and initiating recalls.
2. 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))
Your firm released OTC drug products to the United States market without testing the identity and strength of each active ingredient. For example, your firm failed to test for the active ingredients, (b)(4), in your (b)(4)products. Testing is essential to ensuring that the drug products you manufacture meet established specifications for the required chemical attributes.
We acknowledge your commitment to discontinue the manufacture and distribution of (b)(4) products until analytical methods for (b)(4) active ingredients have been established and validated or verified. However, your response is inadequate. You failed to provide details for establishing that your OTC drug products in distribution meet their specifications.
In response to this letter, provide a list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision. The list should include:
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 as of the date of this letter.
A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
3. 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).
During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC (b)(4). For example, your QU failed to ensure:
Full testing of drug products and review of their results are performed prior to batch release.
Contract laboratory used for identity testing is qualified following your written procedures.
Cleaning validation of shared (b)(4) tanks include justifications for the worst-case sampling locations following your cleaning validation procedure.
Written procedures for sampling and testing of the (b)(4) system are followed.
Procedures to review electronic data generated from GC, HPLC, IR, and TOC systems are written and followed.
Controlled records, including logs, are maintained to track receipt of all components used to manufacture drug products.
Every OOS result is appropriately investigated and each investigation is extended to all affected batches, as applicable.
In your response, you admitted that due to cash flow problems you “were unable to ensure all products were completely tested and ensure conformance with all pre-determined specification prior to be shipped out”. You also submitted numerous CAPA to address each example of your quality unit failures cited above.
Because you failed to include supporting documentation, your response is inadequate and cannot be fully evaluated. You also failed to conduct a comprehensive review of your quality unit to identify deficiencies. You did not provide evidence that you have implemented procedures that ensure adequate control over your drug manufacturing processes. In addition, you failed to include a plan to address the quality of your drugs that were manufactured without appropriate quality oversight.
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 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.
Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and assure a continuing state of control.
· A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures. Describe how your firm will ensure all phases of investigations are appropriately conducted.
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.
4. Your firm failed to maintain an adequate written record of each complaint (21 CFR 211.198(b)).
You firm failed to maintain a complete and accurate record of your complaint investigations. You opened investigations B-18002 and B-19001 in response to complaints of poor (b)(4) for batches manufactured in Wuhan. In these investigations you stated that you evaluated reserve samples and found no deficiencies. However, you had previously stated that all reserve samples were lost for batches manufactured at your Wuhan site and therefore reserve samples were not available for evaluation.
In your response, you stated that testing was performed on reserve samples manufactured in your Hubei facility. Your response is inadequate because testing a batch that is different from the complaint batch does not provide you with batch specific information needed to identify potential quality defects in the complaint batch.
In response to this letter, provide:
· The status of lots identified in investigations B-18002 and B19001.
· Your plan for evaluating complaints for batches manufactured in your Wuhan facility.
· The process you will follow if a complaint cannot be appropriately investigated. Indicate the corrective actions you will take including notifying customers and initiating recalls.
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 https://www.fda.gov/media/119570/download.
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, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your 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.
A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
The violations cited in this letter are not intended to be an all-inclusive statement 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 August 22, 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 continuing to refuse admission of articles manufactured at Bingbing Pharmaceutical (Hubei) Co., Ltd, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, 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:
Carlos M. González
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 3014538973.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
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