Recipient NameMr. Guokang Li
- Hangzhou Zhongbo Industrial Co., Ltd.
Yuhang District, Changle Industrial Zone
- Issuing Office:
- Center for Drug Evaluation and Research
Warning Letter 320-19-02
Return Receipt Requested
November 27, 2018
Mr. Guokang Li
Hangzhou Zhongbo Industrial Co., Ltd.
Yuhang District, Changle Industrial Zone
Hangzhou, Zhejiang, 311123
Dear Mr. Li:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hangzhou Zhongbo Industrial Co., Ltd. at Yuhang District, Changle Industrial Zone, Hangzhou, Zhejiang, from April 23 to 27, 2018.
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).
We reviewed your May 18, 2018, 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 (21 CFR 211.165(a)).
You released over the counter (OTC) drug products to the U.S. market without conducting finished product quality testing. You received a testing report from your contract laboratory, (b)(4), dated March 23, 2018, for your (b)(4). This testing was carried out on a small batch of your drug product. You used the results from this report to release Batch No. (b)(4) of your (b)(4). Your records show that you began manufacturing Batch No. (b)(4) on April 2, 2018, more than a week after the date of your contract laboratory’s report. Further, this report contained results for microbial enumeration but not for assay testing.
In your response, you stated that you will revise your procedure and ship batches after you complete production and after “a[n] overall inspection.” However, you did not indicate whether you will ship your product only after completing all required finished product tests using a representative sample.
In response to this letter, provide your revised finished product release procedure. Your procedure should include the completion of manufacturing and product quality release testing before shipping. It should specify appropriate release tests of finished drug product samples that are taken at statistically appropriate intervals.
In addition, provide testing by an independent CGMP-qualified laboratory of each finished product distributed to the United States within expiry, to demonstrate if they met established quality criteria before release. For any product that failed to meet established quality criteria before release, provide your detailed corrective action plan including notifying customers or recalling drug products.
2. 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 such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
You do not have long-term stability testing data to support your (b)(4) expiration dates for your finished product. You based the expiration dates on only three months of accelerated stability testing. The accelerated stability testing does not have written justification for the number of lots tested, the number of units sampled and tested, the storage conditions, the testing interval, or the critical quality criteria, including assay.
In your response, you said that you plan to test retention samples from product manufactured two years ago. You did not indicate that your retention sample testing will include testing of all critical attributes, including assay. You did not explain where you will obtain these samples for testing, as, during the inspection, you said that you retain samples for only (b)(4). Further, your response did not provide a plan for establishing and executing written stability protocols, including long-term stability testing. You stated that your customer and their third-party testing laboratory determine the stability program for your products. However, you maintain responsibility for the quality of your drugs, including your stability testing program, regardless of agreements with your customer or any third-party testing laboratory.
In response to this letter, provide a comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but should not be limited to, a remediated standard operating procedure describing your stability program; stability-indicating methods; stability studies to support each drug product in its container-closure system before distribution is permitted; 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; and specific attributes to be tested at each station.
3. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and (2)).
Your firm failed to test incoming raw materials for their identity, purity, strength, and other appropriate quality attributes. There is no assurance that the (b)(4) used to manufacture your finished drug product conforms to appropriate quality attributes, including microbiological specifications. During the inspection, you indicated that you do not test your (b)(4) inactive ingredients for identity or other quality attributes, and that you accept test results based on your suppliers’ certificate of analysis (CoA).
In your response, you said that you will use a third-party laboratory to conduct microbial tests (b)(4) for the (b)(4) used to manufacture your finished drug product, and that you will work with a third party on testing inactive ingredients. However, you did not: (1) provide scientific rationale to support the frequency of your (b)(4) testing; (2) specify the (b)(4) attributes you will test; (3) state when the testing will start; or (4) state when you will implement inactive ingredient testing.
In response to this letter, provide:
- A detailed plan, including all relevant procedures and implementation dates, to ensure the quality of the water used in your manufacturing operations. This plan should include scientific justification for your chosen testing frequency.
- Describe in detail how you plan to test each incoming component lot for conformity with all appropriate written specifications for purity, strength, and quality. If you intend to accept your suppliers’ CoA in lieu of testing each component lot for purity, strength, and quality, describe how you plan to establish the reliability of your suppliers’ test results for these attributes at regular intervals. Regardless of your plans for CoA verification, include a commitment to test every incoming component lot (both active and inactive ingredients) for identity. Also provide your revised procedure remediating these deficiencies and your timeline for implementation.
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 are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. 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/downloads/drugs/guidances/ucm353925.pdf.
Quality Unit Authority
Your inspectional history indicates that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.
Repeat observations at facility
In a previous inspection, dated July 18 to 21, 2016, FDA cited similar CGMP observations. These repeated failures demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.
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 third party perform a comprehensive audit of your entire operation for CGMP compliance, and that they evaluate the sufficiency, completion, and effectiveness of any corrective actions and preventive actions you have implemented, 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 fully resolving all deficiencies and ensuring ongoing CGMP compliance.
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 September 28, 2018.
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 Hangzhou Zhongbo Industrial Co., Ltd. at Yuhang District, Changle Industrial Zone, Hangzhou, 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:
Jason F. Chancey
Consumer Safety Officer
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 No. 3008229416.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research