Recipient NameMr. Qicai Fu
Recipient TitleGeneral Manager
- Hangzhou Guoguang Touring Commodity Co.,Ltd.
No. 8 Yushun Road
Jingshan Town, Yuhang District
- Issuing Office:
- Center for Drug Evaluation and Research
Via UPS Warning Letter 320-19-08
Return Receipt Requested
December 14, 2018
Mr. Qicai Fu
Hangzhou Guoguang Touring Commodity Co., Ltd.
No. 8 Yushun Road
Jingshan Town, Yuhang District
Hangzhou, Zhejiang, 311116
Dear Mr. Fu:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hangzhou Guoguang Touring Commodity Co., Ltd. at No. 8 Yushun Road, Jingshan Town, Yuhang District, Hangzhou, Zhejiang, from April 17 to 20, 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 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 11, 2018, response 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 establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You have not conducted adequate cleaning validation studies to demonstrate that your cleaning procedures for non-dedicated production equipment are adequate to prevent cross-contamination between the products manufactured at your facility. During our inspection, we observed that you manufacture several (b)(4) over-the-counter (OTC) drug products, including (b)(4), on shared equipment you use to manufacture nondrug products, including an (b)(4) product.
In your response, you stated that your firm will validate your current cleaning procedures for non-dedicated equipment retrospectively, to show that product residues were removed during cleaning. However, to date you have not provided adequate information about or supporting documentation for your proposed corrective action.
It is unacceptable, as a matter of CGMP, to continue manufacturing drugs using the same equipment that you use to manufacture (b)(4) products.
In response to this letter, discontinue manufacturing drugs and non-pharmaceuticals on shared equipment in your facility. If you intend to continue to manufacture both pharmaceutical and non-pharmaceutical products at your facility, provide a plan to show how you will separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical and (b)(4) product manufacturing operations.
In addition, conduct a risk assessment for all drugs you previously produced on equipment shared with (b)(4) products. For each product, assess the risk of potential contamination due to the shared equipment and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.
2. 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 quality unit failed to exercise its authority to approve, release, and distribute OTC drug products before all analytical testing was completed and reviewed. In addition, your firm approved and released OTC drug products that did not meet their final specification. For example:
For (b)(4) batches of (b)(4), your sales manager was provided with test results from your contract laboratory that were out of specification (b)(4) for (b)(4) assay. The batches were distributed without the quality unit’s review of the failing test results.
A batch of (b)(4) (Lot (b)(4)) was released by your quality unit on August 3, 2017, and was shipped on August 7, 2017, before your firm received the results of assay testing.
In your response, you provided an updated standard operating procedure and the associated training records concerning the release of OTC drug products with inadequate quality oversight.
However, your response is inadequate because you have not determined the root cause of this violation.
In response to this letter:
Perform a root cause assessment to determine the underlying factors that resulted in your quality unit’s failure to exercise its authority. This should include a thorough evaluation of your quality agreements with your customers to clarify roles and responsibilities.
Perform a review of all lots of OTC drug products within expiry that were distributed in the United States to determine if your firm released additional OTC drug products that did not conform to established specifications or appropriate manufacturing standards. Based on the results of your review, take prompt and appropriate corrective actions, such as customer notifications and product recalls.
3. 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 distributed (b)(4) lots of (b)(4) and (b)(4) lots of (b)(4) to the U.S. supply chain without testing the identity, strength, purity, and quality of the active ingredient. Additionally, all your OTC drug products have a specification for the absence of (b)(4); however, this test was not performed during finished product testing. Furthermore, you have not established any specifications for the “(b)(4)” used in all your OTC drug products, nor is any testing performed on the “(b)(4).”
In your response, you provided assay testing results for products within expiry that have been distributed in the United States. However, these products have not been tested according to all your specifications, including the absence of (b)(4). Furthermore, you did not provide any established component specifications for the “(b)(4)” used in all your OTC drug products.
In response to this letter, provide:
A summary of test results obtained from the testing of retain samples of all your OTC drug products within expiry that have been distributed in the United States. Include test results for identity and strength of active ingredients, and all other appropriate chemical and (b)(4) quality attributes.
Your component specifications for the “(b)(4)” used to manufacturer your OTC drug products.
Your firm failed to establish 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 did not have an adequate stability testing program to demonstrate that the chemical and (b)(4) properties of your OTC drug products remain acceptable throughout their labeled expiry period. For example, your stability testing program does not include an assay determination of the active ingredient(s) in your OTC drug products. In your response, you committed to performing adequate stability studies to justify the expiration dating and storage conditions of your OTC drug products, as well as retain sample testing, to ensure the adequacy of your OTC drug products currently on the market. We acknowledge that you ceased distributing all your OTC drug products in the United States; however, you have not put any interim measures in place for your OTC drug products currently on the market within expiry.
In response to this letter:
Provide the stability test results for all your OTC drug products distributed in the United States within expiry, using stability-indicating methods to determine if the results meet specifications. If you obtain out-of-specification results, take prompt and appropriate corrective actions, such as customer notifications and product recalls.
Perform a comprehensive assessment and corrective and preventative action (CAPA) to ensure the adequacy of your stability program. Your CAPA should include, but should not be limited to, a remediated standard operating procedure (SOP) 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.
CGMP Consultant Recommended
If your firm resumes manufacturing drugs for the U.S. market, 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.
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/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf.
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 October 5, 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 Guoguang Touring Commodity Co., Ltd. at No. 8 Yushun Road, Jingshan Town, Yuhang District, 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:
CDR Frank Verni, R.Ph., MPH
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. 3008785460.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research