| Public Health Service Food and Drug Administration |
Silver Spring MD 20993 |
Department of Health and Human Services
Warning Letter
VIA UPS MAIL
WL: 320-11-018
08/05/2011
Mr. Qijiang Cai
Executive Vice President
Zhejiang Casing Animal By-Products Co. Ltd.
Tonglu Development Zone, No. 369 Dong Xing Road
Tonglu, Zhejiang 311500
People’s Republic of China
Dear Mr. Cai:
During our November 1-4, 2010 inspection of your drug manufacturing facility, Zhejiang Casing Animal By-Products Co. Ltd. located at Tonglu Development Zone, No. 369 Dong Xing Road, Tonglu, Zhejiang, 311500, People’s Republic of China, investigators from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of drugs. These deviations cause your (b)(4) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We acknowledge your written response to the Form FDA 483, submitted on December 3, 2010. However, because this response was received more than 15 business days after the Form FDA 483 was issued, the response has not been considered. We plan to evaluate your response to the Form FDA 483, along with any other written material provided, as a direct response to this Warning Letter.
Specific deviations observed during the inspection include, but are not limited, to the following:
1. Failure of your quality unit to review completed laboratory control records of critical process steps before release of the drug for distribution.
For example, your quality unit fails to review the (b)(4) ((b)(4)) and proton-nuclear magnetic resonance (HNMR) laboratory control records prior to the release of (b)(4) for distribution.
The inspection reported that your firm subcontracts with (b)(4), located at (b)(4), to perform the (b)(4) test to ensure that your (b)(4) is from (b)(4) origin, and does not contain presence of (b)(4) or (b)(4) contamination. Your firm also subcontracts with the (b)(4), located at (b)(4), to perform HNMR testing and assure the (b)(4) produced by your firm is free from ((b)(4)). However, the raw data to support the release of the (b)(4) lots to the United States distributor were not available for review from the contract laboratory during the inspection.
Your contract testing laboratory for HNMR only provides you with partial spectra zoomed in on the range for (b)(4) and (b)(4). We are concerned that your quality unit is not reviewing the entire spectrum for other potential impurities or contaminants. All documents related to the testing of your (b)(4) should be reviewed and approved by your quality unit according to established procedures. Contract laboratories are an extension of your operations and, as such, your quality unit is responsible for all data acquired at the contract laboratories you choose to use.
2. Failure to have a system in place to evaluate suppliers, and failure to adequately test each batch of incoming materials intended to be used in drug production.
Your firm uses (b)(4), and (b)(4) for the manufacture of (b)(4). However, your firm accepts these materials based on a supplier’s certificate of analysis (COA) but does not have a system in place to evaluate suppliers. In addition, your firm fails to perform identity tests on each batch of incoming raw material prior to release of the materials for production. Instead, you accept these materials based only on the unevaluated supplier’s certificate of analysis (COA).
3. Failure of your quality unit to evaluate raw materials prior to release and use in drug production operations.
The inspection revealed that your firm recovers (b)(4) from the purification processes and reuses the recovered solvent without performing any test to ensure the purity and quality of the recovered solvent.
4. Your quality unit fails to conduct and document regular product quality reviews for the (b)(4) produced to verify the consistency of the process.
The inspection revealed that the quality unit does not perform an annual evaluation of the process to ensure that it remains in a validated state. In your response, include the following:
• A review of all critical in-process controls and critical test results
• A review of all batches that failed to meet established specifications
• A review of all critical deviations or non-conformances, and related investigations
• A review of any changes carried out to the process or analytical methods
• A review of all quality-related returns and complaints (formal or informal from all customers)
• A review of adequacy of corrective actions implemented (also include the conclusions)
The deviations detailed in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to continue to ship (b)(4) to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Additionally, your firm is neither registered nor has it listed every drug in commercial distribution in the United States with FDA, as required by 21 C.F.R. § 207.40 and section 510(i) of the Act [21 U.S.C. § 360(i)]. Information on how to register and list is available at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm. You must complete the required registration and listing and provide evidence that you have fulfilled these requirements in your response to this letter.
Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer. In addition, failure to correct these deviations may result in FDA refusing admission of articles manufactured at Zhejiang Casing Animal By-Products Co. Ltd., Tonglu Development Zone, No. 369 Dong Xing Road, Tonglu, Zhejiang, 311500, People’s Republic of China, into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)] in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute (b)(4), and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI #3007925588.
If you believe that your December 3, 2010, written response to the Form FDA 483 fully explains the actions you have taken to prevent similar violations in the future, please communicate that to us in writing within fifteen (15) working days. As noted above, we plan to evaluate your written response to the Form FDA 483 along with any other written material provided as a direct response to this Warning Letter. You may reference the response dated December 3, 2010, in your response to this letter.
If you have questions or concerns regarding this letter, contact Milva E. Meléndez, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0662
Fax: (301) 847-8741
Sincerely,
/Steven Lynn /
Steven Lynn
Acting Director
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research (b) (4)
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