Beanne Chemical Co. 12/19/12
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
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CERTIFIED MAIL WL: 320-13-05
RETURN RECEIPT REQUESTED
December 19, 2012
Mr. James Ling Hocklai
Vice General Manager
Herdsman Enterprises Co., Ltd.
No. 166, 6 Fl, Section 5, Roosevelt Road
Taipei, Taiwan 11677
Dear Mr. James Ling Hocklai:
During our May 2-4, 2012 inspection of your pharmaceutical manufacturing facility, Beanne Chemical Co. located at Shengang District, Taichung City, Taiwan, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) 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, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
Our inspection also revealed that your firm failed to fulfill its registration obligations under Section 510(i)(1) of the Act and its listing obligations under Sections 510(i)(2) and 510(j), which is prohibited under Section 301(p). 21 U.S.C. 360(i)(1) and (2), 360(j), and 331(p).
We acknowledge receipt of your firm’s correspondence dated September 16, 2012.
Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:
- Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
For example, your firm failed to appropriately validate the manufacturing processes of the (b)(4) Cream (b)(4) containing (b)(4) and (b)(4), (b)(4) Medication containing (b)(4), and (b)(4) Cream containing (b)(4). Our inspection revealed that your firm did not validate any of the manufacturing steps to produce the finished products being shipped to U.S. market. Your firm management stated during the inspection that process validation, cleaning validation, and equipment qualification have not been conducted.
In response to this letter, you should include evidence that your firm has successfully validated the manufacturing processes for (b)(4) containing (b)(4) and (b)(4), (b)(4) Medication containing (b)(4), and (b)(4) containing (b)(4).
- Your firm failed to establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product (21 CFR 211.110(a)).
For example, your firm does not perform adequate in-process tests for the (b)(4) containing (b)(4) and (b)(4), (b)(4) Medication containing (b)(4), and (b)(4) Cream containing (b)(4). During review of the batch records for these products, our investigator found that your firm conducted no in-process testing. Your firm’s management stated to the investigator that no procedure is in place to conduct sampling and testing of in-process materials. The only testing you conduct on your products is finished product testing.
In your response to this letter, please include provisions for appropriate sampling and testing of in-process materials of each batch of finished products sent to the U.S. market. Include a strong scientific and quality assurance rationale for your in-process sampling and testing approach (e.g., addressing variability in the process and use of suitable statistical procedures). In addition, please provide your firm’s rationale for release of lots to the U.S. market without assurance of quality provided by adequate in-process testing.
- Your firm failed to establish 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)).
For example, your firm has no stability testing program to support the (b)(4) ((b)(4)) year expiration date for (b)(4) Cream (b)(4) and the (b)(4) ((b)(4)) year expiration date for (b)(4) Cream with (b)(4) manufactured and shipped to the U.S. market. During the inspection, your management indicated that no stability studies have ever been conducted for any of your U.S.-marketed products.
In response to this letter, describe your action plan for the lots within expiry distributed to the U.S. market. Provide documentation to support the current expiration dates assigned to your drug products currently in U.S. distribution. Also, provide a commitment to ensure that each of your drug products is routinely tested according to a stability program that your quality unit approves and that addresses each of the requirements described in 21 CFR 211.166.
- Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).
For example, your firm failed to maintain all the laboratory raw data used to support the release of finished product lots. During the inspection, the investigator requested the raw data from the finished product testing described in the certificates of analysis. However, your firm management stated that your firm does not maintain records of the raw data for each of the finished products shipped to the U.S. market. We are concerned that the certificates of analysis include test results for total aerobic microbial count, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, arsenic, lead, mercury, and skin irritation, but no raw data is available to ensure that the analyses were conducted correctly or that the results reported were within specifications. Moreover, the certificates of analysis for (b)(4) containing (b)(4) and (b)(4) do not include the determination of labeled claims for each lot analyzed. Without the data to confirm content of the labeled, active ingredients, (b)(4) and (b)(4), your quality unit did not have sufficient justification to support a decision to release the product.
In your response to this letter, describe your raw data retention plan. In lieu of providing the raw data to support your release for distribution in the U.S. of products within expiry, describe your action plan for all products in distribution that you released without this supporting data. During the inspection, your firm management discussed the possibility of using a third party contractor to perform finished product testing. If you choose to contract with another party to provide release testing activities, then provide in your response to this letter the name and address of this contract laboratory as well as a copy of your quality agreement with the contract laboratory. Additionally, describe your plan for testing active ingredients in each of your finished products distributed to the U.S. market.
Additionally, the investigator documented that your firm lacks proof of equipment qualification and cleaning validation. In response to this letter, please provide documentation of validated cleaning methods for, and qualification of, all shared equipment used in the manufacture of products shipped to the U.S. market. FDA strongly suggests your firm perform a comprehensive assessment of manufacturing operations to ensure that they conform with CGMP.
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 the violations identified above and for preventing their recurrence and the occurrence of other violations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA continuing to refuse admission of articles manufactured at Beanne Chemical Co. located at Shengang District, Taichung City, Taiwan into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). 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 CGMP 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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute (b)(4) containing (b)(4) and (b)(4), (b)(4) Medication containing (b)(4) and (b)(4) Cream containing (b)(4), for each, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3003721123.
Please send your reply to the following address:
10903 New Hampshire Ave.
White Oak Building 51, Room 4237
Silver Spring, MD 20993
Steven J. Lynn
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research