Taiwan Three Mast Pharmaceutical Co.Ltd. 12/17/12
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||Silver Spring, MD 20993|
CERTIFIED MAIL WL: 320-13-04
RETURN RECEIPT REQUESTED
December 17, 2012
Mr. Sam Huang
Taiwan Three Mast Pharmaceutical Co., Ltd.
No. 3, Jingzhong Road
Tainan City, Taiwan
During our April 23, 2012 through April 27, 2012 inspection of your pharmaceutical manufacturing facility, Taiwan Three Mast Pharmaceutical Co., Ltd., located at No. 3, Jingzhong Road, Yongkang District, Tainan City, Taiwan, an investigator 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. In addition, your Imbue Pain Relief Patch is an unapproved drug in violation of Sections 301(d) and 505(a) of the Act.
We acknowledge receipt of your firm’s correspondence dated October 4, 2012.
Our investigator observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm does not 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)).
For example, your firm has not established assay method(s) to determine the strength of the active ingredients menthol and/or methyl salicylate for any of your finished drug products containing these ingredients. Your firm only identifies these active ingredients by thin layer chromatography (TLC).
In response to this letter, provide scientifically sound and appropriate written test procedures, sampling plans, and specifications for your finished drug products. Provide test results to demonstrate that retain samples conform to final specifications for all drug product batches within expiry that have been distributed to the United States, and describe corrective actions for any non-conforming batches. Furthermore, your response should include your commitment to perform adequate finished product testing of all future drug product batches.
2. Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or examined, as appropriate, and released for use by the quality control unit (21 CFR 211.84(a)). Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).
For example, your firm does not perform any testing on incoming lots of menthol and methyl salicylate active pharmaceutical ingredients (APIs) prior to use in production. Rather, you relied solely on certificates of analysis (COA) provided by the suppliers even though you had neither conducted an identity test nor established the reliability of the suppliers’ analyses through appropriate validation of the suppliers’ test results.
In your response to this letter, describe procedures for conducting at least one specific identity test for each incoming raw material before releasing it for use in your finished drug products. Include a description of your sampling procedure for raw materials and the number of samples to be tested for each incoming lot. Provide details on each test method to be used with the supporting analytical method validation. Provide test results for your reserve samples, within retention period, of each lot of menthol and methyl salicylate APIs that were used in the manufacture of finished drug products distributed to the U.S. market. Additionally, you should include your API supplier qualification procedures and results.
3. Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess (21 CFR 211.100(a)).
For example, your manufacturing processes for Imbue Pain Relief Patch, Panlax Herbal Patch, Panlax Herbal Balm, and Panlax Herbal Cream are not validated. Your firm has manufactured and distributed these drug products to the U.S. market since 2010.
In response to this letter, provide validation protocols with scientifically justified acceptance criteria and results of the validation studies. If you have not completed your process validation, please provide a schedule with milestones for its completion. Describe in-process controls your firm will institute to ensure that your process is performing as intended. We recommend that you consider reviewing the FDA guidance for industry entitled Process Validation: General Principles and Practices, available online at http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf.
4. Your firm failed to establish and follow written procedures to evaluate, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures (21 CFR 211.180(e)).
For example, your firm failed to conduct annual product reviews of all drug products distributed to the U.S. since 2010. In response to this letter, provide written procedures for the review of drug products on an annual basis, including but not limited to, provisions for reviewing complaints, recalls, returned or salvaged drug products, and investigations associated with deviations or batch failures. Also, explain how your firm will ensure that future annual product reviews are conducted.
5. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).
For example, your firm does not provide CGMP training to employees. In response to this letter, provide a copy of your CGMP training program and a timeline for completion of training for all employees.
We are concerned about your firm’s failure to comply with fundamental CGMPs, including the lack of testing of raw materials and finished drug products, unvalidated manufacturing processes, and the lack of basic CGMP training at your facility. Our inspection also revealed that your firm has not conducted qualification activities for any equipment used in the manufacture of your drug products or validated cleaning activities performed in your manufacturing facility. To ensure that your drug products meet the quality and purity characteristics that they purport, or are represented to possess, please refer to the CGMP regulations at 21 CFR Parts 210 and 211, which can be accessed at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm. We also recommend that you seek the advice of a third party consultant for assistance with a complete evaluation to determine the improvements needed at your facility to conform to the CGMP requirements.
Unapproved Over-the-Counter (OTC) Drug
In addition to the CGMP violations, your firm also manufactures an over-the-counter (OTC) external analgesic drug product that violates sections 301(d), and 505(a) of the Act, (21 U.S.C. §§ 331(d) and 355(a)).
Based on a review of the product labeling collected during the 2012 inspection of your facility, Imbue Pain Relief Patch is a drug, as defined in section 201(g) of the Act, (21 U.S.C. § 321(g)), because it is intended for use in the cure, mitigation, treatment, or prevention of disease, and/or because it is intended to affect the structure or any function of the body of man.
Drug products intended for topical administration for OTC indications related to pain are being evaluated under the OTC Drug Review. The Tentative Final Monograph (TFM) issued on February 8, 1983 for OTC External Analgesics (48 Fed. Reg. 5852) is part of this evaluation.
Imbue Pain Relief Patch is a product that is marketed for use as an external analgesic. The External Analgesics TFM does not include indications specific to bursitis and tendonitis. Additionally, we are not aware of an OTC product for topical application to treat these conditions having been available in the U.S. market as an OTC drug at the inception of the OTC Drug Review. Therefore, this product is not eligible for that review. Thus, the current marketing of Imbue Pain Relief Patch violates sections 301(d) and 505(a) of the Act (21 U.S.C. §§ 331(d) and 355(a)) because it is a new drug, as defined by section 201(p) of the Act (21 U.S.C. § 301(p)) and it is not the subject of an approved new drug application.
In addition, we remind you that in accordance with 21 CFR 330.1(e), it is your responsibility to ensure the inactive ingredients in your OTC drug products must be safe and suitable for each OTC formulation.
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 Taiwan Three Mast Pharmaceutical Co., Ltd., Yongkang District, Tainan City, Taiwan 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 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 the drug product(s) at issue, provide the date(s) and reason(s) you ceased production.
Please send your reply to the following address:
An T. Vu, Ph.D.
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 Avenue
Silver Spring, MD 20993
Office of Manufacturing and Product Quality
Office of Compliance