美国FDA警告信-台湾三帆制药有限公司

巴西木

台湾三帆制药有限公司。12年12月17日

卫生和人类服务部	公共卫生服务 食品和药物管理局（FDA）
	马里兰州Silver Spring 20993

警告信

CERTIFIED MAIL                                                                          WL：320-13-04
要求回执

2012年12月17号



黄子先生
总经理
台湾帆制药有限公司
，敬路3号
永康市区
台湾台南市，

尊敬的黄先生：

在我们的四月23日到四月27日2012年，2012年检查药品生产设施，台湾三帆药业有限公司，有限公司，位于3号，敬路，研究者从美国，台湾，台南市永康区，食品和药物管理局（FDA）身分版显著违反现行良好生产规范（CGMP）的规定，成品制药，标题21，美国联邦法规，配件210和211。这些违规行为造成的药物产品（S）内掺假的意义，第501条（一）（2）（B）的“联邦食品，药品和化妆品法”（该法），21 USC 351（A）（2 ）（B），所采用的方法，或使用的设施或控制，其生产，加工，包装，或持有不符合，或不符合经营或管理，CGMP。另外，你的力量强化止痛修补程序违反该法第301（d）和505（A）是一个未经批准的药物。

我们已收到贵公司的信件，日期为2012年10月4日。

我们的调查人员在检查过程中观察到具体的侵权行为，包括但不限于以下：

CGMP违反

1。    你公司不有，每个批次的药品，适当的实验室测定，满意的一致性药物产品的最终规格，包括身份和实力的各有效成分，释放前（21 CFR 211.165（一）） 。

例如，您的公司还没有建立的检测方法（S）的强弱来决定的有效成分薄荷脑和/或水杨酸甲酯任何含有这些成分的成品药产品。你的公司只有确定这些活性成分的薄层色谱法（TLC）。

在这封信中，提供科学合理的和适当的笔试程序，抽样计划，和成品药产品的规格。提供测试结果表明，保留任何不符合批次样品符合最终规范已分发到美国的所有药物产品批次内到期，并描述纠正措施。此外，你的反应应该包括你的承诺，未来所有的药物产品批次进行适当的成品检验。

2。    公司失败，不使用每个直到很多很多的成分，药品容器和密封件被采样，测试，或检查（如适用），并释放用于质量控制部门（21 CFR 211.84（一））。你的公司未能符合所有适当的书面规格的纯度，强度，和质量测试每个组件的样品（21 CFR 211.84（D）（2））。

例如，你的公司不执行任何传入之前，在生产中使用大量的薄荷脑和水杨酸甲酯的活性药物成分（API）的测试。相反，您仅依赖，即使你既没有进行身份测试通过适当的验证供应商的测试结果，也没有建立供应商的可靠性分析由供应商提供的分析证书（COA）。  

在这封信你的回应，说明至少一个鉴别检验每一个进厂的原材料进行发布之前，为成品药产品在使用的过程。中包括原料和被测试为每个传入的特定数目的样本取样程序的说明。每个测试方法被用于支持分析方法的验证提供细节。提供您的留样的测试结果，在保留期内，薄荷脑和水杨酸甲酯的API分发到美国市场的成品药产品的制造中所使用的每一批。此外，您还应该包括你的API供应商资格的程序和结果。

3，    你的公司未能建立适当的书面程序，对生产和过程控制，以确保药品制造的身份，实力，质量，和/或纯度，他们声称或表示拥有（21 CFR 211.100（一） ）。

例如，您的的制造工艺灌输疼痛补丁，Panlax中药贴剂，中草药膏Panlax，​​草本精华和Panlax不验证。你的公司已经制造和分发这些药物产品到美国市场自2010年以来。

在这封信中，提供科学合理的验收标准和验证研究结果的验证协议。如果你还没有完成工艺验证，请提供一个时间表完成的里程碑。详细说明过程中的控制你的公司机构，以确保你的进程按计划进行。我们建议，你考虑检讨FDA行业指南“ 工艺验证的一般原则和做法，可在网上http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf。

4，    你的公司未能建立，并按照书面程序进行评估，至少每年一次，每个药物产品的质量标准，以确定是否需要药物的产品规格或生产或控制程序（21 CFR 211.180（E））的变化。

例如，您公司的所有药品分发给美国自2010年以来每年进行产品的评论。在这封信中，提供书面的审查程序的药品在年度基础上，包括但不限于规定审查投诉，召回，退回或回收的药品，并与偏差或批量故障调查。此外，公司将如何确保今后的年度产品评论进行。

5     你的公司未能确保每个人从事生产，加工，包装，或持有药品生产的教育，培训和经验，或它们的任意组合，以使该人执行他或她指定的功能。（21 CFR 211.25（一））。

例如，您的公司不向员工提供CGMP培训。在这封信中，提供一个副本的的CGMP培训计划和时间表完成对所有员工的培训。

我们关注您的公司未能遵守的基本cGMPS则可使吸光度，包括原料和成品药产品缺乏测试，未经验证的制造工艺，以及缺乏基本的CGMP培训在您的设备。我们的检查还透露，公司已不生产的药品或在您的生产设施进行有效的清洗活动中使用任何设备进行认证活动。为了确保药品符合质量和纯度的特点，他们声称，或表示拥有，请参阅CGMP法规21 CFR 210和211，可以访问 http://www.accessdata.fda的.gov /脚本/ CDRH / cfdocs / cfCFR / CFRSearch.cfm的。我们还建议您咨询的第三方顾问的协助与一个完整的评估，以确定在您的工厂需要改进，以符合CGMP的要求。

未经批准的柜台交易（OTC）药物

此外的CGMP侵犯的，你的公司也生产过的非处方（OTC）的外部镇痛药产品，违反该法第301（d）和505（A），（21 USC§§331（D）和355（a）条）。

基于产品标签检查你的设施在2012年收集的审查，注魔疼痛补丁是一种药物的定义，在该法第201（g），（21 USC§321（g）条），因为它是拟中使用的治愈，缓解，治疗或预防疾病，和/或，因为它的目的的结构产生影响，或人的身体的任何功能。

正在评估用于局部用药OTC的适应症与疼痛的药物产品在OTC药品审查。暂定1983年2月8日发行的最终专着（TFM）的OTC外用止痛剂（48联邦注册5852）是本次评测的一部分。

灌输止痛修补程序是作为外部镇痛药，用于销售的产品。外用止痛剂，TFM不包括具体的滑囊炎和肌腱炎的迹象。此外，我们是不知道的局部应用治疗这些疾病已在美国市场作为非处方药OTC药品审查开始时的一个OTC产品。因此，这个产品是不是该检讨的资格。因此，目前的市场灌输止痛修补程序违反了第301（d）和505（一）法“（21 USC§§331（D）和355（A）），因为它是一种新的药物，所定义的部分201（P）的法令（21 USC§301（P）），它是不批准的新药申请的主题。

此外，我们提醒您，在符合21 CFR 330.1（E），这是你的责任，以确保在您的非处方药产品必须是安全和合适的非活性成分，每个OTC制剂。

这封信中提到的侵犯人权行为，并不打算成为一个包容各方的名单在您的设备存在侵犯。你是负责调查和确定上述侵犯行为的原因，为防止其复发和其他违规行为的发生。

直到所有的修正已经完成，并FDA已确认改正的违法行为和贵公司的符合CGMP，FDA拒绝审批任何新的应用程序或补充上市公司作为药物产品的制造商。此外，你的失败来纠正这些违规行为，可能会导致在FDA继续拒绝承认台湾三桅杆药业有限公司，公司进入美国，台湾，台南市永康区，在生产的物品。的文章是拒绝接纳根据该法第801（A）（3），21 USC 381（A）（3），控制的生产过程中使用的方法和不出现，以符合CGMP内该法第501（A）（2）（B）的意思，21 USC 351（A）（2）（B）。

15个工作日内收到这封信，请以书面形式通知该办公室已经采取了纠正和防止发生侵权行为的具体步骤，并提供支持性文件的副本。如果你不能完成纠正行动，15个工作日内，延迟的原因和状态的日期，你已经完成了更正。此外，如果你已不再生产或分发药物产品（S）的问题，提供的日期（S）和停止生产的原因（S）。

请发送您的回复至以下地址：

一个T.武，博士
合规主任
美国食品和药物管理局
药物评价和研究中心
办公室生产和产品质量
国际药品质量处
白橡，51楼
10903新罕布什尔大道
马里兰州Silver Spring 20993


真诚的，
/ S /                                                                       
史蒂芬琳
主任
办公室生产和产品质量
合规办公室

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最后更新日期：2013年1月4日

Taiwan Three Mast Pharmaceutical Co.Ltd. 12/17/12

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Silver Spring, MD  20993

Warning Letter

CERTIFIED MAIL                                                                         WL: 320-13-04
RETURN RECEIPT REQUESTED

December 17, 2012



Mr. Sam Huang
General Manager
Taiwan Three Mast Pharmaceutical Co., Ltd.
No. 3, Jingzhong Road
Yongkang District
Tainan City, Taiwan

Dear Mr. Huang:

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:

CGMP Violations

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.
Compliance Officer
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


Sincerely,
/S/                                                                       
Steven Lynn
Director
Office of Manufacturing and Product Quality
Office of Compliance

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Page Last Updated: 01/04/2013

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典型的洋泾浜嘛

彩虹

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冰城

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幻影

网页翻译的》？完全不能准确表达原文意思。

云水泱泱

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法国梧桐

楼主 你还不如直接贴英文，