FDA发布天津中安药业进口禁令

julia朱玉姣

http://www.accessdata.fda.gov/cms_ia/importalert_189.html

信息来自FDA官网，链接如上。

FDA于2016年2月11日发布了针对天津中安药业的进口禁令。

syhorchid

坐沙发

syhorchid

中安药业，加油啊。

一沙一叶

原来才公布啊

albertchen

FDA本是要在2015年9月检查中安药业的，可惜大爆炸让FDA取消了检查，使中安上次的警告信无法翻身——其实也翻不了身。

大海

继续努力，整改不行吗，

zysx01234

能说的具体一点吗

北重楼

这就是代价

质量小兵

学习一下。

kslam

June 10, 2014


Mr. Li Zhengen
General Manager
Tianjin Zhongan Pharmaceutical Co. Ltd.天津中安药业有限公司
No. 188 Fukang Road
Xiqing District
Tianjin 300384
China

Dear Mr. Li Zhengen:

During our September 23-27, 2013 inspection of your pharmaceutical manufacturing facility, Tianjin Zhongan Pharmaceutical Co. Ltd., located at No. 188 Fukang Road, Xiqing District, Tianjin, China, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations of current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). These deviations cause your APIs 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.
在2013年9月23日~27日，对位于中国天津市西青区复康路188号的天津中安药业有限公司进行了检查，在检查过程中，USFDA的检察官发现在API的生产中存在验证偏离CGMP的现象。这些偏差导致API产品不符合联邦食品药品及化妆品法案的第501(a)(2)(B)条和21 U.S.C. 第351(a)(2)(B)条：药品检测方法，设施及控制，生产，工艺，包装或者储存不符合CGMP要求或者不按照CGMP要求进行操作和管理。

We have conducted a detailed review of your firm’s response and note that it lacks sufficient corrective actions.
我们仔细回顾了你们公司的回复并且注意到，你们的回复中缺少有效的整改措施。

Our investigator observed specific deviations during the inspection, including, but not limited to, the following:
我们的检查官在检查过程中发现了的偏差如下（包括但不局限于）：


1. Failure to adequately complete and follow written procedures for cleaning equipment and its release for use in API manufacture, and to maintain adequate records of major equipment usage.
关于设备清洁，清洁后允许其用于API生产以及主要设备的使用记录的书面程序不足：


Your firm failed to ensure that employees adequately cleaned (b)(4) after use. Your (b)(4) equipment cleaning standard operating procedures (SOP-HE 063-02 - instruction 4.2.2.1, SOP-HE 064-02 – instruction 4.3.4.3, and SOP-HE 055-02 – instruction 4.2.1.1), require that employees visually inspect equipment after the cleaning process. Our inspection found (b)(4) in the manufacturing workshop for (b)(4) with various levels of contamination and foreign objects inside, including what looked like the remains of a pen in one of the (b)(4). Your employees had labeled this equipment as clean. These (b)(4) are used for the manufacture of multiple APIs.
你们公司没有能够保证员工在生产之后对设备进行充分的清洁。你们的xx设备清洁标准操作程序（SOP-HE063-02的4.2.2.1，SOP-HE-064-02的4.3.4.3，以及SOP-HE055-02的4.2.1.1），规定员工在清洁后进行目视检查。我们的检察官发现生产车间里用于xx的xx里面有各种程度的污染以及异物，包括看上去像是笔的东西。这些xx用于多种API的生产。

In addition, your firm’s production system did not maintain equipment logs or other documents that adequately record manufacturing operations performed on individual pieces of equipment.
另外，你们公司的生产体系中没有包含设备运行日志或者文件，不能保证单个设备的生产操作过程有足够的记录。

We note that your production operation supervisors and Quality Unit (QU) failed to detect and correct these deficient cleaning practices.
我们认为，你们的车间主任们和质量部不能发现和纠正这些清洁活动中的不足。

Your response is inadequate because it does not address the extent of these deficient practices throughout your facility, or the impact on the quality of your active ingredients. Additionally, you do not commit to maintain equipment logs or other documents that record all of the manufacturing operations performed on individual pieces of equipment.
由于你们的回复没有能够处理这些设备清洁活动上的不足项或者对产品质量的影响，因此是不充分的。另外，你们没有承诺做设备运行日志或者其他文件用来记录单个设备上进行的所有生产操作。

In response to this letter, you should prepare and implement a corrective action plan sufficient to address and prevent the recurrence of these deficiencies. The corrective action plan should detail the systemic improvements to be made, including, but not limited to, improved management oversight of cleaning operations, commitment to maintain individual equipment records (e.g., equipment logs), and training all relevant personnel in cleaning procedures. You should also demonstrate the sufficiency and effectiveness of this corrective action plan.
作为对本次警告信的回复，你们应该准备和完成一个整改计划，以充分的处理和预防这些不足项的反复出现。这个整改计划应该详细叙述整个系统性的提高，包括但不局限于：提高清洁操作的检查管理，承诺做单个设备的记录（例如设备日志），对所有相关人员进行清洁程序的培训。你们还应该证明这个整改计划的有效性和充分性。

2. Failure to conduct adequate change control to evaluate all changes that could affect the production and control of intermediates or APIs.
变更控制不充分，不足以保证能对所有影响生产和中间体或者API控制的变更进行评价。

a. Your firm failed to identify, document, evaluate, and approve several changes in production. Specifically, the equipment referenced in the flow chart in Drug Master File (DMF) (b)(4) for the manufacture of (b)(4) API differed from the equipment actually used. The DMF (b)(4) flow chart contains a step for (b)(4) that follows the (b)(4) step. Firm officials stated that your firm no longer conducted the (b)(4) during the manufacture of this API. You did not evaluate whether this change was appropriate based on its impact on product quality, or validate the effectiveness of change implementation. In addition, you failed to conduct a change control investigation or document the significant changes in your manufacturing process as required by your change control SOP SMP-QA 009-08.
你们公司没有能够识别、记录、评价和批准好几个生产上的变更。具体的讲，在DMF中引用的用于xxAPI生产的设备与实际使用的不同。DMF流程图中包含在xx步骤后有一部xx步骤。公司领导声称你们公司已经不再使用xx生产这个API。你们没有基于产品质量角度对这个变更的合适性进行评价，也没有验证实施该变更的有效性。另外，你们也没有根据变更控制SOP SMP-QA-009-08的要求对生产工艺的变更进行变更控制调查和记录重要的变更。

b. Your firm failed to conduct a change control investigation or document the significant changes in(b)(4) systems as required by your change control procedure SMP-QA 009-08. In the (b)(4) system used for the manufacture of (b)(4) APIs, you connected an (b)(4) device via (b)(4) hose to a port on the(b)(4) system piping ((b)(4)) at the entrance to holding tank #V20129. Furthermore, in the (b)(4) system used for the manufacturing of (b)(4) USP, you relocated the (b)(4) tank; you extensively altered the piping system throughout the facility; and you added an (b)(4) unit. Also, the drawings for both systems were not current.
你们没有根据变更控制SOP SMP-QA-009-08的要求在xx系统中进行变更控制调查和记录重要的变更。在生产xxAPI使用的xx系统中，你们使用了一个xx设备通过xx软管连接到xx系统管道至储罐#V20129。并且，在生产xx的USP中，你们转移了xx罐。你们大范围的更改设备的管道系统，还增加了一个xx单元。而且，两个系统的图纸均不是最新的。

In your response, you state that you revised and implemented procedure SMP-QA-009-08 “SMP for Changes Control” on June 20, 2012. Although you had previously trained your employees in this procedure, the examples described above show that they failed to comply with it. Your response does not contain significant detail on how you will ensure compliance with procedure SMP-QA-009-08. In addition, the revised procedure indicates that it does not apply retroactively to existing equipment for which critical changes have been made without adequate change control.
在你们的回复中，声称你们已经修订和执行了变更控制程序SMP-QA-009-08,（2012.6.20）。尽管你们已经预先对员工培训了该程序，但是上述的例子说明员工没有遵守这个程序。你们的回复中没有包含关键的细节关于你们如何保证SMP-QA-009-08的实施。另外，升级后的程序规定了不需要对现有设备（在没有充分的变更控制下，已经进行了重大变更的）进行追溯。

In response to this letter, you should conduct a retrospective assessment of all changes you have made to equipment and procedures used in the manufacture of all (b)(4) and (b)(4) APIs. Provide the report of this assessment and the impact of these changes on product quality. Also, describe how your firm will correct the deficient change management system and ensure full implementation and compliance in the future.
作为对本次警告信的回复，你们应该对所有用于生产xx和xxAPI的设备和工艺上的变更进行追溯性的评价。提供评估报告以及评估这些变更对产品质量的影响。并且，描述你们公司将如何对变更管理体系的不足进行整改并保证将来能够全面遵守和执行。


3. Failure to adequately review and investigate product deviations.
对产品偏差的调查和回顾不足

During our inspection, the investigator observed that the (b)(4) manufacturing workshop (b)(4), used for (b)(4)steps, contained significant particulate material, (b)(4) fluid, and a plastic tube (apparently from a pen) in the bottom of the various (b)(4). These (b)(4) were labeled as clean. The samples collected of the residues were insufficient to allow for an adequate investigation. You did not initiate an investigation prior to the investigator’s observation. Your investigation consisted of a high performance liquid chromatography (HPLC) assay test for(b)(4), the last API manufactured in that (b)(4), even though the sample was a complex mixture of (b)(4)phases. You conducted no further testing, and disposed of the sample after the HPLC analysis.
在检查过程中，检查官发现用于xx步骤的xx产品生产车间xx，在各种xx底部都有明显的颗粒状物质，xx液，以及塑料管子（明显来自于笔），这些xx的状态是清洁。从这些残留物中收集的样品不足以支持一个充分的调查。在检察官发现之前，你们没有启动调查程序。你们的调查包含对这个xx最后生产的API进行HPLC含量检测，尽管样品是一个多相的复杂的混合物，你们并没有进行更深入的检测，而是在HPLC检测后就处理了样品。

In your response, you state that you revised procedure SMP-QA-007-03 “SMP of Deviation” to address these issues. Your response in insufficient because it does not describe or address the extent of these problems, or their impact on the quality of your APIs.
在你们的回复中，声称升级了偏差程序SMP-QA-007-03以处理这些事件。但是回复并不充分，因为没有描述或者处理这些问题的严重程度，或者对产品质量的影响。

In response to this letter, you should provide an assessment of your deviations system. Provide a corrective action plan to ensure adequate investigations are conducted for all deviations. This includes, but is not limited to, hiring qualified personnel to perform investigations, improving the training program, maintaining a sufficient number of staff, conducting timely remediation, and improving deviation investigation procedures.
作为对本次警告信的回复，你们应该提供一个对你们偏差体系的评估。提供一个整改措施以保证所有偏差都能得到充分的调查。包括但不局限于，招聘质量专员组织调查，加强培训，保持充足的人员数量，实施及时的补救措施，以及改进偏差调查程序。

We also note that you did not adequately control your Certificates of Analysis (COAs). Your employees in the Foreign Trade Office generated and issued COAs for your products, and your Quality Unit did not control, or retain records of all such COAs. For example, the (b)(4) USP API, batch #(b)(4), was imported into the U.S. with a different COA than the one you retained on record for that batch. You should investigate this significant recordkeeping deficiency, and ensure control of all of the COAs you issue for your products. It is your responsibility to ensure that all of your documents are properly controlled and maintained in compliance with CGMPs.
我们还注意到，你们对COA的控制不充分。由外贸部的员工制作和发布你们产品的COA，而你们的质量部不作控制，或者保留这些COA的记录。比如，xxUSP API，批号#xx，发给美国的COA与你们保存的记录不一致。你们应该调查记录存档上的严重不足，并且保证你们发布的所有产品的COA得到控制。保证所有文件得到恰当的控制以及完全遵守CGMP是你们的责任。

Your firm’s inadequate qualification of critical production equipment is also a concern. Specifically, you did not maintain current technical drawings of any (b)(4), or the (b)(4) production equipment used in manufacturing of(b)(4), and (b)(4) APIs. In addition, the qualification documents for these (b)(4) did not include important installation verification parameters such as material of construction, the volume capacity, (b)(4), configuration/location of (b)(4), or material of (b)(4). You should ensure that the contact surfaces of your production equipment are not reactive, additive, or absorptive so as to prevent impact on the quality of your products beyond appropriate limits.
你们公司不能对关键的生产设备进行充分的确认也是我们担心的一个问题。具体的讲，你们没有制作任何xx，或者用于生产xx和xxAPI的xx生产设备的现行的技术图纸。另外，这些xx的确认文件中没有包含重要的安装确认的参数，如材质，容积，xx，结构/安装位置，xx材料。你们应该保证与产品接触的设备表面是不发生反应的，不含添加剂的，不被吸收的，以防止使你们的产品质量超出规定的限度。

Executive management has the responsibility to ensure the quality, safety, and integrity of the products manufactured at your facility. A fundamental part of this responsibility is ensuring timely investigation and resolution of issues to prevent the distribution of defective products. FDA strongly recommends that your executive management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP regulations. As part of these efforts, it is imperative that you build a robust quality system, and assure proper management oversight of operations and quality. Your inability to detect and prevent the above deficient practices, as well as other deficiencies found during the inspection, indicate that your current quality system is ineffective at achieving overall compliance with CGMP.
行政管理者有责任保证你们生产的产品的质量、安全和完整。这些责任最基本的一部分就是保证及时对事件进行调查和解决以防止不合格品的产生。FDA强烈建议你们的行政管理者马上承诺按照全球制造业的标准进行一个综合性的评价，以保证完全遵循CGMP规范。作为其中一部分，有必要建立一个有力的质量体系，保证防止以上不足项的发生，也包括审计中发现的其他不足项，也就是说，你们现有的质量体系，按照全面的CGMP要求来讲，是无效的。

Due to continuing CGMP issues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that the APIs you manufacture have the appropriate identity, strength, quality, and purity.
鉴于你们公司持续的质量事件，我们建议你们聘用一个拥有适当的CGMP经验的第三方顾问，评估你们公司的设备、程序、工艺和系统以保证你们生产的API拥有适当的同一性、优点、质量和纯度。

Please note that a guidance document entitled “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” (ICH CGMP guidance), prepared under the auspices of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, describes current good manufacturing practice (CGMP) for the manufacture of APIs. The guidance is intended to help ensure that all APIs meet the standards for quality and purity they purport or are represented to possess. FDA considers the expectations outlined in ICH Q7, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality assurance, in determining whether a firm’s APIs have been manufactured, processed, packed, and held according to current good manufacturing practice under section 501(a)(2)(B) [21 USC 351(a)(2)(B)] of the Act. To obtain the ICH CGMP guidance document for your reference, please refer to the following page of FDA’s website: http://www.fda.gov/cder/guidance/4286fnl.htm.
Furthermore, we remind you that you are required to submit any addition, deletion, or other change to the information in your Drug Master File (DMF) to the FDA under 21 CFR 314.420. Additionally, you are required to notify each person authorized to reference the information in your DMF of the pertinent changes.

The deviations cited in this letter are not intended to be an all-inclusive list 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, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

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 an API manufacturer. In addition, your failure to correct these deviations may result in FDA refusing admission of articles manufactured at Tianjin Zhongan Pharmaceutical Company Limited located at 188 Fukang Road, Xiqing District, Tianjin, China into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may be 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 deviations, 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 APIs at issue, provide the dates and reasons you ceased production. Please identify your response with FEI # 3003671775.
Please send your reply to:


Joseph Duran
Compliance Officer
FDA/CDER/OC/OMPQ/DIDQ
10903 New Hampshire Ave
White Oak Building 51, Room 4237
Silver Spring, MD 20993

xhf123456

体系失控了，整改有难度。

wyb737496

中国的GMP认证检查报告，没有写得这么有深度

albertchen

作为食品添加剂的咖啡因还可以继续卖给美国境内的百事可乐吗？！

gabfghy990205

代价很惨重

将军119

中国的GMP认证检查报告，没有写得这么有深度

也能达到这个深度，就是时限不知道是多久，一万年，太久了，.........

［金业顺］

好有深度的检查报告！