FDA警告信：匈牙利TEVA（节译）

该公司被FDA于2016年5月27日发布66-40项下进口禁令。本警告信官方发布网址为：http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm525640.htm

Warning Letter 320-17-01

Via UPS                                                                                      

Return Receipt Requested

October 13, 2016

Mr. Erez Vigodman

President & CEO

Teva Pharmaceutical Works Pvt. Ltd.

5th Basel Street

P.O. Box 3190

Petah Tikva 4951033

Israel

Dear Mr. Vigodman,

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Teva Pharmaceutical Works Pvt. Ltd. at 2100 Godollo, Tancsics Mihaly ut 82, Godollo, Hungary, from January 21 to 29, 2016.

美国FDA于2016年1月21-29日检查了你们位于匈牙利的生产工厂。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信总结了你们制剂生产CGMP严重违规情况。参见21CFR第210和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

由于你们生产、加工、包装和保存的方法、设施和控制不符合CGMP要求，你们的药品根据FDCA的定义被认为是掺假药品。

We reviewed your firm’s February 22, 2016, response in detail and acknowledge receipt of your subsequent correspondence.

我们详细审核了你们于2015年11月6日发来的回复。

Our investigators observed specific violations including, but not limited to, the following.

在我们检查期间，我们的调查人员发现的违规情况包括但不仅限于以下：

1.    Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed. (21 CFR 211.192)

你们公司未能彻底调查已销售和未销售的批产品所有未解释的差异、批不合格和药品成分不符合其质量标准。

You did not adequately investigate media fill and sterility test failures. These failures indicate that there is a lack of adequate sterility assurance in your manufacturing facility.

你们未能充分调查培养基灌装和无菌检测不合格。这些不合格情况显示你们的生产设施里缺乏足够的无菌保证。

a.    Media Fills 培养基灌装

You did not adequately investigate media fill contamination in your aseptic manufacturing lines. For example, media fill run(b)(4), performed September 14-16, 2015, in the closed Restricted Access Barrier System (RABS) small volume parenteral line in (b)(4), yielded 31 contaminated units. In addition, media fills for other filling lines at your facility yielded one or more contaminants.

你们没有充分调查你们无菌生产线上的培养基灌装污染。例如，2015年9月14-16日进行的培养基灌装轮次XX，是在密闭的限制进入隔离系统（RABS）小容量注射剂生产线上做的，有31个单位被污染。另外，你们工厂的其它的灌装线的培养基灌装也有一个或更多的污染物。

You attributed the contamination in these media fills to aseptic technique breaches by different operators. Various breaches were identified relating to set-up, filling, and changing of the filling tank. However, your investigations were insufficient. For example, you failed to identify the microorganisms found in the contaminated units. It is imperative that you determine the identity of microorganisms found in media filled units in order to adequately understand the potential sources and scope of the contamination.  

你们将这些培养基灌装污染归因于不同操作人员的无菌技术差异。在装配、灌装和更改灌装罐中发现有不同偏离情况。但是，你们的调查并不充分。例如，你们未能对受污染单位中的微生物组织进行鉴别。你们很有必要对培养基灌装单位中发现的微生物进行鉴定，以充分了解污染的可能来源以及污染的范围。

Any contamination in a media fill run indicates a potentially significant sterility assurance problem and should be thoroughly investigated.

所有在培养基灌装中发生的污染都意味着可能有重大的无菌保证问题，应进行彻底调查。

b.    Sterility Test Positive Investigations 无菌检查阳性调查

You also did not thoroughly investigate sterility test positives. For example, your investigation of  a sterility test failure for (b)(4) injection (batch (b)(4)) did not adequately assess the hazards in the aseptic manufacturing operation that led to the sterility failure. You also did not determine whether other batches made on the same production line were affected.  

你们也没有对无功检查阳性进行彻底调查。例如，你们的对XX注射剂的无菌检测失败的调查并没有对无菌生产操作中导致无菌失败的危险进行充分评估。你们也没有确定是否在同一生产线上有其它批次受到影响。

In addition, you invalidated multiple sterility test positive results obtained during batch release testing. However, we note that your firm uses a sterility test (b)(4) as well as a sterility testing kit that minimizes potential for adventitious contamination that could cause false positives.

此外，你们宣布多个批放行检测中得到的无菌检测阳性结果为无效结果。但是我们注意到你们公司所使用的无菌检测XX和无菌测试盒可以将会导致假阳性的异物污染风险降至最小。

Your response is inadequate. In response to this letter, provide the following information:

你们的回复是不充分的。在回复此函时，请提供以下信息：

• a comprehensive review of all sterility positive and media fill failure investigations since January 2014 to reassess your root causes, corrections, conclusions, and effect of your lack of aseptic processing control on the sterility of marketed commercial batches.  
• 对所有自2014年1月以来无菌阳性结果和培养基灌装失败调查进行全面审核，重新评估你们的根本原因、纠正措施、结论以及你们缺乏无菌工艺控制对上市销售的批次的无菌性的影响。
• revised media fill contamination investigation standard operating procedures (SOP), including but not limited to identification of microorganisms from each contaminated unit, thorough assessment of possible causes, and assurance of appropriate corrective actions to prevent contamination.
• 修订培养基灌装污染调查标准操作程序（SOP），包括但不仅限于对每个受污染单位的微生物组织的鉴定、对可能原因的彻底评估，以及确保适当的纠正措施来防止污染。
• revised sterility failure investigation SOP, including but not limited to a thorough assessment of potential manufacturing root causes, identification of actions to prevent contamination, and assurance that invalidation of a sterility positive does not occur unless there is a robust and conclusive laboratory root cause.
• 修订无菌失败调查SOP，包括但不仅限于对潜在生产根本原因的彻底评估，制订防止污染的措施，以及确保只有在确实可归结的化验室根本原因找到时才会宣布无菌阳性结果无效。
• a retrospective evaluation of videos of your aseptic manufacture of all in-date batches distributed to the United States to determine contamination hazards posed by deficient aseptic practices. Also review the video of the production activities associated with the (b)(4) injection sterility failure to help identify the source of contamination in that batch.
• 对所有已销售到美国的批次的无菌生产录像进行回顾性评估，确定有缺陷的无菌操作所具有的污染风险。还要回顾与XX注射剂无菌失败相关的生产活动，以协助识别出该批次里的污染来源。
• a thorough assessment of the adequacy of your facility, equipment, and process. Determine failure modes relating to design, control, and maintenance. Include a comprehensive corrective action and preventive action (CAPA) plan that fully identifies microbial contamination risks throughout your operation and describes improvements to assure high confidence in the sterility of your products.
• 对你们的设施、设备和工艺的充分性进行彻底评估。确定与设计、控制和维保相关的失败模式。包括全面CAPA计划，其中完整识别出你们全部操作中的微生物污染风险，措施确保你们药品中高置信度无菌的改进措施。
  

2.    Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. (21 CFR 211.113(b))

贵公司未能建立和遵守适当的书面程序，用以防止理应无菌的药品的微生物污染，包括对所有无菌和灭菌工艺的验证。(21 CFR 211.113(b))

a.    Poor Aseptic Behavior 不良无菌行为

During the inspection, our investigators observed poor aseptic processing techniques that had been previously videotaped at your facility. For example, video from September 8 and 9, 2015, showed the following during the set-up and filling of the sterile injectable drug (b)(4):

在检查中，我们的调查人员发现你们工厂之前录像中使用的不良无菌操作技术。例如，2015年9月8日的录像显示在无菌注射药品XX的装配和灌装过程：

• an operator passing a pen directly over the stopper bowl to another operator.
• 一名操作人员将一支笔直接从塞子盘上面递给另一名操作人员。
• an operator sitting on the clean room floor during set-up of the filling line and not changing the gown after standing up.
• 一名操作人员在装配灌装生产线时坐在洁净区地板上，在站起来以后没有更衣。
• operators leaning against the cleanroom walls.
• 操作人员靠在洁净间的墙上。
• an operator leaving the RABS (b)(4) open for extended periods of time during filling line set-up, even when he was not working in the immediate area.
• 一名操作人员在灌装生产线装配期间让某RABS敞开时间过长，甚至当他不在紧邻区工作时也是这样。
  

Your response is inadequate. In response to this letter, provide the following:

你们的回复是不充分的。在回复此函时，请提供以下：

• a risk assessment of the poor aseptic techniques observed during the inspection.
• 在检查期间发现的不良无菌技术的风险评估。
• a broader evaluation of any additional aseptic technique breaches that have occurred in your operation (e.g., through review of videos).
• 对你们操作中（例如，通过对录像的审核）发生的所有其它无菌技术违规进行更广泛的评估。
• updated information to demonstrate that each of your aseptic processing lines is in a state of control.
• 更新信息以证明你们的每条无菌工艺生产线处于受控状态。
  

In addition to implementing enhancements to your aseptic processing operation design, describe how you will improve staff competencies, supervisory oversight of daily operations, and other controls.

除了改进你们的无菌工艺生产设计外，还应描述你们要如何改善员工的合格程度，对日常操作的监管以及其它控制。

b.    Mechanical Failure During Media Fill 在培养基灌装中的机械性失败

Your firm rejected numerous integral vials during media fill batches due to mechanical problems or other causes without appropriate justification. For example, media fill batch (b)(4) was aborted due to a mechanical failure of the conveyor belt motor. Although 3,696 integral vials had been filled, the vials were not incubated, and the media fill was invalidated without adequate justification. Your firm indicated that it would have released a commercial batch as a sub-lot under these circumstances.

你们公司在培养基灌装批中因为机械问题和其它原因拒收了大量的完整西林瓶，但没有适当的论证。例如，XX培养基灌装批由于传送带马达机械故障中断。虽然已经灌装了3696个完整的西林瓶，但这些瓶没有进行培养，培养基灌装被宣布无效，而没有充分的论证。你们公司显示在此情形下作为子批号放行了一个商业批次。

You also did not have a procedure describing production and disposition practices after such a mechanical failure.

你们也没有程序描述此类机械故障之后生产和处置做法。

Your response is inadequate. In response to this letter, provide the following:

你们的回复是不充分的。在回复此函时，请提供以下文件：

• a list of commercial batches rejected as a result of mechanical problems or other reasons and the CAPA that was implemented in each case.
• 一份由于机构故障或其它原因拒收的商业批次清凌晨，以及各种情形下所实施的CAPA。
• a list of all media fills conducted since January 2011 with fill date, number of units run, number of units incubated, number of positive units, and annotation of whether the fill was aborted.
• 所有自2011年1月以来培养基灌装清单，包括灌装日期、灌装单位数量、培养单位数量、阳性单位数量、以及该灌装过程中否被中断的说明。
• descriptions of circumstances under which any portion of a media fill batch was incubated as a separate segment, and whether you detected any positive units.  
• 你们将培养基灌装批的一部分作为单独一段进行培养的情形的描述，以及是否发现阳性单位。
• changes made to your written procedures to ensure that media fills accurately simulate actual production practices and to address when it is appropriate to abort a media fill run.
• 对书面程序的修改，以确保培养基灌装准确模拟实际生产做法，说明什么时候中断培养基灌装运行是适当的。
  

3.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas. (21 CFR 211.42(c)(10)(iv))

贵公司未能建立适当的系统，监控无菌工艺处理区域的环境条件。(21 CFR 211.42(c)(10)(iv))

Your SOP G010291 System of Microbiological Environment Monitoring includes microbial alert and action levels. Per the SOP, no more than (b)(4) colony forming unit (CFU) is permitted on two hands in Grade A (ISO 5) areas where personnel perform critical interventions during filling, line set-up, and other aseptic activities. In Grade B (ISO 7) areas, which are described as filling, filtration, capping, or changing rooms, no more than (b)(4) CFUs are permitted on two hands, and there is an alert level at (b)(4) CFUs.

你们的SOP G010291“微生物环境监测系统”包括微生物警戒和行动限。根据SOP，A级（ISO5级）洁净区里灌装、生产线装配和其它无菌活动中实施关键扰动操作的人员的监测限度为不超过XXCFU/双手。在B级（ISO7级）洁净区，用于灌装、过程、轧盖、更衣间，限度为不超过XXCFU/双手，警戒限为XXCFU。

However, when our investigators observed operators performing activities which should adhere to Grade A levels (hands in open RABS and under laminar air flow), your firm officials stated that the operators were held to Grade B levels. Furthermore, your firm failed to justify allowing (b)(4) CFU on the (b)(4) of operators who perform Grade A interventions without any potential follow-up. Such instances should trigger an alert or action condition that, at a minimum, should lead to trending and may indicate the need for further investigation.

但在在我们的调查人员观察操作人员实施应该符合A级水平（双手放在敞开的RABS里，在直流空气流中）的活动时，你们公司的管理人员说操作人员是在B级水平。另外，你们公司未能论证实施A级扰动操作的人员限度为XXCFU，但没有任何可能的跟踪。此类情况引发警戒或行动条件，至少，应该导致趋势分析，可能会发现需要进一步调查。

In response to this letter, provide a comprehensive retrospective review and risk assessment of personnel and environmental monitoring data since January 1, 2015. In addition, describe how future monitoring will be conducted in different classified aseptic processing areas to ensure that action and alert levels are commensurate with the operations being performed in the specified area.

在回复此函时，请提交一份对2015年1月1日以来的人员和环境监测数据全面的回顾审核和风险评估。此外，描述将来要如何对不同级别无菌工艺区域进行监测，以确保行动限和警戒限与在特定区域实施的操作相当。

4.    Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. (21 CFR 211.160(b))

贵公司未能建立化验室控制，包括科学合理和适当的质量标准、取样计划、检验方法，以确保组件、药品容器、密闭器、中间体、标签和药品符合适当的鉴别、剂量、质量和纯度标准。(21 CFR 211.160(b))

The suitability test you performed in (b)(4) failed to meet acceptance criteria for sterility testing. Specifically, a positive control sample did not exhibit growth of (b)(4) during sterility testing for (b)(4) mg/mL solution (b)(4). Your firm did not investigate this failure of media to support growth. Unsuitable sterility test methods increase the probability that your quality control test will not detect a non-sterile product.

你们对XX批进行的稳定性测试不符合无菌测试的可接受标准。具体地说，一个阳性控制样品在XX溶液无菌检查中没有生长。你们公司没有对此培养基无法生长进行调查。不适当的无菌检验方法增加了你们QC检验检不出非无菌药品的可能性。

Your response is inadequate. In response to this letter, provide the following:

你们的回复是不充分的。在回复此函时，请提供以下信息：

• a thorough investigation into the root cause of the positive control test failure, including your CAPA plan.
• 对阳性控制检测失败的根本原因进行彻底调查，包括你们的CAPA计划。
• a comprehensive investigation of each of your sterility test methods and their ability to reproducibly promote microbial growth in the presence of product.
• 对你们的每个无菌检测方法，及其在有产品时重复促生长能力进行全面调查。
• your latest plans for performing microbial testing (which was suspended during the inspection).  
• 你们实施（在检查中被搁置的）微生物检测的最新计划。
  

5.    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))

贵公司未能确保化验室记录，包括从所有确保符合既定质量标准所需的检测中产生的完整数据。(21 CFR 211.194(a))

Our investigators observed colony counts for environmental and personnel monitoring that did not match your official records. For example, one contact plate from a Grade B area had a reported result of (b)(4) CFU, but our investigator counted (b)(4) CFUs on the plate. Five other plates had reported results of (b)(4) CFU, although our investigator counted(b)(4) CFU on each plate.

我们的调查人员发现环境和人员监测中微生物计数不符合你们正式的记录。例如，一个B级区接触碟报告结果为XXCFU，但我们调查人员对碟中计数结果为YYCFU。5个其它碟报告结果为XXCFU，但我们调查人员对每个碟计数为YYCFU。

Inaccurate reporting of environmental and personnel monitoring data undermines your ability to evaluate and maintain a state of control in your aseptic processing operation.

环境和人员监测数据报告不准确，削弱了你们评估和维护你们无菌工艺操作状态的能力。

6.    Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records. (21 CFR 211.68(b))

贵公司未能对计算机或相关系统实施适当的控制以确保只有经过授权的人员才可以对主生产和检验记录和其它记录进行修改。(21 CFR 211.68(b))

Your stand-alone computer systems lacked controls, such as routine audit trail review and full data retention, to prevent analysts from deleting data. Although you implemented a procedure to begin reviewing audit trails of your high performance liquid chromatography (HPLC) Empower system on January 11, 2016, you had not performed any reviews prior to our inspection. Furthermore, the procedure you implemented on January 11 required (b)(4) random audit trail review (b)(4).

你们的独立计算机系统缺乏控制，例如日常审计追踪审核和全面数据保留，以防止化验员删除数据。虽然你们实施了一个程序，对你们的HPLC上EMPOWER系统从2016年1月11日开始审核审计追踪，你们在我们检查之前都没有做过任何审核。另外，你们从1月11日开始实施的程序要求对审核追踪进行随机审核。

We acknowledge your commitment to strengthening your procedures to assure user access restrictions and implement audit trails for computerized systems. However, simply activating audit trail functions and instituting user controls are insufficient to correct the data integrity problems observed at your facility and to prevent their recurrence. In response to this letter, provide details of your retrospective review of the HPLC and other laboratory data, such as Fourier transform infrared spectroscopy, gas chromatography, UV spectrophotometry, and (b)(4) analyzer data. Indicate the period covered in your review and your rationale for selecting that timeframe.

我们知晓你们承诺要加强你们的程序，确保用户登录限制，对计算机化系统实施审计追踪。但是，只是简单地激活审计追踪功能，设置用户控制是不足以纠正在你们工厂所发现的数据完整性问题，防止其再次发生的。在回复此函时，请提供你们对HPLC和其它化验室数据的回顾性审核详细信息，例如傅立叶红外光谱、GC、紫外分光光谱和XX分析仪数据。说明你们审核所覆盖的时间段，以及你们选择此时间段的理由。

7.    Your firm failed to follow adequate written procedures for the preparation of master production and control records designed to assure uniformity from batch to batch. (21 CFR 211.186(a))

贵公司未能遵守足够的书面程序，制订主生产和检验记录，用以确保批间一致。(21 CFR 211.186(a))

Our investigators found quality-related documents in a waste bin. Among these documents were an incomplete sterility test data sheet, a form used to track the movement of (b)(4) samples, a media fill incubation card, and others. The incomplete sterility test data sheet had been filled out to track information about a “(b)(4)” sterility check. After an error was observed on the original data sheet, the record was torn and discarded with no written explanation.

我们的调查人员在一个垃圾箱里发现了质量相关文件。在这些文件中有一张不完整的无菌检测数据页、一张用于追踪样品流向的表格、一张培养基灌装培养卡和其它文件。不完整的无菌检测数据页已经填写了部分数据是XX无菌检查的信息。在发现原始数据表上有一个错误之后，有人把记录撕毁并丢弃，没有书面解释。

CGMP Consultant Recommended 建议CGMP顾问

Based upon the nature of the violations we identified at your firm, we strongly recommend that your consultant, who should be qualified as set forth in 21 CFR 211.34, assist your firm in meeting CGMP requirements. Your consultant should provide a thorough assessment of your entire operation to identify contamination hazards, assist in remediation of sterility assurance in your facility, improve your quality system, and certify readiness. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.

根据我们在你们工厂发现的违规情况，我们强烈建议你们应该按21CFR211.34设定的要求进行确认，协助你们公司符合CGMP要求。你们的顾问应对你们整体操作进行彻底评估，识别出污染危险，协助弥补你们设施里的无菌保证，改进你们的质量体系，和准备工作。你们聘用顾问并不减少你们公司符合CGMP的义务。你们公司的高级管理层仍负有全部责任来解决所有缺陷，保证持续CGMP符合性。

Additional Guidance on Aseptic Processing 无菌工艺的其它指南

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing, online athttp://www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf.

参见FDA指南文件“无菌工艺生产的无菌药品---CGMP”，有助于你们在使用无菌工艺生产无菌药品时符合CGMP要求。在线下载地址如上。

Data Integrity Remediation  数据完整性弥补措施

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide the following.

你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。我们知道你们聘请了顾问来审计你们的操作，协助符合FDA要求。在回复此函时，提供以下资料：

A.  A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括：

• A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
• 详细的调查方案和方法学；对评估所覆盖的所有化验室、生产操作和系统的总结，以及对你们意在排除的操作中所有部分的论证。
• Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
• 与现有的和已离职的员工进行面谈，找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
• An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
• 你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。描述你们工厂操作中发现数据完整性问题的所有部分。
• A comprehensive retrospective evaluation of the nature of the data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
• 一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
  

B.  A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.

对你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。

C.  A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:

你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：

• A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.
• 详细的CA计划，描述你们如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。
• A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
• 一份完整的描述你们数据完整性问题的根本原因的描述，包括认定当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
• Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
• 临时描述，描述你们已采取的行动，或即将采取用以保护患者确保你们药品质量的努力，例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。
• Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
• 长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。
• A status report for any of the above activities already underway or completed.
• 对上述活动已开展或已经完成的状态报告。
  

Conclusion

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations in all your facilities.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) 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.

FDA placed your firm on Import Alert 66-40 on May 27, 2016.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.

Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Teva Pharmaceutical Works Private Limited Company, located at 2100 Godollo, Tancsics Mihaly ut 82, Godollo, Hungary, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, 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 FD&C Act, 21 U.S.C. 351(a)(2)(B).

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Lixin (Leo) Xu, M.D., Ph.D.

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3002875215.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Center for Drug Evaluation and Research

来源：Julia