久久医药网
久久医药网
概要：
FDA昨夜公布了其对梯瓦制药分公司制药厂的警告信，该警告信列举了这家药厂的重大缺陷如下：
1、未能充分调查培养基灌装和产品无菌测试失败结果。如，未受污染样品中的微生物进行鉴别、未能彻底调查无菌测试阳性结果和没有确定在同一生产线生产的其他批次是否受到影响。
2.在该厂的监控录像记录中发现无菌操作不规范。如：
（1）操作员将笔直接穿越胶塞斗上方拿给另一个操作员。
（2）操作员坐在洁净室的地板上，并且在站起来后没有更换洁净衣。
（3）操作员靠在洁净室的墙上。
（4）长时间打开RABS(b)(4)，甚至在人员离开时仍然没有关闭。
3、培养基灌装过程中出现机器故障而将已分装的样品剔除没有培养，并且培养基灌装被宣布无效而没有充分的论证。
4、未能建立一个适当的系统来监测无菌加工区域的环境条件。
5、无菌检查时，阳性对照样品没有生长没有进行进行调查。
6、检察人员核对了其环境和人员监测菌落计数数量与样品实际菌落数量，其结果不相符。
7、HPLC审计追踪没有审核。
8、检查员在一个垃圾箱发现与质量相关的文件。在这些文件中有一份不完整的无菌测试记录,一张培养基灌装培养卡，和其他文件。在原始数据表发现一个错误后,记录在没有书面解释的情况下被撕毁和丢弃。
该公司已被FDA于2016年5月27日发布66-40项下进口禁令。
这封警告信说描述的详细缺陷如下：
Warning Letter 320-17-01
Return Receipt Requested
October 13, 2016
Mr. Erez Vigodman
President & CEO
Teva Pharmaceutical Works Pvt. Ltd.
梯瓦制药分公司制药厂
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 21CFR, 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被认定为掺假。
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 limitedto, 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)
贵公司未能彻底调查已销售和未销售的批产品或其组分任何不明原因的差异或不符合其质量标准。(21 CFR 211.192)
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.
未能充分调查培养基灌装和无菌测试失败。这些失败表明生产设施缺乏足够的无菌保障能力。
a.Media Fills
培养基罐装
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.
未能充分调查无菌生产线培养基灌装的污染。例如,2015年9月14-16进行的培养基灌装第 (b)(4)run, 在(b)(4) 密闭式限制进入隔离系统（RABS）小容量注射剂生产线有31个样品阳性。此外,贵厂其他线的培养基灌装也有一个或多个阳性样品。
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中的污染归因于不同操作者的无菌操作技术违规。 认为是与装配,灌装,灌装储罐的更换等相关的各种违规操作。但是,你的调查不够充分。例如,你们未能对已发现的受污染样品中的微生物进行鉴别。你们有必要确定培养基灌装样品中的微生物信息，以便充分掌握潜在的污染源和污染范围。
Any contamination in a media fill run indicates a potentially significant sterility assurance problem and should be thoroughly investigated.
培养基灌装测试中出现的任何污染表明存在潜在的重大的无菌保障问题,应该进行彻底调查。
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.
你们也未能彻底调查无菌测试阳性结果。例如,你们对(b)(4)注射剂((b)(4)批无菌测试失败的调查没有充分评估无菌生产操作导致无菌失败的危害。你也没有确定在同一生产线生产的其他批次是否受到影响。
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.
另外,你宣布多个批放行测试中得到的无菌测试阳性结果为无效。然而,我们注意到贵公司使用无菌测试(b)(4)以及无菌试剂盒，外来污染导致假阳性的可能性是很低的。
Your response is inadequate. In response to this letter, provide the following information:
你们的答复是不充分的。回复此函请提供以下信息:
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.
一份对自2014年1月起的所有无菌阳性和培养基灌装失败调查的全面审查，以重新评估你们的根本原因,纠正措施,结论,以及缺乏无菌工艺控制对市售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.
修订的培养基灌装污染调查标准操作程序(SOP)，包括但不限于每个污染样品的微生物鉴别,彻底调查可能原因，以及适当的纠正措施以防止污染。
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，包括但不限于全面评估潜在的生产过程根本原因，制定防止污染措施，确保只有在确实可归结的实验室根本原因找到时才可以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.
一份关于售往美国的效期内的所有批次产品的无菌生产过程的视频的回顾性评价，以确定无菌保障能力不足带来的污染危害。同时，回顾与(b)(4)注射剂无菌失败相关的生产活动视频，以便识别该批污染来源。
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.
一份关于你们的设施,设备,和工艺的充分性的彻底评估。确定与设计、控制和维护相关的失效模式。包括一份全面的纠正预防措施(CAPA)计划，充分识别在整个操作过程中的微生物污染风险，并确定改进
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循适当的书面程序来防止无菌药品的微生物污染，包括所有无菌和灭菌工艺的验证。
a.Poor Aseptic Behavior
无菌操作不规范
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):
检查期间，我们的检查员发现了无菌工艺技术方面的不足，这些不足录制在贵厂以前录制的录像里面。例如，在2015-09-08和2015-09-09的录像中，在无菌注射药品的装配和分装过程中存在如下问题：
an operator passing a pen directly over the stopper bowl to another operator.
一个操作员将笔直接穿越胶塞斗上方拿给另一个操作员
an operator sitting on the clean room floor during set-up of the filling line and not changing the gown after standing up.
在装配分装线过程中，一个操作员坐在洁净室的地板上，并且在站起来后没有更换洁净衣。
operators leaning against the cleanroom walls.
操作员靠在洁净室的墙上。
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.
在分装线装配过程中，一个操作员长时间打开RABS (b)(4)，甚至在其不在该区域操作的时候仍然没有关闭。
Your response is inadequate. In response to this letter, provide the following:
你们的回复是不充分的。回复此函，请提供如下：
a risk assessment of the poor aseptic techniques observed during the inspection.
一份对在检查期间发现的关于无菌技术方面的缺陷的风险评估。
a broader evaluation of any additional aseptic technique breaches that have occurred in your operation (e.g., through review of videos).
一份对发生在你们的操作中的任何无菌技术方面的其他违规的更广泛的评估。
updated information to demonstrate that each of your aseptic processing lines is in a state of control.
更新你们每一条无菌加工线处于受控状态的证明性信息。
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.
除了加强你们的无菌加工操作的设计，描述你们将如何改善员工技能、监督日常的操作，以及其他方面的控制。
b.Mechanical Failure During Media Fill
培养基灌装过程中出现机器故障处理不当
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.
贵公司在培养基灌装过程中由于机器故障或其它原因剔除了许多完整的瓶子而没有适当的论证。 例如，培养基灌装批次(b)(4)由于传送带电机故障中止。尽管已经分装了3696瓶完整的样品，这些样品没有被培养，并且培养基灌装被宣布无效而没有充分的论证。贵公司表明在商业生产时这种情况下是会将产品作为一个小批放行的。
You also did not have a procedure describing production and disposition practices after such a mechanical failure.
你们也没有规程描述在遇到这种机器故障后的生产和处理措施。
3.Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas. (21 CFR 211.42(c)(10)(iv))
贵公司未能建立一个适当的系统来监测无菌加工区域的环境条件。
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含微生物警戒和行动限。根据SOP，在分装、装机和企图无菌操作过程中人员进行关键干预的A级区域，双手不高于(b)(4)CFU是允许的。在B级区域，即分装、过滤、轧盖及更衣室，双手不高于(b)(4)CFU是允许的。并且还有(b)(4)CFU的警戒限。
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.
然而，当我们的检查员看到操作人员进行本应该在A级条件下保护的活动（手在开放式RABS里面操作并在层流下保护）时，贵公司的官员说这些操作员是符合B级的。另外，贵公司未能解释在A级进行干预的操作员，其(b)(4)上允许(b)(4)CFU而未进行任何潜在的跟进的合理性。这种情况会引发警戒或行动条件，至少，应该导致趋势分析，可能需要进一步调查。
In response to this letter, provide a comprehensive retrospective reviewand risk assessment of personnel and environmental monitoring data sinceJanuary 1, 2015. In addition, describe how future monitoring will be conductedin different classified aseptic processing areas to ensure that action andalert levels are commensurate with the operations being performed in thespecified 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 controlsthat include scientifically sound and appropriate specifications, standards,sampling plans, and test procedures designed to assure that components, drugproduct containers, closures, in-process materials, labeling, and drug productsconform 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 meetacceptance criteria for sterility testing. Specifically, a positive controlsample 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 ofmedia to support growth. Unsuitable sterility test methods increase theprobability that your quality control test will not detect a non-sterileproduct.
你们对 (b)(4) 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 (b)(4) 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。
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))
贵公司未能确保实验室记录包含来源于所有确保符合符合既定规格和质量标准的测试的完整数据。(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菌落计数与正式记录不匹配。例如,一个B级区的接触皿报告结果为(B)(4)CFU,但是与我们的调查员数的接触皿上(B)(4)的CFU数不符。其他五个接触皿报告结果为(b)(4)CFU,但是与我们的检查员数的(b)(4) CFU不符。
Inaccurate reporting of environmental and personnel monitoring data undermines your ability to evaluate and maintain a state of control in your aseptic processing operation.
报告环境和人员监测数据不准确，会削弱你们评估和维持无菌工艺操作中的控制状态的能力。
6.Your firm failed to exercise appropriate controlsover computer or related systems to assure that only authorized personnelinstitute 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 audittrail review and full data retention, to prevent analysts from deleting data.Although you implemented a procedure to begin reviewing audit trails of yourhigh 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 audittrail 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 assureuser access restrictions and implement audit trails for computerized systems.However, simply activating audit trail functions and instituting user controlsare insufficient to correct the data integrity problems observed at yourfacility and to prevent their recurrence. In response to this letter, providedetails of your retrospective review of the HPLC and other laboratory data,such as Fourier transform infrared spectroscopy, gas chromatography, UVspectrophotometry, and (b)(4) analyzer data. Indicate the period coveredin 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))
贵公司未能遵守充分的书面程序来准备主生产记录和控制记录，用以确保批间一致性。(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.
我们的检查员在一个垃圾箱发现与质量相关的文件。在这些文件中有一份不完整的无菌测试记录（一个用来跟踪(b)(4)样品的流向的表格）, 一张培养基灌装培养卡，和其他文件。这份不完整的无菌测试数据表已经填写了“(b)(4)”无菌检查的跟踪信息。在原始数据表发现一个错误后, 记录在没有书面解释的情况下被撕毁和丢弃。
