FDA警告信（吉林XXX公司）中英文对照

巴西木

FDA警告信（吉林XXX公司）中英文对照

--------来自天道酬勤

Warning Letter
警告信

Dear Mr. Li:
During our August 24-28, 2009 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Jilin Shulan Synthetic Pharmaceutical Co., Ltd. located at No. 2066 Peoples Main Road, Shulan City, Jilin Province, People’s Republic of China (PRC) 132600, an investigator from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of 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.
We have reviewed your firm’s response of October 12, 2009, and note that it lacks sufficient corrective actions.

李先生，你好！

2009年8月24日至8月28日，FDA对吉林舒兰合成药业股份有限公司（地址位于吉林省舒兰市人民大路2066号）原料药厂房的检查过程中，检查员发现了有显著违反 APIcGMP的偏差。根据501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)]的规定，这些偏差导致你们的API被视为掺假药品。

我们已经审核了你们公司2009年10月12日的回复，并注明了回复内容缺少足够的纠正措施。
Specific deviations observed during the inspection include, but are not limited, to the following:
检查中发现的具体缺陷包括，但不限于以下内容：
1.    Production personnel fail to ensure that all production deviations are reported and evaluated, and that critical deviations are investigated and the conclusions are recorded.
生产人员未能确保所有的生产偏差被报告和评估了，且不能保证所有的关键偏差得到了调查，且结论也报告了。
For example, during the (b)(4) of (b)(4) sub-batch (b)(4), our investigator observed that the pressure and temperature of the (b)(4) equipment fell out of range (below (b)(4) mPa and (b)(4)°C). The investigator observed no initiation of an investigation into this deviation and received no assurance that an investigation would take place. Any deviations from processing parameters should be documented and explained, whereas critical deviations should be thoroughly investigated.
例如：在一份子生产（实施的）记录中，检查人员发现所使用的一台设备的工作压力及温度均超出既定的范围（低于XXXmPa和XXX°C），同时发现对此偏差未启动偏差调查，回复中也未保证将进行调查。对于关键偏差应进行彻底调查，生产参数的任何偏差都应记录并说明，
In addition, the investigator observed a shift change while sub-batch (b)(4) was undergoing (b)(4), in which operators from the new shift had not reported to their duty stations for more than 30 minutes after their shift began. You should have adequate systems in place to ensure that critical operations are witnessed, or are subjected to another appropriate control.
另外，检查人员发现在批次XXX的生产还在进行过程中，交接班后新班次的操作人员在本班次开始工作后超过30分钟还未报告其已到岗。你们应有适当的系统来确保关键操作是得到证实的（受控的），或者有其他方面合适的控制。
2.    Master production records do not include complete production instructions.
主生产记录未包括完整的生产操作说明
Your master production records do not include all steps in the production of (b)(4) and your batch production records are not accurate reproductions of your master production records. The master production record does not include the (b)(4) stage of the (b)(4) production.
你们的主生产记录未包括生产过程中的全部步骤，批生产记录未准确复制主生产记录的内容。主生产记录未包括生产的xx步骤。
Your October 12, 2009 response states you will revise your DMF for (b)(4) USP to include the information regarding (b)(4) treatment and the manufacturing of  (b)(4). However, you provide no evidence to show that these steps have been included in your master batch records. We are also concerned that you did not comprehensively evaluate the manufacturing process, for this and other drugs, in its entirety to ensure that all steps are included in your master batch records and your DMF. Adequate batch records are a critical part of a manufacturing operation because they provide confidence that the established procedures were followed, processes were controlled, and quality API was manufactured.
你们于2009年10月12日回复说你们将修订DMF文件，将涉及的xx处理及其生产操作纳入其中。但你并没有提供证据说明已将这些步骤纳入你们的主生产记录中。我们也很关注你们并未对该药物及其他药物的生产过程进行全面的评估，以确保所有的步骤都包含在主批记录和DMF文件中。作为生产操作的关键部分，完善的批记录能够证明生产操作是按照既定程序进行并是受控的，以生产出符合质量的API。
In addition, there is no assurance that the (b)(4) obtained from the (b)(4) recovering steps included in your current process is of adequate quality. Please provide information on studies performed to characterize the (b)(4) obtained from this part of the process.
另外，你们无法保证在现行工序中回收步骤得到的(b)(4)的质量。请提供所做的研究资料，对由此工艺获得的产品的特性进行阐明。
3.    The buildings and facilities used in the manufacture of (b)(4) USP are not designed and constructed to facilitate cleaning, maintenance, and operations as appropriate to the stage of manufacture. Facilities are not designed to minimize potential contamination.
生产厂房和设施的设计与建造不利于清洁、维护、生产操作。厂房未设计成可以减少潜在污染的发生。

Your facility consists of surfaces that are not easy to clean and can potentially lead to product contamination. In (b)(4) your “ Clean Room” our investigator observed peeling foil-faced tape, which was used to seal wall and ceiling joints. Our investigator observed accumulated debris within wall and floor joints throughout your (b)(4) USP production facility. You used adhesive tape around hoses in the (b)(4) and (b)(4) rooms that became covered in production material. The (b)(4) routinely spills onto the floor of the (b)(4) rooms, causing the undersurfaces of your (b)(4) to become rusty and caked with production materials. The investigator also observed (b)(4) accumulation on the rusty stairs in the (b)(4) room. When your personnel cleaned the (b)(4) area in response to our investigator’s comments regarding caked material on the underside of the (b)(4) your personnel used mops soaked in dirty water. Your October 12, 2009 response includes some corrective actions concerning the noted deficiencies that make your facility difficult to clean, but we are concerned that you have only addressed items specifically pointed out by our investigator during the inspection. We request that you fully evaluate your current cleaning procedures. You should also thoroughly assess the adequacy of your facility design to facilitate cleaning and minimize potential contamination, as well as the training provided to your employees on appropriate cleaning procedures and to ensure CGMP.
设施的表面不易清洁，这会对产品造成潜在的污染。检查人员在洁净区发现了脱落的铝箔面胶带，该胶带是用于密封墙壁和天花板之间缝隙的，在墙壁与地板的链接处发现了积累的废弃物。你们用胶带缠绕管道，使得其表面布满了生产原料。长期洒落在地板上的生产物料使得地板生锈，出现斑点。检察官还发现(b)(4)房间的楼梯布满了锈迹。当你们的员工根据检查官的意见，对(b)(4)下面的物料斑点进行清洁时，其所使用的拖把是在脏水中浸泡的。在2009.10.12的回复中，你们对这一使得你们的设施不易清洁的严重缺陷采取了一些正确的整改措施，但我们注意到你们只是对我们在审计中指出的具体问题进行了处理。我们要求你们对现行的清洁程序进行全面评估。你们应对设施的设计有利于清洁，有利将潜在的污染减少到最低的充分性进行仔细评估，同时就合适的清洁程序对你们的员工进行培训，以确保符合CGMP的要求。
You continued to use the (b)(4) in the (b)(4) area, although approximately 5% of the (b)(4) cover was peeling due to rust. You state in your October 12, 2009 response that you repaired the deteriorated cover of this (b)(4) and that your corrective action plan includes a recheck of all production equipment, and the strengthening of the check and maintenance for equipment in the future. However, you provide no information regarding what other equipment was identified as needing repair, the repairs conducted, or supporting documentation to show that your preventive maintenance program was improved.
尽管(b)(4)有近乎5%的表面因生锈而脱落，但你们仍然使用处于(b)(4)区域的(b)(4)。你在2009.10.12的回复中解释说你门修复了(b)(4)的表面，制定了一个包括重新检查所有设备的正确的维护计划，以加强以后对设备的检查与维护。然而，你们未能提供哪些设备需要修复以及是否修复的信息，也没有文件证明你们的预防维护计划得到了提高。
Our investigator observed (b)(4) uncovered carts containing approximately (b)(4) in the corridor adjoining production areas. You state in your October 12, 2009 response that all in-process (b)(4) contained in the carts should be covered and stored in their dedicated room during their temporary storage period. However, you have not provided updated procedures implementing this new requirement, or training documentation to ensure all pertinent personnel were trained in this procedure.
检查官在邻近生产区域的走廊上发现了可能存放有(b)(4)的未覆盖的容器。你在2009.10.12的回复中解释说，使用中的(b)(4)，在其临时储存期间，都应放置在密封的容器中，并存放在其专门的房间。然而你未提供最新的程序来落实这一新的要求，并培训这一文件以确保所有相关的人员都接受了培训。
In addition, you provided no information regarding the disposition of the (b)(4), observed uncovered in the corridor adjoining production areas during the inspection.
另外，你们未提供对于检查中发现的放置在与生产区域邻近走廊上的未密封的(b)(4)，你们是如何处置的具体信息。
The investigator also observed that doors leading to corridors and adjoining rooms throughout the “(b)(4)  Clean Room” building (including the (b)(4) room) failed to close properly during production. You indicate in your October 12, 2009 response that all doors would be checked and repaired if necessary. However, we are concerned that you have not addressed the failure of your personnel to identify this and other deficiencies, nor have you identified a mechanism through which future problems will be reported and addressed.
检查官发现洁净区内走廊与邻近房间之间的门在生产期间无法彻底的关闭。你在2009.10.12的回复中说你们会根据需要对所有的门进行检查机维修。然而，我们注意到，你们既没有处理员工未能识别这种及其他缺陷的问题，也未建立一个报告并处理以后问题的机制。
4.    Your Quality Unit failed to reject APIs contaminated with foreign material.
你们的质量部门未拒收被异物污染的API
For example, (b)(4) lot numbers (b)(4) were reprocessed after the breakage of an overhead light. These lots were retested and renumbered as (b)(4), respectively.
例如：顶灯破碎之后，批号为(b)(4)的(b)(4)被返工。这些批号分别被重新检测并重新编为批号(b)(4)
We are concerned that you did not reject the two lots once they became contaminated with glass and other material associated with the broken overhead light. Please provide your rationale for reprocessing these batches and explain what steps you took to ensure these final API lots, and other lots produced in the same equipment, were not contaminated with foreign material from the broken light. In addition, we request that you provide a detailed description of the corrective actions you implemented to prevent future recurrence of this type of incident.
我们发现你们未拒收曾被玻璃及其他与顶灯破碎有关物质污染的两个批号的产品。请解释你们返工这些批次的原因，并说明你们采取了什么措施来确保这些最终的API批次及其他利用该设备生产的批次未被来自于顶灯破碎的异物所污染。同时，我们要求你们提供你们为预防这类事故重复发生的详细的纠偏措施。
We note that your firm performs maintenance operations at the same time that production activities are occurring. Please be advised that this is an inappropriate practice.
我们注意到你们公司在生产的同时进行维护操作。请注意，这样做是不合适的。
You also identified black spots in the (b)(4) API lot number (b)(4). Your deviation states, “Operators shake off the floating material on the (b)(4) into the materials.” Please provide an explanation for what is meant by this statement. It is unclear if you have identified the source of these “black spots,” but you reprocessed this lot and identified it as (b)(4). Please provide your investigation regarding the identity of this contamination and your rationale for reprocessing this batch.
你们在批号为(b)(4)的(b)(4)API中发现了黑点，偏差调查声明是操作人员将(b)(4)上不固定的材质抖落到物料中。请你们解释这种声明的具体含义。你们在不清楚的确认黑点来源的情况下就对该批API进行了返工，并就认定其为(b)(4)。请提供有关确认该污染的调查报告及返工该批的依据。
Also, please provide us with your procedures for placing reprocessed batches on stability and inform us if your firm placed these and other batches on stability.
同时，请你们提供返工批次的稳定性考察的程序，并告知我们你公司是否对这些及其他批进行了稳定性试验。
5.    You lack scientifically sound and appropriate test procedures to ensure APIs conform to established standards of quality and/or purity.
你们缺少科学正确及恰当的检测程序以确保API符合既定的质量或纯度标准
For example, you routinely failed to utilize a suitable standard for the spectral comparison during the FTIR testing of (b)(4) Instead, you compared sample spectra with the spectrum of (b)(4) in the Chinese Pharmacopeia. The  USP requires that you compare the spectrum of your test sample with that of your reference standard. Your October 12, 2009 response states that you have strengthened laboratory management and made it a requirement to compare the spectrum from every batch to the spectrum obtained from the reference substance in routine testing. However, you provide no details as to how you strengthened laboratory management, and you include no updated procedures requiring the comparison of the sample spectrum to that of the reference standard. You also provide no documentation to show adequate training of your personnel in the new testing procedures.
例如：在红外检测中，你们一直未使用合适的标准对照图谱。你们将样品图谱与中国药典中的图谱进行对照。USP要求将样品图谱与对照品进行对照。在2009.10.12的回复中，你们声明已经加强了实验室的管理，并要求在日常的检测中将每批次的图谱都与对照品图谱进行对照。然而，你们未提供加强实验室管理的具体细节，也未提供要求将样品图谱与引用的标准图谱进行对照的最新的程序，也未提供就新的检测程序对员工进行充分培训的证明性文件（培训记录）
You failed to include testing for method precision and ruggedness in your HPLC Assay Method Validation SHY1110-004-00-2 for (b)(4) USP. We are concerned that you have not established the degree of reproducibility or repeatability of the analytical procedure under normal operating conditions. In addition, you failed to establish adequate system suitability parameters to ensure that the complete testing system (including instrument, reagents, columns, and analysts) continues to operate suitably for the intended application. You currently only use one standard injection for system suitability, which is unacceptable.
对于(b)(4) USP 的HPLC含量测定分析方法验证（SHY1110-004-002）中，你们未对方法的精密度及耐用性进行验证。我们注意到你们未确认正常操作条件下该分析方法的重现性或重复性。同时，未建立合适的系统适用性参数（包括仪器、试剂、色谱柱、分析员）以确保整个检测系统持续地适用于指定用途。目前，你们仅进一针标准溶液作为系统适用性，这是不能接受的。
In addition, you evaluate the HPLC signal to noise ratio and analyze the baseline for drift annually. Your October 12, 2009 response indicates that you revised the Standard Operating Procedure (SOP) for calibration of the HPLC to increase the frequency of these determinations to every (b)(4) months. Our concern is that you may not be evaluating the signal to noise ratio during system suitability. Evaluation of the signal to noise ratio during system suitability is a normal laboratory practice when testing low level impurities or degradant content by HPLC. Furthermore, you only compare the working standards to the (b)(4) USP reference standard annually. Please provide your scientific rationale and stability assessment of the working standard solution to justify performing the verification of the suitability of the working standard annually.
另外，你们对HPLC的信噪比及分析基线的漂移每年仅进行一次评估。2009.10.12的回复中，你声明你们修订了HPLC校验的SOP，增加了校验的频率，每(b)(4)月校验一次。我们注意到在系统适用性中你们可能未评估信噪比。当使用HPLC检测少量的杂质或降解物时，评估系统适用性中的信噪比是一种常规的实验操作，此外，工作标准品与USP标准品，每年只对照一次。请提供科学合理说明以及工作标准溶液的稳定性评估，以说明对工作标准溶液的适用性每年做一次确认是合理的。

6.    Personnel fail to wear clothing suitable for the manufacturing activity with which they are involved to protect (b)(4) USP from contamination.
员工未穿着适合生产操作的服装，以防止(b)(4) USP受到污染。
During this inspection, the investigator observed individuals in the “ (b)(4) Clean Area” (including (b)(4) areas) with open toe or open foot sandals, torn plastic booties, wearing no masks, and wearing no gloves. We are concerned that you have not assessed the adequacy of these practices during drug manufacturing operations, particularly during the latter steps of (b)(4) USP manufacturing. Your October 12, 2009 response states that the Standard Operating Procedure (SOP) for “Clean area management Procedures for Personnel Passing In and Out” was updated to stipulate that all visitors and personnel operating in the clean area should wear gloves, masks, and white shoes, instead of slippers. However, you have not provided this SOP in your response, nor have you provided any documentation indicating that the appropriate personnel have been trained on this updated SOP.
检察官在审计时发现，(b)(4)洁净区（(包括b)(4)区域）的多个人员穿着露脚趾或脚的拖鞋、破损的塑料 、未带口罩和手套。我们担心你们未对药品生产操作中，特别是(b)(4) USP生产的后续步骤中的这些行为的适用性进行评估。在2009.10.12的回复中，你们声明修订了关于“人员进出洁净区的管理程序”的SOP，明确了所有参观者及在洁净区操作的员工都应穿戴手套、口罩、白色的鞋子替代拖鞋。然而，你在回复中既未提供该SOP，也未提供表明相关人员已接受该新SOP培训的培训记录。
7.    Your Quality Unit fails to ensure that new and modified equipment used in the manufacture of (b)(4) USP are qualified and suitable for their intended use.
质量部门不能确保用于(b)(4) USP生产的新设备或调整过的设备是被确认过的且适合其预期用途的
During the inspection, our investigator observed (b)(4), used in the production of (b)(4) USP, operated by low, high, stop, and reset buttons. Your practice of listening to the (b)(4) in order to detect problems while in operation is not adequate. Also, you failed to perform equipment calibration for this equipment. Your October 12, 2009 response states that you installed calibrated display devices for the rotational speed of the (b)(4) but you failed to demonstrate that the (b)(4) and the designated rotational speeds are suitable for their intended use. Please provide the qualification documentation for your (b)(4) in your response.
检察官在审计中发现，用于(b)(4) USP生产(b)(4) 是通过低、高、停止、重启按钮来操作的。你们利用聆听(b)(4)的声音来察觉运行中的问题是不充分的。同时，你们未对该设备进行校验。2009.10.12的回复中，你声明你们安装了转速的校验过的显示装置，但你未说明(b)(4)及指定的转速符合其预期用途。请在你的回复中提供关于(b)(4)的确认文件
You have not qualified the (b)(4) used in your (b)(4) process. There is no description of the detectable (b)(4) sizes, or feed speed in your procedures. Furthermore, your (b)(4) procedures in SOP 1308-062 “ (b)(4) Finished Product Finished Position SOP” state: “When (b)(4) rings, operator should stop feeding material and check the material once again. If no abnormal situation is found, the material can pass, but if the (b)(4) rings again, the questioned material will be kept alone and treat as unqualified product.” This practice is unacceptable. Material that causes your (b)(4) to sound should not be deemed acceptable material once it is passed through the (b)(4) a second time. Please indicate how you intend to address this issue.
你未对(b)(4)工序中使用的(b)(4)进行确认。在程序中未见有对可检测的(b)(4)尺寸或加料速度的描述。此外，你们在(b)(4)程序SOP1308-062“(b)(4)成品生产结束SOP”中称“当(b)(4)响起，操作人员应停止加料，并再次检查物料，若未发现异常情况，可继续加料，如果声音再次响起，则该问题物料将单独存放，并作为不合格品处理。”这种操作是不能被接受的。引起(b)(4)响声的物料在其第二次通过(b)(4)是不应被认为是可以接受的。请声明你们将如何处理这一问题。
During the inspection, the investigator observed a rusted balance and counterweight in the (b)(4) area that appeared to be unusable. These pieces of equipment are used to weigh reagents, including (b)(4). During the inspection, you painted over the rust on both the balance and the counterweight, but there continues to be no assurance that either is suitable for use in its current condition. In addition, the operational range of the scale is (b)(4), whereas your production records indicate that the balance is used to weigh (b)(4) of (b)(4). Production equipment should only be used within its qualified operating range.
审计中，检察官发现在(b)(4)区域放置有看起来不能使用的生锈的天平及砝码。这些仪器部件是称量试剂用的，包括(b)(4)。检查中，你们在该天平及砝码上刷了油漆，但这不能持续保证它们适用于现行的环境条件。另外，其称量范围是(b)(4)，但你的操作记录表明该天平用于称量(b)(4)的(b)(4)。生产设备应只能在其确定的操作范围内使用。
8.    Your Quality Unit does not maintain revision histories and, therefore, fails to control the issuance, revision, and withdrawal of all documents.
质量部门未保留修订历史，未控制所有文件的发放、修订、撤销。
For example, standard operating procedures (SOPs) and batch records do not include version numbers or effective dates. Your lack of document control can lead to the use of outdated procedures or work instructions. Your October 12, 2009 response states that you have revised all your SOPs to provide version control numbers, but we are concerned with the APIs that were previously manufactured under uncontrolled procedures. You provide no information regarding which SOPs and batch records were not previously identified with version control numbers, nor did you provide an example of your master batch records for (b)(4) USP, including the version control number. In addition, you fail to address your general approach to document control. Please provide the procedures and associated training you have in place to ensure that revision histories will be maintained, and that only the most current documents will be available for use.
例如：SOPs及批记录无版本号或生效日期。缺少对文件的控制会导致使用过期的程序或说明。2009.10.12的回复，你声明你们已经修订了所有的SOPs,增加了其版本的控制号，但我们关注的是之前利用未控制的程序生产的API。
你们既没有提供哪些SOPs及批记录在之前未经版本控制号确定的详细信息，也没有提供一个包含有版本控制号的(b)(4)的主批记录。另外，你未说明文件控制的常规方式。请提供相关的程序及培训以确保修订历史被保存，以及确保只有最新的文件才能使用。
During this inspection, you indicated to our investigator that your firm has only shipped (b)(4) to the United States for use in (b)(4), and that you have not shipped product to the United States for use in pharmaceutical products. However, our records indicate that you have distributed (b)(4) USP, as well as (b)(4) USP and (b)(4) USP, to the United States for use in pharmaceutical products. In future correspondence please include clarification on this issue.
审计中，你们告诉检察官你公司仅向销售美国用于的(b)(4)生产的(b)(4)，而未向美国销售用于用于制剂生产的产品。然而，我们的记录表明你们曾向美国销售用于制剂生产的(b)(4)及(b)(4)和(b)(4)。下次来信请就这一问题进行说明。

冰城

警告内容挺严厉了，交叉污染、设施维护不到位、操作人员不在岗、偏差预防措施不到位，都是严重问题了。

幻影

检察官在审计时发现，(b)(4)洁净区（(包括b)(4)区域）的多个人员穿着露脚趾或脚的拖鞋、破损的塑料 、未带口罩和手套。

管理水平可见一斑。

JL052

又见FDA 警告信                                   

宝丽金

FDA官员在吐槽啊，觉得他中间两段吐得略感爽快呢。最后一段有点这么个意思-嘿，还想撒谎，看吧，被我抓住小辫子了吧，下次给我老实点！

一沙一叶

宝丽金 发表于 2014-5-8 16:05
FDA官员在吐槽啊，觉得他中间两段吐得略感爽快呢。最后一段有点这么个意思-嘿，还想撒谎，看吧，被我抓住小 ...

点评很透彻

依凡

一手资料啊！{:soso_e102:}

wangcy200808

彩板缝隙打胶脱落，包裹的管道外壁堆积物料粉尘，掉落的粉尘腐蚀地面，设施表面不易清洁。洁净区人员穿的鞋露脚趾、不带口罩与赤手等这么多问题。感觉这家公司也不怎么样啊，怎么通过的FDA认证呢？

WLQZLL

谢谢楼主分享，学习了！

红叶舞秋山

谢谢分享啊