FDA对北京太洋药业发出警告信 (拒绝FDA进行检查牛！)

Your Preferred Partner to Compliance

October 19, 2016

Mr. Qi Hai Liang

Vice General Manager

Beijing Taiyang Pharmaceutical Industry Co., Ltd.

No. 1 Shuang Qiao East Road, Chaoyang District

Beijing, 100121

China

Dear Mr. Liang:

The U.S. Food and Drug Administration (FDA) arrived at your drug manufacturing facility, Beijing Taiyang Pharmaceutical Industry Co., Ltd., located at No. 1 Shuang Qiao East Road, Chaoyang District, Beijing, on November 16, 2015, to conduct an inspection.

FDA在2015年11月16日检查了你们在北京朝阳的生产场所。

Our investigators documented that your firm limited and/or refused an FDA inspection. Under the Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA), section 707, 21 U.S.C. 351(j), your drugs are adulterated in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and refused inspection.

我们调查人员记录下了你们公司限制和/或拒绝FDA检查。根据FDCA及修正案第707.21U.S.C.351（j），你们的药品被认为是掺假药，因为你们的药品生产、加工、包装或保存所用的场所的所有者或操作人员限制或拒绝检查。

Our investigators also documented that your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to current good manufacturing practice (CGMP). Accordingly, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

我们的调查人员还记录下了你们生产、加工、包装或保存所用方法、设施或控制不符合CGMP。因此你们的药品根据联邦食品药品和化妆品法案21 U.S.C. 351(a)(2)(B)第501(a)(2)(B)条被认为是假药。

We reviewed your firm’s December 9, 2015, response in detail.

我们已经详细审核了你们于2015年12月9日给出的回复，也收到了之后的回复。

This letter summarizes your limitation of an inspection and significant deviations from CGMP for active pharmaceutical ingredients (API). Our investigators observed specific deviations including, but not limited to, the following.

我们的调查员在检查中发现了一些问题，包括但不仅限于以下：

1. Your firm delayed, denied, or limited an inspection, or refused to permit the FDA inspection.

贵公司延误、拒绝或限制检查，或不允许FDA进行检查。

On November 16, 2015, our investigators observed through a window a warehouse containing numerous drums bearing your company’s label. When our investigators requested access to this warehouse, you barred them from entering the warehouse to examine the containers or the material in them without giving a reasonable explanation.

在2015年11月16日，我们的调查人员从窗外看到一个仓库里放着许多桶，桶上有你们公司的标签。当我们的调查人员要求进去这个仓库时，你们拦住他们不让进去该仓库检查这些桶和桶内的物料，但没有给出合理解释。

The following day, you gave our investigators access to the warehouse. However, upon entry they observed that a significant number of drums had been removed and were not available for inspection. When they asked about the drums they had observed the previous day, you provided no explanation of the whereabouts or contents of the drums.

第二天，你们让调查人员进去了这个仓库，但是，进去后他们发现许多桶已经被移走了，无法查看。当他们询问前一天所看到的桶的情况时，你们没有解释桶的情况及其中的物料。

You delayed FDA’s access to the warehouse and limited FDA’s inspection by removing the drums before our investigators could inspect them.

你们延误了FDA进入仓库，在FDA检查那些桶之前移走了这些桶，从而限制了FDA的检查。

2. Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards.

未能维护从所有为确保符合既定质量标准所实施的化验室检测中产生的完整数据。

Our investigators observed systemic data manipulation across your facility. They documented unexplained deletions of laboratory test results. They discovered that you repeated tests until you obtained acceptable results and that you failed to investigate out-of-specification or otherwise undesirable test results. Your firm relied on these falsified and manipulated test results to support batch release and stability data. Your firm routinely re-tested high performance liquid chromatography (HPLC) samples and deleted previous chromatograms without justification. Your management acknowledged that employees in your quality control laboratory have access, authority, and the ability to delete and repeat HPLC injections when undesirable results were encountered prior to reporting final results.

我们的调查人员在你们整个工厂发现有系统性数据篡改情况。他们记录下了化验室结果没有解释就被删除的情况。他们发现你们重复检测直到获得可接受的结果，你们未对OOS和其它不满意的结果进行调查。你公司依赖这些伪造和篡改的检验结果来支持批放行和稳定性试验数据。你公司通常对HPLC样品进行重复检测，然后删除之前的色谱图，而没有解释。你们的管理层知晓QC里的员工有登录权限，可以在碰到不满意结果时删除和重复HPLC进样，然后再报告最终结果。

Your response states repeated testing was due to quality control operators continuously injecting solvents until a stable baseline was achieved. The response also states the results of repeated tests were deleted to decrease the number of saved chromatograms on your hard drives. Any data created as part of a CGMP record must be evaluated by the quality unit as part of release criteria and maintained for CGMP purposes. In order to exclude data from the release criteria decision-making process, you must have valid, documented, scientific justification for its exclusion.

你们的回复说重复检测是因为QC操作人员持续进样溶剂，直到基线稳定。回复还说重复检测的结果被删除，是为了减少你们硬盘上存贮色谱图的数量。所有作为CGMP记录的一部分创建的数据都必须由质量部门作为放行标准的一部分进行评估，并为了CGMP的目的进行保存。要想从放行标准决策流程中排除数据，你们必须具备有效的记录下的科学论证来支持这种排除。

Reducing the number of records on your hard drives is not a sufficient justification for excluding data. Your response is inadequate because you have not shown how you will correct the data manipulation and falsification practices discussed above, nor have you demonstrated how you will ensure that all CGMP test results are retained and considered by your quality unit as a part of batch release.

减少硬盘上记录的数量并不能充分支持对数据的排除。你们的回复是不充分的，因为你们没有显示出你们要如何来纠正上面讨论的数据篡改和伪造行为，也没有说明你们将如何确保所有CGMP检验结果都被保存，并由你们质量部门作为批放行的一部分考虑。

3. Failure to ensure that all quality-related activities are recorded at the time they are performed.

未能确保所有与质量相关的活动都在其实施时即行记录。

In the production area, our investigators witnessed an employee backdating production batch records for seven batches of (b)(4) (batches (b)(4) to (b)(4)) and transcribing data from a master template record. Furthermore, analysis of the transcribed data for these seven (b)(4) batches and for approximately 40 batches of (b)(4) API, indicated that you did not record data contemporaneously and that missing data was later falsified so the official records would appear complete.

在生产区域，我们的调查人员亲眼看到一位员工倒签7批（批号XX到YY）生产批记录日期，将数据从主模板记录上转抄。还有，对这7批和近40批某原料药的转抄数据进行分析显示你们并没有同步记录数据，然后在后期伪造了缺失的数据，这样让正式记录看起来是完整的。

In the laboratory area, our investigators observed a laboratory analyst attempting to remove a large pile of loose documentation from the HPLC instrumentation room. Upon reviewing the pile of documents, investigators found a significant number of partially completed quality control data worksheets and scratch-paper records containing sample weight values. Our investigators compared these to the official quality control data worksheets and found numerous discrepancies in weights and calculations.

在化验室区域，我们的调查人员发现一名化验员试图从HPLC仪器室拿走一大堆松散的文件记录。在查看了这堆文件后，调查人员发现大量未完整的QC数据记录表，以及有刮擦痕迹的纸质记录，其中有样品重要数值。我们的调查人员将这些记录与正式的QC数据记录表进行了对比，发现许多重量和计算不一致。

Your response indicates that prior to this inspection you were operating without any document controls. You state that you revised procedures to ensure that distribution of all blank batch records and quality control documents would be done by the quality unit, and that controlled documents would now be identified with a “blue stamp.” However, unless the quality unit controls it by appropriate pagination and reconciliation or other appropriate means, a stamp system is insufficient to ensure that data is recorded contemporaneously. Your response also fails to investigate quality control worksheet and production batch record discrepancies to determine whether the data you relied on for drug release decisions was accurate.

你们回复显示在检查之前，你们的操作没有任何文件控制。你们说你们修订了程序，以确保所有空白批记录和QC记录将由质量部门来发放，受控文件现在都盖上了“蓝色章”。但是，如果质量部门仅是使用盖章系统，而没有适当的页码编制和复核或其它适当的方式来控制记录，是不足以确保数据的同步记录的。你们的回复也没有调查QC记录表和生产批记录不一致的情况，来决定你们所依赖做出批放行决策的数据是否准确。

4. Failure to maintain batch production and laboratory control records to determine compliance with established API specifications before a batch is released or distributed.

未能维护批生产和QC记录，在批放行或销售之前决定其是否符合既定的原料药质量标准。

On November 16, 2015, you told our investigators that you had stopped manufacturing (b)(4) API in September 2015. However, during our inspection, our investigators reviewed HPLC and gas chromatogram electronic audit trails that indicated you conducted multiple HPLC and GC analyses on (b)(4) batches of (b)(4) API from November 5 to 6, 2015 (batch numbers (b)(4) to (b)(4)).

在2015年11月16日，你们告诉我们调查人员你们已于2015年9月停止生产某原料药。但在在我们检查期间，我们调查人员审核HPLC和GC电子审计追踪时，记录显示你们在2015年11月5-6日间对该原料药多个批次做了多个HPLC和GC分析（批号XX到YY）。

By your batch numbering system, these batch numbers correspond to batches manufactured in November 2015, two months past the date that you said you ceased production. During the inspection, you could not provide batch production records for these batches, nor did your instrument-use logbooks reflect the testing of these batches. Furthermore, the assay and related substance injection results for these (b)(4) batches had been deleted, according to your laboratory analyst, and could not be produced for review during the inspection.

根据你们的批号给定系统，这些批号对应的批次是在2015年11月生产的，在你们宣称生产停止的日期过后2个月。在检查期间，你们不能提供这些批次的批生产记录，你们也不能提供反映这些批次检测的仪器使用日志。还有，这些批次的含量和有关物质进样结果被删除了，根据你们化验员的说法，在检查期间无法生成供审核。

Your response reiterates that your company did not manufacture (b)(4) API batches with batch numbers of (b)(4)through (b)(4) and the test results that our investigators reviewed and asked about during the inspections were from old samples and tests performed for training purposes. Your response is inadequate because you did not explain how analyses for non-existent batches could be labeled with official unique batch numbers, nor did you explain how your laboratory control system permits the exclusion of analytical results, whether for training or other reasons, without justification.

你们的回复反复说你们公司没有生产某原料药某批号，检查人员在检查期间所审核和询问的是来自一些旧的样品，这些检测的目的是为了培训。你们的回复是不充分的，因为你们没有解释为什么并不存在的批次分析会被冠以正式的唯一批号，你们也没有解释你们的QC系统如何会允许分析结果在没有论证前提下被排除，不管是因为培训还是其它原因。

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

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

在本函中引用的偏差并无意成为完整的问题清单。你们有责任调查这些偏差，确定其原因，防止其再次发生，防止其它偏差。

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.

如果贵公司正考虑采取某些行动，可能会导致你工厂所生产的药品的供应中断，FDA要求你们立即联系CDER药品短缺人员，请发邮件至上述邮箱，这样我们可以与你们一起以最有效的方式让你们回复符合法律要求的状态。联系药品短缺办公室也会让你履行所有可能义务，根据21 U.S.C. 356C(a)(1)要求报告药品生产中断情况，让FDA在可能时即行考虑需要采取何种措施（必要时）来避免短缺，保护依赖贵公司药品的患者健康。

FDA placed your firm on import alerts 99-32 and 66-40 on April 28 and April 29, 2016, respectively.

FDA已将你公司分别于2016年4月28日和29日列在进口禁令99-32和66-40中。

Until you correct all deviations 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.

在贵公司完成所有纠正措施，FDA确认贵公司符合CGMP之前，FDA会暂停贵公司作为药品生产商所提交的所有新申报和增补申报。

Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Beijing Taiyang Pharmaceutical Industry Co., Ltd., Beijing, 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).

如果贵公司未能纠正这些问题，FDA将会根据联邦食品药品和化妆品法案21 U.S.C. 38 (a)(3)第801(a)(3)部分条款，拒绝许可所有在北京太阳制药有限公司生产的产品。由于生产方法和控制不符合联邦食品药品和化妆品法案21 U.S.C. 351 (a)(2)(B)第501(a)(2)(B)部分CGMP要求，在其条件下生产的所有产品将被FDA拒绝进入。

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 deviations 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.

在收到此函15个工作日内，请书面通知以下办公室你们已采取的纠正和预防本函所列问题再次发生的详细措施。如果你不能在15个工作日内完成纠正措施，请说明延误的原因，以及完成纠正措施的预计日期。

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

电子回复请发至上述邮箱或邮件发至以下地址：

Joseph R. Lambert, Consumer Safety 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 3003828267.

请写明你的FEI号3003828267。

Sincerely,