FDA给浙江某药厂的警告信（节译）

Warning Letter: 320-16-26

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Return Receipt Requested

                                                                       

August 11, 2016

Mr. Siwei Yang, President

Zhejiang Hisoar Pharmaceutical Co., Ltd.

100 Waisha Road

Jiaojiang District

Taizhou City, Zhejiang Province

China 318000

Dear Mr. Yang:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Hisoar Pharmaceutical Co. at 100 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province, from August 10 to 13, 2015.

美国FDA于2015年8月10-13日检查你们位于浙江台州椒江外沙的浙江海翔药业有限公司。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

本警告信总结了原料药严重违反CGMP的问题。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).

鉴于你们生产、加工、包装和保存的方法、设施或控制不符合CGMP要求，你们的原料药根据FDCA501(a)(2)(B)和21 U.S.C. 351(a)(2)(B)规定被判定为掺假药品。

We reviewed your firm’s September 3, 2015, response in detail and acknowledge receipt of your subsequent responses.

我们详细审核了贵公司于2015年9月3日及之后发出的回复。

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

我们的检查人员发现的具体违规情况包括但不仅限于以下：

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

未能维护化验室内进行测试期间产生的完整数据，无法确保其符合既定质量标准。

During the inspection, FDA investigators discovered a lack of basic laboratory controls to prevent changes to your electronically-stored data and paper records. When you encountered suspect and out-of-specification (OOS) results, you retested samples until you obtained desirable results. You did not investigate, review, or report original results. You relied on incomplete records to evaluate the quality of your drugs and to determine whether your drugs conformed to established specifications and standards.

在检查期间，FDA检查人员发现贵公司缺乏基本的实验室控制，无法防止对你们的电子存贮数据和纸质记录进行更改。当你们碰到可疑和OOS结果时，你们对样品进行复验直到获得想要的结果。你们并未调查、审核或报告原始结果。你们依赖于不完整的记录来评估你们药品的质量，决定你们的药品是否符合既定的质量标准。

For example, during the inspection, we reviewed electronic data from your high performance liquid chromatography (HPLC) system. An unknown impurity peak was present when the original three-month stability sample of (b)(4) batch (b)(4)was run on October 9, 2014. This unknown peak was OOS and would have caused the sample to fail for unknown impurities, but it was not included in the official record for this stability test. Instead, an analyst ran a new sample to obtain a passing result on October 10, 2014, and only the passing result from the second sample was reported in the official record.

例如，在检查期间，我们审核了你们HPLC系统中的电子数据。在2014年10月9日某批次的3个月稳定性试验的原始样品检测中出现了一个未知杂质峰。此未知杂质峰是OOS，应该判定样品未知杂质不符合标准，但这个结果没有放进此稳定性的正式检测记录中。一个化验员在2014年10月10日进行了新样品的检测，并获得了符合标准的结果，在正式记录里只报告了第二个样品的符合标准的结果。

In your response, you stated that the analyst thought that the unreported OOS value was related to the reference solution and not the sample being tested. You said the analyst was afraid of making mistakes, and invalidated the data without notifying management. You acknowledged that the data should not have been invalidated without an OOS investigation and committed to revise procedures.

在你们的回复中，你们声称化验员以为未报告的OOS值是对照液的，而不是供试样品的。你们说化验员害怕犯错，因此没有通知管理人员就将该数据无效了。你们知道该数据不应该不经过OOS调查就宣布无效，并且承诺要修订程序。

2.    Failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent manipulation and omission of data.

未能防止未经授权即进入或改变数据，未能提供足够的控制来防止对数据的篡改和省略。

During the inspection, we observed that your laboratory systems lacked access controls to prevent deletions or alterations to raw data. For example, our investigator reviewed the electronic folder containing data files generated when your firm tested (b)(4) batches of (b)(4) API for residual solvents by gas chromatography (GC). The investigator compared the file names in the folder with the metadata generated by the Chemstation software you used to operate your GC system, and found that two chromatograms had been deleted from the system. Because there were no controls restricting operators’ or supervisors’ abilities to alter or manipulate the data, an analyst had completed two runs and deleted the results, and then changed the subsequent file names in the folder where reported data was stored to make it appear that the deleted runs never occurred.

在检查期间，我们发现你们的化验室系统缺乏登录控制，无法防止对原始数据的删除或修改。例如，我们检查员审核了包括有数据文件的电子文件夹，其中是你们GC检测某批原料药残留溶剂的。检查员将文件夹里的文件名称与你们用来运行GC系统的CHEMSTATION工作站产生的元数据进行了比较，发现系统里有2份色谱图被删除了。由于没有控制来限制操作人员或主管修改或伪造数据的权限，一个化验员做了2针测试，然后删除了结果，之后修改了存贮所报告的数据的文件夹中的文件名，让它看起来象是没有删除过样品运行一样。

In your response, you stated that two injections were deleted from the system because the analyst believed that an unstable baseline made retaining the files unnecessary. You also confirmed that your software had no access controls and that your analysts had authorization to delete data.

在你们的回复中，你们声称从系统里删除这2针是因为化验员相信没有必要将基线不稳定的色谱数据保留下来。你们还确认你们的软件没有权限控制，你们的化验员可以删除数据。

3.    Failure to record activities at the time they are performed.

未能在活动实施的同时进行记录。

During the inspection, we observed that you did not have worksheets for recording microbial test results and that you failed to contemporaneously document microbial limits test results for (b)(4) API batch (b)(4).

在检查期间，我们发现你们没有记录纸来记录微生物检测结果，你们没有同步记录某批原料药的微生物限度测试结果。

In your response, you stated that tests for microbial limits were not routine for (b)(4). The microbiologist documented test methods and results “when she had time,” and “there was a possibility that our QC microbiologist documents results by memory instead of document (sic) at time of operation.” Your response did not demonstrate the reliability of any data recorded and reported in the past.

在你们的回复中，你们声称你们的微生物限度检测对该原料药来说并不是常规检测。微生物化验员在“有时间时”记录了检测方法和结果，“可能我们的微生物化验员在操作时默记了结果，而没有写下来”。你们的回复并无法证明过去所记录和报告的任何数据是可靠的。

In your response to this letter, provide:

在你们回复此函时，请提交：

• microbial limits retest data of all (b)(4) API batches within expiry
• 某原料药尚在有效期内所有批次的微生物限度复验数据
• your review of all microbial test methods to verify suitability for intended use
• 你们对所有微生物限度检测的审核以核查其是否适合既定用途
  

Delay producing records during inspection

在检查中延迟提供记录

Some records that our investigators requested during the inspection were not available for review.

在检查中，我们检查人员要求查看的一些记录无法提供。

For example, during the inspection of the microbiology laboratory, our investigators requested the completed microbial QC worksheet for (b)(4) API batch (b)(4). Your laboratory staff led our investigators out of the lab to another room where, according to your staff, the completed document was located. After approximately 30 minutes outside of the laboratory without being provided the completed worksheet, our investigators reentered the microbiology lab and observed a microbiologist with a partially-completed QC worksheet for the batch in question.

例如，在对微生物化验室的检查期间，我们检查人员要求查看某批次原料药填写好的微生物QC操作记录。你们的化验室员工把检查人员领出了实验室，领到另一个房间，根据你们员工的说法，填写完整的记录放在那个房间里。在化验室外面呆了约30分钟之后，仍没有给我们检查人员提供填写好的记录，我们检查人员重新进入到微生物化验室，发现一个微生物化验员拿着刚才索取那个批号的填写一半的QC操作记录。

Later, a member of your laboratory staff told our investigators that, contrary to initial statements, the “original” completed QC worksheet never existed.

之后，你们的一位化验室员工告诉我们检查人员说，与之前所说的相反，“原始”填写完整的QC操作记录从来都没有的。

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be adulterated under section 501(j) of the FD&C Act. We recommend that you review FDA’s guidance for industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf

当所有者、运营商或代理延误、否决、限制或拒绝检查，则根据FDCA 501(j)的规定将其生产的药品判定为掺假药品。我们建议你们查看FDA行业指南“延误、否决、限制或拒绝药品检查的情形”。

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.
• 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.

FDA placed your firm on Import Alert 66-40 on January 20, 2016.

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.

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. Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Zhejiang Hisoar Pharmaceutical Co. Ltd., 100 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province, 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 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.

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

Tracie H. Sharp

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 3003735151.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

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