FDA警告信：河北裕兴（节译）

Via UPS                                                                                      Warning Letter 320-16-31

Return Receipt Requested

September 6, 2016

Mr. Wang Yufeng

Chairman of the Board

Hebei Yuxing Bio-Engineering Co. Ltd.

Xicheng District, Ningjin County

Hebei 055550

China

Dear Mr. Wang:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Hebei Yuxing Bio-Engineering Co. Ltd. at Xicheng District, Ningjin County, Hebei, from August 17 to 21, 2015.

美国FDA于2015年8月17-21日检查了你们河北的工厂。

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

此警告信总结了你们原料药生产中违背CGMP的重大偏差。

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 Cosmetics Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

鉴于你们生产、加工、包装和存贮所用方法、设施或控制不符合CGMP，你们的原料药根据法规属于掺假药品。

We reviewed your firm’s September 9, 2015, response and acknowledge receipt of your subsequent correspondence.

我们审核了你们公司于2015年9月5日及之后提交的回复。

During our inspection, our investigator observed specific deviations including, but not limited to, the following.

在我们检查期间，我们的调查人员发现具体偏差包括，但不仅限于以下：

1.    Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards.

化验室检验记录中没有包括所有用以确保产品符合既定质量标准的化验室测试中所生成的完整数据。

Your quality control laboratory failed to record and maintain complete data from analyses of your (b)(4) ((b)(4)) API. For example:

你们的QC化验室未能记录和维护你们某原料药分析中所产生的完整数据。例如：

• Prior to conducting official analyses,your quality control laboratory performed “experimental” analyses on product batches to assess whether your API met specifications, but failed to document these “experimental” tests in official laboratory records or to justify their exclusion. Our investigator found the results of 2,404 high performance liquid chromatography (HPLC) injections in a folder titled “Experimental” on instrument SZG-002-006l. Your quality unit indicated that these “experimental” injections were being conducted in all (b)(4) chromatographic units in your quality control laboratory. Your management provided different explanations in an attempt to justify the practice, including “fear” that the sample results would not pass.
• 在实施正式分析之前，你们的QC化验室做了“试验”分析以评估你们的原料药是否符合质量标准，但并没有在正式化验室记录上记录此“试验”检测，也没有论证将其排除。我们的调查人员在SZG-002-0061仪器中发现一个标题为“试验”的文件夹里有2404个HPLC进样结果。你们的质量部门说这些“试验”进样是在你们QC化验室所有色谱单元里做的。你们的管理人员给出了不同解释，试图论证这种做法的合理性，包括“害怕”样品结果不合格。
• Our review of the audit trails of chromatographic systems SZG-002-009, -010, -011, and -012 documented that your laboratory analysts deleted raw chromatographic data on multiple occasions. Your firm indicated that analysts may have been testing the system and may have deleted associated files. You also indicated that the deleted files may represent aborted analyses. However, we documented that some audit trail entries of deleted raw data files contained batch numbers for actual batch samples being tested. There is no assurance that laboratory records and raw data are accurate and valid.
• 我们审核了色谱系统SZG-002-009、-010、-011和-012中记录的审计追踪，你们化验员多次删除了原始色谱数据。你们公司说化验员可能是在测试系统，可能已经删除了相关文件。你们还说被删除的文件可能是分析中断。但是，我们记录了许多被删除的数据文件的审计追踪，其中有实际批次样品的批号。因此，你们化验室记录和原始数据没有准确度和有效性保证。
  

We acknowledge your decision to revise your current procedure for the testing of (b)(4). In response to this letter, provide a summary of how your chromatography procedures will conform to U.S. Pharmacopeia requirements, including those for the establishment of system suitability.

我们知悉你们决定修订你们目前的XX检测程序。在回复此函时，请提供你们将如何让你们的色谱程序符合美国药典的要求的摘要，包括如何建立系统适用性。

In addition to deciding to revise your (b)(4) testing procedure, in your response you commit to acquiring additional chromatographic instruments, restricting certain chromatographic instruments to specific analyses, installing a new data control system, upgrading instrument software, and enabling data integrity features included in the laboratory software.

除了决定修订你们的XX检测程序外，在你们回复中，你们承诺要申购更多的色谱仪器、限制我的天空的色谱仪用于特定的样品分析、安装新的数据控制系统、升级仪器软件以及激活化验室软件中的数据完整性功能。

Your response is inadequate. None of your explanations justify your failure to maintain complete records, nor do they support your practice of substituting repeat tests after failing results. Acquiring new instruments, installing new and upgraded software, and enabling various features on software are only effective if you have implemented appropriate procedures and systems to ensure that your quality unit reviews all production and control data and associated audit trails as part of the batch release process.

你们回复是不充分的。你们的解释没有论证你们未能维护完整记录，也不能支持你们在不合格结果之后替代重复检测的做法。申请新的仪器、安装新的和升级软件、激活软件上各种功能只有当你们实施适当的程序和系统来确保你们质量部门审核所有生产和检验数据及相关审计追踪作为批放行过程的一部分时才是有效的。

2.    Failure to follow and document laboratory controls at the time of performance, and failure to document and explain any departures from laboratory procedures.

在实施时未能遵守和记录化验室控制，未能记录和解释与化验室程序不符合的情况。

During the inspection, your firm provided our investigator a chromatogram for an assay analysis of (b)(4) batch (b)(4) dated August 30, 2014, at 9:46:39 a.m. Your firm later submitted to FDA a different chromatogram corresponding to the same analysis, instrument, date, time, and batch. The second chromatogram appears exactly the same as the one provided during the inspection, but it includes a different method file name, column type and serial number, and system temperature. Both versions of these documents cannot represent the actual assay analysis that you conducted for batch (b)(4) on August 30, 2014, at 9:46:39 a.m.

在检查中，你们公司给我们检查人员提供了X批次的含量分析色谱图，检验日期为2014年8月30日上午9：46：39。你们公司后来提交给FDA一份不同的图谱，对应的是相同的分析、仪器、日期、时间和批次。第二张图与检查期间提供的图谱是完全一样的，但它包括有一个不同的方法文件名、柱子型号和序列号以及系统温度。文件的两个版本无法代表你们在2014年8月30号上午9:46:39所做的某批的实际含量分析。

3.    Failure of the quality unit to ensure that all critical deviations are investigated and resolved.

质量部门未能确保所有关键偏差都被调查和解决。

At the time of the inspection, your firm had documented 67 deviations regarding microbiological contamination found or related to the (b)(4)step for (b)(4). These deviations occurred between January 1 and August 20, 2015, but our investigation documented that microbiological contamination has been a persistent and unresolved problem at your firm since 2013. Over time, your firm has identified four potential causes:

在检查期间，发现你们公司记录了67个微生物污染及X步骤的偏差。这些偏差发生在2015年1月1日至8月20日宰，但是我们的调查记录了微生物污染自2013年以来就一直存在并且没有得到解决。你们公司找出了4个可能的原因：

• contaminated (b)(4) supply due to inadequate (b)(4) controls
• 由于XX控制不充分导致XX污染
• failing (b)(4) of the (b)(4) in the (b)(4) tank (b)(4) systems
• X罐X系统X操作失败
• production operator errors
• 生产操作人员失误
• inadequate sterilization of the supplement tanks used to store materials before they are discharged into the (b)(4) tanks
• 用于存贮向X罐加料用物料补给罐灭菌不充分
  

However, you have not definitively identified the specific root causes(s) of your microbiological contamination problems, nor have you taken appropriate corrective actions and preventive actions.

但是，你们并没有确定你们微生物污染问题的具体根本原因，也没有采取适当的纠正措施和预防措施。

In response to this letter, provide the report of your thorough investigation to identify the root cause(s) and your corrective action and preventive action plan.

在回复此函时，请提交你们彻底调查识别出根本原因的报告以及你们的CAPA计划。

Data Integrity Remediation

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 strongly recommend that you retain a qualified consultant to assist in your remediation.

In response to this letter, provide the following.

A.    A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

• 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.
• 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.
• 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.
• A comprehensive retrospective evaluation of the nature of the testing 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.
  

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.

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

• 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.
• 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.
• 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.
• 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.
  

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.

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 July 8, 2016.

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 Hebei Yuxing Bio-Engineering Co. Ltd., Xicheng District, Ningjin County, Hebei, 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:

Jason F. Chancey, 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 3008996626.

Sincerely,

/S/           

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

来源：

Julia

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