20160512 FDA警告信（上海泰亨）节译

Via UPS                                                                                       Warning Letter: 320-16-11

Return Receipt Requested



May 12, 2016



Mr. Yusheng Fang, CEO & President

Tai Heng Industry Co., Ltd.

2715 Long Wu Road, Building 2

Shanghai Juke Biotech Park

Shanghai, China, 200231



Dear Mr. Fang:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tai Heng Industry Co., Ltd., 2715 Long Wu Road, Building 2, Shanghai Juke Biotech Park, Shanghai, China from May 4–11, 2015.

FDA于2015年5月4-11日检查了你公司位于上海聚科生物园区的工厂。

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

警告信中汇总了重大的原料药CGMP违规。

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).

由于你们的方法、设施或生产控制、加工、包装或保存不符合CGMP，你们的原料药被作为掺假药。

We reviewed your firm’s May 28, 2015, response in detail and acknowledge receipt of your subsequent responses.

我们详细审核了你们公司于2015年5月28日的回复，并且我们也收到了你们后面的回复。

Our investigator observed specific deviations during the inspection, including, but not limited to, the following.

我们的调查员在检查期间发现了一些偏差，包括但不仅限于以下：

1.     Failure to adequately investigate out-of-specification results and implement appropriate corrective actions.

未能对OOS结果进行充分调查，实施适当的纠正措施

The investigator found that batch samples were routinely retested following failing or atypical results until acceptable results were obtained. Failing or atypical results were not investigated or included in official laboratory control records.

调查人员发现批样品经常在不合格或结果异常之后进行复测直到获得可以接受的结果。不合格或导演结果没有进行调查，也没有包括在正式化验室控制记录中。

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

未能防止未经授权的进入或改变数据，提供充分的控制防止篡改和忽略数据。

During the inspection, an FDA investigator discovered a lack of basic laboratory controls to prevent changes to your firm’s electronically stored data and paper records. Your firm relied on incomplete records to evaluate the quality of your drugs and to determine whether your drugs conformed with established specifications and standards.

在检查期间，FDA审核人员发现缺乏基本的实验室控制，无法防止对你们公司电子存贮数据和纸质记录的变更。你们公司依赖于不完整的记录来评估你们药品的质量，确定你们药品是否符合既定质量标准。

Our investigator found that your firm routinely re-tested samples without justification, and deleted analytical data. We observed systemic data manipulation across your facility, including actions taken by multiple analysts and on multiple pieces of testing equipment.

我们调查人员发现你们公司经常未经论证即重新测试样品，删除分析数据。我们在你们整个工厂发现系统性数据篡改，包括多个化验员采取的措施，以及分析设备多个部件的措施。

Specifically, your Quality Control (QC) analysts used administrator privileges and passwords to manipulate your high performance liquid chromatography (HPLC) computer clock to alter the recorded chronology of laboratory testing events.

尤其是你们QC化验员使用了管理者权限和密码来篡改你们的HPLC电脑时钟，改变化验室检测事件的记录时序。

3.     Failure to record activities at the time they are performed, and destruction of raw data.

未能在实施活动时记录活动，销毁原始数据。

Your employees did not complete batch production and control records immediately after activities were performed. Your operators used “mock” sheets (copies of the uncontrolled copy of the master production records) to capture critical manufacturing data. Your employees then completed and backdated batch production records days after operations ended.

你们的员工未能在活动执行之后立即完整批生产和批分析记录。你们的操作员使用“模拟”页（主生产记录的不受控复印件的复印件）来捕获关键生产数据。你们员工然后在操作结束数日之后完成批生产记录，并倒签日期。

Our investigator noted discrepancies between the “mock” sheets and the complete batch production record that your firm represented as the official record for that lot. Because of your uncontrolled documentation practices, you could not produce evidence that your batch production records were accurate.

我们调查人员注意到“模拟”页和你们公司提供的完整的作为正式的批生产记录之间的差异。因为你们不受控的文件记录做法，你们不能提供证据证明你们的批生产记录是准确的。

Batch production records must be generated contemporaneously and include complete and accurate information on the production and control of each batch. The practice of using unbound, uncontrolled loose paper, in conjunction with backdating records, raises additional concerns about the integrity, authenticity, and reliability of all your data, and the quality of your API.

批生产记录必须同步产生，并且包括每个批次完整准确的生产和检验信息。使用未装订的、不受控的松散纸张的做法，加上倒签日期，使得我们担心你们所有数据的完整性、真实性和可靠性，以及你们原料药的质量。

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 from CGMP.



If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of drugs produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Staff immediately at drugshortages@fda.hhs.gov so that we 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 in the manufacture of your drug under 21 U.S.C. 356C(a)(1), 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. In appropriate cases, you may be able to take corrective actions without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.



After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence.



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 your commitment to hire a third party to perform (b)(4) audits of your quality system, but we feel that an (b)(4) audit is inadequate. We recommend more frequent reviews of your quality system for more timely oversight and compliance with CGMP. We also recommend your third party audit include appropriate evaluation of sophisticated electronic systems and the possibility of data integrity manipulation of such systems.



In your response to this letter, provide the following.



1.     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 all data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential batches were identified should evaluate all data integrity lapses.  



2.     A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses  of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.



3.     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 that are already underway or completed.



If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay.



Until you completely correct all deviations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Tai Heng Industry Co., Ltd., 2715 Long Wu Road, Building 2, Shanghai Juke Biotech Park, Shanghai, China 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).



Send your reply to:

            Kevin Maguire

            Compliance Officer

            U.S. Food and Drug Administration

            White Oak, Building 51, Room 4359

            10903 New Hampshire Avenue

            Silver Spring, MD 20993

            USA



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



Please identify your response with FEI 3006986091.





Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

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