FDA签发对中国某公司的警告信（数据完整性问题）

签发日期：2015年4月6日

生产商：Yunnan Hande Bio-Tech. Co. Ltd. （云南汉德生物技术有限公司）

检查时间：2014年4月14-17日

主要缺陷：

1、 未能防止无授权进入或更改数据，未能提供足够的控制来防止数据删除和遗漏。

具体描述：你们缺乏控制来防止未经授权的捏造化验室电子原始数据。特别是你们的红外光谱仪没有权限控制来防止原始数据的删除和做假。另外，该仪器的计算机软件没有激活的审计追踪功能来记录对数据的更改，包括原始结果信息、更改数据的人员身份以及更改时间。捕捉这些批生产质量关键数据的审计追踪应作为批审核和放行过程的一部分来进行审核。

我们知道你们承诺对红外软件进行升级，增加全面追踪功能，符合CGMP要求。在你们回复中，你们还承诺要获得关于化验室计算机系统获取的所有数据的XXX存档的信息，评估其它仪器的软件升级。但是，你们的回复不够充分，因为你没有说明你们要如何保证原始分析数据的完整性，以及在完成你们的CAPA计划之前如何维护数据。

在回复本函时，请提供你们的保证你们生产操作中产生的电子数据，包括化验室检验数据不会被删除或伪造的综合CAPA计划。你们公司应实施控制，防止数据删除或缺失，对更改数据人员进行身份识别，并解释更改的原因或理由。这样的变更应根据已建立的适当的程序来进行。你们的回复应指明可能会受到未防数据做假充分控制影响的你们化验室设备和其它生产相关设备。

2、 你们质量部门未能保证原料经过适当的测试并报告结果

检查记录表明你公司的一个分析员对所有批次的XXX，原料药均没有做红外鉴别试验，但这是你们质量控制放行的一部分。2014年4月2日，这个化验员把红外光谱仪里的同样品名样品的XXX批号和XXX批号文件名称给改了，用来放行之前生产的两个批号YYY和YYY。

在你们2014年5月1日的回复中，你们承认该化验员篡改了鉴定是试的结果，用于另2批号的放行批准。这种做法是不能接受的，引起了对于你公司化验室分析的完整性的担忧。化验室控制记录必须包括每个测试中准确真实的所有原始数据记录，包括仪器生成的各种图表和图谱。这些记录必须进行适当的识别和维护用以证明每一个原料药的批次在放行前均经过检测，并符合放行质量标准。

你们的回复是不充分的，因为你们没有进行全面的调查和回顾性审核来确定这种数据做假行为的程度。对记录进行草率的审核不能保证其它人员没有伪造或不准确地报告检测数据。审核不够充分还因为你们没有审核其它计算机系统产生的数据，例如HPLC或GC来确定是否这些系统产生的数据也被篡改或做假了。

3、 你们质量部门没有履行其职责来保证你工厂所生产的原料药符合CGMP要求，符合已建立的质量和纯度标准。

例如，你们质量部门没有能发现你们化验室伪造红外原始数据，虚报结果用于原料药YYY批和YYY批的批准和放行。

你们的回复中说你们修订了你们的数据审核程序，包括了对同一时期内所检测批次的交叉比较的要求。另外，你们承诺要加强工作流程，通过保证数据的可追溯性和培训数据追踪审核员来防止将来的数据做假。

你们的回复是不充分的，在其中你们没有全面说明你们质量部门的未能发现和防止化验室文件捏造或篡改文件的问题。另外，你们的回复不完整，因为你们没有提供综合性计划来保证所有用于进入你工厂生产的原料药的质量和纯度数据的完整性。

Warning Letter

via UPS                                                                                                         

WL: 320-15-09

April 6, 2015

Ms. Huang Lei

Chairman of the Board

Yunnan Hande Bio-Tech. Co. Ltd.

No. 3 Platform Jinding Tech-Zone

Kunming, Yunnan Province 650033

P.R. China

Dear Ms. Lei:

During our April 14, 2014 through  April 17, 2014 inspection of your manufacturing facility, Yunnan Hande Bio-Tech Co. Ltd., located at No. 3 Platform Jinding Tech-Zone, Kunming, Yunnan Province, China, investigators from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) regulations for the manufacture of active pharmaceutical ingredients (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 conducted a detailed review of your firm’s response dated May 1, 2014 and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated May 31, 2014, July 1, 2014, July 31, 2014, August 29, 2014, September 30, 2014, October 30, 2014, and November 28, 2014.

Our investigators observed specific deviations during the inspection, including, but not limited to, the following:

1.    Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

You lacked controls to prevent the unauthorized manipulation of your laboratory's electronic raw data. Specifically, your infrared (IR) spectrometer did not have access controls to prevent deletion or alteration of raw data. Furthermore, the computer software for this equipment lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change. Audit trails that capture such critical data about the quality of your batch production should be reviewed as part of the batch review and release process.

We acknowledge your commitment to upgrade the IR software by adding full audit trail capabilities in compliance with CGMP. In your response, you also commit to obtain information about the (b)(4)archival of all data obtained on laboratory computerized systems, and to evaluate software upgrades to other instrumentation. However, your response is inadequate because you have not specified how you will ensure the integrity of raw analytical data or maintain data before you complete your planned corrective actions and preventive (CAPA) actions.

In response to this letter, provide your comprehensive CAPA plan for ensuring that electronic data generated in your manufacturing operations, including laboratory testing, cannot be deleted or altered.  It essential that your firm implement controls that prevent the omission of data, and record information about changes to existing data, such as the date of the change, identity of person who made the change, and an explanation or reason for the change. Any such changes should be made in accordance with an established and appropriate procedure. Your response should address your laboratory equipment and any other manufacturing-related equipment that may be affected by the lack of adequate controls to prevent data manipulation.

2.    Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.

The inspection documented that an analyst at your firm failed to perform the IR identity test for all lots of (b)(4), API, as part of your quality control release. Instead, the analyst at your firm altered the file name in the spectrophotometer containing the sample identification information for (b)(4) API lot # (b)(4), tested on April 2, 2014, to support the release of two previously manufactured lots, # (b)(4)and (b)(4).

In your response dated May 1, 2014, you admit that an analyst altered the identity test result for lot #(b)(4) to approve and release lots # (b)(4) and # (b)(4). This practice is unacceptable and raises serious concerns regarding the integrity and reliability of the laboratory analyses conducted by your firm. Laboratory control records must include accurate and truthful documentation of all raw data generated during each test, including graphs, charts and spectra from laboratory instrumentation. These records must be properly identified and maintained to demonstrate that each API lot was tested and met the release specification before the lot is released.

Your response is inadequate because you did not perform a comprehensive investigation and a retrospective review to ascertain the extent of this data alteration practice. A cursory review of records does not ensure that other personnel did not manipulate or inaccurately report test data. The review was also insufficient because you did not review data generated from other computerized systems such as high performance liquid chromatography or gas chromatography to determine if data generated by these systems were also manipulated or altered.

3.    Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.

For example, your quality unit failed to detect that your laboratory altered IR raw data and misrepresented the results for approval and release of (b)(4), API lots# (b)(4) and (b)(4).

Your response indicates you revised your data review procedure to include the requirement for cross lot comparison review for batches tested during the same period. Additionally, you commit to strengthen work processes to prevent future data manipulation by ensuring the data is traceable and training the reviewers on data tracking.

Your response is inadequate in that it does not fully address the failure of your quality unit to detect and prevent the manipulation or alteration of laboratory documents. Additionally, your response is incomplete because you have not provided a comprehensive plan to ensure the integrity of all data used to assess the quality and purity of APIs manufactured at your facility.

SUMMARY

The above examples are serious CGMP deviations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated at your facility to support the safety, effectiveness, and quality of the drug products you manufacture. We strongly recommend that you hire a qualified third party auditor/consultant with experience in detecting data integrity problems to assist you with coming into compliance with CGMP requirements. However, it is your responsibility to ensure that any third party audit includes appropriate evaluation of sophisticated electronic systems and the vulnerability to data integrity manipulation of such systems.

In response to this letter, provide the following to the Agency:

1.    A comprehensive evaluation of the extent of the inaccuracy of the reported data.  As part of your comprehensive evaluation, provide a detailed action plan to investigate the extent of the deficient documentation practices noted above;

2.    A risk assessment regarding the potential effect on the quality of drug products.  As part of your risk assessment, determine the effects of your deficient documentation practices on the quality of the drug product released for distribution; and

3.    A management strategy for your firm that includes the details of your corrective action and preventive action plan.

a)    As part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as contacting your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, monitoring of complaints, and/or other steps to assure the quality of the product manufactured under the violative conditions discussed above.

b)    In addition, as part of your corrective action and preventive action plan, describe the actions you have taken or will take, such as revising procedures, implementing new controls, training or re-training personnel, or other steps to prevent the recurrence of CGMP violations, including breaches of data integrity.

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.  

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, 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 Program 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 action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at Yunnan Hande Bio-Tech Co., Ltd, Kunming, China into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may be subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), 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 Act, 21 U.S.C. 351(a)(2)(B).

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of deviations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the APIs at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002808537.

Please send your reply to: Kevin Maguire, Compliance Officer; 10903 New Hampshire Avenue Building 51 Room 4237; Silver Spring, MD 20993.

Sincerely,

/S/

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research