昨日，FDA官网发布了关于浙江医药有限公司新昌制药厂的警告信，涉及缺陷主要为数据完整性（数据可靠性）问题。这些缺陷如下：

1、实验室控制记录没有包括所有根据已有规程和标准执行的符合性检测中获取的完整数据。

2、未能对计算机化系统实施充分的控制，以防止未经授权的进入或改变数据，未能提供足够的控制来控制数据删除。

3、未能在执行活动时及时记录

浙江医药发布公告称，涉及新昌制药厂出口到美国的原料药2015年美国市场销售额为6026.1万元；2016年一季度销售额为2200.7万元，毛利为1180.9万元。

该公司表示，该警告信目前对公司生产、经营没有造成实质性影响，新昌制药厂将抓紧整改，并及时作出回复。公司将以此为契机，狠抓质量管理，切实提高合规水平。

关于这封警告信的正文如下：

Dear Mr. Yue:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Medicine Co., Ltd., Xinchang Pharmaceutical Factory, at 98 East Xinchang Dadao Road, Xinchang, Zhejiang, from June 15–18, 2015.

美国食品和药物管理局（FDA）于2015年6月15日~18日检查了你们的药品制造工厂，浙江医药有限公司新昌制药厂，位于浙江新昌县新昌大道路东98号。

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

这封警告信总结了活性药物成分（API）的现行良好制造规范（cGMP）的重大偏离。

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

鉴于贵公司方法、设施以及生产控制，工艺，包装以及储存不符合cGMP，贵公司的API依据联邦食品、药品和化妆品法(21U.S.C351（a）（2）（B）)第501（a）（2）（B）项下认定为掺假或次品。

We reviewed your firm’s July 8, 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07月08日的回复，并且我们也收到了你们后面的回复。

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

我们的调查员发现了一些偏差，包括但不仅限于以下：

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

实验室控制记录没有包括所有根据已有规程和标准执行的符合性检测中获取的完整数据。

Your laboratory personnel conducted unofficial testing without appropriate documentation, justification, and investigation.

你们的实验室人员执行非正式的测试，没有适当的文件、论证和调查。

Our inspection found that analysts performed multiple gas chromatography (GC) analyses of(b)(4)samples for residual solvents. Analysts performed these unofficial analyses and recorded them in separate “R&D” folders before conducting the officially reported sample analyses. The original, unofficial analyses stored in separate R&D folders were not part of the official quality control records for your API, and your firm did not consider the results of these unofficial analyses to evaluate the quality of your API or make batch release decisions for numerous batches of API.

我们的检查发现分析人员对XX样品执行多次残留溶剂的气相分析。分析人员在进行正式报告的样品分析之前进行这些非正式检验并记录在单独的“R&D”文件夹中。保存在单独的R&D文件夹中的原始非正式的分析没有作为你们API的正式的质量控制记录的一部分，并且你们公司没有考虑这些非正式分析的结果来评估你们API的质量或进行批放行决定。

Our investigator reviewed chromatograms found in the R&D folders and noted that some displayed large unknown peaks that were not reported in the official records for the same samples. The presence of such peaks in the chromatograms may indicate the presence of unknown and uncharacterized impurities (including potential contaminants) in your drugs.

我们的检察人员审查了在R&D文件夹中的色谱图并注意到图中许多未知峰没有报告在相同样品的正式报告中。在色谱图中存在这样的峰预示着在你们的药品中存在未知的和不典型的杂质（包括潜在的污染物）。

In your response, you stated that from April to July 2013 you performed “pre-trial” sample analyses for residual solvent testing of(b)(4)batches to check system suitability. You also stated you were not testing into compliance and attempted to attribute the unknown peaks found in your “pre-trial” sample analyses to operator error. FDA considers the use of an actual sample in test, prep, or equilibration runs as a means of disguising testing into compliance, a violation of CGMP.

在你们的回复中，你们说从2013年4月到7月你们对残留溶剂执行了“预审”样品分析以检查系统适用性。你们还说你们没有测试到合格并试图把你们的“预审”样品分析中发现的未知峰归结为操作人员失误。FDA认为在检测、准备或仪器平衡时使用一个实际的样品是掩盖符合性导向检测的方法，是违反CGMP要求的。

2.Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to provide adequate controls to prevent omission of data.

未能对计算机化系统实施充分的控制，以防止未经授权的进入或改变数据，未能提供足够的控制来控制数据删除。

Our investigator found that your GC system used to test for residual solvents in(b)(4)lacked controls to prevent manipulation, data deletion, and unauthorized access. For example, operators responsible for generating CGMP records had full administrator rights to access the computers containing temporary data prior to routine transfer of the data to a server. All analysts shared a common login ID and password. Your use of universal administrator privileges and a single common login/password meant that actions could not be traced to specific individuals. Additionally, because the audit trail feature on the system’s software was not configured to create a file history for all activities executed by the user during analysis, your electronic data was exposed to manipulation and/or deletion without traceability.

我们调查人员发现你们用于XX批检测残留溶剂的GC系统缺乏控制，不能防止篡改、删除数据，以及未经授权的进入。例如，负责制作CGMP记录的操作人员有全部的计算机管理员权限在数据被常规地转移至服务器之前登录存有临时数据的计算机。所有化验员共用一个相同的登录帐号和密码。你们使用了通用的计算机管理员李娜，和单一通用的登录密码表示所做的操作无法追踪至具体的个人。另外，由于系统软件的审计追踪并没有进行参数设置，为分析期间用户实施的所有活动创建一个文件历史，你们的电子数据暴露于篡改和/或删除之下，并且没有可追踪性。

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

未能在执行活动时及时记录

During the inspection, our investigators observed(b)(4)different analysts pre-dating or backdating results in your API quality control laboratory. Analysts were observed using pre-dated laboratory worksheets to document system suitability testing for high performance liquid chromatography (HPLC) analyses for(b)(4)purity testing. The worksheets were dated five days before the tests that they purported to document were actually carried out. Our investigators also observed analysts signing and dating microbiological testing laboratory worksheets five days before the test results would be available and backdating laboratory worksheets for impurities and content testing by four days.

在检查期间，我们的调查员发现XX不同的化验员将你们原料药QC实验室的结果提前或倒签日期。发现化验员使用提前写好日期的实验室记录表来记录HPLC的XX纯度检测系统适用性测试分析。检验记录日期是他们实际实施测试之前的5天的日期。我们调查人员还发现在微生物检验记录上，化验员在能够获得检验结果之前5天就签字并注明了日期，杂质和含量检测记录则是倒签了4天之前的日期。

Data Integrity Remediation

数据完整性弥补

Yourquality 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.

你们质量体系没有充分保证用以支持你们生产的药品的安全性、有效性和质量数据的准确性和完整性。我们强烈建议你们聘请一位有资质的顾问来协助你们弥补此问题。在回复此函时，请提供：

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

一个数据记录和报告不准确程度的全面调查。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.

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 analytical 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 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.

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 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.

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. If you cannot complete corrective actions within 15 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 Zhejiang Medicine Co., Ltd., Xinchang Pharmaceutical Factory, at 98 East Xinchang Dadao Road, Xinchang, Zhejiang, 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).