FDA警告信：佐藤药品工业株式会社

上周，FDA官网挂出关于日本佐藤药品工业株式会社的警告信（日本代购们注意了），根据该警告信，这家日本公司涉及缺陷包括：重复检验、删除不合格数据、某些设备没有审计追踪、原始数据未保留、OOS调差不彻底等。具体如下：

GMP办公室翻译组

翻译：流浪的沙子

校对：Owen

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Sato Yakuhin Kogyo Co., Ltd.

佐藤药品工业株式会社

地址： 

9-2, Kannonji-Cho, Kashihara City

Nara Prefecture

634-8567, Japan

〒634-8567 奈良县橿原市観音寺町9番地の2

1. Your firm failed to ensure that laboratory records include complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)(4)).

实验室记录未能确保包含符合既定标准的完整数据。

Reliance on incomplete data

依赖不完整数据

Our investigator reviewed the audit trails generated by your high performance liquid chromatography (HPLC) system for impurities testing that you conducted on (b)(4) (lots (b)(4), (b)(4), (b)(4)). The audit trail showed that you performed this testing in duplicate. The audit trail indicated that you conducted a chromatography sequence analyzing impurities on samples of these lots beginning at (b)(4) on April14, 2014. The audit trail showed that a new sequence was started approximately 24 hours later, at (b)(4) on April 15, 2014, for impurities testing that again included samples for lots (b)(4), (b)(4), and (b)(4). None of the 19 chromatograms generated in the first sequence were maintained and available for review. Only the second set of chromatograms was maintained and relied upon in releasing lots (b)(4), (b)(4), and (b)(4) for use in the manufacture of products for the U.S. market. You could not provide any rationale for not maintaining the original data, and you failed to document a scientific justification for repeating the analysis.

我们的检查员审核了HPLC系统XX产品XX批次的杂质检查的审计追踪。该审计追踪显示你们重复进行该测试。审计追踪表明你们于2014年4月14日执行了一个色谱序列分析这些批次样品的杂质。该审计追踪显示你们于大约24小时后，2014年4月15日又开始了一个新的序列进行包括这几批在内的杂质检查。第一个序列所产生的19个色谱图没有一个得到保存和审核。你们只保存了第二个序列的色谱图，并以此来进行美国市场的批次的放行。你们未能提供任何理由不保存这些原始数据，也没有记录重复测试的具体理由。

Failure to appropriately maintain data

未能适当的维护数据

You do not maintain electronic data on your ultraviolet-visible spectrophotometer UV SP-502 which you use for content uniformity and identity testing of (b)(4) capsules, and it does not have an audit trail.

你们没有维护紫外-可见分光光度计UV SP-502上用于XX胶囊的含量均匀度和鉴别检验的电子数据，并且没有审计追踪。

In your response, you acknowledged that your data integrity controls were deficient. You stated that the chromatography software version was upgraded and that you are retaining all electronic data as of June 1, 2016. You also committed to upgrade UV SP-502 and to appropriately control access to data for this instrument. In addition, you provided the revised procedure, Procedure on Testing Records (QC Standard 3-C-017), which stipulates, “All the data generated from any analytical devices should be kept as records.” However, your response is inadequate. You have not conducted a retrospective review to determine how your failure to maintain complete records affected the quality of your drugs. Moreover, you have not shown how your revised laboratory procedures prevent the deletion, manipulation, or exclusion of data from the records relied upon for batch release and other quality review decisions.

在你们的回复中，你们承认你们的数据可靠性控制的不足。你们说色谱软件版本已经升级并且你们从2016年6月1日起保存了所有的电子数据。你们也承诺升级UV SP-502紫外-可见分光光度计并适当控制数据访问权限。另外，你们提供了修订后的《检验记录规程》（QC标准3-C-017），规定了“任何分析仪器产生的数据应被作为记录保存”。然而，你们的回复是不充分的，你们没有进行一个回顾性检查审核来确定这些未能完整保存的记录是否影响你们的产品质量。再者，你们没有说明你们修订后的实验室规程如何防止赖以进行批次放行和其他质量回顾决策的记录中的数据的删除、篡改或者排除。

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

未能彻底调查批产品或其成分不明原因的偏离或不符合其标准，不管这批是否放行销售。

Your analysts told our investigator that, until June 1, 2016, they were permitted to perform repeat testing without scientific justification or documentation. They also told our investigator that they were not required to maintain the data from the original results when performing investigations of system suitability failures, suspected errors, or out-of-trend results. Our investigator reviewed records of your investigations for a two-year period and found that you recorded only two minor deviations in the production area and no out-of-specification investigations.

你们的分析员告诉检查员他们被允许在没有具体论证和记录的情况下进行重复检验，直到2016年6月1日。他们还告诉检查员在进行系统适应性失败、可疑错误和OOS结果的调查时，他们不要求维护原始结果的数据。我们的检查员审核了你们两年内的调查记录并发现你们只记录了关于生产领域的两个微小偏差并且没有OOS。

In your response you stated, “The analysts will not make the decision to perform re-analysis at their discretion and the investigation shall be conducted on the initial failure and the testing results shall be verified.” In addition, you stated that you will revise your procedure (Procedure on Unexpected Testing Results (OOT), QC Standard 3-C-006) to require that records be retained. However, you failed to describe the role of the quality unit in this procedure. Include this procedure as a part of your response to this letter.

你们回复说“分析员将不会再自作主张进行重复分析，并将会在第一次检验失败时进行调查，检验结果将会被核实”。另外，你们说你们将会修订你们的规程《非预期检验结果规程（OOT）》，QC标准3-C-006，规定记录应被保存。然而，你们未能在该规程中描述质量部门的角色。回复此函请把该规程列入在内。

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, please see two FDA guidance for industry documents:

关于处理失败、OOS、OOT或其他非预期结果和调查记录的更多信息，请见FDA行业指南文件：

·        Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production available online at http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf

制药OOS调查

·        Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance – Records and Reports available online at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm.

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