作者：Julia 来源：Julia法规翻译
Dear Mr. Divi:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Divi’s Laboratories Ltd. (Unit II) at Unit-2, Chippada Village, Visakhapatnam District, from November 29 to December 6, 2016.
美国FDA于2016年11月29日至12月6日检查了你们位于印度的DIVI’S生产工厂。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了原料药生产严重违反CGMP的行为。
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).
由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
Additionally, our investigators documented that your firm limited and/or refused an FDA inspection. Under the FD&C Act, as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA), section 707, 21 U.S.C. 351(j), your drugs are adulterated in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and/or refused inspection.
另外，我们的调查人员记录下了你们公司限制和/或拒绝FDA检查的情况。根据FDCA以及FDASIA第707部分和21 U.S.C. 351(j)，由于生产、加工、包装或存贮场所的所有者或操作人员限制检查和/或拒绝检查，你们的药品为掺假药品。
We reviewed your December 24, 2016, response in detail and acknowledge receipt of your subsequent correspondence.
我们详细审核了你们公司2016年12月24日及之后的回复。
During our inspection, our investigators observed specific deviations including, but not limited to, the following.
我们的调查人员发现的具体问题包括但不仅限于以下：
1. Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
未能确保检验方法科学合格适当，以确保你们的API符合既定的质量和/或纯度标准。
Our investigators observed that the software you use to conduct high performance liquid chromatography (HPLC) analyses of API for unknown impurities is configured to permit extensive use of the “inhibit integration” function without scientific justification. For example, our investigator reviewed the integration parameters you used for HPLC identification of impurities in release testing for (b)(4). These parameters demonstrated that your software was set to inhibit peak integration at four different time periods throughout the analysis. Similarly, in the impurities release testing you performed for (b)(4), your HPLC parameters were set to inhibit integration at four different time periods throughout the analysis.
我们的调查人员发现你们所使用的API未知杂质分析用HPLC分析软件的参数设置允许广泛使用“不积分”功能，而没有科学论证。例如，我们调查人员审核了你们XX放行测试中用于HPLC杂质鉴别的积分参数，这些参数显示出你们的软件被设定为在整个分析中的4个不同时间段不执行积分。类似地，在你们实施的XX杂质放行测试中，你们的HPLC参数被设定为在整个分析过程中有4个时间段不积分。
Inhibiting integration at various points during release testing for commercial batches is not scientifically justified. It can mask identification and quantitation of impurities in your API, which may result in releasing API that do not conform to specifications.
在商业批次放行测试中不同时间点禁用积分没有经过科学论证，这可能会掩盖你们API中杂质的鉴别和定量，导致将不符合质量标准的API放行。
In your response, you stated that you have made several corrective actions, including updating your procedure Peak Integration Techniques for Chromatography to include controls on the use of inhibit integration events. However, your response is inadequate in that it did not provide specific corrective action or supportive documentation for each drug’s chromatographic processing parameters, including API not cited on Form FDA 483. You have not shown how you will ensure that your test methods are appropriate to determine whether your API conform to established standards and specifications. Consequently, the summary data you provided does not demonstrate that previously released lots do not contain excessive levels of unknown impurities.
在你们的回复中，你们声明说你们已采取了几个纠正措施，包括更新你们的程序“色谱峰积分技术”，在其中包括对禁用积分事件的使用控制。但是，你们的回复是不充分的，国灰其中没有提供针对每种药品色谱处理参数的具体纠正措施或支持性文件，包括在FDA483表中所引用的API。你们没有展示出你们要如何确保你们的检验方法适合于确定你们的API是否符合既定标准和质量。因此，你们所提交的数据汇总并不能证明之前已放行的批次不包括未知杂质超水平的情况。
In response to this letter, provide updated analyses of all lots within expiry that take into account any changes to specific test methods and chromatographic parameters.
在回复此函时，请提交更新后的尚在有效期的所有批次分析情况，在其中考虑对具体检测方法和色谱参数的所有变更。
2. Failure to prevent unauthorized access or changes to data and failure 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，未能采取充分的控制来防止对数据的修改和忽略。
During the inspection, our investigators discovered a lack of basic laboratory controls to prevent changes to and deletions from your firm’s electronically-stored data in laboratories where you conduct CGMP activities. Specifically, audit trail functionality for some systems you used to conduct CGMP operations was enabled only the day before the inspection, and there were no quality unit procedures in place to review and evaluate the audit trail data. For example, you used standalone HPLC (2-RD HP/SM/32) to conduct analyses for Drug Master File (DMF) submissions and investigations, such as characterization of a starting material for your (b)(4) DMF. You also used uncontrolled systems to conduct out-of-specification (OOS) investigations for in-process materials used to manufacture (b)(4) API.
在检查期间，我们的调查人员发现你们缺乏基本的化验室控制来防止修改和删除公司化验室的电子存贮数据，而这是你们实施CGMP活动的地方。具体来说，有一些你们用来实施CGMP操作的系统的审计追踪功能是在检查的前一天才激活的，并且质量部门没有制订程序对审计追踪数据进行审核和评估。例如，你们使用了单机版HPLC（2-RD HP/SM/32）来检测DMF申报资料和调查中的样品，例如，你们某DMF中起始物料的结构确证。你们还使用不受控的系统来实施某API生产所用中间物料的OOS调查。
小贴士：
FDA 483 报告，也称现场检查报告，是美国FDA 检查人员根据美国现行法律法规，对企业进行现场检查，对不符合cGMP 的地方进行总结并发给企业。企业需立即针对不符合项进行整改，并在收到483 报告后15个工作日内向FDA 相关部门回复483 中不符合项的整改情况。若FDA 认定企业的答复妥当，并符合现行法律法规的要求，那么企业就避免收到FDA 警告信。FDA 每个财政年都会统计、总结并发布483 表格，其在官网上公布。
