The audit trail for High Performance Liquid Chromatography (HPLC) instrument QCIEQPI40 showed multiple integrations conducted on the 18-month stability tests for unknown impurity content for (b)(4), USP lots (b)(4), without appropriate documentation, justification, and investigation.

HPLC仪器QCIEQP140仪器的审计追踪显示某USP批号某产品18个月稳定性检测有未知杂质含量多个积分，但没有适当的文件记录、论证和调查。

 

Your quality assurance manager agreed that these integrations were inappropriate. When our investigator asked you to reprocess the chromatograms using appropriate integration parameters, the results were out-of-specification for unknown impurity content. Your quality unit must review all pertinent analytical data when making batch release decisions in order to determine batch quality.

你们质量保证部经理认可这些积分是不恰当的。当我们的调查人员要求你们使用适当的积分参数对这些色谱数据进行重新处理时，处理结果显示未知杂质含量超标。你们的质量部门在做出批放行决策时必须审核所有相关的分析数据，以确定批产品质量。

 

In your response, you provided passing 24-month stability results for (b)(4) lots (b)(4), and committed to use the auto integration function. Your response is inadequate because it does not address the failing 18-month stability results for these lots and does not demonstrate how you will ensure that you retain complete and accurate records of all tests.

在你们的回复中，你们提供了该批号24个月的稳定性结果，承诺要使用自动积分功能。你们的回复是不充分的，因为回复并没有对失败的18个月稳定性结果进行说明，也没有证明你们要如何确保你们能够保存所有检测的准确完整记录。

 

2. Failure to follow and document laboratory controls at the time of performance.

未能在实施检验时遵守和记录化验室检验情况。

 

Our investigator observed inconsistently-dated laboratory records. For example, your executed protocol records show that a 24-month time-point stability testing sample of (b)(4), USP batch (b)(4), entered the laboratory on February 14, 2015. Our investigator requested the HPLC data. You provided our investigator HPLC chromatogram printouts showing that the sample was tested on February 12 and 13, 2015: one or two days before your protocol shows that the samples even entered the lab. You were unable to find any raw data corresponding to these tests. The use-log of the HPLC does not contain entries for these runs.

我们的调查人员发现化验室记录日期不一致的情况。例如，你们实施的方案记录显示24个月稳定性测试样品是在2015年2月14日进入化验室的。我们的调查人员要求查看HPLC数据。你们给我们调查人员提供的HPLC图谱打印件显示样品是在2015年2月12日和13日检测的，在你们的方案显示样品甚至还没进到化验室的1-2天之前。你们没有发现对应这些测试的原始数据。HPLC的使用日志也没有这些样品检验运行的记录。

 

In another example, a printed chromatogram from related substance analysis performed by gas chromatography for (b)(4), batch (b)(4), was dated August 26, 2014. The data saved to your computer system from this analysis was dated December 28, 2013: nearly eight months before the date on the printed chromatogram.

在另一个例子中，GC对某批号所做的有关物质分析打印图谱里，日期是2014年8月26日。在你们的电脑系统中存贮的此分析的日期为2013年12月28日：比打印图谱早了接近8个月。

 

In your response, you attributed data discrepancies to software malfunctions, power outages, and personnel shift changes. Your response is inadequate because you have not sufficiently explained how you are improving controls, notwithstanding these claimed sources of discrepancies, to ensure the reliability and accuracy of the data you rely on to evaluate the quality of your drugs.

在你们的回复中，你们将数据不一致归结于软件故障，断电和人员换班。你们的回复是不充分的，因为你们没有充分地解释你们要如何改善你们的控制，不管这些所声明的不一致的原因是什么，都应确保你们赖以评估你们药品质量的数据的准确性。

 Data Integrity Remediation  数据完整性弥补措施

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 that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide the following.
你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。我们知道你们聘请了顾问来审计你们的操作，协助符合FDA要求。在回复此函时，提供以下资料：

A.  A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: 
一份对数据记录和报告不准确性程度的全面调查。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.
详细的调查方案和方法学；对评估所覆盖的所有化验室、生产操作和系统的总结，以及对你们意在排除的操作中所有部分的论证。
Interviews of current and former employees to identify the nature, scope, and root cause of da
ta inaccuracies. We recommend that these interviews be conducted by a qualified third party.
与现有的和已离职的员工进行面谈，找出数据不准确的表现、范围、根本原因。我们建议这些面谈由一个有资质的第三方来实施。
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.
你们工厂数据完整性缺陷的程度的评估。识别出省略、修改、删除、记录销毁、不同步记录填写和其它缺陷。描述你们工厂操作中发现数据完整性问题的所有部分。数据完整性问题的根本原因的描述，包括认定当前行动计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题承担责任的个人仍有能力对你公司对CGMP相关或药物应用数据产生影响。
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.
临时描述，描述你们已采取的行动，或即将采取用以保护患者确保你们药品质量的努力，例如通知你们的客户、召回产品、实施额外测试、向稳定性试验计划中增加批次以确保稳定性、药品申报行动以及加强投诉监测。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.

长期措施，其中描述所有对用以确保你们公司数据完整性的程序、流程、方法、控制、系统、管理监管和人力资源（例如培训、员工提高）的弥补和提升。

A status report for any of the above activities already underway or completed.

对上述活动已开展或已经完成的状态报告。

 

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 in all your facilities.

 

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.

 

FDA placed your firm on Import Alert 66-40 on July 6, 2016.

 

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.

 

Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Srikem Laboratories Pvt. Ltd. Plot No. 17/24, MIDC Taloja, Navi Mumbai, MH 410208, 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).

 

After you receive this letter, respond to this office in writing within 15 working days. 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 working days, state your reasons for delay and your schedule for completion.

 

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

      Carlos Gonzalez, Compliance Officer

      U.S. Food and Drug Administration

      White Oak, Building 51 Room 4359

      10903 New Hampshire Avenue

      Silver Spring, MD 20993

      USA

 

Please identify your response with FEI 3005048741.

 

Sincerely,

 

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research