FDA警告信：印度DIVI'S

  Warning Letter 320-17-34

April 13, 2017

Mr. Kiran S. Divi

Director and President of Operations

Divi’s Laboratories Ltd. (Unit II)

Unit-2, Chippada Village

Annavaram Post Bheemunipatnam Mandal

Visakhapatnam District

Andhra Pradesh 531162

India

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。

We acknowledge the corrective actions described in your response, including enabling audit trail functionality for all chromatographic systems in your laboratories, as well as procedural updates that require review and evaluation of the data generated by these systems. However, your response did not demonstrate how the specific controls you have implemented prevent deletion or alteration of data, nor have you shown how you will ensure that these controls are documented, implemented, and followed.

我们收到了你们回复中所述的纠正措施，包括激活你们化验室所有色谱系统的审计追踪功能，更新程序，在其中要求对这些系统所产生的数据进行审核和评估。但是，你们的回复没有说明你们已实施了哪些具体的控制来防止数据删除或修改，也没有展示你们将如何来确保这些控制有记录、有实施以及有跟踪。

3.      Limiting access to or copying of records

限制获得记录和复制记录

Your firm limited access to or copying of records that our investigators were entitled to inspect. For example, our investigators requested records of your audit trail data from all chromatographic systems used to test drugs for the U.S. market at your facility. The files you ultimately provided (in the form of Excel spreadsheets rather than direct exports from your chromatographic software) were not the original records or true copies, and showed signs of manipulation. The records you did provide contained highlighting, used inconsistent date formats, and lacked timestamp data; these features are inconsistent with original data directly exported from chromatographic testing software.

你们公司限制了我们调查人员获取和复制检查所需记录。例如，我们调查人员要求你们调取你们工厂生产的销往美国的药品检测所用所有色谱系统的审计追踪记录。而最终你们所提供的记录（以EXCEL表格提供，而不是直接从你们的色谱软件输出）并不是原始记录或其真实副本，显示出修改的痕迹。你们提供的记录包括有着重显示，使用了不一致的日期格式，缺乏时间戳数据。这些特点与从色谱检测软件直接输出的原始数据是不一致的。

Our investigators and their supervisor explained at least twice that the data you provided was not representative of actual audit trail data from the chromatographic systems, and requested that you provide the original, unmodified records. Your firm stated, without reasonable explanation, that you could not provide the requested audit trail records. When our investigators explained that your failure to provide the requested records would be documented as a refusal, you acknowledged the refusal.

我们的调查人员及其主管解释了至少2次说你们所提供的数据不能代表实际的色谱系统审计追踪数据，要求你们提供原始的、未经修改的记录。你们公司声称你们不能提供所要求的审计追踪记录，并没有合理解释。当我们的调查人员解释你们未能提供所需的记录会被记录为拒绝检查时，你们知晓该行为是拒绝检查行为。

Our investigators documented other instances in which your firm limited the inspection by providing some, but not all, of the records requested by the FDA investigator that FDA had authority to inspect. At multiple times during the inspection, FDA requested records of CGMP activities performed in your R&D laboratories at the behest of your quality unit. However, you limited the inspection by providing only a subset of the requested records, and our investigators also found at least one of the requested records shredded in the trash. Finally, our investigators requested chromatograms to substantiate your claim that you had identified and quantitated the impurities in (b)(4), but you never provided the records that our investigators asked for to support your claim.

我们的调查人员记录了你们公司限制检查的其它情况，你们只提供了部分而不是全部FDA调查人员所索取的官方有权检查的记录。在检查中有多次FDA索取你们研发实验室代表你们质量部门实施的CGMP活动记录，但你们限制检查，只提供了一部分所索取的记录，而我们的调查人员也发现至少有一份索取的记录被扔在了垃圾桶。最后，我们的调查人员索取色谱图来证明你们说你们在XX中鉴别和定量的杂质，但你们从头到尾都没有提供调查人员所要求的记录来支持你们的声明。

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, athttps://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf.

当所有者、操作人员或代理延迟、否决、限制或拒绝检查时，该药品将根据FDCA第501(j)部分被认为是掺假药品。参见FDA指南。

Data Integrity Remediation 数据完整性弥补

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.

你们的质量体系不能充分确保数据是完整准确的，用以支持你们所生产药品的安全性、有效性和质量。我们知晓你们正聘用一位顾问来审计你们的操作，协助你们符合FDA要求。

In response to this letter, provide the following.

在回复此函时，请提交以下内容：

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 data 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。
• A comprehensive retrospective evaluation of the nature of the 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.
• 一份对数据完整性缺陷状况的全面回顾性评估。我们建议由一个有资质的第三方里具有该领域专业水平的专家评估所有数据完整性问题。
  

B.  A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.

对你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。

C.  A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:

你们公司的管理策略，包括你们全球CAPA计划详细情况。你们的策略应包括：

• 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.
• 详细的CA计划，描述你们如何确保你们生成的所有数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的数据。
• 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 or drug application data at your firm.
• 一份完整的描述你们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。
  

FDA considers the expectations outlined in ICH Q7 in determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, for guidance regarding CGMP for the manufacture of API, athttps://www.fda.gov/downloads/Drugs/.../Guidances/ucm073497.pdf.

FDA在确定API生产是否符合CGMP要求时，考量的依据是ICH Q7中列出的要求。参见FDA指南文件。

You are required to submit any addition, deletion, or other change to your Drug Master File to the FDA under 21 CFR 314.420. You are also required to notify each person authorized to reference the information in the DMF about pertinent changes. Failure to annually update the DMF can cause delays to FDA’s review of pending applications, and may result in FDA initiating proceedings to close the DMF.

你们应根据21 CFR 314.420向FDA提交对你们DMF文件的增加、删除或其它变更。你们还应通知所有引用DMF中信息的授权人相关变更。未能对DMF进行年度更新可能会导致FDA延误审核待批准申报，可能导致FDA启动关闭DMF的程序。

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 your facility.

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 and 99-32 on March 20, 2017.

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 Divi’s Laboratories Ltd. (Unit II) at Unit-2, Chippada Village, Visakhapatnam District 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:

           

Marisa Heayn

Consumer Safety 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 3004149463.

Sincerely,

/S/

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research