FDA警告信：印度Wockhardt Limited（节译）

Via UPS                                                                                  Warning Letter 320-17-13

Return Receipt Requested

December 23, 2016

Dr. Habil Khorakiwala

Founder, Chairman and Group CEO

Wockhardt Limited

Bandra Kurla Complex, Bandra (East)

Mumbai, Maharashtra 400051

India

Dear Dr. Khorakiwala:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Wockhardt Limited, Plot No. 138 G.I.D.C. Estate District Bharuch, Ankleshwar, Gujarat, from December 7 to 15, 2015.

FDA在2015年12月67-15日检查了你们在印度古吉拉特邦的生产场所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, 21 CFR parts 210 and 211, and significant deviations from CGMP for active pharmaceutical ingredients (API).

本警告信总结了严重违反制剂CGMP，21CFR第210和211部分，以及原料药CGMP的情况。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs 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).

我们的检查人员还记录了你们的生产、加工、包装和保存方法、设施或控制不符合CGMP要求，因此你们的药品根据FD&C法案21 U.S.C. 351(a)(2)(B)第501(a)(2)(B)部分定义被认定为掺假药品。

We reviewed your January 15, 2016, response in detail and acknowledge receipt of your subsequent correspondence.

我们详细审核了你们2016年1月15日及之后提交的回复。

During our inspection, our investigator observed specific violations and deviations including, but not limited to, the following.

在检查期间，我们的调查人员发现的违规情况包括但不仅限于以下：

Sterile API Violations 无菌原料药违规情况

1.  Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

你公司未能制订和遵守适当的书面程序，用以防止理应无菌的药品受到微生物污染，其中包括对所有无菌和灭菌工艺的验证（21 CFR 211.113(b)）。

During the airflow analysis (smoke study) of aseptic connections on your (b)(4) equipment inside the laminar air flow (LAF) ISO-5 area, our investigator identified air flow disturbances and turbulence. Under dynamic conditions, air did not sufficiently sweep across and away from sterile connections, so the sterility of any product processed under these conditions could be compromised.

在层流罩（LAF）ISO-5区域内的某设备无菌连接的气流分析（发烟试验）中，我们调查人员发现气流扰动和湍流。在动态环境下，空气不能充分扫过并从无菌连接处排出，因此在此条件下加工的所有药品的无菌性无法保证。

Furthermore, in our review of the smoke study, we identified multiple aseptic technique breaches during aseptic connection of the (b)(4) equipment. Your equipment design and aseptic processing operator competencies appear to contribute to the lack of unidirectionality. Aseptic processing equipment should provide for appropriate ergonomics that enable operators to reproducibly conduct aseptic manipulations. In addition, it is critical that your aseptic processing operators have the knowledge and skills to practice strict aseptic techniques. Even operations that have been successfully qualified can be compromised by poor operational, maintenance, or personnel practices.

另外，我们审核发烟试验时，发现在某设备的无菌连接中有多个无菌技术问题。你们的设备设计和无菌处理操作人员资质貌似与不能保证垂直气流有关。无菌加工设备应提供适当的人体工程学保证，使得操作人员可以重复实施无菌操作。此外，你们的无菌操作人员要有实践严格无菌技术的知识和技能是很关键的。即使是经过成功确认的操作也可能会由于不良操作、维护或人员做法而有问题。

In response to this letter, perform a full review of aseptic processing equipment design and aseptic techniques. Provide your corrective and preventive action (CAPA) plan. Include a video DVD of all smoke studies for LAF-711, LAF-712, and LAF-713 conducted following CAPA implementation.

在回复此函时，请对无菌加工设备设计和无菌技术进行全面审核。提交你们的CAPA计划。包括LAF-711、LAF-712和LAF-713在CAPA实施后所进行的所有发烟试验的视频DVD。

2.  Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

你公司未能确保生产人员穿着适于保护药品免受污染的服装（21 CFR 211.28(a)）。

Our investigator observed employees working in gowns that had unraveled stitching extending from hoods, zippers, and pants. Your firm approved these gowns for operations. Employees wore them while manufacturing sterile (b)(4) USP API and sterile (b)(4) API. Five of 10 garments released for use in aseptic production areas had loose fibers or other damage. Per your procedures, you should have discarded these garments. You determined that inadequate lighting and ineffective operator training were root causes.

我们的调查人员发现员工穿着的洁净服从头罩、拉链到裤子的珩缝都有开线。你们公司批准使用这些洁净服让操作人员穿戴。员工在生产无菌XX的USP原料药和无菌XX原料药时都着着这些衣服。10套发放在无菌生产区域使用的衣服里有5套衣料松散或有其它破损。根据你们的程序，你们应该丢弃这些衣服。但你们确定的根本原因却是照明不足，员工培训效果不好。

Your response is inadequate because it does not include your assessment of washing, drying, ironing, sterilizing, or other operations that may contribute to sterile garment damage. It also does not address the need to limit the number of sterilizations. Our investigator noted that you sterilize gowns numerous times. These excessive sterilizations lead to breakdown of gown fibers.

你们的回复是不充分的，因为其中没有包括你们对于可能会引起无菌衣破损的清洗、干燥、熨烫、灭菌和其它操作的评估。其中也没有说明需要限制灭菌的次数。我们的调查人员注意到你们已经对无菌衣灭菌了无数次。过多灭菌会导致无菌衣纤维破损。

Your aseptic processing gowns were inadequate to prevent contamination of your sterile products with particles and microorganisms shed from employees’ bodies. Your firm must use garments that are suitable for aseptic processing.

你们的无菌操作衣不足以防止你们的无菌药品受到来自员工身体脱落的颗粒物和微生物的污染。你们公司必须使用适合无菌工艺的防护服。

In response to this letter, provide an action plan that describes how your firm will do the following.

在回复此函时，请提交行动方案，在其中描述你们将如何执行以下操作：

• Select appropriate gown suppliers. Include the role of the quality unit in making supplier selection and ongoing qualification decisions.
• 选择适当的洁净衣供应商，包括质量部门在供应商选择和持续确认决策方面的作用。
• Reduce your maximum number of gown sterilizations to ensure that gowns are discarded before they show signs of breakdown. Provide the maximum number of re-sterilizations you will allow, and describe how you will document and validate this procedure.
• 降低你们对无菌衣灭菌的最大次数，以确保无菌衣在显示出破损迹象之前就被丢弃。请提交你们将制订的重复灭菌最多允许次数，并说明你们要如何记录和验证此程序。
• Correct your visual inspection procedures for sterile garments to improve detection and rejection of defective garments.
• 纠正你们对无菌防护服的目视检查程序，以加强对有缺陷防护衣的发现和拒绝。
• Ensure that the quality unit makes final decisions relating to release of raw materials and supplies (e.g., garments) you use in production.
• 确保是由质量部门做出旅行原料和你们生产用品（例如防护衣）相关的最终决策。
• Conduct a risk assessment of the effects of damaged garments on your drugs.
• 对破损防护衣对你们药品产生的影响进行风险评估。
  

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

你们公司未能确保化验室记录中包括为确保药品符合既定质量标准所实施的测试中产生的完整数据。(21 CFR 211.194(a)).

While reviewing gas chromatography data on instrument QA/G07, our investigator found unreported results, including an out-of-specification (OOS) test result for raw materials. You did not investigate this OOS result or explain why you excluded the failing result from the official record.

在审核仪器QA/G07上的气相色谱数据时，我们的调查人员发现未报告的结果，包括原料的一个OOS结果。你们没有对此OOS结果进行调查，也没有解释为什么你们在正式记录中排除了该不合格结果。

Our investigator also found that you reported only two of three chromatographic injections of sterile (b)(4) batch (b)(4)during in-process (b)(4) sample testing for residual solvent. You did not explain why you excluded the third injection. You decommissioned this instrument in July 2014 without reviewing the instrument data.

我们的调查人员还发现你们在无菌XX批号YY中控ZZ样品残留溶剂检测中，只报告了3针中的2针结果。你们没有解释为什么你们排除了第3针结果。你们在2014年7月将该仪器退役时没有对此仪器中的数据进行审核。

Your response indicates that you have initiated a retrospective review of high performance liquid chromatography (HPLC) and gas chromatography (GC) data over a multi-year period. Your response is inadequate because it does not explain the depth of your electronic data review, or commit to a comprehensive retrospective review of raw data from all laboratory equipment and systems.

你们的回复中说你们已经启动针对几年期间HPLC和GC数据的回顾性审核。你们的回复是不充分的，因为其中没有解释你们电子数据审核的深度，也没有承诺你们会对所有的化验室仪器和系统中原始数据进行全面的回顾性审核。

In response to this letter, include a detailed update of the HPLC and GC electronic chromatographic data review. Include the total number of injections during the period, the number that your retrospective audit examined, and all anomalies and deviations observed. Specify the date of the test, products involved, all relevant results obtained, and batch (or other purpose) for which the testing was done. See Data Integrity Remediation caption below for our full request, including a determination of whether the data may have been associated with any drug applications.

在回复此函时，请包括一份对HPLC和GC电子色谱数据审核的详细更新，在其中包括在此期间的总进样针、你们回顾性审计所检查的针数，以及所发现的所有异常和偏差。列明检测的日期、涉及的产品、获得的所有相关结果，以及所检测的批号（或其它目的）。参见以下数据完整性弥补说明，其中有我们的全部要求，在回复中要说明是否有数据与药品申报有关。

4.  Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

你们公司未能对计算机和相关系统进行适当的控制以确保只有经过授权的人员才可以对主生产和主检验记录和其它记录进行修改(21 CFR 211.68(b))。

Our investigator found that you have not validated 12 computerized systems in your quality control laboratory. These systems are used for your stability chambers, ultraviolet (UV) and infrared (IR) spectrophotometers, and for thin layer chromatography (TLC).

我们的调查人员发现你们没有对化验室里12套计算机化系统进行验证。这些系统用于你们的稳定性考察箱、紫外和红外光谱仪以及TLC。

We acknowledge your commitment to validate your computerized systems. However, your response is inadequate.

我们知道你们承诺要验证你们的计算机化系统，但是你们的回复是不充分的。

In response to this letter, include your assessment of the data generated from these stability chambers, UV and IR spectrophotometers, and TLC equipment.

在回复此函时，请包括你们对于这些稳定性考察箱、紫外和红外光谱仪以及TLC设备产生的数据的评估。

API Deviations 原料药违规

5.  Failure to record activities at the time they are performed, and destruction of original records.

未能在活动实施时进行记录，未记录原始记录的销毁。

Data Recorded in Personal Diaries (Unofficial Notebooks) 在个人日记中记录的数据（非正式笔记本）

In your process development laboratory, our investigator found several unofficial notebooks recording sample preparation for OOS investigations, route-of-synthesis experiments, and scale-up data. Our investigator found discrepancies between these unofficial notebooks and the official data retained by your quality unit.

在你们的工艺研发实验室，我们的调查人员发现几本非正式记录本记录了OOS调查样品制备、合成路线实验和放大数据。我们的调查人员发现这些非正式记录本和你们质量部门所保存的正式数据有差异。

Destruction of CGMP Documentation CGMP文件记录的销毁

CGMP documentation was discarded without being assessed by your quality unit. Our investigator found torn and shredded equipment maintenance documents, raw material labels, and change control work orders in your scrap yard awaiting incineration. Your staff lacked knowledge of your corporate procedure for the destruction and incineration of documents.

CGMP文件记录没有经过质量部门评估就被丢弃了。我们的调查人员在你们待焚烧废置场里发现被撕毁和碎掉的设备维护文件、原料标签、变更控制工作指令。你们的员工对于文件销毁和焚烧管理程序缺乏了解。

In your response, you indicate that you have implemented corporate procedure CQA/021 to address the destruction of uncontrolled and controlled documents, and that you have retrained your employees.

在你们的回复中，你们说你们已经实施了公司程序CQA/021，在其中说明了非受控文件和受控文件的销毁，并且重新培训了你们的员工。

Your response is inadequate because you did not assess how your document-control practices affected your distributed products.

你们的回复是不充分的，因为你们没有评估你们的文件控制规范对你们销售的药品会产生什么影响。

Data Integrity Remediation 数据完整性补救措施

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 strongly recommend that you retain a qualified consultant to assist in your remediation.

你们的质量体系未能充分确保用以支持你们生产的药品的安全性、有效性和质量的数据的准确性和完整性。我们强烈建议你们聘用具备资质的顾问来协助你们进行补救。

In response to this letter, provide the following.

在回复此函时，请提交以下资料：

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 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。
  

Conclusion

Violations and deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations and deviations, for determining the causes, for preventing their recurrence, and for preventing other violations and 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 August 5, 2016.

Until you correct all violations and 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 violations and deviations may also result in FDA continuing to refuse admission of articles manufactured at Wockhardt Limited, Plot No. 138 G.I.D.C. Estate District Bharuch, Ankleshwar, Gujarat, 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 within 15 working days. Specify what you have done since our inspection to correct your violations and 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:      

            Rafael Arroyo

            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 3002808500.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research