翻译： JULIA  来源： Julia法规翻译

Warning Letter 320-18-40

March 09, 2018

V.N. Gopalkrishnan, CEO

Malladi Drugs &Pharmaceuticals Limited

No 9, G.S.T. Road, St. ThomasMount, Chennai 600 016, India 

Dear V.N. Gopal krishnan:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Malladi Drugs& Pharmaceuticals Limited, Unit 1, at 67 SIPCOT Industrial Complex,Ranipet, Vellore District, Tamil Nadu, from September 4 to 8, 2017.

美国FDA于2017年9月4-8日检查了你们位于印度泰米尔纳德邦的Malladi Drugs & Pharmaceuticals Limited, Unit 1生产场所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

本警告信总结了API生产严重违反CGMP的行为。

Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot 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), 21U.S.C. 351(a)(2)(B).

由于你们的API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API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。

We reviewed your September 2017 response in detail.

我们已详细审核了你公司2017年9月的回复。

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

检查期间，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 use appropriate precautions to minimize the risk of API contamination where open equipment is used. 使用开放设备时未使用适当的预防措施以降低API污染风险。

Parts of your facility inwhich API production is conducted are open to the outdoors. Our investigator observed vermin, such as birds and insects, in the facility near open equipment used for drug manufacturing. Their presence puts your drugs at risk of contamination.You failed to take adequate precautions to prevent the risk of contamination while producing drugs using open equipment.

你工厂部分API生产区域为露天环境。我们调查人员在药品生产所用的开放设备附近厂区发现有害虫，如鸟和昆虫。这使得你们的药品处于污染风险中。你公司未采取足够的预防措施来防止在开放设备中生产药品时的污染风险。

You committed to corrective and preventive actions (CAPA), but your response is inadequate because you failed to address the potential risk to product quality and safety.

你们承诺采取CAPA，但你们的回复是不充分的，因为你们未解决产品质量和安全的潜在风险问题。

In response to this letter, provide a risk assessment for all drugs within their re-test date manufactured and distributed within the United States. Include an evaluation of all (b)(4), drug intermediates, and drugs potentially contaminated by vermin.

在回复此函时，请提交一份在美国销售且仍在复验期内的所有药品的风险评估。其中应包括对所有XX、药品中间体和可能受到害虫污染的药品的评估。

2.     Failure to have equipment of the appropriate design and suitability for its intended use and cleaning for the manufacture of API. 设备未进行适当设计，适合其既定用途和API生产清洁。

You use (b)(4) vessels in the (b)(4) and (b)(4) stages of your production process. In your response, you indicate that (b)(4) water is used for cleaning the (b)(4) vessels. However, your cleaning processes are insufficient. You lack justification that you can prevent contamination from foreign matter and other impurities that may seep from the (b)(4). Further, your equipment is difficult to reproducibly clean.

你们在你们生产工艺的XX和XX步骤中使用了XX罐。在你们的回复中，你们说XX罐清洁使用的是XX水。但是，你们的清洁程序是不充分的。你们缺乏论证证明你们可以防止从XX渗入的异物和其它杂质。还有，你们的设备的清洁难以重复。

Your response also states thatthe (b)(4) is kept partially full with water for up to (b)(4) because the (b)(4) when it is fully dry. Using vessels made of (b)(4) and partially filled with standing water may increase the risk of drug contamination. In addition, equipment surfaces should be easily cleanable, and constructed to prevent additive, absorptive, or reactive characteristics.

你们的回复还说保持XX装一部分水直至XX，因为如果全干会XX。使用XX材质的罐并且装一部分静止水，可能会增加药品污染的风险。另外，设备表面应易于清洁，其结构应防止渗出、吸收或反应特性。

In response to this letter: 在回复此函时

• Commit to replacing your unacceptable (b)(4) equipment with equipment composed of materials that are suitable for their intended use.

• 请承诺采用适合其既定用途的材质组成的设备替换你们不可接受的XX设备

• Provide a risk assessment for any drugs within their re-test date manufactured using inappropriate equipment and distributed within the United States. Determine whether any of your equipment surfaces are reactive, absorptive, or additive so that drug quality, purity, or safety may be affected.

• 请提交一份风险评估，评估仍在其复验期内使用不恰当设备所生产并销售至美国的药品。确定是否你们有任何设备表面有反应、吸收或渗出使得药品质量、纯度或安全性受到影响。

3.     Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 未能证明你们的生产工艺可以重复生产出符合其预定质量属性的API。

During our inspection, you acknowledged that you failed to adequately validate your (b)(4) API drug manufacturing process. In addition, our inspection found that your process lacked adequate control during the (b)(4) step. Twenty-four batches yielded out-of-specification test results for an unspecified impurity over approximately two years. Your firm rejected these nonconforming batches and reprocessed some of them.

在我们检查期间，你们说你们未对你们的XX API药品生产工艺进行足够的验证。另外，我们的检查发现你们的工艺在XX步骤中缺乏足够的控制。约2年中有24批均有OOS结果，检出非特定杂质。你们公司拒收了这些不符合批次，有些批次进行了返工。

Prior to the manufacture of process qualification batches, a manufacturer should identify all significant sources of variability and develop robust controls throughout the operation.Your process validation program failed to sufficiently address process parameters and other variables in the commercial manufacturing operation to support process reproducibility. It is essential that your process validation program provide substantial information and data to determine if the process can consistently produce acceptable quality products under commercial manufacturing conditions.

在生产工艺确认批次之前，生产商应找出所有操作中所有波动的来源，并建立稳健的控制。你们的工艺验证计划未能充分说明商业化生产操作中工艺参数和其它变量以支持工艺可重复性。你们的工艺验证计划必须提供实质性信息和数据来确定工艺是否可在商业化生产条件下一致地生产出具有可接受质量的产品。

In your response, you also acknowledged that your investigations and timeliness of response to the batch failures was inadequate, and that process changes were initiated without formal change management. You also provided data from many batches that met specifications for impurity and identity. However, this data is not are placement for adequate process design, control, CAPA and change management, and does not sufficiently support your claim that your process is robust.

在你们的回复中，你们承认过去你们的调查和时间表是不充分的，工艺变更启动没有正式变更管理。你们还提供了许多杂质和鉴别符合质量标准的批次数据。但是，这些数据并不能取代充分的工艺设计、控制、CAPA和变更管理，不足以支持你们声明说你们的工艺是稳健的。

Your firm does not have anadequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation athttp://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.

你们公司没有充分的持续计划监测工艺控制以确保稳定性生产操作和一致的药品质量。参见FDA工艺验证指南。

In response to this letter, provide: 在回复此函时，请提交

• A data-driven and scientifically sound process validation program that identifies all sources of variability, establishes robust design and controls, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle. Also, include your process qualification protocol and results from your recent validation study.

• 一份基于数据的科学合理的工艺验证计划，在其中识别出所有波动的来源，建立稳健的设计和控制，确保在产品生命周期中基于持续基础对批内和批间波动监管。还有，包括你们工艺验证方案和你们最近的验证研究中所得的结果。

• The results from your stability study of validation batches.

• 验证批次稳定性研究所得结果。

• A comprehensive, independent evaluation and remediation of your change management system. The evaluation should include, but not be limited to, assuring changes are appropriately justified, approved by your quality unit, and evaluated for effectiveness. Also, include a retrospective assessment of all changes executed outside an appropriate change management process since September 1, 2015, and the effect on product quality.

• 对你们变更管理系统的全面、独立评估以及弥补措施。评估应包括但不仅限于确保变更经过适当的论证、经过你们质量部门批准，以及进行有效性评估。还有，应包括对所有2015年9月1日以来不在适当变更管理程序中所执行的变更的回顾性评估，以及其对产品质量的影响。

• A comprehensive, independent evaluation and remediation of your CAPA system. The evaluation should include but not be limited to a retrospective analysis of the effectiveness of all CAPAs since September 1, 2015.

• 对你们CAPA系统的全面、独立评估以及弥补措施。评估应包括但不仅限于对2015年9月1日以来所有CAPA有效性的回顾性分析。

• An assessment of drug quality risk and toxicity of the (b)(4) impurity. Also, provide an updated investigation into the impurity, including the specification established for it and verification that your process improvements (including automation) have been effective. 

• 药品质量风险以及XX杂质毒性的评估。还有提供一份对杂质的更新调查，包括为其建立的质量标准，并确认你们的工艺改进（包括自动化）是有效的。

CGMP consultant recommended GMP顾问建议

Based upon the nature of thedeviations we identified at your firm, we strongly recommend engaging aconsultant qualified to evaluate your operations and assist your firm inmeeting CGMP requirements. Your use of a consultant does not relieve yourfirm’s obligation to comply with CGMP. Your firm’s executive management remainsresponsible for fully resolving all deficiencies and ensuring ongoing CGMPcompliance.

依据违规情况，我们强烈建议你们使用一位具备资质的顾问来协助你们公司符合CGMP要求。你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。

Conclusion 结论

Deviations cited in thisletter 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.

此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。

FDA placed your firm on Import Alert 66-40 on December 13, 2017.

FDA已于2017年12月13日将你公司置于进口禁令66-40清单中。

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.

在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。

Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Malladi Drugs & Pharmaceuticals Limited, Unit 1, at 67SIPCOT Industrial Complex, Ranipet, Vellore District, Tamil Nadu, 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, 21U.S.C. 351(a)(2)(B).

未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。

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.

在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。

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

LT Matthew Schnupp, Pharm.D.

Consumer Safety Officer

U.S. Food and DrugAdministration

White Oak Building 51, Room4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your responsewith FEI 3005115135.

Sincerely,

/S/ 

Francis Godwin

Acting Director

Office of ManufacturingQuality

Office of Compliance

Center for Drug Evaluation andResearch

CC:     

R. Ravichandran, VicePresident–Manufacturing

Malladi Drugs &Pharmaceuticals Limited, Unit-1

67, SIPCOT Industrial Complex

Ranipet, Vellore District

Tamil Nadu, India 632403