前言

 

2025年2月18日，FDA发布了一篇在2025年2月6日给Tyche Industries Ltd的警告信。FDA在检查中发现堤喀工业有限公司在药品生产过程中存在严重的CGMP偏差，涉及数据完整性、设备清洁、物料鉴别和质量单位职责履行等多个方面。以下是详细介绍：

 

1、未能记录所有质量相关活动：

公司管理层承认存在伪造数据的行为，例如在生产过程中未开启干燥箱的情况下伪造温度数据。

生产、质量保证和质量控制部门的管理人员参与了“倒填日期计算表”的准备工作，并将其交给调查人员。

公司的记录实践不符合CGMP要求。

 

2、设备清洁与维护不足：

FDA记录了生产设备中存在铁锈样残留物和裸露足迹，但设备标签显示已清洗并准备好使用。

公司未能提供有效的清洁程序，以防止污染或物料残留。

公司未能充分解释如何防止类似问题再次发生。

 

3、未能对进厂生产物料进行鉴别：

用于生产原料药的进厂物料未经过充分的鉴别测试。

公司未能说明是否对所有原材料进行了鉴别测试，以及如何防止新的原材料再次出现类似偏差。

 

4、质量单位（QU）职责履行不充分：

QU未能确保CGMP记录的完整性，未能对每一批次及其相关信息进行完整和最终的审核。

QU未能有效监督整个运营过程，确保对适当实践的遵守。

 

5、数据完整性问题：

公司的质量体系未能确保数据的准确性和完整性。

公司未能充分评估数据完整性问题的范围，包括通过面谈现任和前任员工以及全面审查数据记录。

 

基础信息

 

产品:Drugs

 

参考编号:320-25-41

 

检查日期：2024年8月12日至16日

 

收件人:Mr. Sandeep Gokaraju

 

警告信正文

 

Warning Letter320-25-41

 

February 6, 2025

 

Dear Mr. Gokaraju:

 

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tyche Industries Ltd, FEI 3004790309, at 6-223, Sarpavaram (V), Kakinada, from August 12 to 16, 2024.

 

美国美国食品药品监督管理局(FDA)于2024年8月12日至16日检查了您的药品生产工厂——堤喀工业有限公司(FEI 3004790309 ),地址为:6-223，Sarpavaram (V), Kakinada。

 

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs).

 

这封警告信总结了活性药物成分(原料药)与现行良好生产规范(CGMP)的重大偏差。

 

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

 

因为你的生产、加工、包装或保存的方法、设备或控制不符合CGMP，你的原料药属于《联邦食品、药品和化妆品法案》(FD&C法案)第501(a)(2)(B)节，21 U.S.C. 351(a)(2)(B)定义的掺假。

 

We reviewed your September 4, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 

我们详细审查了您2024年9月4日对我们的FDA 483表格的回复，并确认收到您随后的信函。

 

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

 

在我们的检查过程中，我们的调查员观察到具体的偏差，包括但不限于以下内容。

 

1.Failure to record all quality-related activities at the time they are performed.

 

1.未能在执行时记录所有与质量相关的活动。

 

Your quality unit (QU) failed to ensure the integrity of CGMP records. For example, during the inspection, a member of your management stated that two of your operators admitted to falsifying temperature data for a drying oven that was not turned on during the manufacture of a(b)(4) batch, which later failed to meet the residual solvents specification. In addition, an Assistant Manager in Production, an Assistant Manager in Quality Assurance, and a Quality Control Manager admitted to participating in the preparation of a “backdated calculation sheet” that was given to our investigator.

 

你的质量部门(QU)未能确保CGMP记录的完整性。例如，在检查过程中，贵公司管理层的一名成员表示，贵公司的两名操作员承认伪造了一个干燥箱的温度数据，该干燥箱在(b)(4)批次的生产过程中没有打开，后来不符合残留溶剂质量标准。此外，生产部门的一名助理经理、质量保证部门的一名助理经理和质量控制经理承认参与了“倒填日期计算表”的准备工作，并将其交给了我们的调查人员。

 

Your documentation practices were not indicative of a facility that is in compliance with CGMP.

 

你们的记录实践表明你们的工厂并不符合CGMP。

 

Your response is inadequate. You state that you plan to hire a consultant to identify data integrity gaps and prepare and implement an action plan by June 30, 2025, approximately ten months from the conclusion of the inspection, which documented serious questionable data integrity practices. In addition, you state that you removed some of the employees involved in these incidents from CGMP-related activities, but you do not explain what was done to prevent the other employees involved in these activities from further data integrity deviations. Finally, you do not fully evaluate the scope of data integrity lapses at your firm, including by interviewing current and former employees and comprehensively reviewing data records.

 

你的回复是不充分的。您表示，您计划聘请一名顾问来确认数据完整性差距，并在2025年6月30日前制定和实施一项行动计划，大约是检查结束后的十个月，而该检查记录了严重有问题的数据完整性问题。此外，您表示，您将这些事件中涉及的一些员工从CGMP相关活动中除名，但您没有解释采取了什么措施来防止这些活动中涉及的其他员工出现进一步的数据完整性偏差。最后，您没有充分评估贵公司数据完整性失误的范围，包括通过面谈现任和前任员工以及全面审查数据记录。

 

Significant findings in this letter indicate that your QU is not fully exercising its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances:Q8(R2) Pharmaceutical Development at https://www.fda.gov/ media/71535/ download, Q9 Quality Risk Management at https://www.fda.gov/media/167721/download and Q10 Pharmaceutical Quality System at https://www.fda.gov/ media/71553/download.

 

这封信中的重要发现表明您的QU没有完全行使其权力和/或职责。您的公司必须向QU提供适当的权限和足够的资源，以履行其职责并始终如一地确保药品质量。有关建立和维护符合CGMP的质量体系的指南，请参见FDA指南:https:/ /www.fda.gov/media/71535/download,的Q8(R2)制药开发，https://www.fda. gov/media/167721/download的Q9质量风险管理和https://www.fda.gov/media /71553/download.的Q10制药质量体系。

 

In your response to this letter, provide:

 

在回复此信时，请提供:

 

A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

 

一项全面的评估和补救计划，以确保您的质量单位（QU）被赋予足够的权力和资源，能够有效运作。评估还应包括但不限于以下内容：

 

o A determination of whether procedures used by your firm are robust and appropriate.

 

对贵公司所采用程序的稳健性和适宜性的评估。

 

o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

 

QU监督整个运营过程的规定，以评估对适当实践的遵守情况。

 

o A complete and final review of each batch and its related information before the QU disposition decision.

 

在QU做出放行决策之前，对每一批次及其相关信息进行完整和最终的审核。

 

o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

 

对调查的监督和批准，以及履行所有其他QU职责，以确保所有产品的鉴别、规格、质量和纯度。

 

A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

 

对整个制造和实验室操作中使用的文件记录系统进行全面评估，以确定记录实践中的不足之处。包括一份详细的纠正措施和预防措施(CAPA)计划，该计划将全面修正贵公司的记录实践，以确保贵公司在整个运营过程中保留可归属的、清晰的、完整的、原始的、准确的同步记录。

 

2.Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the APIs beyond the official or other established specifications.

 

2.未能清洗设备和器具以防止污染或物料的残留，而污染或残留会改变原料药的质量，使其超出官方或其他已确定的质量标准。

 

FDA documented rust-like residues inside(b)(4) non-dedicated (b)(4) used in the production of (b)(4). In addition, FDA documented bare footprints inside another (b)(4) used in the production of (b)(4). Each (b)(4) was labeled that it had been cleaned and was ready for use.

 

美国食品和药物管理局记录了用于生产(b)(4)的非专用(b)(4)中的铁锈样残留物。此外，FDA记录了用于生产(b)(4)的另一个(b)(4)内部的裸露足迹。每个(b)(4)都贴有标签，说明已经清洗干净，可以使用。

 

Inadequately cleaned and maintained manufacturing equipment can lead to potential cross- contamination that could compromise your API’s quality and safety.

 

不充分的清洁和维护生产设备会导致潜在的交叉污染，危及你的原料药的质量和安全。

 

Your response is inadequate. You state that you reviewed the quality of the products manufactured in the impacted equipment since February 2024, but you do not describe how you conducted this review, nor the reason you limited your review to this timeframe. In addition, you do not adequately explain how you will prevent the failure to clean equipment after personnel enter inside it from recurring. Finally, you state that personnel entering inside equipment should “wear cloth shoe cover after removing shoe,” but failing to wear suitable clothing, including appropriate footwear, poses an unacceptable risk to the product.

 

你的回复是不充分的。您表示，自2024年2月以来，您审查了受影响设备中生产的产品的质量，但您没有说明您是如何进行审查的，也没有说明您将审查限制在这一时间范围内的原因。此外，你没有充分解释你将如何防止人员进入设备后无法清洁设备的情况再次发生。最后，您声明进入设备内部的人员应该“脱鞋后穿上布鞋套”，但是未能穿上合适的衣服，包括合适的鞋子，会给产品带来不可接受的风险。

 

In your response to this letter, provide:

 

在回复此信时，请提供:

 

Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

 

您的CAPA计划对设施和设备实施常规的、警惕的运营管理监督。除其他事项外，该计划应确保及时发现设备/设施性能问题、有效执行维修、遵守适当的预防性维护计划、及时对设备/设施基础设施进行技术升级，以及不断完善的管理审评制度。

 

A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

 

对您的清洁效果进行全面、独立的回顾性评估，以评估交叉污染危害的范围。包括残留物的识别，其他可能未被适当清洗的生产设备，以及对交叉污染的产品是否已放行销售的评估。评估应确定清洁程序和实践的任何不足之处，并涵盖用于生产多种产品的每件生产设备。

 

Your CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning for all products and equipment; and all other needed remediations.

 

您的CAPA计划，基于对您的清洁计划的回顾性评估，包括对您的清洁过程和实践的适当补救，以及完成时间表。为设备清洗的生命周期管理提供您的程序中的漏洞的详细总结。描述清洁计划的改进，包括清洁效果的提高；改进对所有产品和设备适当清洁的持续验证；以及所有其他需要的补救措施。

 

3.Failure to test the identity of each batch of incoming production material.

 

3.未能对每批进厂的生产物料进行鉴别。

 

Your incoming raw material used to manufacture API intended for the U.S. market was not adequately tested. For example, you did not test the(b)(4) used as a raw material in the production of (b)(4) for identity.

 

用于生产美国市场原料药的进厂物料没有经过充分的测试。例如，没有对在(b)(4)的生产中用作原料的(b)(4)进行鉴别测试。

 

Your response is inadequate. You state that you “initiated the activity” to test(b)(4) for identity. However, you do not address whether all other raw materials are tested for identity or how you will prevent this deviation from recurring with new raw materials.

 

你的回答是不充分的。您声明您“发起了活动”来进行(b)(4)的鉴别。但是，您没有说明是否所有其他原材料都经过了鉴别测试，或者您将如何防止新的原材料再次出现这种偏差。

 

In your response to this letter, provide:

 

在回复此信时，请提供:

 

A comprehensive, independent review of your material system to determine whether all suppliers of raw materials, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable raw materials, containers, and closures.

 

对您的物料系统进行全面、独立的审查，以确定所有原材料、容器和密封件的供应商是否都是合格的，以及物料是否指定了适当的有效期或复验期。审查还应确定来料控制是否足以防止使用不合适的原料、容器和密封件。

 

The chemical and microbiological quality control specifications you use to test and release each incoming batch of raw material for use in manufacturing.

 

化学和微生物质量控制标准，用于测试和放行每批用于生产的原材料。

 

A description of how you will test each raw material batch for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificates of analysis (COAs) instead of testing each raw material batch for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming raw material batch.

 

描述你将如何测试每一批原料是否符合所有适当的标准，包括鉴别、规格、质量和纯度。如果您打算接受供应商的分析证书(COAs)的任何结果，而不对每批原材料的规格、质量和纯度进行测试，请说明您将如何通过初始验证和定期再验证来建立供应商结果的可靠性。此外，还应承诺对每批来料至少进行一次特定的鉴别测试。

 

A summary of results obtained from testing all raw materials to evaluate the reliability of the COA from each raw material manufacturer. Include your standard operating procedure that describes this COA validation program.

 

从测试所有原材料获得的结果的总结，以评估来自每个原材料制造商的COA的可靠性。包括描述此COA验证计划的标准操作程序。

 

A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

 

您的计划摘要，该计划旨在对您生产的药品进行检验的合同设施进行认证和监督。

 

Data Integrity Remediation

 

数据完整性补救

 

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. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

 

你的质量体系没有充分确保数据的准确性和完整性，以支持你生产的药物的安全性、有效性和质量。请参阅FDA的指导文件《数据完整性和符合药物CGMP 》,以获取建立和遵循符合CGMP的数据完整性规范的指导，网址为https://www.fda.gov/media/119267/download.

 

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:

 

我们强烈建议您聘请合格的顾问来帮助您进行补救。作为对这封信的回复，请提供:

 

A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

 

对数据记录和报告的不准确程度进行全面调查，包括在美国销售的药物的数据审查结果。包括数据完整性问题的范围和根本原因的详细描述。

 

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

 

对观察到的失败对药品质量的潜在影响的当前风险评估。您的评估应包括对由于数据完整性缺失而影响的药物放行给患者带来的风险的分析，以及对正在进行的操作带来的风险的分析。

 

A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

 

贵公司的管理战略，包括全面的CAPA计划的细节。详细的纠正措施计划应描述您打算如何确保贵公司产生的所有数据的可靠性和完整性，包括微生物和分析数据、生产记录以及提交给FDA的所有数据。

 

 

Conclusion

 

结论 

 

 

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

 

这封信中引用的偏差并不是您工厂中存在的所有偏差的清单。您负责调查和确定任何偏差的原因，并负责防止其再次发生或其他偏差的发生。

 

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on January 2, 2025.

 

FDA于2025年1月2日将贵公司提供进口到美国的产品置于进口警报66-40。

 

Correct any deviations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any deviations.

 

及时纠正任何偏差。FDA可能会拒绝批准将贵公司列为药品制造商的新申请或补充申请，直到任何偏差得到完全解决，并且我们确认贵公司符合CGMP。我们可能会重新检查，以确认您已经完成了对任何偏差的纠正措施。

 

Failure to address any deviations may also result in the FDA continuing to refuse admission of articles manufactured at Tyche Industries Ltd in Kakinada, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused 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).

 

根据《FD&C法案》第801(a)(3)节,《美国法典》第21卷第381(a)(3)节，未能解决任何偏差还可能导致FDA继续拒绝将堤喀工业有限公司生产的产品输入美国。根据《FD&C法案》第501(a)(2)(B)节,《美国法典》第21卷第351(a)(2)(B)节的含义，在此授权下的有掺假嫌疑的物品可能会被扣留或拒绝入境，因为其制造中使用的方法和控制措施似乎不符合CGMP。

 

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any deviations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

 

这封信通知您我们的发现，并为您提供解决上述不足的机会。收到此信后，请在15个工作日内以书面形式回复本办公室。请具体说明您为解决任何偏差并防止其再次发生所做的工作。作为对这封信的回复，您可以提供更多信息供我们考虑，因为我们将继续评估您的活动和实践。如果您不能在15个工作日内完成纠正措施，请说明您延迟的原因和您的完成时间表。

 

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3004790309 and ATTN: Russell Riley.

 

将您的电子回复发送到CDER-OC-OMQ-Communications@fda.hhs.gov。请在回复中注明FEI 3004790309和收件人:Russell Riley。