前言

 

2025年2月18日，FDA發布了一篇在2025年2月6日給Tyche Industries Ltd的警告信。FDA在檢查中發現堤喀工業有限公司在藥品生產過程中存在嚴重的CGMP偏差，涉及數據完整性、設備清潔、物料鑒別和質量單位職責履行等多個方面。以下是詳細介紹：

 

1、未能記錄所有質量相關活動：

公司管理層承認存在偽造數據的行為，例如在生產過程中未開啟干燥箱的情況下偽造溫度數據。

生產、質量保證和質量控制部門的管理人員參與了“倒填日期計算表”的準備工作，并將其交給調查人員。

公司的記錄實踐不符合CGMP要求。

 

2、設備清潔與維護不足：

FDA記錄了生產設備中存在鐵銹樣殘留物和裸露足跡，但設備標簽顯示已清洗并準備好使用。

公司未能提供有效的清潔程序，以防止污染或物料殘留。

公司未能充分解釋如何防止類似問題再次發生。

 

3、未能對進廠生產物料進行鑒別：

用于生產原料藥的進廠物料未經過充分的鑒別測試。

公司未能說明是否對所有原材料進行了鑒別測試，以及如何防止新的原材料再次出現類似偏差。

 

4、質量單位（QU）職責履行不充分：

QU未能確保CGMP記錄的完整性，未能對每一批次及其相關信息進行完整和最終的審核。

QU未能有效監督整個運營過程，確保對適當實踐的遵守。

 

5、數據完整性問題：

公司的質量體系未能確保數據的準確性和完整性。

公司未能充分評估數據完整性問題的范圍，包括通過面談現任和前任員工以及全面審查數據記錄。

 

基礎信息

 

產品:Drugs

 

參考編號:320-25-41

 

檢查日期：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.

 

美國美國食品藥品監督管理局(FDA)于2024年8月12日至16日檢查了您的藥品生產工廠——堤喀工業有限公司(FEI 3004790309 ),地址為:6-223，Sarpavaram (V), Kakinada。

 

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

 

這封警告信總結了活性藥物成分(原料藥)與現行良好生產規范(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).

 

因為你的生產、加工、包裝或保存的方法、設備或控制不符合CGMP，你的原料藥屬于《聯邦食品、藥品和化妝品法案》(FD&C法案)第501(a)(2)(B)節，21 U.S.C. 351(a)(2)(B)定義的摻假。

 

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

 

我們詳細審查了您2024年9月4日對我們的FDA 483表格的回復，并確認收到您隨后的信函。

 

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

 

在我們的檢查過程中，我們的調查員觀察到具體的偏差，包括但不限于以下內容。

 

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

 

1.未能在執行時記錄所有與質量相關的活動。

 

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.

 

你的質量部門(QU)未能確保CGMP記錄的完整性。例如，在檢查過程中，貴公司管理層的一名成員表示，貴公司的兩名操作員承認偽造了一個干燥箱的溫度數據，該干燥箱在(b)(4)批次的生產過程中沒有打開，后來不符合殘留溶劑質量標準。此外，生產部門的一名助理經理、質量保證部門的一名助理經理和質量控制經理承認參與了“倒填日期計算表”的準備工作，并將其交給了我們的調查人員。

 

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

 

你們的記錄實踐表明你們的工廠并不符合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.

 

你的回復是不充分的。您表示，您計劃聘請一名顧問來確認數據完整性差距，并在2025年6月30日前制定和實施一項行動計劃，大約是檢查結束后的十個月，而該檢查記錄了嚴重有問題的數據完整性問題。此外，您表示，您將這些事件中涉及的一些員工從CGMP相關活動中除名，但您沒有解釋采取了什么措施來防止這些活動中涉及的其他員工出現進一步的數據完整性偏差。最后，您沒有充分評估貴公司數據完整性失誤的范圍，包括通過面談現任和前任員工以及全面審查數據記錄。

 

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.

 

這封信中的重要發現表明您的QU沒有完全行使其權力和/或職責。您的公司必須向QU提供適當的權限和足夠的資源，以履行其職責并始終如一地確保藥品質量。有關建立和維護符合CGMP的質量體系的指南，請參見FDA指南:https:/ /www.fda.gov/media/71535/download,的Q8(R2)制藥開發，https://www.fda. gov/media/167721/download的Q9質量風險管理和https://www.fda.gov/media /71553/download.的Q10制藥質量體系。

 

In your response to this letter, provide:

 

在回復此信時，請提供:

 

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:

 

一項全面的評估和補救計劃，以確保您的質量單位（QU）被賦予足夠的權力和資源，能夠有效運作。評估還應包括但不限于以下內容：

 

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

 

對貴公司所采用程序的穩健性和適宜性的評估。

 

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

 

QU監督整個運營過程的規定，以評估對適當實踐的遵守情況。

 

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

 

在QU做出放行決策之前，對每一批次及其相關信息進行完整和最終的審核。

 

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

 

對調查的監督和批準，以及履行所有其他QU職責，以確保所有產品的鑒別、規格、質量和純度。

 

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.

 

對整個制造和實驗室操作中使用的文件記錄系統進行全面評估，以確定記錄實踐中的不足之處。包括一份詳細的糾正措施和預防措施(CAPA)計劃，該計劃將全面修正貴公司的記錄實踐，以確保貴公司在整個運營過程中保留可歸屬的、清晰的、完整的、原始的、準確的同步記錄。

 

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.未能清洗設備和器具以防止污染或物料的殘留，而污染或殘留會改變原料藥的質量，使其超出官方或其他已確定的質量標準。

 

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.

 

美國食品和藥物管理局記錄了用于生產(b)(4)的非專用(b)(4)中的鐵銹樣殘留物。此外，FDA記錄了用于生產(b)(4)的另一個(b)(4)內部的裸露足跡。每個(b)(4)都貼有標簽，說明已經清洗干凈，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.

 

不充分的清潔和維護生產設備會導致潛在的交叉污染，危及你的原料藥的質量和安全。

 

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.

 

你的回復是不充分的。您表示，自2024年2月以來，您審查了受影響設備中生產的產品的質量，但您沒有說明您是如何進行審查的，也沒有說明您將審查限制在這一時間范圍內的原因。此外，你沒有充分解釋你將如何防止人員進入設備后無法清潔設備的情況再次發生。最后，您聲明進入設備內部的人員應該“脫鞋后穿上布鞋套”，但是未能穿上合適的衣服，包括合適的鞋子，會給產品帶來不可接受的風險。

 

In your response to this letter, provide:

 

在回復此信時，請提供:

 

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計劃對設施和設備實施常規的、警惕的運營管理監督。除其他事項外，該計劃應確保及時發現設備/設施性能問題、有效執行維修、遵守適當的預防性維護計劃、及時對設備/設施基礎設施進行技術升級，以及不斷完善的管理審評制度。

 

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.

 

對您的清潔效果進行全面、獨立的回顧性評估，以評估交叉污染危害的范圍。包括殘留物的識別，其他可能未被適當清洗的生產設備，以及對交叉污染的產品是否已放行銷售的評估。評估應確定清潔程序和實踐的任何不足之處，并涵蓋用于生產多種產品的每件生產設備。

 

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計劃，基于對您的清潔計劃的回顧性評估，包括對您的清潔過程和實踐的適當補救，以及完成時間表。為設備清洗的生命周期管理提供您的程序中的漏洞的詳細總結。描述清潔計劃的改進，包括清潔效果的提高；改進對所有產品和設備適當清潔的持續驗證；以及所有其他需要的補救措施。

 

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

 

3.未能對每批進廠的生產物料進行鑒別。

 

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.

 

用于生產美國市場原料藥的進廠物料沒有經過充分的測試。例如，沒有對在(b)(4)的生產中用作原料的(b)(4)進行鑒別測試。

 

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。您聲明您“發起了活動”來進行(b)(4)的鑒別。但是，您沒有說明是否所有其他原材料都經過了鑒別測試，或者您將如何防止新的原材料再次出現這種偏差。

 

In your response to this letter, provide:

 

在回復此信時，請提供:

 

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.

 

對您的物料系統進行全面、獨立的審查，以確定所有原材料、容器和密封件的供應商是否都是合格的，以及物料是否指定了適當的有效期或復驗期。審查還應確定來料控制是否足以防止使用不合適的原料、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.

 

化學和微生物質量控制標準，用于測試和放行每批用于生產的原材料。

 

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.

 

描述你將如何測試每一批原料是否符合所有適當的標準，包括鑒別、規格、質量和純度。如果您打算接受供應商的分析證書(COAs)的任何結果，而不對每批原材料的規格、質量和純度進行測試，請說明您將如何通過初始驗證和定期再驗證來建立供應商結果的可靠性。此外，還應承諾對每批來料至少進行一次特定的鑒別測試。

 

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.

 

從測試所有原材料獲得的結果的總結，以評估來自每個原材料制造商的COA的可靠性。包括描述此COA驗證計劃的標準操作程序。

 

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

 

您的計劃摘要，該計劃旨在對您生產的藥品進行檢驗的合同設施進行認證和監督。

 

Data Integrity Remediation

 

數據完整性補救

 

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.

 

你的質量體系沒有充分確保數據的準確性和完整性，以支持你生產的藥物的安全性、有效性和質量。請參閱FDA的指導文件《數據完整性和符合藥物CGMP 》,以獲取建立和遵循符合CGMP的數據完整性規范的指導，網址為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:

 

我們強烈建議您聘請合格的顧問來幫助您進行補救。作為對這封信的回復，請提供:

 

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.

 

對數據記錄和報告的不準確程度進行全面調查，包括在美國銷售的藥物的數據審查結果。包括數據完整性問題的范圍和根本原因的詳細描述。

 

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.

 

對觀察到的失敗對藥品質量的潛在影響的當前風險評估。您的評估應包括對由于數據完整性缺失而影響的藥物放行給患者帶來的風險的分析，以及對正在進行的操作帶來的風險的分析。

 

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.

 

貴公司的管理戰略，包括全面的CAPA計劃的細節。詳細的糾正措施計劃應描述您打算如何確保貴公司產生的所有數據的可靠性和完整性，包括微生物和分析數據、生產記錄以及提交給FDA的所有數據。

 

 

Conclusion

 

結論 

 

 

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.

 

這封信中引用的偏差并不是您工廠中存在的所有偏差的清單。您負責調查和確定任何偏差的原因，并負責防止其再次發生或其他偏差的發生。

 

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日將貴公司提供進口到美國的產品置于進口警報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.

 

及時糾正任何偏差。FDA可能會拒絕批準將貴公司列為藥品制造商的新申請或補充申請，直到任何偏差得到完全解決，并且我們確認貴公司符合CGMP。我們可能會重新檢查，以確認您已經完成了對任何偏差的糾正措施。

 

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).

 

根據《FD&C法案》第801(a)(3)節,《美國法典》第21卷第381(a)(3)節，未能解決任何偏差還可能導致FDA繼續拒絕將堤喀工業有限公司生產的產品輸入美國。根據《FD&C法案》第501(a)(2)(B)節,《美國法典》第21卷第351(a)(2)(B)節的含義，在此授權下的有摻假嫌疑的物品可能會被扣留或拒絕入境，因為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.

 

這封信通知您我們的發現，并為您提供解決上述不足的機會。收到此信后，請在15個工作日內以書面形式回復本辦公室。請具體說明您為解決任何偏差并防止其再次發生所做的工作。作為對這封信的回復，您可以提供更多信息供我們考慮，因為我們將繼續評估您的活動和實踐。如果您不能在15個工作日內完成糾正措施，請說明您延遲的原因和您的完成時間表。

 

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

 

將您的電子回復發送到CDER-OC-OMQ-Communications@fda.hhs.gov。請在回復中注明FEI 3004790309和收件人:Russell Riley。