近日，FDA發布了對中國藥科大學儀器分析中心的警告信，警告信中披露該單位作為一個合同檢測實驗室，業務中包含對藥物API和中間體的USP樣品進行檢測，FDA對其進行延伸檢查并發現以下缺陷：

 

未能建立實驗室控制記錄

 

樣品測試記錄僅包含兩行數字，沒有標題或抬頭。在檢查期間，該單位解釋說，這些數字代表樣品的檢測日期、批號和處理數據。

 

檢測記錄未記錄樣品制備、檢測程序和系統適用性

 

在檢測結果發送給與客戶之前，未對所有測試記錄進行第二人審核

 

未能確保在檢查期間隨時提供實驗室記錄。

 

該單位告知檢查人員，2023 年 11 月之前的測試數據都存儲在外部硬盤驅動器上。但是，當檢查人員要求查看此數據時，他們表示可能很難找到數據，因為有許多歸檔的硬盤驅動器，并且只有歸檔人員才能檢索數據。

 

計算機化系統沒有足夠的控制措施來防止未經授權的訪問或更改數據。其中，檢驗儀器還用于學術教學和研究，不同用戶共享同一個具有完全管理訪問權限的登錄 ID。

 

在檢查期間被問及是否跟蹤任何偏差和實驗室錯誤時，該單位回答說他們只提供測試結果。

 

該單位的實驗室主管表示，該單位不參與CGMP 活動，但是，FDA表示：他們的客戶將數據用于 CGMP 目的。

 

FDA在警告信中表示：該單位作為合同檢測實驗室，必須了解自己有責任完全按照 CGMP 進行作，并將這些藥物測試過程中遇到的任何不合格結果或重大問題告知所有客戶。

 

警告信翻譯如下：

 

Dear Mr. Shen:

 

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Center for Instrumental Analysis of China Pharmaceutical University, FEI 3005037448, at Zhongyang Road, No. 24 Tongjiaxing Road, Nanjing, Jiangsu, from September 18 to 20, 2024.

 

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

 

FDA 于2024 年 9 月 18 日至20 日檢查了位于江蘇省南京市通嘉興路 24 號中陽路的中國藥科大學儀器分析中心（FEI 3005037448）。 本警告信總結了活性藥物成分 （API） 與CGMP的重大違規。

 

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

 

由于你們的制造、加工、包裝或保存方法、設施或控制不符合CGMP，你們所測試的 API 按照FD&C 法案501（a）（2）（B）、21 U.S.C. 351（a）（2）（B）被認定為摻假。

 

We reviewed your September 23, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 

我們詳細審閱了你們于 2024 年 9 月 23 日對FDA 483的回復，并確認收到你們的后續信件。

 

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

 

在我們的檢查過程中，我們的檢查人員觀察到了具體的缺陷，包括但不限于以下：

 

1. Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure your API and intermediates complies with established specifications and standards.

 

未能建立實驗室控制記錄，其中包括從所有實驗室測試中獲得的完整數據，以確保API 和中間體符合既定規范和標準。

 

Your firm is a contract testing laboratory that analyzes APIs and intermediates, including samples of crude(b)(4), (b)(4), and (b)(4) USP, for the presence of (b)(4) using 1H Nuclear Magnetic Resonance spectroscopy (NMR).

 

貴單位是一家合同檢測實驗室，使用 1H 核磁共振波譜 （NMR） 分析 API和中間體，包括粗品 （b）（4）、（b）（4） 和 （b）（4） USP 樣品中是否存在（b）（4）。

 

Your firm failed to ensure that laboratory testing records were complete. For example, your test record of samples, “(b)(4)(USP) Experiment Records” for Lot (b)(4) contained only two lines of numbers with no explanation headers or titles. During the inspection, you explained that these numbers represented the testing date, lot number, and processing data for (b)(4) samples you analyzed for your customers. Further, the testing records did not document sample preparation, the test procedure(s), and system suitability. Additionally, not all the testing records were reviewed by a second person prior to the results being shared with your customers.

 

貴單位未能確保實驗室檢測記錄完整。例如，你們的樣品測試記錄，XX批次的“XX（USP）實驗記錄”僅包含兩行數字，沒有說明標題或抬頭。在檢查期間，你們解釋說，這些數字代表你們為客戶分析的 （b）（4） 樣品的檢測日期、批號和處理數據。此外，檢測記錄未記錄樣品制備、檢測程序和系統適用性。此外，在與客戶共享結果之前，并非所有測試記錄都由第二人審核。

 

Your firm also failed to ensure that laboratory records were readily available during the inspection. You informed our investigators that your(b)(4) 1H NMR testing data before November 2023 were stored on external hard drives. However, when our investigators requested to review this data, you stated that it might be difficult to locate the data because there were many archived hard drives and only the archiving personnel could retrieve the data. As a result, you did not provide any CGMP data stored on the external hard drives for review during the inspection. We acknowledge that you provided limited data after the inspection.

 

貴單位也未能確保在檢查期間隨時提供實驗室記錄。你們告知我們的檢查人員，你們在2023 年 11 月之前的 （b）（4） 1H NMR 測試數據都存儲在外部硬盤驅動器上。但是，當我們的檢查人員要求查看此數據時，你們表示可能很難找到數據，因為有許多歸檔的硬盤驅動器，并且只有歸檔人員才能檢索數據。因此，在檢查期間，你們沒有提供存儲在外部硬盤驅動器上的任何CGMP 數據以供審計。我們也知道你們在檢查之后提供了有限的數據。

 

Additionally, your firm failed to ensure that your computerized systems, such as the computers used to control to the NMR equipment, and to store raw data files or process data, have adequate controls in place to prevent unauthorized access or changes to data. The NMR equipment was also used for academic teaching and research, and it appears that various users shared one login ID with full administrative access.

 

此外，貴單位未能確保你們的計算機化系統（例如用于控制NMR 設備以及存儲原始數據文件或過程數據的計算機）具有足夠的控制措施來防止未經授權的訪問或更改數據。NMR 設備還用于學術教學和研究，似乎不同的用戶共享同一個具有完全管理訪問權限的登錄 ID。

 

In your response, you acknowledge your failure to keep adequate records and have now established procedures outlining requirements for laboratory documentation and sample tracking. You also state that you implemented user management settings on your computerized system and completed the system validation.

 

在你們的回復中，你們承認未能保存足夠的記錄，并且現在已經建立了概述實驗室文件和樣品追溯要求的程序。你們還聲明在計算機化系統上實施了用戶管理設置并完成了系統驗證。

 

Your response is inadequate because the procedures appear to lack sufficient detail to be effective. Moreover, you did not consider a retrospective review and risk assessment to evaluate the potential impact of the inadequate documentation and lack of access controls, along with their associated risks, on the validity of your test results.

 

你們是回復是不充分的，因為這些程序似乎缺乏足夠的細節來確保有效。此外，你們沒有考慮進行回顧性審查和風險評估，以評估文件不充分和缺乏訪問控制及其相關風險對測試結果有效性的潛在影響。

 

In response to this letter, provide:

 

回復此函，請提供：

 

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

 

對整個實驗室操作中使用的文件系統進行全面評估，以確定文件記錄實踐不足的地方。包括詳細的糾正措施和預防措施計劃，全面糾正你們的文件記錄實踐，以確保在整個操作過程中保留可追溯、清晰、完整、原始、準確、同步的記錄。

 

A risk assessment     summarizing the potential impact of inadequate documentation on product     quality, and a commitment to notify customers of any deficiencies.

 

一份風險評估總結文件不充分對產品質量的潛在影響，并承諾將任何缺陷通知客戶。

 

A risk assessment     summarizing the potential impact of lack of access controls of the     computers and NMR equipment on product quality, and a commitment to notify     customers of any deficiencies.

 

一份風險評估總結計算機和 NMR 設備缺乏訪問控制對產品質量的潛在影響，并承諾將任何缺陷通知客戶。

 

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.

 

請參閱 FDA指南《藥物 CGMP 的數據完整性和合規性》，了解有關在建立和遵循 CGMP 合規數據可靠性實踐的指南。

 

2. Failure of your quality unit to ensure that drugs are appropriately tested and the results are reported.

 

質量部門未能確保藥物得到適當的測試并報告結果。

 

You failed to establish a quality unit (QU), including defining responsibilities and procedures applicable to a QU. Additionally, when asked during the inspection whether you track any deviations and laboratory errors, you responded that you only provide testing results. Your laboratory director stated that the firm is not involved in CGMP activities, however, your customers used your data for CGMP purposes.

 

你們未能建立質量部門（QU），包括制定適用于 QU 的責任和程序。此外，在檢查期間被問及你們是否跟蹤任何偏差和實驗室錯誤時，你們回答說你們只提供測試結果。你們的實驗室主管表示，貴單位不參與CGMP 活動，但是，你們的客戶將你們的數據用于 CGMP 目的。

 

Without an adequate QU and quality system in place, there is inadequate assurance that controls are implemented to ensure that your CGMP testing operations are performing in a state of control.

 

如果沒有足夠的 QU 和質量體系，就無法充分保證實施控制措施來確保你們的 CGMP 測試操作在受控狀態下執行。

 

In your response, you state that you established a quality department and provided supporting documentation, including standard operating procedures. Your response is inadequate as your procedures appear to lack sufficient detail and comprehensive coverage of all the systems supporting your CGMP testing operations.

 

在回復中，你們聲明建立了質量部門并提供了支持文件，包括標準操作程序。你們的回復是不充分的，因為你們的程序似乎缺乏足夠的細節并全面覆蓋支持 CGMP 測試操作的所有系統。

 

In response to this letter, provide:

 

回復此函，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:

 

全面的評估和補救計劃，以確保你們的 QU 獲得有效運行的權限和資源。評估還應包括但不限于：

 

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

 

確定貴單位所使用的程序是否穩健和適當。

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

 

在整個操作過程中進行QU 監督的規定，以評估對適當做法的遵守情況。

A complete and final review of the laboratory record for each sample and its related information before the QU disposition decision.

 

在 QU 處置決定之前，對每個樣本的實驗室記錄及其相關信息進行完整和最終的審查。

Oversight and approval of investigations and discharging of all other QU duties to ensure validity of the laboratory test results without having negative impact on identity, strength, quality, and purity of your customers’ drug products.

 

監督和批準調查并履行所有其他 QU 職責，以確保實驗室檢測結果的有效性，而不會對客戶藥品的特性、強度、質量和純度產生負面影響。

 

A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedures to ensure changes, such as changes to or deviations from a validated test method, are justified, reviewed, investigated, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.

 

對變更管理系統進行全面、獨立的評估。此評估應包括，但不限于，你們的程序，以確保變更，例如對已驗證的分析方法的變更或偏差，由你們的QU論證、審查、調查和批準。你們的變更管理程序還應包括確定變更有效性的規定。

 

An adequate QU overseeing all elements of CGMP is necessary to consistently ensure drug product quality. Your firm’s quality systems are inadequate. See FDA’s current thinking on quality systems in the FDA guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download for help in implementing quality systems and risk management approaches.

 

一個適當的 QU監督 CGMP 的所有要素對于始終如一地確保藥品質量是必要的。貴單位的質量體系不足。請參閱 FDA 指南《藥品 CGMP 法規的質量體系方法》中 FDA 對質量體系的當前考量，以幫助實施質量體系和風險管理方法。

 

Responsibilities of a Contract Testing Lab

 

合同測試實驗室的職責

 

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your customers. It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification results or significant problems encountered during the testing of these drugs.

 

FDA 將承包商視為制造商自身設施的延伸。你們不符合CGMP 可能會影響你們為客戶檢測的藥物的質量、安全性和有效性。你們必須了解自己有責任完全按照 CGMP 進行操作，并將這些藥物測試過程中遇到的任何不合格結果或重大問題告知所有客戶。