近日，FDA 發布了Natco Pharma Limited的483缺陷報告，其中提及在線粒子系統的相關的數據完整性缺陷：

檢查人員在粒子監測系統軟件中檢索到的11份環境監測報告，發現電子數據與附在生產批記錄上的正式報告副本之間存在差異。

檢查人員將電子報告與批記錄中的超行動限打印報告進行比較時，發現結果已從超行動限（不合格）改為不超行動限。

該公司管理層承認，操作人員將在線粒子數據保存在U盤中，然后主管在指定的臺式機上打印測試報告，FDA表示：這種工作流程使得在數據生成點與正式報告之間存在數據被篡改的可能，并判定該公司在數據完整性方面存在重大缺陷。

在線粒子同一采樣點多個批次多次采樣結果均不合格，未啟動事件報告或調查。

該公司操作人員將這些在線粒子不合格結果的報告打印并附在批記錄中。盡管QA部門對這些打印件進行了審核，但并未發現或處理這一偏差。FDA表示：這表明質量監督不足。

至少發現了57起即首次采樣不合格，隨后重新采樣，然后合格的事件。盡管這符合該公司SOP“如采樣點超出限度，且是由于人員移動造成的，則在同一位置重復采樣。”但是沒有提供文件證明不合格是否確實是由于人員移動造成的。

超過300 份無菌操作期間的環境監測報告未打印并附在批記錄中。

翻譯如下：

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

無菌區域在環境條件監測系統方面存在缺陷。

Your firm operates XX non - viable particle monitoring equipment XX used to perform XX generate test data for non - viable (NVP) count used in environmental monitoring and cleanroom and qualification activities in Grade A, Grade B, Grade C, and Grade D areas in support of aseptic manufacturing operations in your Unit XX Aseptic processing used for manufacturing XX mg / ml and XX mg / ml product for the US market.

貴公司使用 XX 非活性粒子監測設備進行非活性（NVP）計數測試，數據用于 A 級、B 級、C 級和 D 級區域的環境監測、潔凈室及確認活動，以支持XX 毫克 / 毫升和 XX 毫克 / 毫升產品的無菌生產操作。

During our review, we observed that your quality unit does not review the electronic data generated, stored and archived, only using printout as primary data.

在我們的檢查過程中，我們注意到貴公司質量部門未能審核所生成、存儲和歸檔的電子數據，僅將打印件作為主數據。

During our review of the electronic data for non - viable (NVP) during aseptic operations, it was found to be inadequate.

在我們對無菌操作期間非活性（NVP）電子數據的審查中，發現其存在缺陷。

For example, for eleven (11) final sample report results for XX µm and XX µm particles retrieved from the software (electronic data) for XX discrepancies were observed between the electronic data and the official reported hardcopy final results attached to production batch records.

例如，從軟件（電子數據）中檢索到的 11 份關于 XX µm和 XX µm粒子的最終樣品報告結果顯示，電子數據與附在生產批記錄上的正式報告副本的最終結果之間存在 XX 差異。

This issue affected XX batches from 11/02/2023 to 04/16/2024:

此問題影響了 2023 年 11 月 2 日至 2024 年 4 月 16 日期間的 XX 批產品：

(Injection XX mg/vial, non - US commercial batch).

（注射劑 XX 毫克 / 瓶，非美國商業批次）。

Upon comparison of the electronic data reports (soft copy) to the printed over action limit data reports in the batch records (hard copy), it was observed that results had been altered from over the action limit (non - conforming) to below the action limit.

在將電子數據報告（軟拷貝）與批記錄中的超行動限打印數據報告（硬拷貝）進行比較時，發現結果已從超行動限（不合格）改為不超行動限。

The firm's management acknowledged that prior to July 2024, operators saved data on USB drives and supervisors printed test reports on their assigned desktops, a practice since discontinued. This workflow appears to have allowed for potential manipulation of data between the point of generation and official reporting, representing a significant gap in your firm's data integrity.

貴公司管理層承認，在 2024 年 7月之前，操作人員將數據保存在 U盤中，然后主管在指定的臺式機上打印測試報告，這一做法此后已停止。這種工作流程似乎使得在數據生成點與正式報告之間存在數據被篡改的可能，這表明貴公司在數據完整性方面存在重大缺陷。

B. For XX batches

B. 對于 XX 批次

For the injection from 04/16/2024 to 06/06/2025, your firm failed to follow your own standard operating procedure (SOP No. VPD/137 - 12, "Procedure for Operation and Monitoring of Non - Viable Particle Count by XX" effective 02/17/2025) for handling out - of - limit NVP results. The SOP stipulates that if a sampling location fails to be within the limit, an incident report should be initiated with performing an investigation. However, for all XX batches, the same locations were sampled multiple times with failing results until a passing result was eventually obtained, without initiating the required incident reports or investigations. Furthermore, operators printed all data reports, including those with failing results, and attached them to the batch records. Despite Quality Assurance review of these hardcopy printouts, this deviation to the SOP was not identified or addressed. This practice demonstrates a lack of adherence to established procedures and inadequate quality oversight.在 2024 年 4 月 16 日至 2025 年 6 月 6 日的注射劑生產中，貴公司未能遵循企業標準操作規程（SOP編號 VPD/137 - 12，“XX非活性粒子計數操作與監測程序”，于 2025 年 2 月 17 日生效）來處理超出限度的非活性粒子（NVP）結果。該操作規程規定，如果采樣點超出限度，應啟動事件報告并進行調查。然而，對于所有 XX 批次，相同的采樣點多次采樣結果均不合格，直到最終獲得合格結果，期間未啟動所需的事件報告或調查。此外，操作人員打印了所有數據報告，包括那些不合格結果的報告，并將其附在批記錄中。盡管質量保證部門對這些硬拷貝打印件進行了審核，但并未發現或處理這一偏差。這種做法表明缺乏對既定程序的遵守以及質量監督不足。

C. Additionally, across XX NVP equipment unit

C. 此外，在 XX 非活性粒子設備單元中

at least 57 different instances were identified where the first sample failed, and the sample was subsequently retested and passed. While this aligns with your SOP's allowance for retesting, the procedure specifically states, 'if a sampling location fails to be within the limit, and the high counts are due to personnel movement, repeat the sampling at the same location.' However, there was no documentation by operators to indicate whether the failures were indeed due to personnel movement, making it impossible to verify if the retesting was justified according to the procedure.

至少發現了 57 起即首次采樣不合格，隨后重新采樣，然后合格的事件。雖然這符合貴公司操作規程中對重新采樣的允許規定，但該程序特別指出，“如果采樣點超出限度，且高計數是由于人員移動造成的，則在同一位置重復采樣。” 然而，操作人員沒有提供文件證明不合格是否確實是由于人員移動造成的，因此無法根據程序確認新采樣是否合理。

D. Finally, your operators failed to print and attach to batch records environmental monitoring data during aseptic operations that appeared to be within specification, resulting in the omission ofrelevant data from batch documentation and preventing proper review by the Quality Unit. Additionally, your firm failed to properly document and review environmental monitoring activities in the change room. Despite a procedure requiring monitoring XX to more than 300 data reports were printed out, documented, or reviewed by your production or quality units.

D. 最后，貴公司操作人員未將無菌操作期間的（據說）合格的環境監測數據打印并附在批記錄中，導致批記錄中遺漏了相關數據，且質量部門無法進行適當審核。此外，貴公司未能妥善記錄和審核更衣室的環境監測活動。盡管有程序要求對 XX 進行監測，但超過 300 份數據報告未被貴公司生產部門或質量部門打印、記錄或審核。