近日，FDA 发布了Natco Pharma Limited的483缺陷报告，其中提及在线粒子系统的相关的数据完整性缺陷：

检查人员在粒子监测系统软件中检索到的11份环境监测报告，发现电子数据与附在生产批记录上的正式报告副本之间存在差异。

检查人员将电子报告与批记录中的超行动限打印报告进行比较时，发现结果已从超行动限（不合格）改为不超行动限。

该公司管理层承认，操作人员将在线粒子数据保存在U盘中，然后主管在指定的台式机上打印测试报告，FDA表示：这种工作流程使得在数据生成点与正式报告之间存在数据被篡改的可能，并判定该公司在数据完整性方面存在重大缺陷。

在线粒子同一采样点多个批次多次采样结果均不合格，未启动事件报告或调查。

该公司操作人员将这些在线粒子不合格结果的报告打印并附在批记录中。尽管QA部门对这些打印件进行了审核，但并未发现或处理这一偏差。FDA表示：这表明质量监督不足。

至少发现了57起即首次采样不合格，随后重新采样，然后合格的事件。尽管这符合该公司SOP“如采样点超出限度，且是由于人员移动造成的，则在同一位置重复采样。”但是没有提供文件证明不合格是否确实是由于人员移动造成的。

超过300 份无菌操作期间的环境监测报告未打印并附在批记录中。

翻译如下：

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

无菌区域在环境条件监测系统方面存在缺陷。

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.

贵公司使用 XX 非活性粒子监测设备进行非活性（NVP）计数测试，数据用于 A 级、B 级、C 级和 D 级区域的环境监测、洁净室及确认活动，以支持XX 毫克 / 毫升和 XX 毫克 / 毫升产品的无菌生产操作。

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.

在我们的检查过程中，我们注意到贵公司质量部门未能审核所生成、存储和归档的电子数据，仅将打印件作为主数据。

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

在我们对无菌操作期间非活性（NVP）电子数据的审查中，发现其存在缺陷。

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，从软件（电子数据）中检索到的 11 份关于 XX µm和 XX µm粒子的最终样品报告结果显示，电子数据与附在生产批记录上的正式报告副本的最终结果之间存在 XX 差异。

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

此问题影响了 2023 年 11 月 2 日至 2024 年 4 月 16 日期间的 XX 批产品：

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

（注射剂 XX 毫克 / 瓶，非美国商业批次）。

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.

在将电子数据报告（软拷贝）与批记录中的超行动限打印数据报告（硬拷贝）进行比较时，发现结果已从超行动限（不合格）改为不超行动限。

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.

贵公司管理层承认，在 2024 年 7月之前，操作人员将数据保存在 U盘中，然后主管在指定的台式机上打印测试报告，这一做法此后已停止。这种工作流程似乎使得在数据生成点与正式报告之间存在数据被篡改的可能，这表明贵公司在数据完整性方面存在重大缺陷。

B. For XX batches

B. 对于 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 日的注射剂生产中，贵公司未能遵循企业标准操作规程（SOP编号 VPD/137 - 12，“XX非活性粒子计数操作与监测程序”，于 2025 年 2 月 17 日生效）来处理超出限度的非活性粒子（NVP）结果。该操作规程规定，如果采样点超出限度，应启动事件报告并进行调查。然而，对于所有 XX 批次，相同的采样点多次采样结果均不合格，直到最终获得合格结果，期间未启动所需的事件报告或调查。此外，操作人员打印了所有数据报告，包括那些不合格结果的报告，并将其附在批记录中。尽管质量保证部门对这些硬拷贝打印件进行了审核，但并未发现或处理这一偏差。这种做法表明缺乏对既定程序的遵守以及质量监督不足。

C. Additionally, across XX NVP equipment unit

C. 此外，在 XX 非活性粒子设备单元中

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.

至少发现了 57 起即首次采样不合格，随后重新采样，然后合格的事件。虽然这符合贵公司操作规程中对重新采样的允许规定，但该程序特别指出，“如果采样点超出限度，且高计数是由于人员移动造成的，则在同一位置重复采样。” 然而，操作人员没有提供文件证明不合格是否确实是由于人员移动造成的，因此无法根据程序确认新采样是否合理。

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，贵公司操作人员未将无菌操作期间的（据说）合格的环境监测数据打印并附在批记录中，导致批记录中遗漏了相关数据，且质量部门无法进行适当审核。此外，贵公司未能妥善记录和审核更衣室的环境监测活动。尽管有程序要求对 XX 进行监测，但超过 300 份数据报告未被贵公司生产部门或质量部门打印、记录或审核。