本文罗列了近年来GMP检查中的关于生产系统数据完整性的10大缺陷，以及建议的补救措施。如下，供大家参考！

 

Examples of Data Integrity Citations and their Possible Mitigations

生产系统数据完整性缺陷示例及其可能的补救措施

 

1 Audit Trail

审计追踪

 

“There are total (b)(4) standalone manufacturing equipment which are not equipped with HMI/PLC/SCADA system. There is no time stamped audit trail, data management, alarm management, archival and retrieval of records on these standalone manufacturing equipment.” [33]

“总共（b）（4）单机版生产设备没有配备人机界面HMI / 可编程序逻辑控制器PLC / 监控与数据采集SCADA系统。在这些单机版生产设备上没有带时间戳的审计追踪，数据管理，报警管理，归档和检索。“[33]

 

“Our investigator found that your (b)(4)system used for (b)(4) and (b)(4) testing lacked access controls and audit trail capabilities.

“我们的检查人员发现用于（b）（4）和（b）（4）测试的（b）（4）系统缺乏访问控制和审计追踪功能。

 

For example, all employees had administrator privileges and shared one user name, so actions could not be attributed or traced to specific individuals. This exposed your electronic data to manipulation and/or deletion without traceability.” [34]

例如，所有员工都具有管理员权限并共享一个用户名，因此无法归因或跟踪操作的特定个人。这使您的电子数据暴露于篡改和/或删除而无法追踪的风险中。“[34]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Master and reference data review

主数据和参考数据审查

 

CQA/CPP identified and risk assessed

确定CQA / CPP并评估风险

 

Data mapping

数据映射

 

Deviation/incident Reports

偏差/异常报告

 

Report approval

报告批准

 

Including audit trail review as part of the batch report where exceptions are reported

将审计追踪审查作为批报告的一部分，以报告例外情况

 

Technical controls to ensure audit trails are always active

技术控制以确保审计追踪始终处于激活状态

 

2 Calibration

校准

 

“You failed to calibrate and maintain written records for the scale used to weigh components, including active ingredients,

prior to their addition into the manufacturing process (21 CFR 211.68(a)).” [35]

“你没有校准和维护用于在投料前称量组分（包括活性物质）的秤的书面记录（21 CFR 211.68（a））。“[35]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Implement calibration management procedures

实施校准管理程序

 

Periodically review that they are effective

定期审查它们是否有效

 

Automatic system indication of calibration state

自动系统指示校准状态

 

3 Security and Access Controls

安全和访问控制

 

“Our investigators observed that information technology (IT) staff at your facility share usernames and passwords to access your electronic storage system for (b)(4) data. Your IT staff can delete or change directories and files without identifying individuals making changes. After a previous inspection in which FDA observed similar deficiencies, you committed to eliminate these and other data integrity vulnerabilities.” [36]

“我们的检查人员观察到，贵工厂的信息技术（IT）人员共用用户名和密码访问你们的电子存储系统的（b）（4）数据。你们的IT人员可以删除或更改目录和文件，但未能确定谁进行了更改。在之前的检查中，FDA发现了类似的缺陷，你们承诺消除此项以及其他数据完整性漏洞。“[36]

 

“…the computer in your quality unit area did not have controls to restrict access and prevent unauthorized changes to data files and folders. All employees had access to your Annual Product Review (APR) spreadsheet. The desktop computer containing the APR was not locked.” [37]

“...质量部门的计算机没有限制访问的控制措施以防止对数据文件和文件夹的未经授权的更改。所有员工都可以访问你们的年度产品回顾（APR）电子表格。包含APR的台式计算机未锁定。“[37]

 

“The Electronic Logbook (eLog) System V1.0.0. is used for Instrument, Equipment, Area Operation and Cleaning usage log for Production, Warehouse, and Quality Control departments…” “The review of the audit trail for Electronic Logbook (eLog) System Version 1.0.0 in Unit 2 revealed that the “Reviewer” role has more (full) rights to the system than the “Administrator” and the system is managed by QC.” [38]

“生产，仓库和QC部门的仪器，设备，洁净区操作和清洁使用日志使用电子日志（eLog）系统V1.0.0.... ” “对电子日志（eLog）系统版本1.0.0单元2的审计追踪审查显示“审核人”拥有比“管理员”更多（完全）的权限，且系统是由QC人员管理的。“[38]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Access and security management

访问和安全管理

 

Segregation of duties

职责分离

 

Data securely stored, use of relational databases in place of flat file storage

数据安全存储，使用关系型数据库而不是平面文件存储

 

System periodic review

系统定期审查

 

4 Manipulation of System Time 

篡改系统时间

 

“Specifically, your Quality Control (QC) analysts used administrator privileges and passwords to manipulate your high performance liquid chromatography (HPLC) computer clock to alter the recorded chronology of laboratory testing events.” [39]

“特别是，你们的质量控制（QC）分析人员使用管理员权限和密码来篡改高效液相色谱（HPLC）计算机的时间来改变实验室测试事件的时间顺序记录。“[39]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Lock down access to clocks

锁定对时钟的访问

 

Synchronize time Automatically

自动同步时间

 

5 Retention

保存

 

“Your firm failed to maintain production, control, or distribution records associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180).” [40]

“贵公司未能保存与药品生产，控制或分销相关记录至失效期后至少一年（21 CFR 211.180）。”[40]

 

“Our investigator also noted that your firm copied raw data to a CD and then deleted the data from the system to free space on the hard drive. Files copied to the CD were selected manually; the selection process was not supervised. Without audit trail capabilities or supervised file selection, there was no assurance that all raw data files were copied to the CD before they were permanently deleted from the system.”[34]

“我们的检查人员还指出，贵公司将原始数据复制到CD中，然后将数据从系统中删除，来释放硬盘驱动空间。复制到CD的文件是手动选择的; 选择过程没有受到监督。文件的选择如果没有审计追踪功能或监督，则无法保证在从系统中永久删除之前，所有原始数据文件都已复制到CD中。“[34]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Retention procedure, including the need to verify readability of archived data after any software upgrades/ downgrades

保存程序，包括任何软件升级/降级后需要验证保存数据的可读性

 

6 Failure to record activities at the time they are performed.

未能在执行活动的同时记录活动。

 

“Our investigator found numerous examples of your failure to record manufacturing operations contemporaneously with their performance. For example, our investigator discovered blank batch production records that were pre-signed by your operator, partially-completed batch records, and batch records with data changes in pencil without any justification.” [41]

“我们的检查人员发现了大量的例子，说明你们未能在生产操作的同时进行记录。例如，我们的检查人员发现了已由你们的操作人员事先签名的空白批生产记录，部分填写的批记录，以及没有任何理由用铅笔更改数据的批记录。“[41]

 

“Your employees did not complete batch production and control records immediately after activities were performed. When QA reviewers noticed missing entries in the batch records, they made a list of all the missing items on separate, uncontrolled pieces of paper that were provided to the production manager. Data were later entered into CGMP documents after operations had already ended as though they had been entered at the time of the operation.” [42]

“你们的员工未能在活动完成后立即完成批生产和控制记录。当QA审核人员注意到批记录不完整时，他们在单独的、不受控的纸条上罗列所缺少的条目，交给生产经理。随后，在生产操作已经结束之后，数据才被填入到CGMP记录中，就像在操作时已经输入了一样。“[42]

 

“FDA investigators identified instances of non-contemporaneous documentation of batch production activities. Two uncontrolled Excel spreadsheets were used to record discrepancies and certain in-process drug quality data. This data was initially missing in the batch manufacturing record. Your firm later entered this data into batch records and backdated them.” [43]

“FDA检查员发现出了批生产和文件记录不同步的实例。两个不受控制的Excel电子表格用于记录异常和某些生产过程中的质量数据。该数据刚开始不是填写于批生产记录中的。贵公司后来将这些数据输入批记录并倒填了日期。“[43]

 

“A critical deficiency was cited with regardsto data integrity of GMP records, entries were seen to be made when personnel were not present on site, documentation was seen that was not completed contemporaneously despite appearing to be completed in this manner.”[44]

“关于GMP记录的数据完整性，发现了一个严重缺陷，人员不在现场，但可以看到此人的记录，文件看起来是以这种方式完成，而不是（与生产操作）同时完成的。”[44]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Second person verification of results

第二人确认结果

 

Data auditing

数据审核

 

User SOP

用户SOP

 

Training on Good Documentation Practices

良好文件规范培训

 

Use MES that forces contemporaneous recording and sequence of steps

使用MES（生产执行系统）以强制同步记录和按工序生产

 

Move spreadsheets to a validated EDMS or replace with avalidated application

将电子表格转移到经验证的EDMS（电子文档管理系统）或使用经验证的应用程序替代

 

7 Batch Data Review

批数据审核

 

“Your firm’s Quality Control Unit (QCU) failed to review and approve drug product production and control records. For example, your QCU did not identify discrepancies between your batch production records and your product labeling for the type and concentration of active ingredient in your (b)

 

(4) gel and lotion products.” [45]

 

“贵公司的质量控制部门（QCU）未能审查和批准药品生产和控制记录。例如，QCU未能发现批生产记录中（b）（4）凝胶和乳液产品中活性成分的型号和浓度与产品标签之间的不符。“[45]

 

“Our inspector reviewed several batch records and found use of white-out correction liquid, unintelligible data, and/or missing information such as density test results and the date of approval of the batch. Several entries were over written and crossed out with no signature, date, or explanation.

 

“我们的检查人员审查了几个批记录，发现使用了白色涂改液、模糊不清的数据和/或信息缺失，如密度测试结果和产品批准日期。多项内容被覆盖并划掉，没有签名，日期或解释。

 

In addition, laboratory test results (e.g., viscosity, density, appearance, and odor) lacked initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.” [46]

 

此外，实验室测试结果（例如粘度，密度，外观和气味）缺少第二人字母缩写或签名，以表明原始记录已经过审核，准确，完整和符合既定标准。“[46]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Batch data review Procedure

批数据审核规程

 

Data auditing

数据审计

 

Second person verification of results

结果双人复核

 

Manual data/ transcribed data review

审查手写数据/转录数据

 

Training on Good Documentation Practices

良好文件规范培训

 

Automated Data checks

数据自动化检查

 

Validation of accurate transfer of data across interfaces

不同接口间数据准确传输的验证

 

8 Deliberate Falsification

故意伪造

 

“Our investigator discovered that your firm was destroying original batch records and backdating revised replacement pages. For example, our investigator found original pages from five (b)(4) batch records (batches(b) (4) to (b)(4)) discarded outside your facility. Your quality control unit approved revised and backdated master batch record pages that your firm created to replace the discarded pages. The original data were subsequently transcribed and backdated to the time of production. Quality and production managers allowed this practice.” [47]

 

“我们的检查人员发现贵公司正在销毁原始批记录并在替换页倒填日期。例如，我们的检查人员发现了你们在工厂外丢弃了五个（b）（4）批记录（批次（b）（4）至（b）（4））的原始页。你们的质量控制部门批准了贵公司修改后且倒签日期的主批记录页，替换了丢弃的页面。原始数据随后被转录并回倒签回生产的时间。质量和生产经理允许这种做法。“[47]

 

“Furthermore, your quality unit failed to identify data integrity issues in 11 batch production records reviewed by our investigator. Your production manager admitted that he falsified the signatures of other employees in the “Prepared By,” “Reviewed By,” “Approved By,” and “Authorized By” sections.” [48]

“此外，你们的质量部门未能识别我们检查人员审查的11个批生产记录中的数据完整性问题。你们的生产经理承认他在“起草人”，“审核人”，“批准人”和“授权人”中伪造了其他员工的签名。“[48]

 

“Severe GMP violations related to the implementation of sound computerised systems in the quality control facilities were committed, that could lead/could have lead to the falsification of data. It was impossible to verify that the decision to approve raw material and final API was based on valid and accurate data” [49]

“在质量控制设施中实施的计算机化系统中发现的严重GMP违规，可能会导致/可能已经导致数据的伪造。无法确认批准原辅料和最终API的决定是基于有效和准确的数据“[49]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Data integrity awareness training 

数据完整性意识培训

 

Open culture

开放的文化

 

Data auditing

数据审计

 

Automated entries and automated data capture to secure records

自动化输入和自动数据捕获以安全记录

 

Assessment of system prior to purchase, followed by best practices for system implementation and validation

购买前评估系统，然后在系统实施和验证阶段实施良好实践规范。

 

Implement a data integrity policy that clearly states the consequences for deliberately falsifying records or intentionally disregarding procedures

实施数据完整性策略，明确说明故意伪造记录或藐视规程的后果

 

9 Incomplete Records Kept

 

记录保存不完整

 

A. Discarded training records 

A.丢弃的培训记录

 

Our investigators observed discarded original personnel training records. Your procedure 3-040-127, Use of the Schulungsdatenbank (Learning Management System) in the Supply Center Leverkusen requires these records to be maintained. In your response, you committed to retain original training records. However, you did not reassess your program to ensure that personnel were trained and capable of performing their assigned functions.

我们的检查人员发现了丢弃的人员培训原始记录。你们的规程3-040-127《勒沃库森供应中心Schulungsdatenbank（培训管理系统）的使用》要求保存这些记录。在你们的回复中，你们承诺保存培训原始记录。但是，你们没有重新评估你们的程序，以确保人员经过培训并能够执行其指定的功能。

 

B. Discarded automated visual inspection machine parameters 

B. 废弃的自动灯检机参数

 

In a (b)(4) department office waste bin, our investigators observed discarded forms used to document and set inspection parameters for your automated tablet visual inspection machinery. These parameters are used to accept or reject tablets. In your response, you noted that you documented and approved final set-up parameters, “but historically the calculations generated in support of those parameters have not been preserved.” 

在（b）（4）部门办公室垃圾箱中，我们的检查人员发现了丢弃的表格，用于记录和设置自动药片灯检机的检查参数。这些参数用于接受或拒绝药片。在你们的回复中，你们说你们记录并批准了最终设置参数，“用以支持这些参数的计算未能保留。”

 

You indicate that programming the visual inspection machine to detect defects may not be a CGMP activity. We note that the parameters of this machinery are used to discriminate between acceptable and unacceptable tablets. Accordingly, entering reliable settings into machine programming is part of CGMP.” [50]

你们指出对灯检机进行编程以检测缺陷可能不是CGMP活动。我们注意到该机器的参数用于区分可接受和不可接受的片剂。因此，在机器编程中输入可靠的设置是CGMP的一部分。“[50]

 

“Your electronic data logs did not retain alarm messages indicating when certain manufacturing parameters exceed their limits during production operations. Specifically, you didnotmaintainelectroniclogrecordsofthein- processcontrolalarmsforyour(b)(4)hydrogel coating machine, your (b)(4) checkweigher, and your (b)(4) packager.” “In your response, you providedalistofequipmentyouwill review for electronic data controls, but your response did not address the need to maintain a record of all deviations in the batch record in accordance with 21 CFR Part 211.188, and it lacked a global remediation to ensure electronic record retention.” [51]

“你们的电子数据日志未包括报警信息，以指示在生产操作期间，生产参数何时超出其限度。具体而言，你们没有保留（b）（4）水凝胶涂布机，（b）（4）检重秤和（b）（4）包装机的过程控制报警的电子日志记录。”“在你们的回复，你们提供了一份将会检查电子数据控制的设备清单，但你们的回复没有说明需要按照21 CFR Part 211.188将所有偏差的记录保留在批记录中，并且缺少一个全局补救措施来确保电子记录保存。”[51]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Traceability

可追溯性

 

Master data definition (routings / recipes, metadata) 

主数据界定（工艺路线/配方，元数据）

 

System configuration and exception reporting

系统配置和异常报告

 

Collation of completed data into batch record

将完成的数据整理到批记录中

 

Automation of data routings

数据记录自动化

 

Training on Good Documentation Practices

良好文件规范培训

 

10 System Data Integrity Functions Not Validated

未验证系统数据完整性功能

 

“Electronic records are used, but they do not meet systems validation requirements to ensure that they are trustworthy, reliable and generally equivalent to paper records.” [52]

“有使用电子记录，但这些电子记录不符合系统验证要求，无法确保它们可信，可靠并且与纸质记录等效。”[52]

 

“Computer system validation for theWinKQCL software (endotoxin testing) is deficient in that the functionality testing related to user access and data security did not include challenges  to demonstrate that data cannot be altered, manipulated or deleted.”[53]

“WinKQCL软件（内毒素测试）的计算机系统验证存在缺陷：用户访问和数据安全相关的功能测试未能包括挑战以证明数据无法被更改，操纵或删除。”[53]

 

“Your firm utilizes Electronic Logbook (eLog) System Version 1.0.0 in Unit 2 facility to document the all activities including results of analytical data for laboratory equipment and production. Your firm processed Change Control #CCP-IO-135-14-0009 toimplement Logbook System Version 1.0.0 in Unit 2. Your firm did not execute a validation protocol including a validation summary report for the software Electronic Logbook System Version 1.0.0.” [38]

“贵公司在2号工厂中使用电子日志（eLog）1.0.0版系统来记录所有活动，包括实验室设备和生产的数据分析结果。贵公司进行了变更控制＃CCP-IO-135-14-0009，在2号工厂实施日志系统版本1.0.0。贵公司没有执行验证方案，包括软件电子日志系统版本1.0.0的验证总结报告。“[38]

 

Possible Mitigations/ Controls

可能的补救/控制措施

 

Computerized systems validation life cycle to be followed for all GMP systems.

所有GMP系统都要遵循计算机化系统验证生命周期。