本文羅列了近年來GMP檢查中的關于生產系統(tǒng)數(shù)據(jù)完整性的10大缺陷，以及建議的補救措施。如下，供大家參考！

 

Examples of Data Integrity Citations and their Possible Mitigations

生產系統(tǒng)數(shù)據(jù)完整性缺陷示例及其可能的補救措施

 

1 Audit Trail

審計追蹤

 

“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]

“總共（b）（4）單機版生產設備沒有配備人機界面HMI / 可編程序邏輯控制器PLC / 監(jiān)控與數(shù)據(jù)采集SCADA系統(tǒng)。在這些單機版生產設備上沒有帶時間戳的審計追蹤，數(shù)據(jù)管理，報警管理，歸檔和檢索。“[33]

 

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

“我們的檢查人員發(fā)現(xiàn)用于（b）（4）和（b）（4）測試的（b）（4）系統(tǒng)缺乏訪問控制和審計追蹤功能。

 

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，所有員工都具有管理員權限并共享一個用戶名，因此無法歸因或跟蹤操作的特定個人。這使您的電子數(shù)據(jù)暴露于篡改和/或刪除而無法追蹤的風險中。“[34]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Master and reference data review

主數(shù)據(jù)和參考數(shù)據(jù)審查

 

CQA/CPP identified and risk assessed

確定CQA / CPP并評估風險

 

Data mapping

數(shù)據(jù)映射

 

Deviation/incident Reports

偏差/異常報告

 

Report approval

報告批準

 

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

將審計追蹤審查作為批報告的一部分，以報告例外情況

 

Technical controls to ensure audit trails are always active

技術控制以確保審計追蹤始終處于激活狀態(tài)

 

2 Calibration

校準

 

“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]

“你沒有校準和維護用于在投料前稱量組分（包括活性物質）的秤的書面記錄（21 CFR 211.68（a））。“[35]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Implement calibration management procedures

實施校準管理程序

 

Periodically review that they are effective

定期審查它們是否有效

 

Automatic system indication of calibration state

自動系統(tǒng)指示校準狀態(tài)

 

3 Security and Access Controls

安全和訪問控制

 

“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]

“我們的檢查人員觀察到，貴工廠的信息技術（IT）人員共用用戶名和密碼訪問你們的電子存儲系統(tǒng)的（b）（4）數(shù)據(jù)。你們的IT人員可以刪除或更改目錄和文件，但未能確定誰進行了更改。在之前的檢查中，F(xiàn)DA發(fā)現(xiàn)了類似的缺陷，你們承諾消除此項以及其他數(shù)據(jù)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]

“...質量部門的計算機沒有限制訪問的控制措施以防止對數(shù)據(jù)文件和文件夾的未經(jīng)授權的更改。所有員工都可以訪問你們的年度產品回顧（APR）電子表格。包含APR的臺式計算機未鎖定。“[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]

“生產，倉庫和QC部門的儀器，設備，潔凈區(qū)操作和清潔使用日志使用電子日志（eLog）系統(tǒng)V1.0.0.... ” “對電子日志（eLog）系統(tǒng)版本1.0.0單元2的審計追蹤審查顯示“審核人”擁有比“管理員”更多（完全）的權限，且系統(tǒng)是由QC人員管理的。“[38]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Access and security management

訪問和安全管理

 

Segregation of duties

職責分離

 

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

數(shù)據(jù)安全存儲，使用關系型數(shù)據(jù)庫而不是平面文件存儲

 

System periodic review

系統(tǒng)定期審查

 

4 Manipulation of System Time 

篡改系統(tǒng)時間

 

“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]

“特別是，你們的質量控制（QC）分析人員使用管理員權限和密碼來篡改高效液相色譜（HPLC）計算機的時間來改變實驗室測試事件的時間順序記錄。“[39]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Lock down access to clocks

鎖定對時鐘的訪問

 

Synchronize time Automatically

自動同步時間

 

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]

“貴公司未能保存與藥品生產，控制或分銷相關記錄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]

“我們的檢查人員還指出，貴公司將原始數(shù)據(jù)復制到CD中，然后將數(shù)據(jù)從系統(tǒng)中刪除，來釋放硬盤驅動空間。復制到CD的文件是手動選擇的; 選擇過程沒有受到監(jiān)督。文件的選擇如果沒有審計追蹤功能或監(jiān)督，則無法保證在從系統(tǒng)中永久刪除之前，所有原始數(shù)據(jù)文件都已復制到CD中。“[34]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

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

保存程序，包括任何軟件升級/降級后需要驗證保存數(shù)據(jù)的可讀性

 

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

未能在執(zhí)行活動的同時記錄活動。

 

“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]

“我們的檢查人員發(fā)現(xiàn)了大量的例子，說明你們未能在生產操作的同時進行記錄。例如，我們的檢查人員發(fā)現(xiàn)了已由你們的操作人員事先簽名的空白批生產記錄，部分填寫的批記錄，以及沒有任何理由用鉛筆更改數(shù)據(jù)的批記錄。“[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]

“你們的員工未能在活動完成后立即完成批生產和控制記錄。當QA審核人員注意到批記錄不完整時，他們在單獨的、不受控的紙條上羅列所缺少的條目，交給生產經(jīng)理。隨后，在生產操作已經(jīng)結束之后，數(shù)據(jù)才被填入到CGMP記錄中，就像在操作時已經(jīng)輸入了一樣。“[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檢查員發(fā)現(xiàn)出了批生產和文件記錄不同步的實例。兩個不受控制的Excel電子表格用于記錄異常和某些生產過程中的質量數(shù)據(jù)。該數(shù)據(jù)剛開始不是填寫于批生產記錄中的。貴公司后來將這些數(shù)據(jù)輸入批記錄并倒填了日期。“[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]

“關于GMP記錄的數(shù)據(jù)完整性，發(fā)現(xiàn)了一個嚴重缺陷，人員不在現(xiàn)場，但可以看到此人的記錄，文件看起來是以這種方式完成，而不是（與生產操作）同時完成的。”[44]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Second person verification of results

第二人確認結果

 

Data auditing

數(shù)據(jù)審核

 

User SOP

用戶SOP

 

Training on Good Documentation Practices

良好文件規(guī)范培訓

 

Use MES that forces contemporaneous recording and sequence of steps

使用MES（生產執(zhí)行系統(tǒng)）以強制同步記錄和按工序生產

 

Move spreadsheets to a validated EDMS or replace with avalidated application

將電子表格轉移到經(jīng)驗證的EDMS（電子文檔管理系統(tǒng)）或使用經(jīng)驗證的應用程序替代

 

7 Batch Data Review

批數(shù)據(jù)審核

 

“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]

 

“貴公司的質量控制部門（QCU）未能審查和批準藥品生產和控制記錄。例如，QCU未能發(fā)現(xiàn)批生產記錄中（b）（4）凝膠和乳液產品中活性成分的型號和濃度與產品標簽之間的不符。“[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.

 

“我們的檢查人員審查了幾個批記錄，發(fā)現(xiàn)使用了白色涂改液、模糊不清的數(shù)據(jù)和/或信息缺失，如密度測試結果和產品批準日期。多項內容被覆蓋并劃掉，沒有簽名，日期或解釋。

 

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，實驗室測試結果（例如粘度，密度，外觀和氣味）缺少第二人字母縮寫或簽名，以表明原始記錄已經(jīng)過審核，準確，完整和符合既定標準。“[46]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Batch data review Procedure

批數(shù)據(jù)審核規(guī)程

 

Data auditing

數(shù)據(jù)審計

 

Second person verification of results

結果雙人復核

 

Manual data/ transcribed data review

審查手寫數(shù)據(jù)/轉錄數(shù)據(jù)

 

Training on Good Documentation Practices

良好文件規(guī)范培訓

 

Automated Data checks

數(shù)據(jù)自動化檢查

 

Validation of accurate transfer of data across interfaces

不同接口間數(shù)據(jù)準確傳輸?shù)尿炞C

 

8 Deliberate Falsification

故意偽造

 

“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]

 

“我們的檢查人員發(fā)現(xiàn)貴公司正在銷毀原始批記錄并在替換頁倒填日期。例如，我們的檢查人員發(fā)現(xiàn)了你們在工廠外丟棄了五個（b）（4）批記錄（批次（b）（4）至（b）（4））的原始頁。你們的質量控制部門批準了貴公司修改后且倒簽日期的主批記錄頁，替換了丟棄的頁面。原始數(shù)據(jù)隨后被轉錄并回倒簽回生產的時間。質量和生產經(jīng)理允許這種做法。“[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，你們的質量部門未能識別我們檢查人員審查的11個批生產記錄中的數(shù)據(jù)完整性問題。你們的生產經(jīng)理承認他在“起草人”，“審核人”，“批準人”和“授權人”中偽造了其他員工的簽名。“[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]

“在質量控制設施中實施的計算機化系統(tǒng)中發(fā)現(xiàn)的嚴重GMP違規(guī)，可能會導致/可能已經(jīng)導致數(shù)據(jù)的偽造。無法確認批準原輔料和最終API的決定是基于有效和準確的數(shù)據(jù)“[49]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Data integrity awareness training 

數(shù)據(jù)完整性意識培訓

 

Open culture

開放的文化

 

Data auditing

數(shù)據(jù)審計

 

Automated entries and automated data capture to secure records

自動化輸入和自動數(shù)據(jù)捕獲以安全記錄

 

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

購買前評估系統(tǒng)，然后在系統(tǒng)實施和驗證階段實施良好實踐規(guī)范。

 

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

實施數(shù)據(jù)完整性策略，明確說明故意偽造記錄或藐視規(guī)程的后果

 

9 Incomplete Records Kept

 

記錄保存不完整

 

A. Discarded training records 

A.丟棄的培訓記錄

 

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.

我們的檢查人員發(fā)現(xiàn)了丟棄的人員培訓原始記錄。你們的規(guī)程3-040-127《勒沃庫森供應中心Schulungsdatenbank（培訓管理系統(tǒng)）的使用》要求保存這些記錄。在你們的回復中，你們承諾保存培訓原始記錄。但是，你們沒有重新評估你們的程序，以確保人員經(jīng)過培訓并能夠執(zhí)行其指定的功能。

 

B. Discarded automated visual inspection machine parameters 

B. 廢棄的自動燈檢機參數(shù)

 

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）部門辦公室垃圾箱中，我們的檢查人員發(fā)現(xiàn)了丟棄的表格，用于記錄和設置自動藥片燈檢機的檢查參數(shù)。這些參數(shù)用于接受或拒絕藥片。在你們的回復中，你們說你們記錄并批準了最終設置參數(shù)，“用以支持這些參數(shù)的計算未能保留。”

 

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]

你們指出對燈檢機進行編程以檢測缺陷可能不是CGMP活動。我們注意到該機器的參數(shù)用于區(qū)分可接受和不可接受的片劑。因此，在機器編程中輸入可靠的設置是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]

“你們的電子數(shù)據(jù)日志未包括報警信息，以指示在生產操作期間，生產參數(shù)何時超出其限度。具體而言，你們沒有保留（b）（4）水凝膠涂布機，（b）（4）檢重秤和（b）（4）包裝機的過程控制報警的電子日志記錄。”“在你們的回復，你們提供了一份將會檢查電子數(shù)據(jù)控制的設備清單，但你們的回復沒有說明需要按照21 CFR Part 211.188將所有偏差的記錄保留在批記錄中，并且缺少一個全局補救措施來確保電子記錄保存。”[51]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

Traceability

可追溯性

 

Master data definition (routings / recipes, metadata) 

主數(shù)據(jù)界定（工藝路線/配方，元數(shù)據(jù)）

 

System configuration and exception reporting

系統(tǒng)配置和異常報告

 

Collation of completed data into batch record

將完成的數(shù)據(jù)整理到批記錄中

 

Automation of data routings

數(shù)據(jù)記錄自動化

 

Training on Good Documentation Practices

良好文件規(guī)范培訓

 

10 System Data Integrity Functions Not Validated

未驗證系統(tǒng)數(shù)據(jù)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]

“有使用電子記錄，但這些電子記錄不符合系統(tǒng)驗證要求，無法確保它們可信，可靠并且與紙質記錄等效。”[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軟件（內毒素測試）的計算機系統(tǒng)驗證存在缺陷：用戶訪問和數(shù)據(jù)安全相關的功能測試未能包括挑戰(zhàn)以證明數(shù)據(jù)無法被更改，操縱或刪除。”[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]

“貴公司在2號工廠中使用電子日志（eLog）1.0.0版系統(tǒng)來記錄所有活動，包括實驗室設備和生產的數(shù)據(jù)分析結果。貴公司進行了變更控制＃CCP-IO-135-14-0009，在2號工廠實施日志系統(tǒng)版本1.0.0。貴公司沒有執(zhí)行驗證方案，包括軟件電子日志系統(tǒng)版本1.0.0的驗證總結報告。“[38]

 

Possible Mitigations/ Controls

可能的補救/控制措施

 

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

所有GMP系統(tǒng)都要遵循計算機化系統(tǒng)驗證生命周期。