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嘉峪檢測網(wǎng) 2022-12-05 00:53
本文羅列了近年來GMP檢查中的關(guān)于生產(chǎn)系統(tǒng)數(shù)據(jù)完整性的10大缺陷，以及建議的補(bǔ)救措施。如下，供大家參考！
Examples of Data Integrity Citations and their Possible Mitigations
生產(chǎn)系統(tǒng)數(shù)據(jù)完整性缺陷示例及其可能的補(bǔ)救措施
1 Audit Trail
審計(jì)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(jī)版生產(chǎn)設(shè)備沒有配備人機(jī)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(jī)版生產(chǎn)設(shè)備上沒有帶時(shí)間戳的審計(jì)追蹤，數(shù)據(jù)管理，報(bào)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(jì)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(quán)限并共享一個(gè)用戶名，因此無法歸因或跟蹤操作的特定個(gè)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(fēng)險(xiǎn)中。“[34]
Possible Mitigations/ Controls
可能的補(bǔ)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(fēng)險(xiǎn)
Data mapping
數(shù)據(jù)映射
Deviation/incident Reports
偏差/異常報(bào)告
Report approval
報(bào)告批準(zhǔn)
Including audit trail review as part of the batch report where exceptions are reported
將審計(jì)追蹤審查作為批報(bào)告的一部分，以報(bào)告例外情況
Technical controls to ensure audit trails are always active
技術(shù)控制以確保審計(jì)追蹤始終處于激活狀態(tài)
2 Calibration
校準(zhǔn)
“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(zhǔn)和維護(hù)用于在投料前稱量組分（包括活性物質(zhì)）的秤的書面記錄（21 CFR 211.68（a））。“[35]
Possible Mitigations/ Controls
可能的補(bǔ)救/控制措施
Implement calibration management procedures
實(shí)施校準(zhǔn)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(zhǔn)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(shù)（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(jìn)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(xiàng)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(zhì)量部門的計(jì)算機(jī)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(quán)的更改。所有員工都可以訪問你們的年度產(chǎn)品回顧（APR）電子表格。包含APR的臺式計(jì)算機(jī)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(chǎn)，倉庫和QC部門的儀器，設(shè)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(jì)追蹤審查顯示“審核人”擁有比“管理員”更多（完全）的權(quán)限，且系統(tǒng)是由QC人員管理的。“[38]
Possible Mitigations/ Controls
可能的補(bǔ)救/控制措施
Access and security management
訪問和安全管理
Segregation of duties
職責(zé)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(guān)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(shí)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(zhì)量控制（QC）分析人員使用管理員權(quán)限和密碼來篡改高效液相色譜（HPLC）計(jì)算機(jī)的時(shí)間來改變實(shí)驗(yàn)室測試事件的時(shí)間順序記錄。“[39]
Possible Mitigations/ Controls
可能的補(bǔ)救/控制措施
Lock down access to clocks
鎖定對時(shí)鐘的訪問
Synchronize time Automatically
自動同步時(shí)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(chǎn)，控制或分銷相關(guān)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(fù)制到CD中，然后將數(shù)據(jù)從系統(tǒng)中刪除，來釋放硬盤驅(qū)動空間。復(fù)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(jì)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(fù)制到CD中。“[34]
Possible Mitigations/ Controls
可能的補(bǔ)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(yàn)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(shí)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(chǎn)操作的同時(shí)進(jìn)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(chǎn)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(chǎn)和控制記錄。當(dāng)QA審核人員注意到批記錄不完整時(shí)，他們在單獨(dú)的、不受控的紙條上羅列所缺少的條目，交給生產(chǎn)經(jīng)理。隨后，在生產(chǎn)操作已經(jīng)結(jié)束之后，數(shù)據(jù)才被填入到CGMP記錄中，就像在操作時(shí)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(chǎn)和文件記錄不同步的實(shí)例。兩個(gè)不受控制的Excel電子表格用于記錄異常和某些生產(chǎn)過程中的質(zhì)量數(shù)據(jù)。該數(shù)據(jù)剛開始不是填寫于批生產(chǎn)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(guān)于GMP記錄的數(shù)據(jù)完整性，發(fā)現(xiàn)了一個(gè)嚴(yán)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(chǎn)操作）同時(shí)完成的。”[44]
Possible Mitigations/ Controls
可能的補(bǔ)救/控制措施
Second person verification of results
第二人確認(rèn)結(jié)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(xùn)
Use MES that forces contemporaneous recording and sequence of steps
使用MES（生產(chǎn)執(zhí)行系統(tǒng)）以強(qiáng)制同步記錄和按工序生產(chǎn)
Move spreadsheets to a validated EDMS or replace with avalidated application
將電子表格轉(zhuǎn)移到經(jīng)驗(yàn)證的EDMS（電子文檔管理系統(tǒng)）或使用經(jīng)驗(yàn)證的應(yīng)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(zhì)量控制部門（QCU）未能審查和批準(zhǔn)藥品生產(chǎn)和控制記錄。例如，QCU未能發(fā)現(xiàn)批生產(chǎn)記錄中（b）（4）凝膠和乳液產(chǎn)品中活性成分的型號和濃度與產(chǎn)品標(biāo)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(gè)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(jié)果和產(chǎn)品批準(zhǔn)日期。多項(xiàng)內(nèi)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(shí)驗(yàn)室測試結(jié)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(zhǔn)確，完整和符合既定標(biāo)準(zhǔn)。“[46]
Possible Mitigations/ Controls
可能的補(bǔ)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(jì)
Second person verification of results
結(jié)果雙人復(fù)核
Manual data/ transcribed data review
審查手寫數(shù)據(jù)/轉(zhuǎn)錄數(shù)據(jù)
Training on Good Documentation Practices
良好文件規(guī)范培訓(xùn)
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(zhǔn)確傳輸?shù)尿?yàn)證
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(gè)（b）（4）批記錄（批次（b）（4）至（b）（4））的原始頁。你們的質(zhì)量控制部門批準(zhǔn)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(zhuǎn)錄并回倒簽回生產(chǎn)的時(shí)間。質(zhì)量和生產(chǎn)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(zhì)量部門未能識別我們檢查人員審查的11個(gè)批生產(chǎn)記錄中的數(shù)據(jù)完整性問題。你們的生產(chǎn)經(jīng)理承認(rèn)他在“起草人”，“審核人”，“批準(zhǔn)人”和“授權(quán)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(zhì)量控制設(shè)施中實(shí)施的計(jì)算機(jī)化系統(tǒng)中發(fā)現(xiàn)的嚴(yán)重GMP違規(guī)，可能會導(dǎo)致/可能已經(jīng)導(dǎo)致數(shù)據(jù)的偽造。無法確認(rèn)批準(zhǔn)原輔料和最終API的決定是基于有效和準(zhǔn)確的數(shù)據(jù)“[49]
Possible Mitigations/ Controls
可能的補(bǔ)救/控制措施
Data integrity awareness training
數(shù)據(jù)完整性意識培訓(xùn)
Open culture
開放的文化
Data auditing
數(shù)據(jù)審計(jì)
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(shí)施和驗(yàn)證階段實(shí)施良好實(shí)踐規(guī)范。
Implement a data integrity policy that clearly states the consequences for deliberately falsifying records or intentionally disregarding procedures
實(shí)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(xùn)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(xùn)原始記錄。你們的規(guī)程3-040-127《勒沃庫森供應(yīng)中心Schulungsdatenbank（培訓(xùn)管理系統(tǒng)）的使用》要求保存這些記錄。在你們的回復(fù)中，你們承諾保存培訓(xùn)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(xùn)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(jī)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(shè)置自動藥片燈檢機(jī)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(fù)中，你們說你們記錄并批準(zhǔn)了最終設(shè)置參數(shù)，“用以支持這些參數(shù)的計(jì)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(jī)進(jìn)行編程以檢測缺陷可能不是CGMP活動。我們注意到該機(jī)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(jī)器編程中輸入可靠的設(shè)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(bào)警信息，以指示在生產(chǎn)操作期間，生產(chǎn)參數(shù)何時(shí)超出其限度。具體而言，你們沒有保留（b）（4）水凝膠涂布機(jī)，（b）（4）檢重秤和（b）（4）包裝機(jī)的過程控制報(bào)警的電子日志記錄。”“在你們的回復(fù)，你們提供了一份將會檢查電子數(shù)據(jù)控制的設(shè)備清單，但你們的回復(fù)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(gè)全局補(bǔ)救措施來確保電子記錄保存。”[51]
Possible Mitigations/ Controls
可能的補(bǔ)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(bào)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(xùn)
10 System Data Integrity Functions Not Validated
未驗(yàn)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(yàn)證要求，無法確保它們可信，可靠并且與紙質(zhì)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(nèi)毒素測試）的計(jì)算機(jī)系統(tǒng)驗(yàn)證存在缺陷：用戶訪問和數(shù)據(jù)安全相關(guān)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(shí)驗(yàn)室設(shè)備和生產(chǎn)的數(shù)據(jù)分析結(jié)果。貴公司進(jìn)行了變更控制＃CCP-IO-135-14-0009，在2號工廠實(shí)施日志系統(tǒng)版本1.0.0。貴公司沒有執(zhí)行驗(yàn)證方案，包括軟件電子日志系統(tǒng)版本1.0.0的驗(yàn)證總結(jié)報(bào)告。“[38]
Possible Mitigations/ Controls
可能的補(bǔ)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(jì)算機(jī)化系統(tǒng)驗(yàn)證生命周期。
來源：GMP辦公室
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