DataIntegrity: 2020 FDA Data Integrity Observations in Review
數(shù)據(jù)完整性：2020年FDA數(shù)據(jù)完整性缺陷分析
In 2020 thusfar, numerous warning letters have been issued from the FDA citing dataintegrity violations. Common findings violate principles of ALCOA+, 21 CFR Part11, and the FDA’s data integrity guidance document. Some of these findingsinclude:
2020年至今，F(xiàn)DA以數(shù)據(jù)完整性違規(guī)為由發(fā)出了許多警告信。常見發(fā)現(xiàn)違反了 ALCOA+、21 CFR Part 11 和 FDA 數(shù)據(jù)完整性指南。其中一些缺陷包括：
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Deletion or manipulation of data
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數(shù)據(jù)刪除或操縱
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Aborted sample analysis withoutjustification
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無正當(dāng)理由中止的樣品分析
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Invalidated OOS results without justification
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判定 OOS 結(jié)果無效而未經(jīng)論證
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Destruction or loss of data、
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數(shù)據(jù)缺失或丟失
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Failure to document workcontemporaneously
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未能在工作時同時記錄
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Uncontrolled documentation
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不受控的文件
Data integrity is of utmost importance inany CGMP manufacturing setting now more than ever. While data integrityguidance is not a new concept, there is increased scrutiny of data integrityand 21 CFR Part 11 compliance as electronic records have become the industrystandard. For manufacturers trying to attain a high degree of data integrity,the FDA’s Data Integrity and Compliance with Drug CGMP Guidance for Industrydocument is a great tool to frame an approach to vigorous internal policies.This document is repeatedly referenced in FDA warning letters when companiesare in violation of principles stated in the guidance. This document encouragesmanufacturers to implement effective and robust strategies to ensure thataccurate and secure data management systems are in place and routinelymonitored by the quality unit.
數(shù)據(jù)完整性在任何 CGMP 制造環(huán)境中都比以往更加重要。雖然數(shù)據(jù)完整性指南并不是一個新的概念，但隨著電子記錄已成為行業(yè)標(biāo)準(zhǔn)，對數(shù)據(jù)完整性和 21 CFR Part 11符合性的監(jiān)管也日益加強。對于試圖獲得高度數(shù)據(jù)完整性的制造商來說，F(xiàn)DA 的數(shù)據(jù)完整性和符合藥物 CGMP 行業(yè)指南是制定實施有力內(nèi)部政策的方法的重要工具。當(dāng)公司違反指南中規(guī)定的原則時，F(xiàn)DA 警告信中反復(fù)引用這些文件。本文鼓勵制造商實施有效和穩(wěn)健的戰(zhàn)略，以確保準(zhǔn)確和安全的數(shù)據(jù)管理系統(tǒng)到位，并由質(zhì)量部門定期監(jiān)控。
Anotherstandardized tool referenced in numerous data integrity guidance documents formanaging data integrity risks is ALCOA+. ALCOA+ provides a set of principles tobe applied to all CGMP records; Attributable, Legible, Contemporaneous,Original, Accurate, Complete, Consistent, Enduring, and Available. AlthoughALCOA+ is not the final word for data integrity compliance, using theseprinciples to challenge data generation and management strategies provides astrong framework for internal data management policies. Managing data integrityrisks is essential to the safety, purity, quality, and efficacy of drugproducts.
許多數(shù)據(jù)完整性指南中引用的另一個用于管理數(shù)據(jù)完整性風(fēng)險的標(biāo)準(zhǔn)化工具是ALCOA +。ALCOA +提供了一套適用于所有CGMP記錄的原則：可歸屬，清晰，同步，原始，準(zhǔn)確，完整，一致，持久和可用。盡管ALCOA +并不是保證數(shù)據(jù)完整性合規(guī)性的最終詞匯，但使用這些原則來對標(biāo)數(shù)據(jù)生成和管理策略可為內(nèi)部數(shù)據(jù)管理策略提供強大的框架。管理數(shù)據(jù)完整性風(fēng)險對于藥品的安全性，純度，質(zhì)量和有效性至關(guān)重要。
21 CFR Part11 is also exceptionally important for data integrity of electronic records andelectronic signatures. 21 CFR Part 11 is a legally binding statute thatcompanies must comply with when generating electronic records. There are manyways that validated instruments, software, and procedures can manage andmitigate data integrity risks and demonstrate compliance to 21 CFR Part 11.Software should be chosen that does not allow for data modification without apermanent record and that creates records attributable to who did the work,when, and why. Once an appropriate software is chosen, it should be validatedto the rigors of 21 CFR Part 11 and data integrity guidance to activelydemonstrate complete compliance and secure data. This year alone, numerouswarning letters have been issued for data integrity violations. Many are obviousviolations while some are discreet and could go undetected. The following areexamples of data integrity observations issued from the FDA thus far in 2020and considerations for avoiding such observations.
21 CFR Part 11對于電子記錄和電子簽名的數(shù)據(jù)完整性也非常重要。21 CFR Part11是具有法律約束力的法規(guī)，公司在生成電子記錄時必須遵守該法規(guī)。經(jīng)過驗證的儀器，軟件和程序可以通過多種方式來管理和減輕數(shù)據(jù)完整性風(fēng)險，并證明其符合21 CFR Part11的規(guī)定。應(yīng)選擇在沒有永久記錄并創(chuàng)建可歸因于誰？何時？什么原因？的記錄情況下不會允許進行數(shù)據(jù)修改的軟件。一旦選擇了合適的軟件，就應(yīng)該通過21 CFR Part11以及數(shù)據(jù)完整性指南的嚴格驗證，以證明完全符合和數(shù)據(jù)安全。僅今年，就違反數(shù)據(jù)完整性的問題發(fā)出了許多警告信。許多是明顯的違規(guī)行為，而有些則是謹慎不易發(fā)現(xiàn)的。以下是FDA到目前為止在2020年發(fā)布的數(shù)據(jù)完整性缺陷項的示例，以及避免此類缺陷的注意事項。
In March ofthis year a manufacturing site was found to be intentionally shredding anddestroying records. Additionally, the site failed to integrate certainchromatography peaks due to disabled peak detection, which was against itsprocedure. Furthermore, investigation into unknown chromatography peaks was notconducted per procedure. This same company produced OOS results that were notproperly investigated and replaced the OOS with a resample repeatedly,resulting in three failed results and an insufficient laboratory investigation.This occurred before accepting the fourth passing result. Based on guidance,data should never be destroyed, replaced, or overridden. Data should beprotected and enduring. When data result in an unknown or OOS, the event shouldbe documented and thoroughly investigated. Corrective and preventative actionsshould also be taken to protect the data lifecycle.
在今年3月，FDA發(fā)現(xiàn)一個制造工廠故意粉碎并破壞了記錄。另外，由于禁用了峰檢測，該工廠未能積分某些色譜峰，這與該公司的程序不符。此外，沒有按照程序?qū)ξ粗V峰進行研究。該公司產(chǎn)生的OOS結(jié)果未經(jīng)適當(dāng)調(diào)查，并反復(fù)用重新取樣代替OOS，導(dǎo)致三次測試結(jié)果不合格，實驗室調(diào)查不足，然后在第四次得到合格結(jié)果并接受該結(jié)果。根據(jù)指南，絕不能銷毀，替換或覆蓋數(shù)據(jù)。數(shù)據(jù)應(yīng)受到保護并持久。當(dāng)數(shù)據(jù)導(dǎo)致未知或OOS時，應(yīng)記錄該事件并進行徹底調(diào)查。還應(yīng)采取糾正和預(yù)防措施來保護數(shù)據(jù)生命周期。
Another FDAobservation this year found employees signing logbooks and batch records thatshould have been reviewed in weeks past. This clearly violates the“contemporaneous” requirement of ALCOA+. The gathering, review, and release ofdata should be documented contemporaneously, that is, at the time the work isperformed. Procedures should dictate this requirement and analysts should betrained to document work at the time of completion to avoid discrepancies. Manysoftware platforms take the work out of this for users by permanently recordingwho performed the work, when, and why in a secure audit trail – all in realtime, with the inability to edit. These are all examples of overt dataintegrity violations. It is critical for any CGMP site to review, maintain,secure, and retain CGMP documentation. While many of these observations areovert violations, and some even appearing intentional, many violations areinadvertent and difficult to detect.
FDA今年的另一項缺陷項，員工簽署了本已在過去幾周內(nèi)完成審查的日志和批記錄。這顯然違反了ALCOA +的“同步”要求。數(shù)據(jù)的收集，審查和發(fā)布應(yīng)同時（即在執(zhí)行工作時）記錄。程序應(yīng)規(guī)定此要求，分析人員應(yīng)進行培訓(xùn)，以便在完成工作時記錄其工作，以免出現(xiàn)差異。許多軟件平臺通過在安全的審計追蹤上永久記錄誰執(zhí)行這項工作，何時以及為什么，為用戶解決了這一問題，而這些工作都是實時進行的，并且無法進行編輯。這些都是公開數(shù)據(jù)完整性違規(guī)的示例。對于任何CGMP工廠而言，查看，維護，保護和保存CGMP文件記錄都是至關(guān)重要的。盡管這些缺陷中有許多是明顯違規(guī)，甚至有些是故意的，但也有不少是無意的，很難發(fā)現(xiàn)的。
The FDAstated a recent finding from another company for aborted chromatography sampleset runs. Although aborting a run is not necessarily forbidden, in the rareinstances where a run must be aborted, there should be clear procedures andaborted runs should be investigated thoroughly. These actions were notperformed by this company for the aborted runs. The same warning letter alsostated deleted data as a finding. Data should never be deleted and everythingpossible should be done to secure and retain all CGMP data. Again, manysoftware platforms eliminate the risk of deleting data all together by makingthis action prohibited. A warning letter issued to another company found thatthe company was printing uncontrolled copies of batch records and maintenancesheets. These copies were pre-printed and kept in an unsecured area. The samecompany could not locate raw data from a standard curve from an analyticalassay. Analysts and operators should be properly trained to retrieve all datapertaining to CGMP processes for inspectors or to make important qualitydecisions regarding batch disposition. They were also found to be usingscrappieces of paper to record data of an analytical assay. Another company wasfound unable to produce laboratory data on product batches, violating theavailable principle of ALCOA+. A laboratory technician reported that raw datais routinely discarded. These observations all pose many data integrityconcerns — data on uncontrolled scraps of paper and loss of data violate almostevery principle of ALCOA+. Documents should be controlled and in original formto avoid loss or obstruction of original data.
FDA對另一家公司的缺陷項是色譜樣品組運行中止。盡管不一定非要中止運行，但在極少數(shù)情況下必須中止運行的情況下，應(yīng)有明確的程序，并且應(yīng)徹底調(diào)查所中止的運行。該公司未針對已中止的運行執(zhí)行這些操作。同一封警告信還指出數(shù)據(jù)刪除的缺陷。永遠不要刪除數(shù)據(jù)，應(yīng)該盡一切可能保護和保存所有CGMP數(shù)據(jù)。同樣，許多軟件平臺通過禁止執(zhí)行此操作來消除刪除數(shù)據(jù)的風(fēng)險。向另一家公司發(fā)出的警告信發(fā)現(xiàn)該公司正在打印不受控制的批記錄和維修表格的副本。這些副本已預(yù)先打印并保存在不安全的區(qū)域。該公司還無法從分析測定的標(biāo)準(zhǔn)曲線中找到原始數(shù)據(jù)。應(yīng)當(dāng)對分析人員和操作人員進行適當(dāng)?shù)呐嘤?xùn)，以為檢查員檢索與CGMP流程有關(guān)的所有數(shù)據(jù)，或就批處理做出重要的質(zhì)量決策。還發(fā)現(xiàn)他們使用廢紙來記錄分析測定的數(shù)據(jù)。另一家公司被發(fā)現(xiàn)無法提供有關(guān)產(chǎn)品批次的實驗室數(shù)據(jù)，這違反了ALCOA +原則。實驗室技術(shù)人員報告說，原始數(shù)據(jù)通常被丟棄。這些缺陷項都帶來了許多數(shù)據(jù)完整性問題-不受控的廢紙數(shù)據(jù)和數(shù)據(jù)丟失幾乎違反了ALCOA +的每一項原則。文件應(yīng)受控并保持原始格式，以避免丟失或阻塞原始數(shù)據(jù)。
A securequality system must be in place to prevent any intentional or unintentionalloss of CGMP data. Many software programs used with analytical instrumentsprevent loss of data under any circumstance, mitigating risks for such dataintegrity violations mentioned above. Software programs offer audit trails,various user permissions, inability to delete data, and many other features makingit simple to automate compliance to data integrity guidance and 21 CFR Part 11.The bottom line is that data, paper or electronic, must be retained to makeappropriate quality decisions and demonstrate proper control. All the abovefindings were referenced from warning letters issued thus far in 2020 alone.
必須建立安全的質(zhì)量體系，以防止CGMP數(shù)據(jù)有意或無意的丟失。分析儀器使用的許多軟件程序在任何情況下都可以防止數(shù)據(jù)丟失，從而減輕了上述違反此類數(shù)據(jù)完整性的風(fēng)險。軟件程序提供了審計追蹤，多種用戶權(quán)限，數(shù)據(jù)無法刪除以及許多其他功能，使自動遵守數(shù)據(jù)完整性指南和21 CFR Part11變得很簡單。最重要的是，必須保存數(shù)據(jù)，紙質(zhì)或電子數(shù)據(jù)，做出適當(dāng)?shù)馁|(zhì)量決策并證明適當(dāng)?shù)目刂?。以上所有發(fā)現(xiàn)均參考僅在2020年發(fā)布的警告信。
