隨著行業(yè)技術的發(fā)展進步，通常意義的“簡單”類計算機化系統(tǒng)也在發(fā)生著變化，廠家會設計開發(fā)更多的功能模塊，儀器變的相對復雜和高級，儀器的使用也會更加滿足用戶的需求，當“簡單”類計算機化系統(tǒng)變的不再那么簡單，數(shù)據(jù)完整性的控制要求是否也需要相應的更新和匹配，還是可以延用之前的簡單模式管理，本文結合國內外數(shù)據(jù)完整性相關指南及法規(guī)要求，探討“簡單”類計算機化系統(tǒng)的數(shù)據(jù)完整性管理，在此與大家討論分享，屬于此類儀器范疇的有pH計、天平、濾芯完整性測試儀、塵埃粒子計數(shù)器等。

       1、數(shù)據(jù)完整性的基本原則：

       The data and records should be ' attributable, legible, contemporaneous, original' and accurate, complete, consistent, enduring, and available; commonly referred to as "ALCOA+".數(shù)據(jù)和記錄應‘可歸屬、清晰、同步、原始且準確、完整、一致、持久和可用；通常被稱為“ALCOA+”。無論是紙質記錄還是電子記錄，無論是簡單類計算機化系統(tǒng)還是復雜類計算機化系統(tǒng)，在數(shù)據(jù)的生命周期內都應滿足數(shù)據(jù)完整性的基本要求。

       2、簡單類計算機化系統(tǒng)

       2.1 MHRA ‘GXP’ Data Integrity Guidance and Definitions

       Simple electronic systems with no configurable software and no electronic data retention (e.g. pH meters, balances and thermometers) may only require calibration.

       在MHRA數(shù)據(jù)完整性指南的“建立數(shù)據(jù)關鍵性和固有可靠性風險”一節(jié)，簡單的電子系統(tǒng)被定義為：“無參數(shù)設置軟件、無電子數(shù)據(jù)保存功能的電子系統(tǒng)（如pH計、天平和溫度計）”。

       2.2 WHO Guideline on data integrity

       11.4. Where electronic instruments (e.g. certain pH meters, balances and thermometers) or systems with no configurable software and no electronic data retention are used, controls should be put in place to prevent the adverse manipulation of data and to prevent repeat testing to achieve the desired result.

       在WHO的數(shù)據(jù)完整性指南的“計算機化系統(tǒng)”章節(jié)，簡單的電子系統(tǒng)同樣被認定為沒有可配置軟件和沒有電子數(shù)據(jù)保存的系統(tǒng)（如pH計、天平和溫度計），這一點在定義上與MHRA完全一致。無參數(shù)設置軟件、無電子數(shù)據(jù)保存功能的簡單電子系統(tǒng)（如pH計、天平和溫度計）

       2.3 PIC/S GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED GMP/GDP ENVIRONMENTS

       8.9 Direct print-outs from electronic systems

       8.9.1 Some very simple electronic systems, e.g. balances, pH meters or simple processing equipment which do not store data, generate directly-printed paper records.

       PIC/S 良好數(shù)據(jù)完整性管理規(guī)范中的簡單類系統(tǒng)指直接打印輸出類電子系統(tǒng)：一些非常簡單的計算機化系統(tǒng)例如，天平、酸度計；或簡單的處理儀器，不存儲電子數(shù)據(jù)，直接生成打印的紙質記錄。

       2.4 PA/PH/OMCL (08) 69 R7 – Validation of Computerized Systems – Core document

       Table I: Categorisation of computerised systems (based on Reference 6)

       簡單類計算機化系統(tǒng)：簡單的軟件、有限的用戶配置，例如：酸度計、天平、UV-VIS、自動旋光儀、天平、TLC分析儀等。(備注：復雜系統(tǒng)的UV/VIS指色譜系統(tǒng)配套的檢測系統(tǒng))

       總結：按照以上業(yè)界比較認可的典型的數(shù)據(jù)完整性指南，簡單類的計算機化系統(tǒng)通常被定義為無參數(shù)設置或有限的用戶配置軟件、無電子數(shù)據(jù)保存功能、僅能直接打印的計算機化系統(tǒng)。OMCL中計算機化系統(tǒng)的分類中，將計算機化系統(tǒng)按照復雜程度和用戶可配置程度進行了分類，其中簡單類計算機化系統(tǒng)涵蓋了直接打印輸出的電子系統(tǒng)及具備電子數(shù)據(jù)存儲的計算機化系統(tǒng)。

       3、“簡單”類計算機化系統(tǒng)數(shù)據(jù)完整性控制點及風險點

       3.1 WHO Guideline on data integrity

       11.4. Where electronic instruments (e.g. certain pH meters, balances and thermometers) or systems with no configurable software and no electronic data retention is used, controls should be put in place to prevent the adverse manipulation of data and to prevent repeat testing to achieve the desired result.

       對于簡單類計算機化系統(tǒng)，應該采取控制措施防止數(shù)據(jù)被篡改，防止為了得到想要的結果而重復測試。

       3.2 PIC/S GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED GMP/GDP ENVIRONMENTS

       As a minimum, simple systems should have normal and admin users, but complex systems will typically require more levels of users (e.g. a hierarchy) to effectively support access control.

       對于簡單的系統(tǒng)，至少有普通及管理員賬戶，對于較復雜的系統(tǒng)需要更多的賬戶等級支持用戶登錄管理。

       It is acknowledged that some very simple systems lack appropriate audit trails; however, alternative arrangements to verify the veracity of data should be implemented, e.g. administrative procedures, secondary checks and controls.

       通常來說，大家比較公認的，對于一些簡單的計算機化系統(tǒng)缺少相應的審計追蹤，這種情況，應采取相應的替代的措施來實施核對數(shù)據(jù)的真實性，例如，管理性的文件，第二人的復核等控制措施。

       3.3 APIC Practical risk-based guide for managing Data Integrity

       對于直接打印輸出無電子數(shù)據(jù)存儲的計算機化系統(tǒng)，按照APIC的系統(tǒng)分類，應屬于第三類：

       Category 3: An electronic system with some limited manual adjustable input data and the generated CGxP data is not stored but printed out. Typical examples could be potentiometric titrators not connected to a PC, balances with printer.

       第三類系統(tǒng)的建議控制要求如下（以嚴重性高為例）：

       1、良好的記錄管理：記錄受控發(fā)放回收及平衡、相關GXP信息打印完整

       2、外圍記錄：儀器使用的追溯性。

       3、權限管理：時間日期鎖定。

       4、記錄歸檔保存（紙質記錄）。

       備注：對于僅能人工觀察，但是可以配備打印功能的計算機化系統(tǒng)，比如很多稱量系統(tǒng)，目前更多的監(jiān)管要求必須配備打印功能，升級變?yōu)锳PIC的三類系統(tǒng)。

       4、“簡單”類計算機系統(tǒng)的多變性

       隨著行業(yè)技術的發(fā)展進步，通常意義的“簡單”類計算機化系統(tǒng)也在發(fā)生著變化，廠家會設計開發(fā)更多的功能模塊，儀器變的相對復雜和高級，儀器的使用也會更加滿足用戶的需求。

       4.1 系統(tǒng)對接至其它系統(tǒng)

       以嚴重程度較高的用于放行測試儀器為例，該儀器為直接打印輸出無電子數(shù)據(jù)存儲的計算機化系統(tǒng)，但可經(jīng)過接口將數(shù)據(jù)傳輸至另一個系統(tǒng)，用戶配置開發(fā)后，將該儀器組態(tài)并入LIMS系統(tǒng)，該儀器按照APIC分類表，則劃為第四類儀器：

       Category 4: An electronic system with some limited manual adjustable input data and the generated CGxP data is not stored but sent via an interface to another system, e.g., a cat 5 or 6. Typical examples could be temperature sensors

       以嚴重程度較高的用于放行測試的儀器為例，該儀器為直接打印輸出無電子數(shù)據(jù)存儲的計算機化系統(tǒng)，對于第四類計算機化系統(tǒng)建議的要求：

       ● 良好的記錄管理：記錄受控發(fā)放回收及平衡。

       ● 接口驗證：確認數(shù)據(jù)傳輸對接功能。

       ● 權限管理：需用戶權限管理，至少兩級權限，管理員及普通用戶

       ● 記錄歸檔保存（按照LIMS數(shù)據(jù)文件管理）

       4.2 系統(tǒng)具備電子數(shù)據(jù)存儲

       隨著行業(yè)技術的發(fā)展進步，通常意義的“簡單”類計算機化系統(tǒng)也在發(fā)生著變化，廠家會設計開發(fā)更多的功能模塊，例如，增加了電子數(shù)據(jù)存儲功能，該儀器按照APIC分類表，則劃為第五類儀器：

       Category 5: An electronic system where CGxP data are permanently stored, and these CGxP data are not modified by the user to generate results (static CGxP data). Examples could include UV instruments or IR instruments used for identification testing, in line particle size and TOC testing

       以嚴重程度較高的用于放行測試的儀器為例，該儀器具備電子數(shù)據(jù)存儲功能，對于第五類計算機化系統(tǒng)建議的最低要求：

       ● 良好的記錄管理：記錄受控發(fā)放回收及平衡。

       ● 登錄控制：啟用。

       ● 權限管理：需用戶權限管理，至少兩級權限，管理員及普通用戶。

       ● 審計追蹤：系統(tǒng)審計追蹤。

       ● 數(shù)據(jù)備份：每天進行備份。

       4.3 相關法規(guī)定

       MHRA 數(shù)據(jù)完整性指南中對于此類特殊儀器也進行了相關規(guī)定如下：

       Where the basic electronic equipment does store electronic data permanently and only holds a certain volume before overwriting; this data should be periodically reviewed and where necessary reconciled against paper records and extracted as electronic data where this is supported by the equipment itself.

       如果基本電子設備不存儲電子數(shù)據(jù)，或僅提供打印的數(shù)據(jù)輸出（例如，天平或pH計），則打印件構成原始數(shù)據(jù)。如果基本電子設備能存儲電子數(shù)據(jù)，但只保存一定量，然后就會被寫滿覆蓋，則應定期對此數(shù)據(jù)進行審核，必要時與紙質記錄進行數(shù)量平衡，如果設備本身支持時還應作為電子數(shù)據(jù)提取出來。

       5、不再簡單的“簡單”類計算機化系統(tǒng)是否可以簡單化管理？

       當簡單類的計算機化系統(tǒng)更新升級后具備電子數(shù)據(jù)存儲功能，是否可以不啟用這些功能，仍然按照打印數(shù)據(jù)作為原始數(shù)據(jù)進行管理？

       ● 實例1：2023年 FDA審計印度某公司的部分483缺陷，里邊提到了具備電子數(shù)據(jù)存儲功能的儀器未開啟，以打印數(shù)據(jù)作為原始數(shù)據(jù)管理，對于儀器中的電子數(shù)據(jù)未進行審核備份等。

       Your firm operates(b)(4) filter integrity test equipment in support of general and (b)(4) parenteral manufacturing operations. During our review of the (b)(4) equipment and software, it was observed that the firm was not aware of the equipment data storage capability and consequently does not review or backup the electronic data generated and stored on the equipment, only using printer printouts as primary data. Per your firm's management, the data capability storage for this equipment is up to 200 tests, after which the data is overwritten with the most recent data.

       你們公司使用的過濾器完整性測試儀，用于注射劑的生產(chǎn)操作。在我們對設備和軟件的審查中，發(fā)現(xiàn)貴公司沒有意識到設備的數(shù)據(jù)存儲能力，因此沒有審核或備份設備上產(chǎn)生和存儲的電子數(shù)據(jù)，只使用打印的數(shù)據(jù)作為原始數(shù)據(jù)。據(jù)貴公司的管理人員稱，該設備的數(shù)據(jù)容量存儲最多可達200條測試數(shù)據(jù)，達到200條數(shù)據(jù)后，后續(xù)的數(shù)據(jù)將被最新的數(shù)據(jù)覆蓋。

       ● 實例2：2024 FDA審計印度另一家公司的483報告中同樣指出了具備電子數(shù)據(jù)存儲和備份功能的儀器，功能未啟用，使用打印的數(shù)據(jù)作為原始數(shù)據(jù)，并且打印條的時間日期倒簽等問題被發(fā)現(xiàn)。

       OBSERVATION 7

       There are no controls to prevent operators from changing the date and time on the Climet nonviable particle count equipment. Operators stated they had changed the date and time to back date printouts. Additionally, the instIUillent is capable of storing and backing-up electronic data, but the function is not used.

       The Oxi 73 10 Dissolved Oxygen Meter allows automatic saving of electronic data that can be backed up to a USB or transfe1Ted through a connected computer, but these capabilities are not being used.

       沒有相應的控制措施來防止塵埃粒子計數(shù)器更改日期和時間，分析員承認更改了日期和時間，并對打印條進行倒簽；另外，該儀器具備電子數(shù)據(jù)存儲和電子數(shù)據(jù)數(shù)據(jù)備份功能，未啟用；Oxi 73 10 Dissolved Oxygen Meter可以實現(xiàn)自動存儲電子數(shù)據(jù)，數(shù)據(jù)可以通過USB或傳輸?shù)诫娔X，這些功能未啟用。

       ● 實例3：在近期國內某藥廠的FDA審計483報中，同樣是對于此類儀器的電子數(shù)據(jù)的管理提出了相關問題。

       A)Your firm operate (b)(4) portable non-viable particle monitoring equipment used to perform and generated test data for non-viable particle (NVP) count used in environment monitoring /cleanroom qualification activities in Grade Band Grade C areas in support of general (b)(4) parenteral manufacturing operations. (b)(4) equipment have no time stamped audit trail, data management, alarm management, and archival and retrieval of records capabilities.

       貴公司使用(b)(4)型懸浮粒子計數(shù)器為B級和C級潔凈區(qū)的環(huán)境監(jiān)測/潔凈區(qū)確認中的懸浮粒子項目提供檢測數(shù)據(jù)。這個儀器的審計追蹤、數(shù)據(jù)管理、報警管理、數(shù)據(jù)歸檔、數(shù)據(jù)調閱活動均無時間戳證明。

       B) Your firm operates(b)(4) integrity test equipment and integrity equipment use in support of general (b)(4) parenteral manufacturing operations. The mentioned equipment does not have time stamped audit trail, data management, alarm management, and archival and retrieval of records capabilities.

       貴公司使用(b)(4)型完整性測試儀和(b)(4)型完整性儀，為仿制藥(b)(4)注射劑的生產(chǎn)操作提供支持。這個儀器無時間戳的審計追蹤，無數(shù)據(jù)管理、報警管理、數(shù)據(jù)歸檔、還原功能。

       綜上三封FDA483報告，對于簡單類的計算機化系統(tǒng)更新升級后具備電子數(shù)據(jù)存儲功能，監(jiān)管機構要求應啟用這些功能，實現(xiàn)更好的數(shù)據(jù)管理，因為這些功能啟用會帶來更好的數(shù)據(jù)安全，數(shù)據(jù)的可追溯性更強，能夠更好的防止數(shù)據(jù)被篡改，防止為了得到想要的結果而重復測試。

       同時在MHRA的數(shù)據(jù)完整性指南中也明確指出了：企業(yè)應啟用滿足當前法規(guī)期望的相關系統(tǒng)，對于系統(tǒng)進行相應的升級更新配備相應的功能。

       It is expected that companies should be implementing systems that comply with current regulatory expectations2

       2 It is expected that GMP facilities with industrial automation and control equipment/ systems such as programmable logic controllers should be able to demonstrate working towards system upgrades with individual login and audit trails (reference: Art 23 of Directive 2001/83/EC).

       6、“簡單”類計算機系統(tǒng)風險及控制措施

       表格取自ISPE data integrity by design 12 Appendix D2 – Instrument Devices with

       Electronic Record Storage，對于缺少賬戶管理、審計追蹤、數(shù)據(jù)備份等相關問題，ISPE指南給出了中期控制措施及長遠的控制措施。

       對于沒有審計追蹤功能的儀器如何處理，在數(shù)據(jù)完整性的法規(guī)中也有明確的規(guī)定，具體如下

       ● MHRA ‘GXP’ Data Integrity Guidance and Definitions

       Where relevant audit trail functionality does not exist (e.g. within legacy systems) an alternative control may be achieved for example defining the process in an SOP, and use of log books. Alternative controls should be proven to be effective.

       Where add-on software or a compliant system does not currently exist, continued use of the legacy system may be justified by documented evidence that a compliant solution is being sought and that mitigation measures temporarily support the continued use.

       如果沒有相關的審計追蹤功能（例如，歷史遺留系統(tǒng)內），可以采用替代的控制來達成目的，如在一個SOP中規(guī)定該過程，使用日志本。應證明替代控制是有效的。如果目前沒有軟件插件或合規(guī)系統(tǒng)，可以通過書面證據(jù)來論證繼續(xù)使用老系統(tǒng)，證明正在尋求合規(guī)的解決方案，而風險緩解措施暫時支持繼續(xù)使用。

       ● PICS Good Practices for Data Management and Integrity in Regulated GMP-GDP Environments

       Audit trail Expectation

       Consideration should be given to data management and integrity requirements when purchasing and implementing computerized systems. Companies should select software that includes appropriate electronic audit trail functionality.

       Companies should endeavor to purchase and upgrade older systems to implement software that includes electronic audit trail functionality.

       It is acknowledged that some very simple systems lack appropriate audit trails; however, alternative arrangements to verify the veracity of data should be implemented, e.g. administrative procedures, secondary checks and controls. Additional guidance may be found under section 9.10 regarding hybrid systems.

       Potential risk of not meeting expectations/items to be checked

       If no electronic audit trail system exists a paper based record to demonstrate changes to data may be acceptable until a fully audit trailed (integrated system or independent audit software using a validated interface) system becomes available.

       在采購和使用計算機化系統(tǒng)時，應考慮數(shù)據(jù)管理和數(shù)據(jù)可靠性要求。公司應選擇包含適當?shù)碾娮訉徲嬜粉櫣δ艿能浖?。公司應盡力采購及升級舊系統(tǒng)，從而能夠運行具有電子審計追蹤功能的軟件。眾所周知，一些非常簡單的系統(tǒng)缺乏適當?shù)膶徲嬜粉?。但是，應采用其他方式核實?shù)據(jù)真實性，例如：管理性程序，二次復核和控制。如果沒有電子審計追蹤系統(tǒng)，可以使用能夠證明數(shù)據(jù)更改的紙質記錄，直至審計追蹤系統(tǒng)（集成系統(tǒng)或使用經(jīng)驗證的界面的獨立審計軟件）可用。

       ● WHO Guideline on data integrity

       11.12. Where a system cannot support ALCOA+ principles by design (e.g. legacy systems with no audit trail), mitigation measures should be taken for defined temporary periods. For example, add-on software or paper based controls may be used. The suitability of alternative systems should be justified and documented. This should be addressed within defined timelines.

       11.12.如果系統(tǒng)設計無法支持ALCOA +原則（例如，沒有審計追蹤的遺留系統(tǒng)），應在規(guī)定的臨時期間采取緩解措施。例如，可以使用附加軟件或紙質化控制。替代系統(tǒng)的適用性應經(jīng)過論證并用文件記錄。應在規(guī)定時限內解決。‘’

       7. 總結分析

       隨著行業(yè)技術的發(fā)展進步，通常意義的“簡單”類計算機化系統(tǒng)也在發(fā)生著變化，廠家會設計開發(fā)更多的功能模塊，儀器變的相對復雜和高級，儀器的使用也會更加滿足用戶的需求，當“簡單”類計算機化系統(tǒng)變的不再那么簡單，數(shù)據(jù)完整性的控制策略也需要相應的更新和匹配，延用之前的簡單模式管理存在極大的合規(guī)性風險，這些功能啟用會帶來更好的數(shù)據(jù)安全，數(shù)據(jù)的可追溯性更強，能夠更好的防止數(shù)據(jù)被篡改，防止為了得到想要的結果而重復測試，同時對于較老的歷史遺留系統(tǒng)，數(shù)據(jù)完整性的相關風險應進行識別，應給出中期控制措施(使用附加軟件或紙質化控制等)及長遠的控制措施，在采購和使用計算機化系統(tǒng)時，應考慮數(shù)據(jù)管理和數(shù)據(jù)可靠性要求，公司應選擇包含適當?shù)碾娮訉徲嬜粉櫣δ艿能浖?/p>