前言：

       作為制藥行業(yè)的GMP實(shí)驗室，每天都會(huì )有大量的數據產(chǎn)生，按照數據承載的載體可以分為電子的數據、紙質(zhì)的數據或者混合的數據（Hybrid system），按照數據的類(lèi)型可大致分為檢測放行的數據、驗證相關(guān)數據或外圍輔助系統產(chǎn)生數據等，如此多的數據和記錄中，有哪些需要第二人的復核？

       1.目的：實(shí)驗室數據的第二人復核指分析員完成檢測后，第二人對于檢測結果的準確性的復核，本文結合國內外GMP法規、指南及數據完整性對于數據復核的相關(guān)要求，探討實(shí)驗室那些數據需要第二人的復核。

       2.術(shù)語(yǔ)：在展開(kāi)討論前，我們先了解下法規指南中關(guān)于審核和復核的相關(guān)術(shù)語(yǔ)：

       Review 審核

       Double check 再次確認

       Four-eyes principle (a contemporaneous reading by a second analyst) 四眼原則

       Independent verification 獨立復核

       A contemporaneous enumeration 同步計數

       A contemporaneous verification 同步復核

       Review need to be performed in real-time 實(shí)時(shí)審核

       3.法規和指南規定（第二人復核）

       3.1Medicines & Healthcare products Regulatory Agency (MHRA) ‘GXP’ Data Integrity Guidance and Definitions

       Where the data obtained requires manual observation to record (for example results of a manual titration, visual interpretation of environmental monitoring plates) the process should be risk assessed and depending on the criticality, justify if a second contemporaneous verification check is required or investigate if the result could be captured by an alternate means.

       對于人工觀(guān)察并記錄的數據，例如手工滴定，環(huán)境監測平皿計數，應基于風(fēng)險及數據的關(guān)鍵程度，論述第二人的同步確認是否需要或者檢測的結果用其他可替代的途徑獲取。

       3.2PICS Good Practices for Data Management and Integrity in Regulated GMP-GDP Environments 202107

       Additional controls should be considered when critical test interpretations are made by a single individual (e.g. recording of microbial colonies on agar plates). A secondary review may be required in accordance with risk management principles. In some cases this review may need to be performed in real-time. Suitable electronic means of verifying critical data may be an acceptable alternative, e.g. taking photograph images of the data for retention.

       當關(guān)鍵檢測是由單人進(jìn)行解讀時(shí)（例如，記錄瓊脂平皿上的微生物菌落），應考慮額外的控制。根據風(fēng)險管理原則，可能需要進(jìn)行二次審核。在某些情況下，這種審核可能需要實(shí)時(shí)進(jìn)行?？梢越邮懿捎煤线m的電子手段核實(shí)關(guān)鍵數據作為替代方法，例如：對數據拍照留存。

       3.3USP 1117 MICROBIOLOGICAL BEST LABORATORY PRACTICES

       An important data integrity threat with microbiological testing resides with falsification of data and intentional omission of testing results. To control this risk, the company culture and ethical standards are essential as well as the application of a rigorous quality management system.

       微生物檢測的一個(gè)重要的數據完整性威脅在于偽造數據和故意遺漏檢測結果。為了控制這種風(fēng)險，公司文化和道德標準以及嚴格的質(zhì)量管理體系的應用是必不可少的。

       For the compendia sterility test that combines criticality of the test and higher risk of misinterpretation of results, it is now a standard practice to have a second analyst perform a contemporaneous evaluation of the sample (in test media) for microbial growth. Nonetheless, applying uncritically a contemporaneous reading by a second analyst (four-eyes principle) for all samples and microbiological tests is not recommended. Precision in counts may vary from one analyst to another (even if they are trained and qualified) as colonies may overlap, swarm over media, etc., allowing for misinterpretation. Microbiology is a “l(fā)ogarithmic science”; sample size is statistically weak and testing procedures have inherent variability. By tolerating no differences in counts, a high number of non-critical deviations will be generated, thus consuming resources unreasonably. As an alternative to a contemporaneous enumeration, a contemporaneous verification by a second person that the testing activity is performed correctly may be executed for higher risk tests. A second person could verify, for instance, if the reading of results is correctly executed according to the procedure, if the result on the Petri plate is correctly transcribed onto the GMP recording sheet (i.e. if growth is observed this is captured in the GMP sheet), and if the description of the sample corresponds to the description on the GMP recording sheet. An assessment of the risk due to a misinterpreted result and its impact on patient safety is performed to determine the high risk test outlined above.

       考慮到檢測項目的關(guān)鍵性和結果易出現差錯的無(wú)菌檢測，現在的通用的做法是讓第二名分析人員對樣品(培養基中)進(jìn)行微生物生長(cháng)的同時(shí)觀(guān)察。盡管如此，不建議對所有樣品和微生物測試不加批判地應用由第二個(gè)分析人員(四眼原則)同時(shí)進(jìn)行讀數。計數的精度可能因分析人員而異(即使他們受過(guò)訓練并有資格)，因為菌落可能重疊，聚集在培養基上，等等，允許誤解。微生物學(xué)是一門(mén)“對數科學(xué)”；樣本大小在統計上是微弱的，測試程序具有內在的可變性。如果不允許計數上的差異，就會(huì )產(chǎn)生大量的非關(guān)鍵偏差，從而不合理地消耗資源。作為同時(shí)枚舉的一種替代方法，由第二個(gè)人同時(shí)驗證測試活動(dòng)是否正確執行，可以用于更高風(fēng)險的測試執行驗證。第二個(gè)人可以確認，例如，結果的讀取是否按照程序正確執行，培養皿上的結果是否正確轉錄到GMP記錄頁(yè)上(即，如果觀(guān)察到生長(cháng)，則在GMP記錄頁(yè)上記錄)，并且樣品的描述是否與GMP記錄頁(yè)上的描述相對應。對錯誤解釋結果的風(fēng)險及其對患者安全的影響進(jìn)行評估，以確定上述高風(fēng)險測試。

       3.4WHO ECSPP TRS 1033 Annex 4 Guideline on data integrity 202103

       Example 3: Data entry

       Data entry includes for example sample receiving registration, sample analysis result recording, logbook entries, registers, batch manufacturing record entries and information in case report forms. The recording of source data on paper records should be done using indelible ink, in a way that is complete, accurate, traceable, attributable and free from errors. Direct entry into electronic records should be done by responsible and appropriately trained individuals. Entries should be traceable to an individual (in electronic records, thus having an individual user access) and traceable to the date (and time, where relevant). Where appropriate, the entry should be verified by a second person or entered through technical means such as the scanning of bar-codes, where possible, for the intended use of these data. Additional controls may include the locking of critical data entries after the data are verified and a review of audit trails for critical data to detect if they have been altered. The manual entry of data from a paper record into a computerized system should be traceable to the paper records used which are kept as original data.

       數據錄入包括如下示例，例如樣品接收登記、樣品分析結果記錄、日志錄入、登記、批生產(chǎn)記錄錄入以及病例報告表中的信息。在紙質(zhì)記錄上記錄源數據時(shí)，應使用不可擦除的墨水，且以完整、準確、可追溯、可歸屬且沒(méi)有錯誤的方式記錄。應由負責任的，經(jīng)過(guò)適當培訓的人員直接錄入電子記錄。錄入應可追溯到個(gè)人（在電子記錄中，單個(gè)用戶(hù)訪(fǎng)問(wèn)），并且可追溯到日期（和時(shí)間，如相關(guān)）。在適用情況下，錄入應由第二人核實(shí)，或盡可能針對這些數據預期用途通過(guò)技術(shù)手段錄入，例如條形碼掃描。其他控制可能包括：在數據核對后鎖定關(guān)鍵數據錄入，以及審查關(guān)鍵數據的審計追蹤以檢測數據是否被更改過(guò)。經(jīng)數據從紙質(zhì)記錄手動(dòng)錄入到計算機化系統應該可以追溯到所使用的作為原始數據保存的紙質(zhì)記錄。

       3.5 EU gmp Annex 11: Computerized Systems

       6. Accuracy Checks

       For critical data entered manually, there should be an additional check on the accuracy of the data. This check may be done by a second operator or by validated electronic means. The criticality and the potential consequences

       關(guān)鍵數據的手動(dòng)輸入應由第二個(gè)操作員或經(jīng)驗證的計算機化方法復核。

       3.6 PICS Good Practices for Data Management and Integrity in Regulated GMP-GDP Environments 202107

       9.7 Data capture/entry for computerized systems.

       - All manual data entries of critical data should be verified, either by a second operator, or by a validated computerized means.

       - 所有關(guān)鍵數據的手動(dòng)輸入應由第二個(gè)操作員或經(jīng)驗證的計算機化方法復核。

       3.7 對比分析：

       ● 對于人工觀(guān)察并記錄的實(shí)驗室檢測數據（例如手動(dòng)滴定、平皿計數等），MHRA和PICS數據完整性指南中均要求要基于風(fēng)險和數據的關(guān)鍵程度，必要時(shí)第二人同步復核或采取可替代的數據獲取方式，

       ● USP 1117中規定，微生物檢測的一個(gè)重要的數據完整性威脅在于偽造數據和故意遺漏檢測結果，考慮到檢測項目的關(guān)鍵性和結果易出現差錯的無(wú)菌檢測，現在的通用的做法是讓第二名分析人員對樣品(培養基中)進(jìn)行微生物生長(cháng)的同時(shí)觀(guān)察。盡管如此，考慮到微生物檢測項目的特殊性不建議對所有樣品和微生物測試不加批判地應用由第二個(gè)分析人員(四眼原則)同時(shí)進(jìn)行讀數。

       ● 對于人工錄入的關(guān)鍵數據需要第二個(gè)操作員或經(jīng)驗證的計算機化方法復核，EU GMP Annex 11 和PICS及WHO數據完整性指南中均有相關(guān)規定。

       思考：綜合上述分析，應基于風(fēng)險和數據的關(guān)鍵程度來(lái)決定是否需要第二人復核，如何進(jìn)行數據關(guān)鍵程度的風(fēng)險評估。

       4. 實(shí)驗室關(guān)鍵數據的評估

       4.1 WHO Guidance on good data and record management practices

       Critical GXP：data with a direct impact on patient safety or product quality

       關(guān)鍵數據：數據直接影響到病人的安全或最終產(chǎn)品的質(zhì)量。

       4.2 Medicines & Healthcare products Regulatory Agency (MHRA)

       ‘GXP’ Data Integrity Guidance and Definitions

       4. Establishing data criticality and inherent integrity risk

       4.1 Data has varying importance to quality, safety and efficacy decisions. Data criticality may be determined by considering how the data is used to influence the decisions made.

       數據關(guān)鍵性及數據完整性風(fēng)險

       數據對于藥品質(zhì)量、安全及有效性的影響存在差異，數據的關(guān)鍵程度可以通過(guò)對于相關(guān)決策的影響程度來(lái)判定。

       4.3 PICS GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED GMP/GDP ENVIRONMENTS/ EU GMP DT Q&As

       5.4 Data criticality

       5.4.1 The decision that data influences may differ in importance and the impact of the data to a decision may also vary. Points to consider regarding data criticality include:

       Which decision does the data influence?

       For example: when making a batch release decision, data which determines compliance with critical quality attributes isnormally of greater importance than warehouse cleaning records.

       What is the impact of the data to product quality or safety?

       For example: for an oral tablet, API assay data is of generally greater impact to product quality and safety than tablet friability data.

       數據的關(guān)鍵性

       數據對于決策的影響與數據的重要性有關(guān)，數據對于決策的影響也存在差異，數據關(guān)鍵性的考慮點(diǎn)如下：

       數據影響到什么決策？

       例如：放行決策，影響到關(guān)鍵質(zhì)量屬性的測試要比倉庫清潔記錄重要。

       對于產(chǎn)品質(zhì)量和安全性的影響

       例如：口服片劑，API含量檢測數據要比片劑的松脆度關(guān)鍵。

       Additional controls should be considered when critical test interpretations are made by a single individual (e.g. recording of microbial colonies on agar plates). A secondary review may be required in accordance with risk management principles. In some cases, this review may need to be performed in real-time.

       4.4 EMA guidance on good manufacturing practice and good distribution practice questions and answers

       How can data criticality be assessed?

       The decision that data influences may differ in importance and the impact of the data to a decision may also vary. Points to consider regarding data criticality include:

       Which decision does the data influence?

       For example: when making a batch release decision, data which determines compliance with critical quality attributes isnormally of greater importance than warehouse cleaning records.

       What is the impact of the data to product quality or safety?

       For example: for an oral tablet, API assay data is of generally greater impact to product quality and safety than tablet dimensions data.

       數據的關(guān)鍵性

       數據對于決策的影響與數據的重要性有關(guān)，數據對于決策的影響也存在差異，數據關(guān)鍵性的考慮點(diǎn)如下：

       數據影響到什么決策？

       例如：放行決策，影響到關(guān)鍵質(zhì)量屬性的測試要比倉庫清潔記錄重要。

       對于產(chǎn)品質(zhì)量和安全性的影響

       例如：口服片劑，API含量檢測數據要比片劑的尺寸關(guān)鍵。

       Additional controls should be considered when critical test interpretations are made by a single individual (e.g. recording of microbial colonies on agar plates). A secondary review may be required in accordance with risk management principles. In some cases, this review may need to be performed in real-time.

       4.5 APIC Practical risk-based guide for managing Data Integrity

       Data severity assessment: within CGxP data, different levels of severity can be defined as a function of its use. Typically, this is linked to the stage of manufacturing following the principle of increasing CGxP outlined in ICH Q7. Alternatively, other factors such as impact on final product quality can be taken into account to further differentiate between severity categories.

       數據關(guān)鍵程度的評估應基于生產(chǎn)的步驟及對于最終產(chǎn)品質(zhì)量的影響

       4.6 PDA 80 Data integrity management system for pharmaceutical laboratories

       Data integrity controls should be based on quality risk management principles such as ICH Q9, that is, the level of controls, verification, and oversight should be commensurate with the criticality of the data to patient safety and with the risk to data accuracy, completeness, fabrication or falsification.

       數據完整性控制應基于質(zhì)量風(fēng)險管理原則，如ICH Q9，即控制、復核和監督的水平應與數據對患者安全的重要性以及數據準確性、完整性、偽造或偽造的風(fēng)險相一致。

       A risk matrix can be established using criticality of the test and maturity of the quality system and use of risk reducing technology. Data criticality can be established based on whether the test is for a critical quality attribute (CQA), such as a sterility test; a critical process control (CPC), such as an environmental monitoring test; or an in process control or other test, such as environmental monitoring for nonsterile products. Figure 7.21 shows a risk matrix applied to data integrity. In this example, the matrix is used to establish which microbiological tests require second person verification prior to approving test results.

       結合檢驗的關(guān)鍵性、質(zhì)量體系的成熟度和降低風(fēng)險的技術(shù)，可以建立風(fēng)險矩陣?？梢愿鶕y試是否為關(guān)鍵質(zhì)量屬性(CQA)(如無(wú)菌檢查)來(lái)確定數據的關(guān)鍵性，關(guān)鍵工藝控制(CPC)，如環(huán)境監測試驗；或者過(guò)程控制/其他測試，如非無(wú)菌產(chǎn)品的環(huán)境監測。下圖顯示了應用于數據完整性的風(fēng)險矩陣。在本例中，矩陣用于確定在批準測試結果之前，哪些微生物測試需要第二人復核。

       微生物實(shí)驗室數據關(guān)鍵程度矩陣圖：

       4.7 對比分析：

       數據的關(guān)鍵程度應基于數據對于產(chǎn)品放行決策的影響和數據對于產(chǎn)品質(zhì)量和病人用藥的風(fēng)險。

       5.總結：

       5.1QC內部需要人工觀(guān)察并記錄的相關(guān)數據不同于電子數據或打印輸出數據，此類(lèi)數據的追溯性相對較弱，出現人為差錯后的可檢測手段較電子數據或打印輸出數據相對較少，結合相關(guān)數據完整性指南的要求，對于QC內部需要人工觀(guān)察并手動(dòng)記錄的數據，應結合影響產(chǎn)品放行決策和對病人用藥的安全性的影響進(jìn)行數據關(guān)鍵性的評估，基于數據關(guān)鍵性及其風(fēng)險，考慮進(jìn)行第二人復核來(lái)降低風(fēng)險。

       5.2同時(shí)對于關(guān)鍵數據的第二人復核的“同步/實(shí)時(shí)”，是否有時(shí)間限要求？應基于數據的可追溯性，選擇適當的策略進(jìn)行：

       ● 數據承載的載體后續不可得，例如手工滴定分析，應做到同步并及時(shí)的結果復核；

       ● 數據承載的載體可得但隨時(shí)間的推移，檢測結果會(huì )發(fā)生變化，例如溶液顏色，應做到同步并及時(shí)的結果復核；

       ● 數據承載的載體可得可追溯，例如無(wú)菌檢測，應在數據承載的載體（培養基）銷(xiāo)毀前完成復核，可參考USP1117微生物樣品觀(guān)察時(shí)限的要求，觀(guān)察的上午或下午完成檢測結果的復核；需要注意的是微生物的平皿計數測試，雖載體可得可追溯，但平皿觀(guān)察環(huán)境及培養時(shí)間可能對于后續的微生物生長(cháng)產(chǎn)生影響，建議及時(shí)進(jìn)行復核。

       ● 對于關(guān)鍵數據的人工錄入的第二人復核，可采取上述的原則進(jìn)行。

       備注：文中法規和指南的英文部分為法規和指南原文，中文部分為作者解讀和翻譯，供參考。