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本期文章討論了滿足歐洲數(shù)據(jù)可靠性要求的實(shí)踐。

A HPLC laboratory for pharmaceutical quality control is used as an example in which data for the batch release of a finished medicinal product is generated. A schematic representation of the underlying process is shown in Figure 1.

以用于藥品質(zhì)量控制的HPLC實(shí)驗(yàn)室為例子，其中產(chǎn)生了藥品的批次放行數(shù)據(jù)。底層流程的示意圖如圖1所示。

Figure 1 Quality control and batch release

圖1 質(zhì)量控制和批放行

What types of data (in accordance with the WHO guidance) are collected in a chromatography laboratory? The most important types are listed below:

色譜實(shí)驗(yàn)室需要收集哪些類型的數(shù)據(jù)（根據(jù)WHO指南）？最重要的類型如下：

● data from the tested batch and data on personnel who carry out and control the testing process

● 測(cè)試批次的數(shù)據(jù)以及執(zhí)行和控制測(cè)試過程的人員的數(shù)據(jù)

● sampling and sample storage data, records and observations

● 取樣和樣品儲(chǔ)存數(shù)據(jù)、記錄和觀察

● weighing and sample preparation, standards and reagents used

● 稱重和樣品制備，使用的標(biāo)準(zhǔn)品和試劑

● qualification and calibration data for the pipettes and balances used

● 所使用的移液器和天平的確認(rèn)和校準(zhǔn)數(shù)據(jù)

● qualification data for all of the devices used

● 所有使用的設(shè)備的確認(rèn)數(shù)據(jù)

● instrument control data (detector wavelength range, flow, temperature, etc.)

● 儀器控制數(shù)據(jù)（檢測(cè)器波長(zhǎng)范圍、流量、溫度等）

● sequence data in full

● 序列數(shù)據(jù)完整

● data to be recorded (e. g. data rate, integration parameters, etc.)

● 要記錄的數(shù)據(jù)(例如：數(shù)據(jù)速率、積分參數(shù)等)

● chromatography testing data (initial electronic data, peak areas)

● 色譜檢測(cè)數(shù)據(jù)（初始電子數(shù)據(jù)、峰面積）

● processed data from chromatography testing (processed electronic data)

● 從色譜測(cè)試中處理的數(shù)據(jù)（處理的電子數(shù)據(jù)）

● measuring process and device-specific calibrations

● 測(cè)量過程和設(shè)備特定的校準(zhǔn)

● device-specific calculations

● 特定于設(shè)備的計(jì)算

● peak areas after integration

● 積分后的峰面積

● HPLC calibration data

● HPLC校準(zhǔn)數(shù)據(jù)

● calculation data (software-based or completed manually)

● 計(jì)算數(shù)據(jù)（基于軟件或手工完成）

● trend analyses

● 趨勢(shì)分析

● all system suitability test results

● 所有系統(tǒng)適用性測(cè)試結(jié)果

● reports generated from electronic data (sample-list printouts, chromatograms, etc.)

● 從電子數(shù)據(jù)生成的報(bào)告（樣本列表打印輸出、色譜圖等）

● audit trail data and all deviations and changes

● 審計(jì)追蹤數(shù)據(jù)和所有偏差和變更

● documented observations

● 記錄到的觀察

● if applicable, calculations carried out using external software (LIMS, Excel) = derived data, results (reportable result), evaluation (with OOS, OOE, OOT)

● 如果適用，使用外部軟件（LIMS, Excel）進(jìn)行計(jì)算=導(dǎo)出的數(shù)據(jù)、結(jié)果（可報(bào)告的結(jié)果）、評(píng)估（使用OOS、OOE、OOT）

All of this data should comply with the ALCOA principles – and, in an ideal situation, the ALCOA plus principles

所有這些數(shù)據(jù)都應(yīng)符合ALCOA原則——在理想情況下，還應(yīng)符合ALCOA+原則

Figure 2 ALCOA principles of data integrity

圖2 ALCOA數(shù)據(jù)可靠性原則

A number of these requirements are already contained in the EUGMP Guidelines, i.e. they were introduced before the recent publication of data integrity specifications.

其中一些要求已經(jīng)包含在歐盟GMP指南中，即它們是在最近發(fā)布數(shù)據(jù)可靠性規(guī)范之前提出的。

Key aspects of data integrity during the generation of data are examined below. It will be shown that the definition of data is of major importance for a project. The difference between raw data and metadata is not discussed here because the differentiation is difficult. The general term data is used instead. This approach is also taken by the FDA.

下面將研究數(shù)據(jù)生成過程中數(shù)據(jù)可靠性的關(guān)鍵方面。這表明，數(shù)據(jù)的定義對(duì)于一個(gè)項(xiàng)目是非常重要的。這里不討論原始數(shù)據(jù)和元數(shù)據(jù)之間的區(qū)別，因?yàn)楹茈y區(qū)分。取而代之的是通用術(shù)語數(shù)據(jù)。FDA也采用了這種方法。

A number of conflict situations that often arise in relation to data integrity requirements are examined below.

下面將審查與數(shù)據(jù)可靠性要求有關(guān)的一些經(jīng)常出現(xiàn)的沖突情況。

● Access to the key functions of the control and evaluation software (e.g. switching off the audit trail, changing the system time) must be restricted, e.g. limited to IT personnel.

● 必須限制訪問控制和評(píng)估軟件的關(guān)鍵功能（如關(guān)閉審計(jì)跟蹤、更改系統(tǒng)時(shí)間），如僅限于IT人員。

● Access to control and evaluation software must be based on individual login accounts. Group access or anonymous logins should not be possible. User privileges should be limited to the individual job profile.

● 訪問控制和評(píng)估軟件必須基于個(gè)人登錄帳戶。組訪問或匿名登錄應(yīng)該避免。用戶權(quán)限應(yīng)該僅限于單個(gè)崗位職責(zé)。

● A complete qualification and validation of all computers and the control and evaluation systems is absolutely essential.

● 所有計(jì)算機(jī)、控制和評(píng)估系統(tǒng)的完全確認(rèn)和驗(yàn)證是絕對(duì)必要的。

● A review of audit trails should be carried out before data-based decisions are made. This must be completed before the project is concluded and/or the collected data is used for batch release. Actions must be defined and/or put in place for deviations so that an appropriate investigation can be initiated and completed.

● 在做出基于數(shù)據(jù)的決策之前，應(yīng)進(jìn)行審計(jì)追蹤的審查。這必須在項(xiàng)目結(jié)束和/或收集的數(shù)據(jù)用于批次放行之前完成。必須定義和/或?qū)ζ畈扇⌒袆?dòng)，以便啟動(dòng)和完成適當(dāng)?shù)恼{(diào)查。

● Test runs and the generation of data for testing purposes are not permitted during testing prior to batch or raw material release if these processes are not carried out in accordance with defined protocols during qualification, validation or the system suitability test.

● 如果在確認(rèn)、驗(yàn)證或系統(tǒng)適用性測(cè)試期間，這些過程沒有按照規(guī)定的方案進(jìn)行，則在批次或原料放行前的測(cè)試期間，不允許測(cè)試運(yùn)行和測(cè)試數(shù)據(jù)的生成。

● There has to be a reason for every subsequent modification, and the reason must be completely and transparently documented. This applies in particular to reintegration and generally to manual integration and changes to manual data entries such as calculation factors, weights and quantities.

● 每一個(gè)后續(xù)的修改都必須有一個(gè)原因，并且這個(gè)原因必須被完整且透明地記錄下來。這特別適用于重新積分，一般適用于手動(dòng)積分和手動(dòng)數(shù)據(jù)條目的更改，如計(jì)算因子、重量和數(shù)量。

● There has to be a reason for every repeated analysis, and the reason must be completely and transparently documented. This type of situation is limited to the investigation of OOS, OOE and OOT results as well as deviations, e.g. failed injections. Repeats can also be indicated when a root cause analysis is carried out. For all repeats, prospectively defined processes must be in place and documentation must be mandatory.

● 每一個(gè)重復(fù)的分析都必須有一個(gè)原因，并且原因必須完整和透明地記錄下來。這種情況僅限于對(duì)OOS、OOE和OOT結(jié)果以及偏差的調(diào)查，例如進(jìn)樣失敗。當(dāng)執(zhí)行根本原因分析時(shí)，還可以進(jìn)行重復(fù)。對(duì)于所有重復(fù)，預(yù)先定義的過程必須到位，文檔必須是強(qiáng)制性的。

● If data lacks robustness and accuracy, e.g. due to an incomplete, unsuitable or old validation or calibration, it may not be used. This can be the case when response factors are used that represent device-specific values, but have not been established as such, or when response factors are not checked and corrected when a device is replaced.

● 如果數(shù)據(jù)缺乏穩(wěn)健性和準(zhǔn)確性，例如，由于不完整、不合適或舊的驗(yàn)證或校準(zhǔn)，它可能不被使用。這種情況可能發(fā)生在響應(yīng)因子被用來表示設(shè)備特定的值，但還沒有建立成這樣的情況下，或者當(dāng)設(shè)備被替換時(shí)響應(yīng)因子沒有被檢查和校正。