PDA TR 80：手动积分指南、审计跟踪以及电子数据管理等

Data Processing and Peak Integration

数据处理和峰的积分

Chromatographic software uses dynamic peak detection algorithms and automatic peak detection algorithms. Integrating the chromatograms using software to apply the integration events, such as peak width, threshold, height, and area, etc., and then visually observing the peak integration for its correctness is generally recommended. The inherent or analytical variations and combination of various and drifting baselines in which the auto-integration will either underreport or overintegrate the peak areas.

色谱软件使用动态寻峰算法和自动寻峰算法。通常建议先用软件积分色谱来处理像峰宽、阈值、峰高及峰面积等需要积分的情形，再人工确定积分的正确性。因为一些固有的或分析变化或两者皆有以及基线漂移的原因，自动积分将会使峰面积偏大或者偏小。

Once acquired, the electronic raw data of the measurements (measured values and metadata) are stored and available for processing. Some acquired electronic raw data already represent usable results (e.g., weight, temperature, and humidity). Other acquired electronic raw data, such as intensity values correlated with time or wavelength and generated by chromatography or spectroscopy, require further processing to obtain usable results (e.g., retention times, peak areas, and amounts). These processes, such as integration and calibration, are defined by processing parameters or calibration factors and affect only the resultant data after processing, but not the acquired electronic raw data. In contrast to the acquired electronic raw data, the processing parameters, such as integration events and calibration curves, may be changed during data evaluation. The changed processing parameters, methods, and processed data should be identified by versioning (i.e., number of times reprocessed) either on the results or from the audit trail data (25).

实验的电子原始数据（测试结果和元数据）一经（色谱软件）获取，将会被（软件）存储并可用来进行处理。那些诸如重量、温度、湿度等电子原始数据在被获取后即可直接作为结果；而其他由色谱或光谱产生的与时间或波长相关的电子原始数据，则需要经过进一步处理才能够得到如保留时间、峰面积以及物质的量等可以被使用的结果。像积分和校正这些仅由处理参数或校准因子所定义的处理过程，它们只影响处理后的最终结果，而对电子原始数据没有影响。与获得的（确定的）电子原始数据相反，在数据评估过程中，积分事件和校正曲线等处理参数可能发生改变。改变了的处理参数，方法以及处理后的数据应该标示版本控制的方法标记在结果或在审计追踪中。

Integration events should be defined through standard algorithms, and metadata and should be associated with respective raw data files. In such cases, the analyst adjusts the integration events to obtain proper peak integration. As chromatography is a comparative technique, the consistent integration events should be applied for the entire set of chromatograms, as much as possible, or published along with the chromatograms. Figure 6.3.7-1 represents an overlaid chromatogram of the standard and a sample (of the same concentration) integrated with the same integration events. Integrating small peaks, closer peaks, negative peaks, drifting peaks, and peak-to-valley requires time and skill. Integrating peaks manually is not recommended and should be avoided to the extent possible.

积分事件应该通过标准算法和元数据进行定义，且处理后的结果应与各自的原始文档进行关联。只有这样，分析师才可以通过调整积分事件从而获得适当的峰面积积分。因为色谱是一种比对技术，所以应尽可能的将同一积分事件应用于整个色谱图集或和整个色谱图一起发布。图 6.3.7-1表示标准品和某浓度下的样品通过同样的积分事件进行积分，并一同呈现在同一色谱图中。对小峰、接近峰、负峰、漂移峰以及峰谷进行积分需要时间和技巧。不推荐手动积分，且应尽可能避免进行手动积分。

QC laboratories should have procedures in place that require authorization to perform manual integration and for procedures to track such events to avoid unnoticed or unevaluated cases that may affect the accuracy of the results. PDA defines manual integration as a process used by a person to manually integrate the peak height or area by modifying the baseline of the chromatogram with use of chromatographic software. The conditions and circumstances when manual integration would be allowed should be predefined (e.g., complexity of the sample matrix). Generally, a good chromatographic data system would be able to render consistent and reliable baselines for an overwhelming majority of injections within a chromatographic run. When consistently bad chromatographic peaks and baseline issues are encountered, having good documentation should not be the only way to address the issue. In this circumstance, the goal should be to improve the system and ensure that the data generated is reliable and consistent.

QC实验室应建立需要授权才能进行手动积分的程序并追踪此类事件（注：手动积分）的程序，避免因为人员忽视或者未评估而影响结果的准确性。PDA将手动积分定义为：由人员使用色谱软件修饰色谱图的基线来人为对峰高或者峰面积进行积分的过程。应当事先定义允许进行手动积分的条件和情形（如：复杂的样品基质）。通常，一个良好的CDS系统应该能够在色谱运行中为绝大多数进针提供连续且可靠的基线。当色谱峰连续比较差且发生基线发生问题时，将问题完整的记录下来并不是唯一的解决途径。在这种情况下，应该以改善系统并确保产生的数据真实可信为目的。

The Quality Unit  should define standard protocols for processing data to include the following, which may be instrument or application-specific:

质量部门应定义处理数据的标准方案，可以是针对仪器或特定应用。方案应包含以下内容：

• Reprocessing peaks

  峰重新处理

• Applyingin strument/application-specific integration events/algorithms

  使用仪器/特定软件的积分事件/算法

• Fully integrating peaks

  峰完全积分

• Inhibiting ordisregarding any peaks in the test chromatogram (e.g., blank peaks, placebo peaks, solvent peaks) without scientific justification; examples where justification is needed include counter ion and reagent interactions with a sample

  禁止在没有科学论证的情况下，忽略测试色谱图中的任何峰值（如：空白峰，安慰剂峰，溶剂峰）。如样品与反离子或试剂相互反应需要科学论证。

• Applying thesame integration events for all samples in the sample set  or sequence andjustifying any change in integration events.

  对处在同一样品集或序列的样品采用同样的积分事件，并说明积分事件的任何改动。

Peak integration is the process used by a chromatographic system to determine the peak height and width and obtain the quantitation of the peak of interest. Certain USP monograph methods specify inhibiting integration at specified zones in the chromatographic run. USP <621> states that peaks can be disregarded by setting the thresholds in the integration to at least half of those below reporting threshold(32). Thereby, utilizing the built-in capability of the chromatographic data acquisition software to inhibit integration of peaks from solvent, mobile phase, placebo, and counter ions in impurity analysis in a common industry practice. Firms should scientifically evaluate and judiciously determine whether to use the inhibit integration functionality. Peaks in the chromatographic analysis may be excluded in the event of a known abnormality. Unknown peaks should be integrated and investigated according to the firm’s quality procedures.

峰（自动）积分是色谱系统用来确定目标峰峰高和峰宽以及定量的过程。某些USP专论方法指出在色谱运行时禁止（系统）对特定区域进行积分。USP<621>指出只有在通过对积分中的阈值进行设置（低于报告阈值一半以上）（32），才可以将那些低于报告阈值一半以上的峰忽略。因此，行业的普遍做法是，在杂质分析时利用色谱数据采集软件（CDAS）来防止对溶剂、流动相、安慰剂和反离子产生的峰进行积分。公司应科学合理的评估和决定是否使用抑制积分功能。在异常已知的情况下，可以将谱图分析中的一些峰排除。而未知峰应根据公司的质量程序进行积分和调查。

Manual integration is the process used by the analyst to integrate the peak height or area by modifying the baseline of the chromatograph using software(49). Manual integrations may be required for R&D and biological labs. Though in QC labs, manual interagtion may be necessary or acceptable only under special circumstances (e.g., complex chromatography due to sample matrix interferences, poor resolution, co-elution of peak of interest, problem with the baseline, or  software with limited capabilities); however, manual integration is not generally accepeable for assay. Manual integration should not be left to an analyst’s discretion; it should be performed only according to an approved procedure, with documented approval from a supervisor and results appropriately documented. A mature quality system will review these instances as part of continual improvement of methods and  equipment. Modern chromatographic software identifies and displays manually integrate peaks. Figure 6.3.7-2 represents a model chromatogram with manually intergrate peaks and software integrated peaks.

手动积分是分析师通过使用软件对色谱图基线进行修改从而对峰高或峰面积进行积分的过程（49）。研发和生物实验室可能需要（对色谱图）手动积分。尽管对于QC实验室，手动积分可能仅在特殊情况（如：由于样品基质的干扰所引起的复杂图谱；分辨率差；目标峰的共洗脱，基线问题以及系统能力有限）下是必需的或可接受的；但手动积分还是不适合应用于化验。手动积分只有在得到主管书面批准且结果正确记录后，根据批准程序才能进行，而不应该由分析师自行决定。一个成熟的质量体系应审查这些实例，作为方法和设备改进的一部分。现在的色谱软件已可以识别和标示出手动积分峰。Figure 6.3-7.2 是一个模型色谱图，它同时展现了手动积分峰和软件积分峰。

Printed chromatographic should be presented in visible scale as per the respective analysis(peak top visible for assay or single analysis, peak base clearly visible for purity analysis). After integration, results may be publish or electronically stored. If results are reprocessed, permission from supervisor is required. Those types of events may be noted in a log (paper of electronic) for quick reference.

打印出的色谱图应以可见比例形式呈现各个分析项需要的内容，如对于含量和单个分析项，峰顶应可见；对于纯度分析，峰基应可见。在积分后，结果应能够输出或以电子形式存储。如果结果被重新处理了，那么应得到主管的许可。可以将这些时间记录在日志（纸质或电子形式）中，以供快速参阅。

Figure 6.3.7-3 illustrates a chromatogram in proper scale and visibility to determine the proper integration. Common practice across the industry is to present a visible and clear baseline for multicomponent analysis and the entire peak for single-peak analysis.

Figure 6.3.7-3以一个有着适当比例和可见的色图谱来说明适当的积分。行业内通常的做法是为多组分分析提供清晰可见的基线，而为单峰分析提供整个色谱峰。 

Figure 6.3.7-4a represents to the chromatogram printed in large scale, where peak integration is not visible. Figure 6.3.7-4b represents the same chromatogram with printed proper scaling, where peak trimming and missing peak integrations are visible, revealing possible intentional data manipulation.

Figure 6.3.7-4a是一张以最大比例打印的色谱图，其中峰值积分并不可见。Figure 6.3.7-4b是同样的色谱图以适当的比例打印，其中可以看到峰值修正和缺失峰的积分，揭示了可能的有意的数据操作。

Assay analysis, dissolution, and content uniformity involve a single analyte/peak analysis where the content will be calculated against a known standard. Gaussian peaks, with allowed system suitability characteristics of accuracy and precision, are expected in these types of analysis. Normal Gaussian peaks should be integrated exactly where the peak starts and finishes. The peak integragtion represented in these types of analysis is illustrated in Figures 6.3.7-5a-f.

含量，溶出度以及含量均一性包含了对单一分析物/峰按照已知标准进行计算的分析项目。在这些类型的分析项目中，都期望其具有准确和精确的系统适应性特征的高斯峰。正常的高斯峰应该确切地从色谱峰起始位置开始积分到截止为止结束积分。Figure 6.3.7-5a-f 展现了这些类型测试代表性的峰积分。

Figure 6.3.7-5a is the unprocessed signal of  a  single component analysis. Figure 6.3.7-5b represents raw data integrated with proper integration events and displayed in visible scaling. Figure 6.3.7-5c represents the peak integrated by trimming to yield low area. (Associated risk: Reporting fewer peak areas leads to less assay or dissolution or lower content values.) Figures 6.3.7-5d-f represent the raw data integrated with improper integration events, which presents more area. (Associated risk: Reporting more peak areas leads to more assay or dissolution or higher content values.)

Figure 6.3.7-5a是单组分分析的未处理的信号峰。Figure 6.3.7-5b表示的是对原始数据以适当的积分事件进行积分并以可见的比例呈现。Figures 6.3.7-5c 表示的是通过修整积分而产生了低面积的峰。（相关风险：报告峰面积的减少会导致含量或溶解度的降低或含量值的减少）Figures 6.3.7-5d-f 表示的是对原始数据用不适当的积分事件进行积分会表达更多的面积。（相关风险：报告峰面积的增加会导致含量或溶解度的增加，或含量值的增加）

Data manipulation of chromatograms by manually manipulating the integrated peaks is one factor the FDA has cited in Warning Letters(50-53). In these illustrations, all the integrations presented are made through chromatographic software by adjusting integration events. Chromatographic software will indicate which peaks are maually integrated. Laboratory management should have appropriate controls in place for detecting the data compromises made by applying the wrong integration events.

手动操作积分峰对色谱图进行数据处理是FDA在警告信中引用的一个因素。在这些图示中，所有的积分都是通过调整色谱软件的积分事件来完成的。色谱软件会标示出哪些峰是手动积分的。实验室应该有适当的控制措施以检测应用了错误的积分事件而造成的数据损毁。

Figures 6.3.7-6a-c and Figures 6.7.7-7a-c show integration errors that occur for multicomponent analysis (peak groups) , such as related substances analysis/chromatographic purity analysis. In both cases,fewer peak areas will reported.

Figure 6.7.7-6a-c 和Figure 6.7.7-7a-c展示的是在如成分分析/色谱纯度分析这种多组分分析（峰组）中的发生的积分错误。这两种情况下，报告的峰面积都会减少。

A hybrid system refers to analytical equipment for which both electronic and paper documentation combine to build the record. Analytical balances, autotitrators, polarimeters, dissolution apparatus,and pH meters, for example, are instruments managed by firmware that provides paper records. Per MHRA balances and pH meters without software are considered simple systems (5).To comply with regulatory requirements, a firm must ensure that the original data generated is retained and/or that the record archived represents a true copy of the data (2).

混合系统是指以电子和纸质文档相结合形成记录的分析设备。 例如，分析天平，自动滴定仪，旋光仪，溶出仪和pH计，都是由纸质记录的固件管理的仪器。根据MHRA，不带软件的天平和pH计被认为是简单系统（5）。为了符合法规要求，公司必须确保所生成的原始数据得到保存和/或存档的记录能够代表数据的真实副本（2）。

Several models of the above-listed equipment (balance, auto titrator, polarimeter, dissolution apparatus, and pH meter) with various functionalities are available in the market. Equipment with features including software,audit trail functionality, and storage capacity along with equipment with firmware,without electronic audit trail storage capacity, are considered analytical laboratory computerized systems (ALCS). For example, if a laboratory balance connected to a computer or with integrated software, this balance qualifies as ALCS (discussed further in Section 6.3) and is not in the scope of hybrid systems . As shown in Figure 6.2-1,simple systems with or without analytical data storage capability are both considered to be hybrid systems.

市面上有多种具有各种功能的上述设备的型号（天平，自动滴定仪，旋光仪，溶出仪和pH计）。 具有包括软件，审计跟踪功能和存储能力等功能的设备，被认为是分析实验室计算机化系统（ALCS），而只有固件但没有电子审计跟踪、存储功能的这不是。 例如，如果实验室天平连接到计算机或集成软件，则此天平符合ALCS定义（在6.3节中进一步讨论），而不属于混合系统。 如图6.2-1（混合系统数据流）所示，具有或不具有数据存储能力的简单系统都被认为是混合系统。

HybridSystems — Associated Risks

混合系统-相关风险

The major risks associated with data integrity in the data governance of laboratory hybrid systems should be monitored by quality personnel on a regular basis and include, but are not limited to, the following:

实验室混合系统数据治理中与数据完整性相关的主要风险应由质量人员定期监控，包括但不限于以下内容：

• Lack of traceability for all the data generated (lack of password control, lack of audit trail capability and/or intentional inactivation of audit trail, and vulnerability of date and time to manual change)

  所有生成的数据缺乏可追溯性（缺乏密码控制，缺乏审计跟踪能力和/或故意停用审计跟踪，以及日期和时间易于手动更改）；

• Lack of understanding of the functionality and available features

  缺乏对功能和可用功能的理解

• Lack of second-person

  缺少第二人的复核

• Testing into compliance or duplicate prints of the same record

  测试直至合格或复制同一记录

• Poor restoration, backup, or single-point failure (hard drive)

  恢复，备份不佳或单点故障（硬盘）

• Lack of controls to retain source electronic data and data that is “complete” and includes all metadata,which may be due to access to the computer clock, recycle bin, and data files in operating system files

  具备计算机时钟，回收站和操作系统文件中的数据文件的访问权限，缺乏控制以保留源电子数据和包括所有元数据在内的完整数据

• Lack of adequate second-person verification that printed data is a true copy of original data electronic data or a representative summary of the source electronic data, including all metadata and results

  缺乏充分的第二人复核以确认打印数据为原始电子数据的真实副本或源数据的代表性总结，包括所有元数据和结果

Many of these risks also occur in full electronic systems if adequate controls are not in place.

如果没有适当的控制措施，其中许多风险也会出现在完全的电子系统中。

HybridSystems — Qualification

混合系统-确认

Most vendors provide a standard validation protocol defining the functional criteria and controls ofthe hybrid system.The firms Quality Unit is responsible for ensuring that these controls, validation criteria, and iinstrument operational qualifications are properly understood and implemented. IF required, the Quality Unit should implement company-designed controls to govern the intendeduse of the system. Please note that all types of data have the potential for manipulation, particularly in CSV text or PDF format. Some additional examples of limitations that should be checked are:

大多数供应商提供标准验证方案，定义混合系统的功能标准和控制措施。公司质量部门负责确保这些控制措施、验证接受标准和仪器运行资确认正确理解和实施。 如果需要，质量部门应实施符合公司实际的控制，以监管系统的预期用途。 请注意，所有类型的数据都有可能被操纵，特别是CSV文本或PDF格式。应该检查的一些其他限制示例包括：

Data format and storage capacity. The data sorage format, , limits, and storage capacityshould be known to identify possible risks, e.g.,data that is not stored in its original format, or can be formatted in “CSV,” “ Unix code formatter,” or saved as a spreadsheet or PDF.Systems withinsufficient data storage capacity may result in data being overwritten or not saved.

数据格式和存储容量。 应该知道数据存储格式，限制和存储容量以识别可能的风险，例如，未以其原始格式存储的数据，或者可以格式化为“CSV”，“Unix代码格式化程序”，或保存为 电子表格或PDF。 数据存储容量不足的系统可能会导致数据被覆盖或未被保存。

Data backup and archival capabilities.Tlie process of data backup, archival, and retrieval ofdata should be controlled and tested. Ideally, backups will be automated to eliminate errors and/or incomplete data transfer.

数据备份和归档功能。数据备份，归档和数据检索程序应得到控制和测试。理想情况下，备份将自动执行，以消除错误和/或不完整的数据传输。

Cross-platform data capabilities .The requirements for viewing, printing, or analyzing dataon acomputer should be known and tested,, e.g., if the data is stored in CSV text or PDF format,it may be viewed directly. Most data (such as Karl Fischer equipment for measuring moisture)may require installation of a specific software program to store and interpret this data; in that case, software validation may be required, and the software should be checked for additional features,such as data compatibility with commonly used software (e.g., PDF generators and spreadsheets).

跨平台数据功能。 应该理解并测试在计算机上查看，打印或分析数据的要求，例如，如果数据以CSV文本或PDF格式存储，则可以直接查看。大多数数据（例如用于测量水分的Karl Fischer设备）可能需要安装特定的软件程序来存储和解释这些数据; 在这种情况下，可能需要软件验证，并且应检查软件的附加特征，例如与常用软件（例如，PDF生成器和电子表格）的数据兼容性。

Data integrity when copied to computer.If data or results are being copied to a computer,the possibility of data manipulation must be tested to define the controls and limitations for data copying and printing;for example, if the data is stored in spreadsheet format, the date and time of acquisition, identity, result,etc ., might be open to manipulation.

复制到计算机时的数据完整性。如果将数据或结果复制到计算机，则必须测试数据被篡改的可能性，以明确数据复制和打印的控制和限制，例如，如果数据以电子表格格式存储， 则其日期和时间可能会被篡改。

Data handling.If an analytical instrument (e.g., balance) does not have the functional capability to store and manage the data or the critical metadata, the printed data may be considered as the original record, only when that record is a complete and accurate copy of the complete data and metadata generated by the instrument .Firms engaged in the manufacture and testing of pharmaceutical products who process information electronically should have laboratory equipment that meets CGMP standards for the processing and maintenance of electronic data. The entire end-to-end data handling process, from the point of generation of the electronic signalin thesourcesystem through to final decision-making based upon thissource data, needs to be assessed for dataintegrity risks and designed to reduce these risks through a combination of appropriate technicaland procedural controls. The Quality Unit is ultimately responsible for ensuring that appropriate procedures are in place for storing and protecting electronic records and restricting access to those files. One best practice is to identify an independent system administrator with specialized expertise to be responsible for storing and protecting electronic records.

数据处理。如果分析仪器（例如，天平）不具有存储和管理数据或关键元数据的功能，则只有当该记录为仪器生成的数据和元数据的完整准确副本时，打印数据才可以被视为原始记录。从事医药产品的制造和测试的公司在做电子信息处理时，应该拥有符合CGMP标准的实验室设备，用于处理和维护电子数据。从源系统中的电子信号生成到基于该源数据的最终决策，需要评估整个端到端数据处理过程数据完整性风险，并通过适当的技术和程序控制相结合降低这些风险。质量部门最终负责确保制定适当的程序来存储和保护电子记录并限制对这些文件的访问。最佳做法是指定一个独立的具有专业知识的系统管理员，负责存储和保护电子记录。

Results output .The results from hybrid systems (pH meters, balances, and titrators) shouldbe printed with date-and- time stamp, raw data, metadata, measurement values, sample identity,batch number, file names, and calculated values.

结果输出。混合系统的打印结果应包含日期和时间戳，原始数据，元数据，测量值，样品标识，批号，文件名和计算值（pH计，天平和滴定仪）的结果。

Backup and data review.For hybrid systems that are not connected to computers,ideally a report (event log) can be printed (meaning published in PDF)with every analysis or, at least, printed periodically. Publishing or viewing event logs may not always be possible on hybrid analytical equipment; therefore, data integrity should be ensured by periodic Quality Unit checks for date and time breaches, data breaches, weights-on-results calculations vs. analytical scale printouts, checks against the timing of other instruments, and periodic data reconciliation (results stored on the instrumentvs. recorded in an equipment logbook). Any breach in data or of established laboratory criterias hould be investigated according to laboratory SOPs and applicable regulatory guidance.

备份和数据审查。 对于未连接到计算机的混合系统，理想情况下，可以在每次分析时打印报告（包括事件日志）（意味着以PDF格式发布），或者至少定期打印。 在混合分析设备上，发布者可能无法查看事件日志; 因此，应通过质量部门定期检查日期和时间违规，数据违规，结果权重计算与分析比例打印输出，检查其他工具的时间安排以及定期数据核对（结果存储在仪器，并记录在设备日志中）。任何数据违规或不符合既定实验室标准应根据实验室SOP和适当的监管指南进行调查。

Data lifecycle management .Periodic data backups, if applicable, should be implemented and archived. Archived data should be stored according to Quality Unit procedures. Archived data isgenerally stored off- site and should be checked for ease of data retrieval. Backup data should be more readily accessible.

数据生命周期管理。应定期进行数据备份（如果适用）并归档。 存档数据应根据质量部门的规程进行存储。 存档数据通常存储在异地，应检查以便于数据检索。备份数据应该更容易访问。

Deficiencies that have been cited in FDA Warning Letters include:

FDA警告信中引用的缺陷包括：

Investigators found that laboratory analysts did not document the balance weights at the timeof sample weighing. Specifically, sample weights used in calculations were created after the chromatographic runs(38).

调查人员发现实验室分析员没有在样品称重时记录样品重量。具体而言，计算中使用的样品重量是在色谱运行后创建的（38）。

A review of the Karl Fischer electronic records revealed an OOS result that was not reported. The passing results reported on the data sheets were generated from another sample tested an hour after the initial OOS results were obtained on the same day (39).

对Karl Fischer水分检测仪电子记录的审查结果显示，有一个OOS结果未被报告。数据表上报告的显示“通过”的结果是在同一天获得初始OOS结果后一小时测试的另一个样本中生成的（39）。

Electronic Data Governance

电子数据管理

ln the current analytical laboratory environment, the key factors, discussed in this section, need to be considered for data governance. Analytical equipment controlled by firmware may not be able to publish audit trails. If not, the Quality Unit should implement a procedure to check for data compromises on any equipment for which this is the case. Controls should be similar for all equipment and data integrity should be ensured on all equipment. A logbook for data backup and deletion should also be maintained.

在当前的分析实验室环境中，需要考虑本节中讨论的关键因素来进行数据管理。 由固件控制的分析设备可能无法发布审计追踪。 如果没有审计追踪，质量部门应该实施一个程序来检查在这种情况下任何设备上的数据违规。 对所有设备的控制应相似，并且应确保所有设备的数据完整性。 还应对数据备份和删除建立日志。

A high-level diagram of electronic data governance in an analytical laboratory is presented in Figure 6.6-1.

图6.6-1给出了分析实验室中较高层次的电子数据管理。

Data Backup and Storage

数据备份和存储

The Quality Unit should develop a procedure for data backup and determine at what intervals it will be performed. Hybrid systems have temporary electronic storage that is overwritten (e.g., calibration curves on pH meters); this printed/published record is the primary data source. This electronic information is not intended for backup or long-term retention. Analytical equipment on which electronic data is generated should be included in the data backup. Copying data onto discs as a backup is recommended to protect against the potential failure of the server or Cloud. The data copied onto the discs should be checked for completeness and accuracy. To ensure the safety of the data, common industry practice is to maintain two copies of the data at different locations. Any Cloud-based storage service should be GXP-compliant (5)» Wherever possible, a risk-based cold backup (a scheduled backup without any manual intervention) should be planned to avoid surprises and regulatory complications.

质量部门应制定数据备份程序，并确定其执行的间隔时间。混合系统具有可被覆盖（例如，pH计上的校准曲线）的临时电子存储器;其打印/发布的记录是主要数据源。其电子信息不会备份或长期保存。数据备份应包括所有生成电子数据的分析设备。建议将数据复制到光盘上作为备份，以防止服务器或云的潜在故障。应检查复制到光盘上的数据的完整性和准确性。为了确保数据的安全性，通常的做法是在不同位置保存两份数据。任何基于云的存储服务都应符合GXP标准（5）。在可能的情况下，应计划基于风险的冷备份（无需任何人工干预的计划性备份），以避免意外和监管困难。

It is strongly recommended that electronic signatures, if adopted, comply with 21 CFR Part 11 requirements and include date and time stamps.

强烈建议电子签名（如果采用）应符合21 CFR Part 11要求并包含日期和时间戳。

The laboratory data governance manual is useful for consolidating current information about laboratory equipment and data procedures and may contain sections such as those listed below.

实验室数据管理手册对于整合有关实验室设备和数据程序的最新信息非常有用，可包含如下内容：

• Details of all laboratory equipment

  所有实验室设备的详细信息

• Details of all equipment software, including version information

  所有设备软件的详细信息，包括版本信息

• Laboratory equipment procedure numbers

  实验室设备规程编号

• Data handling procedures, list of audit trails published or reviewed, each typical information captured

  数据处理程序，需要发布或审核的的审计追踪列表，捕获的每个原始数据信息

• List of all users of all software and their roles

  软件的所有用户列表及其角色

• Server(s)details

  服务器详细信息

• Data backup frequency

  数据备份频率

• Risk analysis and mitigation plan

  风险分析和解决计划

• Names and contact information of key personnel and vendors

  关键人员和供应商的名称和联系信息

Table 6.6.1-1 represents a model table from a laboratory data governance manual. Preparing this manual and keeping it current is a good practice, one that makes a laboratory audit more efficient.

表6.6.1-1给出了实验室数据管理手册的表格模板。 好的做法是制订该手册并保持更新，可以使实验室审核更有效率。

Table 6.6.1•1 Example of a Table in a Laboratory Manual

实验室手册中的表格示例

Routine Checks of Data and Multiple Equipment in the Laboratory

实验室数据和各类仪器的日常检查

The Quality Unit should schedule regular data reconciliation to detect data compromises early. Creating a data flow of the entire laboratory from the top down will provide an excellent overview of where mistakes or breaches might occur. Random checks of employee shifts or timing logs against equipment should be performed to check data integrity. Synchronization of raw data across the instruments can be verified to expose data manipulation by random checks, such as checking the injection time and balance printout/PDF time for sample weighing and reconciling data periodically on instruments, represented in Figure 6.6.2-1.

质量部门应安排定期数据检查，以尽早发现数据违规。对整个实验室的数据创建1个自上而下的数据流，可以很好地概览可能发生错误或漏洞的地方。 应对员工班次或设备时间日志进行随机检查以检查数据的完整性。可以通过随机检查检查不同仪器间原始数据的同步性, 以发现数据操纵，例如检查同一个样品的进样时间和天平打印输出/ PDF的时间，并定期核对仪器数据，如图6.6.2-1。

Examples of what to look for on some instruments are:

不同仪器的检查应该检查的内容用举例如下：

• Titrator: Data stored on the internal memory vs. number of records in the instrument log book

  滴定仪：存储在内部存储器中的数据 VS 仪器日志中的记录数量

• HPLC: Number of injections vs. number of logbook entries or number of results

  高效液相色谱仪：进样次数 VS 日志条目数或结果数

• UV, IR： Number of data files vs. number of logbook entries.

  紫外、红外：数据文件数 VS 日志条目数

Communications with Chromatographic Software Vendors

与色谱软件供应商沟通

Since instrumental software may have some exceptional behavior, firms should document the communications with software vendors regarding clarification/remediation of error messages, warning messages, software bugs, and other issues that may be identified in audit trails, or other operations that need support from the vendor. These issues, communicated over the phone or via email, should be documented and will basis for change of procedures or initiation of new controls. Often vendor call centers or tech support groups allot a ticket number or tag number that can be referenced. In addition, there may be issues or restrictions in the software that a vendor would identify and communicate to all users through website notification or email communication. Firms should assess and document how those communications will be evaluated and how a determination is made regarding the effect on GMP operations. Recordings of audit trails and other critical data are recommended to be checked on a periodic basis to have belter control and understanding of software issues. If any anomalies are as observed they should be investigated immediately, and if they are suspected as software issues they should be communicated to the vendor for next steps of investigation.

由于仪器软件可能具有某些特殊行为，因此，公司应记录与软件供应商的通信，以澄清/修复错误信息，警告信息，软件BUG以及可能在审计追踪中识别的其他问题，或其他需要供应商支持的操作。通过电话或电子邮件传达的这些问题应记录在案，并作为程序修订或启动采取新的控制的基础。供应商呼叫中心或技术支持部门通常会分配可以引用的票号或标签号。此外，软件中可能存在问题或限制，供应商可识别并通过网站通知或电子邮件通知所有用户。公司应评估和记录如何评估这些信息以及如何确定对GMP操作的影响。建议定期检查审计追踪的记录情况和其他关键数据以更好地控制和理解软件问题。如果发现任何异常，应立即调查，如果怀疑它们是软件问题，则应将其传达给供应商，以便进行下一步的调查。

Presenting Data on Request in Electronic Format for Audits and Inspections

以电子格式提交审计和检查要求的数据

Auditors and health authority inspectors may request that electronic data be copied onto portable media (such as a USB or portable hard drive) or in a readable format (such as PDF, Microsoft Excel, or text) for their review evidence. Copying data from a validated system compliant with 21 CFR Part 11 or EU GMP Annex 11 onto media or into a readable format that does not maintain the original metadata should be avoided if possible. If data is transferred onto media or into a readable format, verification that the data and metadata are a true copy is recommended. Uncontrolled use of the copy-and-paste function can be prone to error and give the impression that original data has been altered or falsified. Establishing an SOP that governs how to copy and save data from laboratory systems is highly recommended. The SOP should describe the standard queries and reports that can be generated for audit and inspection purposes and the controls in place to ensure the accuracy of non-routine reports. Printing or exporting injection logs with all the details, such as injection time and sample name, may not be readily possible on some chromatographic software.

审计员和卫生当局检查员会要求将电子数据复制到便携式媒体（例如USB或便携式硬盘驱动器）上或复制为可读格式（例如PDF，Microsofit Excel或TxT）复制作为其检查证据。如果可能，应避免将符合2I CFR Part 11或EU GMP附录11的经过验证的系统中的数据复制到介质或复制为可读格式而不保存其原始元数据。如果数据传输到媒体或转为可读格式，建议验证数据和元数据是否为真实副本。不受控制地使用复制粘贴功能可能容易出错，并给人以原始数据被改变或伪造的印象。建议建立一个SOP来管理如何从实验室系统复制和保存数据。该SOP 应描述可为审计和检查目的生成的标准查询和报告, 以及为确保非常规报告的准确性而制定的控制措施。在某些色谱软件中, 可能无法轻易打印或导出带有所有详细信息 (如进样时间和样品名称) 的进样日志。