苏州的一天（2024.11.23）-学习札记⑧ 静态数据？

歪说歪有李

HowStatic Are Static Data?

静态数据有多静态?

R.D.McDowall, RD McDowall Ltd, Bromley, Kent, UK

A balance printout is a fixed record,and is also called static data. But how static are static data when the weightis used in a chromatographic analysis? Also, have some regulatory dataintegrity guidance documents failed to comply with their own regulations?

分析天平打印输出是一个确定的记录，也称为静态数据。但是，当质量用于色谱分析时，静态数据有多静态呢?此外，是否有一些法规数据完整性指南未能符合其自身的规则?

Data integrity continues to be a major topic for regulatedpharmaceutical laboratories, which has resulted in health authorities issuingguidance documents to ensure the reliability and integrity of goodmanufacturing practice (GMP) records (1-5). Some of the guidance refers to GMPrecords and data as being either static or dynamic (2-5). Static and dynamicdata are generally accepted terms, as seen in other data integrity publications(6-8).

数据完整性仍然是受监管制药实验室的一个主要主题，这导致卫生当局发布指导文件，以确保GMP记录的可靠性和完整性(1-5)。一些指南将GMP记录和数据称为静态或动态(2-5)。静态和动态数据是普遍接受的术语，正如在其他数据完整性出版物中看到的那样(6-8)。

Defining Static and Dynamic Data 定义静态和动态数据

Table 1 presents the definitions of static and dynamic data, withexamples quoted from question 1(d) from the FDA Data Integrity Guidance (4).The definition of static data gives the impression that nothing happens afterthe record is created and they remains immutable for the record retentionperiod. In contrast, dynamic data require interpretation by an analyst toobtain the reportable result. As you can see from Table 1, chromatography dataand spreadsheets are examples of dynamic data; static data involve a balanceprintout.

表1给出了静态和动态数据的定义，并引用了FDA数据完整性指南(4)中的问题1(d)中的示例。静态数据的定义，给人的印象是，在记录创建后原封就只，并且在记录保存期间保持不变。相比之下，动态数据需要分析人员解释才能获得可报告的结果。从表1中可以看出，色谱数据和电子表格是动态数据的例子;静态数据包括分析天平打印输出。

What I want to discuss in this "Questions of Quality"instalment is that some static data are inputs into dynamic data processing. Inthese circumstances, static data are converted into dynamic data. However,creating a static record where the weight is manually entered into achromatography data system (CDS) is an inefficient and error-prone process.Instead, laboratories should automate the complete process to eliminate thestatic data and enable sharing of all analytical data for review and to complywith the complete criterion of ALCOA+. Furthermore, the focus on printouts fromanalytical instruments (5) is inconsistent with US and EU regulations forkeeping current with technology (9,10), in addition to some recent FDA warningletters (11-13) that will be discussed later.

在本期“质量问题”中，我想讨论的是一些静态数据是动态数据处理的输入。在这些情况下，静态数据被转换为动态数据。然而，创建一个静态记录，手动将质量输入色谱数据系统是一个效率低下且容易出错的过程。相反，实验室应该自动化整个过程，以消除静态数据，并允许共享所有分析数据以供审查，并遵守ALCOA+的完整标准。此外，对分析仪器打印输出的关注(5)与美国和欧盟保持技术最新的法规(9,10)不一致，此外还有一些最近的FDA警告信(11-13)，将在稍后讨论。

TABLE 1: Static and dynamic data  definitions and examples from the 2018 FDA Data Integrity Guidance (4)    表1:2018年FDA数据完整性指南中的静态和动态数据定义和示例(4)
Static Data 静态数据	Dynamic Data 动态数据
Static is used to indicate a fixed-data  record    Static用于表示一个确定数据的记录	Dynamic means that the record format  allows interaction between the user and the record content    动态是指记录格式允许用户和记录内容之间的交互
Paper record or an electronic image    纸质记录或电子图像	A dynamic chromatographic record may  allow the user to change the baseline and reprocess chromatographic data so  that the resulting peaks may appear smaller or larger.    动态色谱记录可允许用户更改基线并重新处理色谱数据，以便所得到的峰可能看起来更小或更大。    It also may allow the user to modify  formulas or entries in a spreadsheet used to compute test results....    它还可以允许用户修改用于计算测试结果的电子表格中的公式或条目....

Static and Dynamic Data in Practice实践中的静态和动态数据

CDS dynamic data as presented in Table 1 require a user to interpretpeak integration for each data file in the sequence. One more requirement fordynamic data is that they must remain dynamic throughout the record retentionperiod (2), therefore:

表1中所示的色谱数据系统动态数据要求用户解释序列中每个数据文件的峰值积分。对动态数据的另一个要求是，它们必须在整个记录保存期间(2)保持动态，因此:

• Electronic records are primary and printoutsare secondary in the data set. 在数据集中，电子记录是主要的，打印输出是次要的。

• Paper alone can never be the GMP record from anelectronic record generated by a computerized system. 单独的纸质GMP记录永远无法与计算机化系统生成的电子记录相媲美。

• Hybrid records are tolerated currently but twodata integrity regulatory guidance documents encourage their replacement (3,5). 混合记录目前是允许的，但两份数据完整性监管指导文件鼓励其替代(3,5)。

• Dynamic data cannot be printed to PDF andstored in an informatics application. 动态数据不能打印为PDF并存储在信息学应用程序中。

The PDF file is a static electronic record as a user cannot interactwith it.

PDF文件是一个静态的电子记录，因为用户不能与它交互。

In contrast, once static data have been created, the user cannotinteract with them. Right? 相反，一旦创建了静态数据，用户就不能与之交互。对吧?

But are static data really static with no further user interaction?

但是，如果没有进一步的用户交互，静态数据真的是静态的吗?

How Static are Static Data? 静态数据到底有多静态?

Back to the laboratory bench and imagine you are weighing eithersample aliquots or a reference standard on an analytical balance and theweighing sequence (for example, vessel weight, tare, material weight) isprinted out. It is generally accepted that this is a static record where thebalance printout is attached to a laboratory notebook or analytical batchrecord. Indeed, the 2021 PIC/S guidance in section 8.9.1 (5) states:

回到实验室工作台，想象您正在分析分析天平上称重样品等分或参考标准，称重顺序(例如，容器质量，皮重，材料质量)被打印出来。一般认为这是静态记录，分析天平打印输出附在实验室笔记本或分析批记录上。的确，2021年PIC/S指南第8.9.1(5)节规定:

Some very simple electronic systems, e.g., balances which do notstore data, generate directly- printed paper records. These types of systemsand records provide limited opportunity to influence the presentation of databy (re-) processing, changing of electronic date/time stamps. In thesecircumstances, the original record should be signed and dated by the persongenerating the record and information to ensure traceability, such as sampleID, batch number, etc. should be recorded on the record. These original recordsshould be attached to batch processing or testing records.

一些非常简单的电子系统，如不存储数据的天平，直接生成打印的纸质记录。这些类型的系统和记录通过(重新)处理、更改电子日期/时间戳来影响数据表示的机会有限。在这些情况下，原始记录应由生成记录的人签名并注明日期，并应在记录上记录诸如样品ID、批号等信息以确保可追溯性。这些原始记录应附在批处理或检测记录后。

This approach is repeated in the FDA data integrity guidance inquestion 10 (4)：

该方法在FDA数据完整性指南问题10(4)中重复:

10. Is it acceptable to retain paperprintouts or static records instead of original electronic records fromstand-alone computerized laboratory instruments, such as an FT-IR instrument? 是否可以保留纸张打印或静态记录，而不保留单机版实验室仪器(如红外光谱仪)的原始电子记录?

A paper printout or static record may satisfy retention requirementsif is the original record or a true copy of the original record (see §§211.68(b}, 211. 188, 211. 194, and 212.60). During data acquisition on, forexample, pH meters and balances may create a paper printout or static record asthe original record. In this case, the paper printout or static record, or atrue copy, must be retained (§ 211. 180)

如果纸质打印输出或静态记录是原始记录或原始记录的真实副本，则可以满足保留要求(见§§211.68(b}， 211.188,211.194，212.60)。在数据采集过程中，例如，pH计和天平可能会创建纸质打印输出或静态记录作为原始记录。在这种情况下，必须保留纸质打印输出或静态记录，或真实的副本(§211.180)

The stated regulatory expectation of both the PIC/S and FDA guidancedocuments for simple analytical instruments is for paper printouts that areattached to an analytical batch record or a laboratory notebook. Whilst thereis limited ability to interfere with the printout, without an audit trail ande-records, weighing can be repeated until the "right" result isobtained. Whether a static record is the right approach shall be discussedlater in this column.

PIC/S和FDA对简单分析仪器的指导文件的规定监管要求是，用于附在分析批记录或实验室笔记本上的纸质打印件。虽然干扰打印输出的能力有限，但在没有审计追踪和电子记录的情况下，可以重复称重，直到获得“正确”的结果。静态记录是否为正确的方法将在本专栏稍后讨论。

Static Data are an Integral Part of an AnalyticalProcedure静态数据是分析程序的一个组成部分

Simple instruments such as balances generate data that are criticalto the whole of an analytical procedure because the values are inputs to anyquantitative chromatographic analysis, for example：

天平等简单仪器产生的数据对整个分析程序至关重要，因为这些值是任何定量色谱分析的输入，例如:

• Determination of purity纯度测定

• Stability testing稳定性测试

• Impurity determination杂质测定

• Residual solvent measurement残留溶剂测定

Here static data become an integral component of a dynamic data process. 在这里，静态数据成为动态数据过程的一个组成部分。

However, many laboratories still haveinappropriately designed data processes for the small instruments that generatecritical data on paper printouts. This is compounded by manually entering theweight into a computerized system or spreadsheet, resulting in transcriptionerror checking by the reviewer. 然而，许多实验室仍然为用于在纸上打印输出产生关键数据的小型仪器设计不适当的数据处理方法。这种情况还会因人工将质量输入计算机化系统或电子表格而加剧，导致审核人进行抄写错误检查。

We can look at this situation further in figure1; on the left of the diagram is the generation of a static data record thebalance printout. On the right, weights of samples and standards are manuallyentered into a CDS that generates dynamic data used to generate the reportableresult Here we can see the conversion of static data into dynamic data. If theanalyst entering weights into the CDS mistypes a value that must be correctedlater with a corresponding audit trail entry, what was static data on theprintout is now dynamic data in the CDS. This poses a key question:

我们可以在图1中进一步查看这种情况;在图表的左侧是生成静态数据记录，即分析天平打印输出。在右侧，将样本和标准的质量手动输入到生成动态数据的色谱数据系统中，用于生成可报告的结果。在这里，我们可以看到静态数据向动态数据的转换。如果在色谱数据系统中输入质量的分析人员输入了错误的值，稍后必须使用相应的审计追踪条目进行纠正，那么打印输出上的静态数据现在就是色谱数据系统中的动态数据。这就提出了一个关键问题:

Why make data static first, only to make itdynamic later?

为什么先使数据静态，然后才使其动态?

                              

Is Regulatory Guidance Correct? 监管指南正确吗?

The heading poses a fundamental question:Where is the event horizon when considering if data are static or dynamic?Consider the situation on the left side of Figure 1:

标题提出了一个基本问题:考虑数据是静态的还是动态时，框框在哪里?考虑图1左侧的情况:

•      StaticData: Analytical balance and printout in isolation:

静态数据:分析分析天平和单独打印输出;

Weigh sample + print 称重样本+打印

result = static data 结果=静态数据

•      DynamicData: The balance and sample weight are integral parts of an overall CDSanalytical procedure:

动态数据:分析天平和样品质量是整个色谱数据系统分析程序的组成部分;

Weigh sample + print result + type weight into CDS + acquire data +generate result = dynamic data

称量样本+打印结果+将质量输入色谱数据系统 +获取数据+生成结果=动态数据

The dynamic equation only takes a high-level view of an analyticalprocedure, what also must be considered are all the contextual metadatagenerated throughout the process.

动态等式只是分析程序的高级视图，这当然必须考虑整个过程中生成的所有上下文元数据。

The records generated are a mixture of paper printouts (in yellow)and electronic records (in green) and yet more paper, as shown in Figure 2.Whilst there may be some static data records generated at the start with samplepreparation and the balance printout, the overall process generates dynamicdata.

生成的记录是纸张打印输出(黄色)和电子记录(绿色)以及更多纸张的混合物，如图2所示。同时，在样品准备和分析天平打印输出开始时可能会生成一些静态数据记录，但整个过程生成动态数据。

We now have an analytical procedure that generates hybrid records.

我们现在有了生成混合记录的分析程序。

Even if the instrument data system in Figure 2 were to useelectronic signatures, only one item of paper would be eliminated (the paperprintout on the right of the figure). A hybrid analytical procedure stillremains.

即使图2中的仪器数据系统使用电子签名，也只会消除一项纸张(图右侧的纸张打印输出)。混合记录的分析程序仍然存在。

Figure 2 shows the complete record set that needs to be reviewed andarchived, but the problem is that there are several static paper records pluselectronic records.

图2显示了需要审查和存档的完整记录集，但问题是这个记录集要有几个静态的纸质记录还要再加上电子记录。

Are hybrid analytical procedure records an adequate situation to bein?

分析程序混合记录是否适当?

The one regulatory guidance document that advocates process efficiencyis the WHO Good Record and Data Management Practices Guidance from 2016 (3),which states in section 5.6:

倡导流程效率的一份监管指导文件是2016年WHO良好记录和数据管理实践指南(3)，其中第5.6节指出:

A data management programme developed and implemented on the basisof sound QRM principles is expected to leverage existing technologies totheir full potential.

根据健全的质量管理原则制定和执行的数据管理方案预计将充分利用现有技术发挥其潜力。

This, in turn, will streamline data processes in a mannerthat not only improves data management but also the business processefficiency and effectiveness, thereby reducing costs and facilitatingcontinual improvement.

反过来，这将简化数据流程，不仅可以改善数据管理，还可以提高业务流程的效率和有效性，从而降低成本并促进持续改进。

It is unusual to find a regulatory guidance document recommendingbusiness process efficiencies and effectiveness. However, there are two pointsto be made here:

很少能找到推荐业务流程效率和有效性的监管指导文件。然而，这里有两点需要说明:

1.   Use informatics solutions tostreamline processes.

使用信息学解决方案来简化流程。

2.   Eliminate paper and have only asingle medium to review and retain.

淘汰纸张，只使用一种介质来审核和保留。

This is coupled with the statements that "hybrid systems arenot encouraged" and "hybrid systems should be replaced at the earliestopportunity" (3). The same approach should be applied to hybrid analyticalprocedure records because it is not just computerized systems but alsoprocesses that require assessments of data vulnerabilities (2,3,5).

这与“不鼓励混合系统”和“混合系统应尽早更换”的说法相结合(3)。同样的方法应该应用于分析程序混合记录，因为它不仅是计算机化系统，而且还需要评估数据漏洞的过程(2,3,5)。

However, are static records from simple instruments and the use ofhybrid systems acceptable in the third decade of the 21st century? To find theanswer we need to travel back to 1978.

然而，在21世纪的第三个十年，来自简单仪器的静态记录和混合系统的使用是否可以接受?

为了找到答案，我们需要回到1978年。

Understanding the c in cGMP 了解cGMP中的c

Most analytical scientists working in a quality control oranalytical development laboratory will refer to GMP regulations; however, theformal title of 21 CFR 211 is Current Good Manufacturing Practice for FinishedPharmaceutical Products or cGMP regulations.

大多数在质量控制或分析开发实验室工作的分析科学家将参考GMP法规;然而，21 CFR 211的正式名称是《药品成品生产质量管理规范》或cGMP法规。

Is current important? What does current mean?

现行重要吗?现行是什么意思?

A question was posed in the introduction of this white paper:

在这份白皮书的介绍中提出了一个问题:

Are the regulators failing to follow their regulations and guidancewhen it comes to the regulated analytical laboratory? To answer this question,we must go back to 29 September 1978 where the preamble to FDA regulation 21CFR 211 on Current Good Manufacturing Practice for Finished PharmaceuticalGoods can be found. Preamble comment 17 has the following statements that havebeen edited for brevity (9):

在被监管的分析实验室方面，监管机构是否没有遵循他们的规定和指导?为了回答这个问题，我们必须回到1978年9月29日，在那里可以找到FDA法规21 CFR 211关于成品药品cGMP的序言。序言评论17中有以下陈述，为简洁起见经过编辑(9):

Several comments objected to the word "current" in thetitle and text of the regulations…

几条评论反对《条例》标题和正文中的“当前”一词……

Several of these comments reflect, the Commissioner believes, amisunderstanding regarding the use of the word "current"…

专员认为，这些评论中有几条反映出对“当前”一词的使用存在误解……

Although the practices must be "current" in the industry,they need not be widely prevalent. 虽然这些做法必须在行业中是“当前”的，但它们不一定要广泛流行。

Congress did not require that a majority or any other percentage ofmanufacturers already be following the proposed mandated practices as long asit was a current good manufacturing practice in the industry e.g., it has beenshown to be both feasible and valuable in assuring drug quality.

国会并没有要求大多数或任何其他百分比的生产商已经遵循提议的强制性规范，只要它是行业中当前的良好生产规范，例如，它已经被证明在保证药品质量方面是可行的和有价值的。

The takeaway message from this is that laboratories must keepcurrent with technologies and implement new approaches and systems to keep "current".This is also mirrored in a page on the FDA website (14) that says:

从中得到的信息是，实验室必须与最新的技术保持同步，并实施新的方法和系统以保持“最新”。这也反映在FDA网站的一个页面上(14)，上面说:

Accordingly, the "C" in CGMP stands for"current," requiring companies to use technologies and systems thatare up to date in order to comply with the regulations. Systems and equipmentthat may have been "top-of-the-line" to prevent contamination,mix-ups, and errors 10 or 20 years ago may be less than adequate by today'sstandards.

因此，cGMP中的“c”代表“current”，要求企业使用最新的技术和系统，以符合法规。10年或20年前在防止污染、混淆和错误方面可能是“顶级”的系统和设备，以今天的标准来看可能是不够的。

Is this approach to keeping current unique and only applicable tothe FDA?

这种方法是当前唯一的并且只适用于FDA吗?

No, it is mirrored in Article 23, §1 of European Directive 2001/83/EC (10) that requires a marketing authorization holder to:

不，这反映在欧洲指令2001/83/ EC(10)第23条§1中，要求上市许可持有人:

After a marketing authorization has beengranted, the marketing authorization holder shall, in respect of the methods ofmanufacture and control provided for in Article 8(3)(d) and (h), takeaccount of scientific and technical progress and introduce any changes thatmay be required to enable the medicinal product to be manufactured and checkedby means of generally accepted scientific methods.

上市许可获得批准后，上市许可持有人应就第8(3)(d)和(h)条规定的生产和控制方法考虑科学和技术进步，并引入任何可能要求的变化，以使药品能够通过普遍接受的科学方法生产和检查。

Therefore, both FDA and EU regulations expect laboratories to keepup with technologies and be subject to continual improvement as required by ICH10 on Pharmaceutical Quality Systems (15) and EU GMP Chapter 1 (16).

因此，FDA和EU法规都希望实验室跟上技术的发展，并按照ICH 10药品质量体系(15)和EU GMP第1章(16)的要求进行持续改进。

However, the situation in many laboratories does not match the requirementseither to keep current or to take account of scientific and technical progress.In general, a lazy approach is prevalent: if it was good enough lastinspection, it will be good enough for the next one. Further arguments mayinvolve citing a lack of money for investment. These cease immediately afterreceiving regulatory citations when money for remediation flows like water overNiagara Falls.

然而，许多实验室的情况并不符合要求，既不能保持与时俱进，也不能考虑科学和技术进步。总的来说，一种懒惰的做法是普遍存在的:如果上次检查够好，下次检查也会够好。进一步的论证可能会涉及到以投资资金不足为理由。当修复资金像尼亚加拉瀑布的水一样流动时，这些项目在收到监管通报后立即停止。

Apart from the WHO guidance presented above, none of the regulatoryguidance documents really consider the requirement for keeping current.

除上述WHO指南外，没有任何一份监管指导文件真正考虑到保持最新的要求。

This is particularly the situation with PIC/S PI-041 and the FDAquotations cited earlier for simple instruments to print outputs (4,5). Dothese guides leave the pharmaceutical industry with a complacent attitude thatpaper records are OK?

PIC/S PI-041以及之前引用的用于打印输出的简单仪器的FDA行情尤其如此(4,5)。这些指南是否让制药行业沾沾自喜地认为纸质记录就足够了?

Digitization of the Laboratory 实验室的数字化

Keeping current with respect to GMP and digitization of a regulatedlaboratory are two sides of the same coin. Both require automation,computerization, and elimination of paper records that result in completeelectronic records in the same informatics system, thus making records and dataeasy to search and share.

保持GMP和规范实验室的数字化是同一枚硬币的两面。两者都要求自动化、计算机化和消除纸质记录，从而在同一信息系统中形成完整的电子记录，从而使记录和数据易于搜索和共享。

One approach to keeping current withexisting technology is shown in Figure 3. The informatics applications usedare:

图3显示了一种与现有技术保持同步的方法。所使用的信息学应用有:

• Laboratory information management system(LIMS), shown in yellow, for managing sample information and collating testresults;

实验室信息管理系统(LIMS)，显示为黄色，用于管理样本信息和整理测试结果;

• Instrument data system, typically developed bythe instrument manufacturer, is interfaced with an analytical balance(interfacing other instrument types is also possible);

仪器数据系统，通常由仪器制造商开发，与分析分析天平接口(也可以与其他类型的仪器接口);

• CDS in green; 绿色的是色谱数据系统;

• Laboratory execution system (LES), in blue, isan option for documenting sample preparation and transferring data to the CDS.

蓝色的实验室执行系统(LES)，是记录样品制备和将数据传输到色谱数据系统的功能包。

Sample and batch information are transferred to the LIMS and thendownloaded to the LES and CDS applications. Sample preparation is automatedusing the LES and the information, such as dilutions, by the CDS. In Figure 2,the weight from the analytical balance is manually entered into thechromatography data system, which is slow and error-prone. In Figure 3, we havean instrument data system with an electronic workflow that acquires the balancesample weight and transfers it to the CDS. Further technical controls ensurethat the right type of balance is used or even a specific instrument identifiedby its serial number. There is an audit trail to ensure that samples are notweighed into compliance.

样品和批信息传输到LIMS，然后下载到LES和色谱数据系统应用程序。使用LES和色谱数据系统的信息(如稀释度)自动制备样品。在图2中，来自分析分析天平的重量被手动输入色谱数据系统，这是缓慢且容易出错的。在图3中，我们有一个仪器数据系统，该系统具有电子工作流，可获取分析天平样品重量并将其传输到色谱数据系统。进一步的技术控制确保使用正确类型的分析天平，甚至是由其序列号标识的特定型号。有一个审计追踪，以确保样品不被称量为“合规”。

The CDS now has all the data required. The sequence is run.Chromatographic data files are interpreted and a reportable result generated.Second person review is accomplished electronically in the various informaticssystems.

色谱数据系统现在拥有所需的所有数据。序列运行，积分色谱数据文件并生成可报告的结果。第二人审查在各种信息学系统中以电子方式完成。

The scope of review is limited by effective use of validatedtechnical controls within the application, for example:

审查的范围受到应用程序中有效验证过的技术控制的限制，例如:

• No user has deletionprivileges, so a reviewer does not need to look for deleted data.

没有用户具有删除权限，因此审阅者不需要查找已删除的数据。

• Data can only be stored in a single location;therefore, no searches need to be conducted for orphan data.

数据只能存储在单个位置;因此，不需要对单例数据进行搜索。

• Audit trails in the applications highlightmodified data, allowing a reviewer to review by exception (5).

应用程序中的审计追踪突出显示修改的数据，允许审查员额外审查(5)。

The informatics applications ensure that all data are complete,consistent, and accurate. This approach also leverages existing technologies asadvocated by the WHO data integrity guidance discussed earlier (3), in additionto meeting the expectation of current in cGMP (9,17).

信息学应用确保了所有数据的完整、一致和准确。这种方法还利用了前面讨论的WHO数据完整性指南所倡导的现有技术(3)，除了满足当前cGMP的期望(9,17)。

If required, the values from many results sets can be monitored fortrends as required by EU GMP Chapter 6.9 (18) or used to identify errors. Thiswork would not be possible with static data without extensive manual data entryinto a spreadsheet.

如果需要，可以按照欧盟GMP第6.9(18)章的要求监控多个结果集的值，以确定趋势或用于识别错误。如果没有大量的手工数据输入到电子表格中，那么使用静态数据是不可能完成这项工作的。

The Regulatory Driver for Laboratory Digitization 实验室数字化的监管驱动因素

The FDA are keeping current in cGMP by interpreting the sameregulation differently over time. For example, there is no explicit mention ofaudit trail review in 21 CFR 211 regulations, the bulk of which was issued in1978 (9). However, since 2005 and the Able Laboratories fraud case (19), theregulatory expectation of the FDA is that audit trail entries must be reviewed.EU GMP has taken a different and better approach by updating Annex 11 forComputerized Systems where there is an explicit requirement for audit trailreview of GMP-relevant changes and deletions (20). Audit trail review is now afeature of all regulatory authority data integrity guidance documents (1-5).

随着时间的推移，FDA通过对同一个法规的不同时期的解释来保持cGMP的最新状态。例如，有21 CFR 211法规没有明确提到审计追踪审查，其中大部分是在1978年发布的(9)。然而，自2005年和Able Laboratories欺诈案(19)以来，FDA的监管期望是必须审查审计追踪条目。欧盟GMP采取了不同的、更好的方法，更新了计算机化系统附录11，其中明确要求对GMP相关的更改和删除进行审计追踪审查(20)。审计追踪审查现在是所有监管机构数据完整性指导文件的一个特征(1-5)。

Another, less subtle, driver for automation is evidenced by somerecent FDA warning letters. In July 2020, FDA issued warning letters to StasonPharmaceutical (11) and Tender Corporation (12). Although they were cited underdifferent clauses of 21 CFR 211, the extensive remediation required by the FDAwas virtually identical for the two companies. A detailed review of these twowarning letters and a discussion on understanding the cost of non-compliance isavailable (21).

另一个不那么微妙的自动化驱动因素是最近FDA的一些警告信。2020年7月，FDA向Stason Pharmaceutical(11)和Tender Corporation(12)发出了警告信。尽管它们被引用在21 CFR 211的不同条款下，但FDA对这两家公司所要求的广泛补救措施实际上是相同的。对这两封警告信的详细审查和对理解违规成本的讨论是可用的(21)。

One specific remediation requirement for both organizations was:

两个组织的一个具体补救要求是:

• Technological improvements to increase theintegration of data generated through electronic systems from standaloneequipment (e.g., balances, pH meters, water content testing) into the LIMSnetwork.

技术改进，以增加通过电子系统从单机版的设备(例如，天平，pH计，含水量测试)生成的数据集成到LIMS网络。

This is a clear message that paper records from standalone systemsare not acceptable. The citation also mentions a LIMS network, which caninclude different informatics applications such as LIMS, LES, ELN, andinstrument data systems, as shown in Figure 3.

这是一个明确的信息，来自单机版系统的纸质记录是不可接受的。引文还提到了一个LIMS网络，它可以包括不同的信息学应用，如LIMS、LES、ELN和仪器数据系统，如图3所示。

It is better to acknowledge the problems in your laboratory and havea plan to remediate them at your pace rather than have a tight deadline imposedto appease a regulatory authority. It is much cheaper as well.

最好是承认你的实验室存在的问题，并有一个计划来按照你的速度进行补救，而不是强加一个严格的期限来安抚监管机构。这样做也便宜得多。

However, is interfacing a balance to a LIMS the only way forwards?

然而，将分析天平连接到LIMS是前进的唯一途径吗?

Connecting the balance to an instrument data system may be a betteroption as additional metadata can be acquired during the weighing process toensure the integrity of data. As shown in Figure 3, the instrument data systemhas the advantage of using the weights from a balance in another instrumentworkflow. Also, the use of an instrument data system also provides thelaboratory with additional resilience if the LIMS is unavailable due to loss ofconnectivity to the central system or the Cloud.

将分析天平连接到仪器数据系统可能是一个更好的选择，因为在称重过程中可以获得额外的元数据，以确保数据的完整性。如图3所示，仪器数据系统的优点是可以在另一个仪器工作流程中使用分析天平获得的质量。此外，如果LIMS由于失去与中央系统或云的连接而造成不能使用，使用仪器数据系统还可以为实验室提供额外的冗余能力。

If an analytical instrument is purchased, how a laboratory uses itcan also result in a regulatory citation as BBC Group found out in a warningletter in August 2021 (13):

BBC集团在2021年8月的警示信中发现，如果购买了分析仪器，实验室如何使用它也会导致监管引用(13):

Your viscometer and UV-vis spectrophotometer had the capability tosave data from product/ material testing. Despite having this capability, youranalysts failed to save the complete, dynamic testing data, and therefore thedata was not available for review by the FDA investigator.

你们的粘度计和紫外-可见分光光度计能够保存产品/材料测试的数据。尽管有这种能力，你们的分析人员未能保存完整的、动态的检测数据，因此数据无法用于FDA调查员的审查。

If an instrument has the capability to store electronic records andthis feature is not used, it can result in a regulatory citation. Equally so,an old instrument operating in a laboratory without the capability to eitherconnect to a printer or store data is a problem. It falls into the FDA argumentthat it is not top of the line (14), as discussed above.

如果仪器具有存储电子记录的能力，但未使用此功能，则可能导致监管引用。同样，在实验室里操作的旧仪器，既不能连接打印机，也不能存储数据，也是一个问题。正如上文所讨论的，FDA认为这种行为不是最佳的(14)。

If a laboratory does not digitize there can be expensive remediationcosts, with a timescale determined by the need to convince a regulator that thecompany is serious about compliance.

如果一个实验室没有数字化，可能会有昂贵的补救成本，其时间尺度取决于说服监管机构满意的认为：该公司对符合监管规则是认真的。

Business Driver for Laboratory Digitization 实验室数字化的业务驱动力

Regardless of the regulations, organizations should considerdigitization from a business efficiency perspective alone. Quality control (QC)testing is often at the end of manufacturing and can be seen as slowing therelease of a batch of product. If a laboratory was more efficient with analysisand release of the certificate of analysis, what would be the impact on companycash flow if each and every batch were released to the market one day earlier?The way to do this is to work smarter and work electronically throughdigitization of the laboratory and the removal of paper.

无论法规如何，组织机构都应该仅从业务效率的角度考虑数字化。质量控制(QC)测试通常是在制造的最后阶段，可以被视为减缓了一批产品释放的速度。如果一个实验室在分析和放行分析证书方面效率更高，那么如果每批产品都提前一天投放市场，对公司现金流会有什么影响?要做到这一点，就要通过实验室的数字化和纸张的去除，更智能地工作，电子化地工作。

The Covid-19 pandemic has forced laboratories to view a new way ofworking—some analysts working in the laboratory and others remotely. This canonly work if data are electronic and not on paper.

Covid-19大流行迫使实验室审视一种新的工作方式——一些分析师在实验室工作，另一些则远程工作。这只有在数据是电子的而不是纸上的情况下才能起作用。

You cannot share paper remotely. Imagine doing laboratory work suchas second person review remotely in an electronic environment. Review of dataand audit trail entries as well as signing results and reports can be performedremotely. Trending can also be performed electronically to meet therequirements of EU GMP Chapter 6.9 (18). You cannot do these tasks with workingpractices that involve static data and hybrid records.

你无法远程共享纸张。想象一下在电子环境中远程进行第二人复核等实验室工作。数据和审计追踪条目的审查以及签署结果和报告可以远程执行。也可以通过电子方式进行趋势分析，以满足EU GMP章节6.9(18)的要求。您不能使用涉及静态数据和混合记录的工作实践来完成这些任务。

Conclusion结论

Some static data are less static than others because the values aremanual inputs into a dynamic analytical procedure. Original records from simpleinstruments must be complete and include all metadata and must be subject toreview. However, the review includes transcription error checking, which is aslow and error-prone process.

有些静态数据不一定多静态，因为这些值是手动输入到动态分析程序中的。来自简单仪器的原始记录必须是完整的，包括所有元数据，并且必须接受审查。但是，审查包括抄写错误检查，这是一个缓慢且容易出错的过程。

Regulatory guidance documents on data integrity—with the exceptionof that from the WHO—do not discuss the need for regulated laboratories to keepcurrent but should do so to be compliant with the regulations that they aresupposed to enforce. However, the benefits of managing data in a fullyelectronic process provides significant business benefits and regulatorycompliance, with data stored in one medium. This approach facilitates efficiencyand effectiveness including ease of performing data analytics.

关于数据完整性的监管指导文件(WHO的指导文件除外)没有讨论受监管实验室需要保持最新，但应该这样做，以符合他们应该执行的法规。然而，在一个完全电子化的过程中管理数据的好处提供了显著的业务好处和法规遵从性，数据存储在一个介质中。这种方法促进了效率和有效性，包括执行数据分析的便利性。

This is the way to keep current with cGMP.

这是与cGMP保持同步的方法。

Acknowledgement确认

I would like to thank Gunnar Danielson for helpful comments duringthe preparation of this column.

我要感谢Gunnar Danielson在准备本专栏期间提供的有用意见。

Reference参考文献

1) MHRA, GMPData Integrity Definitions and Guidance for Industry 2nd Edition (Medicines andHealthcare Products Regulatory Agency, London, UK, 2015).

2) MHRA,GXP Data Integrity Guidance and Definitions (Medicines and Healthcare Products

Regulatory Agency, London, UK,2018).

3) WHO,Technical Report Series No.996 Annex 5 Guidance on Good Data and RecordsManagement Practices (World Health Organization, Geneva, Switzerland, 2016).

4) US Food andDrug Administration, Guidance for Industry Data Integrity and Compliance WithDrug CGMP Questions and Answers (FDA, Silver Spring, Maryland, USA, 2018).

5) PIC/S,PI-041 Good Practices for Data Management and Integrity in Regulated GMP / GDPEnvironments Draft (Pharmaceutical Inspection Convention / PharmaceuticalInspection Cooperation Scheme, Geneva, Switzerland, 2021).

6) GAMP GuideRecords and Data Integrity (International Society for PharmaceuticalEngineering, Tampa, Florida, USA, 2017).

7) GAMP GoodPractice Guide: Data Integrity - Key Concepts (International Society forPharmaceutical Engineering, Tampa, Florida, USA, 2018).

8) GAMPGood Practice Guide: Data Integrity by Design (International Society forPharmaceutical Engineering, Tampa, Florida, USA, 2020).

9) 21 CFR 211,Current Good Manufacturing Practice for Finished Pharmaceuticals, FederalRegister, 43(190), 45014–45089 (1978).

10) Directive2001/83/EC of the European Parliament and of the Council of 6 November 2001 onthe Community code relating to medicinal products for human use, OfficialJournal of the European Union 311, 67 (2001).

11) FDAWarning Letter Stason Pharmaceuticals, Inc. (2020). Available from:https://www.fda.gov/inspections- ... nc-604889-07082020.

12) FDAWarning Letter Tender Corporation (2020). Available from:https://www.fda.gov/inspections- ... on-599789-07232020.

13) FDAWarning Letter BBC Group Limited (2021). Available from:https://www.fda.gov/inspections- ... ed-614659-08042021.

14) Foodand Drug Administration, Facts About the Current Good Manufacturing Practices

(CGMPs) (2021). Available from: https://www.fda.gov/drugs/pharmaceuticalquality-resources/facts-about-currentgood-manufacturing-practices-cgmps.

15) ICH, Q10 Pharmaceutical Quality Systems(International Conference on Harmonisation, Geneva, Switzerland, 2008).

16) EudraLex, Volume 4 Good Manufacturing Practice (GMP)Guidelines, Chapter 1 Pharmaceutical Quality System (European Commission,Brussels, Belgium, 2013).

17) European Union Directive 2001/83/EC on MedicinalProducts for Human Use (European Commission, Brussels, Belgium, 2001).

18) EudraLex, Volume 4 Good Manufacturing Practice (GMP)Guidelines, Chapter 6 Quality Control (European Commission, Brussels, Belgium,2014).

19) AbleLaboratories Form 483 Observations. 2005. Available from:https://www.fda.gov/media/70711/download.

20) EudraLex, Volume 4 Good Manufacturing Practice (GMP)Guidelines, Annex 11 Computerized Systems (European Commission, Brussels,Belgium, 2011).

21) R.D. McDowall, Spectroscopy 35(11),13–22 (2020).

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