苏州的一天（2024.11.23）-学习札记⑧ 靜態數據？

歪說歪有李

HowStatic Are Static Data?

靜態數據有多靜態?

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?

分析天平打印輸出是一個確定的記錄，也稱爲靜態數據。但是，當質量用于色譜分析時，靜態數據有多靜態呢?此外，是否有一些法規數據完整性指南未能符合其自身的規則?

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題，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)。静态和動態數據是普遍接受的术语，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 定義靜態和動態數據

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給出了靜態和動態數據的定義，並引用了FDA數據完整性指南(4)中的問題1(d)中的示例。靜態數據的定義，給人的印象是，在記錄創建後原封就只，並且在記錄保存期間保持不變。相比之下，動態數據需要分析人員解釋才能獲得可報告的結果。從表1中可以看出，色譜數據和電子表格是動態數據的例子;靜態數據包括分析天平打印輸出。

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“質量問題”中，我想討論的是一些靜態數據是動態數據處理的輸入。在這些情況下，靜態數據被轉換爲動態數據。然而，創建一個靜態記錄，手動將質量輸入色譜數據系統是一個效率低下且容易出錯的過程。相反，實驗室應該自動化整個過程，以消除靜態數據，並允許共享所有分析數據以供審查，並遵守ALCOA+的完整標准。此外，對分析儀器打印輸出的關注(5)與美國和歐盟保持技術最新的法規(9,10)不一致，此外還有一些最近的FDA警告信(11-13)，將在稍後討論。

TABLE 1: Static and dynamic data  definitions and examples from the 2018 FDA Data Integrity Guidance (4)    表1:2018年FDA數據完整性指南中的靜態和動態數據定義和示例(4)
Static Data 靜態數據	Dynamic Data 動態數據
Static is used to indicate a fixed-data  record    Static用于表示一個確定數據的記錄	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戶和记录内容之间的交互
Paper record or an electronic image    紙質記錄或電子圖像	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戶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....    它还可以允许用戶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实践中的静态和動態數據

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動態數據要求用戶解释序列中每个数据文件的峰值積分。对動態數據的另一个要求是，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. 動態數據不能打印为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，因为用戶不能与它交互。

In contrast, once static data have been created, the user cannotinteract with them. Right? 相反，一旦创建了靜態數據，用戶就不能与之交互。对吧?

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

但是，如果没有进一步的用戶交互，靜態數據真的是静态的吗?

How Static are Static Data? 靜態數據到底有多静态?

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:

回到實驗室工作台，想象您正在分析分析天平上稱重樣品等分或參考標准，稱重順序(例如，容器質量，皮重，材料質量)被打印出來。一般認爲這是靜態記錄，分析天平打印輸出附在實驗室筆記本或分析批記錄上。的確，2021年PIC/S指南第8.9.1(5)節規定:

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.

一些非常簡單的電子系統，如不存儲數據的天平，直接生成打印的紙質記錄。這些類型的系統和記錄通過(重新)處理、更改電子日期/時間戳來影響數據表示的機會有限。在這些情況下，原始記錄應由生成記錄的人簽名並注明日期，並應在記錄上記錄諸如樣品ID、批號等信息以確保可追溯性。這些原始記錄應附在批處理或檢測記錄後。

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

該方法在FDA數據完整性指南問題10(4)中重複:

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? 是否可以保留紙張打印或靜態記錄，而不保留單機版實驗室儀器(如紅外光譜儀)的原始電子記錄?

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對簡單分析儀器的指導文件的規定監管要求是，用于附在分析批記錄或實驗室筆記本上的紙質打印件。雖然幹擾打印輸出的能力有限，但在沒有審計追蹤和電子記錄的情況下，可以重複稱重，直到獲得“正確”的結果。靜態記錄是否爲正確的方法將在本專欄稍後討論。

Static Data are an Integral Part of an AnalyticalProcedure靜態數據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：

天平等簡單儀器産生的數據對整個分析程序至關重要，因爲這些值是任何定量色譜分析的輸入，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，靜態數據成为動態數據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，許多實驗室仍然爲用于在紙上打印輸出産生關鍵數據的小型儀器設計不適當的數據處理方法。這種情況還會因人工將質量輸入計算機化系統或電子表格而加劇，導致審核人進行抄寫錯誤檢查。

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:

我們可以在圖1中進一步查看這種情況;在图表的左侧是生成靜態數據记录，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動態數據的色谱数据系统中，用于生成可报告的结果。在这里，我们可以看到靜態數據向動態數據的转换。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，那么打印输出上的靜態數據现在就是色谱数据系统中的動態數據。这就提出了一个关键问题:

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

爲什麽先使數據靜態，然後才使其動態?

                              

Is Regulatory Guidance Correct? 監管指南正確嗎?

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:

標題提出了一個基本問題:考慮數據是靜態的還是動態時，框框在哪裏?考慮圖1左側的情況:

•      StaticData: Analytical balance and printout in isolation:

靜態數據:分析分析天平和單獨打印輸出;

Weigh sample + print 称重样本+打印

result = static data 结果=靜態數據

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

動態數據:分析天平和樣品質量是整個色譜數據系統分析程序的組成部分;

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=動態數據

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.

動態等式只是分析程序的高級視圖，這當然必須考慮整個過程中生成的所有上下文元數據。

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靜態數據记录，但整个过程生成動態數據。

We now have an analytical procedure that generates hybrid records.

我們現在有了生成混合記錄的分析程序。

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.

即使圖2中的儀器數據系統使用電子簽名，也只會消除一項紙張(圖右側的紙張打印輸出)。混合記錄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.

圖2顯示了需要審查和存檔的完整記錄集，但問題是這個記錄集要有幾個靜態的紙質記錄還要再加上電子記錄。

Are hybrid analytical procedure records an adequate situation to bein?

分析程序混合記錄是否適當?

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:

倡導流程效率的一份監管指導文件是2016年WHO良好記錄和數據管理實踐指南(3)，其中第5.6節指出:

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

根据健全的質量管理原则制定和执行的数据管理方案预计将充分利用現有技術發揮其潛力。

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.

反過來，這將簡化數據流程，不僅可以改善數據管理，還可以提高業務流程的效率和有效性，從而降低成本並促進持續改進。

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

很少能找到推薦業務流程效率和有效性的監管指導文件。然而，這裏有兩點需要說明:

1.   Use informatics solutions tostreamline processes.

使用信息學解決方案來簡化流程。

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

淘汰紙張，只使用一種介質來審核和保留。

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).

這與“不鼓勵混合系統”和“混合系統應盡早更換”的說法相結合(3)。同樣的方法應該應用于分析程序混合記錄，因爲它不僅是計算機化系統，而且還需要評估數據漏洞的過程(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世紀的第三個十年，來自簡單儀器的靜態記錄和混合系統的使用是否可以接受?

爲了找到答案，我們需要回到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《药品成品生产質量管理规范》或cGMP法规。

Is current important? What does current mean?

現行重要嗎?現行是什麽意思?

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

在這份白皮書的介紹中提出了一個問題:

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…

幾條評論反對《條例》標題和正文中的“當前”一詞……

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

專員認爲，這些評論中有幾條反映出對“當前”一詞的使用存在誤解……

Although the practices must be "current" in the industry,they need not be widely prevalent. 雖然這些做法必須在行業中是“當前”的，但它們不一定要廣泛流行。

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.

國會並沒有要求大多數或任何其他百分比的生産商已經遵循提議的強制性規範，只要它是行業中當前的良好生産規範，例如，它已經被證明在保證藥品質量方面是可行的和有價值的。

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:

從中得到的信息是，實驗室必須與最新的技術保持同步，並實施新的方法和系統以保持“最新”。這也反映在FDA網站的一個頁面上(14)，上面說:

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”，要求企業使用最新的技術和系統，以符合法規。10年或20年前在防止汙染、混淆和錯誤方面可能是“頂級”的系統和設備，以今天的標准來看可能是不夠的。

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

這種方法是當前唯一的並且只適用于FDA嗎?

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.

上市許可獲得批准後，上市許可持有人應就第8(3)(d)和(h)條規定的生産和控制方法考慮科學和技術進步，並引入任何可能要求的變化，以使藥品能夠通過普遍接受的科學方法生産和檢查。

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，並按照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，許多實驗室的情況並不符合要求，既不能保持與時俱進，也不能考慮科學和技術進步。總的來說，一種懶惰的做法是普遍存在的:如果上次檢查夠好，下次檢查也會夠好。進一步的論證可能會涉及到以投資資金不足爲理由。當修複資金像尼亞加拉瀑布的水一樣流動時，這些項目在收到監管通報後立即停止。

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，沒有任何一份監管指導文件真正考慮到保持最新的要求。

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 實驗室的數字化

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和规范實驗室的數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:

圖3顯示了一種與現有技術保持同步的方法。所使用的信息學應用有:

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

實驗室信息管理系統(LIMS)，顯示爲黃色，用于管理樣本信息和整理測試結果;

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

儀器數據系統，通常由儀器制造商開發，與分析分析天平接口(也可以與其他類型的儀器接口);

• 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.

藍色的實驗室執行系統(LES)，是記錄樣品制備和將數據傳輸到色譜數據系統的功能包。

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.

樣品和批信息傳輸到LIMS，然後下載到LES和色譜數據系統應用程序。使用LES和色譜數據系統的信息(如稀釋度)自動制備樣品。在圖2中，來自分析分析天平的重量被手動輸入色譜數據系統，這是緩慢且容易出錯的。在圖3中，我們有一個儀器數據系統，該系統具有電子工作流，可獲取分析天平樣品重量並將其傳輸到色譜數據系統。進一步的技術控制確保使用正確類型的分析天平，甚至是由其序列號標識的特定型號。有一個審計追蹤，以確保樣品不被稱量爲“合規”。

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，積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:

審查的範圍受到應用程序中有效驗證過的技術控制的限制，例如:

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

没有用戶具有删除权限，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.

數據只能存儲在單個位置;因此，不需要對單例數據進行搜索。

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

應用程序中的審計追蹤突出顯示修改的數據，允許審查員額外審查(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).

信息學應用確保了所有數據的完整、一致和准確。這種方法還利用了前面討論的WHO數據完整性指南所倡導的現有技術(3)，除了滿足當前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，那么使用靜態數據是不可能完成这项工作的。

The Regulatory Driver for Laboratory Digitization 實驗室數字化的監管驅動因素

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:

兩個組織的一個具體補救要求是:

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

技術改進，以增加通過電子系統從單機版的設備(例如，天平，pH計，含水量測試)生成的數據集成到LIMS網絡。

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.

這是一個明確的信息，來自單機版系統的紙質記錄是不可接受的。引文還提到了一個LIMS網絡，它可以包括不同的信息學應用，如LIMS、LES、ELN和儀器數據系統，如圖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，並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，將分析天平連接到LIMS是前進的唯一途徑嗎?

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.

將分析天平連接到儀器數據系統可能是一個更好的選擇，因爲在稱重過程中可以獲得額外的元數據，以確保數據的完整性。如圖3所示，儀器數據系統的優點是可以在另一個儀器工作流程中使用分析天平獲得的質量。此外，如果LIMS由于失去與中央系統或雲的連接而造成不能使用，使用儀器數據系統還可以爲實驗室提供額外的冗余能力。

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集團在2021年8月的警示信中發現，如果購買了分析儀器，實驗室如何使用它也會導致監管引用(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.

你們的粘度計和紫外-可見分光光度計能夠保存産品/材料測試的數據。盡管有這種能力，你們的分析人員未能保存完整的、動態的檢測數據，因此數據無法用于FDA調查員的審查。

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.

如果儀器具有存儲電子記錄的能力，但未使用此功能，則可能導致監管引用。同樣，在實驗室裏操作的舊儀器，既不能連接打印機，也不能存儲數據，也是一個問題。正如上文所討論的，FDA認爲這種行爲不是最佳的(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.

如果一個實驗室沒有數字化，可能會有昂貴的補救成本，其時間尺度取決于說服監管機構滿意的認爲：該公司對符合監管規則是認真的。

Business Driver for Laboratory Digitization 實驗室數字化的業務驅動力

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，就要通过實驗室的數字化和纸张的去除，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大流行迫使實驗室審視一種新的工作方式——一些分析師在實驗室工作，另一些則遠程工作。這只有在數據是電子的而不是紙上的情況下才能起作用。

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。您不能使用涉及靜態數據和混合记录的工作实践来完成这些任务。

Conclusion結論

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.

有些靜態數據不一定多静态，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，並且必须接受审查。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.

關于數據完整性的監管指導文件(WHO的指導文件除外)沒有討論受監管實驗室需要保持最新，但應該這樣做，以符合他們應該執行的法規。然而，在一個完全電子化的過程中管理數據的好處提供了顯著的業務好處和法規遵從性，數據存儲在一個介質中。這種方法促進了效率和有效性，包括執行數據分析的便利性。

This is the way to keep current with cGMP.

這是與cGMP保持同步的方法。

Acknowledgement確認

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參考文獻

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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苏州的一天（2024.11.23）-学习札记⑦ 数据质量

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