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Important Questions and Answers concerning theAudit Trail Review 审计追踪审核方面重要问答
Actually, the topic 'data integrity' hasmoved into the focus of many national and international inspections. TheAmerican FDA has sent many Warning Letters concerning comprehensive deviationsobserved. Therefore the regulatory authorities request not only an assurance ofthe product quality but they also demand that each company has a clear strategyhow the integrity of critical data can be assured over its complete life cycle.Here, the review of the audit trail plays a decisive role. Despite the numerousguidelines published on this topic since 2015 it often remains unclear whichrequirements exist concerning the audit trail review and how they can beimplemented in practice. 事实上，“数据完整性”主题已经成为许多国家和国际检查的关注焦点。美国FDA已经发布了其所发面的综合性缺陷相关的许多缺陷信。因此，药监机构不仅要求保证产品质量，还要求每个公司对于如何在完整生命周期中保证关键数据完整性具有清楚的策略。这里，对审计追踪的审核起到了具有决定性的作用。虽然自2015年以来，关于此主题已发布了无数的指南，但对于审计追踪审核中有哪些要求，以及如何在实践中执行仍然不是很清楚。
For this reason the Webinar 'Audit TrailReview' was carried out in February 2017. Its aim was to address the mainelements of data integrity and audit trail reviews: 为此，2017年2月开办了“审计追踪审核”网络教程。其目的是解决数据完整性和审计追踪审核方面的主要要素：
Regulatory overview with emphasis on the requirements of MHRA and Annex 11 法规概览，重点关注MHRA和附录11的要求
Classification of data - which are critical data? 数据分类---哪些是关键数据？
Classification of systems - which systems are relevant? 系统分类---哪些系统是相关系统？
What Audit Trails are important?什么 审计追踪是重要的？
What shall I do with legacy systems without audit trail? 没有审计追踪的遗留系统要怎么办？
Who shall review Audit Trails? 谁应该审核审计追踪？
How is the review documented? 审核过程要如何记录？
Process and documentation in case of deviations? 如有偏差，要如何处理和记录？
Dr. Wolfgang Schumacher has been the speaker. He looksback on more than 30 years experience in the pharmaceutical industry.Dr. Wolfgang Schumacher 是演讲者。他回顾了制药行业中30余年的经验。
He has received more than 50 questions concerning thewebinar. Naturally, he could not reply to all them immediately after thewebinar. Thankfully, Dr. Schuhmacher has answered all questions in writing.Hereinafter you find the first part of the questions and answers. A furtherselection is planned for a later time. 他已经收到了50余个关于网络教程的问答。自然，他不可能在网络教程之后立即回复所有的问题。值得感激的，Dr. Schuhmacher已经回答了所有书面问题。下面你会看到这些问答的第一部分，另一部分计划在迟些时候发出。
1. Are the analytical data arising in the courseof the validation of analytical procedures critical data?Answer: No, since these data are released with the completion of thevalidation process and it only presents the basis for future analyses.Therefore there is only an indirect criticality; no audit trail review isrequired. 问：在分析方法验证过程中产生的分析数据是否关键数据？ 答：不是。由于这些数据在验证过程完成之后即放行，只能代表将来分析的基础。因此这只是间接关键性，不需要进行审计追踪审核。2. The calibration of 2. The calibration of equipment influences thecorrectness of data. Does this mean that the calibration is critical?A: Since the calibration influences the patient safety only indirectly no audittrail review is required. 问：设备校正会影响数据的正确性。这是否意味着校正是关键的？ 答：由于校正只会间接影响患者安全，因此不需要审计追踪审核。
3a.: Practical example: What about a reactor controlfrom production that has neither user management nor a password or an audittrail etc.? Is it allowed to continue using this control?A: It is definitively recommended to plan a replacement. The time ofreplacement depends on the product manufactured with the reactor. This definesthe criticality. 问：实践例子：如果反应釜的生产控制没有用户管理，也没有密码或审计追踪等，会怎么样？是否允许继续使用此类控制？答：绝对建议计划对此进行更换。替换时间取决于反应釜所生产的药品。这是关键的。
3b. Practical example: What about a reactor controlfrom production that has neither user management nor a password or an audittrail etc.? (The control concerned is the control of a reactor which is usedfor the manufacture of intermediates and APIs but not of final products). Is itallowed to continue using this control or does it have to be withdrawn fromuse?Answer: Thank you for clarifying the question. I donot think it is necessary to replace the reactor control immediately if it isused for the production of an intermediate. Recommendation: Assess all systemsand equipment and arrange them according to priority classes (for instance byusing a rather simple FMEA). This is used to define when to deal with thepriority classes, for example Prio 1= until the end of 2017, Prio 2=until the end of 2018 etc… 问：实践例子：如果反应釜的生产控制没有用户管理，也没有密码或审计追踪等，会怎么样？（让你涉及的受控反应釜是用于中间体和API生产，但不用于制剂生产）。是否可以继续使用这些控制，还是必须停止使用？答：谢谢你对问题的澄清。如果反应釜用于中间体的生产，我不觉得有必要立即替换此反应釜控制。建议：评估所有系统和设备，依据优先级别来对其进行安排（例如，使用相对简单的FMEA）。用此种方法来界定需要在何时处理不同优先级别，例如，第1优先=2017年年底，第2优先=2018年年底等……
4. Is the audit trail review prior to the release ofeach batch a regulatory requirement or is it only recommended so far?A: Annex 11 requires the audit trail review. Inspectors consider the release ofbatches to be the most critical process of all. 问：在放行每个批次之前，是否有法规要求执行审计追踪审核，还是说截止目前只是建议？答：附录11要求进行审计追踪审核。检查员认为批放行是所有内容中最关键的流程。
5. Hybrid systems: No audit trail retrofittingpossible. What can be done?A: First of all I would clarify all other criteria (access, user/admin profile,safety). How critical is this data? Plan a replacement according to theclassification of the criticality (= priority) if the data is critical. 问：混合系统：审计追踪是无法翻新的。这要怎么办呢？答：首先，我要澄清所有其它标准（登入、用户/管理概况、安全性）。这些数据有多关键？如果数据关键，则依据关键等级（=优先级）来计划替换。
6. Role concept: Is a user allowed to carry out areintegration? (GC-system)A: As far as I can see, the answer to this is 'no'. This should first be authorisedby the Head of Laboratory stating the reason. 问：角色概念：一个用户是否允许执行重新积分？（GC系统）答：以我所见，回答是“不允许”。这首先要由化验室最高领导授权，并说明理由。
7. It is difficult to carry out the separation betweenthe persons of administrator and user in the CDS. Is it possible that theadmin and the user being the same person?A: This is possible but it needs to be described in a SOP. 问：在CDS里面很难将管理者与用户分开来。是否可能将管理者和用户授予同一人？答：可以，但需要在SOP里描述。
8. Process validation data are category 3 data -therefore no audit trail review is required. But isn't it required to carry outa review for the generation of validation measuring data?A: As you have stated correctly, validation data have the criticality ofcategory 3.It is very unlikely that the user will carry out changes since there is noreason for falsification - in contrast to the batch release. 问：工艺验证数据是第3类数据---因此，不需要审计追踪审核。但是否需要对验证测量数据生成情况进行审核呢？答：你所述是对的，验证数据的关键类别为3。由于并没有造假理由，因此用户不大可能对其进行修改----这与批放行情况是相反的。
9. Hello, is is useful to review the 'windowseventviewer' for GxP devices?A: This is a good idea but it will probably not be realistic as too many eventswould be reported. Its use would anyway only be worth considering for systemswhich save data locally, and thank God this isn't done by many modern systemsanymore. 问：你好，对GXP装置审核“视窗事件查看器”是否有用？答：这是个好主意，但可能并不现实，因为这里面会报告太多事件。只有当数据保存于本机时才认为值得考虑使用此方法，谢天谢地，许多现代化系统已经不再这么做了。
10a.: Must the report for a riew of the audit trail begenerated by the system itself? Or is it possible to use another system whichis better suited for carrying out analyses?A: Strictly speaking, the audit trail must be generated by the system itself('system generated audit trail'). Which other system do you have inmind? 问：审计追踪审核报告必须由系统本身生成吗？还是说可以使用另一个更为适当的系统来执行该分析？答：严格来说，审计追踪必须由系统本身生成（系统生成审计追踪）。你觉得有什么其它系统呢？
10b. I think, I did not express myself very clearlywhen asking the question: Is it only reviewed whether the process is stillfunctioning in the course of the periodic reviews - hence, if the audit traildata is still recorded? Meaning: Functionality is documented by IT with a fewsamples.A: Very correct!问：我想，我刚才问问题时没讲的太清楚：是否只是审核定期审核的时间间隔内，该流程仍在起作用---因而，是否仍有记录下审计追踪数据？也就是说，由IT记录采用少数样本来记录其功能。 答：非常正确！（译者：这个问题，说实话，真心没看懂）
11. May the Head of Laboratory have admin rights forexample to carry out the audit trail review?A: Yes, as long as she/he does not operationally process analysesherself/himself. 问：化验室的负责人是否可以持有管理员权限，例如，实施审计追踪审核？ 答：可以，只要她/他并不亲自执行分析操作。
12. Is it possible for a user to have two systemaccounts? One as a user and one as administrator or reviewer?A: Yes, in small organisational units. Guarantee by means of an SOP that theadmin account will NOT be used operationally. 问：一个用户是否可以有2个系统账号？一个作为用户，另一个作为管理者或审核员？ 答：可以。在小型组织单元中是可以的。通过SOP的方法来保证管理者账号不会被用来进行操作。
13. Do you know a system that fulfils all requirementsfor the audit trail function of a CDS?A: So far there are hardly any systems on the market which allow to carry outthe review with a minimum effort. Unfortunately, this is also true for modernsystems as Empower 问：你是否知道有哪个CDS系统满足审计追踪功能的所有要求？答：截止目前，市场上几乎没有任何系统可以不费吹灰之力就执行审核。不幸的是，先进如Empower 3的系统也是这样。
14. File based data retention: Deletion is possibleoutside the software. How is it possible to 'build in' safety?A: Yes, in systems that can store locally on the HD of the user it is possibleto set up two local user profiles. Then, for instance, the system stores dataonly on the profile the user cannot access. 问：基于数据保存的文件：在软件以外可以删除。怎么才能“增强”安全？ 答：对于可以将数据存贮于本地用户硬盘上的系统，是可以设定2种本地用户配置的。所以，比如，可以让系统将数据存贮在用户角色不能进入的地方。
15. What are metadata?A: Data concerning data, such as the timestamp.问：什么是元数据？答：数据的数据，例如时间戳。
16. What are manufacturing execution systems?A: Process control systems. 问：什么是生产执行系统？答：工艺控制系统。
17. What do you do with legacy equipment? If no audittrail is available or if 'user login' is not possible?A: The systems have to be replaced in the short or in the long run - accordingto the risks. 问：遗留系统要怎么办？如果没有审计追踪，也没办法执行“用户登录”？ 答：必须在短期内替换这些系统，或者根据风险程度，制订长期计划来替换。
18. Equipment often has a standard audit trail function.A lot of data is recorded (on/off), but only a small part of it is critical orrelevant for a review. What is the best way to proceed when carrying out areview?A: The best way is to configure a report that only shows the critical data butleaves out all the unnecessary elements (such as login/logout). But this has tobe programmed and is expensive. 问：设备通常有一个标准的审计追踪功能。它记录了许多数据（开关），但只有一小部分是关键的或与审核有关。在执行审核时最好的处理方法是什么？ 答：最好的方法是对报告进行参数设置，使其仅显示关键数据，筛除掉所有不必要的要素（例如登录和退出）。但这就必须进行重新编程，这可是很昂贵的。
19. What is the way to proceed in the case offacilities in the production area such as AP production, mixers, filling lineswith variable parameters as concerns classification of data/systems, extent andintervals of review?A: It is best to classify systems and facilities according to ISA95. Then youwill notice that at the bottom levels (field level, PLC, SCADA) no interactionsof the user are permitted. Hence no audit trail review is required. Basis isthe risk analysis of the systems and data. 问：如果生产区域如API生产的设施，混合器、灌装线具有可变参数，有什么办法处理其数据/系统分类，以及审核的程度和时间间隔？ 答：最好对系统和设施依据ISA95进行分类。然后你会发现最底下一层（现场层面，PLC，SCADA）不是允许用户互动的。因此，没有不要求有审计追踪。其基础是对系统和数据所做的风险分析。
20. Whose job is it to carry out the audit trialreview in the laboratory?A: This can be a colleague. The FDA requires 'Quality Unit' (=QA) inthe Draft Guideline. All other Draft Guidelines allow for a peer review. 问：在化验室执行审计追踪审核是谁的工作？ 答：可以是一个同事。FDA在其指南草案中要求“质量部门”（=QA）来做。所有其它指南草案则允许同行审核。
21. Must all electronic data be stored and archived inthe case of a process in the sterile area or is the batch record sufficient?A: You must define what the raw data are. These have to be stored in additionto the batch record. 问：无菌区的工艺，以及批记录充分时，是否所有电子数据都必须存贮和归档？答：你必须定义什么是原数据。除了批记录以外，这些是必须存贮的。
22. Would you consider changes of the parameters /formulations at production facilities as dynamic data? Do I have to considerthem at every batch?A: This data is governed by the change control and is not part of the data fora review. 问：你认为生产设施中参数/配方的变更是否动态数据？我是否必须在每批中都考虑他们呢？答：这些数据是受到变更控制管理的，并不是要审核的数据的一部分。
23. Many of our production processes are documented bymeans of a batch record on paper. What should we do as concerns the review ofthe audit trail? Should we review the good documentation practice in the batchrecord by means of an audit trail review?A: As long as you only document on paper the audit trail review is not relevantfor you, but the 4-eyes-principle for all critical steps. The following isstated in the FDA Guidelines: 'Critical process steps have to be verifiedby a second individual'. 问：我们许多生产工艺是记录在纸质批记录上的。关于审计追踪审核，我们要做些什么呢？我们是否需要采用审计追踪审核方法来审核批记录中的优良记录规范？ 答：如果你只是使用纸质记录，那么审计追踪审核与你不相干，但双人原则适用所有关键步骤。FDA指南中讲到了以下内容“关键工艺步骤必须由第二人审核”。
24 Dynamic data static data. A smallfiltration facility (pressure measurement/flow measurement/temperature) with alocally installed SCADA system would then rather deliver static data?A: That's correct. Static data as the user is not able to change the data. 问：动态数据VS静态数据。一个小的过滤设施（压力测量/流量测量/温度）有一个就地SCADA系统，这算是静态数据吗？答：是。如果用户是无法修改这些数据，它就是静态数据。
25. Batch records are considered to be carriers of rawdata for the documentation of processes. What about trend data that have beenprinted and enclosed to the batch record?A: I do not consider it necessary to always review trend data. 问：批记录被认为是记录工艺原数据的载体。如果将趋势数据打印出来并附入批记录呢？答：我不认为有必要每次都去审核趋势数据。
26. Slide 9: What do you include in systems andequipment?A: Everything that has to be validated and qualified?问：在第9张幻灯中，你在系统和设备中包括哪些东西？ 答：需要验证和确认的所有东西。
27. Is it necessary to perform an audit trail review(ATR) after each measurement/analysis carried out at the equipment in thelaboratory? Who carries out the ATR - laboratory personnel (operator) or theHead of the Laboratory?A: A SOP is required for the ATR for each system that describes the details.The review after completion of the analysis is important. 问：在化验室，是否有必要每次在仪器上执行测量/分析之后均执行审计追踪审核（ATR）？谁来做ATP---化验员人员（操作员）还是化验室负责人？ 答：每个系统都需要有一个SOP来描述详细内容。分析完成之后的审核是很重要的。
We'd like to thank Dr. Schumacher for hiscomprehensive answers to all questions.感谢Dr. Schumacher对所有问题的全面回答！ Of course, this webinar is also available as arecording.
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