与电子表格使用相关的合规性问题汇总基于FDA的警告信.docx

1、与电子表格使用相关的合规性问题汇总基于FDA的警告信与电子表格使用相关的合规性问题汇总基于FDA的警告信 作者： 日期： 与电子表格使用相关的合规性问题汇总基于FDA的警告信电子表格在制药企业中使用的合规性一直是FDA检查的重点之一， FDA警告信中涉及到大量关于电子表格不合规使用的问题。从趋势上看，自2014年开始，警告信涉及电子表格不合规问题的频次有所降低，说明在欧美等成熟市场中，药企通过多年的努力，在数据完整性上做的越来越好。但另外一方面，以2017年1月13日发给意大利一家制药企业的警告信为例，即使在2014年期间使用“非官方”及不受控电子表格的问题都被挖了出来，其回溯的时间较之前的警

2、告信更长，说明FDA对电子表格的关注非但并未降低反而有所提高。CFDA于2015年5月26日正式发布了GMP法规的新附录之一计算机化系统，首次明确提出对计算机化系统的合规要求。2016年9月30日，由CFDA食品药品审核查验中心组织起草的药品数据管理规范(征求意见稿)挂网公开征求意见。从上述两份文件不难看出，CFDA对于数据完整性及计算机化系统的合规要求正在全面与FDA接轨。电子表格作为计算机化系统的重要部分及数据完整性的重要载体，毫无疑问今后也将成为CFDA的监管重点。对于广大国内药企，无论是向外扩张的需求或是适应国内监管的要求，电子表格的合规性使用都已成为必须要认真面对的问题。本文整理了警

3、告信中一些代表性内容，主要有以下几个方面：1）使用到“非正式”或不受控的电子表格；2）没有审计追踪 3）未经验证； 4）数据错误。具体内容详见下表：时间公司or机构原文中文摘要2017年1月13日FACTA FarmaceuticiYou stored original data in an “unofficial” and uncontrolled electronic spreadsheet on a shared computer network drive.In response to this letter:Comprehensively evaluate test samples

4、performed by other analysts from January to September,2014, when the unofficial spreadsheet was in use.Evaluate the extent of uncontrolled spreadsheets at your facility.检查发现该公司存在使用共享网络盘中的“非正式”及不受控的电子表格存储原始数据的情况。FDA要求：1）综合评估使用过非官方电子表格期间内测试的样品；2）评估不受控电子表格的使用及影响程度。2016年8月25日Pan Drugs LimitedFor example

5、, the computer in your quality unit area did not have controls to restrict access and prevent unauthorized changes to data files and folders. All employees had access to your Annual Product Review (APR) spreadsheet. The desktop computer containing the APR was not locked. 质量部门中的计算机没有进行控制以限制访问并防止XX的更改

6、数据文件和文件夹。例如所有员工都能访问该公司的年度产品回顾（APR）电子表格。2016年8月3日Ropack, Inc.Failure to validate computer software for its intended use according to an established protocol when computers or automated data processing systems are used as part of production or the quality system, as required by 21 CFR 820.70(i). For e

7、xample, your firm was utilizing an uncontrolled spreadsheet to track equipment requalification due dates.计算机软件作为产品质量体系的一部分，未按照21 CFR 820.70（i）的要求依据既定方案进行验证。例如该公司使用了一个未受控的电子表格跟踪设备的再确认日期。2015年12月18日Virbac CorporationYour Complaint SOP states that QA shall maintain the customer complaint report files.

8、Your firms QA unit maintains a separate Excel spreadsheet for those complaints that come directly into the Bridgeton QA unit. You have no centralized system for tracking all your complaints. The use of Excel requires many management controls to prevent data alteration, and Excel does not have an aud

9、it trail to identify data changes.该公司 QA部门使用一个单独的Excel表格而非集中式的系统来维护那些直接发到Bridgeton QA部门的投诉。FDA认为使用Excel需要很多管理控制措施来防止数据修改，并且Excel自身没有审计追踪功能来识别数据变更。2015年10月22日Sandoz International GmbHTwo uncontrolled Excel spreadsheets were used to record discrepancies and certain in-process drug quality data.使用两个不受控

10、的Excel电子表格记录偏差和某些药品中控质量数据。2014年7月21日Med-Mizer, Inc.Also, your firm tracks complaintdata on a spreadsheet that contains free form text fields that are not standardized, resulting in an inability to adequately trend the data. For example, when using complaint data from January 1, 2011 to February 19,

11、2014 to trend for “Description of Failure” for “6090,” fourteen complaints are shown. However, thespreadsheetcontains several different descriptions of the same part failure that when totaled resulted in a total count of forty complaints related to the inline coupler, part #6090.”该公司跟踪投诉数据的电子表格，其中包含

12、自由形式的文本字段，这不规范，导致了数据分析中出现问题。例如，一个管理投诉数据的电子表格，因对同一问题“描述失败”包含几种不同的描述，导致使用表格内部公式计算“描述为失败”问题总数时，将原本的14统计为了40。2013年9月27日Aarti Drug LimitedAdditionally, at the Aarti Drug Limited facility (FEI 3009688205), the investigator noticed that the use of the Excel spreadsheets in analytical calculations are neith

13、er controlled norprotected from modifications or deletion. The investigator noticed that the calculation for residual solvent for XXX uses an Excel spreadsheet that has not been qualified. We are concerned about the data generated by your QC laboratory from non-qualified and uncontrolled Excel sprea

14、dsheets.该公司未对用于分析计算的Excel电子表格进行控制和保护，电子表格可被修改和删除。表格未经验证（例如XXX品种的溶剂残留计算表格non-qualified）。FDA对该公司QC实验室使用未经验证及不受控制的电子表格产生的数据表示担心。2012年6月13日Compaa Internacional de ComercioSpecific violations observed during the inspection include, but are not limited, to the following: Your firm has not establishedappro

15、priate controls designed to assure that laboratory records include all data secured in the course of each test, including graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, drug product container, closure, in-process material, or drug pro

16、duct, and lot tested 21 CFR 211.194 (a)(4). Specifically, the inspection revealed that your firm has not established written procedures to control and account for electronically generated worksheetsused by analysts to record analytical test results. Analysts in your QC laboratory print an uncontroll

17、ed number of worksheets from computers throughout the QC laboratory without supervision.检查中发现该企业没有建立适当的控制措施以保证实验室记录被合适地标识或归属至所属对象，这不符合21 CFR 211.194（a）（4）的要求。具体地，该公司没有制定书面程序来控制和说明分析人员用以记录测试结果的电子表格。分析人员在QC实验室的电脑上未受监督地打印了数量不受控制的电子表格。2011年5月16日Aubrey Inc.Failure to validate software used as part of pro

18、duction or the quality system for its intended use according to an established protocol, as required by 21 CFR 820.70(I). For example, your firm did not validate use of anExcel spreadsheet used to calculate the Moisture Vapor Transmission Rate (MVTR) per test procedure XXX Revision B.计算机软件（例如用于计算MVT

19、R的Excel电子表格），作为产品质量体系的一部分，未按照21 CFR 820.70（i）的要求依据既定方案进行验证。2010年10月12日Advanced Testing Laboratory, Inc.We observed 8 of 9worksheetswhere one or more tabs with formula cells were not locked. These worksheets were used for analyzing raw data from drug component and product samples, including XXX. Your

20、 firms SOP 100-G-0110, “Creation and Use of Templates,” stated that cells, in which data is entered, must be locked within their electronictemplate. In your response, your firm states that you will enforce the existing procedure by reviewing the current inventory of electronic data files and disposi

21、ng of non-compliant spreadsheets. In addition, you will retrain analysts on the current procedure. Your response, however, is inadequate because you do not assess whether the raw data results, generated using unlocked templates, are valid.该公司用于分析原料药及制剂样品原始数据的大多数（9个中的8个）电子表格中，均存在一个或多个带公式单元格未被锁定的情况，而这

22、与法规要求及该公司的SOP均不符。在该公司对483的答复中，承诺将加强对现有程序的执行、梳理现有表格并处理不合规表格、同时将对分析人员进行重新培训。但FDA认为其答复是不够的，因为没有对使用未锁定表格处理的原始数据结果进行有效性评估。2010年6月10日Medefil, IncorporatedYour firm has no procedures for controlling laboratory worksheets including changes to worksheets, issuance of laboratory worksheets, and reconciliation

23、 of laboratory worksheets. The worksheet “Internal Communication Batch Release Information” by the warehouse, which is used to identify released product, was created after XXX documented release of finished product for Heparin I.V. Flush Syringes and Normal Saline I.V. Flush Syringes prior to obtain

24、ing media fill results. This sheet is used to communicate batch release information to warehouse operations. Use of this sheet is not documented in any Medefilprocedurenor is control over this sheet documented.该公司没有实验室电子表格的控制（发行、变更、一致性控制等）程序。例如仓库用于识别放行产品的某工作表，它的使用既没有在任何的程序中记录，也没有在工作表本身的记录文件中收到控制。201

25、0年4月20日Capricorn Pharma, Inc.Your firm has failed to exerciseappropriate controls over computer or related systems to assure that changes in master production and control records, or other records, are instituted only by authorized personnel 21 C.F.R 211.68(b).Your firms laboratory analysts have the

26、 ability to access and modify the formulas in theExcel spreadsheetsused to calculate assay results for Guaifenesin and XXX drug products. Due to this unrestricted access, there is no assurance that the formulas in the Excel preadsheets are accurate and valid.该公司未能对计算机或相关系统实施适当的控制，以确保主生产和控制记录或其他记录的变更

27、仅由授权人员实施。例如该公司的实验室分析人员能访问和修改用于计算检测结果的Excel电子表格中的公式。由于这种不受限制的访问，Excel电子表格的准确性和有效性得不到保障。2009年10月5日Phoenix Bio-Tech CorporationFailure tovalidate computer softwarefor its intended use according to an established protocol when computers or automated data processing systems are used as part of production

28、 or the quality system, as required by 21 CFR 820.70(i). We have reviewed your responses and have concluded that they are inadequate because a copy of your revised procedures and the Excel spreadsheet validation protocols/procedures and reports were not provided. It is unclear how you plan to docume

29、nt quality system records that were previously documented in the (b)(4) system.计算机软件（含Excel等自动数据处理系统），作为产品质量体系的一部分，未按照21 CFR 820.70（i）的要求依据既定方案进行验证。因该公司未提供修订程序和Excel电子表格验证方案/程序和报告的相关资料。FDA评估认为其对483答复不够充分。2009年4月27日Hill Dermaceuticals, Inc.Your laboratory records did not include a record of all calcu

30、lations performed in connection with laboratory tests as required by 21 CFR 211.194(a)(5). For example, laboratory notebook #7, page 49, documents the assay results, but not the calculations performed in Test number DSFS D-13 and Test number TG 521 for the analysis of XXX, lot #HI7908. The notebook

31、does not document reference to thespreadsheet calculationused to generate the results. In addition, the assay results generated by the spreadsheet were not verified for accuracy. Your response dated February 16, 2009, states that you have established procedures to ensure that calculations ofmethod v

32、alidationstudies are recorded. TheRecords Management SOP, Section 5.7.4.7, states that the procedures shall define what and how data is to be recorded in respective logbooks. However, this SOP omits instructions to include in the notebook the reference to the spreadsheet calculation used to generate the results, as well as the raw data and calculations. In addition, you continued to release products based o