Assuring E Data Integrity and Part 11 Compliance for Empower How to Configure an Empower Enterprise

Transcription

1 Assuring E Data Integrity and Part 11 Compliance for Empower How to Configure an Empower Enterprise 2013 Waters Corporation 1

2 Agenda Electronic Record regulations, Compliance Policy Guides and Warning Letters Raw Data in the Chromatography Laboratory Designing your Empower process General Security and System Policies Access Management Project Design and Configuration Understanding Empower Audit Trails (brief) Configuring for Electronic Signatures Managing Data Validation and Qualification Other procedures and policies 2013 Waters Corporation 2

3 Gathering and sharing regulatory information 2013 Waters Corporation 3

4 What Is Compliance? Satisfying regulatory agencies and certification organizations that a company's processes are being operated at a level of control that will ensure that their products will meet predetermined safety, efficacy, and quality specifications Waters Corporation 4

5 Electronic Record Regulations 2013 Waters Corporation 5

6 Purpose of Record Policies Ensure Data Integrity Records should be created contemporaneously Retained Reliable o Changes should be noted, reasoned and non repudiated Computer systems should be trustworthy Validated to intended use No resultant decrease in product quality, process control or quality assurance Evidence should be available to prove the above 2013 Waters Corporation 6

7 Chapter 21 Code of Federal Regulations 21 CFR Part 11: Electronic Records; Electronic Signatures 21 CFR Part Current Good Manufacturing Practice for Pharmaceutical Products 21 CFR Part 58 - Current Good Laboratory Practice for Pharmaceutical Products 21 CFR Part Current Good Manufacturing Practice in Manufacturing Packing or Holding of Human Food 21 CFR Part 820 Quality System Regulation for Medical Devices As with FDA regulations, EU regulations have rules overlaid with the electronic record rule (Annex 11) 2013 Waters Corporation 7

8 European Annex 11 Annex 11: Electronic Records; GMP Chapter 4- Documentation Annex 4: Manufacturing of Investigational Drug Product OECD Guidance for the Conduct of Test Facility Inspections and Study Audits OECD Revised Guides for Compliance Monitoring Procedures for GLP As with FDA regulations, EU regulations have rules overlaid with the electronic record rule (Annex 11) 2013 Waters Corporation 8

9 21 CFR Part 11 Controls Administrative Controls: Set policies, assign roles and responsibilities, operator and administrator training, ITIL implementation, auditing Procedural Controls: SOPs and Work Instructions for operation and administration, computer system validation, calibration, network qualification. awareness training Technical Controls: Computerized features like audit trail, backup mechanism, user management and security, electronic signatures and/or digital signatures to assist or enforce administrative and procedural controls 2013 Waters Corporation 9

10 Key Topics of Part 11 Secure Records Back up, archive, records retention policy of ALL data and meta data Easy retrieval of e-records and Human Readable copies controlled access with unique username and password o limit functionality o feeds audit trail Secure computer generated audit trails for any changes to data o What changed, who, when why (and now where) Applications that work Validation Training Electronic Signatures Non repudiation of signature (if using) 2013 Waters Corporation 10

11 Annex 11 to Influence Part 11? PI CFR Part 11 Annex Waters Corporation 11

12 Four new key areas in Annex 11 Supplier Audits: including the requirement to share a summary of your assessment Be sure this is agreed in your vendor NDA agreement Qualification of IT Infrastructure And a formal agreement with IT departments Inclusion of Risk Management In Regulation rather than in Guidance Review of Audit Trails Specifically mentioned Printouts should indicate a change 2013 Waters Corporation 12

13 The Lessons to Learn from FDA 2013 Waters Corporation 13

14 Sunrise Pharmaceuticals Jan 2010 Your firm has not exercised appropriate 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 CFR (b)]. For example, your firm lacks systems to ensure that all electronic data generated in your Quality Control laboratory is secure and remains unaltered. All analysts have system administrator privileges that allow them to modify, overwrite, and delete original raw data files in the High Performance Liquid Chromatography (HPLC) units. In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made Waters Corporation 14

15 Ohm Laboratories 21 st December 2009 Your firm has not exercised appropriate controls over computer or related systems to assure that changes in control records or other records are instituted only by authorized personnel [21 CFR (b)]. For example, one user account is established for two analysts to access the laboratory instrument's software on the computer system attached to HPLC systems.. The user account provides full system administrative rights, including editing of the methods and projects. In addition, data security protocols are not established that describe the user's roles and responsibilities in terms of privileges to access, change, modify, create, and delete projects and data Waters Corporation 15

16 Able Laboratories 483 May Waters Corporation 16

17 Biochem February 2012 Access Control Your firm did not put in place requirements for appropriate usernames and passwords to allow appropriate control over data collected by your firm's computerized systems including UV, IR, HPLC, and GC instruments. All employees in your firm used the same username and password Change Control In addition, you did not document the changes made to the software or data stored by the instrument systems. Raw Data Your firm had no system in place to ensure appropriate backup of electronic raw data and no standard procedure for naming and saving data for retrieval at a later date 2013 Waters Corporation 17

18 Gulf Pharmaceuticals February 2012 Access Control You have not implemented security control of laboratory electronic data. All laboratory analysts share the same password for the HPLCs in the QC analytical chemistry lab and Omnilog in the microbiology lab. Raw Data There is no system in place to ensure that all electronic raw data from the laboratory is backed up and/or retained. Data is deleted to make space for the most recent test results. You also informed our investigators that printed copies of HPLC test results are treated as raw data. Printed Copies Printed copies of HPLC test results from your firm s systems do not contain all of the analytical metadata (for example: instrument conditions, integration parameters) that is considered part of the raw data. We highly recommend that you hire a third party auditor, with experience in detecting data integrity problems, who may assist you in evaluating your overall compliance with cgmp Waters Corporation 18

19 Wockhardt Ltd July 2013 Delayed, denied, limited an inspection Torn raw data records in the waste area o o o Repeatedly asked to see them Presented 20 records, none of which were the missing records Later found raw data records in a different holding bag Unlabeled and partially labeled vials o When the investigator asked a QC Analyst to describe the contents of these vials, the QC Analyst immediately began dumping the contents of the vials into the drainage sink requested the QC data package and raw data testing documentation o no less than six times on (day 1), and again multiple times on (day 2) o Finally got data on close out meeting on day Waters Corporation 19

20 Summary of Findings No Secure Access to only authorized personnel No password Shared user accounts o o Set up that way Shared in an emergency without documentation or justification No controls to limit access to the delete function (among others) Either set up as administrators Or with user type that permit deletion or data manipulation No audit trails Software not equipped with audit trail User not having unique log on prevents correct audit trails No review of audit trails by managers or QA Trial injection data not kept or documented Analyses being repeated without justification, then called trial injections Delaying, denying or limiting an inspection Hiding data or records 2013 Waters Corporation 20

21 Raw Data in the Chromatographic Laboratory 2013 Waters Corporation 21

22 A day in the life of Raw Data Raw Data Quantification Change control Qualification and Maintenance Reporting CDS 2013 Waters Corporation 22

23 FDA.Gov: FAQ on Printed Chromatograms the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211. The electronic record must be maintained and readily available for review by, for example, QC/QA personnel or the FDA investigator 2013 Waters Corporation 23

24 Designing your Empower Process 2013 Waters Corporation 24

25 Design your Process First design your ideal process before creating the user requirement specification Look at current processes Look for bottle necks Look at current calculations Eliminate non compliant spreadsheets Eliminate paper worksheets Eliminate hand calculations Ask for input about ideal process Use outside help to design a process Fresh pair of eyes Vendor support using previous experience in similar industry Employees with experience in previous employment 2013 Waters Corporation 25

26 Empower Versatility Automated Dissolution Calculations Integrity of your HPLC dissolution testing % Dissolved automatically calculated Combined Accounts software for and transfer hardware Vol, solution replace media OR etc Q Factors assessed SOFTWARE ALONE for calculations For online and offline Dissolution 2013 Waters Corporation 26

27 The Automated Process Chromatography to Calculations 2013 Waters Corporation 27

28 General Security and System Policies 2013 Waters Corporation 28

29 Empower Software Security Windows (7 or XP) operating system software is only used to secure the database and raw data records from accidental deletion, corruption or modification Empower Software Security is used to secure specific areas of the application. Access Rights o Functionality o Data Sets (Projects) Audit Entries Password Security Sign Off Privileges This makes it the easiest CDS to run in a compliant way!! (exception is if customer wants to use LDAP for password authentication) 2013 Waters Corporation 29

30 Compliance Requirements: System Set Up and Policies Workstation Data stored on PC in the lab PC hardware failures result in loss of data Expensive to licence a username for every analyst on every workstation Many user names and passwords to maintain Time Stamps from unsecured PC time Access to OS (task manager/explorer) on PC compromises security of data SOP s need to synchronize naming conventions (files, methods, e- records) Client Server Data only stored on server in secured server room RAID technology protects from failure One user licence for every instrument in the lab Single set of passwords Time Stamps from the Server Access to OS of PC does not compromise data security Single data repository ensures uniqueness of ID s 2013 Waters Corporation 30

31 System Policies 2013 Waters Corporation 31

32 Empower System Policies System Policies are labeled, designating Waters recommendation for policies that should be invoked for GxP_ Electronic Records Electronic Signatures However it is the user interpretation that is important! 2013 Waters Corporation 32

33 System Polices: General Application Timeout One password unlocks all my windows Leaves other users windows locked Better than screensaver Disallow annotation tools Consider if relying on paper report review Date and Time Zone display 2013 Waters Corporation 33

34 Access Management 2013 Waters Corporation 34

35 Empower User Types Empower User Types are used to create unique security model for the Empower application, reflecting your designed processes User Types are associated with each User Account There is no limit to the number of User Types One person may have one default user type and be demoted in other project areas Define User Types AFTER you define the workflow processes 2013 Waters Corporation 35

36 Empower User Types 2013 Waters Corporation 36

37 Empower User Accounts Assigns username, password and user types to each User Account Each active/disabled Empower user account requires an Empower license removed Empower user accounts do not use a license Can have multiple user type for one user account Sharing of user accounts is not permitted By the software licensing regulation By the FDA Audit trails in Empower rely on identification of each user accessing the software. Audit trails are useless if people share a common account Equivalent to forging a signature on a GMP document 2013 Waters Corporation 37

38 Creating User Accounts 2013 Waters Corporation 38

39 Empower User Accounts Access User Properties to change the information for each user Users may change their own passwords in this way if they feel their password has been compromised Can be altered by a Group Administrator if one is assigned Eliminates the need for the system administrator to be involved for every change Multiple User Types can be associated to one User Account to log in with different levels of privilege Requires only one licence per user 2013 Waters Corporation 39

40 System Policies: Accounts and Passwords User accounts No replication or deletion User passwords Full history Expiry Entry attempts Length Log on/off behaviour Multiple users per Client Default User interface rules 2013 Waters Corporation 40

41 Limited Entry Attempts 2013 Waters Corporation 41

42 Limited Entry Attempts 2013 Waters Corporation 42

43 Limited Entry Attempts 2013 Waters Corporation 43

44 System Policies: LDAP Password Rules can be defined using Active Directory or LDAP Harmonize passwords across applications Synchronize expiry Add complexity rules 2013 Waters Corporation 44

45 Empower User Groups Empower Groups provide the ability to divide chromatographic information by laboratory, section or department 30 Character limit for Group names Users can be members of multiple Empower Groups A Group administrator can be assigned for each user group This person can alter the properties of ONLY the users in that group and not other users Interface will soon include full names (FR2) 2013 Waters Corporation 45

46 Empower User Groups 2013 Waters Corporation 46

47 Project Design and Configuration 2013 Waters Corporation 47

48 Project Management Empower Projects are folders used to organise chromatographic studies Establish Name Convention Customer Name, Assay Name, Compound, System Name, Analyst Name Determine how long an active Project will be available to receive new samples Decide what to do with inactive Projects Keep them live but prevent acquisition of new data Keep them live but lock completely Develop an archive schedule 2013 Waters Corporation 48

49 Key Questions when creating project structure What criteria is best to search for data? Examples are analyst, system, lab, compound, batch, calculation type, project, animal, ship, customer, lab book, date. How many projects per month/year? How many samples would go into each project per month? Over what time period / which projects would you need to compare data? It is currently not possible to graphically compare data that exist in two separate Empower projects 2013 Waters Corporation 49

50 Example Project Schedules Department Research Research Development Development Sample Frequency Varies in type and Number Small number of instruments Many analysts Many runs but compound varies strict methods of calculation Limited numbers of compounds many types of calculation Scheme Time Period Advantages Analyst Monthly / Quarterly Instrument Monthly / Quarterly Calculation type Monthly / Weekly Compound Monthly / Yearly Flexible Limit the instrument methods in each project Fixed custom calculations in template projects Specific methods in each project 2013 Waters Corporation 50

51 Example Project Schedules Department Stability QC QC raw mats QC Sample Frequency Limited batches over long time period Limited numbers of compounds with strict SOP s Very few formulations Weekly deliveries Very few formulations multiple production lines Scheme Time Period Advantages Batch Compound/ Formulation /SOP Per Ship Complete Study Monthly No time period Easy to compare data, Fixed methods Specific methods in each project easy to find data All data for one delivery together Per Line Monthly Specific methods in each project categorizes similar data 2013 Waters Corporation 51

52 Creating New Projects Use the Project Wizard to create new projects Based on a template project Based on previous months project Can only be created one by one Use the Clone project feature copies project structure and methods copies preferences can create multiple projects at once o One to many o Many to many Need good templates o containing correct structure and methods o with correct naming strategy 2013 Waters Corporation 52

53 New Projects using the Wizard 2013 Waters Corporation 53

54 Using Clone to Create Projects Caffeine Assay March Caffeine Assay Caffeine Assay April Caffeine Assay May Caffeine Assay March Caffeine Assay April Caffeine Assay May Preferable to use Template : Smaller Audit trails 2013 Waters Corporation 54

55 Using Clone to Create Projects Aspirin Assay Aspirin Assay May Assay Project Template Vit C Assay Caffeine Assay Vit C Assay May Caffeine Assay May One project, many copies Clone Multiple projects, one copy Clone Copies methods, custom fields, view filters and preferences Does not copy data 2013 Waters Corporation 55

56 Understanding Empower Audit Trails 2013 Waters Corporation 56

57 System Policies: Projects Determines the audit trail settings of new projects Can never be altered Silent is transparent to user but.. Most regulations require a reason for change Confirm identity requires a username and password for every action Not required by regulations Some companies like it 2013 Waters Corporation 57

58 Traceability - Linking Information to Records Sample Sets Standards used for Calibration Original Processing Method Original Instrument Method Unique Result Calibration Curves Unchanged Raw Data File E-cord information LC/GC System Used Product Code/ Stage Reagent LIMS ID Who Collected Who Processed Who Reviewed Who Approved When What Why 2013 Waters Corporation 58

59 Reviewing Audit Trails: A New tool in FR2 Designed to make the requirement to review Audit trails simpler Launched from Review Brings into one window audit records from Project window Manual results Method changes o Processing, Instrument, Sample Set (alter sample) and Method Set o Allows multiple methods to be compares Compares results from superceded results Where results have been reprocessed Compares Areas, RT, Amount etc between two results 2013 Waters Corporation 59

60 Enhanced Data Review New Result Audit Viewer(RAV) 2013 Waters Corporation 60

61 Configuring for Electronic Signatures 2013 Waters Corporation 61

62 Electronic Signatures in Empower Applied to Reports to mimic the paper based process Set appropriate system policies Designed based on regulatory requirements Designed based on customer feedback 2013 Waters Corporation 62

63 Managing Data 2013 Waters Corporation 63

64 Managing closed projects Once a project is closed do you Archive and delete the project? Archive and leave the project live for further processing? Archive and secure the project from further data acquisition (i.e. process only)? Archive and lock the project from any further activity (i.e. read only)? Leave the project live for a further month before archiving and removing? Leave the project live (or locked) and never archive it? Move the live project to another location? 2013 Waters Corporation 64

65 Securing Completed Projects Project Lock or changing Project Access 2013 Waters Corporation 65

66 Archival Provide a mechanism to save e-records and their metadata for future reference/access Periodically archive data (projects) to secondary media: Tape is not recommended for long term storage o 4-5 year lifetime CD or DVD used to be common Mostly using hard drives o Local standalone (Kit available to backup /archive workstations) o Network drives backed up by corporate o Cloud Drives??? 2013 Waters Corporation 66

67 Use of an Archive Empower Database Preserves the links to all the different types of meta data Sample sets, cal curves, QC controls, Stds, Systems, System Suitability results Ensures data is automatically updated to the same version of software being used in Production Very quickly retrieved Preserved the original results but can be reprocessed if required Database Server Move complete projects older than 6 months Archive Server Same version of Empower, limited users 2013 Waters Corporation 67

68 Archiving Projects Sample Instruments Raw Data Empower Data System Automated & manual archiving of Empower projects in EDM Raw data, processed data and final results are captured in the project Project archive contains all these data Reports & Results Archive Project 2013 Waters Corporation 68

69 Archiving Reports Sample Instruments Raw Data Manual & automated print of reports into SDMS Empower Data System Simply review and Sign off for non Empower users Enables fast integration to alternative applications (eg LIMS or ELN) Reports & Results Archive Project 2013 Waters Corporation 69

70 Validation and Qualification 2013 Waters Corporation 70

71 You Cannot Just Buy a Compliant System Compliance Ready Software Software designed with compliance in mind Full audit trail Easy set up in system policies Easy to retrieve/view off-line 2013 Waters Corporation 71

72 Do you need to validate if you buy a compliant system? YES 2013 Waters Corporation 72

73 Double V Model from GAMP Good Practice Guide: Testing 2013 Waters Corporation 73

74 Topics to Consider for URS for Validation Security Including Part 11 requirements Administration Management tasks Backup /recovery, archiving, legacy data Dealing with upgrades Instrument Control Sample Sequences Processing Integration, Calibration, Quantitation, further processing Reporting 2013 Waters Corporation 74

75 GAMP 5 Leveraging Supplier Involvement Maximize supplier involvement throughout the system life cycle Leverage knowledge, experience and documentation Subject to satisfactory supplier assessment Supplier input may be used for the creation of Functional specifications System configuration Testing Support Maintenance Planning should determine how best to use supplier documentation Including existing test documentation Avoid wasted effort and duplication Assess for suitability, accuracy and completeness 2013 Waters Corporation 75

76 Compliance and Validation Services Regbio Compliance Services Offerings System Requirements Specification Legend Vendor Audit Analytical Instrument Qualification Planning Analytical Systems Specification Installation Qualifcation Extended Software Qualification Installation/ Qualification Routine Compliance Services Routine OQ/PQ Core CSV Service Extended Qualification Extended CSV Service Reporting/ Release 2013 Waters Corporation 76

77 Compliance around the Application: Other Policies and Procedures 2013 Waters Corporation 77

78 Training Procedures Document that all users have received appropriate training Should include Lab users (scientists) Managers QA Reviewers IT / Network Support Engineers Instrument Engineers Validation Specialists Consultants If applicable training should include knowledge of 21 CFR Part 11 and the legal implication of Electronic Signatures 2013 Waters Corporation 78

79 Change Control SOP Changes to system Risk assessment of the change Performance tests Actual impact of changes How documentation should be updated Training updated Consider how to deal with different categories of change: Configuration Changes (Policies / User Types / SOP updates) Microsoft or Empower Hotfix New instrument driver Empower Service Release New Version of Empower 2013 Waters Corporation 79

80 Disaster Recovery SOP Plan for data integrity in case of: Power Interruption/Spike Flood Fire Major Storm Protest/sabatoge Plan data storage areas on/off site Results of annual disaster recovery drill Consider use of High Availability solutions o RAC, DataGuard, Oracle FailSafe Emergency Workgroup or Personal Systems 2013 Waters Corporation 80

81 Backup Define and test a strategy to recover in the event of a disaster Tape is one mechanism o Tapes will wear out o Test backups Now often to hard disk storage or Cloud? Validating and Testing this is key Oracle Hot and Cold Back up Archive Log files Ensure you talk to Waters to Set this up correctly 2013 Waters Corporation 81

82 Empower 3 Compliance for an FDA audit Inspectors want to see that you have implemented the controls that Empower provides for you Unique Usernames for audit trails Default strings for reasons WHY you change objects Password expiry and history Limited access to delete objects in the database Outside Empower procedures are as important Training Daily Backup of data Long Term Archiving Validation of the entire system, including software to demonstrate fit for intended use based on a clear URS is a key aspect Including a clear Change Control procedure 2013 Waters Corporation 82

83 Thank you! 2013 Waters Corporation 83