Improve Data Integrity Practices

Improve Data Integrity
Practices through Real-Life

Examples
IVT Data Integrity Validation
Conference
August 18, 2016
www.QACVConsulting.com 1
Objectives
• How are data integrity issues identified?
• What mechanisms can be established to
prevent data integrity issues?
• How to identify and implement mitigation
measures to reduce or eliminate risks?
Prevent & Detect Data Integrity
Issues
FDA expects that data be reliable and
accurate. CGMP regulations and guidance
allow for flexible and risk-based strategies to
prevent and detect data integrity issues.
Firms should implement meaningful and
effective strategies to manage their data
integrity risks based upon their process
understanding and knowledge management
of technologies and business models.
Current Regulatory Requirements
and Guidance
September
March 2015 2015
April 2016
• MHRA - • WHO - • FDA – Data

GMP Data Guidance on Integrity
Integrity Good Data Guidance
Definitions and Record and
and Management Compliance
Guidance for Practices with CGMP
Industry
Current Regulatory Requirements
and Guidance
July 2016 August 2016 August 2016
• MHRA - GxP • PIC/S - Good • EMA – Data

Data Integrity Practices for Integrity
Definitions Data Guidance
and Management Q&A
Guidance for and Integrity
Industry in Regulated
GMP/GDP
Environments
Data Integrity
What is data integrity and what

does it mean to you?
ALCOA
Data Integrity
 Completeness, consistency, and accuracy of
data.
 Attributable
 Legible  Enduring
 Contemporaneous  Complete
 Original (or true copy)  Consistent
 Accurate  Retrievable
Data – Key Considerations
Data Integrity
Data Availability
Data Retention
What is Data?
•Define data for each system, including each file type.
Chromatography Systems
• Raw Data File
• Integration Parameters
• Quantitation
• Sequence File
Other Laboratory Instruments

• Raw Data File
• Separate Audit Trail Log
MHRA Guidance - Data
Raw Data (Source Data)
 Original records, retained in the format in
which they were originally generated, or as a
‘true copy’. Raw data must be
contemporaneously and accurately recorded
by permanent means.
 The definition of ‘original records’ currently
varies across regulatory documents. By its
nature, paper copies of raw data generated
electronically cannot be considered as ‘raw
data’.
MHRA Guidance - Data
Original record
 Data as the file or format in which it was originally
generated, preserving the integrity (accuracy,
completeness, content and meaning) of the record,
e.g. original paper record of manual observation, or
electronic raw data file from a computerised system
True Copy:
 A copy of original information that been verified as an
exact (accurate and complete) copy having all of the
same attributes and information as the original. A true
copy may be retained in a different electronic file
format to the original record, if required, but must
retain the equivalent static/dynamic nature of the
original record.
FDA Guidance
•It is not acceptable to record data on pieces of paper

that will be discarded after the data are transcribed to a
permanent laboratory notebook.
Similarly, it is not acceptable to store data electronically

in temporary memory, in a manner that allows for
manipulation, before creating a permanent record.
Electronic data that are automatically saved into

temporary memory do not meet CGMP documentation
or retention requirements.
Data Lifecycle
Review / Retain /
Generate Modify Use Destroy
Approve Retrieve
8/23/2016 www.QACVConsulting.com 13
Data Integrity Considerations
FDA Guidance
Key Points
• Define “data” and how it is used
• Static vs dynamic
• Metadata and audit trails
• Review of electronic records
• Validation
• Operation and use of systems
• Reporting and Retention
• Handling of Data Integrity Issues
FDA Guidance
Static & Dynamic Records
Static
• Fixed-data document such as a paper record or an electronic
image.
Dynamic
• Format that allows interaction between the user and the record
content.
• Chromatographic Record
• Allows user to change the baseline.
• Reprocess chromatographic data.
• Resulting peaks may appear smaller or larger.
• Spreadsheet
• User modification of formulas or entries used to compute test
results.
FDA Guidance
Static & Dynamic Records
Review / Retain /
Approve Retrieve
Acceptability of retaining paper printouts or static records

instead of original electronic records from stand-alone
computerized laboratory instruments?
Control strategies must ensure that original laboratory

records, including paper and electronic records, are
subject to second-person review to make certain that all
test results are appropriately reported.
Static / Dynamic Data
FDA Guidance
System Suitability: %RSD < 2.0%
%RSD 3.9%
X

FDA Guidance
Audit Trails
Review / Retain /
Approve Retrieve
Audit trails that capture changes to critical data

be reviewed with each record and before final
approval of the record.
FDA recommends routine scheduled audit trail

review based on the complexity of the system
and its intended use.
FDA Guidance
Audit Trails - Finding
•Upon review of the audit trail configuration within
LIMS, audit trails were turned off for many of the
tables within the XXX Module.
Documentation was not available to justify why the

audit trails for these tables was turned off. For
example,
• The audit trail was not turned on for the XXX table, which is used
when jobs, such as stability time pulls, are cancelled or suspended.
• This was observed by reviewing the audit trail configuration within
the system.
• Audit trail configuration is documented within Design specification,
XXX, YYY, version 2.0, approval date 11-Mar-2016.
Data Lifecycle
Review / Retain /
Approve Retrieve
Specify
Design
Configure Validation
Verify
How can network controls impact
GxP Processes?
Non-Standard
Build
“Standard Build”
X
• Date/time stamp controls
• Network backup
• Access controls
• Audit logs not backed up
• User access not controlled
Data Integrity
ELISA Data Process Flow
ELISA SOftware Company Network LIMS
Protocol
(.xyz file)
Setup Run
Secure
.db File
Sample Network
archived
Analysis Location
Secure
Data Flow
Data File Save .db Data

Network
(.db file) File
Location
.db File backed Backup

up Location
Secure
Export .txt
Network
Data File
Location
.txt File backed Import .txt file LIMS

up to LIMS Database
Data Lifecycle
Review / Retain /
Approve Retrieve
Specify
Design
Configure Validation
Verify
MHRA Guidance
Terms and Definitions
Validation
• Comply with EU GMP Annex 11.
• Requires an understanding of the computerised
system's function within a process.
• The acceptance of vendor-supplied validation data
in isolation of system configuration and intended
use is not acceptable.
• In isolation from the intended process, vendor testing
is likely to be limited to functional verification only, and
may not fulfil the requirements for performance
qualification.
26 www.QACVConsulting.com 26
FDA Guidance
Workflows
Validation of “workflows”
• A workflow, such as creation of an
electronic master production and control
record, is an intended use of a computer
system to be checked through validation.
• If you validate the computer system, but
you do not validate it for its intended
use, you cannot know if your workflow
runs correctly.
Data Integrity
Vendor Supplied Validation Documentation
Approval of Records
• Internal assessment of Stability LIMS
• Vendor Supplied Documentation Provided
• User Requirements Specification
• User Acceptance Test
• URS – Included statement “the system has a ‘configurable option’
for ….. electronic signatures”.
• Requested configuration specification – none available
• Reviewed configuration within system – esigs turned off
• Requested system demonstration – approval by pressing approve button
• Reviewed UAT documentation – esigs functionality passed
• First step of test – turn on esig functionality
• Last step of test – turn off esig functionality
• Record integrity issue – lack of approved stability protocols
FDA Guidance
Controls to manage risks – understand your
data flows
Material
Weight
FDA Guidance
Electronic Signature
ALCOA
Attributable
EDC System
• Issue – system response is slow at times
• Cause – batch jobs being run cause slow system response
• Type of batch jobs? Principle Investigator approval of eCRFS
• How long of a delay? 2-3 hours, sometimes next day
• What date/time is applied for electronic signature?
• Answer: When batch is run.
• Data integrity issue – date and time stamp is not the same as
when PI entered electronic signature user ID and password.
MHRA Guidance
MHRA Guidance
Data Lifecycle
The eClinical Forum and PhRMA EDC Task Group
Electronic Signature Issue
EDC Issue
• System demonstration requested
• Review administrative functions
• Principal Investigator eCRF Signature Page signed by PI
• No Principal Investigator Role in System
• No electronic signature functionality within system
• Requested audit trail for eCRF Page
• Data Entry personnel entered PIs signature onto page
• Requested audit trail for Principal Investigator
• Principal Investigator logged into system one time in 2009
• Study was initiated in 2014
• Principal Investigator is responsible for accuracy of data
• GCP compliance and data integrity issue
Data Integrity Issue
EDC Issue
• EDC system included “parent-child” records
• Used for concomitant medications and adverse events
• After Source Document Verification and PI sign off locking
data additional medications or AE follow-ups were able to be
added to system as child records
• System design and functionality issue
• Required unlocking of database and additional SDV and PI signoff
• Impacted accuracy and completeness of clinical data
• No data had been submitted to FDA
• GCP compliance and data integrity issue
Data Migration - Data Integrity
Issue
Safety Systems
• Outsourced Pharmacovigilance Vendor
• Notified customers of upgrade for drug safety system to
newer version of system.
• Required migration of data from old version to new version
• Vendor halted migration process
• Data was lost during migration process
• Data integrity issue for safety data
Data Changes - Data Integrity
Issue
REMS Issue
• REMS vendor received many requests for data changes from
pharmacies, physicians, etc.
• REMS system was not mature to include data change
capabilities within application.
• Data changes had to be made through database backend.
• Pharmacies and physicians were instructed to submit help desk tickets to
REMS vendor to request data changes.
• No justification or rationale was provided.
• Help Desk tickets were not approved.
• Over 5000 requests for data changes in 7 years
• Data Integrity Issue
•Backup
FDA Guidance and
Restore
Disaster
Recovery
Review / Retain /
Approve Retrieve
Finding
• The site DRP plan has not been tested.
• Disaster recovery plans do not guarantee recovery
time objectives (RTO) that allow compliance with
FDA requirements, such as safety reporting or
recall.
• The DRP allows for a 10 day RTO, which does not
meet FDA requirements for safety reporting and
would not allow for timely recall processes.
Data Integrity Issue
Backup and Restore
• Bioanalytical Laboratory
• Backup and Restore SOP
• Failed backup required a help desk ticket
• 3 failed backups require notification to Director of
Infrastructure Technology
• 5 failed backups require notification to CTO
• Requested backup logs for three months
• No successful backups for June or first two weeks of July
• No help desk tickets generated for month of June
• Director and CTO were not notified
• Director and CTO were not aware of failuers
• Potential Data Integrity Issue
FDA MedSun Reports
The time on the meter read ~3 hours ahead of

time. When the physician read the results, the
results indicated the glucose levels had gone
down (due to the incorrect reading on the
meter). The meter clock stops when the meter
is turned off. When the meter is turned on
again the clock starts, giving an incorrect time
stamp.
FDA MedSun Reports
The system locks up during patient care documentation at
the "save" function. The system locks up only at the save
function, allowing RNs to continue to document critical
patient data only to discover at the end of the case, that
no data will save. In order to get out of the patient chart,
the computer must be re-booted. All patient
documentation is lost. Nurses are forced to do their best
guess as to surgical times, implants, medications, etc
and re-chart the entire document.
This ongoing software program leaves us in a difficult
position - due to the risk of data loss.
Summary
• Understand data flows and data lifecycle
processes.
• Identify and mitigate potential data
integrity risks.
• Ensure adequate and robust validation,
security, and other data integrity controls
are established to minimize data integrity
risk.
Contact Information
Chris Wubbolt
QACV Consulting, LLC
www.QACVConsulting.com
Telephone: 610-442-2250
E-mail: chris.wubbolt@QACVConsulting.com

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Improve Data Integrity Practices

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Available Formats

Improve Data Integrity

Practices through Real-Life

• MHRA - • WHO - • FDA – Data

July 2016 August 2016 August 2016

• MHRA - GxP • PIC/S - Good • EMA – Data

What is data integrity and what

Other Laboratory Instruments

•It is not acceptable to record data on pieces of paper

Similarly, it is not acceptable to store data electronically

Electronic data that are automatically saved into

Acceptability of retaining paper printouts or static records

Control strategies must ensure that original laboratory

System Suitability: %RSD < 2.0%

Audit trails that capture changes to critical data

FDA recommends routine scheduled audit trail

Documentation was not available to justify why the

ELISA SOftware Company Network LIMS

Data File Save .db Data

.db File backed Backup

.txt File backed Import .txt file LIMS

The eClinical Forum and PhRMA EDC Task Group

The time on the meter read ~3 hours ahead of

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