Improve Data Integrity Practices through Real-Life · PDF fileImprove Data Integrity Practices through Real-Life ... Backup Locat ion. ... The eClinical Forum and PhRMA EDC Task Group

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


March 2015

• MHRA -GMP Data Integrity

Definitions and

Guidance for Industry

September 2015

• WHO -Guidance on Good Data and Record

Management Practices

April 2016

• FDA – Data Integrity

Guidance and

Compliance with CGMP

Current Regulatory Requirements

and Guidance


July 2016

• MHRA - GxPData Integrity

Definitions and

Guidance for Industry

August 2016

• PIC/S - Good Practices for

Data Management and Integrity in Regulated GMP/GDP

Environments

August 2016

• EMA – Data Integrity

Guidance Q&A

Data Integrity


What is data integrity and what

does it mean to you?

ALCOA


Data Integrity Completeness, consistency, and accuracy of

data.

Attributable

Legible

Contemporaneous

Original

Accurate

Enduring

Complete

Consistent

Retrievable

(or true copy)


Data Integrity

Data Availability

Data Retention

Data – Key Considerations

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.

8/23/2016 www.QACVConsulting.com 13

Data Lifecycle

Generate ModifyReview / Approve

UseRetain / Retrieve

Destroy

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 GuidanceStatic & 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 GuidanceStatic & Dynamic Records


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.



Destroy

Static / Dynamic Data


FDA Guidance


System Suitability: %RSD < 2.0%

%RSD 3.9% X

FDA GuidanceAudit Trails


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.



Destroy

FDA GuidanceAudit 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



Destroy

Specify

Design

Configure

Verify

Validation


“Standard Build”

• Date/time stamp controls

• Network backup

• Access controls

How can network controls impact

GxP Processes?

Non-Standard

Build

X

• Audit logs not backed up

• User access not controlled

Data Integrity


ELISA Data Process Flow

Data

Flow

LIMSELISA SOftware Company Network

Protocol(.xyz file)

Sample Analysis

Setup Run

Data File(.db file)

Export .txt Data File

Secure Network Location


Save .db Data File

.db File backed up

.txt File backed up

LIMS Database

Import .txt file to LIMS

.db File archived


Backup Location


Data Lifecycle



Destroy

Specify

Design

Configure

Verify

Validation

26

Validation

• Comply with EU GMP Annex 11.

• Requires an understanding of the computerisedsystem'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.

MHRA GuidanceTerms and Definitions


FDA GuidanceWorkflows


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.

28

Data Integrity Vendor Supplied Validation Documentation


Approval of Records

• Requested configuration specification – none available

• 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”.

• Reviewed configuration within system – esigs turned off

• Reviewed UAT documentation – esigs functionality passed

• Record integrity issue – lack of approved stability protocols

• First step of test – turn on esig functionality

• Last step of test – turn off esig functionality

• Requested system demonstration – approval by pressing approve button


FDA GuidanceControls to manage risks – understand your

data flows

Material

Weight

FDA GuidanceElectronic Signature


ALCOAAttributable

EDC System

• How long of a delay? 2-3 hours, sometimes next day

• 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

• 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.

31


31 www.QACVConsulting.com 31

32


32 www.QACVConsulting.com 32

Data Lifecycle


The eClinical Forum and PhRMA EDC Task Group

Electronic Signature Issue


EDC Issue

• Principal Investigator eCRF Signature Page signed by PI

• System demonstration requested

• Review administrative functions

• No Principal Investigator Role in System

• No electronic signature functionality within system

• Principal Investigator logged into system one time in 2009

• Study was initiated in 2014

• Requested audit trail for eCRF Page

• Principal Investigator is responsible for accuracy of data

• Data Entry personnel entered PIs signature onto page

• Requested audit trail for Principal Investigator

• GCP compliance and data integrity issue

Data Integrity Issue


EDC Issue

• 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

• EDC system included “parent-child” records

• Used for concomitant medications and adverse events

• No data had been submitted to FDA

• System design and functionality issue

• Required unlocking of database and additional SDV and PI signoff

• Impacted accuracy and completeness of clinical data

• GCP compliance and data integrity issue

Data Migration - Data Integrity

Issue


Safety Systems

• Notified customers of upgrade for drug safety system to

newer version of system.

• Required migration of data from old version to new version

• Outsourced Pharmacovigilance Vendor

• Vendor halted migration process

• Data was lost during migration process

• Data integrity issue for safety data

Data Changes - Data Integrity

Issue


REMS Issue

• REMS system was not mature to include data change

capabilities within application.

• REMS vendor received many requests for data changes from

pharmacies, physicians, etc.

• Help Desk tickets were not approved.

• 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.

• Over 5000 requests for data changes in 7 years

• Data Integrity Issue

FDA Guidance


•Backup and

Restore

Disaster Recovery

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.



Destroy


Backup and Restore

• 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

• Bioanalytical Laboratory

• No help desk tickets generated for month of June

• No successful backups for June or first two weeks of July

• Director and CTO were not aware of failuers

• Potential Data Integrity Issue

• Requested backup logs for three months

Data Integrity Issue

• Director and CTO were not notified

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 ReportsThe 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.

Chris Wubbolt

QACV Consulting, LLC

www.QACVConsulting.com

Telephone: 610-442-2250

E-mail: [email protected]

43

Contact Information

www.QACVConsulting.com

Documents

Improve Data Integrity Practices through Real-Life · PDF fileImprove Data Integrity Practices through Real-Life ... Backup Locat ion. ... The eClinical Forum and PhRMA EDC Task Group