GXP, E-RAW DATA AND E-ARCHIVE – QA … · The Ivrea Test Facility paperless project GxP, ... 12...

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Dott.ssa Ilaria EnriettoRBM SpA – Merck BiopharmaParma - May 18th 2016

GIQAR

Feedback of GxP & Electronic Archive Round Table (March 21st 2016)

GXP, E-RAW DATA AND E-ARCHIVE –QA PERSPECTIVE

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HOW THE PROGRESS TOUCHED OUR TECHNOLOGIES AND ABOVE ALL OUR MINDSET

GxP, e-raw data and e-archive – QA perspective GIQAR

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HOW THE PROGRESS TOUCHED OUR TECHNOLOGIES AND ABOVE ALL OUR MINDSET

From theory to practice: our experience in using an HPLC-UV/VIS system

Moving from paper-based to electronic data

The Ivrea Test Facility paperless project


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AGIT GUIDELINES

PIC/SGUIDELINE

ELECTRONIC DATA DEFINITIONS

MHRAGUIDELINE


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ELECTRONIC DATA DEFINITIONS

Electronic record: All original laboratory recordsand documentation, including data directly enteredinto a computer through an instrument interface,which are the results of original observations andactivities in a study and which are necessary for thereconstruction and evaluation of the report of thatstudy.

Metadata: Data that describe the attributes of otherdata. Most commonly these are data that describethe structure, data elements, inter-relationships andother characteristics of electronic records.

OECD GLP AdvisoryDocument n. 15

Establishment andControl of Archivesthat Operate inCompliance with thePrinciples of GLP


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ELECTRONIC DATA MANAGEMENT


Life cycle approach to validation/operation of CS

Risk Management as central element on validation process

Data integrity concept and physical/logical security

Fit for purpose intent of usage of CS

Differentiation within qualification and validation concepts

Defined roles and responsibilities (e.g. TFM, SD, QA)

Access privilegies and corresponding training

SLA regulating the agreements between suppliers and Test Facilities

COTS validation depending on risk and complexity of customisation

Change control procedures and configuration control

Data migration concept (data conversion – upgrades – migration to other medium)

Interfaces and corresponding tests

Accuracy checks on data entered manually into electronic systems

Audit trail – incident management

Periodic review

Electronic signatures

E-Archiving GLP OECD Advisory Doc. N.15

Business Continuity and Disaster Recovery

What is new in the GLP OECD Advisory Doc n.17?

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COMPLIANCE FRAMEWORK

21 CFR Part 11

GAMP 5

Annex 11

PIC/S GUIDELINE

AGIT GLP GUIDELINES

GLP OECD Advisory

Document n.17 CS

FDA

MHRA


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OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM

2010: HPLC used in the Formulation Department in order to perform test itemconcentration analysis, formulation stability and homogeneity studies,validation of analytical methods for quantitative and qualitative analyses

2016: the scope is the same as in the past

WHAT HAS BEEN CHANGED?

We will not underline technologic changes in the system, but we will focus on main changes of its usage and data definition/management


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2010:

The system we are referring to is an HPLC system with a ChemStation management software which allows dataacquisition and basic data evaluations using modules for method and run controls, data analysis module for elaboratingacquired data and report layout module. The HPLC system has 2 different accesses for operator (access for performingthe analysis) and manager (access for performing, reviewing, elaborating and reporting results) according to thedifferent required privilegies. Raw-data and metadata are all locally and temporally stored in the systems itself. There isNO electronic archive in place, the capability of the internal memory is low.

All raw-data considering chromatograms, metadata related to set up/calibration/audit trail, derived data from peackintegrations or elaborations performed in excel file sheets are printed and inserted in the paper study folder


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2016:

The system we are reffering to is OpenLAB CDS ChemStation Edition which provides tools for HPLC dataacquisition, analysis and interpretation monitoring instrument parameters, creating the defined methods,generating and printing (if needed) reports and exporting data to the archived system.

As in workstation or networked workstation configurations, the instrument configuration dialog runs on the local PC.A central data storage system can hold all kinds of electronic data independent of any proprietary data formats.



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2016:WHAT HAS BEEN CHANGED THANKS TO THE ADVANCED TECHNOLOGIES

Raw data are stored together in the OpenLAB Data Store (centralized data management) partition withalso all metadata including sample information, data analysis method, chromatographic signals,instrument conditions and above all the audit trail.

All ChemStation methods, sequence templates, report templates, and data files (sequences and singleruns) are uploaded to the file share partition of the virtual server which is identified as GxP Archive.Data can later downloaded back into the ChemStation if required.

With Secure Workstation for OpenLAB CDS ChemStation Edition ChemStation and Data Store are installedtogether on a single workstation computer.

AUDIT TRAIL The transactions that occur during the analysis, including accesses, changes,any errors and the instrument conditions (such as flow, temperature, pressure and solventcomposition for liquid chromatographs) from the start to the end of the analysis are alwaysrecorded and then extracted with every data file. The file includes a review scheme thatindicates if data has been reprocessed. This is an uneditable binary format that ensures theoriginality of the results.



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2016: LOOKING CAREFULLY AT THE AUDIT TRAIL

«Audit Trails need to be availabe and convertible to ahuman readable form and regularly reviewed. Anychange to e-records must not obscure the original entryand be time and date stamped and traceable to theperson who made the change. Audit trail for a CS shouldbe enabled, appropriately configured and reflect the rolesand responsibilities of study personnel. The ability tomake modifications to the audit trail settings should berestricted to authorised personnel. Any personnelinvolved in a study (GLP SD, head of department,analysts) should not be authorised to change audit trailsettings. A system should be in place that ensures a risk-based review of the audit trail functions, its settings andrecorded info GLP QA personnel should be involved».

OECD GLP Advisory Document

Application of the GLP Principles to Computerised Systems n.17



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ACCESSES AND PRIVILEGIES IN THE WORKSTATION

UNIQUE COMBINATION BETWEEN

USERNAME AND PASSWORD FOR EACH EMPLOYEE

Defined rules for psw complexity

Expiry timeframe

Auto log-ff and 3

tentatives max

Administrator

Supervisor

Analyst



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DISASTER RECOVERY PLAN AND BUSINESS CONTINUITY PLAN

All data (primary data – derived data – metadata – audit trail in the original form and in PDF) whichhave been automatically saved after every step on the Workstation itself, are backupped automaticallyeveryday on a dedicated partition of the GxP file share automatically, used as backup folder.

The file shares are controlled accesses partitions where ONLY authorized personnel can have definedpermissions (read or write permission). All permissions list can be checked immediatly by the applicationsor on the server logbooks.

If necessary, data can be retrieved by the backup folder.



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DATA MANAGEMENT

Using a dedicated copy script, after every acquisition the result set containing all data (primary data, derived data,metadata, audit trail in the original form and in PDF) is automatically saved on the server (GxP file share Archive)in the dedicated Data Management folder.

Each folder is identified as «Name of the server / Data / Instrument ID / QUALITY STANDARD / Study Number».

All elaborations (integration, quantification, review, recalculation, elaborations performed on validated Excel files) arealso trackable and saved on the server.

GLP OECD Advisory Doc. Application of GLP Principles to CS n.17


«Raw data: Measurable or descriptive attribute of a physical entity, processor event. The GLP Principles define raw-data as all laboratory records anddocumentation, including data directly entered into a computer through anautomatic instrument interface, which are the results of primaryobservations and activities in a study and which are necessary for thereconstruct and evaluation of the report of that study.

Derived data: They depend on raw-data and can be reconstructed from raw-data (e.g., final concentrations as calculated by a spreadsheet relying onraw-data, result tables as summarised by a LIMS, etc).


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DATA APPROVAL AND QA AUDIT

Final draft data (primary data – derived data – metadata – audit trail in the original form and in PDF)after having been consolidated and approved on Chemstation by the Administrator, are completely«frozen» in the system and then they are manually saved by e-archivist on a dedicated subfolder on theserver partition for QA audit related to the draft study report and corresponding data.

WHO WHAT

WHEN WHY

AU

DIT

TR

AIL I

NFO

QA



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DATA ARCHIVING

After QA audit and study report signature, the Study Director is responsible of granting the archive of the studyconsidering either paper and electronic data. Both processes are managed in parallel by the Archivist and e-Archivist.

Final data (primary data – derived data – metadata – audit trail in the original form and in PDF) are archived by e-archiviston a dedicated folder on the server partition which is identified according to the following folder path: «Name of the server –ARCHIVE – Instrument ID – QUALITY STANDARD – Study Number»

E- ARCHIVIST is the only one with writing access to the folder, just for the time of trasferring the data in the archivedfolder.When the study has been electronically archived, the e-archivist signs a dedicated paper Archive History report that has tobe sent to Study Director for confirmation and then sent to the GxP paper-archive for tracking all types ofdocuments/data/specimens archived for that study.

Every change on the archived folder is detectable by the internal audit trail of the folder itself, where all entries/changesare recorded. All other approved accesses can only have «read» permission.

The study can be de-archived ONLY if the requests comes from TFM (e.g. For HA Inspectors requests) and only havingrecorded TFM de-archiviation approval on a dedicated form sent via mail.



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REQUIREMENTS FOR THE ARCHIVING OF ELECTRONIC RAW DATA

INTEGRITY OF ARCHIVED ELECTRONIC RAW DATA

AVAILABILITY OF ELECTRONIC RAW DATA

LONG TERM ARCHIVING



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THE ROLE OF THE QA IN THE ARCHIVING PROCESS

QA audits all aspect of archiving

Audit to archiving procedure

Roles and responsibilities

and relative personnel access

Study archiving process and

archived studies

Electronic archives and IT Infrastructure



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THE ROLE OF THE QA IN THE ARCHIVING PROCESS

TRAINING

•Specific technical training in order to letthe auditor understand CS functionalitiesand data management

ACCESS

•QA with read access to all systemscointaining electronic raw data

UPDATES

•Be always «future oriented» in order tofollow innovations



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BACKUP AND RESTORE OF THE SERVERS

Server backups are managed according to local SOP everyday and automatically.

QUALIFIED INFRASTRUCTURE composed either by physical servers and virtual servers.

The virtualization platform is composed by a NETAPP storage system composed by 2 physical units. The firstNETAPP which includes virtual servers (containing also GxP File Server defined as GxP electronic Archive) isbackuped LOCALLY (SNAPVAULT) on the second NETAPP and, for Site specific disaster recovery plan and inagreement with Global Corporate Policies, the second NETAPP is replicated (SNAPMIRROR for files) to theDatacenter of the Main HUB of our Company.

Accesses to the Backup systems are only ALLOWED to IT local personnel.

Data restore (e.g. for local data deletion) can be asked to local ITonly following a procedurized process which grant the traceabilityof each step, also for the restore one.

Server restore test have been performed in the OQ phase of thevalidation process and repeated and tested during periodic review.



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QUALIFIED INFRASTRUCTURE DESIGN

The RBM Infrastructure is composed by:

Network (VLAN, racks and switches, routers,firewalls, Wi-Fi access points)

Servers (physical and virtual)

Clients (Merck Biopharma standard clients and non-standard clients)

Printers

Server Room with Anti-fire system, environmentalconditioning control system, access control systemand intrusion prevention system with alarms

IT Infrastructure software tools (e.g. Jenny Portal,LANDesk Management Suite, Push-Portal, SpectrumOneClick for Infrastructure)



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THE PROCESS WE ARE WORKING ON, SHOULD GRANT:



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DATA INTEGRITY CONCEPT

Data Integrity means the degree to which acollection of DATA is complete, consistent andaccurate:

Good Documentation Practices are followed;

Content of Data is trustworthy and reliable(data is valid).



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DATA INTEGRITY CONCEPT

MHRA: All phases in the life of data from initial generation and recording through processing

(including transformation or migration), use, data retention, archive / retrieval anddestruction(MHRA GMP Data Integrity Definitions and Guidance for Industry; March 2015)

Are data (paper and electronic)created/documented following GoodDocumentation Practice?

Are there processes/systems in place toensure data integrity across the entireData Life Cycle?

Is there Quality Management &Governance in place to promote DataIntegrity?



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HOW TO ASSURE DATA INTEGRITY

Key questions to consider when defining riskmitigation strategies (BUSINESS questions):

Do I have all my data?

Am I reviewing all my data?

Has my data been objectively processed?

Am I reporting all my data?



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THE WORK OF QA IN DATA INTEGRITY PERSPECTIVE

Do we include data integrity aspects in our audits?

Do we review the right data (and metadata) when preparing for /performing audits?

Are our auditors adequately trained on the electronic systems to allow aneffective review of original data?

Do we assess quality management systems of vendors for data integrityaspects when performing vendor audits?

Are data integrity risks reflected in our risk assessment tools?

Do we include data integrity aspects when preparing for inspections?

Do we prepare auditees for the methodologies used in data integrityinspections?



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WHAT IS NEXT? PAPERLESS PROJECT!

AIM for the ELECTRONIC NOTEBOOK

Supportive documents to study management (study folders) will no more exist in paper but will be managed electronically by a centralized database where all

supportive info will be documented/scanned.

As soon as validation will be completely GxP compliant, ELN project will be extended to GLP environment dedicated implementation plan will be presented to HA


1) ELECTRONIC NOTEBOOK (ELN)

Used in non-regulated environment. Project on going for extending ELN usage in GLP

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WHAT IS NEXT? PAPERLESS PROJECT!

All Computerised systems will be assessed by selected external SME.

A dedicated gap analysis will be performed in order to identify main areas of improvements

A dedicated checklist will be compiled with all info of each CS.

The project started in GMP enviroment and on June it will be extended to

GLP and GCP Functions

2) DATA INTEGRITY ASSESSMENT

A specific Data Integrity training will be performed by external SME

for Test Facility personnel


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FEEDBACK FROM ROUND TABLE IN ROME:DEEP DISCUSSIONS – GREAT BRAINSTORMING SESSIONS


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THANKS FOR YOUR ATTENTION!

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