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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
GxP, e-raw data and e-archive – QA perspective GIQAR
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AGIT GUIDELINES
PIC/SGUIDELINE
ELECTRONIC DATA DEFINITIONS
MHRAGUIDELINE
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
GxP, e-raw data and e-archive – QA perspective GIQAR
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ELECTRONIC DATA MANAGEMENT
GxP, e-raw data and e-archive – QA perspective GIQAR
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
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
GxP, e-raw data and e-archive – QA perspective GIQAR
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OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
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
GxP, e-raw data and e-archive – QA perspective GIQAR
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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.
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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.
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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.
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
«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).
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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.
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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REQUIREMENTS FOR THE ARCHIVING OF ELECTRONIC RAW DATA
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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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REQUIREMENTS FOR THE ARCHIVING OF ELECTRONIC RAW DATA
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
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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.
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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)
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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THE PROCESS WE ARE WORKING ON, SHOULD GRANT:
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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).
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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?
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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?
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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?
OUR EXAMPLE IN USING AN HPLC-UV/VIS SYSTEM
GxP, e-raw data and e-archive – QA perspective GIQAR
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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
GxP, e-raw data and e-archive – QA perspective GIQAR
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
GxP, e-raw data and e-archive – QA perspective GIQAR
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FEEDBACK FROM ROUND TABLE IN ROME:DEEP DISCUSSIONS – GREAT BRAINSTORMING SESSIONS
GxP, e-raw data and e-archive – QA perspective GIQAR