Analytical Equipment Analytical Equipment Qualification/ValidationQualification/Validation

Overview PresentationOverview Presentation

Pharmaceutical Pharmaceutical Development Feb Development Feb 20052005

Steve HancockSteve Hancock

Equipment Equipment QualificationQualification

What is it?What is it?

Why is it being Why is it being enforcedenforced

The 4 Q’sThe 4 Q’s

What’s currently What’s currently availableavailable

Equipment Equipment Qualification!! Qualification!!

Another Another regulatory regulatory

hurdle or an hurdle or an assurance of assurance of

correctly correctly performing performing equipment.equipment.

Industry Industry standard not standard not

just just PharmaceuticalsPharmaceuticals

What is it?What is it?

Measuring and testing Measuring and testing equipment having an equipment having an effect on the accuracy effect on the accuracy or validity of tests or validity of tests shall be calibrated shall be calibrated and/or verified before and/or verified before putting into service.putting into service.

The procedure starts The procedure starts with the definition of with the definition of an instrument’s an instrument’s intended use.intended use.

Why is this being enforced?Why is this being enforced?

Regulatory Regulatory requirementrequirement

GMP/GLPGMP/GLP

Quality Quality organisationsorganisations

Audits and Audits and inspectionsinspections

FDA WARNING FDA WARNING LETTERLETTER

1. Written procedures had not been established forthe calibration of analytical instruments andequipment in the Quality Control laboratories usedfor raw material, finished API and stability testing of*******. Furthermore, calibration data and resultsprovided by an outside contractor were not checked,reviewed and approved by a responsible Q.C. orQ.A. official.

FDA WARNING FDA WARNING LETTERLETTER

2. The **** systems 2. The **** systems calibrated by an outside calibrated by an outside

contractor did not include contractor did not include verification of the precision verification of the precision (o/o RSD) of the autoinjector (o/o RSD) of the autoinjector at more than one injection at more than one injection

volume, the flow rate below 1 volume, the flow rate below 1 ml/min, or the wavelength ml/min, or the wavelength

accuracy for the wavelength accuracy for the wavelength regions used for testing of regions used for testing of

*****. In addition, the **** 3 *****. In addition, the **** 3 software programs had not software programs had not been verified or validated.been verified or validated.

FDA WARNING LETTERFDA WARNING LETTER

3. Records and 3. Records and documentation of documentation of instrumental equipment instrumental equipment calibrations and laboratory calibrations and laboratory testing are incomplete in testing are incomplete in that they lacked raw data that they lacked raw data spectra chromatograms, spectra chromatograms, and calculationsand calculations

WHERE IS IT DOCUMENTED?WHERE IS IT DOCUMENTED?

CAPsCAPs 045 VALIDATION OF ANALYTICAL EQUIPMENT045 VALIDATION OF ANALYTICAL EQUIPMENT 015 SYSTEM SUITABILITY TESTING FOR 015 SYSTEM SUITABILITY TESTING FOR

INSTRUMENTAL TECHNIQUESINSTRUMENTAL TECHNIQUES

SOPsSOPs Validation Master Plan Validation Master Plan

(used in Pharm Dev)(used in Pharm Dev)

User Requirement Specification User Requirement Specification (URS)(URS)

The users The users definition of the definition of the performance performance requirements of requirements of the equipment.the equipment.

i.e. What do you i.e. What do you want it to do?want it to do?

Design Qualification (DQ)Design Qualification (DQ)

Confirmation that Confirmation that the manufacturer’s the manufacturer’s specification is specification is appropriate for the appropriate for the prospective prospective purchaser’s usepurchaser’s use

Justifies choice, i.e. Justifies choice, i.e. results of results of evaluationevaluation

DQDQ

DQ CAN BE VERY DQ CAN BE VERY SIMPLE FOR REPEAT SIMPLE FOR REPEAT EQUIPMENT e.g. JUST EQUIPMENT e.g. JUST ANOTHER HPLC ANOTHER HPLC SYSTEMSYSTEM

Installation Qualification (IQ)Installation Qualification (IQ)

documents the documents the installation in the installation in the selected user selected user environment environment

inventory checkinventory check environmental locationenvironmental location facility requirementsfacility requirements assembly assembly powers up?powers up? modules modules

communicate?communicate?

Operational Qualification (OQ)Operational Qualification (OQ)

For testing the For testing the equipment in the equipment in the selected user selected user environment to environment to ensure it meets our ensure it meets our defined functional defined functional and performance and performance specificationsspecifications

Pre-approved Pre-approved before usebefore use

Performance Qualification Performance Qualification (PQ)(PQ)

For testing that the For testing that the system consistently system consistently performs as intended performs as intended for the selected for the selected applicationapplication

Periodic calibration / Periodic calibration / maintenancemaintenance

Method specific Method specific system suitability system suitability checkschecks

CHANGE CONTROLCHANGE CONTROL

A process to document A process to document changes made post changes made post qualificationqualification

Need to make a judgement on Need to make a judgement on what testing is required what testing is required following significant changefollowing significant change

(e.g. repairs, moving)(e.g. repairs, moving) Like for like - no requalification Like for like - no requalification

necessarynecessary

Software Change ControlSoftware Change Control

FirmwareFirmware Firmware is embedded software that Firmware is embedded software that

controls an instrument. Occasionally it controls an instrument. Occasionally it may be necessary to update firmware may be necessary to update firmware in order to fix known bugs or to allow in order to fix known bugs or to allow compatibility with upgraded software. compatibility with upgraded software.

It will be necessary to have a change It will be necessary to have a change control form, but the tests carried out control form, but the tests carried out may be simple, for example a before & may be simple, for example a before & after chromatogram.after chromatogram.

Software Change ControlSoftware Change Control

Equipment Make &Type:

Hewlett Packard G1314A BioMAX # 056432

Current Software Chemstation G2170A Version A.06.04

Operating System N/A VMP Reference PD/TM/99/041

Description of change (Attach extra pages if necessary)

Update EPROM on HP UV detector to be compatible withChemstation Version A.06.04

Tests to include internal checks plus Holmium Oxide calibrationby Agilent technician

System suitability run to be compared before and after upgrade

Software Change ControlSoftware Change Control

SoftwareSoftware Software that runs on a PC and controls the Software that runs on a PC and controls the

instrument function and may carry out instrument function and may carry out calculations. There may be several reasons to calculations. There may be several reasons to change software. In order to fix known bugs, to change software. In order to fix known bugs, to add functionality, or to work with a new computer add functionality, or to work with a new computer operating system. It may also be necessary to re-operating system. It may also be necessary to re-load software in the case of a computer crash.load software in the case of a computer crash.

It will be necessary to have a change control form, It will be necessary to have a change control form, but the tests carried will be proportional to the but the tests carried will be proportional to the changes made.changes made.

Software Change ControlSoftware Change ControlChange Control Form for Computer Controlled Analytical Equipment

Equipment Make &Type:

Hewlett Packard HPLC Systems BioMax 065003

Current Software Chemstation Version A.06.04 & 8.0

Operating System Windows NT VMP Reference PD/TM/99/041

Description of change (Attach extra pages if necessary)

Upgrade operating system on PC to IDE 3.4 with associatedVirus Check Software. Carry out Hewlett Packard SoftwareInstallation Qualification check. System suitability data fromfirst HPLC run will be used for Equipment Qualification.

Testing will cover the following instruments, BioMax numbers 064998,064970

RETROSPECTIVE VALIDATIONRETROSPECTIVE VALIDATION

FOR EQUIPMENT IN FOR EQUIPMENT IN EXISTENCE PRIOR TO A EXISTENCE PRIOR TO A FORMAL QUALIFICATION FORMAL QUALIFICATION PROCESS BEING ISSUEDPROCESS BEING ISSUED

NEED TO CONSIDER WHAT NEED TO CONSIDER WHAT TESTING IS REQUIRED TO TESTING IS REQUIRED TO BRING IT UP TO STANDARDBRING IT UP TO STANDARD

SHOULD BE LITTLE NEED SHOULD BE LITTLE NEED FOR RV NOW (as all current FOR RV NOW (as all current equipment should now be equipment should now be qualified)qualified)

Key PointsKey Points

Proper planningProper planning Execution to the planExecution to the plan DocumentationDocumentation Define analytical Define analytical

technique, functional technique, functional & operational & operational specificationsspecifications

Document installationDocument installation Test instrument for Test instrument for

compliance to our compliance to our specificationspecification

For several modules, For several modules, use holistic approachuse holistic approach

Individual modules Individual modules only as diagnosticonly as diagnostic

Test key parameters Test key parameters before and during before and during analysisanalysis

SS, QC samples or SS, QC samples or defined critical defined critical parameters are parameters are acceptableacceptable

S u m m a ry o f P ro ced u re

Y E SP u rch a ser rev ie w s th e te stin g to e nsu re

th a t the eq u ipm en t m ee ts a g re ed accep tan cec rite ria a n d re su lts sa tis fa c to rily do cu m e n ted

N OB e com e s th e re spo n s ib ility o f the

p u rcha se r to ca rry o u tIQ an d O Q te sting

P e rio d ica lly ca rry o u t P Qa s de fin ed in V M P

a n d a s a pp rop ria te ,ch an g e co n tro l

O n sa tis fa co ry com p le tio n o f IQ /O Q te stin g ,o b ta in P D Q A a pp rova l an d s to re

IQ a nd O Q p ro to co ls a n d V S R su m m a ryre p ort in th e e qu ip m e n t re co rds

IQ /O Q tes tin g ca rrie d b y m a n ufa c tu re r?

IQ an d O Q pro toco ls to be a pp rove d b y pu rcha ser (a nd P D Q A fo r O Q )

A g re e w ritte n tes tin g p ro to co l(s) fo r IQ /O Q (w ith m an u fac tu re r if a pp ro pria te )

P u rch a ser to ca rry o u t D Q a n d su itab ly do cu m e nt

P re p a re V M P (o r a fte r D Q )

C re a te U R S

CAP 045CAP 045

Validation of Analytical Validation of Analytical EquipmentEquipment

Drivers for a common Analytical Drivers for a common Analytical Equipment Validation StandardEquipment Validation Standard

Avoid “re-inventing the wheel” within GSKAvoid “re-inventing the wheel” within GSKknowledge sharingknowledge sharingreduced overall effortreduced overall effort

Meet compliance expectations Meet compliance expectations common face to regulatorscommon face to regulators

Reduce variability (OE)Reduce variability (OE)approach - how we validateapproach - how we validateextent - how much we need to doextent - how much we need to doterminology - use a single set for validation terminology - use a single set for validation deliverablesdeliverables

Validation Plan - Balances

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Page Count No. Signatories Days To Review/ Approve

CAP documents are...CAP documents are... ...formal company documents, and as such exist within the QMS framework...formal company documents, and as such exist within the QMS framework

... the company’s way of sharing analytical practice around the community of 3,500 analysts within both R+D and GMS... the company’s way of sharing analytical practice around the community of 3,500 analysts within both R+D and GMS

... not in themselves mandatory, but contain within them mandatory elements (often by cross-referral to policies, or ... not in themselves mandatory, but contain within them mandatory elements (often by cross-referral to policies, or pharmacopoeial monographs and chapters)pharmacopoeial monographs and chapters)

... written by, and for analytical practitioners... written by, and for analytical practitioners

... source material for local procedures and guidelines... source material for local procedures and guidelines

iQMS GSOPs Local Procedures

System-Specific Guidance

EngineeringIT Analytical

iQMSTechnical Processes

e.g. TP09CAPs

e.g. CAP045

GQG1204A

GQG1205

GQG1205A

GQG1204D

GQG1204B

Global Quality Guidelines

1204 1205 5103

Global QualityPolicies

Document Hierarchy

Key themes in CAP045 Key themes in CAP045 document setdocument set ScopeScope

what’s covered and what isn’twhat’s covered and what isn’t

ScalabilityScalability doing enough according to level of risk and complexitydoing enough according to level of risk and complexity

ClassificationClassification an aid to applying the scalability based on “complexity”an aid to applying the scalability based on “complexity”

Consistent with other validation methodologiesConsistent with other validation methodologies for example iQMS, TP09for example iQMS, TP09

Deliverables for the validation life cycleDeliverables for the validation life cycle and how to document the validation effortand how to document the validation effort

All GMS Analytical Equipment

Laboratory-based equipment

Computerised Analytical Equipment

Analytical Equipment used forGxP-related activities

Bespoke

Scope of CAP45

Consider GQG1205 or

TP09Use CAP045.

Use iQMS.Consider TP09

Client-ServerArchitecture-based

systems

Non-computerisedCOTS equipment

Process AnalyticalTechnology

(PAT)

Computerised COTSanalytical equipment

Bespoke

hardware or software

Scope of Systems validated Scope of Systems validated using CAP045using CAP045

Scope - Validation Life CycleScope - Validation Life Cycle Requirements/PlanningRequirements/Planning SpecificationsSpecifications Design Design Qualification TestingQualification Testing ReportingReporting

NOT...NOT...

Validation Maintenance Validation Maintenance activitiesactivities

Change Control, Periodic Change Control, Periodic Review, Training, Review, Training, CalibrationCalibration

DecommissioningDecommissioning

Equipment ClassificationEquipment ClassificationV

alid

atio

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ffort

A B C D E FClassification

none

Simple COTSequipment usedmostly in samplepreparation orotherwise indirectlyused in laboratoryareas. Readingsfrom these are notused to generateGxP data. Typicallyfirmware-based –no data storage,run-timeparameters setwhen used. Notconnected toanothercomputerisedsystem.

Stirrers, hotplates,heating mantles,rotary evaporators,sonicators

Non-electronicCOTS devices andstandards notdepending onelectronic logic,embedded logic orexternal computersystems to controlinstrumentfunction. They donot store data ondurable media orreport information.All criticalparameters areassured by acalibrationprogram,maintenanceprogram or similar.

Direct impact:Rulers, non-digitalthermometers

Indirect impact:check weights,mechanicalfriability testers, U-tube viscometers

Simple, non-programmablefirmware-basedCOTS equipmentthat provides ameasurementreading via a digitaldisplay and/or toan attached printer.Will be calibratedperiodically. Datastorage will belimited to a fewsimple run-timeparameter settings.Not connected toan externalcomputer.

Digitalthermometers,digital callipers, pHmeter, balances,conductivitymeters, digitalviscometers

Firmware basedCOTS systems butwith additionalfeatures such asthe ability to storerun-timeconfigurations asmethods. Couldbe controlled froman externalcomputer orsystem via anelectronicinterface. Usuallywill not storemeasurement dataexcept where datalogging is the mainfunctionality.Calibratedperiodically or atrun-time. No directprogrammableinterface.

Autotitrators, HPLCor GC componentse.g. pumps,column ovens,Chessel chartrecorders

Hardware firmware-based or controlledby an externalcomputer. Standardapplication softwarewhich will allowconfiguration of run-time parameters,instrument control,data acquisition andstandard reportingfunctionality. Non-programmable dataprocessing whichmay involveregulated recordsand signaturesapplicability. Usuallystand-alone, notrelying on separatecontrolling and post-acquisition dataprocessing systems.Typically utilises alocal level of accesscontrol.

Stand-alone UV/Vis,FT-IR spectrometers,HPLC systemsoftware notconnected via CDS.

More complex systemsmostly having PC-based applicationsoftware. Usuallyprogrammable viastandard methodsequence lists. Mayutilise computernetwork functionality.Often these arehardware and softwarecomponents used tocontrol other standardlab equipment. Likelyto involve regulatedrecords/signatures.May acquire and utilisereference data aslibraries, requiringadvanced statistical orpattern recognitiondata processing.Typically usesoperating systemfunctionality for accesscontrol.

Robotic workstationcontrollers e.g.Zymark, some NIRsystems, NMRs, MassSpectrometers

What might the future look like?What might the future look like?

Collaboration within the GSK analytical communityCollaboration within the GSK analytical community reference document sets for preferred equipment (eg Agilent reference document sets for preferred equipment (eg Agilent

and Waters chromatography systems)and Waters chromatography systems)

The means to locate existing validation for your equipment projectThe means to locate existing validation for your equipment project for example a “database” of who has validated what analytical for example a “database” of who has validated what analytical

equipmentequipment NOT a database of all the validation documents themselves!NOT a database of all the validation documents themselves! gives a contact name at the site of interestgives a contact name at the site of interest use validation documentation as a template for your projectuse validation documentation as a template for your project may be able to reference some of it directlymay be able to reference some of it directly assumes a common documentation standard being used e.g. assumes a common documentation standard being used e.g.

CAP templatesCAP templates

Validation Master Plan (VMP)Validation Master Plan (VMP) Validation Master PlanValidation Master Plan

Prepared in advancePrepared in advance

Approved by QAApproved by QA

Defines IQ, OQ, PQ, Change Defines IQ, OQ, PQ, Change Control & Retrospective Control & Retrospective Validation Validation

Useful for frequently Useful for frequently

purchased equipmentpurchased equipment

ReferencesReferences CAP web siteCAP web site

http://iwhc.gsk.com/caphttp://iwhc.gsk.com/cap

Quality Management System web siteQuality Management System web site http://quality.gsk.com/gms/qms/http://quality.gsk.com/gms/qms/

Good Practice examplesGood Practice examples will appear here when availablewill appear here when available http://iwhc.gsk.com/gms-gcv/gcvdefault.htm?http://iwhc.gsk.com/gms-gcv/gcvdefault.htm?

html/GoodPractice.htmhtml/GoodPractice.htm