validation and qualification: a gmp burden or an opportunity?

University of�MilanoͲBicoccaTecnomed�Foundation�

VALIDATION�AND�QUALIFICATION:�A�GMP�BURDEN�OR�AN�OPPORTUNITY?

Sergio Todde

ESRR�’16�– 18th European Symposium�on�Radiopharmacy and�RadiopharmaceuticalsSalzburg 7Ͳ10,�2016

http://ec.europa.eu/health/files/eudralex/vol‐4/2011_intro_en.pdf

HISTORICAL�PERSPECTIVE:�EUͲGMPHISTORICAL�PERSPECTIVE:�EUͲGMP

In EU the need to provide scientific documentationto obtain MA was first set in Directive 65/65/EEC

• Directive 2001/83/EEC• Directive 2003/94/EC• Vol. 4 – Good Manufacturing Practice (GMP)

• Annex 15 – Qualification and validation

VALIDATION:�LEGAL�FRAMEWORKVALIDATION:�LEGAL�FRAMEWORK

ec.europa.eu/health/files/eudralex/vol‐4/2015‐10_annex15.pdf

Last version entered intoforce 1 October 2015

is the action of proving that any procedure, process, equipment, material, activity or system actuallyleads to the expected results

Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation

VALIDATION VS QUALIFICATIONVALIDATION VS QUALIFICATION

Validation

Qualification

ANNEX 15 GMP: FIELD OF APPLICATIONANNEX 15 GMP: FIELD OF APPLICATION

Facilities

Equipment

Utilities

Processes

intermediates

Finishedproduct

packaging

QC

Startingmaterials



Test methods

Cleaning

• Description of the facility• Organizational structure• Description of the RP preparation process(es)• List of premises/production/QC equipment to be qualified• Extent of qualification required for each premise/instrument (e.g.

PQ only vs full DQ, IQ, OQ, PQ) Æ risk assessment• List of utilities to be qualified, and their qualification extent (e.g. gas

distribution system)• Cleaning validation• Analytical method to be validated• Process validation• Change control and deviation management

VALIDATION MASTER PLAN (VMP)VALIDATION MASTER PLAN (VMP)

• Description of the facility (layout, technical characteristics, etc.)

• Equipment to be qualified (e.g. hot cells, automated modules, dispensing system, HPLC, GC, Gamma spectrometer, other small instrumentation) Æ computerizedsystems?

• Cleaning validation (classifiedrooms, automated systems, ifapplicable)

• HVAC qualification• Gas distribution system qualification• Validation of analytical methods• Process Validation

EXAMPLE: VMP IN A RADIOPHARMACYEXAMPLE: VMP IN A RADIOPHARMACY

Validation activities may pose a heavy workload: userisk assessment to carefully define what is really needed

VALIDATION AND RISK ASSESSMENTVALIDATION AND RISK ASSESSMENT

Risks assessment is an integral part of all the activities related to the preparation of radiopharmaceuticals, includingvalidation and qualification. An insufficient risk evaluation maylead to….

VALIDATION AND RISK ASSESSMENTVALIDATION AND RISK ASSESSMENT

Cleaningvalidation

Definingprocess

parameters

Extent of validation of equipment /

utilities

e.g.�IQ,�OQ,�PQvs�PQ�only

e.g.�choose thesampling pointfor�contact plates

e.g.�precursorconcentration,�solution character,specific activity,�etc.

….and more

Implementation

Installation Qualification

Operational Qualification

Performance Qualification

Design specification

Functional specification

URS

USER�REQUIREMENT�SPECIFICATION�(URS)USER�REQUIREMENT�SPECIFICATION�(URS)

USER�REQUIREMENT�SPECIFICATION�(URS)USER�REQUIREMENT�SPECIFICATION�(URS)

• a description of the process / method to be carried out with the specific equipment (e.g. which kind of analytical procedures are to be performed with an HPLC system, the expected impurities, and the related limits, etc.)

• a detailed description of the intended instrument / equipment including computerized systems, if applicable

• a brief description of the room / environment where the instrument / equipment is supposed to be installed

• which utilities (e.g. gas supply, electricity, etc.) are required by the instrument

• required performance of the instrument (e.g. eluent flow range for an HPLC pump, sensitivity for UV detector, etc.)

• documentation to be requested to the manufacturer (e.g. manuals, drawings, schematics, etc.)

• other useful information such as service and technical support

URS for Software

Access control

User privileges

System suitability

Audit trails

Archive storage

Operating system

EXAMPLE:�URS�FOR�A�RADIOͲHPLCEXAMPLE:�URS�FOR�A�RADIOͲHPLC

URS for hardware

Analyticalpump

Flow: 0‐10 ml/min

autoinjector

Precision (CV% < 2), range: 1‐100

Pl

UV + Radioactivitydetector

Precision (CV% < 2,

linearity (R2 ≥ 0.99

Manuals

Power: 220V

EXAMPLE:�URS�FOR�A�DISPENSING�SYSTEMEXAMPLE:�URS�FOR�A�DISPENSING�SYSTEM

GMP requisites

Vial fillingarea in class

«A»

Background in class «B»

SAS for material

introductionin class B

SAS for vialrecovery in class B

Gloves for emergencyoperations

Connectionsfor VHP

Technical requisites

Laminar flow > 0.3 m/sec

Class A in operation

Pressure: ‐100 – (‐250)

Pa

Leak rate < 0.01 h

Temperature < 30°C

Air exchange> 60/h

Manuals, drawings, schematics, P&I

Power: 220V

Gas: compressed air (99.9%)

• FAT are particularly useful in case of complexand/or «large» equipment (e.g. hot cells, dispensing systems)

• They can be performed at the Factory, followingURS (without radioactivity!)

• By the way, they allow to fix problems (if any) directly at the Factory

• SAT may repeat, in part, FAT tests, with additionaltests with radioactivity

• FAT/SAT may significantly reduce the extent of IQ/OQ protocols

FACTORY/SITE ACCEPTANCE TEST (FAT/SAT)FACTORY/SITE ACCEPTANCE TEST (FAT/SAT)

EXAMPLE: FAT FOR DISPENSING SYSTEMEXAMPLE: FAT FOR DISPENSING SYSTEM

Test Methodology Acceptance criteria

Documentation verification Check documents and installed equipment

Installed components are in accordance with the drawings / schematics

Components functionality Check buttons, knobs, lights, etc

Components work asexpected

HEPA filter integrityMeasure aerosol concentration up‐ and downstream the filter

Filter penetration ≤ 0.05

Air changes / h Measure airflow with a proper instrument Air changes / h > 50

Particle contamination Use a calibrated particlecounter

Limits established by annex 1 ‐ GMP

Dispensing accuracy Start a dispensing cycle and weight the vials

Difference betweenexpected and experimental

weight < 3%

IQ is aimed to verify that the facility / system / instrument has been installed correctly, based on the manufacturer’s recommendations and/or the approved specifications of the User

OQ is aimed to verify that the facility / system / instrument are operating properly, and that the response of critical components (e.g. sensors) match with the intended values and within the desired range

The goal of PQ is verify that the facility / system / instrument perform properly and reproducibly in the intended routine conditions set for the specific preparation process, and using approved methods Q

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IQ protocol might include1. Equipment / system specifications2. Spare parts list3. As‐built drawings4. Wiring diagrams5. Piping and installation6. Installation certification statement

OQ protocol might include1. A full system description2. Calibration certification documents3. Testing filters, sensors, temperatures, etc4. Acceptance criteria5. Certification statement

QUALIFICATION: HVACQUALIFICATION: HVAC

Design�qualification is of�paramount importance!

PQ protocol might include1. Testing room pressures2. Verify particle contamination «in operation»3. Verify microbiological contamination «in operation»4. Decay and recovery time verification

QUALIFICATION OF HVAC: INSTRUMENTATIONQUALIFICATION OF HVAC: INSTRUMENTATION

HVAC�qualification may requires equipment and�skillsuncommon in�a�typical radiopharmacy (and�it’s expensive,�too)

• What it has to be cleaned?

• Pre‐requisites: training, SOPs, etc.• Describe Cleaning procedure and cleaning media (solvents, detergents)• Sampling procedure (find a suitable way to collect the contaminants)• Analyze contaminants• Set Acceptance criteria• Risk assessment (identify the chemical/radiochemical/radionuclidic

contaminants; how toxic are they? How easily can they be removed? Etc.)

CLEANING VALIDATION : GENERALCLEANING VALIDATION : GENERAL

Equipment(internalsurface)

Equipment(externalsurface)

room

Describe CleaningProcedure and……

Sampling: choose the most difficult to clean locations, and…….

CLEANING VALIDATION: PREMISESCLEANING VALIDATION: PREMISES

Set acceptance criteria, and analyzecleaning products

n

o

p

…..proper sampling toolsq

r

EXAMPLE: CLEANING VALIDATION OF AN AUTOMATED SYSTEM

EXAMPLE: CLEANING VALIDATION OF AN AUTOMATED SYSTEM

‐ Cleaning procedure: use aproper solvent(s) to clean all the parts that come into contact withIntermediates/products

‐ Sampling procedure: rinse witha proper media all the cleanedparts, collect samples and analyze them with sufficientlysensitive methods

• Automated radiosynthesis system• Dispensing systems • Hot cells • Isolators (e.g. for cell labelling)• Laminar flow hoods• dose calibrators• others…….

QUALIFICATION OF PRODUCTION EQUIPMENTQUALIFICATION OF PRODUCTION EQUIPMENT

- Verify administrative records(e.g order specification, shipment note, etc.)

- Verify design specifications- Check for documentation,

drawings, etc.- Identify installed components

(place labels as required)- Check installation

environment- Check for connections,

tubing, piping, etc

QUALIFICATION OF A SYNTHESIS SYSTEM: IQ

QUALIFICATION OF A SYNTHESIS SYSTEM: IQ

Verification of the temperature sensor calibration status

Set point 1 (60°) Set point 2 (120°C)

# Time Measurementswith calibratedthermometer

Temperature measured by the modulesoftware

# Time Measurementswith calibratedthermometer

Temperaturesmeasured by the modulesoftware

Acceptance criteria: readout temperatures should correspond to temperatures measured with calibrated gauge ± 5%

QUALIFICATION OF A SYNTHESIS SYSTEM: OQQUALIFICATION OF A SYNTHESIS SYSTEM: OQOQ is aimed to verify the functionalities of the automated module. This should include the movement of actuators and the calibration status of the probes (e.g. temperature, pressure, and radioactivity).

QUALIFICATION OF SYNTHESIS SYSTEM: PQQUALIFICATION OF SYNTHESIS SYSTEM: PQ‐ PQ should demonstrate that the automated system is suitable for the intended application in normal

conditions of use.‐ Performance of three complete runs of a representative process covering all normal operations for

the concerned preparation process. ‐ In case of PQ for automated synthesis/dispensing systems, test may be exploited for Process

Validation?PERFORMANCE QUALIFICATION TEST

Automated synthesis system model …..

Batch number Date:F‐18 transfer

Actual duration: Expected duration: max. 5 min

The F‐18 transfer step was performed as expected � Yes � NO

Detected F‐18 activity: _______ MBqPurification of F‐18 using QMA cartridge

Detected activity after purification using QMA: _______MBqSpecification: ≥ 80% of starting the activity has been recovered Complies: � Yes � NO

Nucleophilic substitution reaction

Desired reactortemperature

100 °C Actual temperature:______ °C

Detected activity at the end of the nucleophilic substitution reaction : _______ MBq

Acceptance criteria: The preparation of the desired radiopharmaceutical has to be performed correctly,meeting specification and acceptance criteria for the various parameters, without significant deviations

• Radio‐TLC• Radio‐HPLC• GC• Gamma spectrometer• Endotoxin detection system• pHmeter• Others……• Principles are the same depicted for production equipment

QUALIFICATION OF QUALITY CONTROL EQUIPMENT

QUALIFICATION OF QUALITY CONTROL EQUIPMENT

IQ protocol might include:‐ Environmental conditions‐ Instrument installation (power, circuit

protection)‐ Hardware component/configuration‐ Wiring and cabling‐ Software installation/configuration

VALIDATION OF COMPUTERIZED SYSTEMSVALIDATION OF COMPUTERIZED SYSTEMS

OQ protocols might include:‐ Operator interface and screen displays‐ Check input/output signals‐ Data storage, backup, and restore and

archive‐ Report printouts‐ Alarms, events, and messages‐ Process and safety interlocks‐ System access (security, privileges,

functions)PQ protocols might include:‐ Diagnostic checks‐ Audit trail functions‐ Software verification (e.g. run a

synthesis/dispensing(analysis)‐ Backup and restore methods‐ Effects of power loss and recovery

Computerized system could be�qualified as a�part�of�the�dedicated equipment (e.g.�automatedsynthesis system,�radioͲHPLC,�etc.)

• When analytical method is not included in a Ph. Eur text • When it is described in a Ph. Eur. monograph but it’s used outside

scopes and application of the monograph• When it is newly designed and developed (before its introduction into

routine use)- In case of significant changes in the equipment (e.g. a detector is

replaced with a new one)- Whenever the method is changed, and the change is outside the original

scope of the method- When QC trends indicate that results are changing with time (out of

trends)- When «home» developed methods are better than Ph. Eur. methods

(yes, they are not always the best!)

VALIDATION OF ANALYTICAL METHODS: WHEN?VALIDATION OF ANALYTICAL METHODS: WHEN?

…..and�in�case�a�Ph.�Eur.�monograph exists?

« The test methods given in monographs and generalchapters have been validated in accordance with acceptedscientific practice and current recommendations on analyticalvalidation. Unless otherwise stated in the monograph or general chapter, validation of the test methods by the analystis not required » European Pharmacopoeia, General notices

But…….

VALIDATION OF ANALYTICAL METHODS: WHEN?VALIDATION OF ANALYTICAL METHODS: WHEN?

Ph. Eur. methods have to be tested in the normal routine use (e.g. withSystem Suitability Test (SST))

VALIDATION OF ANALYTICAL METHODS: GUIDELINES

VALIDATION OF ANALYTICAL METHODS: GUIDELINES

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000357.jsp&mid=WC0b01ac0580028e8d

VALIDATION OF ANALYTICAL METHODS: CHARACTERISTICS

VALIDATION OF ANALYTICAL METHODS: CHARACTERISTICS

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000357.jsp&mid=WC0b01ac0580028e8d

Analiytical procedures Identification Impurity tests

Characteristics Quantitative Limit

SPECIFICITY + + +PRECISION:

REPEATABILITY- + -

INTERMEDIATE PRECISION

- + -

ACCURACY - + -LINEARITY - + -

LOD - - +

LOQ - + -

ROBUSTNESS - + -

Validation parameters for�chemical purity determination with�PDA�detector

EXAMPLE: VALIDATION OF A RADIO-HPLC METHOD FOR CHEMICAL AND RADIOCHEMICAL PURITY


Analiytical procedures Identification Impurity tests

Characteristics Quantitative Limit

SPECIFITY +PRECISION:

REPEATABILITY- + -

INTERMEDIATEPRECISION

N.A.

ACCURACY N.A.LINEARITY - + -

LOD N.A.

LOQ N.A.

ROBUSTNESS N.A.

Validation parameters for�radiochemical purity determination with�radiochemicaldetector



• Goal:�objective�proving�or�demonstrating�that�the�process�works�as�intended

• Process validation should be performed afterequipment/utilities/analytical methods havebeen qualified

• In principle, process validation should rarelyfail (otherwise it means that process is notsufficiently known)

PROCESS VALIDATIONPROCESS VALIDATION

• Equipment / utilities have been qualified (IQ, OQ, PQ)• Analytical methods have been validated• Personnel is adequately trained• Design and chemical/radiochemical/ technical details of the

process have been optimized• Process parameters (e.g. yield, radioactive concentration, etc.)

and related acceptance criteria have been defined• Stability of the desired product has already been assessed

(not mandatory, but useful)• Test batches have been prepared, and no significant

deviations from the expected performance of the process have been found

PROCESS VALIDATION: PRE-REQUISITESPROCESS VALIDATION: PRE-REQUISITES

• Which type of validation? (Consider that retrospectivevalidation is no more allowed)

• Definition of process flow diagram, equipment/components, starting materials, in‐process controls (if applicable), composition of the finished product

• Run 3 consecutive batches: if they meet all production (e.g. radiochemical yield, radioactive concentration, etc.) and quality (e.g. RCP, RNP, sterility, etc.), process is validated

• Collect experimental data and documentation (traceability)• Data analysis, summary and conclusions

PROCESS VALIDATIONPROCESS VALIDATION

Media fill

Media�Fill�should�adequately�simulate�actual�production�runs

‐ To qualify a process: three runs on three separate days‐ Manipulations and operation should be performed “as usual”…..‐ ….but without radioactivity‐ During media fill personnel, surfaces and air should be monitored‐ Media fill could be done in “worst‐case» environmental

conditions…..‐ ……and with typical number of personnel‐ Culture media should support the growth

of a wide range of microorganisms

‐ Media fill is a way to validate operators

PROCESS VALIDATION: MEDIA FILLPROCESS VALIDATION: MEDIA FILL

Add 15 mL of culture media (to simulate the radiopharmaceutical)

RP

20 ml

Repeat 2 more times from step (1).At the end, check the samples for sterility

(1) (2)

Simulation of QC sampling of a radiopharmaceuticals in a laminar flow hood

(3)

Draw 2 mL of culture media with a syringe

RP

20 ml

QC

RP QC

Transfer the culture media to a sterile and pyrogen free vial

EXAMPLE: MEDIA FILLEXAMPLE: MEDIA FILL

• Premises and equipment are expected to be qualified• Preparation method, as well as analyticalprocedures, might be not fully optimized, yet

• Indeed, preparation processes for investigationalradiopharmaceuticals are not expected to be valdated with same extent as for routine products , but...

• validation of sterilising processes should be of the same standard as for products authorised for marketing

PROCESS VALIDATION FOR INVESTIGATIONAL RADIOPHARMACEUTICALS

PROCESS VALIDATION FOR INVESTIGATIONAL RADIOPHARMACEUTICALS

• Risk should also be considered to evaluatechanges…….and evaluate re‐qualification

For�instance…..• Change in a critical component (e.g starting materials)• Change or replacement in a critical part of modular equipment (e.g. purification unit, an HPLC detector, dose calibrator, etc.)

• Change in the facility (e.g. refurbishment of lab ceiling)• Change in batch size (e.g. from monodose to multidose)

• Change in product specifications (e.g. increase radioactive concentration)

CHANGE CONTROL AND REVALIDATION CHANGE CONTROL AND REVALIDATION

And…

ANALYTICAL METHODS!!

IS THIS A POSSIBLE OUTCOME FOR THE «VALIDATOR»?

IS THIS A POSSIBLE OUTCOME FOR THE «VALIDATOR»?

……AND IS IT ALL JUST A GMP BURDEN? ……AND IS IT ALL JUST A GMP BURDEN?

…..hopefully no

EXAMPLES: IQ OF HVACEXAMPLES: IQ OF HVAC

Problem: preliminary test of microbiologicaland air particle contamination promptedfor OOS in the dressing room

Action: \check for technical drawings anddocumentation during IQ and verifiyinstallation status

Results: air inlet duct in the dressing room was not tightly connected with properjunction; airflow within the room wasmuch lower than normal

• Other examples:– Components (e.g. sensors, actuators, ducts, etc.) not properly labelled….

– …..components not labelled at all– Components described in the drawing but notinstalled

– Components installed but not described in the drawings……and more

EXAMPLES: IQ OF HVACEXAMPLES: IQ OF HVAC

DQ and IQ are especially useful in case of qualification of HVAC!

• Trend analysis of the preparation process for a routine radiopharmaceutical showedimproved reliability after process validation(which means also qualification/validation of equipment, methods, etc)

• Percentage of successful preparation raisedfrom 80% to 95%

EXAMPLES: PROCESS VALIDATIONEXAMPLES: PROCESS VALIDATION

• Leakage rate test failed during FAT• Sealing replaced: test OK• Also precision dispensing test (without radioactivity) failedduring FAT

• After balance and other components re‐calibration, test passed

EXAMPLES: IQ/FAT TEST ON A HOT CELLEXAMPLES: IQ/FAT TEST ON A HOT CELL

• Cleaning validation allowed to determine the sampling points for microbiological testing(and reduce their number….)

EXAMPLE: CLEANING VALIDATIONEXAMPLE: CLEANING VALIDATION

210

120

210

120

C e lla s xC e lla d x

P C C o n tro llo

f r ig o r ife ro

CP0

1

C P 0 6

CP0

2

C P 0 3

C P 0 4

C P 0 5

C P 0 7

C P 0 9

C P 0 8

CP1

0

C P 1 4

C P 1 5

C P 1 6

CP1

7

C P 1 8C P 1 9

C P 2 0

C P 1 1

C P 1 2CP1

3

• Determination of robustnessallowed to highlight methodweak points

• For instance, the method showedsignificant shift of retention time after small changes to mobile phase ….keep it under control

EXAMPLE: VALIDATION OF ANALYICAL METHODSEXAMPLE: VALIDATION OF ANALYICAL METHODS

LOQ/LOD may help to accept/discard a method in case a highly toxic impurity has to be assessed (e.g. LOQ has to be below the acceptable limit for the above impurity)

THANK YOU FOR YOUR ATTENTION!

validation and qualification: a gmp burden or an opportunity?

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