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3. Validation
(and Qualification)
Basic Principles of GMP
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Validation, Qualification
Two phylosophies:• Validation, qualification (and
calibration) are different, although interrelated activities (e.g. EU GMP)
• Qualification and also calibration belong to validation activities (e.g. WHO GMP)
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Qualification or validation? • A system/equipment must be qualified
to operate in a validated process
• Qualify a system and/or equipment
• Validate a process• Qualification versus validation, e.g. you
qualify the autoclave, while you validate the whole sterilization process
• (and calibrate a measuring instrument!)
Terms
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Validation
IntroductionThree basic principles of Quality
Assurance:
• Quality, safety, efficacy
• Cannot inspect quality into a product
• Processes must be under control (for this, they should be validated, whether they can be under control!
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Validation
Objectives• To review the definition and types of
validation• To understand the requirements for
documentation and key stages in the process of validation
• To consider models for process validation
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Validation
Definition
Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result
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Qualification and validation work require:
• Collaboration of experts
• Budget
• Meticulous and careful
planning
A Validation
Master Plan helps
the manufactur
er and inspectorat
e
Validation
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Validation
Essential Part of GMP• Predetermined protocols• Written reports• Processes and procedures• Periodic revalidation• Specific attention:
– processing process validation
– testing analytical method validation
– cleaning cleaning validation
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ValidationTypes of Manufacturing Process Validation
• Experimental approach– Prospective validation– Concurrent validation
• Analysis of historical data– Retrospective validation
• Revalidation– Periodic revalidation– Revalidation after change
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Prospective validation
• Before starting a new manufacturing process (or after its significant change), or revalidation:
• Manufacturing 3 batches only for validation purposes, all data documented. Reason: to see that the process is under control
• As a rule, these batches are not marketed later, except special decision to do that
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Concurrent validation
• In case of rarely produced medicines (e.g. 2 batches per year: no reason to produce 3 „validation” batches)
• Concurrent validation: during the manufacture of „normal” batches to be marketed
• Strict documentation!
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Retrospective validation
• This validation means the assessment of data generated during previous batch manufacturing
• Only for established technologies, the GMP is strictly applied, defects are rare
• Assessment of data of 10-30 batches, including defective ones (their data are very valuable to see how the process can run out of control!)
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QualificationTypes (Stages) of Qualification
• Design qualification (DQ)• Installation qualification (IQ)• Operational qualification (OQ)• Performance qualification (PQ)
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Design qualification DQ
• E.g. of a manufacturing equipment• Before purchasing!• Collection of data about the similar
equipments available on the market, assessing our needs, resources to buy and to operate, space and maintenance they would need, etc.
• Making the decision
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Installation Qualification IQ
• E.g. of a manufacturing equipment• After purchasing (or critical repair)• Put it on its intended place, connect
with other equipments, electric power, material flow devices
• Collect its documents incl. Operation Manual, etc.
• Its formal „release”: it is ready for working with
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Operational Qualification OP
• E.g. of a manufacturing equipment• „Model manufacturing” experiments
with model materials, similar to those to be used in the real manufacture
• E.g. qualifying an autoclave we use culture-media
• Permit the acceptable fluctuations of parameters, even set the „worst conditions”
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„Worst conditions”
• say, an equipment must be operated within the limits of– temperature: 20 and 35 oC– pressure: 0.9 and 1.2 atm
• The worst cases, when it operates at– 20 oC and 0.9 atm– 35 oC and 1.2 atm– 20 oC 0.9 and 1.2 atm– 35 oC and 0.9 atm
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Performance Qualification PQ
• Similar to the Operational Qualification, but the real manufacture is running
• Permit accepted fluctuations up to their limits (incl. worse conditions, if occur)
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DQ IQ OQ PQ
Certification
GMP Processunder control
Reviewperiodically
TrainingCalibration
Changecontrol
QualificationQualification
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Validation Priorities for Process Validation
Type of process• New
• Existing Sterile products
Non-sterile
Requirement• Every new process before approval for
routine
• All processes affecting the sterility, and manufacturing environment including sterilization stage
• Low dose tablets and capsules: mixing and granulation, content uniformity (possible other parameters)
• Other tablets and capsules: uniformity of mass(possible other parameters)
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Validation
Types of Documentation
• Validation Master Plan (VMP)• Validation protocols (VP)• Validation reports(VR)• Standard Operating Procedures
(SOPs)
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Validation
The Validation Master Plan could consist of:
– Approval page and table of contents– Introduction and objectives– Facility and process description– Personnel, planning and scheduling– Responsibilities of committee members– Process control aspects– Equipment, apparatus, processes and systems to be validated– Acceptance criteria– Documentation e.g.validation protocols and reports– SOPs– Training requirements
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ValidationProtocol
– Objectives of the validation and qualification study
– Site of the study– Responsible personnel– Description of the equipment– SOPs – Standards– Criteria for the relevant products and
processes
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ValidationReport
– Title– Objective of the study– Refer to the protocol– Details of material– Equipment– Programmes and cycles use– Details of procedure and test methods
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Let us spend some time on the Validation Master
Plan now
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Validation
The Validation Master Plan
(VMP)
• Philosophy
• Content
• Strategy
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Validation
Validation Master Plan • Recommendation only• Cover manufacturer’s validation policy and
needs • Provides information on validation
organization
• It should describe:
– why?
– what?
– where?
by whom?
how?
when?
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Validation
Validation Master Plan
• Prospective validation
• Concurrent validation
• Retrospective validation
• Revalidation
• Change control
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Validation
The VMP
• Identifies validation items (products, processes, systems)
• Defines nature and extent of testing expected
• Outlines test procedures and protocols
• Summary document
• Management agreement
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Validation
The VMP helps:
• Management
• Validation team members
• Project leaders
• GMP inspectors
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Validation Activities in VMP• Every validation activity included
• Revalidation
• Validation of new process cycles
• Large validation projects have separate VMPs
• Include reasonable unexpected events
Validation
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Validation
The VMP:
• Enables overview of entire validation
project
• Lists items to be validated with the planning schedule as its heart
• Is like a map
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Validation
The “Introduction” to the VMP• Validation policy• Project scope• Location and timing (including
priorities)• Validation procedures• Standards
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Validation
VMP should state who is responsible for:• Preparing the VMP
• The protocols and SOPs
• Validation work
• Report and document preparation and control • Approval/authorisation of validation protocols
and reports in all stages of validation process
• Tracking system
• Training needs in support of validation
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Validation
VMP should contain:• Cross references to documents
• Specific process considerations
• Specific characteristics briefly outlined
• Validation list (What to validate)– premises, systems and equipment– processes – products
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Validation
VMP should contain, 2:• Descriptions of
– plant (where to validate)– processes – products
• Personnel attributes – expertise and training
• Key acceptance criteria
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VMP should contain, 3:• Format for protocols and other
documentation• List of relevant SOPs (How)• Planning and scheduling (When)• Location (Where)• Estimate of staffing requirements
(Who)• A time plan of the project (When)• Annexes
Validation
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Validation
VMP should contain change control
• Policy and procedure
• Risk assessment
• Authorization
• Failure to properly document changes to the
system means invalidation of the process
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Validation
Changes that require revalidation• Software changes; Controllers• Site changes; Operational changes• Change of source of material• Change in the process• Significant equipment change• Production area changes• Support system changes
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Validation
In summary, a VMP should contain at least:• Validation policy• Organizational structure• Summary of facilities, systems, equipment,
processes to be validated• Documentation format for protocols and
reports• Planning and scheduling• Change control• Training requirements
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Finishing Validation Master Plan, something about the
Validation Protocol and Report
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Validation
WHO Model for Validation Protocol and Report, 1
• Part 1 – Purpose and prerequisites• Part 2 – Presentation of the process• Part 3 – Validation protocol
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Validation
WHO Model for Validation Protocol and Report,
2
• Part 4 – Installation qualification• Part 5 – Qualification protocol/report• Part 6 – Product characteristics
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Validation
WHO Model for Validation Protocol and Report, 3
• Part 7 – Evaluation• Part 8 – Certification• Part 9 – Summary
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Special validation types
Validation of
•cleaning
•manuf. process
•QC related processes
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Cleaning validation
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Cleaning validation
ObjectivesTo review:
• General requirements
• Validation protocol requirements
• How to check limits
• Analytical requirements
• Sampling methods
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Cleaning validation
Why cleaning validation is so important (1)
• Pharmaceuticals can be contaminated by potentially dangerous substances
• Essential to establish adequate cleaning procedures
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Cleaning validation
Why cleaning validation is so important (2)
• “Particular attention should be accorded to the validation of … cleaning procedures” (WHO)
• “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” (PIC/S)
• “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA)
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Possible contaminants• Product residues• Cleaning agent residues and breakdown• Airborne matter• Lubricants, ancillary material• Decomposition residues• Bacteria, mould and pyrogens
Cleaning validation
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Cleaning validation
Strategy on cleaning validation
• Product contact surfaces
• After product changeover
• Between batches in campaigns
• Bracketing products for cleaning
validation
• Periodic re-evaluation and revalidation
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Cleaning validation
Cleaning validation protocol (1)
Should include :
• Objective of the validation
• Responsibility for performing and approving validation study
• Description of equipment to be used
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Cleaning validationCleaning validation protocol (2)
Should include: • Interval between end of production and cleaning,
and commencement of cleaning procedure• Cleaning procedures to be used• Any routine monitoring equipment used• Number of cleaning cycles performed
consecutively
• Sampling procedures used and rationale
• Sampling locations (clearly defined)
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Cleaning validationRecord of cleaning validation
Should include : • Data on recovery studies
• Analytical methods including Limit of Detection and Limit of Quantitation
• Acceptance criteria and rationale
• When revalidation will be required
• Must have management and QA involvement
• Management commitment and QA involvement
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Cleaning validation
Results and reports
• Cleaning record signed by operator, checked by production and reviewed by QA
• Final Validation Reports, including conclusions
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Cleaning validation
Personnel
• Manual cleaning methods are difficult to
validate
• Cannot validate people; can measure
proficiency
• Must have good training
• Must have effective supervision
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Cleaning validation
Microbiological aspects
• Include in validation strategy
• Analyse risks of contamination
• Consider equipment storage time
• Equipment should be stored dry
• Sterilization and pyrogen contamination
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Cleaning validation
How to take samples
• Swab/swatch
• Rinse fluid
• Placebo
• The sample transport and storage conditions should be defined
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Cleaning validation
Swab samples • Direct sampling method• Reproducibility• Extraction efficiency• Document swab locations • Disadvantages
– inability to access some areas– assumes uniformity of contamination surface– must extrapolate sample area to whole surface
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Cleaning validation
Rinse samples
• Indirect method
• Combine with swabs
• Useful for cleaning agent residues
• pH, conductivity
• Insufficient evidence of cleaning
• Sample very large surface areas
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Cleaning validation
Analytical method (1)
• Validate analytical method
• Must be sensitive assay procedure:– HPLC, GC, HPTLC
– pH
– conductivity
– UV
– ELISA
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Cleaning validation
Analytical method (2) Check: • Precision, linearity, selectivity• Limit of Detection (LOD)• Limit of Quantitation (LOQ)• Recovery, by spiking• Consistency of recovery
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Setting limits (1) • Regulatory authorities do not set limits for
specific products
• Logically based
• Limits must be practical, achievable and verifiable
• Allergenic and potent substances
• Limit setting approach needed
Cleaning validation
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Setting limits (2) • Uniform distribution of contaminants not
guaranteed
• Decomposition products to be checked
• Setting limits; cleaning criteria:– visually clean
– 10 ppm in another product
– 0.1% of therapeutic dose
Cleaning validation
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Setting limits: “Visually clean” • Always first criteria• Can be very sensitive but needs
verification• Use between same product batches of
same formulation• Illuminate surface• Spiking studies
Cleaning validation
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Setting limits: “10 ppm”• Historical• In some poisons regulations• Pharmacopoeias limit test• Assumes residue to be harmful as heavy
metal• Useful for materials for which no available
toxicological data• Not for pharmacologically potent material
Cleaning validation
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Setting limits: not more than 0.1%• Proportion of MINIMUM daily dose of
current product carried over into MAXIMUM daily dose of subsequent product
• Need to identify worst case
Cleaning validation
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Other issues• Clean-In-Place (CIP) systems
• Placebo studies
• Detergent residues; composition should be known
• Scrubbing by hand
Cleaning validation
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Cleaning validationQuestions for the GMP Inspector to askQuestions for the GMP Inspector to ask
• How is equipment cleaned?
• Are different cleaning processes required?
• How many times is a cleaning process repeated before acceptable results are obtained?
• What is most appropriate solvent or detergent?
• At what point does system become clean?
• What does visually clean mean?
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Conclusion• The manufacturer needs a cleaning validation
strategy• Assess each situation on its merits• Scientific rationale must be developed
– equipment selection– contamination distribution– significance of the contaminant
• “Visually clean” may be all that is required
Cleaning validation
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Process validation
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Process validationObjectives
To review:
• Validation, risk analysis, and critical steps of processing
• Points to consider in process validation of:– solid dose mixing– tablet compression– sterilization
• Finalization of validation
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Process validationReliable, repeatable, under control
• At least first 3 consecutive batches - repeatable
• Must investigate failures
• The rationale should be documented if experimental method is changed – document deviations, decisions and reasoning
• Does not improve processes
• Should not validate bad processes
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Process validationProcess validationDesign user or process requirements
Install installation qualification
Operate operational qualification
Perform performance qualification
and process validation
Review periodically (+ change control)
DQ, IQ, OQ and PQ
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Process validation
Critical factors or parameters
• Need to be determined
• Need to be monitored during
validation
• May affect the quality of the product
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Process validation
Setting Limits• Marketing authorization limits
– stability specifications
• Release specification• Validation limits
Batch release limits
Marketing authorisation limitsbased on stability specifications
Validation limits
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Determining critical control point: example of a tablet granulation process
• Particle size distribution of the active(s)• Blending time for the powder• Granulating time and speed, • Amount of granulating fluid-binder concentration• Drying time - final moisture content, granule particle size distribution• Granule active content and homogeneity, blending time of external phase
Process validation
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Criticalcontrol
point
Decision as to whether tocompress or not based on
expected yield and actual yield
Process step Operation IQ/OQ/PQ requirements
Criticalcontrolpoint
Measure humidity withhumidity meterXIII
IQ/OQcalibration
Weigh granulate - balanceXIV IQ/OQcalibration
instrumentoperation,
cleaning, careand maintenance
Trainingrecords fortechnician
XV Sieve 3/5
sieve with sieve type 1
XVI Blend3/5
granulatemixer (speed 1, 1 minute)
XVI Blend 2with 3/5
granulate
mixer (speed 1, 30seconds)
IQ/OQ/PQCleaning
validationCleaning, and Blend
uniformity required to beestablished during validation
XVIII Weigh granulate
Process validationDetermining critical control points
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Solid dose mixing (1)• Homogeneity in blending – the
key to quality! • Sampling strategy• Sample site, label, container• Storage • Transport• Sample thief
Process validation
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Solid dose mixing (2)
• In situ analysis
• Methods of analysis
• Statistical analysis – inter-batch
– intra-batch
– within-sample-site
Process validation
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Process validation
Tablet compression variables
• Fill volume • Pre-compression force,
compression force• Turntable speed• Dwell time• Granule size and feed• Ejection force, lubrication
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Process validation
Tablet compressionparameters
Mass
Hardness
Moisture
Friability
Disintegration
Dissolution Thickness
Tablet coating variables Spray rate Inlet and outlet air
temp Coating weight
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Process validation
Sterilization validation (1)
• Sterility test
• Physical measurements
• Chemical and biological indicators
• Loading patterns
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Process validation
Sterilization validation (2)• Cooling fluid or gas• Automated process• Leak tests• Control instrumentation• Steam quality• Heat distribution
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Process validationDry heat sterilization
• Parameters• Air circulation, positive air pressure,
HEPA filter• Advantages
– microorganisms destroyed– depyrogenation possible
• Disadvantages– poor heat transfer– higher temperatures for long periods
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Process validationProcess variation
Controllable causes of variation may include:• Temperature, humidity • Variations in electrical supply• Vibration• Environmental contaminants• Light• Human factors • Variability of materials• Wear and tear of equipment
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Process validationChange control
• Must be a review procedure for validated processes
• From time to time changes may be necessary
• Documented change control procedure needed
• “Like for like" changes do not require re-validation
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Mixing validation liquid and solid dose change control and scale up
• Mixer type and size
• Batch size
• Pilot study scale up
• Limit on the proportion of the scale up
Process validation
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Process validationFinalization of validation process
• Final report required• Summarize and reference protocols and
results• Conclusion required: “Is the process valid”
• Final report should be reviewed and approved by – the validation team
– “authorized person”
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Tablet manufacturing flow chart
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Quality Control related validation
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QC related validation
Introduction
• Why is analytical monitoring necessary?
• What is the purpose of analytical validation?
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QC related validation
ObjectivesTo introduce the concepts of :• Protocol development• Instrument qualification• Analytical procedure• Extent of validation• Method transfer• Chemical and physical, biological, and
microbiological test validation
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Validation of analytical procedures requires:• Qualified and calibrated instruments
• Documented methods
• Reliable reference standards
• Qualified analysts
• Sample integrity
QC related validation
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Validation protocol for analytical method
• Statement of purpose and scope• Responsibilities • Documented test method• List of materials and equipment• Procedure for the experiments for each
parameter• Statistical analysis• Acceptance criteria for each performance
parameter
QC related validation
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Qualification of the instrument
• Make, model and maker’s manual
• Modifications
• Installation and operational qualification
• Calibration programs
• Maintenance schedules
QC related validation
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Characteristics of analytical procedures (1)• Accuracy
• Precision
• Repeatability
• Reproducibility
QC related validation
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Inaccurate &imprecise
Inaccurate butprecise
Accurate butimprecise
QC related validation
Relationship between accuracy and precision
Accurate AND Precise
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Characteristics of analytical procedures (2)
• Ruggedness • Robustness• Variability caused by:
– Day-to-day variations– Analyst-to-analyst– Laboratory-to-laboratory– Instrument-to-instrument– Chromatographic column-to-column– Reagent kit-to-kit– Instability of analytical reagents
QC related validation
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Characteristics of analytical procedures (3)
• Linearity and range• Specificity• Sensitivity• Limit of detection• Limit of quantitation
QC related validation
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Linearity of an analyte in a material
0.010
0.015
0.020
0.025
0.030
0.035
0.040
0.01 0.015 0.02 0.025 0.03 0.035 0.04
Reference material mg/mlCal
cula
ted a
nal
yte
in m
g/m
L Table of values (x,y)
x y # Reference
material mg/mlCalculated
mg/ml
1 0.0100 0.0101
2 0.0150 0.0145
3 0.0200 0.0210
4 0.0250 0.0260
5 0.0300 0.0294
6 0.0400 0.0410
QC related validation
102
Linearity Statistics • Intercept -0.0002• Limit of Linearity and Range
0.005 – 0.040 mg/mL• Slope 1.0237• Correlation coefficient
– Pearson 0.9978– Olkin and Pratt 0.9985
• Relative procedure standard deviation 3.4%
QC related validation
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LOQ, LOD and SNR
• Limit of Quantitation
• Limit of Detection
• Signal to Noise Ratio
noise
Peak ALOD
Peak BLOQ
Baseline
QC related validation
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Different classes of analytical tests• Class A: To establish identity
• Class B: To detect and quantitate impurities
• Class C: To determine quantitatively the concentration
• Class D: To assess the characteristics
QC related validation
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* A degree of bias may be allowed
Characteristic A B quant.
B Limit test
C D
Accuracy
X X X*
Precision X X X
Robustness X X X X X
Linearity and range
X X X
Specificity X X X X X
Limit of detection X
Limit of quantitation
X
QC related validation
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Extent of validation • New methods require complete
validation• Pharmacopoeial methods require
partial validation (or verification)• Significant changes mean partial
revalidation– equipment changes– formula changed– changed suppliers of critical reagents
QC related validation
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Analytical method transfer• Method transfer protocol and procedure
– precision– accuracy– ruggedness
• Written and approved specific test method• Proficiency check• Formal acceptance by new laboratory
QC related validation
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Chemical laboratory validation requirements (1)
• Balances • Chromatography
– HPLC, HPTLC, GC, TLC• Dissolution or disintegration apparatus• Karl Fischer moisture determination• Melting, softening or freezing point apparatus• Ovens, refrigerators, incubators
QC related validation
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Chemical laboratory validation requirements (2)
• pH meter• Polarimeter - optical rotation• Refractometer• Spectrophotometer UV/Vis, IR, FTIR, Raman, AA• Timers• Viscometer• Volumetric equipment
QC related validation
110
QC related validation
Typical validation of HPCL assay (1)
• System suitability (performance check)– system precision– column efficiency – symmetry factor– capacity factor
111
QC related validation
Typical validation of HPLC assay (2)• Method validation
– specificity – accuracy – precision– linearity – robustness
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Biological assays• Can be difficult to "validate"
• "Validity" on a case by case basis
• Strictly adhere to the Biological Testing monographs in pharmacopoeias
QC related validation
113
QC related validation
Microbiological testing requiring validation
• Microbial limit testing
• Microbial count
• Sterility testing
• Preservative effectiveness testing
• Environmental monitoring program
• Biological testing
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Validation of microbial test procedures (1)
• Virtually impossible to completely validate test procedures for every microorganism
• Neutralize /inactivate inhibitory substances, or dilute
• Periodic media challenge• Media QC• Reliable methods
QC related validation
115
Validation of microbial test procedures (2)
• Incubation temperature and time
• Media may not grow all microorganisms
• Variations in media may affect recovery
• Inhibitory disinfectants or preservatives
• Sample– procedures
– handling, storage, transport
QC related validation
116
Microbiological viable count method validation (1)
• Methods – pour plate / spread plate– membrane filtration– Most Probable Number
• Sample size• Test dilution• Inoculation size
QC related validation
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Microbiological viable count method validation (2)
• Membrane filtration conditions
• Incubation conditions
• Acceptance criteria
QC related validation
118
Sterility testing validation requirements
• Media growth promotion, sterility, pH
• Product validation
• Stasis testing
• Environmental monitoring
• Negative controls
• Challenge organisms
QC related validation
119
Personnel - Validation team members • Quality Assurance• Engineering• Manufacturing• Other disciplines may be involved depending
on the product and process:– laboratory, technical services– research and development, regulatory affairs– clinical – chemical engineering– purchasing/planning
Validation
120
ValidationProtocol development (1)
• Identification of process
• Objective and measurable criteria
• Length and duration of the validation
• Shifts, equipment
• Identification and quality of utilities• Identification of operators and operator
training and qualification
121
Validation
Protocol development (2)• Complete description of the process
• Relevant specifications and tests
• Samples and sampling methods
• Special controls or conditions
• Process parameters to be monitored
• Methods for controlling and monitoring
122
ValidationProtocol development (3)
• Objective and subjective criteria used to evaluate the product
• Definition of non-conformance
• Statistical methods
• Maintenance and repairs
• Criteria for revalidation
• Criteria for change control
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GMP Inspector’s check list for validation (1)
Check that the manufacturer has:
• A VMP and multi-functional team for validation
• Planned approach, defined requirements
• Identified and described processes
• Analyse the amount of validation work to perform
Validation
124
GMP Inspector’s check list for validation (2)
Check that the manufacturer has:
• Selected methods and tools for validation
• Created protocols
• Performed DQ, IQ, OQ, PQ and documented results
• Exerted change control, set revalidation time
Validation
125
Validation • A quality tool that makes sense • A prevention-based activity• Expensive• In danger of becoming overwhelming • Risk-based assessment of what needs to
be validated or verified• The process must be under control
Validation: summary
126
We are now validated!
127
Exam topics
128
Validation and Qualification in GMP
• Definitions. What is their difference?
• Their importance
• Describe the 3 process validation types
• Describe the 4 qualification types
• Validation documentation (special emphasis to VMP)
• What is change control, why to do it?
129
Validation of clening processes and analytical procedures in
GMP• Cleaning validation
– Its 2 targets– How to perform it (examples)
• Analytical method validation– List the main method characteristics– Classes of testing for validation– Analytical instrument validation (examples)– Microbiology