module 1, part 3: process validation slide 1 of 22 © who – edm – 12/2001 validation part 3:...
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Module 1, Part 3: Process validation Slide 1 of 22 © WHO – EDM – 12/2001
Validation Part 3:
Process validation
Supplementary Training Modules on Good Manufacturing Practices
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Module 1, Part 3: Process validation Slide 2 of 22 © WHO – EDM – 12/2001
Validation
Objectives 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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Module 1, Part 3: Process validation Slide 3 of 22 © WHO – EDM – 12/2001
Introduction
Validation
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Module 1, Part 3: Process validation Slide 4 of 22 © WHO – EDM – 12/2001
Validation
Reliable, 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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Module 1, Part 3: Process validation Slide 5 of 22 © WHO – EDM – 12/2001
ValidationValidation
Design user or process requirements
Install installation qualification
Operate operational qualification
Validate performance qualification
and process validation
Review periodically (+ change control)
DQ, IQ, OQ and PQ
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Module 1, Part 3: Process validation Slide 6 of 22 © WHO – EDM – 12/2001
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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Module 1, Part 3: Process validation Slide 7 of 22 © WHO – EDM – 12/2001
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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Module 1, Part 3: Process validation Slide 8 of 22 © WHO – EDM – 12/2001
Determining critical control pointexample 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
Validation
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Module 1, Part 3: Process validation Slide 9 of 22 © WHO – EDM – 12/2001
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/PQCleaningvalidation
Cleaning, and Blenduniformity required to be
established during validation
XVIII Weigh granulate Criticalcontrolpoint
Decision as to whether tocompress or not based on
expected yield and actual yield
Process step Operation IQ/OQ/PQ requirements
Validation
Determining critical control points
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Module 1, Part 3: Process validation Slide 10 of 22
© WHO – EDM – 12/2001
Solid dose mixing (1) Homogeneity in blending – the key to quality! Sampling strategy Sample site, label, container Storage Transport Sample thief
Validation
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Module 1, Part 3: Process validation Slide 11 of 22
© WHO – EDM – 12/2001
Solid dose mixing (2) In situ analysis
Methods of analysis
Statistical analysis
inter-batch intra-batch within-sample-site
Validation
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Module 1, Part 3: Process validation Slide 12 of 22
© WHO – EDM – 12/2001
ValidationTablet compression
variables Fill volume Pre-compression force, compression
force Turntable speed Dwell time Granule size and feed Ejection force, lubrication
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Module 1, Part 3: Process validation Slide 13 of 22
© WHO – EDM – 12/2001
ValidationTablet compression
parameters Mass
Hardness
Moisture
Friability
Disintegration
Dissolution Thickness
Tablet coating variables Spray rate Inlet and outlet air
temp Coating weight
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Module 1, Part 3: Process validation Slide 14 of 22
© WHO – EDM – 12/2001
Validation
Lethality of cycle
D value
Z value
F value
Fo value min 8
Thermal Death Curve
1
10
100
90 95 100 105 110 115 120 125
Temperature (oC)
D value (log scale)
Moist heat sterilization
“Z”
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Module 1, Part 3: Process validation Slide 15 of 22
© WHO – EDM – 12/2001
Validation
Sterilization validation (1)
Sterility test
Physical measurements
Chemical and biological indicators
Loading patterns
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Module 1, Part 3: Process validation Slide 16 of 22
© WHO – EDM – 12/2001
Validation
Sterilization validation (2) Cooling fluid or gas
Automated process
Leak tests
Control instrumentation
Steam quality
Heat distribution
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Module 1, Part 3: Process validation Slide 17 of 22
© WHO – EDM – 12/2001
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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Module 1, Part 3: Process validation Slide 18 of 22
© WHO – EDM – 12/2001
Validation
Process 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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Module 1, Part 3: Process validation Slide 19 of 22
© WHO – EDM – 12/2001
Validation
Change 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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Module 1, Part 3: Process validation Slide 20 of 22
© WHO – EDM – 12/2001
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
Validation
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Module 1, Part 3: Process validation Slide 21 of 22
© WHO – EDM – 12/2001
Validation
Finalization 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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Module 1, Part 3: Process validation Slide 22 of 22
© WHO – EDM – 12/2001
Validation
Group Session You are given a tablet
manufacturing flow chart to study
List the critical steps that are required to be validated
List the critical equipment required to be qualified
Identify the variables and construct a table as directed