Process

validation
Module 1, Part 3: Process validation Slide 1 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

Module 1, Part 3: Process validation Slide 2 of 22 © WHO – EDM – 12/2001

 Validation

Introduction

Module 1, Part 3: Process validation Slide 3 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

Module 1, Part 3: Process validation Slide 4 of 22 © WHO – EDM – 12/2001

 Validation
DQ, IQ, OQ and PQ
Design user or process requirements

Install installation qualification

Operate operational qualification

Validate performance qualification

and process validation

Review periodically (+ change control)

Module 1, Part 3: Process validation Slide 5 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

Module 1, Part 3: Process validation Slide 6 of 22 © WHO – EDM – 12/2001

 Validation
Setting Limits
Marketing authorization limits
stability specifications
Release specification
Validation limits

Marketing authorisation limits

based on stability specifications

Batch release limits

Validation limits

Module 1, Part 3: Process validation Slide 7 of 22 © WHO – EDM – 12/2001

 Validation
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

Module 1, Part 3: Process validation Slide 8 of 22 © WHO – EDM – 12/2001

 Validation
Determining critical control points

Module 1, Part 3: Process validation Slide 9 of 22 © WHO – EDM – 12/2001

 Validation
Solid dose mixing (1)
Homogeneity in blending – the key to quality!
Sampling strategy
Sample site, label, container
Storage
Transport
Sample thief

Module 1, Part 3: Process validation Slide 10 of 22 © WHO – EDM – 12/2001

 Validation
Solid dose mixing (2)
In situ analysis
Methods of analysis
Statistical analysis
inter-batch
intra-batch
within-sample-site

Module 1, Part 3: Process validation Slide 11 of 22 © WHO – EDM – 12/2001

 Validation
Tablet compression variables
Fill volume
Pre-compression force, compression
force
Turntable speed
Dwell time
Granule size and feed
Ejection force, lubrication

Module 1, Part 3: Process validation Slide 12 of 22 © WHO – EDM – 12/2001

 Validation
Tablet compression Tablet coating
parameters variables
Mass Spray rate
Hardness Inlet and outlet air temp
Moisture Coating weight
Friability
Disintegration
Dissolution
Thickness
Module 1, Part 3: Process validation Slide 13 of 22 © WHO – EDM – 12/2001
 Validation
Moist heat sterilization
Thermal Death Curve
100
Lethality of cycle
D value
“Z”
D value (log scale)

Z value
10

F value

Temperature (oC)
Fo value min 8
1
90 95 100 105 110 115 120 125

Module 1, Part 3: Process validation Slide 14 of 22 © WHO – EDM – 12/2001

 Validation
Sterilization validation (1)
Sterility test
Physical measurements
Chemical and biological indicators
Loading patterns

Module 1, Part 3: Process validation Slide 15 of 22 © WHO – EDM – 12/2001

 Validation
Sterilization validation (2)
Cooling fluid or gas
Automated process
Leak tests
Control instrumentation
Steam quality
Heat distribution

Module 1, Part 3: Process validation Slide 16 of 22 © WHO – EDM – 12/2001

 Validation
Dry heat sterilization
Parameters
Air circulation, positive air pressure, HEPA filter
Advantages
microorganisms destroyed
depyrogenation possible
Disadvantages
poor heat transfer
higher temperatures for long periods

Module 1, Part 3: Process validation Slide 17 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
Module 1, Part 3: Process validation Slide 18 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

Module 1, Part 3: Process validation Slide 19 of 22 © WHO – EDM – 12/2001

 Validation
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

Module 1, Part 3: Process validation Slide 20 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”

Module 1, Part 3: Process validation Slide 21 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
Module 1, Part 3: Process validation Slide 22 of 22 © WHO – EDM – 12/2001