Supplementary Training Modules on
Good Manufacturing Practices
Validation Part 3:
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)
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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
parameters
Tablet coating
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

Lethality of cycle

D value

Z value

F value

Fo value min 8
D value (log scale)
100
“Z”
10
Temperature (oC)
1
90
95
100
105
Module 1, Part 3: Process validation
110
115
120
Slide 14 of 22
125
© 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