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
Process step Operation IQ/OQ/PQ requirements

Measure humidity with IQ/OQ

XIII calibration instrument Training
humidity meter
operation, records for
cleaning, care technician
XIV Weigh granulate - balance IQ/OQ
and maintenance
calibration

XV Sieve 3/
sieve with sieve type 1
5 IQ/OQ/PQ
XVI Blend Cleaning Critical Cleaning, and Blend
3/5 validation control uniformity required to be
mixer (speed 1, 1 minute)
granulate point established during validation
XVI Blend 2 mixer (speed 1, 30
with 3/5 seconds)
granulate

XVIII Critical Decision as to whether to

Weigh granulate
control compress or not based on
point expected yield and actual yield

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”
 Z value
10
 F value
D value (log scale)

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