This document discusses process validation for pharmaceutical manufacturing. It outlines the objectives of process validation which are to review validation, risk analysis, and critical steps for processes like solid dose mixing, tablet compression, and sterilization. It discusses determining critical process parameters and control points. Specific parameters that should be monitored and validated are identified for various unit operations like mixing, tablet compression, coating, and sterilization. The importance of change control procedures when making changes to validated processes is also covered.

1. 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

2. 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

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

4. 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

5. Module 1, Part 3: Process validation Slide 5 of 22 © WHO – EDM – 12/2001
Validation
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

6. 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

7. 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 limits
based on stability specifications
Validation limits

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

9. Module 1, Part 3: Process validation Slide 9 of 22 © WHO – EDM – 12/2001
Validation
Determining critical control points

10. 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

11. 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

12. Module 1, Part 3: Process validation Slide 12 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

13. Module 1, Part 3: Process validation Slide 13 of 22 © WHO – EDM – 12/2001
Validation
Tablet compression
parameters
 Mass
 Hardness
 Moisture
 Friability
 Disintegration
 Dissolution
 Thickness
Tablet coating
variables
 Spray rate
 Inlet and outlet air temp
 Coating weight

14. 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”

15. 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

16. 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

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

18. 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

19. 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

20. 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

21. 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”

22. 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