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:
q

Validation, risk analysis, and critical steps of processing Points to consider in process validation of: solid dose mixing tablet compression sterilization

Finalization of validation
Slide 2 of 22
WHO EDM 12/2001

Module 1, Part 3: Process validation

Validation

Introduction

Module 1, Part 3: Process validation

Slide 3 of 22

WHO EDM 12/2001

Validation
Reliable, repeatable, under control
q

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

q q

Does not improve processes

WHO EDM Slide 4 of 22 Should not validate bad processes 12/2001

Module 1, Part 3: Process validation q

Validation
DQ, IQ, OQ and PQ
Design Install Operate user or process requirements installation qualification operational qualification

Validate performance qualification and process validation Review periodically (+ change control)
Slide 5 of 22
WHO EDM 12/2001

Module 1, Part 3: Process validation

Validation
Critical factors or parameters
q q q

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
q

Marketing authorization limits

stability specifications

q q

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
q q q q

Particle size distribution of the active(s) Blending time for the powder Granulating time and speed,

Amount of granulating fluid-binder concentration

q

Drying time - final moisture content, granule particle size distribution

Granule active content and homogeneity, WHO Module 1, Partblending time of external phase EDM 12/2001 3: Process validation Slide 8 of 22
q

Validation
Determining critical control points
Process step XIII XIV XV Sieve 3/ 5 XVI Blend 3/5 granulate XVI Blend 2 with 3/5 granulate XVIII Operation Measure humidity with humidity meter Weigh granulate - balance IQ/OQ/PQ requirements IQ/OQ calibration IQ/OQ calibration IQ/OQ/PQ Cleaning validation instrument operation, cleaning, care and maintenance Training records for technician

sieve with sieve type 1 mixer (speed 1, 1 minute) mixer (speed 1, 30 seconds)

Critical control point

Cleaning, and Blend uniformity required to be established during validation

Weigh granulate

Critical Decision as to whether to 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)
q q q q q q

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)
q q q

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
q q

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

q q q q

Module 1, Part 3: Process validation

Slide 12 of 22

WHO EDM 12/2001

Validation
Tablet compression Tablet coating parameters variables
q q q q q q q

Mass Hardness Moisture Friability Disintegration Dissolution Thickness

q q q

Spray rate Inlet and outlet air temp Coating weight

Module 1, Part 3: Process validation

Slide 13 of 22

WHO EDM 12/2001

Validation
Moist heat sterilization
100

Thermal Death Curve

Z
10

Lethality of cycle D value Z value F value Fo value min 8

WHO EDM 12/2001

q q q

D value (log scale)

1 90

Temperature (oC)
95 100 105 110 115 120 125

Module 1, Part 3: Process validation

Slide 14 of 22

Validation
Sterilization validation (1)
q q q q

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)
q q q q q q

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
q q

Parameters Air circulation, positive air pressure, HEPA filter Advantages

microorganisms destroyed depyrogenation possible poor heat transfer higher temperatures for long periods
Slide 17 of 22
WHO EDM 12/2001

Disadvantages

Module 1, Part 3: Process validation

Validation
Process variation
Controllable causes of variation may include: q Temperature, humidity q Variations in electrical supply q Vibration q Environmental contaminants q Light q Human factors q Variability of materials q Wear and tear of equipment
Slide 18 of 22

Module 1, Part 3: Process validation

WHO EDM 12/2001

Validation
Change control
q

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
Slide 19 of 22
WHO EDM 12/2001

Module 1, Part 3: Process validation

Validation
Mixing validation liquid and solid dose change control and scale up
q q q q

Mixer type and size Batch size Pilot study scale up Limit on the proportion of the scale up
Slide 20 of 22
WHO EDM 12/2001

Module 1, Part 3: Process validation

Validation
Finalization of validation process
q q

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
Slide 21 of 22
WHO EDM 12/2001

q q

Module 1, Part 3: Process validation

Validation
Group Session
q

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
Slide 22 of 22
WHO EDM 12/2001

Module 1, Part 3: Process validation