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

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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

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Introduction

Validation

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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

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ValidationValidation

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

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Validation

Critical factors or parameters

Need to be determined

Need to be monitored during validation

May affect the quality of the product

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Validation

Setting Limits Marketing authorization limits

stability specifications Release specification

Validation limits

Batch release limits

Marketing authorisation limitsbased on stability specifications

Validation limits

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Determining critical control pointexample 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

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Criticalcontrolpoint

Measure humidity withhumidity meterXIII

IQ/OQcalibration

Weigh granulate - balanceXIV IQ/OQcalibration

instrumentoperation,

cleaning, careand maintenance

Trainingrecords fortechnician

XV Sieve 3/5

sieve with sieve type 1

XVI Blend3/5

granulatemixer (speed 1, 1 minute)

XVI Blend 2with 3/5

granulate

mixer (speed 1, 30seconds)

IQ/OQ/PQCleaningvalidation

Cleaning, and Blenduniformity required to be

established during validation

XVIII Weigh granulate Criticalcontrolpoint

Decision as to whether tocompress or not based on

expected yield and actual yield

Process step Operation IQ/OQ/PQ requirements

Validation

Determining critical control points

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

Validation

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Solid dose mixing (2) In situ analysis

Methods of analysis

Statistical analysis

inter-batch intra-batch within-sample-site

Validation

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ValidationTablet compression

variables Fill volume Pre-compression force, compression

force Turntable speed Dwell time Granule size and feed Ejection force, lubrication

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ValidationTablet compression

parameters Mass

Hardness

Moisture

Friability

Disintegration

Dissolution Thickness

Tablet coating variables Spray rate Inlet and outlet air

temp Coating weight

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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”

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Validation

Sterilization validation (1)

Sterility test

Physical measurements

Chemical and biological indicators

Loading patterns

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Validation

Sterilization validation (2) Cooling fluid or gas

Automated process

Leak tests

Control instrumentation

Steam quality

Heat distribution

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ValidationDry heat sterilization Parameters Air circulation, positive air pressure, HEPA

filter Advantages

microorganisms destroyed depyrogenation possible

Disadvantages poor heat transfer higher temperatures for long periods

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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

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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

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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

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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”

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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