Process Validation

of
Sterile Liquid Products
By
Weerayut Chirarutsami
23/08/2006

Process Validation

Process validation is establishing documented evidence

which demonstrate that the manufacturing process will
consistently produce a product meeting its predetermined specifications and quality Characteristics.

New Product <==> Trial Batch, Development Batch

Transferred Product <==> Products produced at the sending site
Revalidation Product <==> The original product before revalidation

Process Validation
Type of Process Validation

Prospective

Concurrent

Conducted prior to market the product

Based on information generated during actual
implementation of the process (each batch will be
released separately)

Retrospective (Not recommended for sterile product)

Based on accumulated historical production, testing and

control data

Generally requires data from 10-30 batches

Use data only from batches made by the same process

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Validation of Sterile Product

Sterile Product :
The Products which free of any viable organisms.

Sterility :
Viable microorganisms are absent.

Bioburden :
Total number of viable microorganisms on or in
pharmaceutical product prior to sterilization.

Validation of Sterile Product

Terminal Sterilization :
Operation whereby the product is sterilized separately by
autoclave after filled and packaged using sterilized containers
and closures in critical processing zones.
Aseptic Operation:
Operation whereby the product is sterilized separately by filtering
through 0.2 or less filter, then filled and packaged using
sterilized containers and closures in critical processing zones.

Validation of Sterile Product

Validation Team: Production, QC, QA, Engineer,Planner
#

To prepare the validation protocol

Verify the calibration and maintenance status of equipment

Perform qualification for equipments and system

Verify change control

Schedule the validation activities

Training production operators

Conduct validation study

Monitor the critical steps in manufacturing process

Assure that the approved testing standard is being used

Evaluate all test results,

Prepare the validation report.

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Validation of Sterile Product

Pre-validation Requirements :
Preventive Maintenance for Facilities and Utilities
Calibration of Equipment
Cleaning Validation
Equipment & System Qualification
Raw Materials/Components/Test Methods
Process Justification
Change Control
Training operators
All must be proven suitable and reliable for the manufacturing process
before the process can be validated

Validation of Sterile Product

Process Justification:

To identify critical process steps & process parameter of Mixing

process

To determine the suitable Hold time Period

To confirm the analytical tests that will have to be performed

To define the optimal parameters throughout the overall ampoule

filling process to consistently produce the finished products(filled
ampoules) which meet the established specifications.

To assure that the product is sterile after sterilization process

Validation of Sterile Product

Validation Protocol
A document stating how validation will be conducted,
including test parameters, product characteristics, production
equipment to be used and decision points on what
constitutes acceptable test results

Validation of Sterile Product

Validation Protocol should contain :

Title Page, Review/Approval Page

Purpose and Overview

Equipment List

Ingredients and Component List

Qualification List of Equipment and System

Process Flow Diagram and Description

Equipment Critical Process Parameter

Process Validation Sampling Plan/Testing Requirements

Acceptance Criteria

Stability Requirements

Process for evaluation of any deviations occurring during validation

Conclusion

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Validation of Sterile Product

Equipment Critical Process Parameter:

Mixing Speed

Mixing Time

Gas flushing time

Type and size of filter

Filtering Time and Pressure used

Filling Speed

Temperature and Duration for Terminal Sterilization

Critical Manufacturing Step

Dissolving Step

pH adjustment step

Final mixing step

Filtering Step

Filling Step

Terminal Sterilization Step

Leak Test Step

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Validation of Sterile Product

Critical Processing Parameter
Mixing Speed
Mixing Time
Flushing Time
pH

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Validation of Sterile Product

Critical Processing Steps

Dissolved Active Ingredient

pH Adjustment
Final Mixing
Filtration
Filling
Sterilization
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Validation of Sterile Product

Acceptance Criteria
Dissolved Active Ingredient
pH Adjustment

Clear Solution

pH with in specification

Final Mixing

pH, Appearance, Assay Content,

Bioburden, Holdtime

Filtration

Filter Integrity, Sterility, pH,

Holdtime
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Validation of Sterile Product

Acceptance Criteria
Filling
Sterilization
Leak Test
Visual Inspection

Appearance, Bioburden,
Holdtime, Oxygen Headspace
Sterility, Assay, pH, Endotoxin etc.

No. of Leaked products

No. of Defected products

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Validation of Sterile Product

Product Testing

Validation testing of bulk and F/G must be based on

testing standard release criteria and in-process testing
criteria
Typically involves non-routine sampling/testing throughout
the entire process, with special emphasis on critical
process parameters.
Routine QC release testing should be performed on a
routine sample. These samples should be taken
separately from the validation samples.

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Validation of Sterile Product

Validation Batch:

New product and product transfer, Prospective validation is required

Manufacturing Process, Formula, Equipment and Batch Size have to

be fixed during the validation trials.

Batch Size should be the same size as commercial production batch

The batch size must be fixed for production.

Different lots but same manufacturer of active ingredients should be

used during validation trials.

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Validation of Sterile Product

Validation Batch: Bulk Sampling and Testing

Samples may be taken by

Collecting during Transfer

Using a sampling device

Take at least 2 samples at top, middle and bottom

Individual Testing of sample must be done and the result must meet the
testing standard specification

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Validation of Sterile Product

Qualification of Maximum Bulk Hold Time

The maximum period of time which the bulk can be held prior to
filter, Fill and/or Sterilization
It will be counted after finished final mixing step until transfer to
filter, finished filter until start filling and/or finished filling until start
sterilization
One full scale batch should be held for most practical maximum
time period prior to filter, fill and/or sterilization
If there is not enough support information / qualification done. The
period of 24 hours will be used
Hold time qualification must simulate actual storage condition

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Validation of Sterile Product

Finish Product Testing after Sterilization

Uniformity of filled volume

Sterility

10 samples from each of the beginning and end of the filling run.
Samples must represent all filling nozzles.

Visual Evaluation

Perform testing on filled containers.

Appearance, Color of solution

Other Testing

Assay, pH, Density, Pyrogen or Endotoxin etc.

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Validation of Sterile Product

Validation Report

Validation Team must prepare the report

Report must be reviewed and approved by QA.

Written Notification or either successful completion or failure of the

process validation must be issued to top management.

In case of failure, an investigation must be completed and documented

prior to repeat the validation study.

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Validation of Sterile Product

Changes and Revalidation

Change of any of the following may need revalidation

Formula Composition

Raw Material Source

Manufacturing Process

Manufacturing Location

Equipments

Batch Size

Testing Specification
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Validation of Sterile Product

Changes

Minor: It seems to have no impact on formulation

Intermediate : It could have significant impact on formulation

It is not necessary to validate

Depend on case-by-case (A minimum of 1 trial)

Major : It is likely to have significant impact on formulation

Revalidation is required (A minimum of 3 trials)

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Validation of Sterile Product

Minor Change

Qualitative inactive excipient change deemed minor by

change control review

Process change deemed minor by change control

review

Manufacturing location change with in same building,

same equipment, personnel, procedure and utilities are
used

Equipment change but same design, configuration

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Validation of Sterile Product

Intermediate Change

Active ingredient source or synthesis change deemed

intermediate by change control review

Qualitative inactive excipient change deemed intermediate by

change control review

Manufacturing location change to a different building on the

same site and same utilities, same equipment, personnel, and
procedure are used

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Validation of Sterile Product

Intermediate Change

Process changes, such as mixing times or operating speeds

for solutions.

Change in release specification to a tighter limit caused

original validation results to be out of specification

Extension of the qualified in process hold time for intermediate

or finished product prior to packaging

Equipment change deemed intermediate by change control

review

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Validation of Sterile Product

Major Changes

Quantitative or qualitative formulation change deemed major by

change control review

Inactive excipient or active ingredient source change deemed

major by change control review

Transfer product from on site to another

Significant change in process

Equipment change to a different design, configuration or operating

principle.

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Validation of Sterile Product

Major Changes

New Dosage

Rework Procedure

Process changes deemed major by change control review such as

mixing times or operating speeds for suspensions.

Change in release specification to a tighter limit caused original

validation results and routine production results to be out of
specification

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Validation of Sterile Product

Conclusion

Validation Protocol identifies critical process parameters to be

evaluated and predetermined acceptance criteria

Process must be continually monitored and change control used to

identify need for process revalidation

Production and QA have to review and approve the validation result

Product must be held until the validation get approval

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Re-validation

Regular performance of process simulation studies

Monitoring of environment, disinfection procedures,
equipment cleaning and sterilisation (including
containers and closures)
Routine maintenance and re-qualification of equipment,
e.g. autoclaves, ovens, HVAC (heating, ventilation and
air conditioning) systems, water systems, etc.
Regular integrity testing of product filters, containers,
closures and vent filters
Re-validation after changes

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Process simulation studies (media fills)

Process simulation studies (media fills) are simulating the
whole process in order to evaluate the sterility confidence
of the process.
Process simulation studies include formulation
(compounding), filtration and filling with suitable media.
Simulations are made to ensure that the regular process for
commercial batches repeatedly and reliably produces the
finished product of the required quality. However, each
process simulation trial is unique and so it is not possible to
extrapolate these results directly to actual production
contamination rates.

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Process simulation studies (media fills)

Where

filling takes place over extended periods, i.e.

longer than 24 hours, the process simulation test should
extend over the whole of the standard filling period. In
order to prevent excessively high numbers of units being
filled it is usually acceptable to just run the machine for a
reasonable time, if the validity of the simulation is not
diminished by this procedure.
The fill volume of the containers should be sufficient to
enable contact of all the container-closure seal surfaces
when the container is inverted and also sufficient to allow
the detection of microbial growth.

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Process simulation studies (media fills)

Where

filling takes place over extended periods, i.e.

longer than 24 hours, the process simulation test should
extend over the whole of the standard filling period. In
order to prevent excessively high numbers of units being
filled it is usually acceptable to just run the machine for a
reasonable time, if the validity of the simulation is not
diminished by this procedure.
The fill volume of the containers should be sufficient to
enable contact of all the container-closure seal surfaces
when the container is inverted and also sufficient to allow
the detection of microbial growth.

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Process simulation studies (media fills)

Incubation Temperature
It is generally accepted to incubate at 20-25C for a
minimum of 14 days without having collected data to
support this incubation schedule.
It is similarly acceptable for firms who prefer a two
temperature incubation schedule to incubate at 20-25C
for a minimum of 7 days followed immediately by
incubation at a higher temperature range not to exceed
35C for a total minimum incubation time of 14 days.

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Process simulation studies (media fills)

Acceptance Criteria
Ideally the contamination rate should be zero. However currently the
accepted contamination rate should be less than 0.1 % with a 95 %
confidence level according to the Annex I to the EU/PIC/S Guide to
GMP.

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Acceptance Criteria
FILL MUST MEET THE ACCEPTANCE LIMITS FROM THE FOLLOWING TABLE:

MAXIMUM ACCEPTABLE
CONTAMINATED UNITS
OBSERVED IN THE LOT
0
1
2
3
4
5
6
7
8
9
10
11
12

NUMBER OF GOOD
VIALS INCUBATED
3000
4750
6300
7760
9160
10520
11850
13150
14440
15710
16970
18210
19440

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