PROCESS

VALIDATION
 PURPOSE AND SCOPE

Purpose:
To assist manufacturers in
understanding process
validation requirements.
Scope:
Applies to manufacturing
processes, servicing and
installation.
 DEFINITIONS.

Process validation.
Process validation is establishing
documented evidence, which
provides a high degree of
assurance that a specific process
will consistently produce a product
meeting its pre-determined
specifications and quality
characteristics.
 DEFINITIONS.

Verification.
Confirmation by examination and
provision of objective evidence that
the specified requirements have been
fulfilled.
Process performance
qualification.
Establishing confidence that the
process is effective and reproducible.
 DEFINITIONS.
Product performance
qualification.
Establishing confidence through
appropriate testing that the
finished product produced by a
specified process meets all release
requirements for functionality and
safety.
 DEFINITIONS.
Prospective validation.
Validation conducted prior to
the distribution of either a new
product or product made under
a revised manufacturing
process, where the revisions
may affect the product's
characteristics.
 DEFINITIONS.
Retrospective validation.
Validation of a process for a
product already in distribution
based upon accumulated
production, testing and control
data.
 DEFINITIONS.

Validation protocol.
A written plan stating how
validation will be conducted,
including test parameters,
product characteristics,
production equipment, and
decision points on what
constitutes acceptable test
results.
 DEFINITIONS.
Worst case.
A set of conditions encompassing
upper and lower processing limits
and circumstances, including those
within standard operating
procedures, which pose the greatest
chance of process or product failure
when compared to ideal conditions.
Such conditions do not necessarily
induce product or process failure.
 VALIDATION AND GMP
Validation is an essential and integral
part of Good Manufacturing Practice
(GMP).
Validation is an element of the quality
assurance programme associated with
a particular product or process.
Validation of processes and systems is
fundamental to achieving these goals.
 PROCESSES THAT SHOULD
BE VALIDATED.

Special Processes.
• Special processes are those
for which the product cannot
be fully verified.
• Regulations may require
process validation for special
processes.
EXAMPLE OF A SPECIAL PROCESS

• Clinical or destructive testing

is necessary to show the
process produced the desired
result or product
• Example:
• Testing all package seals
destroys packages
• Sterility testing of filled units
 EXAMPLES OF PROCESSES
THAT SHOULD BE VALIDATED
Sterilization processes.
Clean room ambient conditions.
Aseptic filling processes.
Sterile packaging sealing processes.
Lyophilization process.
Heat treating processes.
Plating processes.
Plastic injection molding processes.
 EXAMPLES OF PROCESSES
THAT MAY BE VERIFIED
Testing for color, turbidity,
total pH for solutions
 VALIDATION

Validation is an essential
control for assuring that the
specifications for the device
and manufacturing process are
adequate to produce a device
that will conform to the
approved design
characteristics
 ELEMENTS OF PROCESS
VALIDATION
Prospective validation.
Prospective validation includes
those considerations that should be
made before an entirely new
product is introduced by a firm or
when there is a change in the
manufacturing process which may
affect the product's characteristics,
such as uniformity and identity.
 KEY ELEMENTS OF
PROSPECTIVE VALIDATION.
Equipment and Process.
The equipment and process(es)
should be designed and/or selected
so that product specifications are
consistently achieved. This should be
done with the participation of all
appropriate groups that are
concerned with assuring a quality
product, e.g., Engineering design,
production operations, and quality
assurance personnel.
 EQUIPMENT : INSTALLATION
QUALIFICATION
Installation qualification studies
establish confidence that the
process equipment and ancillary
systems are capable of consistently
operating within established limits
and tolerances. After process
equipment is designed or selected,
it should be evaluated and tested to
verify that it is capable of operating
satisfactorily within the operating
limits required by the process.
 EQUIPMENT : INSTALLATION
QUALIFICATION
Tests and challenges should be
repeated a sufficient number of times
to assure reliable and meaningful
results. All acceptance criteria must
be met during the test or challenge. If
any test or challenge shows that the
equipment does not perform within
its specifications, an evaluation
should be performed to identify the
cause of the failure.
 EQUIPMENT : INSTALLATION
QUALIFICATION

Corrections should be made

and additional test runs
performed, as needed, to
verify that the equipment
performs within specifications.
 PROCESS: PERFORMANCE
QUALIFICATION
The purpose of performance
qualification is to provide
rigorous testing to demonstrate
the effectiveness and
reproducibility of the process.
This can be done after process
specifications have been
established and equipment is
found suitable based on the
installation studies.
 PROCESS: PERFORMANCE
QUALIFICATION

Each process should be defined

and described with sufficient
specificity so that employees
understand what is required.
Parts of the process which may
vary so as to affect important
product quality should be
challenged.
 PROCESS: PERFORMANCE
QUALIFICATION
In challenging a process to assess
its adequacy, it is important that
challenge conditions simulate
those that will be encountered
during actual production,
including "worst case" conditions.
The challenges should be
repeated enough times to assure
that the results are meaningful
and consistent.
 PROCESS: PERFORMANCE
QUALIFICATION

Each specific manufacturing

process should be
appropriately qualified and
validated.
 STATISTICAL METHODS AND
TOOLS FOR PROCESS
VALIDATION
Nonconformities often occur
because of:
– Errors made.
– Excessive variation.
– Off target processes.
 ERRORS

Mistake proofing methods can reduce

errors.
Make it impossible for errors to occur,
or
Make it impossible for error to not be
detected.
Perform challenge tests to show that
mistake proofing methods work.
EXCESSIVE VARIATION & OFF
TARGET PROCESSES
Capability study measures ability of
process to consistently meet
specifications.
Useful in dealing with excessive
variation and off target processes.
Perform tests at nominal and worst
case conditions.
 UNSTABLE PROCESS VS
STABLE PROCESS
Unstable process is inconsistent
and unpredictable.
Stable process is consistent and
predictable, BUT is it capable?
 STABLE AND CAPABLE
PROCESS

Stable and capable process:

– Is consistent.
– Is predictable.
– Has variation that falls within the
upper and lower specification
limits.
 CONDUCTING A VALIDATION
ACTIVITY: CHECKLIST FOR
VALIDATION ACTIVITY
Form multi- functional team.
Plan approach and define requirements.
Identify and describe process.
Specify process parameters & desired
output.
Decide on verification and / or
validation.
Create master validation plan.
Select methods and tools for validation.
 CHECKLIST FOR VALIDATION
ACTIVITY
Create validation protocols.
Perform IQ, OQ, PQ and document
results.
Determine continuous process
controls.
Control process continuously.
 PROCESS VALIDATION
PROTOCOL
A document showing how
validation will be conducted,
including test parameters, product
characteristics, manufacturing
equipment, and decision points on
what constitutes acceptable test
results.
 PROCESS VALIDATION
PROTOCOL
Include in protocol:
Process to be validated.
Device(s) to be manufactured with
process.
Criteria for successful validation.
Length and duration of validation.
Shifts, operators, equipment to be
used.
Utilities and quality.
More….
 PROCESS VALIDATION
PROTOCOL
Continued:
Operators and operator qualifications.
Complete description of process.
Relevant specifications for product,
components, manufacturing materials,
etc.
Special controls or conditions on
preceding processes during validation.
More………
 PROCESS VALIDATION
PROTOCOL
Continued:
Process parameters to be monitored
and methods for controlling and
monitoring
Product characteristics to be
monitored and methods
Any subjective criteria for
evaluating product
More………
 PROCESS VALIDATION
PROTOCOL
Continued:
Definition of non- conformance.
Statistical methods for data
collection and analysis.
Consideration of maintenance and
repairs of manufacturing
equipment.
Criteria for revalidation.
 INSTALLATION
QUALIFICATION (IQ)
Establishing by objective evidence
that all key aspects of the process
equipment and ancillary system
installation adhere to the
manufacturer’s approved
specification and that the
recommendations of the supplier of
the equipment are suitably
considered.
 OPERATIONAL
QUALIFICATION (OQ)
Establishing by objective evidence
process control limits and action
levels which result in product that
meets all predetermined
requirements.
 PERFORMANCE
QUALIFICATION (PQ)
Establishing by objective evidence
that the process, under anticipated
conditions, consistently produces a
product which meets all
predetermined requirements.
 FOR IQ, OQ AND PQ

Determine:
– What to verify/ measure.
– How to verify/ measure.
– How many to verify/ measure
(statistical significance).
– When to verify/ measure.
Define:
– Acceptance/ rejection criteria.
– Required documentation.
 INSTALLATION
QUALIFICATION (IQ)
Key Objective: Is the
equipment installed correctly?
 INSTALLATION
QUALIFICATION (IQ)

Important IQ considerations:
– Equipment design
– Installation conditions (wiring,
utilities, functionality)
– Calibration, preventive
maintenance, cleaning schedules
– Safety features
– Supplier documentation, prints,
drawings, manuals
 INSTALLATION
QUALIFICATION (IQ)

Important IQ considerations
(contd.).
– Software documentation.
– Spare parts list.
– Environmental conditions.
 INSTALLATION
QUALIFICATION (IQ)

Use equipment supplier

qualification studies as:
– Guides.
– To obtain basic data.
– To supplement installation
qualification.
– Supplier qualification studies usually
are not sufficient to substitute for
IQ.
 OPERATIONAL
QUALIFICATION (OQ)
Key Objectives:
– Develop and challenge process
parameters.
– Establish action levels.
– Determine robustness of process.
– Determine ability to avoid
approaching worst case conditions.
 OPERATIONAL
QUALIFICATION (OQ)

OQ considerations:
– Process control limits
– Software parameters
– Raw material specifications
– Process operating procedures
– Material handling requirements
– Process change control
 OPERATIONAL
QUALIFICATION (OQ)
OQ considerations:
– Training.
– Short term stability and capability
of process.
– Potential failure modes, action
levels and worst case conditions.
– Use of statistically valid techniques
to establish key process
parameters and optimize process.
 PERFORMANCE
QUALIFICATION (PQ)
Key objective: Demonstrate process
will consistently produce acceptable
product under normal operating
conditions.
Challenge process to simulate
conditions during actual
manufacturing.
Include range of conditions defined by
action levels allowed in written SOPs.
Analyze process to determine normal
range of variation for process output.
 PERFORMANCE
QUALIFICATION (PQ)

Analyze process and product

data to identify variation due
to controllable causes.
Eliminate controllable causes
of variation.
 PERFORMANCE
QUALIFICATION (PQ)

Controllable causes of
variation include:
– Temperature.
– Humidity.
– Variations in electrical supply.
– Vibration.
– Environmental contaminants.
 FINAL REPORT

Summarize and reference all

protocols and results.
Provide conclusions regarding
validation status of process.
Validation team and
management should review
and approve report.
 MAINTAINING A STATE OF
VALIDATION.

Monitor and Control.

• Monitor trends to ensure process
remains within established
parameters.
• Investigate causes of negative
trends.
• Take corrective action.
• Consider need for revalidation.
 MAINTAINING A STATE OF
VALIDATION.

Changes in Process and / or

Product.
• Evaluate any changes in
procedures, equipment, personnel,
etc.
• Determine effect on process and
consider need for and extent of
revalidation.
 MAINTAINING A STATE OF
VALIDATION.

Continued State of Control

• Changes in raw materials and / or
processes may be undetected or
considered not significant
• Cumulative changes may affect
process
 MAINTAINING A STATE OF
VALIDATION.

Examples of Reasons for

Revalidation.
• Process change that affects quality or
validation status.
• Negative trend in quality indicators.
• Product design change affects
process.
• Moving process to another facility.
• Change in application of the process.
 REVALIDATION

Evaluate need for revalidation.

Document evaluation.
Include:
– Historical results from quality
indicators.
– Product changes.
– Process changes.
– Changes in external requirements.
 REVALIDATION

Revalidation may be less extensive

than original validation.
Example 1: Purchase of new
equipment.
– Repeat IQ.
– Most of OQ already established.
– Some PQ may need repeating.
 REVALIDATION

Example 2: Change in raw material

supplier.
– IQ need not be repeated.
– Repeat parts of OQ and PQ to fully
understand interaction between
new raw material and process.
 USE OF HISTORICAL DATA
FOR VALIDATION
Sources of historical data include:
• Batch records.
• Manufacturing log books.
• Lot records.
• Control charts.
 USE OF HISTORICAL DATA
FOR VALIDATION
Sources of historical data
(continued):
• Test and inspection results.
• Customer feedback.
• Field failure reports.
• Service reports.
• Audit reports.
 USE OF HISTORICAL DATA
FOR VALIDATION
Validation can be partially based on
historical data.
Relying completely on historical
data is not feasible if:
– Appropriate data not collected.
– Manner of collection does not allow
for adequate analysis.
– Data is pass / fail (usually not
adequate).
 USE OF HISTORICAL DATA
FOR VALIDATION
If data is adequate and
representative, conduct analysis per
written protocol.
Determine if process has:
– Operated in state of control.
– Consistently produced product
meeting predetermined
requirements.
Document analysis.
 SUMMARY OF ACTIVITIES

Initial considerations:
Identify and describe process.
Decide on verification and/ or
validation.
Create master validation plan.
 SUMMARY OF ACTIVITIES

If decision is to validate:
– Form multi- functional team
– Plan approach & define requirements
– Identify & describe processes
– Specify process parameters and output
– Create master validation plan
– Select methods and tools for validation
 SUMMARY OF ACTIVITIES

Maintaining a state of validation

– Monitor and control process
continuously
– Revalidate as appropriate
Thank
you