VALIDATION AND QUALIFICATION PROCESS

VALIDATION
VALIDATION and
QUALIFICATION
Sandeep Cuddapah- Dept. of Validation & compliance

Validation and Qualification
Validation
• Action of proving, in accordance with the principles of GMP, that any
procedure, process, equipment, material, activity or system actually
leads to the expected results
Definition ( FDA)
“ Establishing the documented evidence which provides a high degree of

assurance that a specific process will consistently produce a product of
predetermined specifications and quality attributes.”
(FDA Guidelines 1987)

Qualification
• Action of proving that any premises, systems and items of equipment
work correctly and actually lead to the expected results
Definition ( FDA)
“Process validation is defined as the collection & evaluation of

data, from the process design stage through commercial
production, which establishes scientific evidence that process is
capable of consistently delivering quality product.”
(FDA Guidelines, 2011)

Where did validation come from ?
• Began in 1970’s
• Originally sterilized based.
• Now evolved into all Product, Process and Facility

matters.

Why Validate ?
• Assures Quality
• Regulatory Requirement
• Reduces Cost
• It’s the LAW !

Benefits
Validation can reduce costs by reducing,
• Rejects
• Reworks
• Reliance on In-process controls
• Down time

When it goes wrong …..?
• Reliance on product testing
• Loss of confidence
• Possibility of adulterated products
• Inspection : Observations / 483’s

Validation Terminology
• User Requirement Specification (URS)
• Design Qualification
• Impact Assessment
• Factory Acceptance Testing
• Installation Qualification

• Calibration
• Site Acceptance Testing
• Operational Qualification
• Standard Operating Procedures
• Performance Qualification
• Process Validation
• Change Control

User Requirement Specification (URS)
• A description of the requirements of the facility

(project) in terms of product to be manufactured,
required throughput and conditions in which the
product should be manufactured.
• Approved statements prepared by the user which

defines what is required by the project.

Design Qualification (DQ)
• Documented review of the design, at an appropriate

stage in a project, for conformance to operational
and regulatory expectations.

Impact Assessment
• The process of evaluating the impact of the

operating, controlling, alarming and failure
conditions of a system on the quality of a product

Factory Acceptance Testing (FAT)
Inspection and static and/or dynamic testing of systems

or major system components to support the
qualification of an equipment system conducted and
documented at a supplier site.

Installation Qualification (Definition)
• Documented verification that all aspects of a facility,

utility or equipment that can affect the product quality
adhere to approved specifications and are correctly
installed.
• The process of checking/verifying the installation to

ensure that the critical components meet the
approved specifications and that they are installed
correctly in accordance with design documentation.

Installation Qualification (PURPOSE)
• To establish that the critical components are installed

correctly and in accordance with design documentation
requirements (i.e. PO’s, Contracts etc.), that supporting
documentation is in place and of suitable quality.
• To record the checks and verifications for critical

components in Direct Impact Systems.

IQ Protocol (Contents)
• Approval Page
• Objectives
• System Description
• Responsibilities
• Acceptance Criteria
• Engineering Documentation Requirements
• Records of Signatures
• Qualification Test Equipment/Instrument List
• Product Contact Materials Review
• Utilities Verification
• Control System Verification
IQ Protocol (Contents)
• Instrument/Control Devices Verification

• Equipment Verification
• Piping Installation Verification
• Discrepancy/Justification and corrective Action
• As built P&I Diagrams
• Specifications
• Conclusions
• References
• Modification/ Change Control
• Attachments / Appendices

Basic IQ – Mfg. vessel
• Parameters
• Does the vessel meet the design specification?

• Does the agitator assembly meet the design specification?
• Is the motor housing earthed?
• Is the motor over current device set to correct setting?
• Is all the pipe work connected?
• Are all instruments installed as per P&I diagram?
• Have all the temperature indicators been calibrated?
• Is calibration procedure available?
• Are operation and maintenance manuals available?
• all electrical connections securely and safely fitted?
• Is insulation complete?
• Is vessel clean and free from dirt?
IQ Protocol Approval
• After protocol execution is complete and deviations

evaluated, post execution approval is required.
• Requires sign off by original signatories.
• IQ execution should be complete and approved prior to the

start of OQ.

Operational Qualification (Definition)
• Documented verification that all aspects of a facility, utility or

equipment that can affect product quality operate as
intended throughout all anticipated ranges. It is the process
of testing to ensure that individual components and systems
operate as specified, and how that information is recorded.

Operational Qualification (PURPOSE)
• To establish through documented testing, that all critical

components and direct impact systems are capable of operating
within established limits and tolerances.
• To test parameters that regulate the process or product quality.

To verify the proper operation of controllers, indicators,
recorders, alarms and interlocks, is performed and documented
during the operational qualification testing.

Operational Qualification (Protocol)
• Approval page
• Pre-requisites
• Objectives
• System Description
• Responsibilities
• Acceptance Criteria
• Records of signatures
• Qualification test Equipment/Instruments list
• Alarm and Interlocks test
• Operation testing
• Capacity testing
• Power failure testing
Operational Qualification (Protocol)
• Sequence testing
• Test data sheets
• SOP’s
• Conclusions
• Modification / change control
• Discrepancy/Justification and corrective action
• Operational Qualification Summary
• References
• Attachments/Appendices
• - Verification of test instruments
• - Chart recordings
• - P&I diagrams
• - Printouts
OQ – Mfg. vessel
Parameters
• Have all Installation Qualification been completed for this

system?
• Is the system clean and free from dirt?
• Is the direction of the rotation of agitator correct?
• Check the operation of the agitator emergency stop?
• Check the operation of all agitator controls, both on the main
and local panels?
• Check that the agitator in the vessel free to turn?
• Pressurize the vessel and record the pressure drop for 10 min.
• Perform a vacuum test and record the vacuum drop.

Performance Qualification (Definition)
• Documented verification that all aspects of a

facility, utility or equipment that can affect the
product quality perform as intended in meeting
the predetermined acceptance criteria.

Performance Qualification (Purpose)
• To integrate procedures, personnel, systems and

materials to verify that the utility / environment /
equipment / support systems produces the required
output. This output may be a product contact utility,
sterilization condition or environment.

Performance Qualification (Protocol)
 Approval page Test equipment/Instrument list

Test data sheets
 Pre-requisites
SOP’s
 Objectives References
 System Description Conclusions
Attachments
 Responsibilities
 Acceptance Criteria
 PQ test plan
 Challenge test plan
 Records of signatures

Qualification and Validation
Principle
 Essential part of GMP
 Manufacturer to identify what qualification and validation
work is required
 Prove that critical aspects of work are controlled
 Key elements of qualification and validation defined and
documented

Scope
• Documented evidence to prove that, e.g.

• Premises
• Supporting utilities
• Equipment
have been designed(DQ), installed(IQ), operate(OQ),
perform(PQ) desired action in accordance with GMP.

Scope
• Documented evidence to prove that:
• A specific process will consistently produce a
product meeting its predetermined specifications
and quality attributes
• Also referred to as Process Validation (PV)

Scope
Qualification and validation:
• Applicable to any aspect of operation which may affect

the quality of the product
• Directly or indirectly
• Includes premises, facilities (utilities), equipment,

processes
• Includes significant changes

Planning
• Qualification and validation should be done in
accordance with an ongoing programmed
• Initial qualification and validation
• Annual review
• Maintain continued validation status
• Policy described in relevant documentation, e.g. quality

manual, or Validation Master Plan

Types of Documentation
• Validation Master Plan (VMP)
• Validation protocols
• Validation reports
• Standard Operating Procedures (SOPs)

Equipment validation
Following equipments are identified as critical – for manufacturing:
1. Autoclave
2. Vial/Cartridge Washing Machine
3. Continuous Sterilizing Tunnel
4. Laminar Air Flow units
5. Air Handling Units
6. Transfer Vessels
7. Mobile Tanks
8. Peristaltic Pump
9. Weighing Balance
10. CIP Unit
11. Integrity Tester
12. Syringe Filing Machine

Equipment validation
Following equipments are identified as critical – for
manufacturing:
13. Vial Filling Machine
14. Cartridge Filling Machine
15. Vial Sealing Machine
16. Lyophilizer
17. Inspection Table
18. Labelling Machine
19. Carton Coding Machine
20. Blister Packing Machine
21. Cartonator
22. Shrink Tunnel

1. Autoclave
Critical parameters to be verified:
a) Temperature mapping and biological
indicator results
b) Pressure
c) Equilibration time
d) Fo value
Frequency of validation:
Every 6months
Autoclave
A. heat distribution load (empty chamber)
B. heat penetration load (load items)
Validation Requirements:
• Calibrated temperature data logger and temperature sensors
(Thermocouples).
• Check the item code, supplier, and part number of the wrapping material
used for the wrapping of the autoclave load items and record the same in
the validation report.
• Biological Indicator: Paper strips of Geobacillus stearothermophilus with
a population size greater than 106 CFU (1x 106 CFU-5x 106 CFU) and D
value of 1.5-2.5 minutes should be used for the validation activity. Lot
number and expiry dates for the Biological indicator used in the
validation run should be noted in the Validation report.
• Items to be sterilized as per requirements listed under the respective
sections in the Protocol.
• Procedures for operation of the autoclave (BF/FM/SOP/018) & standard
operating procedure for carrying out the Bowie Dick test
(BF/FM/SOP/029).

Autoclave
Formula for the Fo value calculation:
Fo=Δt 10( T-121.1)/Z
• Fo = the number of minutes to kill a specified number of
microorganisms with Z value of 10◦ C at a temperature of
121.1◦ C.
• t= time interval between successive temperature
measurements.
• T= Temperature achieved at given time interval.
• Z= Temperature change required resulting in a change of the
D-value by one (1) log
• D value = time in minutes, at a specific temperature, to
reduce the surviving microbial population by 90 %( one
logarithmic reduction
Autoclave
Vacuum Leak test (VLT):
Vacuum leak test is done to see leakage into the chamber which
should not increase the specified limit.
Acceptance criteria:
The vacuum must not drop as per required specification i.e.
0.0013 bar/min.
Bowie-Dick Test (Air Removal Test):
1. The test is accurate only when there is no load in the
chamber & is done as per SOP
2. Bowie-Dick test is carried out to verify that the sterilizer's
vacuum phase is removing sufficient amount of air prior to
the introduction of steam into the chamber. It is also to check
for air leaks into the chamber during the sterilization cycle
Autoclave
3. This test shall be done at the beginning of the studies to
ensure the proper removal of the air from the chamber.
Ensure the cleanliness of the chamber.
4. Place the pack near the door and over the drain (100-200 mm
above the chamber floor).
5. After the cycle is complete, remove the pack and open to
examine the indicator sheet.
A uniform black/ brown coloration throughout the paper.

Autoclave
Sl.
Critical Parameter Acceptance Criteria Rationale
No.
Temperature during hold
1 121°C to 124°C HTM-2010
period
Overkill
2 Sterilization hold period Not less than 30 minutes
approach
Chamber pressure during hold In House
3 1.04 Bar to 1.24 Bar
period specification
Temperature difference during
4 heat distribution across the NMT 2 Degrees HTM-2010
chamber
Empty chamber heat
5 Program no. In house
distribution-validation
Pressure should be reduced to
less than 0.5 bar from 1.4 bar
6 Air detector test As per vendor
within 3 minutes. Sterilization
Passed
7 Equilibration time ≤ 30 seconds HTM-2010
2. Vial/Cartridge Washing Machine
a) Temperature of WFI and clarity of WFI & Purified
water
b) Pressure (compressed air/water)
c) Counting efficiency
d) Washing efficiency (Glass powder spiked (15
mg/vial), riboflavin (0.1%) and sodium chloride
(20%))
3 years
3. Continuous Sterilizing Tunnel
a) Temperature mapping
b) Conveyor speed
c) FH value
d) Depyrogenation study
e) HEPA integrity test, non viable particle count,
air velocity
Every 6months
4. Laminar Air Flow units
a) Air velocity (once in a year)
b) Flow pattern(Once in year)
c) HEPA integrity test(Once in six months)
d) Non viable particle count (Once in quarterly)
pressure gauges are calibrated every 6months.

5. Air Handling Units
a) Air flow velocity (once in a year)
b) HEPA integrity test(once in a year)
c) Non viable particle count (every 6months)

6. Transfer Vessels
a) Pressure hold (Maximum working pressure)
12 months and pressure gauges calibrated every
6months.

7. Mobile Tanks
a) Pressure hold (Maximum working pressure)
b) Cleaning efficiency with Riboflavin(During
qualification)
c) RPM of Impeller (During qualification)
These tests are done during qualification and
pressure hold test frequency 12months and
pressure gauges calibrated every 6months.
8. Peristaltic Pump
a) RPM
b) Flow rate
RPM is verified before every use.

9. Weighing Balance
a) Repeatability
b) Eccentricity
c) Uncertainty
d) Linearity
calibration done every day.
Ex: 220 gm Analytical Weighing Balance PQ
Verification of repeatability
1. Reset the value to zero by pressing the tare button and then
confirm the indicator value is zero.
2. Load the weight equivalent to the test load of 200 gm on the
center on the pan, and then record the indicator value.
3. Remove the weight.
4. Repeat the test 10 times by placing the same weight on the
same place record the result.
5. Calculate the standard deviation.
RSD for 10 observation of each weight not more than 0.05% of
weight used .

Verification of Eccentricity:
Reset the value to zero by pressing the tare button and then
confirm the indicator value is zero.
Load a 50 g weight, which is equivalent to the test load, on the
center of the pan (position 1) and then record the indicator
value.
Place weight at 2nd, 3rd 4th and 5th position as per figure and
record the observation.
Check the variation in the weight at different position.
Variation should not be more than 0.05% of weight used.

Verification of Uncertainty:
1. Set an indicated value to zero by pressing the Tare option provided
on the Weighing balance.
2. Load a 200 mg weight, which is equivalent to the test load on the
weighing platform and note down the observation.
3. Remove the weight from the balance.
4. Again place the weight on the balance and note down the reading
5. Remove the weight form the balance.
Repeat the same procedure 10 times at and record the results in the report
and take the printouts. Calculate the Standard deviation
Uncertainty = (3XSD)/ weight used
Standard deviation =
X = Individual variable X = Mean, n = number of readings
Not more than 0.05%
Verification of the Linearity:

1. Set an indicated value to zero by pressing the Tare option
provided on the Weighing balance.
2. Place the minimum weight on the balance as per vendor
qualification document and note the observation.
3. Remove the weight
4. Repeat the test also for other weights mentioned in the table
and note the results.
5. After collecting the result of the entire weight and check that
it is should be within the tolerance limit.
6. Plot a Graph of the observed readings against the Standard
weight used.

Acceptance criteria of the Linearity:

A Straight line shall be formed after joining all the reading with
the origin of the X, Y axis. The difference in the reading should
not be more than 0.05% weight used .

10. CIP Unit
a) Sequence
b) Concentration of chemicals used
c) Conductivity
d) Temperature
All transmitters and pressure gauges are
calibrated every 6months.
11. Integrity Tester
a) Printer test
b) Pressure drop test
c) Diffusion and bubble point test
d) Water intrusion and water flow test
calibration frequency is 12 months.
12. Syringe Filing Machine
a) Sensor verification
b) LAF readings under which machine is installed
c) Temperature, RH, and pressure of the area.
d) Fill volume verification and plunger orientation
e) Filling machine speed
3 years

13. Vial Filling Machine
b) LAF readings under which machine is
installed
d) Fill volume verification
3 years
14. Cartridge Filling Machine
b) LAF readings under which machine is installed
d) Fill volume verification and plunger orientation
3 years

15. Vial sealing machine
b) Machine speed
c) Seal integrity
3 years

16. Lyophilizer
a) Temperature mapping with biological
indicator results
b) Fo value
12 months

17. Inspection Table
a) Light intensity
b) scratch free background
Monthly once light intensity is checked

18. Labeling Machine
a) Conveyor speed
Frequency of validation: NA
NOTE: Regular PM required and critical
parameter verification before every batch

19. Carton Coding Machine
a) Conveyor speed
b) Camera station (optical character
recognition/ optical character Verification)

20. Blister Packing Machine
a) Heating temperature
b) Blister dimentions
c) No form and No fill detection

21. Cartonator
a) Machine speed
b) Speed synchronization between turn table
and cartonator

22. Shrink Tunnel
a) Temperature mapping
b) Conveyor speed
Heater and conveyor speed are calibrated every
6months

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VALIDATION

Sandeep Cuddapah- Dept. of Validation & compliance

“ Establishing the documented evidence which provides a high degree of

(FDA Guidelines 1987)

“Process validation is defined as the collection & evaluation of

(FDA Guidelines, 2011)

Sandeep Cuddapah- Dept. of Validation & compliance

• Originally sterilized based.

• Now evolved into all Product, Process and Facility

Sandeep Cuddapah- Dept. of Validation & compliance

• It’s the LAW !

Sandeep Cuddapah- Dept. of Validation & compliance

Validation can reduce costs by reducing,

Sandeep Cuddapah- Dept. of Validation & compliance

• Reliance on product testing

• Possibility of adulterated products

• Inspection : Observations / 483’s

Sandeep Cuddapah- Dept. of Validation & compliance

• User Requirement Specification (URS)

• Factory Acceptance Testing

Sandeep Cuddapah- Dept. of Validation & compliance

Sandeep Cuddapah- Dept. of Validation & compliance

User Requirement Specification (URS)

• A description of the requirements of the facility

• Approved statements prepared by the user which

Sandeep Cuddapah- Dept. of Validation & compliance

Design Qualification (DQ)

• Documented review of the design, at an appropriate

Sandeep Cuddapah- Dept. of Validation & compliance

• The process of evaluating the impact of the

Sandeep Cuddapah- Dept. of Validation & compliance

Factory Acceptance Testing (FAT)

Inspection and static and/or dynamic testing of systems

Sandeep Cuddapah- Dept. of Validation & compliance

• Documented verification that all aspects of a facility,

• The process of checking/verifying the installation to

Sandeep Cuddapah- Dept. of Validation & compliance

• To establish that the critical components are installed

• To record the checks and verifications for critical

Sandeep Cuddapah- Dept. of Validation & compliance

• Instrument/Control Devices Verification

Sandeep Cuddapah- Dept. of Validation & compliance

• Does the vessel meet the design specification?

• After protocol execution is complete and deviations

• Requires sign off by original signatories.

• IQ execution should be complete and approved prior to the

Sandeep Cuddapah- Dept. of Validation & compliance

• Documented verification that all aspects of a facility, utility or

Sandeep Cuddapah- Dept. of Validation & compliance

• To establish through documented testing, that all critical

• To test parameters that regulate the process or product quality.

Sandeep Cuddapah- Dept. of Validation & compliance

• Have all Installation Qualification been completed for this

Sandeep Cuddapah- Dept. of Validation & compliance

• Documented verification that all aspects of a

Sandeep Cuddapah- Dept. of Validation & compliance

• To integrate procedures, personnel, systems and

Sandeep Cuddapah- Dept. of Validation & compliance

 Approval page Test equipment/Instrument list

Sandeep Cuddapah- Dept. of Validation & compliance

Sandeep Cuddapah- Dept. of Validation & compliance

• Documented evidence to prove that, e.g.

Sandeep Cuddapah- Dept. of Validation & compliance