Reference
Summary
Performance Qualification
Qualification Stages
Qualification Approach
Introduction
BY ANWAR MUNJEWAR
CLEANROOM
QUALIFICATION
CLEANROOMS AND ASSOCIATED CONTROLLED ENVIRONMENTS
Introduction
Cleanroom & Clean zone
QUALIFICATION- Action of proving that any premises,
systems and items of equipment work correctly and
actually lead to the expected results. The meaning of
the word “validation” is sometimes extended to
incorporate the concept of 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.
SPECIFICATION- A list of detailed requirements with
which the products or materials used or obtained
during manufacture have to conform. They serve as a
basis for quality evaluation.
CLEAN AREA- An area with defined environmental
control of particulate and microbial contamination,
constructed and used in such a way as to reduce the
introduction, generation, and retention of contaminants
within the area
CLEAN ZONE- Defined space within which the number
concentration of airborne particles is controlled and
classified, and which is constructed and operated in a
manner to control the introduction, generation and
retention of contaminants inside the space
AIRBORNE PARTICLE- Solid or liquid object suspended
in air, viable or non-viable, sized between 1 nm and
100 μm
HEATING, VENTILATION, AND AIR CONDITIONING
(HVAC)- is the technology of indoor and vehicular
environmental comfort. Its goal is to provide thermal
comfort and acceptable indoor air quality.
Qualification Approach
Including V-Model
Planning Quality Risk Commissioning
Assessment Testing /
Reports
1 2 3
Develop Quality Risk Commissioning
Commissioning & Assessments Testing
Qualification Plan
• Project Scope • Impact Assessment • Design
• System Boundaries • System Specification/Review
• Roles & • Components • Factory Acceptance
Responsibilities • Utilize risk Testing
• Deliverables assessment tools • Installation Verification
• FMEA • Functional Testing
• Fishbone • Summary Reports
Diagram
Qualification Performance Acceptance &
Testing / Qualification Release
Reporting
4 5 6
Installation/ Performance Approval & Release
Operational Qualification
Qualification
• Installation • Performance • Approval from SMEs
Qualification Qualification • Authorized by Head
• Operational • Challenge Study Quality
Qualification • Regulatory • Release for Process
• Summary Reports Requirements Verification &
• System/Equipment • Summary Reports Commercial Production
release for
performance
qualification
V- MODEL FOR SYSTEM & EQUIPMENT QUALIFICATION
URS PQ
User Requirement
Specification Performance Qualification
CHANGE CONTROL
DQ OQ
Design Qualification Operational Qualification
FAT IQ
Factory Acceptance Test Installation Qualification
Commissioning /
Site Acceptance Test
Qualification Stages
URS, DQ, FAT, IQ & OQ
USER REQUIREMENT
SPECIFICATION
The detailed specification for required
equipment, facilities, utilities or systems.
Defines the quality and GMP
requirements.
URS is generated for more complex
system and will be a point of reference
throughout the validation life cycle
(IQ/OQ/PQ).
URS specification forms the basis for
testing during the performance
qualification (PQ).
USER REQUIREMENT
SPECIFICATION
Details of Site
Category of Product
Productivity Requirements
Safety Features
Regulatory Requirements
Dimension and MOC
Automation / Computerized System
Environmental Conditions
DESIGN QUALIFICATION
Documented verification that the design of facilities, The DQ shall be completed prior to delivery of the
systems and equipment is suitable to meet equipment , and if possible, prior to any factory
requirements relating to user requirements acceptance testing (FAT) or site acceptance testing (SAT).
specification and current good manufacturing
practices.
Annex 2 of WHO Guidelines for Pharmaceuticals defines;
Qualification and Validation should establish and
provide documentary evidence that the premise,
supporting utilities and equipment have been designed
in accordance with requirements of the GMP. Design Illustration of Pharmaceutical Facility
DESIGN QUALIFICATION
Design Qualification shall comply with GMP
and in detail against each points of URS.
Design Qualification can be also called as
Design Specification or Design Verification.
In case of complicated or more advanced automated
system the Design Qualification can be sub-divided as
Functional Design Specification and Hardware Design
Specification.
P&ID Diagrams, Layout drawings , functional design Documents
specification, hardware design specification, Advance System
component data sheet, material certificates Terminology
User Specification
The design qualification normally a desk-based exercise, which is utilized to identify flaws or issues in the design of the system.
FACTORY ACCEPTANCE TEST
Physical Verification
Overall Dimension
A test conducted at the vendor’s premises to
verify that the system, equipment or utility, as
Component & MOC Verification
assembled or partially assembled, meets
Make, Model, Location, Serial No and
expected specifications. MOC testing by Positive material testing
The FAT will have a protocol, which will be
provided by Vendor and approved by Document Verification
Client before execution. It is important to Calibration Certificate, Traceability
note here that it is recommended that the documents, Test certificates
Factory Acceptance Test will be performed
for critical equipment, as relevant. Operation Verification
Key functionality testing, alarms, safety
feature verification and other system
specific tests
Drawing & Layouts
G.A Drawing, Electrical Drawing, I/O list
and P&ID Diagram verification
Note: FAT/ SAT are preferred but not mandatory, Depends on the
system, vendor & client agreement.
INSTALLATION QUALIFICATION
“Qualification and Validation should establish and provide documentary evidence that the premises , supporting utilities
and equipment have been built and installed in compliance with their design specification.”
The Installation Qualification section of qualification determines that the system/equipment, as installed, meets the
requirement of the design drawings and specifications.
Each type of system/ equipment may be subject to a different set of IQ tests depending on the system.
Physical Verification Utilities & Equipment Identification of Components Drawing Verification Document Verification
Overall dimension of All the Utilities and Identification and All the as-built G.A drawing, Calibration Certificates,
system/equipments equipment installed at verification of installed Electrical drawings, P&ID Traceability Certificates,
appropriate location as per components as per drawing drawing and equipment Technical specification
pre-approved protocol and IQ protocol. layouts need to be verified documents, operational
manual, MOC certificates etc.
Annex 2, WHO Guideline for Pharmaceuticals
OPERATIONAL QUALIFICATION
“Qualification and Validation should
establish and provide documentary evidence It is designed to verify that the
system/equipment meets the required
that the premise, supporting utilities and
operating parameter ranges and can be
equipment operate in compliance with their controlled at such. This testing must be done
design specification”. using test methods described in the protocols.
Documented verification that the system or In the case of utilities, testing will be carried
subsystem performs as intended over all out to determine that the system can
anticipated operating ranges. adequately service all users at normal peak
loads. In order to demonstrate reproducibility,
replicate testing may be performed.
START OQ should include but is not limited to the
following;
Test based on process knowledge
Test to confirm upper and lower limits
Operational, Cleaning & maintenance procedure
Alarm Testing, Training & Calibration of
instruments
T E S T
OPERATIONAL QUALIFICATION
M E T H O D S
For classification purposes EN/ISO 14644-1 methodology
OF CLEANROOM
defines both the minimum number of sample locations and
the sample size based on the class limit of the largest
considered particle size and the method of evaluation of the
data collected. EN/ISO 14644-3 define the test method,
apparatus and evaluation of collection of test data.
Air Flow Velocity and Air Changes Per Hour
Installed Filter Integrity Test
Air Pressure Difference Test
Airborne Particle Concentration (NVPC)
Area Recovery Test
Temperature and Humidity Test
Air flow direction and Visualization
Containment Leak Test
ISO 14644
Performance Qualification
Qualification and Validation should establish and
provide documentary evidence that a specific
process will consistently produced its
predetermined specifications and quality
attributes.
It is designed to verify that the
system/equipment meets the required
performance parameter ranges and can
be controlled at such.
It is designed to establish a performance
baseline to provide assurance that the
system can operate as intended.
Tests, using production materials, qualified substitutes or simulated
products proven to have equivalent behavior under normal
operating conditions with worst case batch sizes where appropriate.
Tests to confirm upper and lower operating limits, and/or “worst
case” conditions.
TEST METHODS Air Flow Direction And
Visualization Test
Air Velocity and Air In-Operational Condition
Changes Per Hour
Temperature &
Installed Filter Humidity Test
System Leakage Test
Recovery Test
Air Pressure
Difference Test
Microbiological
Airborne Particle
Monitoring
Concentration
Settle Plate Monitoring
Non-Viable Particle Count Air Sampling
Contact Plate / Surface Monitoring
Air Velocity & Air Changes Per Hour
Purpose Purpose
To demonstrate airflow direction and its uniformity of velocity To determine the rate expressing number of air changes per unit
conform to the design and performance specifications. of time, calculated by volume of air supplied to a room, in m3/hr,
divided by the room volume, in m3
Apparatus Apparatus
Thermal Anemometer, Vane type anemometer, pitot-static tube & Thermal Anemometer, Vane type anemometer, pitot-static tube &
manometer, air flow capture hood with measuring device. manometer, air flow capture hood with measuring device.
Precaution Precaution
Correct Probe direction, Sufficient time for measurement, & Correct Probe direction, Sufficient time for measurement, &
measuring plane perpendicular to supply air flow. measuring plane perpendicular to supply air flow.
Procedure Procedure
Minimum number of measuring points (grid cells) should be ∑ 𝐴𝐴𝐴𝐴𝐴𝐴 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 ×60
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 =
determined by 𝑁𝑁 = 10 × 𝐴𝐴 (𝐴𝐴 − area in m2) 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
At least one point(five measuring sample; 4 corners & 1 centre) Total air flow shall be calculated by submission of average airflow
should be measured for each filter outlet or fan-filter unit. velocity of each terminal filter of respective room.
Average airflow velocity shall be calculated for each filter.
Test Report Test Report
Type of test & measurements, measuring conditions, calibration Type of test & measurements, occupancy state and result of
status, measuring location & distance from the filter, occupancy measurements.
state and result of measurements.
Installed Filter System Procedure
Measure Air-velocity.
Test Report
Test Method
Measure Up-stream concentration Calibration Status
Leakage Test Scan entire downstream face of
filter, perimeter, seal joints and
Filter ID & Location
Upstream Concentration
filter frame. Acceptance Criteria
To confirm that the final high efficiency air filter system
Held at a 3 cm or less. Scan at a Downstream Result
is properly installed by verifying the absence of bypass
rate of 5 cm/s with overlapping
leakage in the air filter installation, and that the filters
strokes.
are free of defects (small holes and other damage in
the filter medium, frame, seal and leaks in the filter
bank framework).
Aerosol
Generator
Photometer
Digital Display Unit To verify the capability of the cleanroom air movement system to
maintain the specified pressure differential between the cleanroom
and its surroundings.
The test is applicable to each of the designated occupancy state.
The pressure differences between each individual cleanroom, clean
Air Pressure zone and the connected adjacent room(s) should be measured.
The pressure can be measure through permanent installed
Difference
measuring points.
When the measured differential pressure is lower than an agreed
value, direction of flow between rooms should be confirmed by
Test flow visualization methods.
Report shall include but not limited to following;
Test Conditions
Measuring Instruments Calibration Status
Analogue Gauge
Cleanliness Class
Occupancy State
Actual Observed Value
Acceptance Criteria
Airborne Particle Concentration
Non-Viable Particle Count test
Area of Area of
1. Purpose NL NL
Cleanroom ≤ Cleanroom ≤
To determine the cleanliness level of 2 1 76 15
the area is characterize by the
maximum allowable numbers of 0.5μm 4 2 104 16
and 5.0μm particles per cubic meter of 6 3 108 17
air at a designated location.
8 4 116 18
10 5 148 19
2. Deriving the number of sampling
24 6 156 20
location
28 7 192 21
Derive the minimum no. of sampling location NL
from the Table 1 mentioned in ISO 14644-1, 32 8 232 22
area of clean room less than 1 m2 to 1000 m2 36 9 276 23
For Area (A) >1000 m2 by following formula; 52 10 352 24
NL = 27 x (𝐴𝐴⁄1000)
56 11 436 25
Schematic Diagram representation with 64 12 636 26
rational/justification of each placed location in
room 68 13 1000 27
72 14
Airborne Particle Concentration
Non-Viable Particle Count test
Light Scattering Airborne
3. Sampling Procedure Particle Counter
Setup Particle Counter as per OEM recommendation of inhouse SOP.
Sampling probe shall be positioned towards airflow.
Ensure the selected occupancy state established.
Single Sampling Volume as per following;
20
𝑉𝑉𝑠𝑠 = × 1000
𝐶𝐶 𝑛𝑛, 𝑚𝑚
𝐶𝐶 𝑛𝑛, 𝑚𝑚 – Largest considered particle size for designated class/Grade
Record the results of each sample measurements as the number of particles in
each single volume of the considered particle sizes appropriate to the relevant
ISO/EU cleanliness classes.
4. Test Report
Instrument ID
Calibration Status
Date/Time of Study & Duration of
sample in time or volume.
Cumulative number of particles at each
location.
Average Concentration of particles.
Microbiological
Monitoring
Microbiological environmental
monitoring is a means of
demonstrating an acceptable
microbiological quality in the
controlled environment and
detecting changes in a timely
manner.
Settle Plate Air Sampling Contact Plate
Settle plates can detect bacteria Volumetric air samples can Contact plates should be used to
and fungi that descend in the quantify bacteria and fungi detect microorganisms on
column of air over the plate. suspended in the air space surfaces that could lead to
Exposure Time – Not more than 4 surrounding open product. product contamination.
hours. Sample Volume- 1000 lit. Incubation Period- 5 Days
Incubation Period – 5 Days Incubation Period - 5 Days
SCDA 90 mm Plates SCDA 90 mm Plates RODAC 55 mm Plates
Recovery Test
To determine whether the cleanroom or clean zone is capable Recovery performance is evaluated by using the 100:1 or
of returning to a specified cleanliness level within a finite time, 10:1 recovery time and/or the cleanliness recovery rate.
after being exposed briefly to a source of airborne particulate Setup the particle counter at a worst-case location at
challenge. sampling interval of 1 min..
The considered particle size used in this test should be
less than 1 μm i.e. 0.5 μm
Area Recovery Graph
Note the time at which particle concentration reached
450000
100x of targeted particle concentration threshold i.e. t100n.
400000
Number of Particle
350000 Note the time at which particle concentration reaches the
300000 targeted particle concentration cleanliness level i.e. tn.
250000
200000 The 100:1 recovery time is represented by;
150000 t0,01 = (tn − t100n)
100000
50000 Test Report;
0 Measuring Instrument Details & Calibration Status
[Link] [Link] [Link] [Link] [Link] [Link] Occupancy State
Time Result of Measurements
Graphical Representation for recovery rate
Temperature
& Humidity
Monitoring
To verify the air temperature & relative humidity levels
are within the control limits over the pre-defined time
period.
A 24 hours to 72 hours temperature mapping with
schematic location diagram & rationale/justification for
measuring locations as agreed between vendor and client.
Apparatus Report
Wired or Wireless Digital Instrument Details & Calibration
Thermometers Status, Raw Data, Occupancy State,
Average Value
AIR FLOW DIRECTION
AND VISUALIZATION
To demonstrate that the airflow direction, its uniformity
of velocity by means of visualization and conform to the
design and performance specifications.
Apparatus: Aerosol Generator, Fog Generator
(Water/Glycols/Alcohols)
Image processing techniques method used for air visualization by
tracing the generated fog/mist by fog generator.
Video frames or films used for quantitative characterization of
airflow by two-way dimensional air velocity vectors in area.
Test Report;
Occupancy State
Filter ID & Location
Air pressure difference before start of study
Evaluation of Video frames
Summary
what we have learned ?
Introduction Qualification Qualification Performance
Definitions
Qualification
Approach Stages Qualification
Validation Qualification Planning URS Test Methods
Specification
V- Model for Systems Air Velocity & ACPH
Clean Area DQ Installed Filter Integrity Test
Clean Zone
Air Borne Particles FAT/SAT Air Pressure Difference Test
Air Borne Particle Count
IQ & OQ Microbiological Monitoring
Temperature & Humidity
Area Recovery
Air Flow direction &
Visualization
Reference
Annex 2 of WHO “Guidelines for Pharmaceutical”
Annex 1 of EU Guidelines Volume 4 “Manufacture
of sterile medicinal products”
Annex 15 of EU Guidelines Volume 4 “Qualification
and Validation”
Annex 1 of PIC/S “Manufacture of sterile medicinal
products”
Part- 1 of ISO 14644 “Classification of air
cleanliness by particle concentration”
Part- 3 of ISO 14644 “Test Methods”
Thank You…
in
anwarmunjewar
