REQUALIFICATION
PROTOCOL OF HVAC SYSTEM
BUILDING
- X, XXX FACILITY
|
1.0 OBJECTIVE:
The objective
of this protocol is to provide procedure for the Requalification of the HVAC
system of Building–‘X’ XXX-Facility and to provide the documented evidence that
the system is capable to continuously supply the clean and conditioned air with
the specified quality attributes thereby establishing its dependability.
Implementation of new ISO-14644-1, 2nd
edition 2015. Refer change control no.: XXXXX
2.0 SCOPE:
This protocol covers all aspects
of Requalification for the HVAC system (AHU, LAF, Tunnel, Pass Box and Garment
Cubicles), which are located in Building–‘X’, XXX-facility .
3.0
ResponsiB1litIEs:
Qualification team comprising the representatives from the
following departments shall be responsible for execution of the plan as per
this protocol.
DEPARTMENT
|
RESPONSIBILITY
|
Sterility assurance services
Sterility assurance services
|
Executive
(Junior/Senior):
·
Shall prepare the requalification protocol/report
as per cGMP requirement and organization’s quality norms.
·
Shall ensure that the raw data is complying with
the acceptance criteria as mentioned in the protocol.
·
Shall report any abnormality and take corrective
and preventive action in coordination with respective department head.
|
Asst.
Manager/Deputy Manager:
·
Shall review the protocol and report.
·
Shall ensure that the raw data is complying with
the acceptance criteria as mentioned in the protocol.
|
|
HOD/Designee:
·
Shall review and approve the protocol and report.
·
Shall ensure that the raw data is complying with
the acceptance criteria as mentioned in the protocol.
|
|
Operator/Executor:
·
Shall ensure and follow the procedure as written
in the protocol.
·
Shall ensure that the raw data is complying with
the acceptance criteria as mentioned in the protocol.
·
Shall report any abnormality and take corrective and
preventive action in coordination with respective department head.
|
|
Production
|
HOD/Designee:
·
Shall review the protocol and report.
|
Operator:
·
Shall ensure and follow the procedure as written
in the protocol.
·
Shall operate the equipment during execution.
·
Shall give necessary support to the qualification
team.
|
|
Engineering
|
HOD/Designee:
·
Shall review the protocol and report.
|
Executive/Designee:
·
Shall operate the equipment during execution.
·
Shall provide the technical support for
execution.
|
|
Microbiology
|
HOD/Designee:
·
Shall review the protocol and report.
|
Analyst:
·
Shall analyze the sample, prepare the report and
submit to QA.
·
Shall give necessary support to the qualification
team.
|
Note: - In case of qualification performed by External
agency/vendor, certificates and raw data shall be prepared by vendor and
reviewed by quality assurance department.
4.0 Statement of Purpose
The purpose of this protocol is to provide an
outline for the Requalification of the manufacturing and testing areas for the
designed cleanliness levels.
5.0 DEFINITIONS
5.1 Air Exchange rate.
Rate of air exchange expressed as number of
air changes per unit of time and calculated by dividing the volume of air
delivered in the unit of time by the volume of space.
5.2 Average air flow rate
Averaged volume of air per unit of time to
determine the air exchange rate in a cleanroom or clean zones.
5.3 Non unidirectional air
flow
Air distribution where the supply air
entering the clean zone, mixes with
internal air by means of induction.
5.4 Unidirectional air flow
Controlled air flow through the entire cross section of clean zones with steady
velocity and approximately parallel steam lines.
5.5 Supply airflow rate
Air volume supplied into an installation
from final filters or air ducks in unit of time.
5.6 Total air flow rate
Air volume that passes through section of
installation in unit of time.
5.7 Uniformity air flow
Unidirectional air flow pattern in which
the point to point reading of velocities are within a defined percentage of
average air flow velocity.
5.8 PAO (poly alpha olefin)
A mono-depressed test aerosol of sub-micron
particles generated to challenge (evaluate integrity) of HEPA filters.
5.9 Aerosol challenge
Challenging of a filter or an installed
filter system by test aerosol.
5.10 Aerosol generator
System where in aerosol is mixed with particle
free dilution air in a known volumetric ratio to reduce concentration.
5.11
Installed filter leakage test
Test performed to confirm that the final
filters are properly installed by verifying that there is absence of bypass
leakage in the installation and that
filters and the grid system is free of defects and leak.
5.12 Aerosol
A gaseous suspension
of fine (100 µm or smaller in size) solid or liquid particles.
5.13 Aerosol photometer
Light-scattering
mass concentration indicating instrument which uses a forward scattered optical
chamber to make
measurements.
5.14 Scanning
Method for disclosing leaks in units, where
by the probe inlet of an aerosol photometer is moved in overlapping strokes
across the defined filter area.
5.15
Particle
Solid are liquid object which, for purposes
of classification of air cleanliness, falls within a cumulative distribution
that is based upon a threshold (lower limit) size in the range from 0.5µm to
5.0µm.
5.16 Particle
size
Diameter of a sphere that produces a response,
by a given particle – sizing instrument that is equivalent to the response
produced by the particle being measured.
5.17
Particle
concentrations
Number of individual
particle for unit volume of air.
5.18
Particle size
distribution
Cumulative
distribution of particle concentration as a function of particle size.
5.19 Occupancy
states
As- Built
|
Condition where the installation is
completed with all services’ connected and functioning but with no production
equipment, materials and personnel present.
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At- Rest
|
Condition where the installation is
complete with equipment installed and operating but with no personnel present.
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Operational
|
Condition where the installation is
complete with equipment installed and operating with
personnel present.
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6.0 INTRODUCTION TO
CLEAN ROOMS & HVAC SYSTEMS
·
The manufacture of sterile
products was carried out in clean areas, where entry of air was restricted by
airlocks for personnel and/or for equipment and materials.
·
Clean areas are maintained to
an appropriate cleanliness standard and supplied with air which has passed through
filters of an appropriate efficiency.
·
The various operations of
component preparation, product preparation and filling were carried out in
separate areas within the clean area.
·
Clean areas for the manufacture
of sterile products are classified according to the required characteristics of
the environment. Each manufacturing operation has an appropriate environmental
cleanliness level in the operational state in order to minimize the risks of particulate
or microbial contamination of the product or materials being handled.
·
For the manufacture of sterile
medicinal products 4 grades can be distinguished
Grade
A: The local zone for high risk operations, e.g.
filling zone, stopper, prefilled syringes and vials, making aseptic connections.
Normally such conditions are provided by a laminar air flow work station.
Laminar air flow systems provide a unidirectional air flow with homogeneous air
speed at working position in open clean room applications. The maintenance of
laminarity should be demonstrated and validated.
Grade
B: For aseptic preparation and filling, this is the
background environment for the grade A zone.
Grade
C and D: Clean areas for carrying out less critical
stages in the manufacture of sterile Products.
·
Classification
Clean rooms and clean air devices are classified
as per following
Airborne classification in the European
Union guide to good manufacturing practice guideline .
·
Clean room
The Manufacturing area in BBIL has been
divided into two areas, as critical (aseptic processing area) and non-critical areas
(non-aseptic processing area). The formulation and sterile filtration, filling
and sealing are carried out in critical areas Grade-A surrounded by Grade-B.
These areas have been provided with separate airlocks for personnel and dynamic
pass box for material transfer. All the clean rooms are monitored by BMS System.
Clean areas wall and floors are designed
with smooth easily cleanable and free from any crevices or damage all corners
are rounded to provide easy and effective cleaning.
Safety devices like fire extinguishers,
collapsible safety doors (emergency exit doors) are provided in the clean room areas.
Drains points are provided for required
areas with water seal and sanitary type.
7.0 EQUIPMENT DESCRIPTION
7.1 AHU
The AHU system is designed to circulate the air in the area after
passing it over cooling and heating coils to maintain the required
environmental conditions and passing it through the series of filters to
maintain desired cleanliness level in the area. The air in-take and out-take of
the system is designed to maintain certain degree of pressure gradient in the
area as per the requirement
7.2 LAF
The laminar air flow unit is specially designed to ensure and provide
particle free, bacteria free, clean air environment needed for working area.
This cleaning system also ensures availability of air, free from any kind of
particulate matter, screening out everything down to 0.3µm.
7.3 Pass Box
Pass through hatch is provided with electro magnetically inter
locked doors to avoid simultaneous opening of both the doors, by controlling
the movement of air from one area to the other. Pass through hatch is equipped
with UV lamps with hour meter to kill any bacteria if at all present and a
florescent lamp is provided for lighting purpose.
7.4 Garment Cubicle
Garment Cubicle is to store sterile garments under grade-A
conditions to avoid the contamination and provide a unidirectional airflow.
7.5 Tunnel
Tunnel is used for the depyrogenation of the vials, under grade-A
conditions and provides a unidirectional airflow
8.0
QUALIFICATION
TEST
8.1 Scheduled Requalification
·
Scheduled qualifications shall be performed as per section no.: 9.0.
8.2 Unscheduled qualification
shall be performed through appropriate QMS tool, in case of
· Relocation of equipment from one place to another place
·
Installation of a new equipment, Any major modification to the existing
equipment
·
Replacement of existing HEPA-Filter or critical component.
·
Frequent surpassing of the alert or action limits of routine
environmental monitoring parameters.
8.3 Pre-requisites
Ø
Ensure the identification of the execution team members are
trained and record observation in annexure-1.
Ø Ensure
that all instruments used during the qualification activity are duly calibrated
and attach
the Calibration Certificates to annexure-3.
Ø Review of preventive
maintenance/break down maintenance of
the equipment for last 6 months and record in annexure-4.
Ø Review of incidents and
change controls for minor/major modifications of the equipment for last 6
months and record in annexure-5.
Ø Check the availability of
availability SOP’s related to the equipment record observation in annexure-6.
Last six months viable monitoring data shall be reviewed and attach the same
with Annexure-17.
9.0 QUALIFICATION
TEST PLAN
AND FREQUENCY
9.1 Air Handling Units
S.No
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Test parameter
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Test frequency
|
Acceptance criteria
|
|||||
1.
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Air velocity and air changes per hour
|
Every 6 months ±1month
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Average velocity and subsequent airflow through supply terminals
should meet the design criteria of air change rate as follows.
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|||||
Grade
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Air changes per hour
|
|||||||
B
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Not
less than 60
|
|||||||
C
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Not
less than 40
|
|||||||
D
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Not
less than 20
|
|||||||
2.
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HEPA filter integrity test
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Every 6 months ±1month
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The percentage of leak should be not more than 0.01% for HEPA filters.
|
|||||
3.
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Monitoring
of Room pressure
|
Every 1 year±1month
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Pressure differentials should meet the
requirement as per the layout drawing Reference No. BB/DW/XXX,XX/006.00
|
|||||
4.
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Temperature and %RH monitoring
|
Every 1 year±1month
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Temperature
and relative humidity should meet the requirement as specified. Temperature
should be 23±4°C and relative humidity should be 30-65%RH
|
|||||
5.
|
Air flow pattern test
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Every 2 years ±1month
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Air flow should be from high pressure area to low pressure area
when comparing between two adjacent areas. Air flow should be laminar, unidirectional and without any
turbulent for all the
HEPA in clean room/zone.
|
|||||
6.
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Non-viable particle count monitoring
(“In-operation” & “At-rest” conditions)
|
Every 6 months ±1month
“In operation” – 1 run (Grade-A, B & C)
“At rest” – 1 run (Grade-A, B, C & D)
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Grade
|
Maximum permitted number of particles/m3 equal to or above
|
||||
At rest
|
In operation
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|||||||
0.5 µm
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5.0 µm
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0.5 µm
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5.0 µm
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|||||
A
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3520
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20
|
3520
|
20
|
||||
B
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3520
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29
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352000
|
2900
|
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C
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352000
|
2900
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3520000
|
29000
|
||||
D
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3520000
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29000
|
Not
defined
|
Not
defined
|
||||
7.
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Sound level
test
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Every 2 years ±1month
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Average sound level should be 55db to 65db at working area.
|
|||||
8.
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Light
intensity
test
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Every 2 years ±1month
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For critical areas (Grade B) 950 – 1000
LUX & Non critical areas (Grade C&D) 450 – 500 LUX.
|
|||||
9.
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Recovery
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Every 2 years ±1month
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Area should recover to predefined area
classification within 15 minutes. (Grade-B & C)
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|||||
10.
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Viable particle count monitoring.
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As per SOP: SAS/012
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Refer section No. 10.13.5
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Note: After execution of
the requalification protocol, Summary matrix shall be recorded in the
Annexure-18.
9.2 Laminar air flow units, Pass box, Garment
cub1cle and Tunnel:
S.No
|
Test Parameter
|
Test Frequency
|
Acceptance criteria
|
|||||
1.
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Air velocity
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Every 6 months ±1month
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Equipment name
|
Air velocity
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LAF
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90±20 % FPM.
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|||||||
Pass box
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90±20 % FPM.
|
|||||||
Sterile garment cubicle
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90±20 % FPM.
|
|||||||
Tunnel
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Drying zone
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98±20 % FPM.
|
||||||
Depyrogenation
zone
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157±20 % FPM.
|
|||||||
Cool &stabilization zone
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118±20 % FPM.
|
|||||||
2.
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HEPA filter integrity test
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Every 6 months ±1month
|
The percentage of leak should be not more
than 0.01% for HEPA filters.
|
|||||
3.
|
Differential pressure
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Every 1 year±1month
|
Should be 10-15mm of WC.
For Tunnel drying zone, cooling & stabilization zone 10-15mm of WC and
depyrogenation zone 20-25mm of WC).
|
|||||
4.
|
Air flow pattern test (“In-operation” and
“At-rest”)
|
Every 2 years ±1month
|
Air flow should be laminar, unidirectional and without any
turbulent for all the
HEPA filters of LAF/Pass boxes/ Garment Cubicle/Tunnel.
|
|||||
5.
|
Non-viable particle
count monitoring (“In-operation” &
“At-rest” conditions)
|
Every 6 months ±1month
“In operation” – 1 run (Grade-A, B & C)
“At rest” – 1 run (Grade-A, B, C & D)
|
Grade
|
Maximum permitted number of particles/m3 equal to or above
|
||||
At rest
|
In operation
|
|||||||
0.5 µm
|
5.0 µm
|
0.5 µm
|
5.0 µm
|
|||||
A
|
3520
|
20
|
3520
|
20
|
||||
B
|
3520
|
29
|
352000
|
2900
|
||||
C
|
352000
|
2900
|
3520000
|
29000
|
||||
D
|
3520000
|
29000
|
Not defined
|
Not defined
|
||||
6.
|
Power failure test
|
Every 2
years ±1month
|
Should
reach desired classification (Grade-A) within 15 min.
|
|||||
7.
|
Viable particle count monitoring. ‘In
operation’
|
As per SOP: SAS/012
|
Refer section No. 10.13.5
|
|||||
Note: After execution of the requalification protocol, Summary
matrix shall be recorded in the
Annexure-18.
10.0 QUALIFICATION METHODOLOGY
10.1
Measurement of air velocity & calculation of air changes per hour by digital anemometer:
10.1.1 Purpose:
To demonstrate that the air system is balanced and capable of
delivering air velocities and providing number of air changes per hour in the
respective rooms as per requirement as mentioned in Annexure-2, when
calculated as per the respective room volumes.
10.1.2 Principle:
The test is performed to determine the average airflow velocity,
volume and uniformity in a clean room, as well as to determine air supply
volume flow rate. Air velocity test will be performed and results will be
require to determine the air changes per hour for clean room.
10.1.3 Instrument Details:
Calibrated
digital Anemometer.
10.1.4 Pre-requisite:
Air volumes through supply and return grills and filters should be adjusted
as per the design requirement of air change rate and differential pressure.
This requirement is only for initial qualification.
10.1.5 Test Procedure:
Ø Ensure that the supply blower of the AHU is “ON” prior to the start
of the observations.
Ø The velocity shall be measured at approximately 150 mm to 300 mm
from the filter face
Ø When production apparatus and work benches are installed, it is
important to confirm occurrence of significant air flow variations, Therefore,
the measurement of the uniformity of velocity should not be done at positions
close to these obstructions.
Ø For compliance of air change rate, velocity to be measured at 5
different locations for each Supply grill / diffuser (four corners and center)
with the help of calibrated Anemometer as shown in figure-1. (Refer operation
of Hot wire anemometer SOP No.: SAS/006).
Figure-1
Where V1, V2, V3, V4 & V5
are the measurement locations at supply grill face.
Ø Calculate the average velocity of the air coming from Supply grill /
Terminal filter.
V1
+ V2 + V3 + V4 + V5
|
5
|
Average of air velocity at grill (FPM) =
Ø Calculate the airflow by multiplying the average velocity with the effective
grill area.
Ø Air flow = Average Velocity x Face Area of the
Air Inlet Grill / Filter
= Ft / Min. x Ft 2
= Ft
3 / Min. or CFM
Ø Calculate the total airflow from all the Supply Grill / Terminal
Filter in the room and add values to get the total airflow in the room (CFM).
Ø
Calculate the number of air changes per hour
in the room by using the formula :
|
10.1.6
Observations:
Ø Record the observations of measurement of air velocity and air
changes in Annexure-7.
10.1.7 Acceptance Criteria:
Average velocity and subsequent airflow through supply terminals should
meet the design criteria of air change rate as specified in Annexure-2.
10.1.8 Evaluation of Result:
The result complying with the specification range of individual
velocity of the supply grill shall achieve the desired airflow of the room and
air change rate.
10.2 Measurement of air flow (CFM) & calculation
of air changes per hour by Air capture hood.
10.2.1 Purpose
To
demonstrate that the system is capable of delivering required number of air
changes per hour in the respective rooms as per the requirement mentioned in Annexure-2.
10.2.2 Principle
Airflow
(CFM) test shall be performed and based on the results obtained number of air changes shall be calculated.
10.2.3 Instrument Details :
Air capture hood (An Air Data Multiplier with Accubalance of flow hood capable of
measuring total supply or extract volume from filter housings will be used. The
Flow Hoods work on the Wilson grid principal of air measurement and involves
the collecting hoods gathering the full volume of air and passing it over the
Wilson grid. The pressure readings taken across the grid are fed into the Air
Data Multiplier and the instrument produces a direct readout of the volume
either in imperial or metric units)
10.2.4 Test Procedure
Ø Select the correct size hood to fully cover the filter or terminal
outlet.
Ø Select the Volume Programmer (CFM) on the Processor Programmer.
Ø Read the indicated volume directly from the instrument.
Ø Ensure that capture hood should cover the HEPA filter area
completely and hold the
Hood for a minimum of 10-15 seconds and record the
readings in Annexure-7.
10.2.5 Calculations
for air changes per hour (ACPH):
One air change occurs in a room
when a quantity of air equal to the volume of the room is supplied and/or
exhausted. Air change rates are units of ventilation that compare the amount of
air moving through a space to the volume of the space. This is the volume of
air (usually expressed in cubic feet per minute) exhausted or supplied every
hour divided by the room volume (also usually expressed in cubic feet).
Airflow (CFM) is multiplied by 60 minutes to determine the volume of air
delivered per hour (in cubic feet).
Room
Area (Sq.ft.) = Room Length (ft) x Room Width (ft)
Room
Volume (Cu.ft) = Room Area (Sq.ft) x Room Height (ft)
|
10.2.6
Observations
Record the observation of measurement of air flow and
air changes in Annexure-7.
10.2.7
Acceptance Criteria:
Air flow (CFM) through supply terminals and air changes per hour should meet the design criteria as specified in Annexure-2.
Note: Calculation of air changes per hour shall be carried out either by the
calibrated digital anemometer (or) air capture hood method.
10.3
Air velocity measurement test ( LAF’s , Pass Box,
Garment Cubicle and Tunnel):
10.3.1 Purpose:
To demonstrate that the system is balanced and capable of
delivering air velocities to provide the desired environment.
10.3.2 Principle:
The test is performed to determine air velocity of the HEPA filters to provide
desired environment.
10.3.3 Instrument Details:
Calibrated digital
Anemometer.
10.3.4 Prerequisite:
Ensure the differential pressure is within the limit as per the design.
10.3.5 Test Procedure:
Ø Ensure that the supply blower of the LAF/ Pass box/ Garment Cubicle/Tunnel
is “ON” prior to the start of the observations.
Ø The velocity shall be measured at approximately 150 mm to 300 mm
from the filter face
Ø When production apparatus and work benches are installed, it is
important to confirm occurrence of significant air flow variations, Therefore,
the measurement of the uniformity of velocity should not be done at positions
close to these obstructions
Ø For compliance the velocity to be measured at 5 different locations
for HEPA filter (Four Corners and center) with the help of calibrated
Anemometer as shown in figure 2. (Refer operation of Hot wire anemometer SOP
No.: SAS/006).
Figure-2
Where V1, V2, V3, V4 & V5 are the
measurement locations at supply grill face.
Ø Calculate the average velocity of the air coming from HEPA filter.
V1
+ V2 + V3 + V4 + V5
|
5
|
Average of air
velocity at grill =
10.3.6
Observations:
Record
the observation of measurement of air velocity and in Annexure-7.
10.3.7 Acceptance criteria:
Parameter
|
Acceptance criteria
|
|
LAF
units
|
90±20
% FPM.
|
|
Dynamic
Pass Box
|
||
Sterile
Garment Cubicle
|
||
Mobile Laminar Air flow unit
|
||
Tunnel
|
Drying
zone
|
98 ± 20 %FPM
|
Depyrogenation
zone
|
157± 20%FPM
|
|
Cooling
zone
|
118± 20% FPM
|
|
10.3.8 Evaluation of result:
The result complying with the acceptance criteria of air velocity.
10.4
HEPA filter integrity test:
10.4.1 Purpose:
To confirm that the filter system is properly installed and to
monitor the integrity- leak of the HEPA
filters installed in classified areas / LAF/ Pass Box / Garment Cubicle/ Tunnel.
10.4.2 Principle:
This test is performed to confirm that the HEPA filter is properly
installed by verifying the absence
of side leakage in the installation, filter media is free
of defects, leaks in the filter frame, gasket seals & leaks in the
filter bank frame work. The test is performed by injecting an aerosol challenge
upstream of the filters and immediately scanning downstream of the filters and supporting frame.
10.4.3 Instrument details :
Ø Calibrated Aerosol
Photometer & Aerosol Generator.
Ø PAO Liquid (Poly Alpha Olefin).
10.4.4
Prerequisite:
Filter testing shall be performed only after operational air
velocities have been verified and adjusted wherever necessary.
10.4.5 Test procedure:
Ø Before starting the work take the details of the whole area that to
be validate.
Ø Ensure that required single phase power supply as well as air
connection with 20psi (1.5kg) pressure shall be arranged.
Ø Ensure that the floor and the area as well as equipment is
visually cleaned.
Ø System should be kept ‘ON’ condition, before starting the measurements.
Ø Connect the spike guard to photometer before starting it.
Ø Start the air generate the aerosol particles at 20psi pressure.
Ø Direct the generator face to the return air point or fresh air
intake of the AHU.
Ø Take a tube and connect one end to the filter face Upstream port
and other to the photometer in
upstream mode. Switch on the
photometer and set it to zero.
Ø Put the photometer
to Upstream mode and note the reading, the reading should be in between 20µg/liter to 80
µg/liter.
Ø If it is between the above range than set the value to 100%.wait
until the photometer displays 100% upstream concentration.
Ø Keep the
photometer switch on clear mode and enter Zero for Machine to become Zero. Wait until photometer displays ‘0’.
Ø Now put the switch to Downstream mode and scan the filter by
holding the probe approximately 3 cm from the downstream filter face or the
frame structure.
Ø Scan the corners of HEPA filter for checking the installation
leakages. Scanning rate(Sr) shall be 15/wp cm/s. (Refer SOP No.: SAS/005).
Ø If the leakage is less than 5% of the total media, apply the sealant
wherever leakages found.
Ø Repeat the test after the rectification of the Filter.
10.4.6
Observations:
Record the observations of HEPA filter integrity test as per Annexure-8.
10.4.7 Acceptance Criteria:
The percentage of leak should be not more
than 0.01% for HEPA filters.
10.4.8 Evaluation of Result:
Results, complying with the acceptance
criteria, shall establish the integrity of the HEPA filter suitable for
system.
10.5
Monitoring of Room Pressure and
Differential pressure for equipments:
10.5.1 Purpose:
To
demonstrate the capability of the air system to provide room pressure and to
ensure the DP of equipments.
10.5.2 Principle:
This
test is performed to confirm that provide room pressure and differential
pressure for equipments.
10.5.3 Instrument Details:
Digital electronic micro manometer (digital display).
10.5.4 Prerequisite:
All air
handling units and the equipment’s shall be in continuous operation.
10.5.5 Test Procedure:
Ø To avoid unexpected changes in air pressure and to establish a
baseline, all doors in the
Facility must be closed and no man
movement to be allowed during the observations.
Ø Observe the room pressure through digital electronic micro
manometer.
Ø Monitor the Room pressure and DP of equipments as per the current
SOP’s.
10.5.6
Observations:
Record the
observations in Annexure-10. BMS data & raw data shall be attached with the
re-qualification report.
10.5.7 Acceptance Criteria:
Pressure differentials should meet the requirement as per the layout drawing Reference No. BB/DW/XXX,/006.00 & differential pressure of equipment’s should
be 10-15mm of WC.
10.5.8 Evaluation of Result:
Results,
complying with the acceptance criteria shall indicate that the system is
adequate to provide the
desired room pressure.
10.6
Monitoring of Temperature and %RH:
10.6.1 Purpose:
To
demonstrate the ability of the AHU system to provide Temperature and Relative
Humidity within the specified range.
10.6.2 Principle:
This
test is performed to confirm temperature and relative humidity within the
acceptance criteria.
10.6.3 Instrument details :
Digital
electronic display unit for Temperature and relative humidity.
10.6.4 Prerequisite:
Air
conditioning system shall be in continuous operation prior to performing these
tests.
10.6.5 Test procedure:
Observe
the temperature and relative humidity through respective display unit wherever
installed as per the current SOP.
10.6.6 Observations:
Attach the
BMS data to the report. Record the observations in Annexure-11 (if necessary).
10.6.7 Acceptance criteria:
Temperature
and relative humidity should meet the requirement as specified. Temperature
should be 23±4°C and relative humidity should be 30-65%RH.
10.6.8 Evaluation of result :
Results, complying with the acceptance criteria shall indicate that
the system is adequate to provide the desired environmental condition of temperature
and relative humidity.
Note:
If
necessary, Data loggers shall be
placed in all classified rooms for observation of temperature & %RH. The
data loggers shall be placed near every return air grill of each room as it is
considered as a worst case location.
10.7
Air Flow Pattern Test:
10.7.1 Purpose:
To
describe a procedure for carrying out air flow pattern test by using glycol/dry
ice in hot water/ water fogger during ‘In-operation’ and ‘At-rest’ conditions.
10.7.2 Principle:
The purpose
of air flow pattern test is to confirm the airflow direction, uniform flow, and
to conform the design and performance specifications and, if required, spatial
and temporal characteristics of airflow in the installation.
10.7.3 Prerequisite:
All AHU’s, LAF‘s/ Pass Box/Garment Cubicle/Tunnel
shall be in continuous operation.
10.7.4 Test Procedure (Dry ice fogger
operation method):
Place the dry ice fogger
on a flat, level bench, table or rolling cart.
Ø Fill with
WFI up to ¾ of tank level and ensure that the hose pipe was connected.
Ø Remove the hose cap and add dry ice manually.
Ø Connect optional fog curtain tube to hose to create a fog wall to
visualize air flow.
Ø Refill dry ice to continue fogging or drain WFI by opening the drain
plug and refill fresh WFI.
Ø Expose the smoke near the supply grill / diffusers / filter. And move
the fogger gradually from supply grill / diffusers / filter to return grill /
riser / diffuser / fitters.
Ø Quantity of smoke should be sufficient to demonstrate the flow. It
should not be denser and should not be very less. The airflow pattern
should ensure that entire controlled and specified areas are swept efficiently
by the airflow, in order to ensure that both contamination control and
environmental control are achieved.
10.7.5
Observations:
Observe the air flow pattern as per the
procedure mentioned above and record the study through camera. Record the details as per the Annexure-12. Secure
necessary videotapes / CD and Photographs.
10.7.6 Acceptance Criteria:
Ø Air flow should be from high pressure area to low pressure area
when comparing between two adjacent areas
Ø Air flow should be laminar, unidirectional and without any
turbulent for all the HEPA in clean room/zone
Ø Air flow should be laminar, unidirectional and without any
turbulent for all the HEPA filters of LAF/Pass boxes/ Garment Cubicle/Tunnel.
10.7.7 Evaluation of Result:
Compliance to the
acceptance criteria shall be established.
10.8
Non-Viable Particle Count Test:
10.8.1
Purpose:
To describe a procedure for carrying out Non-Viable
particle count test to classify the clean room installation.
10.8.2
Principle:
This test method specifies the measurement
of air born particle concentrations with size distributions having threshold
size between 0.5µm and 5.0µm. Measurement can be made in any of three defined
occupancy states as-built, at-rest and operational. The measurement is made to
certify the cleanliness classification.
10.8.3
Instrument Used:
Particle counts are measured with a
Discrete Laser Particle Counter with Iso-kinetic probe, which is calibrated
once in a year.
10.8.4 Prerequisite:
Tests covered in preceding sections for Air
velocity measurement and Air change rate calculation, HEPA filter integrity
test and differential pressure control test should be completed and results
should comply with respective acceptance criteria.
10.8.5
Establishment of number of sampling
locations:
Refer the below table to calculate the
minimum number of sampling point locations:
ESTABLISHMENT OF NUMBER
OF SAMPLING LOCATIONS
|
|||
Area of Cleanroom (m2)
less than or equal to
|
Minimum number of
sampling locations to be tested {NL}
|
Area of Cleanroom (m2)
less than or equal to
|
Minimum number of
sampling locations to be tested {NL}
|
2
|
1
|
76
|
15
|
4
|
2
|
104
|
16
|
6
|
3
|
108
|
17
|
8
|
4
|
116
|
18
|
10
|
5
|
148
|
19
|
24
|
6
|
156
|
20
|
28
|
7
|
192
|
21
|
32
|
8
|
232
|
22
|
36
|
9
|
276
|
23
|
52
|
10
|
352
|
24
|
56
|
11
|
436
|
25
|
64
|
12
|
636
|
26
|
68
|
13
|
1000
|
27
|
72
|
14
|
>1000
|
See
below Formula
|
Note: 1) If the considered
area falls between two values in the table, the greater of the two should be
selected.
2) In the case of unidirectional airflow, the
area may be considered as the cross section of the moving air perpendicular
to the direction of the airflow. In all other cases the area may be
considered as the horizontal plan area of the cleanroom or clean zone.
|
|||
When the area of the cleanroom or clean zone is greater than 1000 m2,
apply the below mentioned formula to determine the minimum number of sampling
locations required.
Where, ‘NL’ is
the minimum number of sampling locations to be evaluated, rounded up to the
next whole number, ‘A’ is the area
of the clean room or clean zone in m2.
Ensure that the sampling locations are evenly distributed to cover the
entire area of the clean room and positioned the probe at the working level.
10.8.6 Establishment of sampling volume:
At each sampling location, sample a sufficient
volume of air that a minimum of 20 particles would be detected if the particle
concentration for the largest considered particles size were at the class limit
for the designed Grade .
The single sample volume Vs per
locations is:
VS= 20/Cnm X 1000
Where,
Vs is the minimum single sample volume per locations in liters
Cnm is the limit (number of particle per cubic meter) for
the largest considered particle size specified for the relevant class.
20 is the defined number of particle that could be count if the
particle concentration were at the class limit.
Sampling volume:
S. No
|
Grade
|
Sample
volume/location
|
|
At rest
|
In operation
|
||
1
|
A
|
1000 liters
|
1000liters
|
2
|
B
|
690 liters
|
7 liters
|
3
|
C
|
7 liters
|
2liters
|
4
|
D
|
2liters
|
Not Defined
|
10.8.7 Sampling locations:
Ensure
that the sampling locations are evenly distributed throughout the area of the
clean room and positioned at a working level.
10.8.8 Method:
Ø Particulate counting
shall be carried out at predefined locations as per the layout
drawing Reference No. DW/XXX,/041.03
& DW/XXX,/008.03
Ø Before starting the
work take the details of the whole area that to be validate
Ø Clean all instruments
with 70% IPA before entering in clean area
Ø Ensure that the floor
area as well as equipment is visually cleaned.
Ø System should be kept
ON, 2 hour before starting the measurements.
Ø The particle counter is
kept on a SS trolley and all setting shall be done.
Ø Connect the spike guard
to particle counter before starting counter.
Ø Set the particle
counter as per given details of rooms/equipments.
Ø The sampling shall be
positioned vertically upward.
Ø Switch ON airborne
particle counter.
Ø Set the particle
counter for zero purging before starting the measurements.
Ø Place the probe at
working level height.
Ø Start taking samples at
different locations as per details and take print of readings.
Ø The test is used for
measurement of airborne particle concentration with size distribution having a threshold size between 0.5 µ to 5 µ
to certify the cleanliness of the classified room.
Ø The sampling locations
shall be calculated and are evenly distributed throughout the area of the clean
room and are monitored at the height of the working area.
Ø After completion of
monitoring take the thermal print from the counter and stick the thermal print
on Annexure-13A
and the same annexure should be photocopied or after completion of
monitoring download the data through USB pen drive, and print the same and
attach with the Annexure-13A.
(Refer
operation of Off-line NVPC SOP No.: SAS/003).
10.8.9
Observations:
Ø The cumulative counts of the particle shall be counted for m3
as per EU guidelines.
10.8.10
Acceptance criteria:
The system shall meet the
acceptance criteria for an air borne particulate cleanliness as per section no. 10.8.5.
10.8.11 Evaluation of result :
Results, complying with the acceptance
criteria shall indicate that the system is adequate to provide the desired cleanliness
class in the area.
S.No
|
Qualification Type
|
Test condition
|
Number runs
|
Test shall be performed
in
|
1.
|
Scheduled Requalification
|
At-Rest
|
1 run
|
Grade-A, B, C & Grade-D
|
In-Operation
|
1 run
|
Grade-A, Grade-B &
Grade-C
|
10.8.12 Number of runs for Non-viable particle count:
10.9
Sound Level Test:
10.9.1 Purpose:
To verify that the sound level is in limit in the clean room area
10.9.2 Principle:
This test is performed to confirm that sound level is within the
acceptance criteria in the
clean room area
10.9.3 Instrument Details:
Duly Calibrated Sound Level Meter
10.9.4 Prerequisite:
Tests covered in preceding sections for Air Velocity Measurement and
Air Change Rate calculation, HEPA
filter integrity test and room pressure control test should be completed & results
should comply with respective acceptance criteria
10.9.5
Test Procedure:
Take the reading at working level in 5 different locations in the
room and take the average of the sound in the unit of Decibel (db)
10.9.6 Observations:
Record the sound level test observations in Annexure-14.
10.9.7 Acceptance Criteria:
Average sound level should be 55-65 db at working area.
10.9.8 Evaluation of Result:
Results, complying with the acceptance criteria shall indicate that
the sound level in the clean room is in limits.
10.10
Light Level Test:
10.10.1Purpose:
To verify that the Light level is in limit in the clean room area
10.10.2Principle:
This test is performed to confirm
that light levels are within the acceptance criteria in
the clean room area.
10.10.3Instrument Details:
Duly calibrated light level meter.
10.10.4Prerequisite:
During this test the all equipment’s should be
‘ON’ / operation mode.
10.10.5Test Method:
Take the reading at working level at 5 different
locations in the room and take the average of the light level in the unit of
Lux
10.10.6Observations:
Record
the light level test observations in Annexure-15.
10.10.7Acceptance Criteria:
The
clean room or clean zone shall meet the acceptance criteria for light level as
mentioned below
S.No
|
Cleanliness Class
|
Lighting Level Limit (lux)
|
1
|
Critical Areas (Grade B)
|
950 to 1000 lux
|
2
|
Non Critical Areas (Grade C &
Grade D)
|
450 to 500 lux
|
10.10.8Evaluation of Results:
Results, complying with the acceptance
criteria shall indicate that the light level in the clean room is in limits.
10.11
Recovery Test:
10.11.1
Purpose:
To describe a procedure for carrying out recovery test for critical
areas like Grade-B
& C.
10.11.2 Principle:
This test method species whether
the installation is capable of returning to it’s specified area classification within a finite time, after
being exposed briefly to a source of airborne particulate challenge. Recovery test shall be performed
only in Grade-B & Grade-C.
10.11.3 Instrument Details:
Particle counts are measured
with a discrete laser particle counter with ISO-kinetic probe, which is calibrated once in a year.
10.11.4 Prerequisite:
Tests covered in preceding
sections for Air velocity measurement and air change rate calculation, HEPA
filter integrity test differential pressure control and non-viable particle
count Test should be completed and
results should comply with respective acceptance criteria
10.11.5
Test Method:
Ø Evaluation by 100:1
recovery time.
Ø This test performed only critical areas like Grade B & C (which
are surrounded by grade B) areas (Aseptic Area).
Ø Operate all the AHU’s as per the standard operating procedure
(EMD/001).
Ø Before start the observation, verify the Instrument/s calibration
reports for the adequacy and validity. Attach the calibration certificate.
Ø Set up the particle counter in accordance with the manufacturer's
instructions and the apparatus calibration certificate.
Ø Place the DPC probe at the testing point.
Ø The DPC probe should not be placed directly under the air outlet.
Ø Adjust the single sample volume to the same value used for
determining the cleanliness class. The delay time of the counter from starting
each count to the output recording should be adjusted to not more than 10s.
Ø The particle size used in this test should be less than 1 µm. It is
recommended that the size channel used by the DPC corresponds to that of the
maximum number concentration of the aerosol.
Ø Run the DPC for initial count 1 min when air-handling units are in
ON condition.
Ø Switch OFF the AHU and not down the time.
Ø Raise the initial particle concentration to 100 or more times the
target cleanliness level with an aerosol
Ø Run the Particle counter with 1 min interval with cycle mode. Note
the time when the particle concentration reaches the 100 x target concentration
threshold ( t100n )
Ø ON the AHU and Note down the time.
Ø Run the Particle counter with 1 min interval with cycle mode up to
reach the initial count note. (Refer operation of Off-line NVPC SOP No.: SAS/003).
Ø Note the time when the particle concentration reaches the target
cleanliness level (tn)
Ø The 100 : 1 recovery time is
represented by t0.01= (tn
- t100n)
10.11.6 Observations:
Record the
observations in the Annexure-16. Raw data shall be attached with the report
either in pdf format or raw data shall be pasted directly.
10.11.7 Acceptance Criteria:
Area should recover to predefined area
classification within 15 minutes.
10.11.8 Evaluation of Results:
Results, complying with the acceptance
criteria shall indicate that the Recovery Time within limits.
10.12
Power failure test:
10.12.1
Purpose:
To describe a procedure for carrying out Power failure test for the Equipment like Pass
box, LAF, mobile LAF and Sterile garment cubicle.
10.12.2 Principle:
This test method species whether the
installation is capable of returning to its specified Cleanliness class within
a finite time, after the power failure.
10.12.3 Instrument Details:
Particle
counts are measured with a discrete laser particle counter with ISO-kinetic
probe, which is calibrated
once in a year.
10.12.4 Prerequisite:
Tests
covered in preceding sections for Air velocity measurement and air change rate calculation, HEPA filter integrity
test differential pressure control and non-viable particle count tests should be completed and results should
comply with respective acceptance criteria
10.12.5
Test Method:
Ø This test is performed to know its capability of recovery time i.e.
maintaining of desired grade specifications after power failure.
Ø Operate all the equipment as per the standard operating procedure.
Ø Before the test, verify the Instrument/s calibration reports for the
adequacy and validity. Attach the calibration certificate.
Ø Set up the particle counter in accordance with the manufacturer's
instructions and the apparatus calibration certificate.
Ø Place the DPC probe at the testing point.
Ø The DPC probe should not be placed directly under the air outlet.
Ø Adjust the single sample volume to the same value used for
determining the cleanliness class. The delay time of the counter from starting
each count to the output recording should be adjusted to not more than 10sec.
Ø The particle size used in this test should be less than 1 µm. It is
recommended that the size channel used by the DPC corresponds to that of the
maximum number concentration of the aerosol.
Ø Run the DPC for initial count minimum 1 min when LAF is in ON
condition.
Ø Switch OFF the LAF (Including UPS) and not down the time in
annexure-16.
Ø Run the Particle counter with 1 min interval with cycle mode, then
power shall be ON.
(Note: The particle
counter should be ON with continuous cycle mode @ before and after the Power
failure). Refer SOP No.: PGD/026.
10.12.6 Observations:
Ø Record the observations and results in the Annexure-16.
10.12.7 Acceptance Criteria:
Ø Should reach desired classification within 15 min.
10.13
Viable particle count test:
10.13.1 Purpose:
To determine the air borne microbial contamination level in clean
area
10.13.2 Principle:
This test method is to determine the air borne microbial
contamination level in clean area is within
the acceptance criteria
10.13.3 Test methodology:
Viable particle count monitoring shall be
performed as per the SOP No. xxx.
10.13.4
Observations:
All the
observations of passive & active air sampling details are recorded by the
QC Microbiology department as per SOP No.: xxx. And
the same was attached with Annexure-17.
10.13.5 Acceptance Criteria:
The following limits for
passive & active air sampling shall be followed during monitoring of viable
count. (As per SOP No.: SAS/012).
Viable Particulate Count
Test
|
Viable
Particulate Count results should be within the acceptance criteria as per SOP
No. SAS/012.
|
||||
Passive Air Sampling
|
Active Air Sampling
|
||||
Grade
|
Alert limit
|
Action limit
|
Alert limit
|
Action limit
|
|
A
|
<1
|
1
|
<1
|
1
|
|
B
|
3
|
5
|
6
|
10
|
|
C
|
35
|
50
|
75
|
100
|
|
D
|
85
|
100
|
95
|
200
|
|
10.13.6 Evaluation of Results:
Results, complying
with the acceptance criteria shall indicate that the viable particle count in limits in clean area. The SOP No.: xxxxx shall be followed for monitoring of viable count during the qualification
11.0 ACTION TO BE TAKEN IN
CASE OF QUALIFICATION FAILURE
11.1 Air Velocity Test:
Action to be taken in case air change rate is less than
the design limit in non-unidirectional air flow zone.
Ø During requalification:
Immediate Action:
Ensure that all damper position is in preset marked
location. If change in air change rate is due to reduction in velocity across
the HEPA filter, replace the HEPA filter with new one.
Preventive Action:
Check for any leakage in the duct line, which can
increase the particulate load in the inlet air. Check the preventive
maintenance record of last six-month, whether any leakage in the duct line is
observed. Check that in the last six month any time AHU was shut down for long
period and air change rate was verified during the startup after shut down. In
case of shifting of damper position, investigate for the reason for shifting.
Check the preventive maintenance record, whether damper position is verified.
11.2 HEPA Filter Integrity
Test:
During
requalification:
Different types of leakages and their corrective
actions to be taken are mentioned in the following table.
Description of leakage
|
Corrective action to be
taken
|
Leak from the
gasket and the filter edge
|
Tightening the
filter frame from all sides. If the leak continues to occur, observe the condition
of the gasket. If the gasket is damaged, replace the gasket and perform the
test again. For Gel filled filters, the filter must be removed and checked
for proper filling of the gel in groove.
|
Leak between
the filter and frame
|
Apply silicone
sealant to the leak. (Replace the HEPA filter as per ISO 14644-3).
|
Leak from the
filter medium
|
Apply
silicone sealant to the leak.
(Replace the HEPA filter as per ISO 14644-3).
|
Replacement of HEPA filter:
After
replacement with new HEPA filter, Tests like Air velocity, filter integrity,
Non-viable particle count tests shall be performed.
12.0 DEVIATIONS, DISCRIPENCY
& CORRECTIVE ACTION REPORT:
If any deviations observed during Re-qualification with respect to
protocol the deviation shall be recorded in Annexure-19. If any discrepancy observed during performance qualification with
respect execution, the discrepancy and corrective action shall be handled
through appropriate QMS tool and recorded in Annexure-20.
13.0 CONCLUSION & SUMMARY REPORT:
After
completion of qualification, qualification summary report shall be prepared as
per the protocol and with the details of results of the qualification study. A
conclusion shall be drawn based on the results of qualification study of the
equipment.
14.0 ANNEXURES:
Annexure No.
|
Details of the Annexure
|
Annexure-1
|
Identification of execution team and training
record
|
Annexure-2
|
Equipment details
|
Annexure-3
|
Verification of calibration details
|
Annexure-4
|
Preventive maintenance details
|
Annexure-5
|
Review of incidents and change controls
|
Annexure-6
|
Verification
of availability of SOP’s
|
Annexure-7
|
Measurement of air velocity and
air changes per hour record
|
Annexure-8
|
Measurement of air velocity (LAF,
pass box, garment cubicle and tunnel)
|
Annexure-9
|
HEPA filters integrity testing record
|
Annexure-10
|
Differential pressure monitoring
record
|
Annexure-11
|
Temperature & %RH mapping record
|
Annexure-12
|
Air flow pattern test details
|
Annexure-13
|
Non-viable particle count raw data
record and rationale for the NVPC locations
|
Annexure-14
|
Sound level test record
|
Annexure-15
|
Light level test record
|
Annexure-16
|
Recovery/ Power failure test
record
|
Annexure-17
|
Viable monitoring test results
|
Annexure-18
|
Summary matrix
|
Annexure-19
|
Deviation record
|
Annexure-20
|
Discrepancy and corrective action
report
|
15.0
PROTOCOL HISTORY
Revision No.
|
Change Control No
|
Revision Description
|
03
|
·
Implementation of
revised ISO-14644-1, 2nd edition (2015)
·
95% UCL calculation
removed
·
NVPC monitoring
locations for room wise has been revised.
·
NVPC locations rationale
has been incorporated.
·
Maximum number of
persons allowed for grade B& C during NVPC activity (in-operation
condition) has been incorporated.
·
Pass box classification
changed.
|
16.0 ABBREVIATION:
Abbreviation
|
Extended Form
|
AHU
|
Air Handling
Unit
|
CRQ
|
Cleaning room
qualification
|
CFM
|
Cubic
Feet per Minute
|
LAF
|
Laminar air flow
|
PBX
|
Pass box
|
SGC
|
Sterile garment cubicle
|
HEPA
|
High
Efficiency Particulate Air
|
MOC
|
Material Of Construction
|
PAO
|
Poly Alpha Olefin
|
db
|
Decibels
(Unit of Sound)
|
FPM
|
Feet Per Minute
|
AHU
|
Air Handling
Unit
|
LAF
|
Laminar Air
Flow
|
MOC
|
Material Of
Construction
|
QA
|
Quality Assurance
|
%RH
|
Relative Humidity
|
RPM
|
Revolutions Per Minute
|
WC
|
Water
column
|
SOP
|
Standard
operating procedure
|
BMS
|
Building
monitoring system
|
WFI
|
Water for
injection
|
CD
|
Compact
disc
|
UCL
|
Upper
concentration limit
|
NMT
|
Not more
than
|
NLT
|
Not less
than
|
HVAC
|
Heating
Ventilation and Air Conditioning
|
ACPH
|
Air changes
per hour
|
DP
|
Differential
pressure
|
SS
|
Stain less steel
|
NVPC
|
Non-viable particle count
|
QC
|
Quality control
|
QMS
|
Quality management system
|
SAS
|
Sterility assurance services
|
17.0 REFERENCES
·
ISO 14644-1, 2nd
edition (2015)
·
EUGMP Annexure-1
·
WHO TRS 961 Annexure-5
·
Requalification Protocol no.
RQP/XXX/CRQ/001/01
18.0 PROTOCOL APPROVAL
The signatures listed below
indicate approval of the Re-qualification protocol and certify that it may be
executed.
PREPARED
BY
|
|||
Name
|
Department
|
Designation
|
Signature &Date
|
APPROVED
BY
|
|||
Name
|
Department
|
Designation
|
Signature & Date
|
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