OBJECTIVE:
- To provide a procedure for the Performance Qualification and the Periodic Verification of HVAC Systems, Equipment’s provided with HEPA Filters.
SCOPE:
- The procedure is applicable to all the performance qualifications and the periodic Verifications for the HVAC Systems, Equipment’s provided with HEPA Filters (e.g. LAF units, Biosafety Cabinets, Reverse Laminar Air Flow unit, Dynamic Pass Boxes, Garment Cubicles and Mobile Carts etc.) installed in KPL.
- The procedure describes a systematic procedure to qualify and verify the various HVAC systems, Equipment’s provided with HEPA Filters (e.g. LAF units, Biosafety Cabinets, Reverse Laminar Air Flow unit, Dynamic Pass Boxes, Garment Cubicles and Mobile Carts etc.) installed in Manufacturing and Testing areas.
RESPONSIBILITY:
- Trained personnel/External Testing personnel
- To perform the activities as per procedure.
- To report any non compliance to the procedure
Department Head –
- To ensure the activities are performed as per procedure
- To investigate any non compliance to the procedure
Engineering personnel
- To prepare and execute the protocol with approved external agency
- To prepare the report
- Information Technology
- To provide the support for the safe keeping of data backup / restoration, whenever required.
Quality Assurance personnel –
- To support the engineering personnel for the preparation of the protocol
- To review the protocol and report
ACCOUNTABILITY :
Head Quality Control
- To ensure the procedure is implemented at their site
- To investigate any non compliance to the procedure.
Head Manufacturing –
- To ensure the procedure is implemented at their site
- To investigate any non compliance to the procedure.
Head Engineering
- To ensure the procedure is implemented at their site
- To investigate any non compliance to the procedure.
Head Quality Assurance –
- To ensure implementation of procedure at their site.
- To verify investigation of any non compliance to the procedure
- To ensure the implementation of procedure at KPL.
- To revise the SOP on need base
Precautions during the Qualification activity :
- Ensure that where terminal HEPA filters are affixed the HEPA filter leakage test is carried out by challenging the upstream concentration from appropriate ports within the room.
- If the ports are not available then perform the HEPA filter leakage test from appropriate location provided.
- The scanning probe shall be held at a distance of approx. 3 cm from the downstream filter face. Scanning rate should not exceed 5 cm/sec.
- Scanning shall be done using slightly overlapping strokes and performed over the entire face of each filter, the perimeter of each filter, the seal between the filter frame & the grid structure including joints.
- All the certificates received from the approved external agencies shall be reviewed by KPL.
Qualification/Verification :
| Test | Stage | Qualification/Verification frequency |
| Air Flow Volume and Air Changes | At the start of the Qualification | Once in 6 months ± 15 days for Grade A and B areas of Sterile Manufacturing area and Sterility testing area. Once in 1 year ± 30 days for Grade C and D areas of Sterile area and Sterility testing area. |
| Once in 1 year ± 30 days for all areas of Non Sterile Manufacturing, Dispensing and Sampling areas and Microbiology Lab testing area. | ||
| Filter Integrity (DOP/PAO test) | After Air flow volume and Air changes measurement | Once in 6 months ± 15 days for Grade A and B areas of Sterile Manufacturing area and Sterility testing area. Once in 1 year ± 30 days for Grade C and D areas of Sterile area and Sterility testing area. |
| Once in 1 year ± 30 days for all areas of Non Sterile Manufacturing, Dispensing and Sampling areas and Microbiology Lab testing area. | ||
| Differential Pressure measurement | Routine monitoring and during Filter Integrity test | As per SOP |
| Temperature and Relative Humidity measurement | Routine monitoring and during Filter Integrity test | As per SOP |
Test
Stage
Qualification/Verification frequency
Air Borne Non viable Particle Counts (At rest and In Operation*)
After Filter Integrity test
Once in 6 months ± 15 days for Grade A and B areas of Sterile Manufacturing area and Sterility testing area.
Once in 1 year ± 30 days for Grade C and D areas of Sterile area and Sterility testing area.
Once in 1 year ± 30 days for all areas of Non Sterile Manufacturing, Dispensing and Sampling areas and Microbiology Lab testing area.
Microbial Monitoring
Routine monitoring and during Qualification/ Verification
As per SOP Routine monitoring can be considered if performed after the activity.
For initial qualification follow SOP
Air flow visualization
After Air Borne Non Viable particle count test
Once in 2 years ± 45 days
Recovery study
After Air Borne Non Viable particle count test
Once in 2 years ± 45 days
Containment Leakage test
After Air Borne Non Viable particle count test
Once in 2 years ± 45 days
NOTE:
1.In Initial Qualification, both at rest and in operation condition testing shall be done.
2.In Periodic verification, at any condition (either rest condition or in operation condition) testing shall be done.
Air Velocity Measurements:
Location –1 Location –2
O O
Location -3
O
Location –4 Location -5
O O
Hold the anemometer fan about 150 mm- 300 mm (6-12 inches) from filter face for measuring the filter face velocity and for checking the uniformity of velocity.
Hold the fan of the anemometer till the anemometer reading is stabilized for at least 10 seconds and values shall be recorded.
Note down the air velocity readings against the filter numbers and against the location.
Note: Apart from procedure mentioned above site can perform the activity by another method/instrument as provided by approved external agency and same shall be the part of Protocol. For example Measuring hood can be used for the Air velocity measurement.
In case of Isolator, the number of sampling locations can based on the feasibility of equipment
Procedures –
Air Change per Hour (ACPH) Calculation:
Area of Filter = Length (in Ft.) X Width (in Ft.)
Total air Qty. (CFM) of one supply air grill i.e. Air Volume
= (V1+V2+V3+V4+V5)/5 X Area of filter
= A X V
Total supply air Quantity (SUM of CFM) = CFM of all of supply grills.
CFH (Cubic feet per hour) = SUM of CFM X 60
Volume of room (ft3) = Length (ft.) X Width (ft.) X Height (ft)
Air Changes per hour (ACPH) = SUM of CFH ÷ Volume of room in ft3
Acceptance Criteria:
Unidirectional Air Flow- 90± 20% (72-108 FPM) or 0.45 ± 20% (0.36- 0.54 m/s) . If the working height and distance from filter face is same for the equipment’s with HEPA filters then perform the testing only near the specified distance from the filter face.
The Air Change per hours of all HVAC systems should comply with respective Design Qualification values and should not be less than 20 air changes/hour for Grade D areas, not less than 50 air changes/hour for Grade C areas for all Non Sterile and Sterile Manufacturing areas, Microbiology Lab etc. and not less than 100 air changes/hour for Grade B and A areas of all Sterile Manufacturing areas and Sterility testing areas.
HEPA Filter Integrity Testing:
For 0.3 micron particles of aerosolized Poly Alfa Olefin (PAO) and a sampling rate of 1 cubic feet per minute (CFM).
Set up the aerosol generator and fill the PAO liquid to minimum ½ of its capacity.
The concentration of aerosol challenge upstream of the filter should be between 20mg/m3 and 80mg/m3.
The probe traverse scan rate when using 3 cm X 3 cm square probe should not exceed 5 cm/s.
The probe traverse scan rate when using rectangular probe the maximum scan area should not exceed 15 cm2/s.
Take the upstream concentration at the start, end of filter scanning and intermittently if the machine is tuned OFF or gets reset.
HEPA Filter Integrity Testing:
Terminal HEPA from Clean room (with individual port)
Terminal HEPA from Clean room (without individual port)
Equipment provided with HEPA Filters
AHU/Plenum Mounted HEPA Filters
Failure observed during any activity shall be addressed through respective QMS
Acceptance Criteria:
Leakage rate should not be more than 0.01% of the upstream challenge aerosol concentration.
If any leakages are observed through the corners or the sides of the filter inform engineering department and rectify the leakage.
Also inform to Quality Assurance immediately.
If leakage is more than 0.01% of the upstream aerosol concentration of filters and 0% of the joints of filters then inform engineering department to rectify the leakage.
Repair patches on filters should not exceed maximum of 5%of the total filter face area and the maximum width/length of each patch should not be more than 1.5 inches.
Total number of patches should not exceed 5 numbers/filters.
If the above mentioned limit exceeds, then replace the filter and check the integrity of filter.
If the repairs are done for a filter then the integrity of the filter shall be repeated after repairs.
Maintain a record of filter change, impact of the damage of filter and testing record of the new filter.
Temperature, Relative Humidity and Air pressure differential measurement:
Initial Qualification/Performance Qualification the Temperature, Relative Humidity and Air Pressure differential shall be measured for a period of one (1) hour with an interval of every six (6) minutes on the day of filter integrity test and results shall be recorded .
Air Borne Non Viable Particle count test:
Air Borne Non Viable Particle counting during qualification studies shall be done by sampling for 1m3 (i.e. By sampling 1000 Lts.) of air at each location in Grade A and B.
Air Borne Non Viable particle counting shall be done at the no. of locations as mentioned in the below table and shall be based on the Area of the zone/room.
During Initial Qualification/Performance Qualification the Air Borne Non viable particle counts shall be measured for 1 (one) day at rest condition and then 1 (one) day during operation condition.
During Periodic verification the Air Borne Non viable particle counts shall be measured in any condition (either rest condition or in operation condition).
At rest and In operation conditions can be performed on the same day during periodic verification.
The length of tubing used in the particle counter shall be 1 meter or less in length.
Continuous particle monitoring in a critical locations (Grade A) be carried out only with particle sample tubing lengths of less than 10 feet or approximately 3 meters. For Grade B operations, similar practices shall be considered.
Air Borne Non Viable Particle count test:
No. of Locations as per table given in SOP.
Grade/ ISO
Limit (At Rest)
Limit (In operation)
Grade-A/ ISO 5
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
Grade-B / ISO 6 (LAF/UDAF/UAF/BSC/ RLAF)
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
Grade-B / ISO 6 (Aseptic Rooms)
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 29 particles/m3 of larger than or equal to 5.0 micron
NMT 352000 particles/m3 of larger than or equal to 0.5 micron
NMT 2900 particles/m3 of larger than or equal to 5.0 micron
Grade-C / ISO 7
NMT 352000 particles/m3 of larger than or equal to 0.5 micron
NMT 2900 particles/m3 of larger than or equal to 5.0 micron
NMT 3520000 particles/m3 of larger than or equal to 0.5 micron
NMT 29000 particles/m3 of larger than or equal to 5.0 micron
Grade-D/ ISO 8
NMT 3520000 particles/m3 of larger than or equal to 0.5 micron
NMT 29000 particles/m3 of larger than or equal to 5.0 micron
Not defined
Grade/ ISO
Limit (At Rest)
Limit (In operation)
Grade-A/ ISO 5
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
Grade-B / ISO 6 (LAF/UDAF/UAF/BSC/ RLAF)
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 20 particles/m3 of larger than or equal to 5.0 micron
Grade-B / ISO 6 (Aseptic Rooms)
NMT 3520 particles/m3 of larger than or equal to 0.5 micron
NMT 29 particles/m3 of larger than or equal to 5.0 micron
NMT 352000 particles/m3 of larger than or equal to 0.5 micron
NMT 2900 particles/m3 of larger than or equal to 5.0 micron
Grade-C / ISO 7
NMT 352000 particles/m3 of larger than or equal to 0.5 micron
NMT 2900 particles/m3 of larger than or equal to 5.0 micron
NMT 3520000 particles/m3 of larger than or equal to 0.5 micron
NMT 29000 particles/m3 of larger than or equal to 5.0 micron
Grade-D/ ISO 8
NMT 3520000 particles/m3 of larger than or equal to 0.5 micron
NMT 29000 particles/m3 of larger than or equal to 5.0 micron
Not defined
Microbial Monitoring of HVAC/Areas/Equipment HEPAs:
As per CSOP on Environment Monitoring.
Particulate Count Recovery Test:
Particulate count recovery test is not required for Equipment provided with HEPA which yield unidirectional airflow.
The recovery test can be performed using two methods:
–Evaluation of recovery performance
Switch OFF AHU, Take Particle Counts, Check the time when area gets disturbed, Switch ON AHU, Take Particle Counts, Check the time when area restores back to normal.
–Direct measurement of 100:1-recovery time.
Switch OFF AHU, Take Particle Counts, Induce or allow time when particle change Class, Switch ON AHU, Take Particle Counts, Check the time when area restores back to normal.
Acceptance Criteria: NMT 15 mins.
Air Flow Visualization Smoke test:
Smoke Generator with appropriate wand length and it have sufficient orifice to cover the entire length of HEPA and to maintain the sufficient smoke for clear demonstration of air flow visualization.
Place the smoke of aerosol (Glycol) coming through smoke generator below the supply grill and in front of return grill.
The smoke should move from the HEPA filter to the return air riser.
Also verify the airflow by keeping the doors opened.
The smoke should move from positively pressured area (more pressured area) to negatively pressured area (less pressured area).
The activity shall be carried out in static & dynamic condition.
When visualizing the air flow pattern in Equipment HEPAs the smoke should move from the HEPA filter to the outside of the unit or towards the return air grills provided inside the equipment’s.
Air flow direction shall be verified at working level also when visualizing the flow pattern for Equipment HEPA.
Record the flow direction of fumes /smoke using video camera and at least following details shall be captured in the video (but not limited to):
i) Area identification/ Differential pressure Indicator gauge identification
ii) Equipment Identification
iii) Validation and Calibration status of measuring device
iv) Identification of Return and Supply air filters/Grills
v) Identification of the working condition (Static and Dynamic condition)
Air Flow Visualization Smoke test:
Visually ensure the flow pattern of air inside the cubicle, room, room corners, etc.
Verify the flow with smoke in the External storage Device (storage device should follow ALCOA + principle). External storage devise / server should use for storage purpose. CD / DVD must not be used. Qualification team shall review the same and put the signature on the External storage device.
Video shoot can be carried out with multiple cameras, multiple angles, short shot or long shot or in panorama view to demonstrate effective and actual air flow. Contrast background (opaque / black color against smoke for clear visibility and to avoid reflections).
During the intervention to visualize the impact of this activity on the airflow. e.g. As the operator and tool moves within the Grade A filling line during the intervention, gradually move the smoke source to follow these activities to allow continuous visualization of the impact of the operator’s activities to the first air.
External storage device shall be identified and reviewed / verified of Air flow visualization with smoke w.r.t. by qualification team and put the signature on the same.
Note:
I) External storage device to be provided by external agencies with Air Flow Visualization study data.
II) This external storage device should be identical and accessible for HVAC & Equipment provided with HEPA Filters.
III) The external storage device shall be attached with the qualification documents and it shall be treated & handled as controlled documents.
IV) IT Department shall be provide the Data Backup facility to make it enduring as per ALCOA + concept IT Procedure shall be followed for the same.
Air Flow Visualization Smoke test:
Acceptance Criteria:
Smoke shall travel from Positively pressured area to negatively pressured area and from supply air grills to the return air risers when determined in the clean area or clean zones.
When the air flow visualization is done in Equipment provided with HEPA then
Smoke should flow uniformly/unidirectionally up to the working height or working distance.
Smoke generated should not bounce back from the equipment.
Smoke should sweep away from the equipment.
Smoke should cover full LAF where activity is performed to demonstrate actual air pattern.
Preferably there should be no turbulence or airflow bouncing off the various equipment or any eddies (air moving in a circular pattern).
Smoke should wash over process equipment’s and product pathways (if any) smoothly in one direction, and then continue through the work area towards the floor when flow is viewed for the Equipment provided with HEPA.
Re-qualification criteria:
Substitution of existing HVAC / Equipment provided with HEPA filters with a new system.
Replacement of existing HEPA Filter or critical component like blower, chilling unit, ducting etc.
Any major modification to the existing area or HVAC Equipment provided with HEPA filters.
This study may also be used in case of any sterility failure, media failure, area failure, continuous environment monitoring failure etc.
Containment Leak test:
The test shall be performed to determine if there is intrusion of contaminated air into the clean zones from surrounding non-controlled areas at the same or different static pressure level.
Determine the locations for the test based on the risk assessment or appropriate justified locations and the same shall be documented in protocol.
The test is required to be performed for the Grade A, B and C areas only in Sterile Product Manufacturing areas and Sterility Testing areas.
Procedure if any deviations are observed to the activity:
Failure observed during any activity shall be addressed through respective QMS.
Any deviation observed during Qualification/Periodic Verification or Requalification shall be recorded and investigated.
If the observed deviation does not have any impact on the Qualification/Verification then a final conclusion shall be provided.
If the observed deviation has impact on the Qualification, deviation shall be reported to the concerned department for the corrective action and the Qualification activity shall be redone.
HEPA filter replacement –
Individual site shall follow the site specific SOP to replace the HEPA filters and it’s frequency.
Below criteria can be consider to replace the HEPA filter, but not limited to.
Follow manufacturer recommendation to replace the HEPA filter.
If differential pressure found out of specified range.
If any filter found failing during the periodic qualification, like Air velocity, HEPA filter integrity test, etc.
Unscheduled HEPA filter replacement shall be carried out through respective QMS.
HEPA filter replacement frequency can be rationalized based on below criteria, but not limited to. Risk Assessment shall be required for the same.
Powder generation activity in the area.
Availability of dust collector units.
Usage of area for unit operation like, storage, man/material movement, granulation, compression, filling, testing, PP, etc.
Environment monitoring trends, like, DP, NVPC, Microbial count, Velocity, PAO reading, Pre filters condition, etc.
Post replacement of HEPA filters, complete qualification shall be performed before usage of area.