HVAC SYSTEM RE-QUALIFICATION PROTOCOL PHARMA
TABLE OF CONTENT
- Approval sheet
- Objective
- Scope
- Responsibility
- Qualification Team
- Abbreviation and definition
- Prerequisites
- Precautions and instruction (Health, Safety and Environment)
- Air velocity, Air volume and air Change Per hour measurement
- Procedure for HEPA Filter integrity
- Procedure for Temperature, Relative Humidity and differential Pressure Measurement
- Procedure for nonviable particle count
- Procedure for viable particle count
- Recovery Study
- Airflow Visualization
- Frequency of Performance Qualification
- Deviation
- Performance Qualification Report
- References
Approval Sheet of Protocol
Objective:
To Re-qualify the HVAC system of All area and establish documentary evidence to demonstrate that Air Handling Units, Ventilation Units, Exhaust units, Laminar Air Flow and Reverse Laminar Air Flow units are qualified to perform well within the predetermined acceptance limit of performance as per guidelines outlined in this protocol.
Scope:
This protocol is applicable for Re-Qualification of HVAC system i.e. Air Handling (AHU) Systems, Forced Air Ventilation (FAV) Systems, Laminar Air Flow System (Unidirectional Air Flow Systems) Reverse Laminar air Flow System of Pharmaceutical Formulation Plant of Company Name.
Following parameters are to be evaluated.
Air Velocity, Air Flow Volume and Air Changes.
Differential Pressure. Pressure difference between the installation and its respective surroundings. (Neighboring room / corridor/ others).
HEPA Filter Integrity (DOP/PAO) tests.
Temperature and relative Humidity.
Viable Particle Count. Environmental Monitoring of Manufacturing Area for Microbial Load.
Non viable particle count. Air born particle count level within the clean room ISO Class-8 facility “At-Rest” accordance with ISO 14644.
4.0 Responsibility:
Quality Assurance
Responsible for ensuring the overall Re-Qualification of HVAC system, used to control the environmental conditions of all areas. These responsibilities for HVAC Qualification include:
- Preparation, Review and approval of HVAC Qualification Protocols, Reports.
- Handling of Deviations.
- Training of team involved in HVAC Qualification.
- Compile and review of Report
- Verifying the Qualification activities
- Providing the Drawings and Qualification documents.
Quality Control
These responsibilities for HVAC Qualification include:
- Review and Approval of HVAC Qualification Protocols, Reports.
- Environment monitoring report of manufacturing area for microbial load as per schedule to record all the observations.
- Initiation of Deviations.
Engineering
Responsible for ensuring the
- Review and Approval of HVAC Qualification Protocols & Reports.
- Execution of HVAC Qualification Activities.
- Providing Equipment, components, utensils and area supporting utilities drawings and manpower.
Contractor
Execution of Qualification as per protocol.(If qualification activity is not in house)
Collection of data and preparation of final test certificates.
Qualification Team
Qualification team shall comprise of the representatives from following functions:
- Quality Assurance
- Quality Control
- Engineering
- Contractor (If applicable)
Abbreviation and Definition
Pre Requisite:
Calibration of instruments or equipments used for testing like Anemometer, Aerosol photometer, Non-viable particle counter etc.
Precaution and Instructions (Health, Safety and Environment) :
Wear Nose masks, hand gloves, and proper gowning while carrying out DOP/PAO testing and viable particle count.
Air velocity, Air volume and Air Change Per Hour measurement.
Acceptance Criteria:-
Air Flow velocity (Homogenous air speed) should be within the range of 72 to 108 FPM or 0.36 to 0.54 m/s for laminar air flow system (Unidirectional air flow system) as per EC guide.
If the velocities readings within the limit are not observed then adjust the damper gradually so as to get desired mean air velocity. Even after adjusting the damper velocity is not maintained then an investigation should include review of status of blower, pre filter & HEPA filter, motor and damper etc.
The Air Change per hours of all AHUs should comply with respective Design Qualification Values.
Operating Procedure:-
Air velocity measurement of laminar air flow unit-Vane type Anemometer (unidirectional airflow)
Note: Calibrated Vane type Anemometer should be used for velocity measurement
Switch ON the system/equipment of which air velocity measurement is to be done.
Let the equipment run for 5 Minutes.
Define the measuring plane perpendicular to the supply air flow and divide the measuring plane into grid cells of equal area.
The number of measuring points should be more than the square root of the measuring plane area in square meters and should not be less than 3 points (Ref – ISO 14644 — 3 B.4.2.1.2)
Measurements should be taken at the center of each grid cell.
Switch ON the anemometer. Hold the anemometer-fan about 150 mm from filter face for measuring the filter face velocity and for checking the uniformity of velocity. (Ref — ISO 14644 — 3 B .4.2.1.1)
Hold the fan of the anemometer till the anemometer reading is stabilized for at least 10 seconds duration and values should be recorded.
Note down the air velocity readings and filter number.
Switch OFF the anemometer.
Switch OFF the equipment. If required.
Air velocity measurement of non-unidirectional airflow
Ensure the system / equipment is switched ON of which air velocity measurement to be done.
Systems, which are not running continuously, run those systems 30 minutes before to stable system and measure the reading.
Remove the diffuser/ grill before taking reading, if applicable.
Switch ON the anemometer .Hold the anemometer-fan in a plane parallel to filter/ diffuser/grill. The fan should be held approximately 150 mm from the grill face/ HEPA filter. (Ref – ISO 14644 – 3 B.4.2.2.3)
The number of measuring points should be more than the square root of the measuring plane area in square meters and should not be less than 3 points.
Air flow velocity should be measured at the center of each cell.
Hold the fan of anemometer till the anemometer reading stabilizes or at least 10 seconds duration.
Note down the air velocity readings in Feet per minute (FPM)
Switch OFF the anemometer.
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 = V1+V2+V3+V4+V5 / 5 X Area of filter = A X V
Total supply air Qnty (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)
Procedure for HEPA filter integrity test
Apparatus Required: –
Aerosol Photometer.
Acceptance Criteria:-
Leakage rate is NMT 0.01%.
Operating Procedure:-
Integrity checking of filters should be carried out by using Calibrated photometer.
Following apparatus should be used while integrity testing of filters.
An aerosol photometer having threshold sensitivity below10 microgram / liter
For 0.3 micron particles of aerosolized Di Octyl Phthalate / Poly Alfa Olefin (DOP/PAO) and a sampling rate of 1 Cubic Feet Per Minute (CFM). Set up the Aerosol generator and fill the DOP/PAO liquid to minimum 1/2 of its capacity.
The concentration of aerosol challenge upstream of the filter should be between 10mg/m3 and 100 mg/m3. A concentration lower than 20 mg/m3 can reduce the sensitivity of leak detection.
Terminal HEPA filter for clean room ( having individual upstream port )
Ensure the system is running continuously for about 30 minutes, which the filter integrity checking is to be done.
Ensure the power supply of photometer.
Start the compressed air / Nitrogen gas to generate the test aerosol maintain at minimum pressure 20psi (1.4 kg/cm²) or as per the Aerosol generator.
Direct the test aerosol at the return air point or fresh air intake of the AHU.
Put the photometer selector switch on up stream mode and unit of measurement in %.
Connect the tube of photometer to the up stream port of HEPA housing.
Wait until the photometer displays 100% up stream concentration.
Remove the tube of photometer and close the upstream port of HEPA housing and ensure for Zero Leakage.
Put the photometer selector switch on down stream mode.
Wait until photometer displayed ‘0’ (ZERO).
Measure the down stream concentration by holding the probe approximately 1 inch away from the face of the filter.
Scan the entire filter face including perimeters with the probe of photometer in overlapping strokes,traversing at approximately 2 feet per minute (FPM).
Observe the percentage of leakage directly on the photometer and note down the reading in given format as per Annexure-4. (Photometer detect the leak of every 2 seconds).
If any leakage’s observed through the sealing of the filter inform engineering dept. and get things done.
Inform Quality Assurance and concerned dept.
If leakage is more then 0.01% of the upstream aerosol concentration of filters and 0% of the joints of filters then asks egg. Dept. to repair it.
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 as per point no. 1.3.1 to 1.3.13 and 1.7
A report of filter integrity checking should be maintained and documented.
Terminal HEPA filters for clean room (Without individual upstream port.)
Ensure the system is running continuously for about 30 minutes which the filter integrity checking is to be done.
Start the compressed air / Nitrogen gas to DOP/PAO generator to generate the test aerosol at minimum pressure 20psi (1.4 kg/cm²) or as per the aerosol photometer and monitor the pressure.
Direct the test aerosol at the return air point or fresh air intake of the AHU and that should be after the heating and cooling coil.
Put the photometer selector switch on up stream mode and unit of measurement in %.
Check the up stream concentration of DOP/PAO at main duct of AHU, wait until the photometer displays 100% up stream concentration
Enter the clean room.
Put the photometer selector switch on down stream mode.
Wait until photometer displayed ‘0’ (ZERO).
Measure the down stream concentration by holding the probe approximately 1 inch away from the face of the filter.
Scan the entire filter face including perimeters (Edges) with the probe of photometer in overlapping strokes, traversing at approximately 2 feet per minute (FPM).
Observe the percentage of leakage directly on the photometer and note down the values .(Photometer detects the leak of every 2 seconds).
Inform Quality Assurance and concerned dept.
If leakage is more than 0.01% of the filters and 0% of the joints of filters of the up stream aerosol concentration and then repair it.
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 then 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
A report of filter integrity checking should be maintained and documented.
LAF work station, HEPA module, and garment cubical/cupboard.
Start the LAF of which filter integrity is to be checked.
Record the manometer reading.
Start the compressed air / Nitrogen gas generate the test aerosol at minimum pressure 20psi or as per Photometer make.
Direct the test aerosol at the return air point or fresh air intake of the LAF.
Put the photometer selector switch on up stream mode and unit of measurement in %.
Connect the tube of photometer to the up stream port of HEPA housing.
Wait until the photometer displays 100% up stream concentration.
Put the photometer selector switch on down stream mode.
Wait until photometer displayed ‘0’ (ZERO).
Measure the down stream concentration by holding the probe approximately 1 inch away from the face of the filter.
Scan the entire filter face including perimeters with the probe of photometer in overlapping strokes,traversing at approximately 2 feet per minute (FPM).
Observe the percentage of leakage directly on the photometer note down the reading.
If leakage is more than 0.01% of the filter and 05 for the joints of filters of upstream aerosol concentration then repair it.
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 then 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.
Inform Quality Assurance and concerned dept.
A report of filter integrity checking should be maintained and documented.
Check the air velocity of individual HEPA filter by keeping anemometer probe approximately 6 inch away from the filter.
Note down the reading and if the Avg. reading are not within the acceptable limit replace the filter.
Carry out steps 1.5.1 to 1.5.13 and 1.7 after replacing the filter.
Limits for the Avg. velocity 90 fpm + / – 20%, 0.45m/s +/-20%
AHU / PLENUM MOUNTED HEPA FILTERS
Note: Before entering the AHU /PLENUM he should wear the shoe covers.
Ensure the system is running continuously for about 30minutes which the filter integrity checking is to be done.
Start the compressed air / Nitrogen gas to DOP/PAO generator to generate the test aerosol at minimum pressure 20psi or as per aerosol photometer and monitor the pressure.
Direct the test aerosol at the return air pump on Fresh air intake of AHU.
Put the photometer selector switch on up stream mode and unit of measurement in % mode.
Check the up stream concentration of DOP/PAO after cooling and heating coil and before HEPA at AHU/PLENUM. Wait until the photometer displays 100% up stream concentration.
Remove the tube of photometer and seal AHU / PLENUM port of and ensure for Zero Leakage through port.
Put the photometer selector switch on down stream mode.
Wait until the photometer displays zero.
Open the AHU / PLENUM door and enter inside.
Measure the down stream concentration by holding the probe approximately 1 inch away from the face of the filter.
Scan the entire filter face including perimeters with the probe of photometer in overlapping strokes,traversing at approximately 10 feet per minute (FPM).
Observe the percentage of leakage directly on the photometer note down the reading.
If any leakage’s observed through the sealing of the filter tighten the filter nuts and check again for any leakage.
If leakage is more then 0.01% of the up stream aerosol concentration then repairs it.
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 then 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.
Inform Quality Assurance and concerned dept.
A report of filter integrity checking should be maintain and documented.
DOP/PAO leakage up to 0.01% of the up stream challenge aerosol concentration is allowed for EU – 12 filters and DOP leakage up to 0.01% of the up stream challenge aerosol
Concentration is allowed For EU – 13 filters.
The rejected / faulty filter shall be scraped and shall be incinerated.
Procedure for Temperature and Relative Humidity and Air pressure difference Measurement
Being Done As per respective SOP.
Procedure for Non Viable Particulate count test
Apparatus Required: –
Discrete particulate counter.
Acceptance Criteria:-
| Class | Maximum concentration limits (Particles/m3 of air) for particles equal to and larger than the considered sizes shown below (ISO 14644 ) | |
| 0.5µ | 5 µ | |
| ISO Class- 8 | 3520000 | 29300 |
The average particle concentration at each of the particle measuring location falls below the class limit.
When the total number of locations sampled is less than 10, the calculated 95 % Upper Confidence Limit (UCL) of the particle concentration is below the class limit.
Procedure
Follow the respective locations procedure to enter the clean room.
Calculate the minimum number of location for air sampling by following formula, NL = √A
Where, N -Number of Locations (Rounded up to the higher whole number),
A-is the area of the clean room or clean zone in Square meter.
| o | o |
| o | o |
for example Area of Room = 16m2
N=√A = 4 Location
Distribute the calculated number of sampling location evenly in the clean room or clean zone or as per the authorized protocol at respective location.
Prepare the particle counter for taking the air sample in the clean room or clean zone.
Ensure that particle counter is purged by the purge filter supplied with the particle counter before the start of testing, till the reading obtained is zero.
All the testing should be carried out at working level.
The sampling probe should be positioned pointing to the airflow, in case of non- unidirectional air flow; probe should be directed vertically upward.
Take number of samples as per calculation.
Minimum volume
V = 20 X 1000 / C
V = min. single volume /location expressed in liters.
C = is the class limit (no of particle / m3) for the largest considered particle size specified for the relevant class.
20 = is the defined no of particle that could be counted if the particle concentration were at the class limit.
The volume of sample at least 2 liters / each location and the duration per sampling is minimum 1 min as per ISO 14644-1.
Collect the print out generated by the instrument after the testing and record the values of 0.5 and 5.0 µ particles.
Calculate the average values of each location and mean average of all the locations in a clean room or Zone for respective particle size and report the values in particles/m3 .
Compare the recorded values with (Ref: ISO 14644 – I) selected airborne particulate cleanliness classes for clean rooms and clean zone.
Procedure for monitoring viable particle count test
Is being done As per respective SOP.
Procedure for particulate count recovery test
Apparatus Required: –
Discrete particulate counter.
Acceptance Criteria:-
Clean room takes to return from a contaminated condition to the specified clean room condition. This should not take more than 15 min. In accordance with ISO 14644-3
| Class | Maximum concentration limits (Particles/m3 of air) for particles equal to and larger than the considered sizes shown below (ISO 14644 ) | |
| 0.5µ | 5 µ | |
| ISO Class- 8 | 3520000 | 29300 |
Procedure
Follow the respective locations procedure to enter the clean room.
- Prepare the particle counter for taking the air sample in the clean room or clean zone.
- Ensure that particle counter is purged by the purge filter supplied with the particle counter before the start of testing, till the reading obtained is zero.
- All the testing should be carried out at working level.
- The sampling probe should be positioned pointing to the airflow, probe should be directed vertically upward.
- The volume of sample at least 2 liters / each location and the duration per sampling is minimum 1 min as per ISO14644-1.
Take reading when AHU is ON.
Collect the print out generated by the instrument after the testing and record the values of 0.5 and 5.0 µ particles‘ AT REST’ Condition .
- Put OFF the AHU & start taking reading intermittently every 1 minutes up to 20 minutes, as the reading of particle counts reach the next class of clean room( i.e.. Class 9 for testing of ISO Class 8 clean room) switch on the AHU & determine the time required to attain the class standard from the print outs of particle counter. Time taken to return to its original condition is called Recovery Time.
Procedure for Air flow Visualization smoke test
Apparatus required
Digital video Camera
Required Chemical
Titanium tetra Chloride /Dry Ice
Precaution
Wear all protective cloths and nose mask, gloves and safety glass.
Acceptance criteria
From clean to dirty areas• do not cause cross-contamination• uniformly from laminar flow units. Demonstrated by actual or videotaped smoke tests. In accordance with ISO 14644-3 Annex B7*.
Procedure
- Before executing the activity ensure all precautionary measure.
- Dip the rod which has one end wrapped with the cloth into the chemical if Titanium tetra Chloride chemical used for smoke generation or Dry Ice dip in water /WFI for generation of Smoke
- Coming smoke through Titanium tetra Chloride smeared rod or dry Ice is kept below the supply grill and in front of the return grill.
- Take the videography of smoke flow.
- In videography show the exact area name and supply return grill’s ID.
- Visually ensure the flow pattern of air inside the cubicle.
Frequency Of Performance Qualification
| S. No. | Test Required | Test Frequency |
| 1. | Air Flow Volume and Air Changes | 1 Year ± 1 Month |
| 2. | Filter Integrity (DOP) | 1 Year ± 1 Month |
| 3. | Differential Pressure | 1 Year ± 1 Month |
| 4. | Temperature and Relative Humidity | As per SOP |
| 5. | Non Viable particle count | 6 months ± 1 week |
| 6. | Viable particle count | As per SOP No |
| 7. | Airflow visualization |
Deviations if any
Any deviation observed during Re Qualification shall be recorded and investigated.
If the observed deviation does not have any impact on the Qualification the 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 Qualification activity shall be redone
Performance-Qualification Report
Based on the outcome from this Qualification study, a report shall be prepared by Quality Assurance. The Qualification report shall be reviewed and then approved by all functional heads of all the concerned departments. Qualification Report shall include following:
Cover page of the Report.
Qualification Report Approval Sheet.
Report of Air velocity and ACPH.
Report of filter integrity.
Report of Temperature and Relative Humidity Differential pressure.(Maintained separately as daily log sheets)
Report of nonviable particle count.
Environment Monitoring Report for Passive Air Sampling. (Trend data are keeping separately)
Drain Monitoring Report. (Trend data are keeping separately)
Environment Monitoring Report for Active Air Sampling.(Trend data are keeping separately)
Calibration certificate of Differential pressure gauge.
Calibration certificate of Anemometer.
Calibration certificate of sling type Psychrometer.
Calibration certificate of aerosol photometer.
Calibration certificate of discrete particulate counter.
Qualification Report Summary & Conclusion
Certificate of Completion
HEPA filter details.
Deviation details.
Recovery Study Test Report.
References
ISO 14644 — 1,2,
Clean room Technology-Fundamentals of design, testing and operation-W.Whyte
Common Term Abbreviation
ACPH: Air Changes per Hour
AFS: Air Flow Switch
AHU: Air Handling Unit
DDC: Digital Data Control
DIDW Fan: Double Inlet Double Width Fan
DPS: Differential Pressure Sensor
DPSW: Differential Pressure Switch
DQ: Design Qualification
EA: Exhaust Air
FD: ire damper
FRP: Fiber Reinforced Plastic
HEPA: High Efficiency Particulate Air
MG: Magnehelic Gauge
MOC: Material of Construction
NMT: Not More Than
OQ: Operation Qualification
PQ: Performance Qualification
PUF: Poly Urethane Foam
RH: Relative Humidity
TS/HS: Temperature sensor/heat sensor
SA: Supply Air
URS: User Requirement Specification
FAV: Forced Air Ventilation
LAF: Laminar Air Flow
RLAF: Reverse Laminar Air Flow
FPM: Feet per Minute
TBC: Total Bacterial Count
TFC: Total Fungal Count
Ft: Feet
Dynamic Conditions: Under Manufacturing Conditions
Positive Control: prepared medium inoculated with some organism
Negative Control: Un inoculated Medium or a sterile medium
Aseptic conditions: Under LAF conditions
Uniformity of Air Flow: Unidirectional airflow pattern in which the point -to-point readings of velocities are within the defined percentage of the average airflow velocity
Clean Room: Room in which the concentration of airborne particles is controlled and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the room and which other relevant parameter. For example Temperature, Humidity and Pressure are controlled as necessary
Test Aerosol: Gaseous suspension of solid and /or liquid particles with known and controlled size distribution and concentration
Installed Filter: system composed of filter and grid support system or other housing mounted in the ceiling wall, apparatus or duct
Clean Zone: Dedicated space in which the concentration of airborne particles is controlled and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the zone and in which other relevant parameters. For example Temperature, Humidity and Pressure are controlled as necessary
As Built Occupancy States: The condition where the installation is complete with all services connected and functioning but with no production equipment, materials or personnel present
As Built Occupancy States : The condition where the installation is complete with all services connected and functioning but with no production equipment, materials or personnel present
At Rest Occupancy States: The condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present.
In Operation Occupancy States: The condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.
SOP On Product Change Over during Manufacturing
