Revalidation/Requalification of HVAC system

Revalidation/Requalification of HVAC system

  • objective
  • Scope
  • Responsibility
  • Qualification team
  • Abbreviation and definition
  • Pre-requisites
  • Precautions and instruction (Health, Safety, and Environment)
  • Air velocity, the Air volume, and air Change Per hour measurement
  • Procedure for HEPA Filter integrity
  • Procedure for non-viable particle count
  • Procedure for viable particle count
  • Recovery Study
  • Airflow Visualization
  • Procedure for Temperature, Relative Humidity, and differential Pressure Measurement
  • Frequency Of  Performance Qualification
  • Deviation
  • Performance Qualification Report

Objective: 

To Re qualify the HVAC system of All areas in the unit 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 systems i.e. Air Handling (AHU) Systems, Forced Air Ventilation (FAV) Systems, and Laminar Air Flow systems (Unidirectional Air Flow Systems) Reverse Laminar Air Flow systems to be followed in Unit of Pharmaceutical Formulation Plant.

The following parameters are to be evaluated.

  • Air Velocity, Air Flow Volume, and Air Changes.
  • HEPA Filter Integrity (DOP/PAO) tests.
  • 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” in accordance with ISO 14644.
  • Differential Pressure is the Pressure difference between the installation and its respective surroundings.
  •  (Neighboring room / corridor/ others).
  • Temperature and relative humidity.

Responsibility:

Department Responsibilities
Quality Assurance:Responsible for ensuring the overall Re-Qualification of the 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, and 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 the 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 the 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

Common TermAbbreviation
ACPHAir Changes Per Hour
AFSAir Flow Switch
AHUAir Handling Unit
DDCDigital Data Control
DIDW FanDouble Inlet Double Width Fan
DPSDifferential Pressure Sensor
DPSWDifferential Pressure Switch
DQDesign Qualification
EAExhaust Air
FDFire damper
FRPFiber Reinforced Plastic
HEPAHigh-Efficiency Particulate Air
MGMagnehelic Gauge
MOCMaterial of Construction
NMTNot More Than
OQOperation Qualification
PQPerformance Qualification
PUFPoly-Urethane Foam
RHRelative Humidity
TS/HSTemperature sensor/heat sensor
SASupply Air
URSUser Requirement Specification
No.Number
FAVForced Air Ventilation
LAF Laminar Air Flow
RLAFReverse Laminar Air Flow
FPMFeet Per Minute
SOPStandard Operating Procedure
ImpingeTo invade on
QCQuality Control
SSStainless Steel
IDIdentification
TBCTotal Bacterial Count
TFCTotal Fungal Count
ftFeet
QCQuality Control
Dynamic ConditionsUnder Manufacturing Conditions
Positive Controlprepared medium inoculated with some organism
Negative ControlUn inoculated Medium or a sterile medium
Aseptic conditionsUnder LAF conditions
LuxuriantAmple
Uniformity of Air FlowUnidirectional airflow pattern in which the point-to-point readings of velocities are within the defined percentage of the average airflow velocity
Clean RoomRoom 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 parameters. For example Temperature, Humidity and Pressure are controlled as necessary
QCQuality Control
Test AerosolGaseous suspension of solid and /or liquid particles with known and controlled size distribution and concentration
Installed FilterThe system is composed of a filter and grid support system or other housing mounted in the ceiling wall, apparatus, or duct
Clean ZoneDedicated 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 StatesThe condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present
 as-Built Occupancy StatesThe 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 StatesThe condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.

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 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 the laminar airflow system (Unidirectional air flow system) as per the 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 a review of the status of the blower, pre-filter & HEPA  filter, motor, and damper, etc.

The Air Change per hour of all AHUs should comply with respective Design  Qualification Values.

Operating Procedure:-

Air velocity measurement of laminar airflow 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 airflow 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 the 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 is to be done.

Systems, which are not running continuously, run systems 30 minutes before to stable the system and measure the reading.

Remove the diffuser/ grill before taking a reading, if applicable.

Switch ON the anemometer. Hold the anemometer fan in a plane parallel to the 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.

Airflow velocity should be measured at the center of each cell.

Hold the fan of the 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. 

Revalidation/Requalification

Procedure for HEPA filter integrity test

Apparatus Required: –

Aerosol Photometer. 

Acceptance Criteria:- 

The leakage rate is NMT 0.01%.

Operating Procedure:-

Integrity checking of filters should be carried out by using Calibrated photometer.

The following apparatus should be used while integrity testing of filters.

An aerosol photometer having threshold sensitivity below 10 microgram/liter For 0.3-micron particles of aerosolized Di Octyl Phthalate / Poly Alfa Olefin (DOP/PAO) and a sampling rate of 1 Cubic Foot Per Minute (CFM). Set up the  Aerosol generator and fill the DOP/PAO liquid to a minimum of 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 the 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 the photometer.

10.3.3.3 Start the compressed air / Nitrogen gas to generate the test aerosol maintain at a minimum pressure of 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 upstream mode and unit of measurement in %.

Connect the tube of photometer to the upstream port of HEPA housing.

Wait until the photometer displays 100% upstream concentration.

Remove the tube of the photometer and close the upstream port of the HEPA housing and ensure Zero Leakage.

Put the photometer selector switch on downstream mode.

Wait until the photometer displayed ‘0’ (ZERO).

Measure the downstream 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 the 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. (Photometer detects the leak every 2 seconds).

If any leakage’s observed through the sealing of the filter inform the engineering dept. and get things done.

Inform Quality Assurance and concerned dept.

If leakage is more than 0.01% of the upstream aerosol concentration of filters and 0% of the joints of filters then ask to engineer. Dept. to repair it.

Repair patches on filters should not exceed a 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. A 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 the filter.

A report of filter integrity checking should be maintained and documented.

Terminal HEPA filters for the clean room (Without individual upstream port.)

Ensure the system is running continuously for about 30 minutes before the filter integrity checking is to be done.

Start the compressed air / Nitrogen gas to the DOP/PAO generator to generate the test aerosol at a minimum pressure of 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 upstream mode and unit of measurement in %.

Check the upstream concentration of DOP/PAO at the main duct of AHU, wait until the photometer displays 100% upstream concentration

Enter the clean room.

Put the photometer selector switch on downstream mode.

Wait until the photometer displayed ‘0’ (ZERO).

Measure the downstream 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 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 upstream aerosol concentration and then repair it.

Repair patches on filters should not exceed a 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. A 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 and generate the test aerosol at a minimum pressure of 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 upstream mode and unit of measurement in %.

Connect the tube of photometer to the upstream port of HEPA housing.

Wait until the photometer displays 100% upstream concentration.

Put the photometer selector switch on downstream mode.

Wait until the photometer displayed ‘0’ (ZERO).

Measure the downstream 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 the 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.

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 a 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. A 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 the filter.

Inform Quality Assurance and concerned dept.

A report of filter integrity checking should be maintained and documented.

Check the air velocity of the individual HEPA filters by keeping an anemometer probe approximately 6 inches away from the filter.

Note down the reading and the Avg. reading is 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 30 minutes before the filter integrity checking is to be done.

Start the compressed air / Nitrogen gas in the DOP/PAO generator to generate the test aerosol at minimum pressure of 20psi or as per the aerosol photometer and monitor the pressure.

Direct the test aerosol at the return air pump on the Fresh air intake of AHU.

Put the photometer selector switch on upstream mode and unit of measurement in % mode.

Check the upstream concentration of DOP/PAO after cooling and heating the coil and before HEPA at AHU/PLENUM. Wait until the photometer displays 100% upstream concentration.

Remove the tube of the photometer and seal AHU / PLENUM port and ensure Zero Leakage through the port.

Put the photometer selector switch on downstream mode.

Wait until the photometer displays zero.

Open the AHU / PLENUM door and enter inside.

Measure the downstream 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 the photometer in overlapping strokes, traversing at approximately 10 feet per minute (FPM).

Observe the percentage of leakage directly on the photometer and 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 than 0.01% of the upstream aerosol concentration then repair it.

Repair patches on filters should not exceed a 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. A 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 the filter.

Inform Quality Assurance and concerned dept.

A report of filter integrity checking should be maintained and documented.

DOP/PAO leakage up to 0.01% of the upstream challenge aerosol concentration is allowed for

EU – 12 filters and DOP leakage up to 0.01% of the upstream 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 SOP and recorded. 

Procedure for Non Viable Particulate count test

Apparatus Required: – 

Discrete particulate counter. 

Acceptance Criteria:- 

ClassMaximum concentration limits (Particles/m3 of air) for particles equal to and larger than the considered sizes shown below (ISO 14644 )
0.5µ5 µ
ISO Class- 8352000029300

 The average particle concentration at each of the particle measuring locations 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 locations for air sampling by following the 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 the Square meter.

  o   o
     o   o

for example Area of Room = 16 m2

N=√A

= 4 Location

Distribute the calculated number of sampling locations evenly in the clean room or clean zone or as per the authorized protocol at the respective location.

Prepare the particle counter for taking the air sample in the clean room or clean zone.

Ensure that the 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 the working level.

The sampling probe should be positioned pointing to the airflow, in the case of non- unidirectional airflow; the probe should be directed vertically upward.

Take a 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 particles that could be counted if the particle concentration were at the class limit.

The volume of the sample is at least 2 liters / each location and the duration per sampling is a minimum of 1 min as per ISO 14644-1.

Collect the printout 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 sizes 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 SOP. Specimen data sheets are attached for reference.

Procedure for particulate count recovery test

Apparatus Required: – 

Discrete particulate counter. 

Acceptance Criteria:- 

A 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. 

ClassMaximum concentration limits (Particles/m3 of air) for particles equal to and larger than the considered sizes shown below (ISO 14644 )
0.5µ5 µ
ISO Class- 8352000029300

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 the 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 the working level.

The sampling probe should be positioned pointing to the airflow, the probe should be directed vertically upward.

The volume of the sample is at least 2 liters / at each location and the duration per sampling is a minimum of 1 min as per ISO 14644-1.

Take reading when AHU is ON.

Collect the printout 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 minute up to 20 minutes, as the reading of particle counts reaches the next class of clean room( ie. 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 a particle counter.

Time taken to return to its original condition is called Recovery Time.

Procedure for Airflow Visualization smoke test

Apparatus required

Digital video Camera

Required Chemical

Titanium tetra Chloride/Ice

Precaution

Wear all protective clothes and nose masks, gloves, and safety glasses.

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 measures.

Dip the rod which has one end wrapped with the cloth into the chemical.

The chemically smeared rod is kept below the supply grill and in front of the return grill.

Take the videography of smoke flow.

The videography shows the exact area name and supplies the return grill’s ID.

Visually ensure the flow pattern of air inside the cubicle.

Frequency Of  Performance Qualification 

S. No.Test RequiredTest Frequency
1Air Flow Volume and Air Changes1 Year ± 1 Month
2Filter Integrity (DOP)1 Year ± 1 Month
3Differential Pressure1 Year ± 1 Month
4Temperature and Relative HumidityAs per SOP No:
5Non Viable particle count 6 months ± 1 week
6Viable particle countAs per SOP No:
7.Airflow visualization2 Year ±  2 Month
8.Recovery Study2 Year ±  2 Month

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 an impact on the Qualification, the deviation shall be reported to the concerned

department for the corrective action and the Qualification activity shall be redone

Performance-Qualification Report

18.1 Based on the outcome of 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 the 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 kept separately)

Drain Monitoring Report. (Trend data are kept separately)

Environment Monitoring Report for Active Air Sampling. (Trend data are kept separately)

Calibration certificate of Differential pressure gauge.

Calibration certificate of Anemometer.

Calibration certificate of sling-type Psychrometer.

Calibration certificate of the aerosol photometer.

Calibration certificate of the discrete particulate counter.

Qualification Report Summary & Conclusion

Certificate of Completion

HEPA filter details.

Deviation details.

Recovery Study Test Report.

List of Annexure

S.No.Title of the Annexure
       1.Cover page of the Report
       2.Qualification Report Approval Sheet
       3.Report of Air velocity, volume, and ACPH
       4.Report of Filter Integrity
       5.Report of Temperature and Relative humidity Differential pressure
       6.Report of Nonviable Particle Count
       7.Environment Monitoring Report For Passive Air Sampling
       8.Environment Monitoring Report For Active Air Sampling
       9.Drain Monitoring Report
     10.Sampling Plan for Environmental Monitoring (Main Production)
     11.Sampling Plan for Environmental Monitoring (Liquid Block):
     12.Sampling plan for Environmental Monitoring (RM Stores)
     13.Qualification Report Summary & Conclusion
     14.Certificate of Completion
     15.HEPA filter details
     16.Deviation
     17.Recovery Study Test Report

About Pharmaceutical Guidanace

Alice is the Author and founder of pharmaceutical guidance, she is a pharmaceutical professional having more than 18 years of rich experience in pharmaceutical field. During her career, she works in the quality assurance department with multinational companies i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, and Nectar life Science Ltd. During his experience, she faces many regulatorily audits i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda, Kenya, Tanzania, Zimbabwe. She is currently leading a regulatory pharmaceutical company as a Head Quality. You can join him by Email, Facebook, Google+, Twitter, and YouTube

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