Performance Qualification Protocol for Clean Room

1. INDEX

Content	Page No.
1. Index	1
2. Pre-Approval Sheet	2
3. Objective	3
4. Scope	4
5. Responsibilities	4
6. Introduction	5
7. Equipment and Material	6
8. Air Velocity Test and Calculation of Air Changes Per Hour	6
9. HEPA Filter Integrity Testing	9
10. Air Flow Pattern Test	13
11. Non-Viable Particulate Count Test	14
12. Recovery Study	18
13. Differential Pressure Test	19
14. Temperature Control Test	20
15. Humidity Control Test	21
16. Light Intensity Measurement: (Lux Measurement)	22
17. Noise Level Measurement	23
18. General Requirements	24
19. Annexure	25
20. Reference	35

2. PRE-APPROVAL SHEET

The signing of this approval page of Performance Qualification protocol no. ____________ indicates agreement with the performance qualification approach described in this document. Shall modifications to the performance qualification become necessary, on addendum will be prepared and approved.

PREPARED BY	SIGNATURE	DATE

CHECKED BY	SIGNATURE	DATE

APPROVED BY	SIGNATURE	DATE

3. OBJECTIVE

To establish that the documented evidence of the HVAC System is meeting predetermined specifications performing,

Air velocity (ACPH) measurement
HEPA Filter leak testing (using Hot or Cold DOP)
Airflow pattern test (Smoke test)
Nonviable particulate counts measurement
Recovery test
Monitoring of Differential pressure of the area
Monitoring of Temperature within the area
Monitoring of relative humidity within the area
Area light level measurement (LUX measurement)
Area noise level measurement (dB level)

4. SCOPE

The scope of this study will verify that the HVAC System is effective & reproducible.

FREQUENCY: To be performed once on six months basis except for Temperature, Relative Humidity, and Differential pressure, monitoring on daily basis.

5. RESPONSIBILITIES

A team comprising the representatives of the following functions shall be responsible to undertake the qualification studies.

DESIGNATION	RESPONSIBILITY
Validation Head	Responsible for final review and approval of protocol and report
Validation In charge	Responsible for perform site work within the time bond period.
EDP Staff	Responsible for Prepare Report.

6. INTRODUCTION

The Heating, ventilation & air conditioning system installed on the service floor of any company, It consists of following AHUs & configuration of filters

Sr. No.	Air Handling Units	Room Name	HEPA Filters	Class

7. EQUIPMENT AND MATERIAL

TSI Hot Wire Anemometer / TSI air capture hood
Photometer with Aerosol generator
Fog generator (Smoke generator)
Airborne Non-Viable Particle counter
Calibrated Temperature & Relative Humidity data logger
Light level meter-Lux meter
Noise level meter-dBA meter

8. AIR VELOCITY TEST AND CALCULATION OF AIR CHANGES PER HOUR

OBJECTIVE:

To demonstrate that the required air velocity is delivered by HEPA Filters and to calculate the Air changes per hour for each area.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Air velocity and ACPH	As per design NLT + 20 %

PROCEDURE: [FOR HOT WIRE ANEMOMETER]

STEP	ACTION
1	Switch on the respective air-handling unit (AHU) of the clean room.
2	Ensure that AHU is operational for the last 5 to 10 minutes.
3	Take the relevant details, like No. of the filter area, filter size, room volume, AHU No, design CMH/CFM, and ACPH for each room.
4	Switch `ON’ the calibrated hot wire Anemometer. Check the “Zero” reading on the display.
5	Hold the `velocity measurement’-probe at the working height of 6 inches (approx.150 mm) below the face of the HEPA filter in the clean room.
6	Record air velocity at different points of the HEPA filter i.e. Four corners and one center [Terminal HEPA]. For the HEPA filter list with AHU & room
7	Calculate the average velocity of each filter.
8	Average air velocity at each point.
9	Record velocity. [Reference is made to Annexure-I].

CALCULATION OF AIR CHANGES PER HOUR

STEP	ACTION
1	Measure the filter face area in square meters.
2	Calculate the actual volume of supplied air in each room as below.
3	Airflow discharge [m3/minute] = Air velocity of HEPA filter [m/s] X Filter area [m2] x 60.
4	Calculate the volume of the room in a cubic meter, of which air changes are to be calculated.
5	Calculate the no. of air changes as follows.
6	No. of ACPH = Airflow discharge in room x 60(CMH) x Room volume.
7	For the filling and sealing area, ACPH should not be less than 300.
8	For all the Classified areas, ACPH should not be less than 20.
9	If the air changes in the area are not within the limit, troubleshoot the cause and rectify it.
10	Engineering and QA staff should investigate the reason for the deviation. Engineering will take immediate action to rectify it.
11	Record the ACPH [Annexure-I].

PROCEDURE: [BY CAPTURE HOOD]

STEP	ACTION
1	Switch on the respective air-handling unit (AHU) of the clean room.
2	Ensure that AHU is operational for the last 5 to 10 minutes.
3	Take the relevant details, like No. of the filter area, filter size, room volume, AHU
4	Take the mean velocity reading of each filter [cfm) by capture hood
5	Calculate the CMH of the room by the sum of all filter cfm multiply by 60.
7	Calculate the ACPH of the room i.e.
8	Record the ACPH [Annexure-I]. If done by capture Hood.

9. HEPA FILTER INTEGRITY TESTING

OBJECTIVE:

To demonstrate and validate the filter integrity –leak monitoring of the HEPA filters installed in different areas.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
HEPA Filter Integrity Test With Using Aerosol	An unacceptable leak is a local reading greater than 0.01%

PROCEDURE: (FOR GENERATION OF AEROSOL):

STEP	ACTION
1	Check the Aerosol oil level in the Aerosol generator.
2	Connect Compressed air / Nitrogen gas to the aerosol generator & adjust the pressure regulator to 20PSI.
3	Direct the outlet of the aerosol generator to return duct [riser] or fresh air intake of AHU.
4	Start the aerosol generator by switching on the Compressed air / Nitrogen gas to produce the upstream concentration required for leak detection till the photometer reads the Photometric concentration of 100%.

CALIBRATION OF THE INSTRUMENT [PHOTOMETER]

STEP	ACTION
1	Put the photometer selector switch on upstream mode.
2	Connect the tube of the photometer to the upstream port of the HEPA filter.
3	Wait until the photometer displays 100% upstream concentration.
4	Remove the tube of the photometer and close the upstream port of the HEPA filter and ensure fir zero leakage.
5	Put the photometer selector switch on downstream mode.
6	Wait until the photometer display 0 [ZERO].
	On any installation, the sealing gasket should be considered as part of the filter and this should be scanned separately from the filter pack. Select the sample port; scan the filter pack and the gasket at a distance of 50 to 100 mm. For a filter to efficiency of 0.001% the range selected should be 0.01% and the alarm set for 0.001%, which is 10% of the full scale, which assumes an efficiency of 99.99% against the challenge aerosol.

TESTING PROCEDURE [TERMINAL HEPA FILTER WITHOUT INDIVIDUAL UPSTREAM PORT]

STEP	ACTION
1	Ensure that before starting the activity AHU is operational for 5 to 10 minutes.
2	Ensure that the air velocity, air balancing, and flow adjustments are done before proceeding to the Filter integrity testing of HEPA filters.
3	Check that a sampling point is provided and accessible immediately upstream of the filter to be tested.
4	Start the compressed air/nitrogen gas to the Aerosol generator to generate the test aerosol at a minimum of 20 psi and monitor the pressure.
5	Direct the test aerosol to the riser of the room.
6	Ensure that it is possible to introduce test aerosol so that 100% concentration can be detected at the upstream sampling point.
7	Place the aerosol generator in an accessible position, ideally near the riser, and adjust the aerosol concentration to the specified density.
8	Prior to the generation of the aerosol place the photometer probe downstream of the HEPA filter until the instrument has stabilized.
9	Put the photometer selector switch on upstream mode.
10	Check the upstream concentration of Aerosol at the port provided for a representative HEPA filter for each room; Until the photometer displays 100 % upstream.
11	After getting the upstream conc. & put the selector switch to a clear position and close the upstream Aerosol port.
12	Put the photometer selector switch on downstream mode.
13	Wait until the photometer displays 0.
14	Measure the downstream concentration by holding the probe at approx.1 inch away from the face of the filter.
15	The photometer has a sample flow rate of 1 cfm. Hold the probe at a distance between 50 to 100 mm from the filter face and scan the filter and perimeter by passing the probe in slightly overlapping strokes so that the entire area of the filter and sealing gasket is sampled. The probe traverse rate should not exceed 10 feet per minute.
16	Observe the percentage of leakage directly on the photometer
17	If any leakage is observed through the sealing of the filter tighten the filter nuts and check again for any leakage.
18	If any leakage is more than 0.01% of the upstream aerosol concentration then repair it.
19	Repair the patches on filters should not exceed a maximum of 5% of the total filter face area & maximum width/length of each patch should not be more than 1.5 inches. The total no of patches should not exceed 5 number/filter.
20	If above-mentioned limit exceeds then replace the filter & check the integrity of the filter as per the above procedure.
21	Record the result [Annexure-II].

10. AIR FLOW PATTERN TEST

OBJECTIVE:

To determine airflow pattern of terminal HEPA filters and laminar air flow units.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Air flow pattern of HEPA filter	Unidirectional

PROCEDURE:

STEP	ACTION
1	Start the respective AHU of which the airflow pattern is to be checked.
2	The person carrying out airflow pattern activity should follow cleanroom gowning.
3	Fog generators should be used for smoke generation.
4	During the process, the hands of the operator and the facemask should be covered properly with gloves and a facemask.
5	Expose the smoke at the supply end of the system.
6	Observe the smoke pattern and ensure the following. The airflow pattern should be within specification in order to ensure environmental contamination control. The smoke should be diffused uniformly at supply grill and pass through the return riser.
7	Carry out Videography/ Photography of the entire airflow pattern-checking activity.
8	Record the result [Annexure-III].

11. NON-VIABLE PARTICULATE COUNT TEST

OBJECTIVE:

To establish that zone meets predefined conditions for non-viable particles.

ACCEPTANCE CRITERIA: As Per EU Guide

CRITERIA	ACCEPTANCE
Non-viable particulate count test	Grade	Maximum number of permitted particles per cubic meter equal to or above
		AT REST		IN OPERATION
		0.5-5µm	>5 µm	0.5-5µm	>5 µm
	A	3500	0	3500	0
	B	3500	0	350000	2000
	C	350000	2000	3500000	20000
	D	3500000	20000	Not Defined	Not Defined

PROCEDURE: ESTABLISHMENT OF SAMPLING LOCATION:

STEP	ACTION
1	All components of the clean air system affecting air quality must be operating in accordance with the specification and all aspects of the controlled environment, which contribute to the operational integrity, are complete.
2	Measure on a centered grid pattern determined by dividing the total floor area, into approximately equal areas such that: The number of sub-areas is as specified in any relevant national standard or as agreed between the client and the contractor sampling positions should be at the intersection of the corners of each sub-area and at a height of 900 mm from the floor unless agreed otherwise by the client. Take the required number of samples at the specified flow rate at each point on the grid. These can be determined from the relevant national standards or agreed by the customer.
3	Calculate the number of sampling locations with the formula N = Square root of Room in cubic meters made it to approx. [Reference is made to ISO14644-1].
4	The sampling location shall be evenly distributed throughout the area of the cleanroom or clean zone and positioned at the height of the work activity. In case of additional sampling locations, their number and position will be specified.

ESTABLISHMENT OF SINGLE SAMPLE VOLUME PER LOCATION:

STEP

ACTION

Sample a sufficient volume of air at each location such that a minimum of 20 particles would be detected if the particle concentration for the relevant class were at the class limit for the largest considered particle size.

The single sample volume Vs per location will be determined by

Vs =20x1000 / Cnm Where,

Vs = is the minimum sample volume per location expressed in liters.

Cnm =class limit (number of particles/ m3) for the largest considered particle size specified for the relevant class.

20 = is the defined number of particles that could be counted if particle concentration were at the class limit.

The volume sampled at each location shall be at least 2 liters with a minimum time at each location of 1 minute.

Since particle counters operate at a flow rate of 1CFM, which is equal to 28.3 lits per minute, therefore particle analyzed per cubic feet will need to be multiplied with 35.31 to convert to m3.

Direct measurement with 1 M3 particle counter,

Specifications are: 50 LPM i.e. 1M3 i.e. 1000 liters per 20 minutes. Sample at each location is taken for 20 minutes, which is equivalent to 50 LPM i.e. 1M3/20 minutes. Therefore, for grade A/B/C areas [ISO/5/6/7] and for grade D areas 1 minute per location. Sampling locations are based on the criticality of the work zone [Reference is made to Annexure IV].

SAMPLING AT SPECIFIED LOCATIONS AT WORKING HEIGHT:

STEP	ACTION
1	Start the sampling and take a minimum of single sample volumes from each location and compute the average particle concentration at the specified location.
2	Sampling will be conducted at rest and during operation.

PARTICLE COUNTING AT EACH LOCATION:

STEP	ACTION
1	Switch on the AHU and let it run for 10-15 minutes.
2	Switch `ON’ the particle counter and set the sampling rate as 1.0 cfm (Approximately 28.0 liters/minute).
3	Hold the particle counter probe to the working height at different locations of control/critical areas and take the printout of the particle counts of mentioned locations of control/critical areas.
4	Take the particle count at a different location under HEPA filters covering the total area of the control / critical room as mentioned in the layout & take printouts of the particle count.
6	Switch OFF the particle counter.
7	Get the report of the particle count by the external party (Supplier)
8	Such reports should be preserved by the Quality Assurance department.
9	Particle count test of all control /critical rooms under AHUs to be carried out once in six months or earlier immediately after any major change in AHU facility.
10	Record the results and make the trend of particle count [Reference is made to Annexure IV].

12. RECOVERY STUDY

OBJECTIVE:

To determine the recovery period for the HEPA filters installed in critical areas.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Recovery period	Not more than 10 minutes/As per Design Specification

PROCEDURE:

STEP	ACTION
1	Measure the clean room or clean zone non-viable particulate counts at rest [before disturbing the area for Recovery test].
2	Shut OFF the AHU of required zone.
3	Allow the required zone to reach next higher grade (i.e. Grade B To Grade C).
4	Measure the non-viable particulate counts when area achieve the next higher grade with help of particle counter for one day.
5	Continue the particle counting for at least 5 counts.
6	Start the AHU and measure the particle counts till it the area achieves the desired level of counts approximately equivalent to the initial counts taken at rest before the test.
7	Measure time taken to recovery the initial grade.
8	Record the results and enclose the particle count printouts and calculate the recovery time as- 5 minutes-Initial count after AHU shut OFF X minutes-Time taken by the area to recover to initial counts after getting the next grade. Recovery time = X minutes.
9	Record the result [Reference is made to Annexure-V].

13. DIFFERENTIAL PRESSURE TEST

OBJECTIVE:

To demonstrate the capability of the air system to provide pressure gradient among the different room.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Differential pressure of rooms	As per design sheet + 0.5 mm of water

PROCEDURE:

STEP	ACTION
1	All HVAC systems of the clean room facility are to be in continuous operation when performing these tests.
2	To avoid unexpected changes in pressure and to establish baseline, all doors in sterile facility must be closed and no traffic is to be allowed through the facility during the test.
3	Adjust the Magnehelic gauge to give a reading of zero in accordance with the manufacturer’s instructions.
4	Connect one end of the tubes to the higher-pressure side of the Magnehelic gauge(Calibrated) & place the other end of the tube in the area of higher pressure such that it is free from obstruction and directed away from any airflows.
5	Next, connect one end of the second tube to the lower pressure input side of the Magnehelic gauge and place the other end of the tube in the area of lower pressure such that it is free from obstruction and directed away from any airflows. If the tubing passes a surface ensure that any gap surrounding the tube are sealed.
6	Record the pressure displayed on the Magnehelic gauge three times, for design differential pressure.
7	Record the result [Reference is made to Annexure-VII].

14. TEMPERATURE CONTROL TEST

OBJECTIVE:

To demonstrate the ability of the AHU's to provide the required temperature in critical and controlled areas.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Temperature of controlled areas	NMT 25℃

PROCEDURE

STEP	ACTION
1	Verify that the air conditioning system is operating in the stable condition and all equipment that is specified is running.
2	Divide the room area in four equal zones test as required by the specification or on a grid pattern of 3m x 3m.
3	Use calibrated Data logger to record the temperature.
4	Record the temperature for location in each room.
5	Record the result [Reference is made to Annexure-VI].

16. HUMIDITY CONTROL TEST

OBJECTIVE:

To demonstrate the capability of air handling system to control relative humidity at the specified level in each room in critical area and controlled areas.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Relative humidity in critical area	NMT 50 %
Relative humidity in controlled area	NMT 55%

PROCEDURE:

STEP	ACTION
1	Execute humidity control test after all the air balancing procedure have been concluded and air conditioning system is completely in operation and stable conditions have been achieved
2	Use calibrated Data Logger to record the relative humidity.
3	Record the relative humidity in room as per layout of relative humidity record in each room.
4	Record the result for three consecutive days [Reference is made to Annexure-VI].

16. LIGHT INTENSITY MEASUREMENT: LUX MEASUREMENT

OBJECTIVE:

To determine the lighting level and its uniformity throughout an area at pre- determined points

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Light level	Not less than 300 lux / As per Design Specification

PROCEDURE:

STEP	ACTION
1	Record the light levels on a pre-determined grid pattern/ layout of lux level or in the absence of a specification on a 3m x 3m grid pattern.
2	Divide the room into four equal locations.
3	Record the light level at working height or 750 mm above finished floor height.
4	The area under test must have all fitted lights working and the area structure should be complete also if required emergency lighting levels can be recorded.
5	Record the light levels in lux for each position on the grid [Reference is made to Annexure VII].
6	Note down all variations from the specification if any.

17. NOISE LEVEL MEASUREMENT

OBJECTIVE:

To determine the noise level and its uniformity throughout an area at pre-determined points.

ACCEPTANCE CRITERIA:

CRITERIA	ACCEPTANCE
Noise level	Not more than 85 dB / As per Design Specification

PROCEDURE

STEP	ACTION
1	Verify that the air conditioning system is operating in the stable condition and all equipment that is specified is running [In operational condition].
2	Map out the area under test as required by the specification in a 2400 mm x 2400 mm x grid or on a previously agreed location basis i.e divide the area into fur equal parts.
3	Set the instrumentation to work and ensure unauthorized entry and exits from the room are prevented.
4	Measure the sound levels at work surface height or 750 mm from the finished floor level and layout of noise level.
5	Record the data [Reference is made to Annexure- VII].
6	Note down all variations from the specification if any.

18. GENERAL REQUIRMENTS

The protocol should be signed off (prior to start validation activities).
Under responsibility of the Validation Head, Performance Qualification will be executed.
After execution of required tests, the Validation Head should

Check the results versus the Acceptance Criteria.
Write the report.

The report will be approved by the same persons (or same designations) who has Undersigned the protocol.
The report should contain the following information:

Report of all measurements and/or analytical results
List of all documentation and or certifications.
Check of the results against the Acceptance Criteria.
Conclusions concerning this validation study
Name and designations of persons who has executed the protocol
Any (relevant) deviation from the prescriptions in this protocol and the Justification for the deviation.

19. ANNEXURE

20. REFERENCE

NO.	CODE	TITLE
1	ISO 14644	Clean Room & Associated Environment
2	VMP-2006	Validation Master Plan.
3	SCH.M Pt. I-A	Drug and Cosmetics act 1940.
4	Annex 6	WHO Technical report series No 902, 2002.
5	USP	2005 USP NF the Official compendia of standards.
6	EC GUIDE	EC guide to good manufacturing practice annexure-1 September 2003.