HVAC Validation (Air Handling Units).pdf

HEPA FILTER

1. 1
VALIDATION OF HVAC
SYSTEM
1

2. 2
CONTENTS
➢Introduction
➢AHU
➢HVAC Qualification
➢Validation parameter

3. INTRODUCTION
To understand:
➢The need and reason for pharmaceutical air handling
systems.
➢The technical requirements for air handling systems.
➢Different types of air handling systems.
➢Qualification and Validation requirements
3

4. WHAT IS CLEAN ROOM?
4
A room in which the concentration of airborne
particle is controlled and which is constructed and used in a
manner to minimize the introduction, generation and
retention of particles inside the room and in which other
relevant parameters.
➢e.g.. Temperature, humidity and pressure, are controlled
as necessary.
(ISO 14644-1)

5. WHY CLEAN ROOM NECESSARY?
➢It controls 3 types of contamination transfer
✓Air borne contamination
✓Direct contamination by personnel, equipment etc.
✓Contamination from fluids like cleaning fluids,
solutions etc.
➢As airborne particulate are reduced, chances of particles
entry in the process reduced.
➢Protects product, personnel & environment.
➢Avoid rejection thereby heavy losses in terms of money &
time
5

6. HOW IT IS ACCOMPLISHED?
•A clean room is continuously flushed with highly
filtered air that is forced in through HEPA filters.
6

7. TYPES OF CLEAN ROOMS
➢HorizontalCleanRoom–HorizontalLaminarflow
(HEPAfiltersinawallforcecleanairfromonesideoftheroomto
other.)
➢VerticalCleanRoom–VerticalLaminarflow
(HEPAfiltersontheceilingpushcleanairdowntothefloor.)
7

8. FOUR BASIC PRINCIPLES OF CLEAN ROOM
➢NotToBringAnyDust
➢NotToAccumulateAnyDust
➢NotToGenerateAnyDust
➢ToRemoveAnyDustQuickly
8

9. INTRODUCTION
Air handling systems,
➢Play a major role in the quality of pharmaceuticals.
➢Must be designed properly, by professionals.
➢Must be treated as a critical system.
9

10. INTRODUCTION
The manufacturing environment is critical for product quality.
Environment consists of,
➢Light
➢Temperature
➢Humidity
➢Air movement
➢Microbial contamination
➢Particulate contamination
Uncontrolled environment can lead to product degradation
➢product contamination
➢loss of product and profit
10

11. INTRODUCTION
HVAC consists of,
1.Air conditioner
2.AHUs
3.Dehumidifier / Heater
4.Filters (Pre & HEPA)
5.Dust Extractors
6.Ducting (For delivery of controlled air)
7.Supply Fans
8.Smoke Detector
9.Dampers
10.Humidity / Temperature / Pressure sensors
11.Bag Filters
12.Heating / Cooling Coils
11

12. US FDA
21 CFR part 211
(Requirement for building & Facilities)
Under 211.42 (c)
➢Operation shall be performed within the specifically defined areas and
such other controls, necessary to prevent contamination or mix ups.
➢Temperature and Humidity controlled.
➢An air supply filtered through HEPA filter under positive pressure.
➢A system of monitoring environmental conditions.
Under 211.46 (C)
➢Air filtration system, including pre-filters and particulate matter air
filtration shall be used when appropriate on air supplies to production
areas.
12

13. EU GUIDELINES
(PREMISES & EQUIPMENT)
Under 3.12,
➢Production areas shall be effectively ventilated with air control
facilities including temperature & where necessary humidity and
filtration.
13

14. SCHEDULE –M
PART –1 (GMP FOR PREMISES AND
MATERIALS)
Under point 8.21,
➢The licensee shall prevent mix-ups and cross contamination
of Drug Materials and Drug Products (from environment
dust) by proper air handling system.
Part 1A (GMP for Sterile preparation)
Section 3 –Details of HVAC system
Section 4 –Parameterrs for Validation and
Frequency of Monitoring
14

15. INTRODUCTION
HVAC (AHU) is
HEART
of Pharmaceutical Industries
15

16. INTRODUCTION
HVAC
Area -1
Area -2
Area -3
Area -4
Impure Air
I
M
P
U
R
E
A
I
R
Impure Air
Pure Air
9
0
%
10% Return Air
Exhaust
16

17. CONTAMINATION
What are contaminants ?
Contaminants are
1.Products or substances other than the product being
manufactured.
2.Foreign products.
3.Particulate matter.
4.Micro-organisms.
5.Endotoxins (degraded micro-organisms).
Cross-contamination is a particular case of contamination
17

18. CONTAMINATION
Cross-Contamination
From where does Cross-Contamination originate?
1.Poorly designed air handling systems and dust
extraction systems
2.Poorly operated and maintained air handling systems
and dust extraction systems
3.Inadequate procedures for personnel and equipment
4.Insufficiently cleaned equipment
18

19. CONTAMINATION
Cross-contamination can be minimized by:
1.Personnel procedures
2.Adequate premises
3.Use of closed production systems
4.Adequate, validated cleaning procedures
5.Appropriate levels of protection of product
6.Correct air pressure cascade
19

20. AIR FLOW PATTERNS
Prefilter
AHU
Main filter
Uni-directional TurbulentTurbulent
1
2 3
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21. 21
Workbench (vertical) Cabin/ booth Ceiling
AIR FLOW PATTERNS

22. HVAC QUALIFICATION
➢To ensure that equipment is designed as per requirement,
installed properly.
➢Action of proving that any equipment works correctly and leads
to the expected results.
22

23. HVAC QUALIFICATION
Validation Master Plan
User Requirement Specification
Design Qualification
Installation Qualification
Operation Qualification
Performance Qualification
Re-Qualification.
VALIDATION
23

24. •
This document should contain
➢Validation policy
➢Organizational structure of validation activities
➢Summary of facilities, systems, equipment and processes to
be validated
➢Documentation format to be used for protocols and
reports
➢Planning and scheduling
➢Change control
➢References to documents
THE VALIDATION MASTER PLAN
24

25. USER REQUIREMENT SPECIFICATION
It mainly requires:
➢Room temperatures and relative humidities
➢Clean room classifications for the areas i.e. B. C. or D.
➢Single pass or re-circulated HVAC systems ?
➢Room pressures / Air flow directions
➢GMP requirements.
25

26. USER REQUIREMENT SPECIFICATION
Capacity of HVAC depends on,
1.Room Volume.
2.No. of Air Changes Required.
3.Production / Consumption Data
4.Seasonal fluctuation.
5.Air Classification of Rooms.
6.Future Development.
26

27. USER REQUIREMENT SPECIFICATION
Parameters to be defined in Levels of Protection :
Air cleanliness requirements
1.filters type and position,
2.air changes,
3.air flow patterns,
4.pressure differentials,
5.contamination levels by particulate matter & micro-
organisms.
•User Requirement Specification should be approved by
Production, Engineering and QA Heads.
27

28. Based on the URS supplier designs the equipment-First step
in the qualification of new HVAC systems.
➢It documents the design of the system and will include :
1. Functional Specification.
2. Technical / Performance specification for equipment.
3. Detailed Air Flow Schematics.
4. Detailed layout drawing of the system.
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DESIGN QUALIFICATION

29. DESIGN QUALIFICATION
➢Compliance with GMPs and other regulatory requirements.
➢Ensures that design,
1. meets the user requirements.
2. details facility airflow and pressure cascade philosophy.
3. takes into account process and personnel flow (cross-
contamination issues)
4. Details materials of construction.
5. Details safety requirements.
6. Full details of the intended construction prior to
implementation.
7. Details all equipment that must be ordered.
29

30. INSTALLATION QUALIFICATION
➢System Description
➢Equipment Delivery
➢Utilities / Facility / Environment
➢Assembly & Installation
30

31. INSTALLATION QUALIFICATION
IQ Should include,
➢Instrumentation checked against current engineering
drawings and specifications
➢Verification of materials of construction
➢Installation of equipment and with piping
➢Calibration of measuring instruments requirements
➢Collection and collation of supplier operating and
working instructions and maintenance requirements
31

32. INSTALLATION QUALIFICATION
Practical aspect of IQ(Cont….)
➢Calibration of measuring instruments.
➢Calibration of additionally used instruments.
➢Initial cleaning records.
➢Basic commissioning checks.
➢Maintenance requirements.
➢IQ process checks that the correct components are installed in
the correct location.
➢Materials of construction
➢Spare parts
➢Change controls
32

33. INSTALLATION QUALIFICATION
IQ Document should contain,
➢Instrument name, model, I.D. No., Personnel responsible for
activities and Date.
➢A fully verified installation that complies with the documented
design. (all deviations will have been recorded and assessed.)
➢All equipment documentation and maintenance requirements
would be documented.
➢Completed calibration of measuring instruments.
➢Verification of Materials of construction.
33

34. OPERATION QUALIFICATION
➢ISPE definition : The purpose of OQ is to establish, through
documented testing, that all critical components are capable of
operating within established limits and tolerances.
➢The purpose of OQ is to verify and document that an HVAC
system provides acceptable operational control under “at-rest”
conditions.
34

35. OPERATION QUALIFICATION
Operation Qualification Checks,
➢Ability to provide air of sufficient quality and quantity to
ensure achievement of specified clean room conditions.
➢Ability to maintain temperature, relative humidity and
pressure set points.
➢Ability to maintain any critical parameters stated in the DQ
consistently.
35

36. OPERATION QUALIFICATION
➢Includestheteststhathavebeendevelopedfromknowledge
ofprocesses,systemsandequipment.
➢Teststoincludeaconditionorasetofconditions
encompassingupperandloweroperatinglimits,sometimes
referredtoas‘worstcase’conditions.
36

37. OPERATION QUALIFICATION
➢IQ reports must be completed and signed off.
➢OQ protocols to be written and approved prior to completion.
➢Measurement reports are required to demonstrate achievement
of critical parameters as detailed in DQ.
Eg:* All relevant SOPs should be in place
* Temperature measurement report
* Humidity measurement report
* Differential pressure measurement report
* Air flow direction measurement report
* Room particle count measurement report
* All drawings etc. –done in ‘as-built’ status
* All maintenance/ cleaning instructions available
* All O & M staff to be trained to use and maintain the system.
* Sign off. (Compliance Certificate by Engineering Dept & QA)
37

38. PERFORMANCE QUALIFICATION
➢The purpose of PQ is to verify and document that an HVAC
system provides acceptable control under ‘ Full Operational ‘
conditions.
➢PQ should follow successful completion of IQ and OQ.
➢PQ verifies that over time, the critical parameters, as defined
in the DQ are being achieved.
38

39. PERFORMANCE QUALIFICATION
PQShouldinclude,
➢Tests,usingproductionmaterials,qualifiedsubstitutesor
simulatedproduct,thathavebeendevelopedfromknowledge
oftheprocessandfacilities,systemsorequipment.
➢Testtoincludeaconditionorsetofconditionsencompassing
upperandloweroperatinglimits.
➢PQisusedtodemonstrateconsistentachievementofcritical
parametersovertime.(undermanufacturingconditions)
➢PQisongoing.
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40. QUALIFICATION
COMPLETE DOCUMENTATION
➢Verification of design documentation, including
✓Description of installation and functions
✓Specification of the requirements
➢Instructions for performance control
➢Operating procedures
➢Maintenance instructions
➢Maintenance records
➢Training of personnel (program and records)
➢Environmental records
➢Discussion on actions if OOS values
➢Walking around the plant
Finally certification (Sign Off) by Engineering, User
(Production) and QA Heads.
40

41. VALIDATION
➢Document act of proving that any procedure, process, system /
equipment ACTUALLY leads to expected results.
➢To ensure that system provides continuously required
environmental conditions.
41

42. VALIDATION PARAMETERS
1.Air flow measurement
2.Room air changes per hour.
3.Filter Integrity Testing (HEPA Leak test)
4.Pressure Differentials
5.Particulate count measurement
6.Recovery test
7.Temperature and Relative Humidity
8.Air Flow Pattern
9.Microbial Count
42

43. VALIDATION PARAMETERS
A.PHYSICALTESTS
A1. NON-VIABLE PARTICLE COUNTS
•Equipment
•Optical Particle Counter (Discrete Particle Counter)
•Air sample is drawn into the instrument & passed through light scattering
device. The signal that this generates is electronically processed to display
particle counts at different size ranges.
•SampleVolume
•1 cubic ft
•Sample Time
•1Min
43

44. ➢SampleLocation(ISO14644)
➢No.ofsamplinglocation=NLTSq.Rt.A
WhereA=AreaofentranceplaninSq.Meter
➢No.oflocationroundedtonearesthigherinteger
➢Minimumlocation3
➢Evenlydistributedwithintheareaundertestandataposition
relatedtotheworkingactivity(typicallyatbenchheight1m
fromthefloorandNMT1Ftfromworkstation.).
VALIDATION PARAMETERS
44

45. ➢Frequency
✓Sch M -6 Monthly
✓GMP compliance –Quarterly
➢AcceptanceCriteria

AT REST IN OPERATION
Grade Maximum number of permitted particles per cubic metre equal to or
above
0.5 5.0 0.5 5.0
A 3520 29 3500 29
B 35,200 293 3,52,000 2930
C 3,52,000 2,930 35,20,000 29,300
D 35,20,000 29,300 Not defined Not defined


VALIDATION PARAMETERS
45

46. A2. PRESSURE DIFFERENTIALS
Introduction
➢Correct degree of overpressure can be maintained relative to
the adjacent areas of lower classification to ensure that air
moves from clean areas to less clean areas.
Equipment
➢Electronicmanometer(portableandeasytouse),
➢Inclinemanometer
SampleLocation
➢Betweenadjacentareasconnectedeitherbyadoororgrille.
➢Frequencyofsampling
➢Continuouslybygauges/manometer&recordeddaily.
VALIDATION PARAMETERS
46

47. –Acceptance Criteria
➢> 10 Pa between classified area & adjacent area of
lower classification
➢> 15 Pa between classified area & unclassified area
–Action
➢HEPA filter blockage
➢Increase fan speed
➢Increase air flow to specific area by altering dampers
VALIDATION PARAMETERS
47

48. A3. AIRFLOW VELOCITY
Equipment:-Anemometer.
➢Readingshouldbetaken10cmfromthesurfaceoffilter.
➢RecordvelocityreadingfromallthefourcornersandtheCentre
ofthefiltersurface.
➢Repeattwiceateachlocation
➢ForGradeAlaminarflowworkstations,theairflowratesshall
be0.3meterpersecond+20%(forverticalflows)and0.45+
20%(forHorizontalflows)
*Novaluemaydeviatefromthemeanbymorethan+20%
VALIDATION PARAMETERS
48

49. ➢Airvelocityexceedingthestatedvaluemaycauseexcessiveair
movement&affectworkzoneprotection.
➢Airvelocitybelowthelimitmaybeinsufficienttomaintain
criticalworkzoneprotection.
Action:Deviationindicatesblockageoffilter
Solution:Alterationoffanspeed
HEPAfilterreplacement
VALIDATION PARAMETERS
49

50. A4. HEPA FILTER INTEGRITY TEST
(DOP Test)
Purpose:Toconfirmthatthereisnodamagetofilter,sealsand
thereisnoleakageofparticles.
Equipment:1.Aerosolgenerator(UsingDioctylphthalate)
2.Photometer
Scanat1inchfromfiltersurface.TraverseatNMT10Ft.Min.
Coverentirerange.
Makeseparatepassesatperipheries.
50
VALIDATION PARAMETERS

51. A5. TEMPERATURE & RELATIVE HUMIDITY
➢Use a sling psycrometer to measure the dry bulb and wet bulb
temperature of the air.
➢Check the wick of the sling psycrometer, it should be always in
wet conditions in order to record correct wet bulb temperature.
➢Sling the psycrometer in air for about a minute’s time and
record the dry bulb and wet bulb temperature.
➢Check the wet bulb depression i.e. difference between dry bulb
and wet bulb temperature.
➢Refer the psycrometric chart to check the relative humidity
corresponding to the dry bulb temperature and wet bulb
depression.
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VALIDATION PARAMETERS

52. ACCEPTANCE CRITERIA
➢Temperature : NMT 27 degree centigrade
➢Humidity: NMT 55 %
➢FREQUENCY:Daily
52
VALIDATION PARAMETERS

53. A6. AIR CHANGE RATE (ACR)
Introduction
➢Conventionalcleanroomsoperateontheprinciplethattheair
suppliedtotheroomisofsufficientquantitytodiluteorremovethe
contaminationgeneratedwithintheroom.
➢Measurementoftheairsupplyvolumeanddeterminationoftheair
changerate(ACR)isameasureofthefrequencyofairturnoverinthe
cleanroom.
➢Thisgivessomeideaastohowquicklycontaminationmayberemoved
fromthecleanroomprovidedthereisacceptablemixingofairinthe
room.
➢TheACRcanbedeterminedbymeasuringthemeanairvelocityatthe
supplyHEPAsorgrillesandcalculatingtheairchangeratebasedon
themeanairsupplyvolumeorbyusingaflowmeasuringhoodwhich
collectsalloftheairfromthesupplyandgivesanairsupplyvolume
directly.
53
VALIDATION PARAMETERS

54. Equipment
➢Anemometer
Samplelocations
➢Atleastfourpositionsaretestedacrossthefilterorgrille
facetoobtainthemeansupplyairvelocity.
Frequencyofsampling
➢Sch M -6 Monthly
➢GMP compliance –Quarterly
54
VALIDATION PARAMETERS

55. Resultsandinterpretationofresults
➢TheACR(perhour)canbecalculatedusingthefollowingformula:
ACR=Airsupplyvolume(m³/s)x3600/Roomvolume(m³)
AirVolume=Sum(Avg.VelocityxFilterarea)
➢WherethereismorethanonesupplyHEPAinaroomtheairsupply
volumeforeachfiltershouldbedeterminedandthevolumessummed
(togiveatotalairsupplyvolume)beforemultiplyingby3600and
dividingbytheroomvolume.
➢Toachievethelevelofcleanlinessinanasepticroomandaclean
supportroomtheACRshouldbegreaterthan20airchangesper
hour.
55
VALIDATION PARAMETERS

56. VALIDATION PARAMETERS
Requirement:ClassB=60,C&D=20ACPH
Action
•Change the filter
•ACRtoberebalanced
B.MICROBIOLOGICALTESTS
➢Solidgrowthmedia(e.g.settleandcontactplates)Soybean
CaseinDigestAgarmediumcanbeusedforbothBacteria&
Fungitested.
➢Therecommendedsizeofsolidmediais90mmindiameter
(forsettleplates)
➢55mm(surfacearea25cm²)forcontactplates.
56

57. •Samplingconditions
➢Samplingintheatrestconditionmaybecontinuedatan
agreedfrequencytomonitorbaselinecontaminationlevels.
➢Theoperationalconditionsandtheactivitiesbeingperformed
atthetimeoftestingshouldberecorded.
•Incubationconditions
➢Incubationofsamples,inverted,at20-25Cforatleast5days
issuitableforthegrowthofmouldandfungi.
➢Incubationofsamples,inverted,at30-35Cforatleast2days
issuitableforthegrowthofbacteria.
VALIDATION PARAMETERS
57

58. VALIDATION PARAMETERS
Total Viable Count
(Guidelines)
Conditions : In operation
Grade EU Schedule –M US Air Sampling
(90mm / 4 Hrs) (90mm / 2 Hrs) (90mm / 4 Hrs) (1000cc)
A <1 <1 <1 <1
B <10 <5 <3 <7
C <100 <50 <5 <10
D <200 <100 <50 <100
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Recommended Limits for microbiological monitoring of clean
areas