Pt05 - HVAC System Design

HVAC Systems and the Pharmaceutical Manufacturing Environment Radisson SAS Hotel, Amsterdam 2008

Validation in Partnership Limited Part 05 – HVAC System Design - Page 1

HVAC Systems and the Pharmaceutical Manufacturing Environment

11



Part 05: HVAC System DesignPart 05: HVAC System Design

David Dickinson, DD Validation Services Ltd.David Dickinson, DD Validation Services Ltd.




22

Part 05/a - HVAC Design ConsiderationsPart 05/a - HVAC Design Considerations




33

HVAC - Principal FunctionHVAC - Principal Function

• Normally, principal function is to control the number of particles within the manufacturing facility environment

• As you move towards aseptic conditions– Ability of the HVAC system to control particulate levels

becomes more and more critical– For Grade B areas, immediately adjacent to Grade A (ISO 5)

aseptic filling areas, design for particle control is essential– The fundamentals of clean room design are to control the

concentration of airborne particles– To design a facility and HVAC system such that particles are

controlled to the correct level• Must understand particle generation mechanisms how these can

be minimised.

• Normally, principal function is to control the number of particles within the manufacturing facility environment

• As you move towards aseptic conditions– Ability of the HVAC system to control particulate levels

becomes more and more critical– For Grade B areas, immediately adjacent to Grade A (ISO 5)

aseptic filling areas, design for particle control is essential– The fundamentals of clean room design are to control the

concentration of airborne particles– To design a facility and HVAC system such that particles are

controlled to the correct level• Must understand particle generation mechanisms how these can

be minimised.




44

Particle GenerationParticle Generation

• The particulate matter can come from three sources: – The air supply– Internal particle generation– Infiltration from adjacent spaces

• To control these airborne particles, all three sources need to be considered.

• The particulate matter can come from three sources: – The air supply– Internal particle generation– Infiltration from adjacent spaces

• To control these airborne particles, all three sources need to be considered.

Air SupplyAir SupplyInfiltrationInfiltration

Internal GenerationInternal Generation




55

Supply Air ControlsSupply Air Controls

• Supply air particle control is relatively easy– Use of HEPA (high-efficiency particulate air) filters

• HEPA Filter Efficiency Comparison– EU14

• Remove 99.995% of particles of the size of 0.15 to 0.3 µmfrom the air

• If there are 350,000/m3 particles of ≥ 0.5µm in the air supply to the filter (Grade C):

– Room air supply would have LESS than 18 particles (≥ 0.5µm) per m3 (Grade A specification is 3,500)

• Considered almost particulate-free!!!!!!!

– EU13 would give 180 particles– EU12 would give 1,800 particles.

• Supply air particle control is relatively easy– Use of HEPA (high-efficiency particulate air) filters

• HEPA Filter Efficiency Comparison– EU14

• Remove 99.995% of particles of the size of 0.15 to 0.3 µmfrom the air

• If there are 350,000/m3 particles of ≥ 0.5µm in the air supply to the filter (Grade C):

– Room air supply would have LESS than 18 particles (≥ 0.5µm) per m3 (Grade A specification is 3,500)

• Considered almost particulate-free!!!!!!!

– EU13 would give 180 particles– EU12 would give 1,800 particles.




66

Internal Particle GenerationInternal Particle Generation

• Internal generation consists of particles from:– Building elements:

• Walls• Floors• Ceilings, etc.

– Equipment:• Conveyors• Moving parts

– Operators - MOST IMPORTANT!!!

• Internal generation consists of particles from:– Building elements:

• Walls• Floors• Ceilings, etc.

– Equipment:• Conveyors• Moving parts

– Operators - MOST IMPORTANT!!!




77

Internal Particle Control – Buildings and Equipment

Internal Particle Control – Buildings and Equipment

• Particles from building– Minimized using hard-surfaced, non-porous

materials such as polyvinyl panels, epoxy painted walls, and glass board ceilings

• Equipment– Best design– Use of correct materials– Proper containment of machinery - outside of clean

space where possible– Use of additional filters, e.g. point of use filters on

utilities such as compressed air.

• Particles from building– Minimized using hard-surfaced, non-porous

materials such as polyvinyl panels, epoxy painted walls, and glass board ceilings

• Equipment– Best design– Use of correct materials– Proper containment of machinery - outside of clean

space where possible– Use of additional filters, e.g. point of use filters on

utilities such as compressed air.




88

Control of Particle Generation by Operators

Control of Particle Generation by Operators

• Operators are the main source of internal particle generation in a cleanroom– Thousands of dead cells are shed from the human

body every minute• Without protection - contribute millions of particulate counts into

a clean room

• Particle generation by operators restricted by– Proper gowning– Minimising activity

• Level and standard of garments and room finishes required - driven by the particle specification of the room

• Best gowned clean room operators will still generate numerous particles per minute to the local environment:– Approx. 700,000 particles of 0.5 µm or larger per

minute

• Operators are the main source of internal particle generation in a cleanroom– Thousands of dead cells are shed from the human

body every minute• Without protection - contribute millions of particulate counts into

a clean room

• Particle generation by operators restricted by– Proper gowning– Minimising activity

• Level and standard of garments and room finishes required - driven by the particle specification of the room

• Best gowned clean room operators will still generate numerous particles per minute to the local environment:– Approx. 700,000 particles of 0.5 µm or larger per

minute




99

Particle Infiltration Control [1]Particle Infiltration Control [1]

• Particles from adjacent spaces – relatively easy to control– If the adjacent area is less clean than the clean room of

concern• Particle infiltration can be minimized by controlling the airflow

direction, so that air flows from the clean room to its adjacentspace

• Accomplished by ensuring the room is operated at a greater pressure to the adjacent (less clean) space/room

• Need to ensure a degree of leakage to encourage correct air flow direction when doors are ajar/open.

• Particles from adjacent spaces – relatively easy to control– If the adjacent area is less clean than the clean room of

concern• Particle infiltration can be minimized by controlling the airflow

direction, so that air flows from the clean room to its adjacentspace

• Accomplished by ensuring the room is operated at a greater pressure to the adjacent (less clean) space/room

• Need to ensure a degree of leakage to encourage correct air flow direction when doors are ajar/open.

E E BB CC DD



1010

Particle Infiltration Control [2]Particle Infiltration Control [2]



1111

Room Particle Level ControlRoom Particle Level Control

• All rooms will have a level of internal particle generation– Without control, particle levels will simply carry on

increasing• For clean rooms

– Particle levels controlled by effective replacement of particle laden air with ‘clean’ air

– 3 factors that dictate this rate of clean-up are:• Amount of air supplied to the room [1]• The size of the room [2]• Effectiveness of ‘clean’ air distribution

– Factors 1 and 2 will give you the air change rate.

• All rooms will have a level of internal particle generation– Without control, particle levels will simply carry on

increasing• For clean rooms

– Particle levels controlled by effective replacement of particle laden air with ‘clean’ air

– 3 factors that dictate this rate of clean-up are:• Amount of air supplied to the room [1]• The size of the room [2]• Effectiveness of ‘clean’ air distribution

– Factors 1 and 2 will give you the air change rate.




1212

Recovery Period versus Air Change Rates [1]


• HVAC systems are quite often designed around a particular particle recovery period required– This may be the deciding criterion for the air change rate

• The following slide shows the relationship between particle recovery rate and air change rates– Calculations involve two major assumptions

• Perfect mixing of supply and room air• Supply air contains essentially zero particles of the size used as

the basis of calculation

• Generally, the higher the classification/specification of the environment, the greater the recovery rate required.

• HVAC systems are quite often designed around a particular particle recovery period required– This may be the deciding criterion for the air change rate

• The following slide shows the relationship between particle recovery rate and air change rates– Calculations involve two major assumptions

• Perfect mixing of supply and room air• Supply air contains essentially zero particles of the size used as

the basis of calculation

• Generally, the higher the classification/specification of the environment, the greater the recovery rate required.




1313



Recovery Period versus Air Change Rate

1

10

100

1000

10000

100000

1000000

10000000

0 10 20 30 40 50 60 70 80 90

Time (minutes)

Part

icul

e C

once

ntra

tion

(log

scal

e)

10 ACH

20 ACH

30 ACH

40 ACH

• The drawing shows how by assuming a simple exponential decay the recovery period changes greatly with air change rate

• To recover from Class 10,000 to Class 100, with 20 air changes per hour, takes approximately 14 minutes, with 30 air changes per hour it takes approximately 9 minutes.

• The drawing shows how by assuming a simple exponential decay the recovery period changes greatly with air change rate

• To recover from Class 10,000 to Class 100, with 20 air changes per hour, takes approximately 14 minutes, with 30 air changes per hour it takes approximately 9 minutes.

.



1414

Particle Generation and Room Air Change Rates [1]


• Very Best Case (assumes instantaneous mixing of air within the total room volume):– For a 10m x 10m x 3m room and 4 clean room operators (using

particle generation rate of 700,000 particles of 0.5 µm or larger per minute per operator):

• Particle generation rate within entire room = approx. 10,000 (0.5 µm or larger) per m3 per minute

• To maintain entire room at Grade B “in operation” limit of 350,000 particles (≥ 0.5 µm per m3) – requires an air change rate of approximately 2 (10,000 x 60 /350,000)

• Very Best Case (assumes instantaneous mixing of air within the total room volume):– For a 10m x 10m x 3m room and 4 clean room operators (using

particle generation rate of 700,000 particles of 0.5 µm or larger per minute per operator):

• Particle generation rate within entire room = approx. 10,000 (0.5 µm or larger) per m3 per minute

• To maintain entire room at Grade B “in operation” limit of 350,000 particles (≥ 0.5 µm per m3) – requires an air change rate of approximately 2 (10,000 x 60 /350,000)

10m

3m

10m



1515



• More realistic estimate (assumes all particles transmitted to local 8 m3 air space around an operator)– Particle generation rate will be 700,000/8 = approx. 90,000

particles of 0.5 µm or larger per m3 per minute– To maintain this area at Grade B “in operation” limit of 350,000

particles of ≥ 0.5 µm per m3 – requires air change rate of approximately 15 (90,000 x 60/350,000)

– To maintain at 100,000 particles requires an air change rate of 54

• More realistic estimate (assumes all particles transmitted to local 8 m3 air space around an operator)– Particle generation rate will be 700,000/8 = approx. 90,000

particles of 0.5 µm or larger per m3 per minute– To maintain this area at Grade B “in operation” limit of 350,000

particles of ≥ 0.5 µm per m3 – requires air change rate of approximately 15 (90,000 x 60/350,000)

– To maintain at 100,000 particles requires an air change rate of 54

10m

3m

10m

2m

2m2m




1616

Effective Air DistributionEffective Air Distribution

• We have seen that particle generation from operators is controlled by continuously removing particles from the area– Effectively ‘flushing’ with filtered air

– The rate of particle reduction is proportional to air supplied and the size of the room (air change rates)

– Effective air distribution is essential to ensure all areas are ‘flushed’ at the desired rate

– Following slide depicts what can happen if you get it wrong!!!

• We have seen that particle generation from operators is controlled by continuously removing particles from the area– Effectively ‘flushing’ with filtered air

– The rate of particle reduction is proportional to air supplied and the size of the room (air change rates)

– Effective air distribution is essential to ensure all areas are ‘flushed’ at the desired rate

– Following slide depicts what can happen if you get it wrong!!!




1717

Ineffective Air DistributionIneffective Air Distribution

Clean RoomClean Room

Terminal Supply HEPA Filters

Terminal Supply HEPA Filters

Clean Room• 30 Air changes/hour by design• Only 2/3 of room with adequate air distribution.

Clean Room• 30 Air changes/hour by design• Only 2/3 of room with adequate air distribution.

Zero – Air ChangesZero – Air Changes

45 – Air Changes

ExtractionExtraction




1818

Part 05/b - Processes & How They ImpactPart 05/b - Processes & How They Impact




1919

Introduction [1]Introduction [1]

• HVAC is often overlooked in the initial planning stages• Contractors with little exposure to, or understanding of,

pharmaceutical product manufacturing requirements, are often involved in the design of HVAC systems

• The main difference between Commercial & Pharmaceutical areas of construction is in the performance expected of the systems

• Pharma products, in particular those that are required to be sterile, present a risk to patient health, if not manufactured to an exacting standard within a closely controlled environment

• HVAC system design influences architectural layout with regards to items such as airlock positions, doorways and lobbies.

• HVAC is often overlooked in the initial planning stages• Contractors with little exposure to, or understanding of,

pharmaceutical product manufacturing requirements, are often involved in the design of HVAC systems

• The main difference between Commercial & Pharmaceutical areas of construction is in the performance expected of the systems

• Pharma products, in particular those that are required to be sterile, present a risk to patient health, if not manufactured to an exacting standard within a closely controlled environment

• HVAC system design influences architectural layout with regards to items such as airlock positions, doorways and lobbies.




2020

Introduction [2]Introduction [2]

• Pharmaceutical HVAC– Careful control over the production environment, in

terms of cleanliness, sterility, containment –biological or product, equipment stability and comfort criteria

• Commercial HVAC– Primarily targeted to achieve human comfort

conditions only, temperature and possibly humidity, but over a much wider tolerance range

• HVAC can not be designed independently of the facility and the process– Manufacturing Process, equipment and facility

layout, finish, fittings and fixtures are equally important

• Facility and HVAC must be designed in tandem in order to achieve the desired end result.

• Pharmaceutical HVAC– Careful control over the production environment, in

terms of cleanliness, sterility, containment –biological or product, equipment stability and comfort criteria

• Commercial HVAC– Primarily targeted to achieve human comfort

conditions only, temperature and possibly humidity, but over a much wider tolerance range

• HVAC can not be designed independently of the facility and the process– Manufacturing Process, equipment and facility

layout, finish, fittings and fixtures are equally important

• Facility and HVAC must be designed in tandem in order to achieve the desired end result.




2121

HVAC Design DriversHVAC Design Drivers

• Major Drivers– Product

• Type• Hazards• Properties• Number of products

– Process• Equipment• Exposure (closed/open)

– Cost• How much money do you have to

spend?– Time

• When do you need the system?– Available space.

• Major Drivers– Product

• Type• Hazards• Properties• Number of products

– Process• Equipment• Exposure (closed/open)

– Cost• How much money do you have to

spend?– Time

• When do you need the system?– Available space.




2222

• HVAC system requirements are closely related to the product(s) and process(es) involved– Nature of product / process

• Sterility – non sterile or sterile products?• Aseptically manufactured or terminally sterilised?• Penicillin, cephalosporins – require dedicated HVAC and

facility

– Closed Processes• Physical segregation of the product from the environment• Less emphasis on the HVAC system!

• HVAC system requirements are closely related to the product(s) and process(es) involved– Nature of product / process

• Sterility – non sterile or sterile products?• Aseptically manufactured or terminally sterilised?• Penicillin, cephalosporins – require dedicated HVAC and

facility

– Closed Processes• Physical segregation of the product from the environment• Less emphasis on the HVAC system!

Understanding the Product & Process [1]





2323



• Open Processes– Product exposed to the atmosphere and to surfaces– Facility / HVAC design / operation will have a greater

CGMP impact:• Critical for aseptic manufacturing areas• Critical for dusty multi-product non-sterile manufacturing

facilities:– Airflow direction important

– Degree of impact determined by both type of process and nature of product.

• Open Processes– Product exposed to the atmosphere and to surfaces– Facility / HVAC design / operation will have a greater

CGMP impact:• Critical for aseptic manufacturing areas• Critical for dusty multi-product non-sterile manufacturing

facilities:– Airflow direction important

– Degree of impact determined by both type of process and nature of product.




2424



• Product properties will also dictate HVAC system requirements (especially open processes)– Sensitivity - Temperature / relative

humidity– Level of operator protection– Dusty or non-dusty

• Company / regulatory rules and guidelines (CGMPs) will also drive requirements.

• Product properties will also dictate HVAC system requirements (especially open processes)– Sensitivity - Temperature / relative

humidity– Level of operator protection– Dusty or non-dusty

• Company / regulatory rules and guidelines (CGMPs) will also drive requirements.




2525

Part 05/c - HVAC ConfigurationPart 05/c - HVAC Configuration




2626

Design Considerations [1]Design Considerations [1]

PRODUCTPROTECTION

PERSONNELPROTECTION

ENVIRONMENTPROTECTION

Cross-contaminationControl

Correct temper-temperature & humidity

Prevent contact with fumes

Acceptable comfort conditions

Avoid fume discharge

Avoid effluent discharge

SYSTEMS

SYSTEM VALIDATION

Contamination(Control)

Avoid dust discharge

GMP MANUFACTURINGENVIRONMENT

Prevent contact with dust

3 Key Areas of Consideration – CGMP HVAC Systems3 Key Areas of Consideration – CGMP HVAC Systems




2727


• HVAC design requirements will significantly influence capital and operating costs. Key areas:– Air change rates

• Increased equipment capacities + additional space

– Differential pressure regime• Drive facility costs

– Filtration• More expensive filter media• Higher fan ratings• Testing

……………………..continued on next slide

• HVAC design requirements will significantly influence capital and operating costs. Key areas:– Air change rates

• Increased equipment capacities + additional space

– Differential pressure regime• Drive facility costs

– Filtration• More expensive filter media• Higher fan ratings• Testing




2828


• Key Areas (continued)– Use of standard equipment

• Filters• Avoid bespoke items• Maintenance• Lead times

– Independent monitoring system• increased capital cost• Improved compliance• Do you want to validate a Building Management System (BMS)?


• Key Areas (continued)– Use of standard equipment

• Filters• Avoid bespoke items• Maintenance• Lead times

– Independent monitoring system• increased capital cost• Improved compliance• Do you want to validate a Building Management System (BMS)?




2929


• Key areas (continued)– Design for ease of maintenance

• Access– Savings in plant space could lead to maintenance costs

beyond original benefit– Air recirculation (ratio of fresh to recycled air)

• Increase in fresh air percentage leads to an increase in conditioning elements capacity

– Challenge to filter longevity» ……………………..continued on next slide

• Key areas (continued)– Design for ease of maintenance

• Access– Savings in plant space could lead to maintenance costs

beyond original benefit– Air recirculation (ratio of fresh to recycled air)

• Increase in fresh air percentage leads to an increase in conditioning elements capacity

– Challenge to filter longevity» ……………………..continued on next slide

Quick access housing gives complete accessibility to the wheel and inside of the fan housing Quick access housing gives complete accessibility to the wheel and inside of the fan housing



3030


• Key areas (continued)– Barrier technology

• Grade A isolator requires grade D background• Can adversely effect production rate• Isolators are high capital costs

– Extent of room or process specific conditioning requirements

• Dehumidifcation in one room rather than the whole suite• Temperature and RH control range

– Extraction• Local independent extraction system

• Key areas (continued)– Barrier technology

• Grade A isolator requires grade D background• Can adversely effect production rate• Isolators are high capital costs

– Extent of room or process specific conditioning requirements

• Dehumidifcation in one room rather than the whole suite• Temperature and RH control range

– Extraction• Local independent extraction system




3131

HVAC Design ReviewHVAC Design Review

• Essential that design is regularly and properly reviewed – BY THE RIGHT PEOPLE

• The level of design review undertaken will depend on– System Impact– Level of complexity / novelty.

• Essential that design is regularly and properly reviewed –– BY THE RIGHT PEOPLE

• The level of design review undertaken will depend on– System Impact– Level of complexity / novelty.




3232

System Impact Versus System Complexity / Novelty

System Impact Versus System Complexity / Novelty

NONENONENONE

INDIRECTINDIRECT

DIRECTDIRECTDIRECT

LOWLOW HIGHHIGH

System ImpactSystem System ImpactImpact

Complexity / NoveltyComplexity / Complexity / NoveltyNovelty

DESIGN REVIEWDESIGN REVIEW

STRUCTURED DESIGN REVIEWSTRUCTURED DESIGN REVIEW

STRUCTURED DESIGN REVIEW + FMEASTRUCTURED DESIGN REVIEW + FMEA

Car ParkCar ParkSite Electrical SupplySite Electrical Supply

Chilled WaterChilled Water

Chart RecorderChart Recorder

Product HVAC (non-sterile)Product HVAC (non-sterile)

Purified Water SystemPurified Water System

Familiar AutoclaveFamiliar AutoclaveNew Autoclave

Sterile facility HVAC

New Autoclave

Sterile facility HVAC

Structured Design Review • Systematic method of reviewing and documenting the design covering: component

criticality, system impact, system boundaries, user requirements, critical process parameters, CGMP etc.)

Structured Design Review • Systematic method of reviewing and documenting the design covering: component

criticality, system impact, system boundaries, user requirements, critical process parameters, CGMP etc.)

.




3333

Part 05/d - Control & Maintenance of the Variable Parameters

Part 05/d - Control & Maintenance of the Variable Parameters




3434

Room Air-Change RatesRoom Air-Change Rates

• Room air change rates – primarily used together with filtration to control particulates– Particle clean-up rate

• Dependant on the supply air volume and room volume– Example: Room (10x10x3m) - 20 air changes per

hour:• Requires air supply flow = 6,000m3hr-1 or 100m3min-1

• Air extraction rate (+ leakage) will be used to control differential pressure – see later.

• Room air change rates – primarily used together with filtration to control particulates– Particle clean-up rate

• Dependant on the supply air volume and room volume– Example: Room (10x10x3m) - 20 air changes per

hour:• Requires air supply flow = 6,000m3hr-1 or 100m3min-1

• Air extraction rate (+ leakage) will be used to control differential pressure – see later.




3535

Differential Pressure (DP) [1]Differential Pressure (DP) [1]

• Normally steps of at least 10Pa required – normally tolerance of ± 2 to 3Pa– Any less and control is difficult

• Trying to hold levels of +1 to +5Pa is next to impossible– Set point needs to be 2 to 3Pa above required level to

ensure substantial compliance• General industry limits

– 15Pa minimum required between unclassified and classified areas

– 10Pa minimum between rooms of different classifications

• Belts and braces – increments of 15 Pa throughout– Beware this can lead to excessive pressures

• Consider use of negative sink air locks

• Normally steps of at least 10Pa required – normally tolerance of ± 2 to 3Pa– Any less and control is difficult

• Trying to hold levels of +1 to +5Pa is next to impossible– Set point needs to be 2 to 3Pa above required level to

ensure substantial compliance• General industry limits

– 15Pa minimum required between unclassified and classified areas

– 10Pa minimum between rooms of different classifications

• Belts and braces – increments of 15 Pa throughout– Beware this can lead to excessive pressures

• Consider use of negative sink air locks

Change Room+30Pa

Corridor+45Pa

Change+60Pa

Primary changelobby+15Pa

Manufacturing+75Pa

0 (reference)

DP = 15Pa

DP = 15Pa

DP = 15Pa

DP = 15Pa

DP = 15Pa

Primary function: Prevent infiltration of particles from one area to another

Primary function: Prevent infiltration of particles from one area to another




3636


• Room pressurisation is achieved by changing the ratio of supply air to extracted air– Room pressure should be neutral (atmospheric pressure) if

supply rate = extraction rate– Room pressure positive if supply rate > extraction rate– Room pressure negative if extraction rate > supply rate

• Easy to achieve + ve pressure in a well sealed room– What about air flow from room to room when doors are

opened?• A level of designed leakage whilst doors are closed required to

provide correct airflow when doors are opened.

• Room pressurisation is achieved by changing the ratio of supply air to extracted air– Room pressure should be neutral (atmospheric pressure) if

supply rate = extraction rate– Room pressure positive if supply rate > extraction rate– Room pressure negative if extraction rate > supply rate

• Easy to achieve + ve pressure in a well sealed room– What about air flow from room to room when doors are

opened?• A level of designed leakage whilst doors are closed required to

provide correct airflow when doors are opened.




3737


• DP Control– Passive

• Achieved by adjusting and fixing the return (extracted) air flow rate against a fixed supply

• Difference between them provides room pressure and small air flow from room to room when doors are opened

…………………………continued on next slide

• DP Control– Passive

• Achieved by adjusting and fixing the return (extracted) air flow rate against a fixed supply

• Difference between them provides room pressure and small air flow from room to room when doors are opened

…………………………continued on next slide



3838


• DP Control (continued)– Passive + Pressure Control Dampers

(Flaps)• Pressure dampers often mounted in

partitions above the door– Allow certain amount of air to pass through

with doors closed– As door is opened the flap closes and allows

more air to pass through door opening– Useful in air balancing

» Factory set on design DP» Air balancing between supply and extract

doesn’t need to be so precise…………………………continued on next slide

• DP Control (continued)– Passive + Pressure Control Dampers

(Flaps)• Pressure dampers often mounted in

partitions above the door– Allow certain amount of air to pass through

with doors closed– As door is opened the flap closes and allows

more air to pass through door opening– Useful in air balancing

» Factory set on design DP» Air balancing between supply and extract

doesn’t need to be so precise…………………………continued on next slide




3939


• DP Control (continued)– Active

• DPs monitored continuously and return air dampers and fan (inverters) modulated to off-set changes in DP

• Doesn’t work across an open door– Some systems can increase room supply to a preset

maximum to protect the open doorway• Require independent controls of high quality with rapid

response– Expensive– Slow response systems will result in unstable facility

pressure control…………………………continued on next slide

• DP Control (continued)– Active

• DPs monitored continuously and return air dampers and fan (inverters) modulated to off-set changes in DP

• Doesn’t work across an open door– Some systems can increase room supply to a preset

maximum to protect the open doorway• Require independent controls of high quality with rapid

response– Expensive– Slow response systems will result in unstable facility

pressure control…………………………continued on next slide




4040


• DP Measurement– Magnehelic gauges

• Very common• Simple and inexpensive• They do have their drawbacks

– Difficult to make all gauges visible to manufacturing area

» All manufacturing room interface DPsshould be readable from manufacturing room

– Often find all facility DP gauges on a single panel

» Should be visible from the facility» Not located in an access corridor

– Easy to miss out-of-compliance conditions• Some have 4 to 20mA transmitters to allow

remote monitoring…………….continued on next slide

• DP Measurement– Magnehelic gauges

• Very common• Simple and inexpensive• They do have their drawbacks

– Difficult to make all gauges visible to manufacturing area

» All manufacturing room interface DPsshould be readable from manufacturing room

– Often find all facility DP gauges on a single panel

» Should be visible from the facility» Not located in an access corridor

– Easy to miss out-of-compliance conditions• Some have 4 to 20mA transmitters to allow

remote monitoring…………….continued on next slide




4141


• DP Measurement Continued– Electronic continuous monitoring

• Differential pressure transmitters• Data acquisition systems• Local readouts• Remote readouts• All parameters constantly monitored

– Monitored against alarms– Local and remote alarms– Event log

• Secure saving of data (21 CFR Part11)

• DP Measurement Continued– Electronic continuous monitoring

• Differential pressure transmitters• Data acquisition systems• Local readouts• Remote readouts• All parameters constantly monitored

– Monitored against alarms– Local and remote alarms– Event log

• Secure saving of data (21 CFR Part11)




4242

Maintaining Air-flow [1]Maintaining Air-flow [1]

• Without a level of flow control, air supply flow rates from the AHU and terminal room supplies would decay:– Related to filter life – level of filter exhaustion– As a filter become ‘dirty’

• Resistance to flow increases• Pressure drop across it increases as flow is maintained• Supply pressure must be increased to maintain flow

• Without a level of flow control– Critical parameters will go out of specification with time

• e.g. room air-change rates and flow velocities

• Without a level of flow control, air supply flow rates from the AHU and terminal room supplies would decay:– Related to filter life – level of filter exhaustion– As a filter become ‘dirty’

• Resistance to flow increases• Pressure drop across it increases as flow is maintained• Supply pressure must be increased to maintain flow

• Without a level of flow control– Critical parameters will go out of specification with time

• e.g. room air-change rates and flow velocities




4343


• Total air-flow from the AHU– Normally controlled by increasing the fan

speed to compensate for the greater resistance to flow from the filters – inverter on fan motorVariable Speed Drive (VSD)

• Regulated from flow measurement in supply

• Air-flow to zones (numerous HEPA filters, e.g rooms) or individual HEPAscan be maintained using:– Constant flow devices– Active control using induct flow

measurement and motorised control dampers

• Total air-flow from the AHU– Normally controlled by increasing the fan

speed to compensate for the greater resistance to flow from the filters – inverter on fan motorVariable Speed Drive (VSD)

• Regulated from flow measurement in supply

• Air-flow to zones (numerous HEPA filters, e.g rooms) or individual HEPAscan be maintained using:– Constant flow devices– Active control using induct flow

measurement and motorised control dampers

Multi-point airflow monitorMulti-point airflow monitor

Motorised zone damperMotorised zone damper




4444


• Adjustable venturi type constant flow device• Adjustable venturi type constant flow device

As the flow decreases, the venturi action reduces the force on the regulator and the spring expands. This moves the regulator outwards allowing more air to pass and so maintaining flow

As the flow decreases, the venturi action reduces the force on the regulator and the spring expands. This moves the regulator outwards allowing more air to pass and so maintaining flow




4545


• Constant flow devices– Located supply ducting to zones (banks of HEPA filters)– Normally assumed terminal HEPA filters will become

exhausted at a similar rate (similar air flow rate to each)• AHU will ensure total flow is constant• Zone constant flow devices will ensure room supply

flow is constant• Helps maintain control of critical parameters:

– Room air change rates– Pressure regimes– Particle levels.

• Constant flow devices– Located supply ducting to zones (banks of HEPA filters)– Normally assumed terminal HEPA filters will become

exhausted at a similar rate (similar air flow rate to each)• AHU will ensure total flow is constant• Zone constant flow devices will ensure room supply

flow is constant• Helps maintain control of critical parameters:

– Room air change rates– Pressure regimes– Particle levels.




4646

Fan Filter Units (FFU)Fan Filter Units (FFU)

• Fan-Powered Units– Self-powered air filter modules have become a

popular substitute for terminal air filtration units because of their flexibility and ease of installation

• Self-adjusting filter units automatically change speeds as external static pressures fluctuate.

• Fan-Powered Units– Self-powered air filter modules have become a

popular substitute for terminal air filtration units because of their flexibility and ease of installation

• Self-adjusting filter units automatically change speeds as external static pressures fluctuate.




4747

Multiple FFUsMultiple FFUs

Supply PlenumSupply Plenum




4848

NotesNotes

• More recently, FFUs have taken a cost conscious direction with the inclusion of built-in intelligence. These new “smart” FFUsoffer a number of new benefits. First, they are powered by DC, which reduces energy consumption by as much as 50%. Second, their fan motors can be monitored and adjusted individually, in groups, or all at one time using a computerized control interface. By controlling the rpm of the fan motor and hence the airflow ofthe FFU, the operator has complete control over the systems at all times.

• Some of these new DC/EC (electronically commutated) motors have a built-in smart chip that detects changes in resistance to airflow through the filter and increases the rpm of the motor tomaintain airflow at the original settings. Due to the longevity of most HEPAs and ULPAs in the cleanroom, however, this feature is becoming less attractive because the payback cycle is too long to be economically justified. Moreover, this type of motor is not as electrically efficient as others currently on the market.

• More recently, FFUs have taken a cost conscious direction with the inclusion of built-in intelligence. These new “smart” FFUsoffer a number of new benefits. First, they are powered by DC, which reduces energy consumption by as much as 50%. Second, their fan motors can be monitored and adjusted individually, in groups, or all at one time using a computerized control interface. By controlling the rpm of the fan motor and hence the airflow ofthe FFU, the operator has complete control over the systems at all times.

• Some of these new DC/EC (electronically commutated) motors have a built-in smart chip that detects changes in resistance to airflow through the filter and increases the rpm of the motor tomaintain airflow at the original settings. Due to the longevity of most HEPAs and ULPAs in the cleanroom, however, this feature is becoming less attractive because the payback cycle is too long to be economically justified. Moreover, this type of motor is not as electrically efficient as others currently on the market.




4949

Airflow [1]Airflow [1]

• Airflow can be used to protect both the product and the operator

• Airflow direction can be controlled by a number of mechanisms (continued on next slide):– Flow from filters to extract – governed by:

• Position of supply and extract points• Size of supply / extract grille• Speed (flow) of supply

– Laminar air flow:» Maintained across a critical work area at a velocity of 0.36 - 0.54

m/s» Can protect the product and the operator

• Principle mechanism for ensuring adequate air sweeps / distribution within rooms.

• Airflow can be used to protect both the product and the operator

• Airflow direction can be controlled by a number of mechanisms (continued on next slide):– Flow from filters to extract – governed by:

• Position of supply and extract points• Size of supply / extract grille• Speed (flow) of supply

– Laminar air flow:» Maintained across a critical work area at a velocity of 0.36 - 0.54

m/s» Can protect the product and the operator

• Principle mechanism for ensuring adequate air sweeps / distribution within rooms.




5050

Airflow [2]Airflow [2]

• Airflow direction can be controlled by a number of mechanisms (continued):– Air flow from room to room

• Positioning of supply and extraction points– Supply points in one room/corridor and extraction points in

another room (see later example)– Protects product from cross-contamination– Protect operators working in adjacent areas from hazards

posed by ‘dusty’ operations• Differential pressure regime and designed leakage

– Air flows from higher pressure to lower pressure– Help prevent cross-contamination– Help prevent adverse air flow (lower classification to higher

classification.

• Airflow direction can be controlled by a number of mechanisms (continued):– Air flow from room to room

• Positioning of supply and extraction points– Supply points in one room/corridor and extraction points in

another room (see later example)– Protects product from cross-contamination– Protect operators working in adjacent areas from hazards

posed by ‘dusty’ operations• Differential pressure regime and designed leakage

– Air flows from higher pressure to lower pressure– Help prevent cross-contamination– Help prevent adverse air flow (lower classification to higher

classification.




5151

Room Airflow PatternsRoom Airflow Patterns

AHUTerminal filtersTerminal filters

1

Turbulent

3

Turbulent

2

Uni-directional

ExtractionExtraction

Room Air-FlowsRoom Air-Flows




5252

Turbulent and Unidirectional Flow

Turbulent and Unidirectional Flow

Turbulent dilution of dirty air

0.45 m/s

Unidirectional / laminardisplacement of dirty air

Unidirectional / laminardisplacement of dirty air




5353

NotesNotes

• The air speed in the uni-directional flow is defined by the WHO at:

– 0.45 m/s for horizontal units– 0.30 m/s for vertical units (most commonly used)

• It is important to know that the WHO definition(*) for the air speed differs from those of other guidelines.

• For the air exhaust, in case of a vertical unit, a low return is more favourable, as the air is better distributed in the room.

• Objects in the room can significantly disturb the flow of air, and even block it, so that there might be pockets without air circulation.

• During the qualification phase, the air flow is visualized if possible, and air samples are taken in different points, to make sure that there are no such pockets, in which case adjustments to the layout or to the air handling systems must be made.

• (*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: 59-60 (Technical Report Series, No. 823). Annex 1, 17.3.

• The air speed in the uni-directional flow is defined by the WHO at:

– 0.45 m/s for horizontal units– 0.30 m/s for vertical units (most commonly used)

• It is important to know that the WHO definition(*) for the air speed differs from those of other guidelines.

• For the air exhaust, in case of a vertical unit, a low return is more favourable, as the air is better distributed in the room.

• Objects in the room can significantly disturb the flow of air, and even block it, so that there might be pockets without air circulation.

• During the qualification phase, the air flow is visualized if possible, and air samples are taken in different points, to make sure that there are no such pockets, in which case adjustments to the layout or to the air handling systems must be made.

• (*) WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: 59-60 (Technical Report Series, No. 823). Annex 1, 17.3.




5454

Cabin/ boothCabin/ boothWorkbench (vertical)Workbench (vertical) CeilingCeiling

Laminar Flow DevicesLaminar Flow Devices



5555

Safety CabinetsSafety Cabinets

Class II Biological Safety Cabinet – Product + Operator ProtectionClass II Biological Safety Cabinet – Product + Operator Protection

A = Operator accessB = Transparent ScreenC = Exhaust HEPAD = Supply HEPA (laminar flow)E = Supply and Exhaust AirF = Fan (supply + exhaust)

A = Operator accessB = Transparent ScreenC = Exhaust HEPAD = Supply HEPA (laminar flow)E = Supply and Exhaust AirF = Fan (supply + exhaust)




5656

NotesNotes

• Uni-directional (laminar) flow units exist mostly as vertical, but also as horizontal, units.

• Often, we are just dealing with LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine.

• In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system.

• Due to the high air velocity, it is important to have objects with good aerodynamical properties under the laminar flow. If not, turbulences and, therefore, particles are unavoidable.

• Laminar flow units are comparatively expensive. Surfaces covered by them should be reduced to a minimum.

• Only the product in a critical production phase, and not the personnel, should be under laminar flow (aseptic filling, sterile blending, etc.). Manual interventions should be restricted to a minimum, and should be recorded and evaluated for possible consequences.

• Uni-directional (laminar) flow units exist mostly as vertical, but also as horizontal, units.

• Often, we are just dealing with LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine.

• In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system.

• Due to the high air velocity, it is important to have objects with good aerodynamical properties under the laminar flow. If not, turbulences and, therefore, particles are unavoidable.

• Laminar flow units are comparatively expensive. Surfaces covered by them should be reduced to a minimum.

• Only the product in a critical production phase, and not the personnel, should be under laminar flow (aseptic filling, sterile blending, etc.). Manual interventions should be restricted to a minimum, and should be recorded and evaluated for possible consequences.




5757

Unidirectional Flow Entire Room

Unidirectional Flow Entire Room

SUPPLY FANSUPPLY FANSUPPLY FANSUPPLY FAN

HEPA FILTERHEPA FILTER

Return PlenumReturn Plenum

Supply PlenumSupply Plenum




5858

Simple Cross-contamination Control [1]Simple Cross-contamination Control [1]

PROCESS ROOMPROCESS ROOM

PROCESS ROOMPROCESS ROOM

CORRIDORCORRIDOR

VentVent

Extraction Grille – to extraction system (may include dust filters)

Extraction Grille – to extraction system (may include dust filters)

Ceiling Mounted Air Supply GrilleCeiling Mounted Air Supply Grille Air flowAir flow

Cross-contamination control – Supply and extraction mechanismCross-contamination control – Supply and extraction mechanism

Not ideally suited for microbiological controlled environmentsNot ideally suited for microbiological controlled environments



5959


Process Room – Door ClosedProcess Room – Door Closed

ExtractExtractGravity DamperGravity Damper



6060


Process Room – Door OpenProcess Room – Door Open

Damper flaps closeDamper flaps close



6161

Dusty ProcessesDusty Processes

• Best place to remove dust is at source• Once dispersed into a room, it becomes more difficult

to remove• Wherever the dust is extracted it has to be dealt with

• Best place to remove dust is at source• Once dispersed into a room, it becomes more difficult

to remove• Wherever the dust is extracted it has to be dealt with

• Baghouse unit connected to various Pharmaceutical operations, such as tablet presses, mixing operations, weighing and encapsulation machines

• Exhaust air is run through a secondary HEPA filter and then a portion of the exhaust air is run back into the air conditioning system.

• Baghouse unit connected to various Pharmaceutical operations, such as tablet presses, mixing operations, weighing and encapsulation machines

• Exhaust air is run through a secondary HEPA filter and then a portion of the exhaust air is run back into the air conditioning system.




6262

Cross-Contamination Control –Differential Pressure

Cross-Contamination Control –Differential Pressure

0

Process Room 1Process Room 1


Material Out Air LockMaterial Out Air Lock

MaterialsEntry

Changing RoomChanging Room

Process RoomAccess Air -Lock


+ +

++

+

+

+

KEYKEY= Reference (bordering rooms)= Reference (bordering rooms)o

Low Level Extraction Grille – to extraction system (may include dust filters)


Ceiling Mounted Air Supply Grille - via terminal HEPA filter


= Air Flow Direction= Air Flow Direction

+ += Pressure of 30 Pa

above reference(1 Pascal = 1 N/m2)

= Pressure of 30 Pa above reference(1 Pascal = 1 N/m2)

+ = Pressure of 15 Pa above reference= Pressure of 15 Pa above reference

Not suitable for aseptic operations Not suitable for aseptic operations




6363

Product Protection – Differential Pressure

Product Protection – Differential Pressure



Material Out Air LockMaterial Out Air Lock

MaterialsEntryMaterialsEntry




KEYKEY

o

Reference (bordering rooms)Reference (bordering rooms)o





++

+

+ Pressure of 15 Pa above referencePressure of 15 Pa above reference

+ + + + Pressure of 30 Pa above referencePressure of 30 Pa above reference

Air Flow DirectionAir Flow Direction

+++ +++

+++ Pressure of 55 Pa above referencePressure of 55 Pa above reference




6464

Nested Manufacturing ZonesNested Manufacturing Zones

External AreasStreet, Offices, Restaurant

Transition ZoneBrings people, materials etc. from external areas to the

manufacturing areas in a controlled mannerClean Area

Provides protective envelope to minimise challenge to critical area

Critical Processing Areae.g. Point of Fill

ChangePeople Change Raw Materials

Com-pounding

RemoveOuters

RemoveOuters

Containers / Closures

Sterilise




6565

Notes on Nested Zone DiagramNotes on Nested Zone Diagram

• Product out not illustrated on the diagram• The diagram shows the increasing protection as you

move towards the product exposure area. In a manufacturing facility air pressures will be such to ensure a cascade of flow from the critical area outward.

• The level of personnel entry and general activity will decrease considerably as you move towards the core of the conceptual diagram

• In a sterile area the zones would have the following classifications:

• Critical area – Class 100, Grade B, ISO 5 - in operation• Clean area – Class 10,000, Grade C, ISO 7 – in

operation• Transition – General Pharmaceutical or ISO 8 (Grade D)

• Product out not illustrated on the diagram• The diagram shows the increasing protection as you

move towards the product exposure area. In a manufacturing facility air pressures will be such to ensure a cascade of flow from the critical area outward.

• The level of personnel entry and general activity will decrease considerably as you move towards the core of the conceptual diagram

• In a sterile area the zones would have the following classifications:

• Critical area – Class 100, Grade B, ISO 5 - in operation• Clean area – Class 10,000, Grade C, ISO 7 – in

operation• Transition – General Pharmaceutical or ISO 8 (Grade D)




6666

Example Aseptic Filling Facility

Example Aseptic Filling Facility

Final Washing / Sterilising TunnelFinal Washing /

Sterilising Tunnel

45 Pa45 Pa

60Pa60Pa 75Pa75Pa

75Pa75Pa

30Pa30Pa

30Pa30Pa

Cooling RoomCooling Room

Aseptic Processing Room

Aseptic Processing Room


AirlockAirlock

AutoclaveAutoclave

Autoclave loading RoomAutoclave loading Room

Component preparationComponent preparation

Packing HallPacking Hall

Critical AreaCritical Area

Critical AreaCritical AreaGrade AGrade A

Grade AGrade A

Critical AreaCritical AreaGrade AGrade A

Grade BGrade B

Grade BGrade B

Grade BGrade B

Grade DGrade D

Grade DGrade D

Grade CGrade C

Grade BGrade B

Grade CGrade C Solution Preparation AreaSolution Preparation Area

30Pa30Pa




6767

Part 05/e - Control & InstrumentationPart 05/e - Control & Instrumentation




6868

Building Management System (BMS) [1]

Building Management System (BMS) [1]

• HVAC control is usually effected by a BMS:– Normally some type of PC based supervisory

application software– PC linked to local area controllers– Local controllers (Modular Building Controllers –

MBC) linked to field instruments and devices• Temperature, pressure, relative humidity, flow instruments• Tachometers• Motorised dampers• Fan speed controllers• Control valves to services• Motor control centres (MCC).

• HVAC control is usually effected by a BMS:– Normally some type of PC based supervisory

application software– PC linked to local area controllers– Local controllers (Modular Building Controllers –

MBC) linked to field instruments and devices• Temperature, pressure, relative humidity, flow instruments• Tachometers• Motorised dampers• Fan speed controllers• Control valves to services• Motor control centres (MCC).




6969

BMS [2]BMS [2]

• BMS (continued)– Similar to SCADA system– Graphic interface (HMI)– Normally used by engineers rather than operators– Main functions:

• Monitor, control and trend conditions – area + AHU• Monitors controls and trends equipment performance• Filter performance monitoring• Maintains air flow to each area:

– Not all control differential pressures in areas• Alarms and associated trends.

• BMS (continued)– Similar to SCADA system– Graphic interface (HMI)– Normally used by engineers rather than operators– Main functions:

• Monitor, control and trend conditions – area + AHU• Monitors controls and trends equipment performance• Filter performance monitoring• Maintains air flow to each area:

– Not all control differential pressures in areas• Alarms and associated trends.

SCADA – Supervisory control and data acquisitionHMI – Human machine interface




7070

BMS [3]BMS [3]

Management Level NetworkManagement Level Network

Building Level Network (BLN) :Building Level Network (BLN) :

Clients:Engineering InterfaceClients:Engineering Interface

Floor Level NetworkFloor Level Network

BMS ServerBMS Server

Field devicesField devicesField instrumentsField instruments MCCsMCCs

Modular Building ControllersModular Building Controllers

Closed / Open NetworkClosed / Open Network

BMS SchematicBMS Schematic



7171

BMS – Facility Control SensorsBMS – Facility Control Sensors

Laboratory Animal Facilities Laboratory Animal Facilities




7272

Control And InstrumentationControl And Instrumentation

• Care required when specifying temperatures and relative humidity requirements for products– Measuring humidity during development work and

applying a specification for manufacturing based on this, without adequate experimentation

• Can cause major design and control issues – Do not over specify parameters

– The tighter the control, the more accurate the instrumentation and the more expensive the HVAC and control system

• Also remember a 1 degree change in temperature will alter the RH by ~ 2.5% without changing the absolute moisture content.

• Care required when specifying temperatures and relative humidity requirements for products– Measuring humidity during development work and

applying a specification for manufacturing based on this, without adequate experimentation

• Can cause major design and control issues – Do not over specify parameters

– The tighter the control, the more accurate the instrumentation and the more expensive the HVAC and control system

• Also remember a 1 degree change in temperature will alter the RH by ~ 2.5% without changing the absolute moisture content.




7373

End of PresentationEnd of Presentation

Any further questions?Any further questions?

Documents

Pt05 - HVAC System Design