Air Conditioning of Clean Rooms for Pharmaceutical Plants

By Pradeep Shankar
Deputy General Manager,
Blue Star Ltd., Mumbai
Pradeep Shankar is a mechanical engineer from V!" Bombay #ith $% years of
e&perience in the design and construction of large central air conditioning plants for
'arious applications
Air, whether it is from outside or recirculated within the area, acts as a vehicle for
bacterial and gaseous contaminants brought in by the movement of people, material, etc.
Since many of these air borne contaminants are harmful either to products or people
working in such environments their removal is necessary on medical, legal, social or
financial grounds.
A super clean environment with controlled temperature and relative humidity has now
become an essential requirement for a wide range of applications in:
Pharmaceutical Plants Ampoule and vial filling, manufacture of antibiotics and
manufacture of liquid injectibles and ointments.
ospitals !ritical areas like operation theatres, "!#$s %intensive care units&,
delivery rooms, units treating burn patients and recovery rooms.
'lectronic "ndustry(Semi !onductors )or manufacture of critical components
such as "!$s %integrated circuits& and other components.
Space *esearch
What Then is a Clean Room?
+he )ederal Standard ,-. ' of #SA defines it as:
/A room in which the concentration of airborne particles is controlled to specified limits0.
+herefore, while designing the airconditioning system for sterile areas in pharmaceutical
plants it is very necessary to study the application, identify various factors affecting the
particulate count and decide the level of contamination that can be permitted.
Room Classification
!lean rooms have been classified into various classes of cleanliness based on the
particulate count by different standards. owever, the most well known classification
comes from #S )ederal Standard ,-. which was published for the first time in 1.23 with
subsequent revisions to ,-.' which is the e4isting standard.
+o meet the demands of air cleanliness classes defined by this standard, the particulate
concentration must not e4ceed specified values.
+he three most commonly specified classes of /clean0 rooms are:
!lass 1-- 5 Particle count not to e4ceed a total of 3,6-- particles per m3 % 1--
particles per cubic foot& of a si7e -.6 microns and larger.
!lass 1-,--- 5 Particle count not e4ceeding a total of 363,--- particles per m3
%1-,--- particles per cubic foot& of a si7e -.6 microns and larger or ,,,.6 particles
per m3 %26 particles per cubic foot&, of a si7e 6.- microns and larger.
!lass 1--,--- 5 Particle count not to e4ceed a total of 3,631,--- particles per m3
%1--,--- particles per cubic foot& of a si7e -.6 micron and larger or ,8,9--
particles per m3 %9-- particles per cubic foot& of a si7e 6.- microns and larger.
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+he airborne contamination level of a clean room is largely dependent on the particle
generating activities going on in the room, besides the personnel who also contribute to
the contamination levels.
+his brings us to the concept of:
< as built
< at rest
< operational clean rooms
=As built$ clean rooms are those which are ready with all services connected but without
equipment and personnel.
=At rest$ clean rooms have the production equipment installed and operating but without
personnel.
=>perational$ clean rooms are active rooms with full production in progress.
Particle counts are to be taken during active periods and at a location which will yield the
particle count of the air as it approaches the work location. >ther intermediate
classifications such as 1---, 6---, etc may also be used.
+he ?A! contractors responsibility generally lies upto the =as built$ or =at rest$ clean
room stage and often the pharma companies specify higher cleanliness levels for these
stages than the $operational$ stage. Some of the areas in pharmaceutical plants with their
=at rest$ and =operational$ levels of cleanliness are listed in Table 1.
Table 1 : Cleanliness levels of some sterile areas
At rest as per
)ed. Std. ,-.
>perational as
per )ed. Std.
,-.
Aseptic filling *oom
%background&
1-- 1-,---
Aseptic receiving area 1-- 1-,---
Aseptic changing room 1-- 1-,---
Solution preparation
room
1-,--- 1-,---
!lean changing room 1-,--- 1--,---
@aterial 'ntry air locks 1-,--- 1--,---
+o summari7e, using currently available equipment and soundly established techniques it
is now possible to identify and quantify the level of airborne contaminants and also study
the behaviour and movement of the air which transports them.
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Types of Clean Rooms
>ne of the ways to differentiate clean rooms is by the air flow pattern used in the room.
+hus we have:
A #nidirectional or Baminar flow clean rooms
A Con5#nidirectional clean rooms
#nidirectional clean rooms are used where low air borne contaminant levels are required,
lower than !lass 1-,---. +hey are generally of two types:
?ertical #nidirectional flow clean rooms where the air flow is vertical =laminar$
in direction, see Figure 1.
ori7ontal #nidirectional where the air flow is hori7ontal =laminar$ in direction,
see Figure .
=Con #nidirectional$ clean rooms are used where levels are required upto around !lass
1-,---, see Figure !.
Airconditioning "ystem #esign for Clean Facility
#esign $b%ectives
Dithin the pharmaceutical industry, the clean facility generally consists of a series of
rooms integrating classes of rooms to match with the requirements of the manufacturing
process.
+here are some basic requirements which must be satisfied so that the air in the sterile
rooms is correct for the activities related to the manufacturing process:
'ach sterile room must be clinically independent from the surrounding area, i.e.
its temperature and relative humidity should be controlled and air pressure
regulated.
!ontamination due to air borne particles should be controlled by an efficient
filtration system.
!ontamination generated within the sterile area, for instance from people, must be
contained and removed before it can cause any harm by carefully selecting the air
flow pattern.
'ffective monitoring of the condi5tions in the system must be carried out from
time to time to ensure that the right conditions are being created for the
manufacturing process. "t is important to understand that the design and function
of the pharmaceutical manufacturing area forms a significant part of Eood
@anufacturing Practices %E@P&, these being the requirements by Eovernmental
Agencies like the )FA, and followed by most of the pharmaceutical companies.
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#esign &ethodology
Gased on several years of e4perience in the design and installation of ?A! systems, it is
possible to use a systematic approach to the design of clean rooms for the pharma
industry. +his step by step approach is briefly as follows:
Analyse the production process, especially the flow of materials and personnel.
+his helps to define the activities in the various rooms and group the rooms
having similar environmental requirements.
Fefine the ?A! requirements system5wise and then room5wise. +he
requirements defined are:
< !leanliness level
< *oom temperature, relative humidity
< *oom pressure
< Air movement direction
!arry out detailed heat load calculations room5wise taking into account fresh air
quantity requirements.
Air handling system design and selection.
Prepare air flow diagrams based on the above mentioned load calculations and
room pressure requirements.
Fevelop detailed layouts, after preparation of design specifications and any
specific requirements. Figure ', is an air flow diagram of a typical sterile system.
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+he efficacy of the system design is based on proper consideration of the following
factors, a brief write up on each of which follows:
A Guilding construction and layout design
A Air handling system
A Selection of air flow pattern and pressurisation of rooms
A )resh air quantity
A Fuct system design and construction
A Selection, location and mounting of filtration system
A Fefumigation requirement
A Performance qualification and validation
(uilding #esign) Construction * +ayout
"f the building layout and its construction are poor there is very little that an
airconditioning system designer can do to satisfy the end5user of the sterile areas. "t is
therefore necessary to consider the most important factor first.
1. Sterile 7ones are normally divided into three sub 7ones:
A @ain sterile 7one or white 7one.
A !ooling 7one which is also a white 7one.
A Set of three change rooms: black, grey and white in ascending order of
cleanliness.
"n order to achieve a pressure gradient, it is imperative that 7ones are located such
that the gradient is unidirectional, i.e. the room with the highest pressure should
be located at one end and the room with the lowest pressure should be located
near the opposite end. +his type of planning can simplify balancing of system
pressures to a great e4tent.
,. 'ntry for people to the main sterile room should be from a set of three change
rooms: black, gray and white. 'ntry for equipment and material must be through
airlocks. Co other area should directly open into the sterile room.
3. "n case any wall of the sterile area is e4posed to the outdoor, care should be taken
that no glass is provided. Any glass window provided in an internal partition
should be sealed.
8. All doors in the sterile area should have airtight construction. Special gaskets
should be provided on the door frame and at the bottom of the door to prevent air
leakage, if necessary.
6. Sharp corners should be avoided between floors, walls and ceiling.
2. +ile joints in the floor should be carefully sealed.
9. 'po4y painting should be carried out in these areas.
H. Special attention should be given to the type of ceiling. +he commonly followed
trend is to eliminate false ceilings and to provide instead a concrete slab on top of
which are located the air handling units and ducting. !utouts in this slab are used
for housing the terminal filters. Access to these filters is from top of the slab. !are
should be taken to adequately reinforce this slab to accommodate the weight of
the air handling units, piping and ducting.
"n such cases the airconditioning system is required to be designed before slab
construction is started in order to provide the following:
a. Bocation and si7e of the cutouts for terminal filters.
b. Bocation and si7e of the cutouts for return air risers and inserts in the slab.
c. Provide floor drain locations for air handling units.
d. Sleeves for drain line and cabling should be provided in inverted beams.
e. "n areas where air handling units are located water proofing must be
carried out. Additional cutouts are required to be left for other services.
f. All cutouts should have curbing at the edge to prevent water seepage into
the working area.
g. @ounting frames for terminal filters(terminal filter bo4es should be
grouted at the time of casting the slab. See Figures , and -.
h. Bighting layout and equipment should be matched with the cut5out
location and si7e.
i. +he ceiling slab should have inverted beam construction in order to avoid
projections into the clean rooms.
.. "n the case of a false ceiling in the sterile area, the following points should be
considered:
a. "nserts should be provided for false ceiling supports and mounting of
filters.
b. +o prevent fungus growth and eliminate air leakage, the false ceiling
should be of non shedding variety, such as aluminium or P?! coated
!*!A sheet.
c. )alse ceiling members should be designed to support part of the weight of
terminal filters.
d. Proper sealing must be provided between panels and between filters and
panels to avoid air leakage.
1-. Dith advances in technology, various clean room products such as, partitions,
doors, windows, false ceiling tiles, coved corners, %all made of non5shedding
material& filter modules etc., are now available ready to use in clean rooms.
@odular clean rooms can now be constructed with various finishes, but the main
principles in the design as in the preceding paragraphs are the same whether the
clean room is =brick I mortar$ or packaged modular design.
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!lick to view the clear picture
Air .andling "ystem #esign
Air handling systems are generally located on a separate equipment floor or 7one in order
to facilitate maintenance without disturbance to the sterile room. +hese generally consist
of a double skin air handling unit comprising a mi4ing bo4 for return air and fresh air
with dampers, a coarse filter section, cooling coil section and fan sections %supply air and
return air& and fine filter sections.
Dhile designing the air handling system the following points should be taken into
consideration:
1. @otors for supply air(return air fans should have two speeds, since during non5
working hours even though air conditioning is not required it is necessary to have
pressurisation in the clean room for all ,8 hours in order to ensure sterility.
,. Dhile selecting the fan, it should be ensured that at the lower speed the fan does
not operate in the un5balanced region. Also the noise level should be kept at its
minimum. )ans should be provided with a shaft seal near the bearings.
3. Another trend is to use ?)F$s %?ariable )requency Frives& on A# and run the
A# at lower speeds at night( holidays. +his helps as a energy saving measure as
well.
8. !ooling coil section should be provided with sandwich type of drain pan to
collect condensate. "t may also be necessary to provide an eliminator after the
cooling coil in order to prevent water carry5over into the system.
6. "n case of a heating coil, at least a -.6 meter space should be kept between coils.
All sections consisting of prefilters, cooling coil, heating coil, etc should be
mounted in between the SA and *A fans.
2. +wo sets of fresh air dampers should be provided, one for 1-J to ,-J and the
second for 1--J of fan capacity. +hese dampers are located on the suction side of
the return air fan. Proper access should be provided in each section of the air
handling unit for routine maintenance and cleaning.
!lick to view the clear picture
Air Flo/ Pattern
+he selection of air flow pattern depends on the cleanliness class of the room )or
e4ample, a room with cleanliness standard of class 1-- must necessarily have laminar
flow throughout, i.e. the whole ceiling or wall must have terminal filters and the return
must be picked up from the opposite side as shown in Figure . Air flow velocities of
-.32 m(s to -.62 m(s %9- fpm to 11- fpm& are recommended as standard design for
laminar flow clean room systems.
)or a room with cleanliness standard of class 1-,--- the required number of terminal
filters can be mounted in the ceiling and the return can be picked up at a low level in the
wall as shown in Figure !. +o achieve class 1-- at the work place, laminar flow benches
can be separately installed inside the room.
+he preferred flow pattern for sterile rooms in pharmaceutical plants is down flow with
clean air supplied from the interior portion of the room ceiling. +his air is supplied at a
much higher pressure than its surrounding area ensuring a higher velocity and pressure in
the clean 7one relative to the perimeter. +his ensures that entrainment of contaminants
into the sterile 7one does not occur.
+he return points are positioned low down in the walls and spaced as symetrically as
building construction allows.
"t has been observed that down flow system is more effective than hori7ontal flow in
reducing the number of bacteria carrying particles in the sterile 7ones. Dhen hori7ontal
flow is used the work place must be immediately in front of the clean air source so that
there is nothing in between which could emit or cause uncontrolled turbulence and
consequent contamination. "n pharmaceutical plants use of laminar flow work benches is
quite common to obtain class 1-- at the work place. See Figure 0.
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"t is also essential to have an adequate number of air changes in such areas in order to
avoid infiltration. "f the volume and pressure of air is inadequate then it is possible that
warmer air will pass through the upper part of open door5ways in one direction and the
cooler air will pass through the lower part in the opposite direction, thus defeating the
object of controlling the sterility.
+he following measures are normally taken to control the air flow pattern and hence the
pressure gradient of the sterile area:
1. +o cater for the proper supply air quantity, balancing dampers should be installed
at critical points.
,. *eturn air grilles are located near the floor and made as long as convenient to
increase the collection of dust particles over a larger area.
3. *eturn air grilles in the main sterile 7ones are located to avoid dead air pockets.
Dhile locating the return grille, care should be taken to avoid placing the grille
near a door opening into an adjoining lower pressure room. +his is done to
prevent creation of a low pressure 7one near the door, thus preventing air leakage
from the low pressure to high pressure room at the time of door opening.
8. *eturn air grilles in the /cooling 7one0 are oversi7ed to take care of supply air of
the cooling areas as well as the leakage air of the main sterile area.
6. >n each return air riser manually operated dampers are provided for control.
+hese dampers should preferably be operated from the non5sterile areas.
2. >pposed blade dampers are provided above each epa filter in order to properly
balance the air distribution system.
Pressurisation of Rooms
Dith reasonably good building construction and airtight doors and windows, it is
normally possible to achieve and maintain the following pressures between various
7ones.
#escription Pressure #ifference
@ain sterile 7one to /cooling0 7one 16 Pa
/!ooling 7one0 to first %white& change
room
1, 5 16 Pa
Getween each change room 1, Pa
Dhile calculating supply air quantities for various rooms, allowances should be made for
process equipments like tunnels, that cross room pressure boundaries and open doors, if
any.
&easurement of Pressure 1radient
Dhile designing the air5conditioning system for sterile areas, one must provide air
pressure measuring devices, such as inclined type of manometers with P?! ( copper
tubing and sensor probes to enable the users to check the pressure gradient from time to
time. +hese manometers can be mounted on a common panel which in turn can be
installed at a convenient location.
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Fresh Air 2uantity
Cormally fresh air intake in sterile areas is designed for 1 to , air changes ( hour in order
to maintain a positive pressure in the sterile area and to cater for normal leakages from
building construction and door openings. owever, if the building construction is very
good and leakage factor is low, the number of fresh air changes can be reduced.
*oughing filters should be provided at fresh air intakes and in the air handling unit before
the coil section.
#uct "ystem #esign and Construction
E" ducting is provided to carry air from the supply air fan discharge to the sterile room
and to bring back air from the return air grilles in the sterile room to the return air fan.
)ollowing precautions should be taken while designing and fabricating the duct system:
1. Fucts should be sealed with silicone sealant at longitudinal joints in order to make
the system airtight.
,. *ubber gaskets should be used at transverse joints.
3. E" flanged joints must be avoided and instead pocket slips or angle iron flanged
joints should be used.
8. Co accoustic insulation should be provided inside the ducts.
6. Fampers provided in the system should be of E" and should have e4tended handle
to accommodate insulation thickness.
2. *eturn air risers should be designed for velocities not e4ceeding . m(s %1H-- fpm&
with a minimum velocity of 2 m(s %1,-- fpm& at the highest point in order to carry
particulate matter along with return air. owever, the inlet velocity at the return
grille should be in the range of 1.6 m(s to , m(s %3-- to 8-- fpm& gradually
increasing the same to 2 m(s to . m(s %1,-- to 1H-- fpm&.
9. *eturn air grilles should be stove enamel(epo4y painted or in SS construction.
H. Provision should be left in each return air riser for periodic cleaning. +oday, duct
cleaning equipment is available for this purpose.
.. Dhenever terminal filters are mounted in the false ceiling, proper sealed access
door should be provided to reach the dampers above each filter.
Filtration "ystem
Terminal .epa Filters
+he terminal filters used in the filtration system are epa filters %high efficiency
particulate air& with efficiency of minimum ....9J down to -.3 microns. +hese filters
use sub5micronic glass fibre media housed in an aluminium framework. +hese filters are
available in two types of constructions: Go4 type and )langed type.
Go4 type filters are more suitable for housing within the ceiling slab cutout where
removal of filter is from above. Dhenever filter removal is not from above e.g. in case of
filter being mounted in false ceiling, flanged type of filters are required. Dith flanged
type of filters, additional housing is also required to facilitate the mounting of filters and
transfer the load to false ceiling members. +hese housings can also be provided with an
alternate arrangement to transfer the filter load to ceiling slab. "t is observed that
whenever the load is transferred to ceiling slab it is difficult to get leak proof joints
between the housing and false ceiling. "n such cases soft silicon compound sealing is
recommended for use between the filter housing and false ceiling panel. Also in order to
prevent transfer of filter load to ducting and to facilitate filter removal %as in the case of
filter removal from above& fle4ible connections of P?! are provided between filter
housing and ducting. Aluminium ( stainless steel slotted type protective grilles can be
provided under the terminal filters. +he housing and grilles should be epo4y(stove enamel
painted. +hese filters are available in thicknesses of 16- mm and 3-- mm %20 and 1,0&
and have pressure drop of ,6mm %10& wg when clean and generally need to be replaced
when the pressure drop e4ceeds 6- mm %,0& wg.
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Pre3filters to .epa Filters
"n order to prolong the service life of epa filters, prefilters are recommended to filter out
majority of particles above 1 micron. "t should be convenient to clean and replace these
filters without disturbing the rest of the filtration system.
@any different types of filters have proved suitable for this application.
Pre5filters are available in various si7es with 16- mm and 3-- mm %20 and 1,0 thickness
and with pressure drop in the range of 6 to 2.6 mm %-.,0 to -.,60 wg.& owever, dust
holding capacity of these filters is poor. +herefore, in case the application requires a
filtration system with good dust holding capacity, bag type filters with fibreglass scrim
cloth media are recommended to give efficiencies ranging from H6J %down to ,-
microns& to ....9J %down to 6 microns&.
Pre5filters are normally mounted in a separate plenum with access door after supply air
fan discharge at an appropriate location. Cormally flanged filters are used for mounting
in such plenums.
Roughing Filter
+hese filters are normally provided before the cooling coil in the air handling unit and at
fresh air intakes. +he following is commonly used:
)ilters with synthetic media sandwiched between FP' layers in thickness of 6- mm
%,0& are highly suitable for such applications. 'fficiency of these filters is in the range of
H-J down to ,- microns and they can be easily cleaned by washing.
#efumigation
Sterile areas are periodically fumigated with formaldehyde vapour and the air is
circulated through areas and air conditioning equipment in order to sterilise the system.
owever, formaldehyde vapour has to be removed effectively after fumigation is over
before starting the actual operations. Furing defumigation 1--J fresh air is provided and
this is fully e4hausted to remove formaldehyde vapour. +o achieve this 3 sets of dampers
are installed in the air conditioning system, as shown in Figure 4.
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Commissioning) Performance and 5alidation of Clean Rooms
A clean room differs from a normal comfort air conditioned space, in the following ways.
1. "ncreased Air Supply : Dhereas comfort air conditioning would require about ,5
1- air changes(hr, a typical clean room, say up to class 1-,---, would require ,- 5
2- air changes. +his additional air supply helps, to dilute the contaminants to an
acceptable concentration.
,. igh 'fficiency )ilters : +he use of epa filters having filtration efficiency of
....9J down to -.3 microns, is another distinguishing feature of clean rooms.
3. +erminal )iltration and Air )low pattern : Cot only are high efficiency filters
used, but a laminar flow is sought Furing normal operation damper Co. ,I8 to
remain open, damper Co. 1I to remain closed. Furing defumigation damper Co.
,I to close, damper Co. 1I3 to open to be achieved.
8. *oom Pressurisation : Dith the increased fresh air intake, clean rooms are
pressurised in gradients. ence the commissioning, performance qualification and
validation of clean rooms ensures that the above mentioned important parameters
are met. +he tests for performance qualification consist of:
a. +emperature and relative humidity checks
b. +erminal epa filter integrity
c. Particle counts in rooms
d. Air velocity profiles for determining room air patterns
e. Pressure differential checks between various rooms of the clean air system
Conclusion
Guilding a clean room is a comple4 e4ercise carried out in order to assure the product
quality within the overall guidelines of good manufacturing practices in the
pharmaceutical industry.
A clean facility must effectively control contamination from personnel, raw materials,
processes and overall construction of the facility. "t is imperative to ensure that the design
is undertaken in a systematic and organised manner so that on completion, the clean
facility meets with the specifications and requirements of the end5user and regulatory
authorities.
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