Deputy General Manager,
Blue Star Ltd., Mumbai
Pradeep Shankar is a mechanical engineer from VJTI Bombay with 24 years of experience in the design and construction of large central air conditioning plants for various 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.
- Hospitals Critical areas like operation theatres, ICU’s (intensive care units), delivery rooms, units treating burn patients and recovery rooms.
- Electronic Industry/Semi Conductors For manufacture of critical components such as IC’s (integrated circuits) and other components.
- Space Research
What Then is a Clean Room?The Federal Standard 209 E of USA defines it as:
“A room in which the concentration of airborne particles is controlled to specified limits”.
Therefore, 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 ClassificationClean rooms have been classified into various classes of cleanliness based on the particulate count by different standards. However, the most well known classification comes from US Federal Standard 209 which was published for the first time in 1963 with subsequent revisions to 209E which is the existing standard.
To meet the demands of air cleanliness classes defined by this standard, the particulate concentration must not exceed specified values.
The three most commonly specified classes of “clean” rooms are:
- Class 100 - Particle count not to exceed a total of 3,500 particles per m3 ( 100 particles per cubic foot) of a size 0.5 microns and larger.
- Class 10,000 - Particle count not exceeding a total of 353,000 particles per m3 (10,000 particles per cubic foot) of a size 0.5 microns and larger or 2,295 particles per m3 (65 particles per cubic foot), of a size 5.0 microns and larger.
- Class 100,000 - Particle count not to exceed a total of 3,531,000 particles per m3 (100,000 particles per cubic foot) of a size 0.5 micron and larger or 24,700 particles per m3 (700 particles per cubic foot) of a size 5.0 microns and larger.
The 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.
This 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.
‘Operational’ 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. Other intermediate classifications such as 1000, 5000, etc may also be used.
The HVAC 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 Fed. Std. 209||Operational as per Fed. Std. 209|
|Aseptic filling Room (background)||100||10,000|
|Aseptic receiving area||100||10,000|
|Aseptic changing room||100||10,000|
|Solution preparation room||10,000||10,000|
|Clean changing room||10,000||100,000|
|Material Entry air locks||10,000||100,000|
To summarize, 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.
Types of Clean RoomsOne of the ways to differentiate clean rooms is by the air flow pattern used in the room. Thus we have:
• Unidirectional or Laminar flow clean rooms
• Non-Unidirectional clean rooms
Unidirectional clean rooms are used where low air borne contaminant levels are required, lower than Class 10,000. They are generally of two types:
- Vertical Unidirectional flow clean rooms where the air flow is vertical ‘laminar’ in direction, see Figure 1.
- Horizontal Unidirectional where the air flow is horizontal ‘laminar’ in direction, see Figure 2.
Airconditioning System Design for Clean Facility
Design ObjectivesWithin 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.
There 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:
- Each sterile room must be clinically independent from the surrounding area, i.e. its temperature and relative humidity should be controlled and air pressure regulated.
- Contamination due to air borne particles should be controlled by an efficient filtration system.
- Contamination 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.
- Effective monitoring of the condi-tions in the system must be carried out from time to time to ensure that the right conditions are being created for the manufacturing process. It is important to understand that the design and function of the pharmaceutical manufacturing area forms a significant part of Good Manufacturing Practices (GMP), these being the requirements by Governmental Agencies like the FDA, and followed by most of the pharmaceutical companies.
Design MethodologyBased on several years of experience in the design and installation of HVAC systems, it is possible to use a systematic approach to the design of clean rooms for the pharma industry. This step by step approach is briefly as follows:
- Analyse the production process, especially the flow of materials and personnel. This helps to define the activities in the various rooms and group the rooms having similar environmental requirements.
- Define the HVAC requirements system-wise and then room-wise. The requirements defined are:
– Cleanliness level
– Room temperature, relative humidity
– Room pressure
– Air movement direction
- Carry out detailed heat load calculations room-wise 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.
- Develop detailed layouts, after preparation of design specifications and any specific requirements. Figure 4, is an air flow diagram of a typical sterile system.
The efficacy of the system design is based on proper consideration of the following factors, a brief write up on each of which follows:
• Building construction and layout design
• Air handling system
• Selection of air flow pattern and pressurisation of rooms
• Fresh air quantity
• Duct system design and construction
• Selection, location and mounting of filtration system
• Defumigation requirement
• Performance qualification and validation
Building Design, Construction & LayoutIf the building layout and its construction are poor there is very little that an airconditioning system designer can do to satisfy the end-user of the sterile areas. It is therefore necessary to consider the most important factor first.
- Sterile zones are normally divided into three sub zones:
• Main sterile zone or white zone.
• Cooling zone which is also a white zone.
• Set of three change rooms: black, grey and white in ascending order of cleanliness.
In order to achieve a pressure gradient, it is imperative that zones 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. This type of planning can simplify balancing of system pressures to a great extent.
- Entry for people to the main sterile room should be from a set of three change rooms: black, gray and white. Entry for equipment and material must be through airlocks. No other area should directly open into the sterile room.
- In case any wall of the sterile area is exposed to the outdoor, care should be taken that no glass is provided. Any glass window provided in an internal partition should be sealed.
- 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.
- Sharp corners should be avoided between floors, walls and ceiling.
- Tile joints in the floor should be carefully sealed.
- Epoxy painting should be carried out in these areas.
- Special attention should be given to the type of ceiling. The 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. Cutouts in this slab are used for housing the terminal filters. Access to these filters is from top of the slab. Care should be taken to adequately reinforce this slab to accommodate the weight of the air handling units, piping and ducting.
In such cases the airconditioning system is required to be designed before slab construction is started in order to provide the following:
- Location and size of the cutouts for terminal filters.
- Location and size of the cutouts for return air risers and inserts in the slab.
- Provide floor drain locations for air handling units.
- Sleeves for drain line and cabling should be provided in inverted beams.
- In areas where air handling units are located water proofing must be carried out. Additional cutouts are required to be left for other services.
- All cutouts should have curbing at the edge to prevent water seepage into the working area.
- Mounting frames for terminal filters/terminal filter boxes should be grouted at the time of casting the slab. See Figures 5 and 6.
- Lighting layout and equipment should be matched with the cut-out location and size.
- The ceiling slab should have inverted beam construction in order to avoid projections into the clean rooms.
- In the case of a false ceiling in the sterile area, the following points should be considered:
- Inserts should be provided for false ceiling supports and mounting of filters.
- To prevent fungus growth and eliminate air leakage, the false ceiling should be of non shedding variety, such as aluminium or PVC coated CRCA sheet.
- False ceiling members should be designed to support part of the weight of terminal filters.
- Proper sealing must be provided between panels and between filters and panels to avoid air leakage.
- With advances in technology, various clean room products such as, partitions, doors, windows, false ceiling tiles, coved corners, (all made of non-shedding material) filter modules etc., are now available ready to use in clean rooms. Modular 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 & mortar’ or packaged modular design.
Air Handling System DesignAir handling systems are generally located on a separate equipment floor or zone in order to facilitate maintenance without disturbance to the sterile room. These generally consist of a double skin air handling unit comprising a mixing box 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.
While designing the air handling system the following points should be taken into consideration:
- Motors for supply air/return air fans should have two speeds, since during non-working hours even though air conditioning is not required it is necessary to have pressurisation in the clean room for all 24 hours in order to ensure sterility.
- While selecting the fan, it should be ensured that at the lower speed the fan does not operate in the un-balanced region. Also the noise level should be kept at its minimum. Fans should be provided with a shaft seal near the bearings.
- Another trend is to use VFD’s (Variable Frequency Drives) on AHU and run the AHU at lower speeds at night/ holidays. This helps as a energy saving measure as well.
- Cooling coil section should be provided with sandwich type of drain pan to collect condensate. It may also be necessary to provide an eliminator after the cooling coil in order to prevent water carry-over into the system.
- In case of a heating coil, at least a 0.5 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 RA fans.
- Two sets of fresh air dampers should be provided, one for 10% to 20% and the second for 100% of fan capacity. These 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.
Air Flow PatternThe selection of air flow pattern depends on the cleanliness class of the room For example, a room with cleanliness standard of class 100 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 2. Air flow velocities of 0.36 m/s to 0.56 m/s (70 fpm to 110 fpm) are recommended as standard design for laminar flow clean room systems.
For a room with cleanliness standard of class 10,000 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 3. To achieve class 100 at the work place, laminar flow benches can be separately installed inside the room.
The preferred flow pattern for sterile rooms in pharmaceutical plants is down flow with clean air supplied from the interior portion of the room ceiling. This air is supplied at a much higher pressure than its surrounding area ensuring a higher velocity and pressure in the clean zone relative to the perimeter. This ensures that entrainment of contaminants into the sterile zone does not occur.
The return points are positioned low down in the walls and spaced as symetrically as building construction allows.
It has been observed that down flow system is more effective than horizontal flow in reducing the number of bacteria carrying particles in the sterile zones. When horizontal 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. In pharmaceutical plants use of laminar flow work benches is quite common to obtain class 100 at the work place. See Figure 7.
It is also essential to have an adequate number of air changes in such areas in order to avoid infiltration. If the volume and pressure of air is inadequate then it is possible that warmer air will pass through the upper part of open door-ways 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.
The following measures are normally taken to control the air flow pattern and hence the pressure gradient of the sterile area:
- To cater for the proper supply air quantity, balancing dampers should be installed at critical points.
- Return air grilles are located near the floor and made as long as convenient to increase the collection of dust particles over a larger area.
- Return air grilles in the main sterile zones are located to avoid dead air pockets. While locating the return grille, care should be taken to avoid placing the grille near a door opening into an adjoining lower pressure room. This is done to prevent creation of a low pressure zone near the door, thus preventing air leakage from the low pressure to high pressure room at the time of door opening.
- Return air grilles in the “cooling zone” are oversized to take care of supply air of the cooling areas as well as the leakage air of the main sterile area.
- On each return air riser manually operated dampers are provided for control. These dampers should preferably be operated from the non-sterile areas.
- Opposed blade dampers are provided above each Hepa filter in order to properly balance the air distribution system.
Pressurisation of RoomsWith reasonably good building construction and airtight doors and windows, it is normally possible to achieve and maintain the following pressures between various zones.
|Main sterile zone to “cooling” zone ||15 Pa|
|“Cooling zone” to first (white) change room||12 - 15 Pa|
|Between each change room||12 Pa|
Measurement of Pressure GradientWhile designing the air-conditioning system for sterile areas, one must provide air pressure measuring devices, such as inclined type of manometers with PVC / copper tubing and sensor probes to enable the users to check the pressure gradient from time to time. These manometers can be mounted on a common panel which in turn can be installed at a convenient location.
Fresh Air QuantityNormally fresh air intake in sterile areas is designed for 1 to 2 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. However, if the building construction is very good and leakage factor is low, the number of fresh air changes can be reduced. Roughing filters should be provided at fresh air intakes and in the air handling unit before the coil section.
Duct System Design and ConstructionGI 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. Following precautions should be taken while designing and fabricating the duct system:
- Ducts should be sealed with silicone sealant at longitudinal joints in order to make the system airtight.
- Rubber gaskets should be used at transverse joints.
- GI flanged joints must be avoided and instead pocket slips or angle iron flanged joints should be used.
- No accoustic insulation should be provided inside the ducts.
- Dampers provided in the system should be of GI and should have extended handle to accommodate insulation thickness.
- Return air risers should be designed for velocities not exceeding 9 m/s (1800 fpm) with a minimum velocity of 6 m/s (1200 fpm) at the highest point in order to carry particulate matter along with return air. However, the inlet velocity at the return grille should be in the range of 1.5 m/s to 2 m/s (300 to 400 fpm) gradually increasing the same to 6 m/s to 9 m/s (1200 to 1800 fpm).
- Return air grilles should be stove enamel/epoxy painted or in SS construction.
- Provision should be left in each return air riser for periodic cleaning. Today, duct cleaning equipment is available for this purpose.
- Whenever terminal filters are mounted in the false ceiling, proper sealed access door should be provided to reach the dampers above each filter.
Terminal Hepa FiltersThe terminal filters used in the filtration system are Hepa filters (high efficiency particulate air) with efficiency of minimum 99.97% down to 0.3 microns. These filters use sub-micronic glass fibre media housed in an aluminium framework. These filters are available in two types of constructions: Box type and Flanged type.
Box type filters are more suitable for housing within the ceiling slab cutout where removal of filter is from above. Whenever filter removal is not from above e.g. in case of filter being mounted in false ceiling, flanged type of filters are required. With flanged type of filters, additional housing is also required to facilitate the mounting of filters and transfer the load to false ceiling members. These housings can also be provided with an alternate arrangement to transfer the filter load to ceiling slab. It 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. In 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) flexible connections of PVC are provided between filter housing and ducting. Aluminium / stainless steel slotted type protective grilles can be provided under the terminal filters. The housing and grilles should be epoxy/stove enamel painted. These filters are available in thicknesses of 150 mm and 300 mm (6” and 12”) and have pressure drop of 25mm (1”) wg when clean and generally need to be replaced when the pressure drop exceeds 50 mm (2”) wg.
Pre-filters to Hepa FiltersIn order to prolong the service life of Hepa filters, prefilters are recommended to filter out majority of particles above 1 micron. It should be convenient to clean and replace these filters without disturbing the rest of the filtration system.
Many different types of filters have proved suitable for this application.
Pre-filters are available in various sizes with 150 mm and 300 mm (6” and 12” thickness and with pressure drop in the range of 5 to 6.5 mm (0.2” to 0.25” wg.) However, dust holding capacity of these filters is poor. Therefore, 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 85% (down to 20 microns) to 99.97% (down to 5 microns).
Pre-filters are normally mounted in a separate plenum with access door after supply air fan discharge at an appropriate location. Normally flanged filters are used for mounting in such plenums.
Roughing FilterThese filters are normally provided before the cooling coil in the air handling unit and at fresh air intakes. The following is commonly used:
Filters with synthetic media sandwiched between HDPE layers in thickness of 50 mm (2”) are highly suitable for such applications. Efficiency of these filters is in the range of 80% down to 20 microns and they can be easily cleaned by washing.
DefumigationSterile areas are periodically fumigated with formaldehyde vapour and the air is circulated through areas and air conditioning equipment in order to sterilise the system. However, formaldehyde vapour has to be removed effectively after fumigation is over before starting the actual operations. During defumigation 100% fresh air is provided and this is fully exhausted to remove formaldehyde vapour. To achieve this 3 sets of dampers are installed in the air conditioning system, as shown in Figure 8.
Commissioning, Performance and Validation of Clean RoomsA clean room differs from a normal comfort air conditioned space, in the following ways.
- Increased Air Supply : Whereas comfort air conditioning would require about 2-10 air changes/hr, a typical clean room, say up to class 10,000, would require 20 - 60 air changes. This additional air supply helps, to dilute the contaminants to an acceptable concentration.
- High Efficiency Filters : The use of Hepa filters having filtration efficiency of 99.97% down to 0.3 microns, is another distinguishing feature of clean rooms.
- Terminal Filtration and Air Flow pattern : Not only are high efficiency filters used, but a laminar flow is sought During normal operation damper No. 2&4 to remain open, damper No. 1& to remain closed. During defumigation damper No. 2& to close, damper No. 1&3 to open to be achieved.
- Room Pressurisation : With the increased fresh air intake, clean rooms are pressurised in gradients. Hence the commissioning, performance qualification and validation of clean rooms ensures that the above mentioned important parameters are met. The tests for performance qualification consist of:
- Temperature and relative humidity checks
- Terminal Hepa filter integrity
- Particle counts in rooms
- Air velocity profiles for determining room air patterns
- Pressure differential checks between various rooms of the clean air system
ConclusionBuilding a clean room is a complex exercise 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. It 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 end-user and regulatory authorities.