By Pradeep Shankar
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:
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.
Clean 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:
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:
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.
One 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:
Non Unidirectional clean rooms are used where levels are required upto around Class 10,000, see Figure 3.
Within 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:
Based 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:
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
Performance qualification and validation
If 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.
Click to view the clear picture
Air 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:
Click to view the clear picture
The 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:
With 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
|Cooling zone to first (white) change room||12 - 15 Pa|
|Between each change room||12 Pa|
While 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.
While 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.
Normally 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.
GI 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:
The 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.
In 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.
These 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.
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. 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.
A clean room differs from a normal comfort air conditioned space, in the following ways.
Building 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.