Professional Documents
Culture Documents
Clean Room
Clean Room
Clean Room
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:
Pharmaceutical Plants Ampoule and vial filling, manufacture of antibiotics and manufacture of liquid injectibles and ointments. Hospitals Critical areas like operation theatres, ICUs (intensive care units), delivery rooms, units treating burn patients and recovery rooms. Electronic Industry/Semi Conductors For manufacture of critical components such as ICs (integrated circuits) and other components. Space Research
factors affecting the particulate count and decide the level of contamination that can be permitted.
Room Classification
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:
Class 100 - Particle count not to exceed a total of 3,500 particles per m (
3
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 m (10,000 particles per cubic foot) of a size 0.5 microns and larger or
3
2,295 particles per m (65 particles per cubic foot), of a size 5.0 microns
3
and larger.
Class 100,000 - Particle count not to exceed a total of 3,531,000 particles per m (100,000 particles per cubic foot) of a size 0.5 micron and larger or
3
24,700 particles per m (700 particles per cubic foot) of a size 5.0 microns
3
and larger.
[top] 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.
At rest as per Fed. Std. 209 Aseptic filling Room (background) Aseptic receiving area Aseptic changing room Solution preparation room Clean changing room Material Entry air locks 100 100 10,000 10,000 10,000 100
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. [top]
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.
Non Unidirectional clean rooms are used where levels are required upto around Class 10,000, see Figure 3.
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.
[top] Design Methodology 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:
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.
[top] 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
8. 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: a. Location and size of the cutouts for terminal filters. b. Location and size 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. In 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. Mounting frames for terminal filters/terminal filter boxes should be grouted at the time of casting the slab. See Figures 5 and 6. h. Lighting layout and equipment should be matched with the cut-out location and size. i. The ceiling slab should have inverted beam construction in order to avoid projections into the clean rooms. 9. In the case of a false ceiling in the sterile area, the following points should be considered: a. Inserts should be provided for false ceiling supports and mounting of filters.
b. 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. c. False 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. 10. 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. [top]
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: 1. 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. 2. 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. 3. Another trend is to use VFDs (Variable Frequency Drives) on AHU and run the AHU at lower speeds at night/ holidays. This helps as a energy saving measure as well. 4. 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. 5. 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. 6. 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.
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. [top]
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:
1. To cater for the proper supply air quantity, balancing dampers should be installed at critical points. 2. 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. 3. 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. 4. 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. 5. On each return air riser manually operated dampers are provided for control. These dampers should preferably be operated from the nonsterile areas. 6. Opposed blade dampers are provided above each Hepa filter in order to properly balance the air distribution system.
Pressurisation of Rooms
With reasonably good building construction and airtight doors and windows, it is normally possible to achieve and maintain the following pressures between various zones.
Description Main sterile zone to cooling zone Cooling zone to first (white) change room Between each change room Pressure Difference 15 Pa 12 - 15 Pa 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.
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). 7. Return air grilles should be stove enamel/epoxy painted or in SS construction. 8. Provision should be left in each return air riser for periodic cleaning. Today, duct cleaning equipment is available for this purpose. 9. Whenever terminal filters are mounted in the false ceiling, proper sealed access door should be provided to reach the dampers above each filter.
Filtration System
Terminal Hepa Filters 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. [top] Pre-filters to Hepa Filters 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. Roughing Filter 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.
Defumigation
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.
[top]
3. 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. 4. 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: a. Temperature and relative humidity checks b. Terminal Hepa 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
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 enduser and regulatory authorities. [top]