In pharmaceutical manufacturing, how space conditions impact the product being made is of primary importance. The pharmaceutical facilities are closely supervised by the U.S. food and drug administration (FDA), which requires manufacturing companies to conform to cGMP (current Good Manufacturing Practices). These regulations, which have the force of law, require that manufacturers, processors, and packagers of drugs to take proactive steps to ensure that their products are safe, pure, and effective. GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mix ups and errors.
The GMP for HVAC services embraces number of issues starting with the selection of building materials and finishes, the flow of equipment, personnel and products, determination of key parameters like temperature, humidity, pressures, filtration, airflow parameters and classification of cleanrooms. It also governs the level of control of various parameters for quality assurance, regulating the acceptance criteria, validation of the facility, and documentation for operation and maintenance.
Various countries have formulated their own GMPs. In the United States, it is regulated by several documents such as Federal Standard 209, code of Federal regulations CFR 210 & 211 etc., which are revised and updated from time to time. The European Community has a “Guide to Good Manufacturing Practice for Medicinal Products” and in the United Kingdom it is BS 5295. The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide, primarily in the developing world. In some countries, the GMP follows largely the country of the principal technology provider.
HVAC system performs four basic functions:
- Control airborne particles, dust and micro-organisms – Thru air filtration using high efficiency particulate air (HEPA) filters
- Maintain room pressure (delta P) – Areas that must remain “cleaner” than surrounding areas must be kept under a “positive” pressurization, meaning that air flow must be from the “cleaner” area towards the adjoining space (through doors or other openings) to reduce the chance of airborne contamination. This is achieved by the HVAC system providing more air into the “cleaner” space than is mechanically removed from that same space.
- Maintain space moisture (Relative Humidity) – Humidity is controlled by cooling air to dew point temperatures or by using desiccant dehumidifiers. Humidity can affect the efficacy and stability of drugs and is sometimes important to effectively mould the tablets.
- Maintain space temperature – Temperature can affect production directly or indirectly by fostering the growth of microbial contaminants on workers.
Each of the above parameters are controlled and evaluated in light of its potential to impact product quality.
Particulate: – Simply stated, airborne particles are solids suspended in the air. The size of contaminants and particles are usually described in microns; one micron is one-millionth of a meter. In English units one micron equals 1/25,400 inch. To give a perspective, a human hair is about 75-100 microns in diameter.
Air, whether it is from outside or re-circulated, acts as a vehicle for bacterial and gaseous contaminants brought in by the movement of people, material, etc. Since many of this air borne contaminants are harmful to products and people, their removal is necessary on medical, legal, social or financial grounds. There are two main sources of particulates, external and internal sources.
External sources consist of the following:
- Outside make-up air introduced into the room: this is typically the largest source of external particulates
- Infiltration through doors, windows and other penetration through the cleanroom barriers
- Make-up air filtration
- Room pressurization
- Sealing of all penetrations into the space
Internal sources consist of the following:
- People in the clean area: people are potentially the largest source of internally generated particulates
- Cleanroom surface shedding • Process equipment
- Material ingress
- Manufacturing processes
- Design airflow path to shield humans from surroundings
- Use of air showers [to continually wash occupants with clean air]
- Using hard-surfaced, non-porous materials such as polyvinyl panels, epoxy painted walls, and glass board ceilings
- Proper gowning procedures, head wear
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.
Cleanroom: – A cleanroom is defined as a room in which the concentration of airborne particles is controlled. The cleanrooms have a defined environmental control of particulate and microbial contamination and are constructed, maintained, and used in such a way as to minimize the introduction, generation, and retention of contaminants.
Cleanroom classifications are established by measurement of the number of particles 0.5 micron and larger that are contained in 1 ft3 of sampled air. Generally, class 100 to 100,000 rooms are used in the pharmaceutical industry. [Note – rooms may be classified as clean at class 1 or 10 for other applications, particularly in the microchip /semiconductor industry].
Cleanrooms classified in the United States by Federal Standard 209E of September 1992 and by the European Economic Community (EEC) published guidelines “Guide to Good Manufacturing Practice for Medical Products in Europe, which are more stringent than U.S. FDA regulations.
U.S FEDERAL STANDARD 209E:- Table below derived from Federal Standard 209E shows the air cleanliness classes:
|Class Names||Class Limits|
|0.5 Micron||5 Micron|
- Class 100 (M 3.5) is the area where the particle count must not exceed a total of 100 particles per cubic foot (3,530 particles per m3) of a size 0.5 microns and larger.
- Class 10,000 (M 5.5) is the area where the particle count must not exceed a total of 10,000 particles per cubic foot (353,000 particles per m3 ) of a size 0.5 microns and larger or 70 particles per cubic foot (2,470 particles per m3), of a size 5.0 microns and larger.
- Class 100,000 (M 6.5) is the area where the particle count must not exceed a total of 100,000 particles per cubic foot (3,530,000 particles per m3) of a size 0.5 micron and larger or 700 particles per cubic foot (24,700 particles per m3 ) of a size 5.0 microns and larger.
- All pharmaceutical facilities belong to one or other class of cleanroom. General acceptance is:
- Tableting facilities – Class 100,000
- Topical & oral liquids – Class 10,000
- Injectables class – Class 100
FACILITY CLASSIFICATION:- Pharmaceutical facility typically consists of a series of integrating classes of rooms to match with the requirements of the manufacturing process. There are some basic requirements that 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 and are produced by “aseptic” processing. Aseptic processing is a method of producing a sterile (absence of living organisms) product. The objective of aseptic processing methods is to assemble previously sterilized product, containers and closures within specially designed and controlled environments intended to minimize the potential of microbiological or particulate contamination.
Cleanrooms classifications differ for sterile and non-sterile areas. These are called by many names viz.:
Non-sterilized operation = controlled area = non-aseptic application
Sterilized operation = critical Area = aseptic application
Controlled Areas: – U.S standards define the “controlled area” as the areas where Non-sterilized products are prepared. This includes areas where compounds are compounded and where components, in-process materials, drug products and contact surfaces of equipment, containers and closures, are exposed to the plant environment.
Requirement – Air in “controlled areas” is generally of acceptable particulate quality if it has a per cubic foot particle count of not more than 100,000 in size range of 0.5 micron and larger (Class 100,000) when measured in the vicinity of the exposed articles during periods of activity. With regard to microbial quality, an incidence of no more than 2.5 colony forming units per cubic foot is acceptable. In order to maintain air quality in controlled areas… airflow sufficient to achieve at least 20 air changes per hour and, in general, a pressure differential of at least 0.05 inch of water gauge (with all doors closed) is recommended.
Critical Areas: – U. S standards define “Critical Areas”, as the areas where Sterilized operations are carried out. These shall have aseptic cleanrooms.
Requirement – Air in “critical areas” is generally of acceptable particulate quality if it has a per cubic foot particle count of not more than 100 in size range of 0.5 micron and larger (Class 100) when measured in the vicinity of the exposed articles during periods of activity. With regard to microbial quality, an incidence of no more than 0.1 colony forming units per cubic foot is acceptable. In order to maintain air quality in sterile areas… laminar airflow at velocity of 90 feet per minute ± 20 and, in general, a pressure differential of at least 0.05 inch of water gauge (with all doors closed) is recommended. No specific air change rate is specified by Fed and EEU standards.
TYPES OF CLEANROOMS: – Cleanrooms are also categorized by the way supply air is distributed. There are generally two air supply configurations used in cleanroom design: –
- Non-unidirectional air flow: – In this airflow pattern, there will be considerable amount of turbulence and it can be used in rooms where major contamination is expected from external source i.e. the make up air. This turbulent flow enhances the mixing of low and high particle concentrations, producing a homogenous particle concentration acceptable to the process. Air is typically supplied into the space by one of two methods. The first uses supply diffusers and HEPA filters. The HEPA filter may be integral to the supply diffuser or it may be located upstream in the ductwork or air handler. The second method has the supply air pre-filtered upstream of the cleanroom and introduced into the space through HEPA filtered work stations. Non-unidirectional airflow may provide satisfactory control for cleanliness levels of Class 1000 to Class 100,000.
- Unidirectional air flow: – The unidirectional air flow pattern is a single pass, single direction air flow of parallel streams. It is also called ‘laminar’ airflow since the parallel streams are maintained within 18 degree – 20 degree deviation. The velocity of air flow is maintained at 90 feet per minute ±20 as specified in Federal Standard 209 version B although later version E does not specify any velocity standards. Unidirectional cleanrooms are used where low air borne contaminant levels are required, and where internal contaminants are the main concern.
They are generally of two types:
- Vertical down-flow cleanrooms where the air flow is vertical ‘laminar’ in direction.
- Horizontal flow where the air flow is horizontal ‘laminar’ in direction.
In vertical down-flow arrangement, clean make-up air is typically introduced at the ceiling and returned through a raised floor or at the base of the side walls. Horizontal flow cleanrooms use a similar approach, but with a supply wall on one side and a return wall on the other. Typically, a down-flow cleanroom consists of HEPA filtered units mounted in the ceiling. As the class of the cleanroom gets lower, more of the ceiling consists of HEPA units, until, at Class 100, the entire ceiling will require HEPA filtration. The flow of air in a down-flow cleanroom bathes the room in a downward flow of clean air. Contamination generated in the room is generally swept down and out through the return. The horizontal flow cleanroom uses the same filtration airflow technique as the down-flow, except the air flows across the room from the supply wall to the return wall.
Between the two, the vertical down-flow pattern yields better results and is more adaptable to pharmaceutical production.
HVAC Cleanroom differ from a normal comfort air-conditioned space: – A cleanroom requires a very stringent control of temperature, relative humidity, particle counts in various rooms, air flow pattern and pressure differential between various rooms of the clean air system. All this requires:
- Increased Air Supply: Whereas comfort air conditioning would require about 2-10 air changes/hr, a typical cleanroom, say Class 10,000, would require 50 – 100 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 cleanrooms.
- Terminal Filtration and Air Flow pattern: Not only are high efficiency filters used, but a laminar flow is sought.
- Room Pressurization: With the increased fresh air intake, cleanrooms are pressurized in gradients. This is important to keep external particulates out of clean spaces.
SYSTEM DESIGN: – The HVAC design process begins with meetings with process engineers, architects, and representatives from the owner or facility user. The process and instrument diagrams (P&IDs) are reviewed, and a general understanding of the process is conveyed to all interested parties. Operation of the facility is reviewed, and any plans for future additions or modifications are discussed.
After the initial meeting, a written basis of design is produced that describes the regulations and codes that will govern the design. Spaces are defined by function, and temperature and humidity requirements are determined. Room classifications are listed and adjacency of spaces and pressure relationships are documented. Any unusual or unique facility requirements must also be designed into the HVAC system at this time, such as emergency backup or redundancy for HVAC systems. This is also the stage of the design process during which alternate studies are conducted to compare options for the HVAC system. The cost of a backup or redundant HVAC supply system may be compared with the cost of product loss or experiment interruption should temperatures or airflow go out of control or specification. Heat recovery from exhaust systems and thermal storage are examples of other potential areas for study. Airflow diagrams are produced that show areas served by a particular air handling system including supply, return, exhaust, and transfer air between spaces. The basis of design also describes major equipment to be used and the level of quality of components and construction material. The efficacy of the system design is based on proper consideration of the following factors:
- Building construction and layout design
- Defining the HVAC requirements system-wise and then room-wise. – Cleanliness level – Room temperature, relative humidity – Room pressure – Air flow pattern
- Cooling load and Airflow compilation
- Selection of air flow pattern
- Pressurization of rooms
- Air handling system
- Duct system design and construction
- Selection, location and mounting of filtration system
- DE fumigation requirement
- Commissioning, performance qualification and validation
- Testing and validation
BUILDING DESIGN, CONSTRUCTION AND LAYOUT: – Proper building design and planning of the flow of personnel, material and equipment is essential for achieving and maintaining the design levels of cleanliness and pressure gradients. If the building layout and its construction are poor there is very little that an air-conditioning system designer can do to satisfy the end-user needs.
- Building Layout: – From an HVAC standpoint it is desirable to keep similarly classified areas as physically close to each other as possible so they can be connected to the same air handling system, thereby minimizing duct runs, cost, and air system complexity. It is also imperative that spaces be arranged to allow people to move around without disrupting the cleanliness or containment of the spaces. It is NOT desirable to mix dirty and clean systems or suites that may allow the possibility of cross-contamination from one suite to another. Leaks can develop in a filter, or some source of contamination could find its way through the air supply or return systems, providing a source for cross-contamination.
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 …in that order. Entry for equipment and material must be through “AIRLOCKS”. No area should directly open into the sterile room.
- Building Construction: – The internal particulate generation always is the focus of any cleanroom design. The internal generation consists of those from building elements such as walls, floor, ceiling, etc., from equipment, and most importantly from operators. The building construction itself has to be “tight” with minimum of uncontrolled infiltration and leakages. This is very important in the case of buildings for formulation and sterile production. Materials used in the construction of the pharmaceutical facilities should be hard-surfaced. There are few special points of interest as noted below:
- All material used is construction should be non-chipping and cleanable. Wall and floor finishes should not shed particulates and should provide self-cleaning surfaces.
- All exposed surfaces should be smooth, impervious and unbroken
- No un-cleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment
- Sharp corners should be avoided between floors, walls and ceiling
- False ceilings and the tile joints in the floor should be completely sealed
- Pipes, ducts and other utilities should be installed so they do not create recesses
- Sinks and drains should be prohibited in grade Class 100 areas
- All doors in the sterile area should have airtight construction. Special gaskets should be provided on the door frame and drop seals provided at the bottom of the door, if necessary.
- Epoxy painting should be carried out in these areas.
HVAC REQUIRMENTS: – Define the HVAC requirements system-wise and then room-wise. The requirements defined are:
1) room temperature,
2) relative humidity,
3) cleanliness level
4) room pressure.
- Room Temperature (T):- Room temperature (T) is not critical as long as it provides comfortable conditions. Generally, areas are designed to provide room temperatures from 67 and 77°F with a control point of 72°F. Lower space temperatures may be required where people are very heavily gowned and would be uncomfortable at “normal” room conditions.
- Relative Humidity (RH):- Relative humidity (RH) on the other hand, is of greater importance in all the production areas. While most of the areas could have a RH of 50 ± 5%, facilities designed for handling hygroscopic powders need to be at 30 ± 5%. Automatic control of the RH is essential for maintaining continued product quality. Control of humidity is necessary for personal comfort, to prevent corrosion, to control microbial growth, and to reduce the possibility of static electricity. We will discuss more about the RH control in the subsequent sections.
- Control Airborne Particles (C):- Of all the design goals, it is the quality of air cleanliness of the space and prevention of contamination which are of utmost importance. Externally generated particulates are prevented from entering the clean space through the use of proper air filtration. The normally accepted air quality standards for both sterilized and non-sterilized areas are tabulated below:
|Operation||Parameters||United States||European Economic Community|
|Non-sterilized product or container
(U.S : Controlled
|Cleanroom type||Class 100,000||Grade C|
|Maximum particle size (0.5 micron or above)||100,000/ft3||350,000/m3|
|Sterilized product or container
(U.S: Critical Area)
|Cleanroom type||Class 100 in Class 10,000 background||Grade A in Grade B background|
|Maximum particle size (0.5 micron or above)||100 /ft3||3,500/m3|
|Maximum viable organisms||0.1 /ft3||Grade A : 1 /m3
Grade B background : 5/m3
|Maximum viable organisms||2.5/ft3||100/m3|
|Maximum particle size (0.5 micron or above)||100 /ft3||3,500/m3|
|Maximum viable organisms||0.1 /ft3||Grade A : 1 /m3
Grade B background : 5/m3
- Room Pressure Differential (DP):- Cleanroom positive pressurization is desired to prevent infiltration of air from adjacent areas. The normally accepted air pressurization standards for both sterilized and non-sterilized areas are tabulated below:
|Operation||Parameters||United States||European Economic Community|
|Non-sterilized product or container
(U.S : Controlled Area)
|Space pressurization||0.05 inch-w.g||Positive|
|Sterilized product or container
(U.S: Critical Area)
|Space pressurization||0.05 inch-w.g or higher||Positive|
COOLING LOADS:- Pharmaceutical buildings as a rule are totally enclosed without any fenestrations. This is to maintain a ‘tight’ building to minimize uncontrolled infiltration. As a result, the room sensible loads are essentially a contribution from process equipment, lighting and personnel. Fan heat from recirculating fans can also be a large heat contributor in clean spaces. The density of equipment loads is low excepting in the tablet manufacturing facility covering granulation, drying and tableting.
Heat-loss calculations must also be made to determine heat loss through walls, roof, and floor. No credit should be taken for process heat gain in this calculation, since the process could be dormant and the space would still need to be maintained at proper temperature.
A major contribution of the cooling load comes from outside air entering the air handling unit. There is also considerable diversity in the equipment loads based on the production patterns. All these result in a low room sensible load density varying from as low as 15 Btu/hr sq-ft to 40 Btu/hr sq-ft. Hence the system design lays emphasis on control and maintenance of relative humidity. The room temperature is normally held at 70°F, whereas the relative humidity is held at 50± 5% in most of the areas. In a few areas it is maintained at 35± 5% or lower depending on the product characteristics.
AIRFLOW SHEETS: – Once the cooling load is determined, the next step is to calculate the dehumidified airflow using psychometric analysis or computer analysis. These results are compared with airflow quantities required to establish the minimum air required to satisfy both the space cooling load requirements and air cleanliness classification.
The airflow sheets should be developed on full-size drawings and should show air quantities supplied, returned, and exhausted from each space. They also must show air transferred into and out of spaces, and, while quantities should be shown, they will probably require field modification to attain pressurization. The airflow sheet is a useful tool for transfer of information to the owner or user, for agency reviews, for transmission of information to HVAC designers, and for other engineering disciplines. These documents are also invaluable to construction contractors and for system checking by construction managers and balancing contractors. Airflow sheets provide a pictorial description of each air system and show how the elements comprising the system are related.
AIRFLOW PATTERN: – The air distribution has to be appropriate with the class of cleanroom. Air turbulence in the space can cause particulates which have settled onto the floor and work surfaces to become re-entrained in the air. Air turbulence is greatly influenced by the configuration of air supply and return grilles, people traffic and process equipment layout.
The following measures are normally taken to control the air flow pattern and hence the pressure gradient of the sterile area:
- Class 100 and lower zones must necessarily have unidirectional (laminar) flow with 100% HEPA filter coverage in the ceiling or wall. Return must be picked up from the opposite side.
- Air flow velocities of 90 fpm ±20 (70 fpm to 110 fpm) are recommended as standard design for Class 100 cleanroom systems.
- The vertical down-flow configuration is preferred. Per EEC standards, laminar work station with vertical flow requires 0.3 m/s velocity whereas the horizontal work stations require 0.45 m/s velocity. 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.
- Class 1000 and above are generally non-unidirectional with the supply air outlets at the ceiling level and the return air at the floor level.
- This air should be supplied at a much higher volume than its surrounding area ensuring a higher velocity and pressure in the clean zone relative to the perimeter.
RETURN AIR SYSTEMS:- The air return system is another critical component of the cleanroom air distribution system. The return points shall be positioned low down near the floor in the walls and spaced as symmetrically as building construction allows. Return grilles shall be made as long as convenient to increase the collection of dust particles over a larger area.
Return air grilles in the main sterile zones should be 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.
On each return air riser manually, operated dampers shall be provided for control. These dampers should preferably be operated from the non-sterile areas.
MIXED AREAS:- It is possible to create Class 100 space within Class 10,000 areas at background. For example, if a small localized operation in big Class 10,000 volume requires Class 100 standard, there is no point to put the entire area as Class 100. This will be very expensive. For such areas, install “localized laminar flow workstations”, which are commercially available in horizontal or vertical flow patterns generally recirculation within the clean space.
AIR CHANGES:- Air change rate is a measure of how quickly the air in an interior space is replaced by outside (or conditioned) air. For example, if the amount of air that enters and exits in one hour equals the total volume of the cleanroom, the space is said to undergo one air change per hour. Air flow rate is measured in appropriate units such as cubic feet per minute (CFM) and is given by
Air flow rate = Air changes x Volume of space/ 60
The normally accepted air change rates for both sterilized and non-sterilized areas are tabulated below:
|Operation||Parameters||United States||European Economic Community|
|Non-sterilized product or container
(U.S : Controlled Area)
|Airflow rate||Minimum 20 air changes/hr||Higher than 20 air changes/hr|
|Sterilized product or container
(U.S: Critical Area)
|Airflow rate||90 ft/min ± 20||Grade A : Laminar work station, vertical 0.3 m/s and horizontal 0.45 m/s
Grade B : Higher than 20 changes per hour
Even though various design guidelines and standards are available, there is no clear-cut guidance for air changes per hour especially for “sterilized areas”.
Table below indicates a typical range of air change rates generally used to achieve the desired room cleanliness classifications and to meet federal and local regulations. These air change rates vary widely in actual practice due to the level of activity, number and type of particulate generators in a room (such as people and equipment), and room size and quality of air distribution. It is generally best to use historic data to establish airflows, which is usually done with significant input from the owner based on past experience or preference. There is nothing sacred about an air change rate as long as minimum airflow rates required by code are maintained. The goal is to achieve desired particulate cleanliness levels and stay at or above a 20 air changes/h minimum.
|Class||ACH||% HEPA Coverage||Air Velocity (FPM)|
|100,000||24 -50||10 – 20%||5 -10|
|10,000||50 – 100||20 – 40%||10 – 20|
|1,000||150 – 200||40 – 60%||25 – 35|
|100||270-330||80 -100%||70 – 110|
Estimation of air change rate:- Most pharmaceutical cleanrooms depend on the principle of dilution to control their particles. The air-change rate leads to dilution of space. Simply put, the dilution rate in terms of air change rate per hour is given by following equation, assuming no infiltration as the room is pressurized:
v = g / (x – s)
- s is the supply air particulate concentration in particles per ft
- v is the supply air volume flow rate in terms of air-change rate per hour
- g is the internal generation rate in particles per ft3 per hour
- x is room or return air concentration in particles per ft3
Of course, in the case that internal generation is significantly higher, more air changes would be required. It is important to note that high air change rate (ACR) equate to higher airflows and more energy use. In most cleanrooms, human occupants are the primary source of contamination. Once a cleanroom is vacated, lower air changes per hour to maintain cleanliness are possible allowing for setback of the air handling systems. Variable speed drives (VSD) should be used on all recirculation air systems allowing for air flow adjustments to optimize airflow or account for filter loading. Where VSD are not already present, they can be added and provide excellent payback if coupled with modest turndowns. The benefits of optimized airflow rates are:
- 1) Reduced Capital Costs:- Lower air change rates result in smaller fans, which reduce both the initial investment and construction cost. A 20 percent decrease in ACR will enable close to a 50 percent reduction in fan size.
- 2) Reduced Energy Consumption:- The energy savings opportunities are comparable to the potential fan size reductions. According to the fan affinity laws, the fan power is proportional to the cube of air changes rates or airflow. A reduction in the air change rate by 30% results in a power reduction of approximately 66%. A 50 percent reduction in flow will result in a reduction of power by approximately a factor of eight or 87.5 percent.
Designing a flexible system with variable air flow can achieve the objectives of optimized airflow rates. Existing systems should be adjusted to run at the lower end of the recommend ACR range through careful monitoring of impact on the cleanroom processes.
PRESSURIZATION:- Pressurization prevents the infiltration from adjacent spaces. Pressurization of clean areas is required to keep products from being contaminated by particulate and/or to protect people from contact with harmful substances by physical means or inhalation. This can be easily accomplished by supplying more air than the cumulative of what is returned, exhausted or leaked from the room.
Standard 209E specifies that the minimum positive pressure between the cleanroom and any adjacent area with lower cleanliness requirements should be 0.05 in. w.g with all entryways closed. During facility operation as doors are opened, the design differential is greatly reduced, but air must continue to flow from the higher to lower pressure space, even though at a reduced flow rate. To maintain a differential of 0.05 in water, a velocity of approximately 900 ft/min (4.7 m/s) should be maintained through all openings or leaks in the room, such as cracks around door openings. In theory the actual required velocity is less, but in actual practice it is prudent to use 900 ft/min. [Note that one-inch water gauge pressure is approximately equivalent to wind velocity of 4000 feet per minute].
The amount of air being returned has a bearing on room pressurization and will depend on the process taking place within the clean space. For a space requiring positive pressurization, the return air volume is typically 15% less than the total supply air volume. 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. Of particular importance is exhaust air from equipment and hoods that may be on or off at different times during occupied periods. These variations must be dynamically compensated for to maintain room pressurization. To maintain the required balance, numerous systems are employed using manual and automatic dampers, constant and variable volume air control boxes, and elaborate airflow sensing devices. These components are combined with control systems and sensing devices to ensure that the room pressurization is maintained.
The pressure gradients are monitored with ‘U’ tube manometers or magnahelic gauges. Alarm and warning systems may also be provided when the pressure gradients are disturbed.
- Pressure Gradient: – There should be a net airflow from aseptic rooms to the non-aseptic areas. This is possible only if there is pressure gradient between two adjacent rooms. Air always flow from high pressure to low pressure region. Pressure between two rooms is differential pressure “DP”
With reasonably good building construction and airtight doors and windows, it is normally possible to achieve and maintain the following pressures between various zones.
|Atmosphere Change Rooms Non-aseptic areas||0 Pa 25 Pa 25 Pa|
|Cooling corridors Access corridors Manufacture Laboratory Filling Rooms Change rooms||45 Pa 35 Pa 55 Pa 55 Pa 25 Pa|
[10 Pa = 1 mm w.g. = 0.04-inch w.g.]
Where major demarcations of pressure are required, air locks are used. These are small rooms with controlled airflows acting as barriers between spaces. It minimizes the volume of contaminated air that is introduced into the cleaner room when its door is opened…remember, with ZERO pressure differential and on open door, the entire volume of the dirtier room can eventually find its way to the cleaner room. It is important that
- Doors open/close FAST (to minimize time of contamination). Both airlock doors should not be opened simultaneously.
- High air changes (high airflow or small volume room) to permit faster “recovery”.
- People use smaller airlock (faster recovery time = less time to wait in airlock)
The pressure differential exerts a force on the door. If the force is too great (0.15 in water/36 Pa), the door may not close fully or may be difficult to open. This is particularly important in large complex facilities where many levels of pressurization may be required. Many facilities now use sliding doors, and it is essential that the seals be carefully designed to allow minimum leakage and proper containment or pressurization.
Alarms that sound to indicate loss of pressurization are valuable features and essential in the HVAC design of critical areas.
BASIC HVAC SYSTEMS: –
- Once –thru Air – Air is conditioned, enters the space and is discarded
- Recirculated Air – Air is conditioned, enters the space and portion is reconditioned. Some may be discarded.
Once – Thru HVAC
- Fresh air – lots of it
- Can handle hazardous materials, although will need to clean up air leaving the space
- Exhaust duct is usually easy to route as high velocity = smaller diameter
- Expensive to operate, especially when cooling and heating
- Filter loading very high = frequent replacement
- Potential need for dust collection/scrubbers/cleanouts
- Labs with hoods, potential hazards
- Bulk Pharmaceutical Chemical (API) plants handling flammable materials
- Oral Solid Dosage (OSD) plants where potent products/materials exposed
- Where high potential of product cross-contamination – segregation
- Some bio API facilities with exposed potent materials
Recirculated HVAC: – In pharmaceutical facilities large quantities of air may be required to promote unidirectional flow and air cleanliness. This is particularly true in a class 100 space. In many cases the large quantities of air exceed the requirements for cooling, so it is desirable and possible to recirculate air within the space and only pass enough air through the air handling unit to perform the heating or cooling.
- Usually less air filter loading = lower filter maintenance and energy cost
- Opportunity for better air filtration
- Less challenge to HVAC = better control of parameters (T, RH, etc)
- Less throw-away air = lower cooling/heating cost
- Return air ductwork routing to air handler may complicate above ceiling
- Chance of cross contamination = requires adequate supply air filtration (a sometimes return air filtration)
- Classified spaces such as sterile manufacture (few airborne materials, very clean return air)
- Finished oral solid dosage (OSD) manufacture where product is not airborne with other products in the facility
- Final bulk APIs, usually with dedicated air handler for each room.
Constant Volume Systems: – The most reliable system for pharmaceutical manufacturing areas is constant volume system with terminal reheat (CVRH). This is because; ensuring constant pressure gradient between the adjacent areas is of prime importance. In a terminal reheat system the air leaving the cooling coil is set at a fixed temperature, and the terminal reheat responds to a space thermostat, turning on heat to satisfy the load. This can waste energy, since air is cooled and then reheated. Many energy codes prohibit this practice for comfort applications, however, where close control of temperature and humidity is required for process areas the energy conservation requirement is waived. The advantages of reheat systems are that humidity is always controlled (since dehumidification always takes place at the cooling coil) and each space or zone that needs temperature control can easily be accommodated by adding a reheat coil and thermostat. Another advantage of the CVRH system is that airflow is constant, which makes balancing and pressurization easier to main maintain. A reheat system is probably the simplest and easiest of all systems to understand and maintain.
Variable Air Volume Systems: – A variable air volume (VAV) system is generally used in administrative areas and some storage spaces where pressure control is not critical, humidity control is not essential, and some variations in space temperature can be tolerated. The VAV system works by delivering a constant temperature air supply to spaces with reductions in airflow as cooling loads diminish. This eliminates the energy used for reheat and saves fan energy, because the total amount of air moved is reduced. Some form of perimeter heating must be supplied for spaces with exterior walls or large roof heat losses. The perimeter heating can be baseboard radiation or some form of air heating using heating coils. Finned radiation or convection heating devices should not be used in clean spaces, since they are not easily cleaned and allow places for unwanted particulate buildup. Combinations of systems can be used, especially if variable quantities of supply and exhaust air are required for fume hoods or intermittent exhausts.
HVAC EQUIPMENT SPECIFICATIONS
Air Handling Unit:- Pharmaceutical air handling systems support clean aseptic environments, so the equipment must be air-tight and epoxy coated.
Conventional air handling units consist of filters, coils, and fans in a metal casing, with an insulation liner applied to the inside of the casing. For pharmaceutical applications the unit casing must be a double skin sandwich of metal with insulation between the metal sheets to provide a smooth, cleanable interior surface that does not foster the growth of organisms.
Units should contain good access doors, view ports, electrical convenience outlets, and interior lighting for maintenance. The casings should be tightly sealed and designed for pressures that are higher than commercial applications due to the generally high system air pressures required for pharmaceutical applications. All sealants and lubricants exposed to the airstream should be food grade to minimize the chance of air contamination.
Chilled water or propylene glycol solutions are generally used for cooling and dehumidification. Direct expansion refrigerant, in which the refrigerant is in the air unit coil, may be used, but these systems are less reliable than chilled water or glycol and are more difficult to control in the narrow air temperature ranges required.
Units designated as draw-through have the coils on the suction side of the fan. Blow-through units have the coils on the discharge side of the fan and have the advantage of a filter downstream of the coils, reducing potential contamination of the supply duct system. On blow through units an air distribution plate must be installed to properly distribute air evenly over the filter and coils.
While selecting the fan, it should be ensured that at the lower speed the fan does not operate in the un-balanced region. Fans should be provided with a shaft seal near the bearings.
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 pre-filters, 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. 100% intake damper is especially useful during “DE fumigation” operation discussed later in the course.
AIR HANDLING UNIT LOCATION:- To avoid cross contamination independent air handling systems should be provided for various discrete operations like manufacturing, coating, tableting, inspection and packing. In some departments there is further segregation of operations which requires a certain degree of control, if not an altogether independent air handling unit.
Air handling systems should be located on a separate equipment floor or zone in order to facilitate service and maintenance without disturbance to the sterile room. They should also be located as close as possible to the main rooms they are serving to minimize larger and longer duct runs.
Location of outdoor air-inlet louvers must be carefully considered. Intakes should be located on the building sidewall high off the ground to minimize dust intake. Intakes should also be away from truck docks or parking lots, where undesirable fumes and particulate are generated. In locating inlets, the prevailing winds should also be considered, and any nearby exhausts or fume concentrations should be avoided to prevent recirculation of exhaust air back into the supply system.
- Exhaust Fans Location: – Building exhausts are generally collected and ducted to exhaust fans in groups or clusters. Exhaust fans should be located as near to the building discharge as possible since this keeps the duct under a negative pressure and any leaks will be into the duct, and not contaminated air from the duct into an occupied space or mechanical room. For this reason, roof locations of fans are preferred, even though this may make service difficult in severe weather conditions. When fans are located in mechanical rooms or interstitial spaces, it is essential to tightly seal the discharge duct before it exits the building in a roof vent or wall louver. Roof penetrations should be kept to a minimum to prevent leaks. Fumes and toxic exhausts should be extended through the roof and terminated well above the roof line in a suitable stack head. Extremely toxic or dangerous active biological agents may require HEPA filtration or other treatment, such as incineration, before exhaust to the atmosphere.
- Return Fans: – Return fans are recommended on systems with long duct returns where pressure drops greater than 0.5 in water (120 Pa) are expected. This allows proper total system balance and minimizes suction pressure required from the supply fan. If a return fan is not used, the capacity of the supply fan can be overextended and it may be difficult to limit and properly control the amount of outside air being admitted to the unit. Outside air fluctuations are also more susceptible to exterior wind conditions. Return fans are also needed when required to provide a negative pressure in rooms that require containment. Return fans can be of standard centrifugal type or an in-line type, which works nicely for installation directly into return ducts in crowded equipment rooms. Return fans may also be required to handle varying quantities of air or provide a constant flow of air at varying pressure conditions. To achieve these conditions some, form of damper control, inlet vane, or variable frequency drive motor control is generally used.
- Redundancy: – If return or exhaust fans are used as part of maintaining containment, it may be desirable to have a backup fan or redundant system. This is essential, if loss of containment can be harmful to humans or would result in an expensive loss of product. Airflow switches, which give a warning in case of fan system failures, are also desirable options for critical systems. The airflow sensing method to prove flow is preferred to an electrical motor indication since the motor could be running with a broken fan belt and the operator would not know that the fan is not moving air.
- Dehumidifiers: – Dehumidifiers are used to control relative humidity (RH) to lower levels. RH of 50±5% can be achieved by cooling the air to the appropriate dewpoint temperature. When chilled water is supplied at 42–44°F to the cooling coils, a minimum dew point of about 50–52°F can be obtained. This results in a minimum room relative humidity of approximately 50% at 70°. Spaces with high moisture content, it is important to use a cooling coil that is deeper i.e. with higher number of rows. Sometimes additional brine cooling coil is incorporated to further dehumidify the supply air. This will lead to lowering of supply air temperatures downstream the cooling coil, which is reheated by hot water coil or electrical strip heaters before dumped into the space. In some cases where hygroscopic (products sensitive to moisture) materials are handled, the room RH requirement may be as low as 30 to 35% and may require the use of chemical dehumidifiers. Chemical dehumidifiers are commercially available air handling units that contain a sorbent material (desiccant) that can be a solid or liquid. Wet dehumidifiers use absorbents that change physically during the process. Lithium salt solutions are generally used to remove moisture from conditioned air and are then regenerated by heat, usually using a steam heat exchanger. Dry dehumidifiers use adsorbents that do not experience phase changes during the process. Silica gel and activated alumna are generally used. A rotating wheel is commonly used to remove moisture from the conditioned air. The wheel is regenerated by passing heated outdoor air over the wheel to dry it out. Steam or electric coils are usually employed for regeneration. Depending on the amount of dehumidification required and the amount of outdoor air (usually with a high moisture content), it may be best to combine the dehumidifier with a conventional air handling unit and only dehumidify a small portion of the air or just the outdoor air. The dehumidifier has a high initial cost compared with a conventional air handling unit. The size should be optimized to do only the required duty with an appropriate safety factor. Knowledgeable vendors in this specialized area should be consulted to find the best combination of dehumidification equipment, system arrangement, and control for the application. These systems also require considerable physical space, energy consumption, and service—important criteria to be considered in system selection.
- Humidifiers: – In drier locations, makeup air may require the addition of moisture for RH control. There are many commercially available humidifiers, but the most commonly used is “steam grid” humidifier. These are controlled by modulation of a steam valve at the humidifier, and include a chamber to prevent condensation and water droplets in the duct. The valve is controlled by a signal located in the return or exhaust airstream or in a room humidistat. A high-limit stat is placed in the duct downstream of the humidifier to override the controlling stat and prevent condensation in the duct. Placement of the humidifier in the duct is critical and must follow the manufacturer’s recommendations to prevent condensation and provide proper dispersion space. It is important to use clean steam, not plant steam, which may contain boiler chemicals and impurities from deteriorating piping and equipment.
DOCUMENTATION: – Good manufacturing practices govern the level of control of various parameters for quality assurance, regulating the acceptance criteria, validation of the facility, and documentation for operation and maintenance. The documentation should cover design, operation and performance qualifications of the system.
- Design Qualification: – The design qualification document should cover all the following issues:
- Identification of various systems, their functions, schematics & flow diagrams, sensors, dampers valves etc., critical parameters & fail-safe positions.
- Layout plans showing various rooms & spaces and the critical parameters like:
- Room temperature
- room humidity
- Room pressures and differential pressures between room and room and passages
- Process equipment locations and power inputs
- Critical instruments, recorders and alarms, if any
- Equipment performance and acceptance criteria for fans, filters, cooling coils, heating coils, motors & drives.
- Duct & pipe layouts showing air inlets, outlets air quantities, water flows and pressures.
- Control schematics and control procedures.
- Operation Qualification: – This is a commissioning documentation which shall provide all the details of equipment various points of performance, test readings, statement of compliance and noncompliance with the acceptance criteria. Broadly the features are as follows:
- Installation date showing manufacturers, model no., ratings of all equipment such as fans, motors, cooling & reheat coils, filters, HEPA filters, controls etc.
- As-built drawings showing equipment layouts, duct and pipe runs, control & fire dampers, settings of various sensors and controllers.
- Contractor’s rest readings covering rotation tests, megger readings, air quantities, temperatures and RH pressures of each space, dry & wet run of controls, air and water balance, HEPA filter integrity tests at final operating velocities testing of limits & alarms.
- Identification of items spaces, parameters not meeting the acceptance criteria but cannot be corrected.
- Performance Qualification: – This is essentially for the system operating under full production conditions and covers among others:
- Identification of agency for commissioning, for equipment and instruments and their calibration.
- Test readings of all critical parameters under full operating conditions and full production, modification of readings in the contractors’ test results, acceptable and unacceptable departures from design qualification and acceptance criteria.
SUMMARY:- HVAC systems in manufacturing portions of facilities are closely supervised by the FDA and must meet other global current good manufacturing practices (cGMP’s). Per US GMP, Design and Construction Features Standard (211.42), sterile area cleanrooms have the following distinct characteristics:
- Air should be of a high microbial quality.
- Air handling system is provided with a central HEPA filter bank along with mandatory terminal filters in order to extend the life of terminal filters.
- The filtration regime is generally three stages with two stages of pre-filters, 10 micron (EU 4), 3 micron (EU 8) and one central final filter 0.3 micron (EU 12) along with terminal HEPA filter.
- All sterile critical operations shall be in a laminar flow work station.
- Critical areas should have a positive pressure differential relative to adjacent LESS clean areas: a positive pressure differential of 0.05 inch of water (12.5 Pa) is acceptable.
- Supply air outlets are provided flush at the ceiling level with perforated stainless steel grilles and terminal absolute filters. Return air grilles to be provided at the floor level with a return air riser for better scavenging
- Walls, floors, and ceilings for cGMP areas are to be constructed of smooth, cleanable surfaces, impervious to sanitizing solutions and resistant to chipping, flaking, and oxidizing.
Maintaining proper pressurization gradient between adjacent spaces is important to prevent infiltration and cross-contamination. Air filtration techniques and air conditioning components shall be constantly monitored and upgraded in order to improve the finished product and reduce energy consumption.
Remember, overstating quality requirements and tolerances may result in unnecessary costs. Higher air flows and pressures require more HVAC capacity. Since most engineering decisions will have an impact on HVAC systems, it is important to recognize opportunities to seek the best engineering solutions.
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