To know about Clean Rooms and their classification, please read the previous article. Let us proceed with the design aspects of the HVAC (Heating Ventilation Air Conditioning) system for pharmaceutical industries.
As per cGMP (current Good Manufacturing Practices), a quality approach is required for manufacturing systems that avoid contamination. HVAC controls the outputs of clean rooms like Temperature, Relative Humidity, Differential Pressures, and Air Flow parameters. Therefore, cGMP for HVAC systems must address the MOC selection, Equipment Cascading, and Personnel and Process movements.
Purpose of HVAC
Two kinds of HVAC system exist;
- Once-Through (air used in clean room and discarded thereafter)
- Recirculated (it uses air, some part discarded and some part re-processed and re-used)
Each of the above two types has their pros and cons tabulated below.
HVAC systems can control various things in an environment including temperature, relative humidity, pressure, airflow, and air quality. We’ll see one by one. The below diagram represents a general scheme for HVAC system.
Differential Pressure (∆P) Across The Areas
Differential pressure means two areas next to each other have different pressures maintained in them. One area would have more pressure than other. The area which comes closer to clean room or itself a clean room must be kept in positive pressure than the adjacent area. This ensures that even if the air-borne particles are present in the adjacent area, they can’t enter the clean room as air flows from the higher pressure area towards the lower pressure area. Air travels through the doors across the areas. Anyway, we’ll see this further.
Relative Humidity (RH)
The most critical part of the HVAC system, Relative Humidity. If this parameter is not controlled, it has the potential to directly affect the drug quality in terms of stability and efficacy. HVAC systems can control RH with the help of suitable dehumidifiers. The term RH differs from Humidity. The actual amount of water vapor present in the air is called Absolute Humidity. While the ratio of the actual amount of water vapor present in the air to the MAXIMUM amount of water vapor the air can hold at that temperature is called Relative Humidity.
Absolute Humidity is not practiced commercially as it does not indicate the point of air saturation with moisture. Whereas, Relative Humidity serves that. Details provided further for better understanding.
Temperature is a comfortable parameter to deal with while manufacturing. It is both, a matter of comfort and a factor that avoids the growth of micro-organisms on working personnel or surroundings.
Apart from mentioned above, HVAC also controls air-borne particles including dust and micro-organisms with the help of HEPA or ULPA filters as we’ve seen in Clean Room and Classification. Before moving on, it is important to know about particulates, which determine the contamination level and its acceptance.
Particulates or Air Borne Particles
Solids present in the air called Particulates or Air-borne particles. They are very minute and required to define in microns. Sometimes, these particulates also termed as Contaminant or Bacteria based on their structure and biology. Two potential sources of contamination for clean rooms mainly classified as External and Internal sources.
Further, there are two types of areas in clean rooms namely,
- Controlled Area (non-sterile application)
- Critical Controlled Area (sterile or aseptic application)
FDA recommends certain parameters that would help to build a quality environment for the clean rooms. Prior to that, one concept you would encounter is Air Changes Per Hour (ACPH). Let us see what it means.
Air Changes Per Hour (ACPH)
It is the “Number of times when the total air volume in the room completely removes and replaces in one hour“. Therefore, when we remove the air from a room completely once in 60 minutes and replace it with other air, would mean 1 ACPH has happened.
Let us see the different FDA recommendations for controlled area and critical area.
|FDA Recommendation||Controlled Area||Critical Area|
|Particle count per cubic feet for 0.5µ or higher particle size exposed during activity||≤ 100,000||≤ 100|
|Bio-burden in CFU (Colony Forming Units) per cubic feet||≤ 2.5||≤ 0.1|
|Air Changes Per Hour (ACPH)||20||Laminar Air Flow: 90 feet/min|
|Differential Pressure in Inch of water column with closed doors||0.05||0.05|
Again, there are two types of configurations to design the clean rooms based on the pattern of airflow pattern inside the room.
Multi-directional Air Flow Pattern
In this, turbulent air conditions are developed and this turbulent air typically capable of protecting the atmosphere from external contaminants. This kind of flow pattern, therefore, most commonly seen in Class 10,000 and Class 100,000 where chances of external contamination are high. Outlined below is a schematic of a multi-directional airflow pattern.
Uni-directional Air Flow
This pattern used for low internal contaminants requirement. The flow of air streams in parallel and single direction is known as uni-directional or laminar airflow with 15 to 20 degrees of deviations.
The parallel direction of airflow occurs either vertically or horizontally based on the application. In the vertical arrangement, air introduced from the top ceiling and returned through walls at the bottom which ensures the airflow pattern is the downside. In the horizontal arrangement, air introduced from one side of the wall and returns through another side which ensures horizontal airflow.
First one i.e. vertical arrangement produces optimum results and therefore considered frequently.
Design Aspects for HVAC System
Before briefing on the design aspects for HVAC, refer below the flow chart showing different activities involved during the design of the HVAC system.
Moving ahead, various factors that contribute the efficiency of HVAC enlisted below.
- Specified HVAC requirements, including room and system itself. Room includes Temperature, Relative Humidity, Clean Room classification, differential pressure, etc.
- Air Flow Pattern
- Design of ducting
- Building and construction layout
- Heat load
- Location of filtration assembly installation
- Commissioning of the HVAC system
- Qualification and Validation documentation
- Releasing the system for commercial application.
Let us elaborate each term sequentially below.
HVAC Specification Requirements
Parameters described below involves requirements or specifications that ensure the HVAC system delivers the quality air in terms of safety and efficacy of healthcare products.
Concerned with comfort for Personnel, Process, and Equipment, clean rooms designed to provide temperatures ranging from 21 to 25°C with a setpoint of 23°C. Sometimes, lower temperature set points preferred when personnel carrying out manufacturing operations with heavy gowns which results in sweat and less comfort.
Relative Humidity (RH)
Relative Humidity of Not More Than (NMT) 55 ± 5% preferred in almost every healthcare industry. However, this much of RH may trouble the areas that handle operations related to hygroscopic powders (moisture-loving). In that case, RH should be reduced to 30 ± 5%. It is recommended to have RH control through proper automation. This helps facilities to work relentlessly without interruptions due to breakdown. If RH not maintained at the specifications can lead to several impacts, including
- Rapid microbial growth
- Metal corrosion
- Personal dis-comfort
- Promoting static charge development
Clean Room Classification
An equally important parameter, the number of contaminants in the air is of prime importance while designing HVAC systems. Different FDA recommendations for the classification of clean room detailed in the table earlier. Now let us see below the summary of different standards and their requirements.
Differential Pressure (∆P)
As discussed earlier, for the differential pressure across two areas, one which is more cleaner holds more pressure than another area. This prevents the migration of particles from the less clean area to a more clean area, as air always travels from high pressure to the low-pressure region. In the same way, like clean rooms, differential pressure also plays an important role in maintaining areas in the required condition. Different recommendations for differential pressures for sterile and non-sterile applications outlined below. Note that, these are recommended values and not requirements. Hence, to be considered as guidance and not as standard.
Inch of Water Gauge or Inch of Water Column: It is the Pressure exerted by a Column of Water having 1-inch height. To maintain the pressure in the room, various devices used which include automatic dampers, air control boxes, pressure sensing devices (magnetic), and pressure monitoring chart recorders. Control systems include alarms and warning indicators for personnel’s attention.
For a major difference in pressure between two areas present, the airlock concept used. Small rooms are introduced creating a barrier between two areas. This means only one door of the airlock room can open at a time, ensuring lower volumes of air transfer. Therefore, doors must open or close as quickly as possible with higher air changes in airlock rooms. That assures less waiting period for the personnel inside the airlock, ultimately reduced movement. To achieve a 0.05-inch water pressure differential across the door, an airflow of 220 CFM roughly through the openings required.
A room that requires positive pressure, the return air volume considered 85% of the total supplied air volume. Note 10 Pa = 1 mmWC = 0.4 inchWG.
Heat Load or Cooling Load
Once the clean room requirements are clearly defined, next step involves cooling load calculations.
Two types of cooling load:
1. Sensible Load
2. Latent Load
Therefore, Total Load = Sensible Load + Latent Load
Number of factors accountable for the same listed below. Heat is liberated or transferred from:
- Lighting systems
- Walls and floors
- Atmospheric air entering Air Handling Units
- Recirculating fans
- Facility construction tightness
These factors cause sensible heat dissipation on a low scale. Therefore, the parameters like temperature and relative humidity maintained to overcome heat loss or gains. Once the heat calculations performed, the next step involves airflow pattern study.
Air Flow Pattern
Class 100 and cleaner areas require laminar airflow. Airflow pattern, as mentioned earlier, preferred from top to bottom. Laminar air is supplied from the HEPA filter installed at the top-side while risers installed at the bottom-side take back the air to the HVAC inlet for re-processing and/or exhaust.
For Class 10,000 and above, airflow is turbulent and may create chunks of microbes in stagnant air pockets because the air being turbulent, does not have proper direction and speed. This creates dead spaces inside the clean room termed as the stagnant air pockets. This becomes an ideal space for micro-organisms to grow.
Air Flow Recommendations
Air flow pattern and differential pressure fixed and maintained with following measures in place;
- Recommended air velocity of 0.3 to 0.45 m/s for Grade A or Class 100 clean rooms.
- Bubble tight dampers in supply and return ducts, which ensures decontamination.
- For some areas which have Class 1000 and Class 100 in the same room, it must use local isolation techniques available in the market with pressure calculations.
- Laminar airflow in Class 100 area with complete coverage of HEPA filters for retention of the microbial entrance. For areas other than Class 100, HEPA coverage drops gradually.
- Class 1000 and above to have an air supply from the top and return from the bottom so that the systematic airflow pattern follows despite turbulent airflow.
- As the Class 100 areas follow the lower class in the background, the volume of air entering must be higher to ensure positive pressure inside the area.
- Return line location includes the lower downside of the wall and closes to the floor. The surface area for the return line must allow more suction of particles to ensure continuous cleanliness. Hence dead air zone areas or immediate door openings of lower-class therefore avoided for installing return grills. These can cause air contamination.
Air Changes and Flow Rates
Hope you read the definition of air changes per hour (ACPH) earlier in this article. Let’s understand how airflow is measured. Unit for Airflow rate is CFM – Cubic Feet per Minute
Air Flow-rate = [Air Changes (per minute) x Volume of Room (cubic feet)] / 60
This part becomes slightly tricky as regulatory guidelines don’t provide either solid recommendations or requirements for Grade A or Class 100 and subsequent areas. Rather ISO provides a wide range mentioned below.
In addition, normally practiced air change rates for aseptic and non-aseptic areas are…
Air Change Rate Calculation
Consider a clean room of Class 100 generating nearly 50 particles per CFM with 99.9% HEPA. Then, the air change rate calculated as:
V = g / (a-b)
V = No. of Air Change Per Hour
g = rate of particle generation per cubic ft per hour
a = return air particulate concentration per cubic ft
b = supply air particulate concentration per cubic ft
g = (50*60) cubic ft per hour
a = 100
b = 10 because HEPA efficiency is 99.9% i.e. (100-99.9)*100 = 10
Therefore, V = (50*60) / (100-10) = 33 ACPH
Implies that ACPH is in direct proportion to the rate of particle generation internally.
Air flow adjustment required in two cases:
- When operating personnel present inside the room pose more chances of contamination
- When the room is idle, and no activities are being performed.
For the 1st case, higher airflow required to maintain cleanliness, and the opposite for the 2nd case. Using a steady airflow mechanism would waste the energy in 2nd case. Hence pumps with variable frequency drive (VFD) are recommended to supply air allowing dynamic conditions as required.
Installation of Filters
When it comes to HVAC design, disregarding the filters can cross-contaminate the air, especially while dealing with finely powdered operations (< 2.5-micron size) such as tablet manufacturing. Also, we can not deny the fact that particle sizes over 2.5 microns also play a role in contaminating the facility.
Therefore, filter selection and sizing become a crucial aspect. A common practice in HVAC design involves the installation of HEPA filters which have 99.97% retention efficiency for a particle size range of 0.25 to 0.3μ. The percentage of particles crossing through such filters is only 0.03%. This means, for example, if return line air contains 10,000 particles per cubic ft or m; when passed through the HEPA filter, only 3 particles are able to cross the filter and enter the room (=10,000*0.0003).
ULPA filters have 99.9997% retention efficiency for the particle size of 0.10 to 0.12μ. Because of such minute and fine efficiency, they’re recommended for Class 10 areas and rarely applied in pharmaceutical industries.
More commonly, flange type HEPA filters used in pharmaceutical industries as they’re ideal for false ceiling mounting. Below the filters, aluminum or SS type of grills installed with an epoxy coating for easy cleaning and avoiding microbial growth downstream of HEPA filter.
Prior to HEPA filters, pre-filters used to restrict big size particles and reduce the load on HEPA filter and increase their life. Pre-filter includes bag type filter of 10″ size.
Testing Filter Performance
The American Society of Heating, Refrigerating, and Air Conditioning Engineers (ASHRAE) developed standards 52.1-1992 and 52.2-1999. These standards classify filters in terms of “Arrestance” and “Efficiency”.
The ability of a filter to capture dust and remove large-sized particles termed Arrestance. Arrestance expressed as;
μa = 1 – Ca / Cb
μa – dust arrestance
Ca – Concentration of dust after filter
Cb – Concentration of dust before the filter
Evaluation of the filter’s ability to remove fine particles from air samples by upstream and downstream measurement of the particle concentration is called Efficiency.
Minimum Efficiency Reporting Value (MERV)
Measurement of filtration efficiency for different particle size range and rated as MERV. This value ranges between 1 and 16. Higher the MERV value, the more the filter efficient.
HEPA Filter Integrity Testing
These filters are tested using the DOP (Di-Octyl Phthalate) method. In this test, particle counting is performed upstream and downstream of the filter using any particle measuring device. The test particles are prepared using condensation of DOP vapors having uniform 0.3μ size. Now, as you saw earlier, we mentioned HEPA filter efficiency as 99.97% with an example of 10,000 particles upstream. In that case, downstream particle count should not exceed 3 to serve the said efficiency.
Air Volume Systems
Basically, there are two types of air volume control systems.
- Constant Air Volume Systems
- Variable Air Volume Systems
Constant Air Volume Systems
A constant pressure gradient between the two areas is important for pharmaceutical manufacturing areas. Wherever proper control over temperature and relative humidity required, an arrangement of heating the air right after the cooling coil is preferred. This ensures controlled humidity because of de-humidification at the cooling coils. Constant Air Volume system also controls pressure for constant airflow.
Variable Air Volume Systems
This kind of system employed in the admin section as in those areas stringency to maintain the parameters has less importance. Contrary to Constant Air systems, these systems save energy in terms of the absence of heating arrangement.
Validation of HVAC
Once the HVAC systems commissioned, qualification and validation activities begin. This documentation has a very critical aspect in terms of a regulatory requirement. We can’t use the system directly for manufacturing until we validate it. Validation provides documentary evidence that the system is designed, installed, and working as intended. Every design aspect of the system is challenged through validation. The validation engineer generally prepares the protocol step by step to cover all design aspects of HVAC. When validation begins, all the documentary evidence such as RH, Temperature Mapping, Pressure Mapping, and other controlled parameters are recorded and archived. Also, all instrumentation calibration also ensured prior to testing any parameter. A suitable approach from process validation would serve the purpose.
Different phases of HVAC validation involve Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). System clearance or hand-over is not allowed till the PQ report releases.
Remember, high airflow and pressure would cause a high capacity for HVAC systems. It is an engineer’s responsibility to provide proper engineering solutions for design and implementation. To prevent contamination or cross-contamination, suitable differential pressure values must be considered. All parts, sub-components, instruments, and control devices must be properly monitored to avoid break-down complexities. Also, a periodic validation strategy should be included in the Validation Master Plan.