World Health Organization 29 December, 2018 Supplementary Training Modules on Good Manufacturing Practice Heating, Ventilation and Air- Conditioning (HVAC) Part 3: HVAC systems and components WHO Technical Report Series, No. 961, 2011. Annex 5 Part 3: HVAC systems and components Section 7

World Health Organization 29 December, 2018 HVAC Objectives In the following slides, we will study the components of air- handling systems in order to: Become familiar with the components Know their functions Become aware of possible problems Objectives: For you, as inspectors, to be able to judge whether the air handling systems which you encounter during your factory inspections are adequate or not, it is necessary to know how such systems work, and to be aware of what problems may arise in terms of the components of the system. Therefore, the objectives of this part of module 3 are to study the components of air handling systems in order to: Become familiar with the components Know their functions Become aware of possible problems

World Health Organization 29 December, 2018 HVAC Main subsystems + Production Room Exhaust air treatment Central air handling unit Terminal air treatment at production room level Fresh air treatment (make-up air) To understand the air handling systems, it is necessary to know what their components are. A conventional Air Handling System has 4 sub-systems: 1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air. 2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed. 3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution). 4. Air exhaust system (filtration).

World Health Organization HVAC 29 December, 2018 Components Components in HVAC may include, depending on need: Filters Fans no fan failure; including supply air fans, return air fans, exhaust air fan, dust extract system fans Driers Drying of air with chemical driers, e.g. rotating desiccant wheel Frost coils for preheating air 7.1 General 7.1.1 There should be no failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan. Failure can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airfl ow reversal. 7.1.2 A schematic diagram of the airfl ow for a typical system serving a low humidity suite is represented in Fig. 23. 7.1.3 Air should be dried with a chemical drier (e.g. a rotating desiccant wheel which is continuously regenerated by means of passing hot air through one segment of the wheel). 7.1.4 The fi gure illustrates the chemical drier handling part of the fresh air/return air mixture on a by-pass fl ow. The location of the chemical drier should be considered in the design phase. Examples of appropriate locations include: — full fl ow of fresh/return air; — partial handling of fresh/return air (by-pass airfl ow); — return air only; — fresh air only; or — pre-cooled air with any of the above alternatives. 7.1.5 Possible additional components that may be required should be considered depending on the climatic conditions and locations. These may include items such as: — frost coils on fresh air inlets in very cold climates to preheat the air; — snow eliminators to prevent snow entering air inlets and blocking airfl ow; — dust eliminators on air inlets in arid and dusty locations; — moisture eliminators in humid areas with high rainfall; and — fresh air pre-cooling coils for very hot or humid climates. 7.1.6 Appropriate alarm systems should be in place to alert personnel if a critical fan fails. 7.1.7 Low-level return or exhaust air grilles are usually preferred. However, where this is not possible, a higher air change rate may be needed to achieve a specifi ed clean area classifi cation, e.g. where ceiling return air grilles are used. 7.1.1 – 7.1.6

World Health Organization HVAC 29 December, 2018 General Pharmaceutical products should be manufactured in areas of appropriate cleanliness Prevent contamination and cross-contamination Design of HVAC dependent on various factors e.g. Outside air quality Recirculation of air (or not) Products and range of products Risk assessment to determine clean room conditions. 7. 1. General   7.1.1 The required degree of air cleanliness in most OSD manufacturing facilities can normally be achieved without the use of high-efficiency particulate air (HEPA) filters, provided the air is not re-circulated or in the case of a single-product facility. Many open product zones of OSD form facilities are capable of meeting ISO 14644-1 Class 8 or Grade D, “at-rest” condition, measured against particle sizes of 0.5 ìm and 5 ìm, but cleanliness may not necessarily be classified as such by manufacturers. A risk assessment should be carried out to determine the cleanroom conditions required and the extent of validation required. 7.1.1

World Health Organization HVAC 29 December, 2018 General Two basic concepts of air delivery a re-circulation system, and a full fresh air system (100% outside air supply). Recirculation – determine the amount of fresh air based on criteria: to compensate for leakage and loss to comply with national building regulations; and for odour control. 7.1.2 There are two basic concepts of air delivery to pharmaceutical production facilities: a re-circulation system, and a full fresh air system (100% outside air supply). For recirculation systems the amount of fresh air should not be determined arbitrarily on a percentage basis, but, for example, by the following criteria: sufficient fresh air to compensate for leakage from the facility and loss through exhaust air systems; sufficient fresh air to comply with national building regulations; and sufficient fresh air for odour control.   7.1.2

World Health Organization HVAC 29 December, 2018 General Validated automated monitoring systems (e.g. Building management systems (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system) - capable of indicating any out-of-specification condition without delay e.g. by means of an alarm Also helps with preventive maintenance and trend logging Critical alarms easily identifiable, visible and/or audible Fan interlock failure matrix Fan failures can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal. 7.1.3 Where automated monitoring systems are used, these should be capable of indicating any out-of-specification condition without delay by means of an alarm or similar system. Sophisticated computer-based data monitoring systems may be installed, which can aide with planning of preventive maintenance and can also provide trend logging.   (This type of system is commonly referred to as a building management system (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system.) If these systems are used for critical decision-making, they should be validated. 7.1.4 Failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal. 7.1.5 All critical alarms should be easily identifiable and visible and/or audible to relevant personnel. 7.1.6 Appropriate alarm systems should be in place to alert personnel if a critical fan fails. A fan interlock failure matrix should be set up, such that if a fan serving a high pressure zone fails, then any fans serving surrounding lower pressure areas should automatically stop, to prevent an airflow reversal and possible cross-contamination. Depending on occupant density, between 1 and 3 ACPH will often satisfy occupancy requirements. 7.1.3 – 7.1.6.

World Health Organization HVAC 29 December, 2018 Air distribution Positioning of supply and extract grilles to provide effective room flushing. Low-level return or exhaust air grilles preferred. If not possible, a higher air change rate may be needed to achieve a specified clean area condition, e.g. where ceiling return air grilles are used. There may be alternative locations for return air 7.2. Air distribution   7.2.1 The positioning of supply and extract grilles should be such as to provide effective room flushing. Low-level return or exhaust air grilles are usually preferred. However, where this is not possible, a higher air change rate may be needed to achieve a specified clean area condition, e.g. where ceiling return air grilles are used. 7.2.2 There may be alternative locations for return air. For example, referring to the Figure Room 1 (low-level return air) and Room 2 (ceiling return air). The airflow diagram in the Figure is an example of a typical system with a lower clean area condition. 7.2.1 – 7.2.2

World Health Organization HVAC World Health Organization 29 December, 2018 The airflow schematics of the system indicates air-handling units with return air or recirculated air, having a percentage of fresh air added. Depending on product characteristics and dust loading it is sometimes preferable to fit filters on return air outlets or in return air ducting.

World Health Organization 29 December, 2018 This figure is a schematic diagram of an air-handling system serving rooms with horizontal unidirectional flow, vertical unidirectional flow and turbulent flow, for rooms 3, 4 and 5, respectively.

World Health Organization 29 December, 2018 HVAC + Production Room Exhaust air Return air (recirculated) Fresh air (make-up air) Supply air Air types There are different air types to be considered within the air handling system: Fresh air (if the plant is of the re-circulation type, it is necessary to replace some of the re-circulating air with fresh air, which is then called make-up air). A proportion of about 15% fresh air is normal, but this proportion can vary, depending on factors such as number of people, National Regulatory Authority requirements, the presence of certain substances in the air, leakage due to pressure control, etc. Supply air to the rooms Exhaust air from the rooms Return air (about 85% is being re-circulated)

World Health Organization HVAC 29 December, 2018 Recirculation systems Increased risk of contamination and cross-contamination. Need HEPA filters (EN1822 classification of H13) HEPA filters may not be required: a single product facility and there is evidence that cross-contamination would not be possible. No dust generated e.g. secondary packing HEPA filters installed in the air-handling unit or terminally placed If terminally mounted - not with flexible ducting If highly toxic processes – never recirculate 7.3. Recirculation system   7.3.1 There should be no risk of contamination or cross-contamination (including by fumes and volatiles) due to recirculation of air. 7.3.2 Depending on the airborne contaminants in the return-air system it may be acceptable to use recirculated air, provided that HEPA filters are installed in the supply air stream (or return air stream) to remove contaminants and thus prevent cross-contamination. The HEPA filters for this application should have an EN1822 classification of H13. 7.3.3 HEPA filters may not be required where the air-handling system is serving a single product facility and there is evidence that cross-contamination would not be possible. 7.3.4 Recirculation of air from areas where pharmaceutical dust is not generated such as secondary packing, may not require HEPA filters in the system. 7.3.5 HEPA filters may be located in the air-handling unit or placed terminally. Where HEPA filters are terminally mounted they should preferably not be connected to the ducting by means of flexible ducting. Due to the high air pressure required for the terminal filter, this connection should preferably be a rigid duct connection. Where flexible ducting is used, it should be as short as possible and properly fixed to withstand duct pressure. 7.3.6 Air containing dust from highly toxic processes and/or solvents or flammable vapours should never be recirculated to the HVAC system. 7.3.1 – 7.3.6

World Health Organization 29 December, 2018 HVAC Ventilation with recirculated air + make-up air Exhaust Unit This slide illustrates a typical re-circulated air setup, where a central unit distributes a mixture of fresh and re-circulated air to different production rooms. A part of the exhaust air is collected in a central duct, treated (filtered) and exhausted. The rest is re-circulated (dotted line). With control dampers, the proportions of fresh and re-circulated air can be adjusted. Central Air-Handling Unit Return air

World Health Organization HVAC 29 December, 2018 Full fresh-air systems  100% fresh air normally used in a facility dealing with toxic products or solvents, where recirculation of air with contaminants should be avoided  Degree of filtration of the exhaust air depends on the exhaust air contaminants and local environmental regulations HEPA filters in the exhaust system normally when handling hazardous materials 7.4. Full fresh-air systems   A system operating on 100% fresh air and would normally be used in a facility dealing with toxic products or solvents, where recirculation of air with contaminants should be avoided. 7.4.1 The required degree of filtration of the exhaust air depends on the exhaust air contaminants and local environmental regulations. HEPA filters in the exhaust system would normally only be required when handling hazardous materials. 7.4

World Health Organization HVAC World Health Organization 29 December, 2018 Example of air treatment in a full fresh-air system

World Health Organization 29 December, 2018 HVAC Ventilation with 100% fresh air (no air recirculation) Washer (optional) Exhaust Unit W This slide illustrates a typical 100% fresh air setup, where a central unit distributes the fresh, treated air to different production rooms. The exhaust air is collected in a central duct, treated (filtered or washed) and eliminated. The degree of exhaust air filtration will depend on contaminants in the exhaust air and also on environmental regulations. Central Air-Handling Unit Production Rooms

World Health Organization HVAC 29 December, 2018 Energy-recovery wheels Risk assessment to determine cross-contamination risks Should not become a source of possible contamination Alternatives include crossover plate heat exchangers and water- coil heat exchangers Prevent air leakage between the supply air and exhaust air exhaust air system operates at a lower pressure than the supply system. 7.4.2 Energy-recovery wheels if used in multiproduct facilities should have been subjected to a risk assessment to determine if there is any risk of cross-contamination. When such wheels are used they should not become a source of possible contamination (see Figure 25). Note: Alternatives to the energy-recovery wheels, such as crossover plate heat exchangers and water-coil heat exchangers, may be used in multiproduct facilities.   7.4.3 The potential for air leakage between the supply air and exhaust air as it passes through the wheel should be prevented. The relative pressures between supply and exhaust air systems should be such that the exhaust air system operates at a lower pressure than the supply system. 7.4.2 – 7.4.3.

World Health Organization HVAC World Health Organization 29 December, 2018 Energy-recovery wheels

World Health Organization HVAC World Health Organization 29 December, 2018 The schematic diagram of the airflow for a typical system serving a low relative humidity suite is represented here. Air can be dried with a chemical drier (e.g. a rotating desiccant wheel which is continuously regenerated by means of passing hot air through one segment of the wheel). Alternative methods of drying air are also available. The figure illustrates the chemical drier handling part of the fresh air/return air mixture on a bypass flow. The location of the chemical drier should be considered in the design phase. The practice of locating the complete chemical drier unit in the production cubicle is not recommended as this could be a source of contamination or cross-contamination. Examples of appropriate locations for the drying wheel could include: — full flow of fresh/return air; — partial handling of fresh/return air (bypass airflow); — return air only; — fresh air only; or — pre-cooled air with any of the above alternatives.

World Health Organization HVAC 29 December, 2018 Components Components in HVAC may include, depending on need: frost coils to preheat the air reheaters for humidity control, moisture eliminators automatic air volume control devices sound attenuators snow eliminators, dust eliminators, fresh air precooling coils 7.5.3 Possible additional components that may be required in air handling should be considered depending on the climatic conditions and locations. These may include items such as: — frost coils on fresh air inlets in very cold climates to preheat the air; — reheaters for humidity control — automatic air volume control devices — sound attenuators — snow eliminators to prevent snow entering air inlets and blocking airflow; — dust eliminators on air inlets in arid and dusty locations; — moisture eliminators in humid areas with high rainfall; and — fresh air precooling coils for very hot or humid climates. 7.5.3

World Health Organization 29 December, 2018 HVAC Filter Silencer Terminal filter Weather louvre Control damper Fan Flow rate controller Humidifier Heating coil Cooling coil with droplet separator Production Room Overview components + Prefilter Exhaust Air Grille Heater Another way to look at an air handling system is to consider the different components and to know their function. Some of the components, particularly the filters, are essential to ensure the quality of the air. We will later consider individual components in detail. Of course, a well-designed air handling system must not only be properly designed, but also properly installed, qualified and maintained (sealed ducts, tight filters). (The trainer should make the audience aware that this slide is just an example, and that all components may not necessarily be present in each system.) Secondary Filter Recirculated air

World Health Organization 29 December, 2018 HVAC Components (1) Weather louvre Silencer Flow rate controller Control damper To prevent insects, leaves, dirt and rain from entering To reduce noise caused by air circulation Automated adjustment of volume of air (night and day, pressure control) Fixed adjustment of volume of air A typical HVAC unit consists of a small number of elements only. It is important that these elements are compatible, properly installed, and fulfilling their goal. Whereas a weather louvre and silencer are less critical elements, the components associated with the flow rate control are essential, as they allow adjustment of the air volumes supplied to the rooms, which in turn forms the base for a pressure differential concept: to have an automated or a fixed system is largely a financial matter, but a fixed system is more difficult to set up. Silencer – check internal lining material of silencer as this can cause contamination.

World Health Organization 29 December, 2018 HVAC Components (2) Heating unit Cooling unit/ dehumidifier Humidifier Filters Ducts To heat the air to the proper temperature To cool the air to the required temperature or to remove moisture from the air To bring the air to the proper humidity, if too low To eliminate particles of predetermined dimensions and/or microorganisms To transport the air Heating and cooling units (batteries), as well as humidifiers are used to adjust the climate in the room (temperature and humidity). Special de-humidifiers, on a dessiccant base, will be addressed later. Filters are one of the main components, as they determine the size of airborne particles that pass through them, and thus the hygiene class. It is wise to protect the finer filters by pre-filters, thus extending their life cycles, and making them less prone to clogging. Ducts transport the air from the air handling units to and from the rooms. Inspectors must verify that ducts do not have internal insulation as this is a great source of contamination.

Control damper for airflow World Health Organization 29 December, 2018 HVAC Air-handling unit Control damper for airflow Humid room air Air heater Regeneration air Adsorber wheel Dry air Dampers to control pressure differentials are important. They can be automated or fixed. As filters get dirty the system pressure losses increase, and if airflow is not regulated, the flow decreases and pressure differentials change. This could cause flow reversal and cross-contamination. Variable speed drives for fan motors are also commonly used to control airflow. In some cases, it is necessary to have very dry air for galenical reasons in certain rooms (production of effervescent tablets and humidity sensitive products in general). To generate dry air, the air supplied to the production is passed over an adsorbant (silicagel, lithium chloride, etc.) where the humidity is removed from the air. The adsorbant is then re-generated, on a continuous or on a batch-wise base. AHU with fan Variable Speed Controller Filter Pressure Gauges De-humidification

Humidifier Silencer Heating and cooling units World Health Organization 29 December, 2018 HVAC Humidifier Silencer Heating and cooling units This slide shows additional elements of the air handling units. For humidification purposes, especially in clean areas, high purity water should be used, to avoid contamination. The silencer is not important from a GMP point of view, but from an environmental one, as ventilation units can be very noisy. Be sure that the silencers are manufactured of suitable materials as the linings of standard silencers can contaminate air with particulates. Depending on the local legislation, the installation of silencers can be mandatory. The cooling unit is important during the hot season. Be aware that stagnating water (condensed water) can bring bacterial growth, which can contaminate the filters, pass through them (depending on their retention properties) and end up contaminating production areas. It is essential that there is no stagnating water. Cooling coils can be sanitized as well. Do remember that, if filters are not properly maintained, micro-organisms may grow through the filters and be carried towards the production rooms.

World Health Organization 29 December, 2018 HVAC HEPA or tertiary filter Primary panel filter This slide shows Primary Panel filters, which are used mainly for lower filtration efficiency or as pre-filters Secondary filters, consisting of mini-pleated media or filter bags, and is used for higher filtration efficiency. HEPA or tertiary filters, usually being the final filter in the system, providing the highest filtration efficiency. Though there is a strong relationship between filter efficiency and cleanroom class, a filter of a high efficiency does not guarantee a high cleanroom class, as many other elements play a role, such as Air flow (how the air is extracted, how well the room is “flushed”) Air speed and number of air changes Positions of air terminals Layout and presence of objects Personnel and clothing Equipment (not all machines are designed to operate in a clean environment!) Proper installation and proper maintenance Secondary filter

Swirl Type air diffusors with terminal filters World Health Organization 29 December, 2018 HVAC 1 2 3 4 The air flows into the rooms via so-called registers (diffusors), which are built and installed in such a way that the air is distributed evenly. Machinery or furniture can block the passage of air from the register to the exhaust point, creating unflushed zones, where counts of particles and micro-organisms could be higher. It is therefore important to consider the content of a clean room, when planning the HVAC system. In many cases, the terminal filter panel and diffusors are incorporated into one unit. It is also important that the air diffuser supplies air evenly and does not induce the circulation of dust in the room – as illustrated by the next slide. Swirl Type air diffusors with terminal filters 1 Filter 2 Tightening frame 3 Register outlet 4 Screw fixation for register

World Health Organization 29 December, 2018 HVAC Problems with components Flow rate controller Control damper Humidifier Cooling battery Filters Ducts Blocked Poorly adjusted, bad pressure differential system Bad water/steam quality/ poor drainage No elimination of condensed water/ poor drainage Incorrect retention rate/damaged/badly installed Inappropriate material/internal insulator leaking Problems may arise with components, with the following consequences: Flow rate controller- Blocked- No control of pressure differentials Control damper - Poorly adjusted - Bad pressure differential systems Humidifier Bad water/ Risks of microbial contamination steam quality Cooling Unit No elimination Risks of microbial contamination of condensed water Filters Incorrect retention Risks of contamination rate (particles, micro-organisms) Damaged Filter integrity fails Badly installed Risks of contamination (particles, micro-organisms) Ducts Inappropriate material Danger of corrosion Leaking duct work Intake of unfiltered air Internal insulation Inability to properly clean