Cleanrooms

Chapter One – What is a Cleanroom?

A cleanroom is a specially designed enclosed space where airborne particulates are minimized or eliminated using an advanced filtration system. These environments are essential for industries that need highly controlled and monitored conditions for producing delicate instruments, medical supplies, or pharmaceuticals. To be classified as a cleanroom, a space must meet specific international standards regarding the number of microns per cubic meter.

According to ISO 14644-1, a cleanroom is:

"… room within which the number concentration of airborne particles is controlled and classified, and which is designed, constructed and operated in a manner to control the introduction, generation and retention of particles inside the room. Only particle populations having cumulative distributions based on threshold (lower limit) particle sizes ranging from 0.1 µm to 5 µm are considered for classification purposes." From ISO 14644-1:2015 Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness by particle concentration. https://www.iso.org/obp/ui/#iso:std :iso:14644:-1:ed-2:v1:en

Cleanroom standards are measured in micrometers. The image above compares a hair follicle to a 90 µm particle of fine sand. For an ISO 1 cleanroom classification, the maximum allowable particulate content per cubic meter is 5 µm.

Chapter Two – Cleanroom Air Flow Systems

There are three methods used to ensure that a Cleanroom can maintain its classification.

1. Air supplied to the room is filtered by high efficiency filters, which are HEPA or ULPA, and the room is pressurized to block contaminants.
2. The materials in construction do not emit contaminants, particles, chemicals, or gases and must be easy to clean.
3. Workers, staff, and operators wear garments that minimize the spread of micro-particles and organisms from skin, hair, and clothing.

The main method for maintaining the appropriate air cleanliness level in a cleanroom is the installation of an air filtration system that adheres to the certified standards set by the International Standards Organization (ISO). There are three types of airflow systems:

• Duct Supply and Duct Return
• Duct Supply and Open Return
• Unidirectional

Below is a description of each:

Duct Supply and Duct Return

Air is ducted directly into and out of the cleanroom. This type of cleanroom is commonly used by manufacturers with stringent guidelines, such as those in the pharmaceutical industry.

Ducted Supply and Open Return

The ducted supply and open return air system is a cost-effective and efficient method of air delivery. Air is ducted directly into the cleanroom and then freely flows out into an open air plenum.

Uni-directional (also referred to as Laminar)

Unidirectional, or laminar, airflow systems direct air in a single direction. These systems maintain controlled airflow with a consistent air velocity from laminar airflow hoods that direct air downward. In most cleanrooms, the downward airflow prevents particulates from settling on surfaces by pushing them out. In a laminar system, air passes through filters that capture microscopic particles.

Cleanroom Air Filters

The filtration system is the most crucial component of a cleanroom, as it maintains the required level of cleanliness. Depending on the design and ISO classification, cleanrooms can have single or multiple filters. Typically, filters are located in the ceiling, allowing air to travel downward from the ceiling to the floor and exit through ducts in the floor.

High efficiency particulate (HEPA) air filters with the capability of capturing 99.97% of dust, pollen, mold, bacteria, and airborne particles with a size of 0.3 μ are standard air filters for cleanrooms and come in various designs to fit the needs of each type of cleanroom. They are made of interlaced fibers that have diameters that are less than 1μ with the distance between the fibers being smaller than 0.5 µ. The random placement of the fibers is disorganized, twisted, and turned to avoid forming any type of pattern.

The complexity of HEPA filters causes a pressure drop in the airflow, which must be compensated for by a fan system to maintain an even and constant flow. This aspect of the filtration process can be costly due to the power required to sustain the airflow. As dirt and debris accumulate on the filter, the pressure drop increases, as it is directly related to the HEPA filter’s airflow rate.

Pre-filters

The pre-filter removes larger particles from the air before the air reaches the HEPA or ultra-low particulate air (ULPA) filters. By removing the larger particles, pre-filters help extend the life of a HEPA or ULPA filters but must be checked regularly since they can reach their capacity rapidly.

ULPA Filters

ULPA filters are akin to HEPA filters but exhibit greater efficiency. They eliminate 99.95% of contaminants measuring 0.12 µm in diameter. The superior efficiency and quality of ULPA filters contribute to their higher cost. Available in various sizes, they offer maximum efficiency with minimal pressure drop.

HEPA Filters

HEPA filters remove 99.99% of particles sized at 0.3 µm. They are widely favored and can remain effective for several years depending on the particulate levels. HEPA filters are known for their minimal pressure drop and high airflow capacity. Below is an image of an industrial-grade HEPA filter featuring an aluminum frame.

The fibers of a HEPA filter are intricately arranged in a random pattern, as depicted in this image.

Capturing microscopic particles is challenging due to their erratic movement caused by Brownian motion, unlike larger dust particles that follow wind currents. The multiple directions of the fibers in a HEPA filter enable them to effectively capture and trap these tiny particles. Below is an image illustrating the placement of HEPA or ULPA filters in a unidirectional system.

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Chapter Three – Cleanroom Classification System

The classification of a cleanroom depends on its particulate matter (PM) concentration, which measures particles and liquids in the air per cubic meter. Typically, the air we breathe contains approximately 35 million particles per cubic meter, with an average size of 0.5 μm.

The primary classification method for cleanrooms is governed by the International Organization for Standardization (ISO), a global body that establishes international standards with representatives from various nations worldwide. ISO 14644 and ISO 14698 outline the standards for cleanrooms, as depicted in the chart below.

ISO Cleanroom Classifications

ISO 14698 defines the methodology and procedures for removing biocontaminants from cleanrooms. ISO 14644 specifies the permissible levels of particulates in a cubic meter of air and includes descriptions of macroparticles. Its latest revision in 2015 focuses specifically on particle concentration.

Cleanroom classifications range from ISO 1, which denotes extremely clean environments, to ISO 9, representing satisfactorily clean conditions comparable to normal room air. The chart below specifies the size and quantity of particles allowed per cleanroom class.

ISO Cleanroom Classifications

The United States' cleanroom classification system was governed by Federal Standard 209E, first published by the Institute of Environmental Sciences and Technology (IEST) in 1963, as shown in the chart below. The IEST system ranged from Class 1, equivalent to an ISO 3 classification, to Class 100,000, similar to an ISO 8 classification. Although some countries still adhere to the IEST system, it was officially retired in 2001 due to obsolescence.

International Classification Systems

While ISO standards have gained widespread acceptance and serve as a guide for most nations, individual countries have also developed their own classification systems. Below are descriptions of some of these systems.

EU GMP (European Union Good Manufacturing Practices)

EU GMP classifications serve as inspection methods for all stages of the production process. Inspections are conducted by experts from participating European nations to ensure public safety. The EU GMP collaborated with the United States Food and Drug Administration to establish Annex 1 as standards for cleanrooms, as illustrated in the chart below.

BS 5295 (British Standard)

BS 5295 defines ten classes of cleanliness standards, as depicted in the chart below. Each classification specifies a range of particulate counts to provide detailed definitions based on particle size. These standards were developed by the British Standards Institute (BSI), which sets codes and specifications for quality management requirements. They help companies achieve certification standards not only in Great Britain but also in other countries.

USP 800 (United States Pharmacopeial)

USP 800 comprises published standards for managing hazardous drugs (HD), implemented in December 2019. The definition of a hazardous drug was established by the National Institute for Occupational Safety and Health (NIOSH), which includes criteria such as carcinogenicity, teratogenicity, reproductive toxicity, organ toxicity, or genotoxicity. USP 800 serves as a cleanroom standard introduced by the US Pharmacopeia (USP) in 2017, updating the previous standards of USP 795 and USP 797.

USP 800 mandates negative pressure, external ventilation, and 12 air changes per hour (ACH) for drug storage areas within cleanrooms. The standards also specify that drugs cannot be received, stored, mixed, prepared, compounded, or dispensed in positive pressure environments.

USP 800 mandates negative pressure, external ventilation, and 12 air changes per hour (ACH) for drug storage areas within cleanrooms. The standards also specify that drugs cannot be received, stored, mixed, prepared, compounded, or dispensed in positive pressure environments.

Chapter Four – Cleanroom Construction

While there exist various construction methods for cleanrooms, all manufacturers must adhere to the guidelines of ISO 14644-1, ISO 14698-1, and FED STD 209E. Modular and portable cleanrooms are sometimes tailored specifically for testing facilities. When planning the construction of a cleanroom, several factors need to be considered, including:

1. Surfaces
2. Equipment
3. Air control system
4. Number of personnel
5. Lighting
6. Doors
7. Viewing panels
8. Humidity control

Each of these factors are described below:

Surfaces

Cleanroom surfaces are smooth, impermeable, and resistant to peeling, flaking, corrosion, and dust accumulation, with no areas for microorganism growth. They must facilitate easy cleaning and accessibility. In microelectronic and semiconductor cleanrooms, surfaces must be smooth to prevent potential electrostatic discharges (ESDs). Surface materials should also be resistant to shattering, denting, cracking, and creasing.

Cleanroom floors are typically made of epoxy resin or PVC. Resin floors are preferred in areas with high mechanical loads due to their exceptional resistance and strength. They are commonly used in rooms with water exposure or high humidity.

PVC floors are more economical and are laid out in tiles. They are used in low little traffic areas where there aren‘t heavy loads.

Equipment

Cleanroom equipment is made from easy-to-clean materials such as stainless steel, polycarbonate, or plastic laminates. This equipment includes a variety of items that are not fixed to the walls or floor, ranging from basic hand tools to showers and pass-throughs.

Here are several types of equipment commonly found in cleanrooms:

Air Control Systems

Cleanrooms necessitate significant airflow and often require precise control of temperature and humidity. Air handling units (AHUs) consume approximately 60% of a facility's power, with cleaner rooms consuming more power. To manage costs associated with AHUs, systems are designed to recirculate air, thereby maintaining stable temperature and humidity levels.

The air control system is crucial in cleanrooms. They typically maintain positive air pressure, causing air to exfiltrate into adjacent areas with lower pressure, and exit through outlets, light fixtures, window frames, ceiling and floor interfaces, and doors. Leakage rates generally range from 1% to 2% in most cases.

When designing a cleanroom, it's important to assess the exfiltration, which measures the amount of air that escapes from the room. In a system involving supply, return, and exhaust, there should be a 10% differential between the airflow of supply and return.

A typical exit route for air in cleanrooms is through doors. The amount of air exfiltrating through a door depends on factors such as the door size, pressure differential across the floor, and the effectiveness of the door seal. For a standard door, air exfiltration typically ranges from 190 cfm to 270 cfm.

To offset exfiltration, airflow must be balanced so that the amount exiting matches the amount entering. During the initial setup of a cleanroom, adjustments are necessary to account for exfiltration. Factors such as turbulence, eddies, equipment, and pressure impact the air exchange rate, which is critical in airflow design.

The diagram below illustrates the exfiltration and infiltration, which determine the air exchange rate in a unidirectional airflow system. In the diagram, 1 represents infiltration and 2 represents exfiltration. These factors are crucial in designing and constructing the air control system.

Number of personnel

The primary source of contamination in cleanrooms is from the people who work in them, as each person sheds approximately one billion skin cells per day. These cells measure 33 µm x 44 µm x 4 µm, and about 10% of them carry microorganisms. Given the potential for contamination from personnel, controlling their numbers is a critical consideration.

According to academic research, only trained personnel should have access to a cleanroom. Additionally, it is crucial for personnel to undergo proper training in cleanroom procedures, including wearing appropriate attire and protective gear. Studies show that a higher number of personnel correlates with increased contamination levels.

Lighting

Cleanroom lighting is tailored to meet specific environmental needs. Unlike the air control system, lighting typically accounts for only 1% of the total operating cost of a cleanroom. Due to the precision instruments used in cleanrooms, the light intensity is very high, measured in foot-candles (lumens per square foot). Each type of cleanroom has lighting specifically designed to serve its unique purposes.

Like all aspects of cleanroom design, the air control system takes precedence, making the planning of lighting demanding and requiring meticulous planning and design. Cleanrooms prioritize energy efficiency with the use of LER lamps, known for their easy maintenance and long lifespan.

Other types of lighting used in cleanrooms include incandescent, high intensity, and LED lights. UV lighting is also utilized in certain cleanrooms to provide additional control over bacteria and contaminants.

In cleanrooms, lighting fixtures are typically housed in steel enclosures with sealed holes and openings using gaskets. Ballasts and lamp holders are designed to be easily removable in order to minimize disruption to cleanroom conditions.

Below is an example of a well-lit cleanroom.

A recent advancement includes automated lighting systems equipped with passive infrared motion detectors, which help conserve energy by ensuring continuous illumination only when needed.

During the cleanroom design phase, engineers calculate the required lux level, which is the unit of illuminance needed for specific tasks. The lux level varies depending on the nature of the work to be performed. The chart below provides a concise overview of lux levels for different tasks.

Additional considerations in establishing suitable lighting include the IP rating of the enclosure and the lighting color, both of which are determined by the nature of the work being conducted. The IP rating assesses how effectively the lights are sealed against environmental contaminants.

Doors

Cleanroom doors play a critical role in sealing the room from external contaminants and preserving the controlled environment. Like every aspect of a cleanroom, doors must be meticulously designed to meet stringent standards. Below are key considerations when evaluating a cleanroom door. Firstly, like all surfaces in cleanrooms, doors must be smooth and impermeable.

• Completely flat
• Easy to integrate into any Cleanroom
• Resistant to bending and shock with a thickness of 60 mm or 2.36 in.
• Air tightness
• Resistant to strong chemicals in cleaning products
• Safety glazed glass
• Resistant to ESDs
• Swing into the room
• High quality hardware
• Able to be locked
• Closed cell non-organic core
• Seamlessly molded
• Fire resistant

Viewing Panels

Viewing panels serve the purpose of enabling operators to work more efficiently and maintain visual contact. They are strategically positioned to facilitate easy access for supervision, inspection, and to eliminate the need for supervisors to enter and perform entry protocols.

Viewing panels must be flush with both sides of the wall, shatterproof, equipped with a desiccant in the void between glass panels, and fire-resistant. In ultraviolet-lit rooms, they are coated to filter out ultraviolet wavelength.

The visual display below showcases examples of different types of viewing panels.

Low Humidity

The relative humidity (RH) in a cleanroom should ideally range between 30% and 60% to maintain a balanced environment that safeguards against excessive moisture or dryness. Balanced humidity levels help mitigate the risk of electrostatic discharge (ESD), which can damage products. Controlling humidity is also crucial for preventing bacterial growth. Two methods employed for humidity control include air conditioning and desiccants, which are substances that promote dry conditions.

Air conditioning in a cleanroom reduces the surface temperature, while desiccants absorb moisture from the air. Desiccants can lower dew points significantly, up to five times lower than an HVAC system. Below is a diagram illustrating a desiccant humidity filter.

Different Levels of Cleanrooms

The cleanliness level of a cleanroom is defined by its air quality. All cleanrooms are constructed with airtight walls, doors, windows, and exceptionally clean air. To transition from one classification to a higher one, increased airflow is required, as air plays a crucial role in removing contaminants. The cleaner the room, the higher the rate of air exchange.

Lower levels of cleanrooms such as ISO level 9 to ISO level 6, cleanliness is based on the amount of air exchanged each hour, while rooms at ISO levels 1 through 5, airflow is measure per second. Equipment and furniture can block airflow and raise a cleanroom‘s level of classification.

There are three different states in the determination of the level of a cleanroom: as built, at rest, and operational. As built refers to the cleanroom‘s performance without people, equipment, or furniture, its built state. At rest is when everything has been added before performing processes.

The level undergoes a significant upward or downward change during full operation, at which point its classification level is determined.

Chapter Five – Rules for Cleanroom Personnel

The primary challenge with cleanrooms is human presence, as people carry contaminants and microorganisms on their skin. Companies implement several measures to control the release of contaminants by personnel. The first step is enforcing the use of specially designed clothing provided by cleanroom suppliers.

The image below is of clothing for a strictly monitored Cleanroom.

The ISO class of a cleanroom dictates the type of clothing that personnel must wear. While OSHA provides guidelines for cleanrooms, it does not set standards specifically for protective clothing.

Listed below are the ISO 14664 clothing requirements for Cleanrooms.

• Hood
• Bouffant hat
• Coverall
• Inner suit worn underneath coveralls
• Boot covers
• Goggles
• Facemask
• Gloves

Cleanroom Clothing Factors

1. Must match the cleanroom‘s risk and hazard analysis.
2. Sturdy to avoid rips or tears
3. Disposable
4. Non-disposable when proper laundry is available
5. Sized to fit worker measurements
6. Delivered in individually vacuum sealed packaging and stored in a cleanroom environment

Disposable clothing is the most common option for Cleanroom clothing, which is disposed of in designated bins. The image below is of a "bunny suit" that is normally white and covers the whole body. All of the labeled items are disposable.

Rules for Cleanroom Personnel

Every company has their own set of rules for Cleanroom use. The list below is a general overview.

• Entering and exiting – thoroughly wash and dry hands. Put on protective clothing. When exiting, dispose of all clothing and wash up a second time.
• Cleaning – walls, floors, and work surfaces must be completely wiped down using SDS (Safety Data Sheet) chemicals. Also, anything that is brought in from the outside needs to be wiped down to remove potential contaminants/particles.
  
  

  

  
  
• Hygiene – personal hygiene must include a daily shower, washing of hair, brushing of teeth, and approved skin care products. Workers should also avoid wearing cosmetics.
• Clothing – personnel may be required to completely change from their street clothing prior to entering the cleanroom. Wool is often prohibited due to the static electricity that it produces.
• Work pace – personnel must move slowly at an even pace to avoid air turbulence.
• Dropped items – items dropped or have fallen on the floor, they are not to be picked up.
• Tools and supplies – are organized and stored in properly labeled containers and cabinets. In addition, items that generate particles are avoided, such as wood, paper, cartons, pencils, etc.
  
  

  

  
  

Chapter Six – Types of Cleanrooms

Several factors contribute to determining the classification of a cleanroom. Airflow is crucial as it dictates the air changes per hour (ACH) and the movement of air, which aids in effectively removing harmful particles from the environment. Additionally, the construction of the cleanroom influences the smoothness of the air exchange rate and overall performance.

Types of Cleanroom Airflow

There are two primary types of airflow used in cleanrooms: unidirectional and turbulent. Unidirectional airflow involves air entering the cleanroom through the filtration system and exiting via the venting system. Typically, the airflow direction is downward, though it can vary based on the cleanroom's design requirements.

In turbulent airflow, also known as vortex airflow, incoming air blends with the existing air within the cleanroom before exiting through wall vents, where it undergoes filtration and recycling. This type of airflow causes the air inside the cleanroom to swirl and form eddies, resulting in a non-directional pattern that collects particles.

In unidirectional or laminar airflow, air moves in a smooth, unobstructed straight line, following a parallel pattern directed horizontally downward. This process sweeps across the cleanroom, gathering contaminants in its flow with a parabolic velocity profile. Laminar airflow hoods direct air jets that move downwards to maintain this controlled flow.

Cleanroom Construction

The term "cleanroom" is a broad term encompassing a variety of designs, configurations, and concepts, ranging from small, portable soft-walled rooms to large-scale production cleanrooms. Despite the diversity in construction types, all cleanrooms must adhere to ISO standards.

Modular Cleanrooms

Hardwall modular cleanrooms feature aluminum supports and rigid walls designed to withstand increased air pressure. The solid walls, typically three inches thick, are constructed from various materials coated with a plastic resin for easy cleaning. These modular cleanrooms are portable, with hard walls that can be disassembled and repositioned as needed.

Softwall

Softwall cleanrooms have walls made of vinyl or other plastic materials. They are small and portable, capable of being positioned close to assembly operations and manufacturing processes. Softwall cleanrooms are an inexpensive method for providing a controlled environment and have ISO ratings of 5 and above. Like modular cleanrooms, softwall cleanrooms have an aluminum or coated steel frame with all of the components of larger cleanrooms in smaller sizes.

Powder Containment

Powder containment cleanrooms serve as a safety measure to shield workers from hazardous and harmful substances. Specifically designed for tasks like weighing, capsule filling, and compounding creams, these cleanrooms ensure effective containment and filtration of hazardous powders, dust, and fumes. They are equipped with specialized airflow and filtration systems, including a recirculation system that continuously cleans particles from the air.

Explosion Proof

All cleanrooms are engineered to be explosion-proof, serving as sealed and self-contained environments. Industries handling volatile substances incorporate additional features to enhance worker safety. Explosion-proof cleanrooms include specialized ceiling components, control panels, and wall panels, along with non-sparking lighting and static dissipative PVC materials to mitigate electrostatic discharge (ESD) risks.

The frames of explosion proof cleanrooms are made of extra strength powder coated steel.

Fire Resistance

Fire resistance is a standard feature in all cleanrooms, as their walls are designed to be chemical, thermal, and fire resistant. To qualify as fire resistant, cleanroom walls must meet ASTM E 84 Class A smoke and fire rating standards, as well as ISO classifications 2 to 9 requirements.

For fire resistance, typical wall construction often incorporates an outer layer of gypsum over a polyurethane core, with surfaces made of vinyl, steel, or aluminum. Gypsum provides the necessary fire resistance, while the surfaces are designed for easy cleaning.

BioSafe Cleanroom

Biosafe cleanrooms are specifically designed for aseptic processes and comply with ISO standards ranging from ISO 4 to ISO 8. These cleanrooms typically feature walls made of stainless steel or powder-coated steel, ensuring ease of cleaning. Like other cleanroom types, biosafe cleanrooms incorporate interlocking panels to withstand vibration and prevent instability.

Most cleanrooms, including biosafe cleanrooms, utilize air supply systems equipped with HEPA filtration, similar to those used in other cleanroom types. Biosafe cleanrooms typically feature a unidirectional airflow pattern in most cases.

Conclusion

• Cleanrooms are specially designed enclosures that are designed to eliminate contaminants and microorganisms.
• The purity of the air in a cleanroom is determined by the number of µm particles there are in one cubic meter of air.
• There are several classifications used to identify a cleanroom. The International Organization of Standardization (ISO) is the most widely accepted.
• There are strict guidelines for clothing worn by workers in a cleanroom.
• The most important component in a cleanroom is its air exchange unit.
• Airflow in a clean room can be unidirectional or turbulent.
• The two construction designs of cleanrooms are modular and permanent or stick.

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