A new part of ISO 14644 – part 14 – came out last year which covers cleanroom equipment specification. Tim Sandle, BPL, looks at why it was introduced and its relevance for those specifying equipment for use inside cleanrooms
Cleanrooms are designed to minimise the ingress of airborne particles (achieved through HEPA or ULPA filters) and to control what happens to particles generated within the cleanroom. Good air flow design — such as turbulent flow — helps to prevent particles from being deposited onto surfaces (particles settle by two primary mechanisms: gravitational sedimentation and turbulent deposition)1. The removal of these particles is achieved through the extraction of room air with the addition of clean air into the room (air exchange rates). The flow of particles in air from a less clean area can also be blocked from entering an area of a higher cleanliness level through positive pressure differentials.
These design principles of cleanrooms (observable through airflow visualisation studies) are well understood and have been in place for decades, enhanced through advances in technology aimed at improving control.2 What is less well-defined are specifications for the equipment being placed into cleanrooms.
Particles in cleanrooms are derived from several sources. In general, particles larger than 1 µm originate from mechanical processes (such as two glass bottles colliding, mechanical abrasion or grinding), or particles of this size are produced from personnel in the form of skin matter shed from the body. The main source of particle generation in cleanrooms is people. Even the best prepared cleanroom garments will not contain all particles produced by the shedding of skin cells or from fibrous material from the garment itself3. A given number of particles deposited into the air-stream will be microbe-carrying particles where bacteria or fungi are carried on rafts of skin detritus.
A secondary source of particles and one, until recently, where no standard has existed is from the equipment placed in cleanrooms. All too often the equipment placed in cleanrooms is not of a suitable design. This has been the case despite claims from some manufacturers that the equipment is suitable for use in an area of a given ISO class.
In cleanrooms particles behave in different ways and their behaviour is governed by a range of factors. These factors will determine the likelihood of particles in the air settling out onto cleanroom surfaces. With multidirectional-design cleanrooms (i.e., turbulent flow areas) air currents do not follow a predictable path. The result of this design configuration is that particles can move in any direction. This variation in movement can mean some particles can be re-entrained from a surface or in poorly designed cleanrooms from the floor. This leads to an increase in airborne particle concentration. Other particles may be deposited from the air-stream and remain on a surface due to physicochemical forces creating semi-permanent attachment. Disposition from the air is more likely as air moves around objects. Depending upon the shape of an object, eddying or ‘recirculation zones’ can form, as might occur with the underside of a desk. It is due to some of these concerns that attention has recently been paid to particles in association with cleanroom equipment.
The ISO 14644 series of standards for cleanrooms began in 1999 with the issue of part 1 of the standard aimed at cleanroom classification.4 This was followed by part 2 in 2001, which covered the steps required to demonstrate continued compliance (both parts 1 and 2 were updated in 2015). Since then, ISO 14644 has expanded into a series of documents covering areas from the chemical contamination of surfaces to the operation of barrier devices such as isolators. In 2016, a new part of the standard was issued: ISO 14644–14 (2016) “Assessment of suitability for use of equipment by airborne particle concentration.”5
ISO 14644–14:2016 specifies the methodology that can be used to assess the suitability of equipment (such as machinery, measuring equipment, process equipment, components and tools) for use in cleanrooms and associated controlled environments in terms of the contribution of the equipment to airborne particle cleanliness. The standard was produced to ensure that equipment situated in cleanrooms meets the requirements of particle control as specified in ISO 14644–1. The level of control required will depend on the class of the cleanroom; here ISO 14644–14 extends to particle sizes ranging from 0.1 µm to 5.0 µm. The focus of the standard is with undifferentiated particles, which means that biocontamination is not specifically addressed. This does not mean biocontamination is not important since a portion of microorganisms on surfaces (expressed as a transfer coefficient) are transferred to and from surfaces by connecting objects or personnel touch)6. The standard also focuses on the design of the equipment and does not address its future use in terms of cleanability.
Based on the ISO 14644–14 guidance, how might equipment be designed for cleanrooms and what should cleanroom managers be looking for? This section of the article highlights some important points of note:
Selection of materials: The types of materials selected for equipment need to be smooth, cleanable and have low particle emissions. To avoid passive particle generation stainless steel is recommended in place of plated or oxide-coated steel (which can shed particles). Paints must always be avoided.
Where required the material should have low electrostatic properties to avoid particles adhering to the equipment (through electrostatic attraction where particles, including microorganisms, are bound onto the surface of equipment instead of remaining airborne). Equipment with a different charge to airborne particles leads to the potential for particles binding (electrostatic attraction) and this presents a separate risk factor to gravitational, aerodynamic or adhesion forces. This arises due to the presence of a net electrical charge on a surface, which can create an electrostatic field that accelerates the deposition of particles onto the surface as differently charged particles move close to it.
The types of material most affected include insulating materials such as glass, Teflon and polymers. These items can become highly charged. The problem is exacerbated when plastics or other insulative devices are contacted, rubbed or handled; here they generate higher static charges.
A related variable that needs to be considered is the cleanroom environment, since surface resistance rises and falls with relative humidity and therefore control of the cleanroom temperature and humidity is often necessary for controlling the static charge of equipment surfaces.
A further point in relation to material selection is, depending upon the temperature ranges of the cleanroom and the operational temperature of the equipment, the materials should have good thermal properties and not be subject to physical changes with an increase in temperature. Thermal properties include conductivity and diffusability. The thermal conductivity is the rate of heat transfer through a material in steady state; whereas the thermal diffusivity is a measure of the transient heat flow through a material.
Non-reactive surfaces: For biopharmaceuticals, the surfaces that contact components, in-process materials or drug products must be non-reactive and not additive or absorptive.
Design of equipment: The equipment design should promote cleanability and minimise occluded surfaces where possible. Occluded surfaces are a concern in higher grade cleanrooms, such as EU GMP Grade B (ISO 14644 class 7 areas). This is because there is a greater opportunity for particles to settle out. Settling out, due to gravitational forces, can happen when air passes over and around a surface. Here the surface drag will slow down the air velocity. This reduction in air velocity occurs when air reaches the ‘boundary layer’. The effect varies from surface to surface although typically it is no more than a few centimetres in thickness from the surface. This is one reason why airflow visualisation studies are a good idea in aseptic processing areas, as a means of assessing where turbulence develops around equipment and for assessing the contamination risk.
The design should also minimise particle generation, i.e., surfaces should be smooth and without joints or cracks. These considerations are pertinent to the philosophy of Quality by Design.
Particles are generated passively (as discussed above) or actively. Active generators of particles include positioning stages and other components with sliding surfaces, such as seals on linear-bearing blocks, ball screws and other metallic strip seals. These aspects of the equipment functionality need to be designed so that particle generation is minimised. Attention also needs to be paid to external electrical cables and air hoses, which can rub over device housings and produce particles.
Sealants can be a source of particle generation, which means carbon black is unsuitable whereas unfilled urethanes that can resist abrasion will be more suitable because they generate fewer particles. Seals can be made from metals or belts; belt-sealing systems generally have substantially lower friction than metal-sealing systems and are preferred. In addition, bearings and ball screws should be isolated.
Oils and lubricants: Oil vapours and droplets can be dispersed in the air from lubricating oils used in bearing and drivetrain devices. For this reason cleanroom grade lubricants need to be selected (such as vacuum-grade, low-vapour pressure, low-migration grease). Often food-grade lubricants are suitable, although the particle size and generation needs to be evaluated.
Cleanability: Although the ease of cleaning the surfaces of the equipment is not immediately addressed by the standard, how easy the surface is to clean is an important consideration. Equipment should be of a suitable size, construction and location to facilitate cleaning, maintenance and proper operations.
Cleanability refers to the ease of cleaning along with ensuring that cleaning agents (detergents) and, perhaps more importantly due to their aggressive nature, disinfectants do not react with the surface material. Some disinfectants can cause corrosion, especially those intended to be sporicidal.
Further factors to consider when selecting the most suitable cleaning agents are: will they damage the equipment (e.g., cause abrasions) or lead to excessive generation of particles through the act of wiping (e.g. wiper quality as well as the interaction between equipment, the wipe and cleaning chemical). The presence of abrasions and cracks to a surface are important since these can harbour microorganisms and disinfectants may be unable to penetrate to inactivate the sessile state organisms.7 In summary, good cleanroom design is important but the design of the equipment going into cleanrooms also requires attention. While this requirement has been considered in the past some products have not been properly evaluated. The new ISO 14644–14 standard provides a starting point for assessing equipment suitability and points raised in this article, including those additional to the standard, can be used to form the basis of a checklist to assess the suitability of cleanroom equipment.
1. W. Whyte, K. Agricola and M. Derks, (2015) Clean Air and Containment Review. 24, 4–9
2. T. Sandle, (2012) Cleanroom Technology. 20(5), 13–17
3. B. Reinmüller, (2001) Royal Institute of Technology, Building Services Engineering Bulletin. No. 56, 54–77
4. T. Sandle and T. Saghee (2017). Cleanroom certification and ongoing compliance. In T. Sandle and M.R. Saghee, Cleanroom Management in Pharmaceuticals and Healthcare, Euromed, Passfield, UK, pp169–184
5. ISO 14644-14:2016 Cleanrooms and associated controlled environments. Assessment of suitability for use of equipment by airborne particle concentration, International Standards Organisation, Geneva
6. W. Whyte and T. Eaton,(2015) Euro. J. of Parenteral and Pharma. Sciences. 20(4), 127–131.
7. T. Sandle (2016) Cleaning and Disinfection. In T. Sandle, (Ed.). The CDC Handbook: A Guide to Cleaning and Disinfecting Cleanrooms. Grosvenor House Publishing: Surrey, UK, pp1–31
About the author
Dr Tim Sandle is Head of Microbiology at Bio Products Laboratory (BPL). He is an expert in cleanroom standards and has written several books including: Pharmaceutical Microbiology: Essentials for Quality Assurance and Quality Control for pharmaceutical microbiologists (Elsevier) and Cleanroom Management in Pharmaceuticals and Healthcare (Euromed), which covers all aspects of cleanrooms from design and qualification to cleaning and microbiological monitoring. He is also an active member of Pharmig, the UK-based association for pharmaceutical microbiologists (www.pharmig.org.uk)