See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/319092669

Applying design and construction standards to cleanroom builds

Article  in  Cleanroom Technology · August 2017

CITATIONS READS

0 512

1 author:

Tim Sandle
The University of Manchester
496 PUBLICATIONS   544 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Learning View project

Endotoxin View project

All content following this page was uploaded by Tim Sandle on 13 August 2017.

The user has requested enhancement of the downloaded file.

 August 2017 15
STANDARDS

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
APPLYING DESIGN AND
been in place for decades, enhanced
through advances in technology aimed at
CONSTRUCTION
improving control.2 What is less well-
defined are specifications for the STANDARDS TO
equipment being placed into cleanrooms.

Particle generation
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
CLEANROOM BUILDS
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
specifiying equipment for use inside cleanrooms
configuration is that particles can move in ISO 14644 has expanded into a series of
any direction. This variation in movement documents covering areas from the
can mean some particles can be chemical contamination of surfaces to the
re-entrained from a surface or in poorly operation of barrier devices such as
designed cleanrooms from the floor. This isolators. In 2016, a new part of the
leads to an increase in airborne particle standard was issued: ISO 14644–14 (2016)
concentration. Other particles may be “Assessment of suitability for use of
deposited from the air-stream and remain equipment by airborne particle
on a surface due to physicochemical forces concentration.”5
creating semi-permanent attachment. ISO 14644–14:2016 specifies the
Disposition from the air is more likely as methodology that can be used to assess
air moves around objects. Depending upon the suitability of equipment (such as
the shape of an object, eddying or machinery, measuring equipment, process
‘recirculation zones’ can form, as might equipment, components and tools) for use
occur with the underside of a desk. It is in cleanrooms and associated controlled
due to some of these concerns that environments in terms of the contribution
attention has recently been paid to of the equipment to airborne particle
particles in association with cleanroom cleanliness. The standard was produced to
equipment. ensure that equipment situated in
cleanrooms meets the requirements of
ISO 14644–14 particle control as specified in ISO
The ISO 14644 series of standards for 14644–1. The level of control required will
cleanrooms began in 1999 with the issue depend on the class of the cleanroom; here
of part 1 of the standard aimed at ISO 14644–14 extends to particle sizes
cleanroom classification.4 This was ranging from 0.1 µm to 5.0 µm. The focus
followed by part 2 in 2001, which covered of the standard is with undifferentiated
the steps required to demonstrate particles, which means that
continued compliance (both parts 1 and 2 biocontamination is not specifically
were updated in 2015). Since then, addressed. This does not mean 䊳
 16 August 2017
STANDARDS
biocontamination is not important since a
䊳
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.
Design of equipment for cleanrooms
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 the
surface.
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
centimeters 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 should be non-reactive and free of
crevices and cracks
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 䊳
 18 August 2017
STANDARDS
䊳
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
View publication stats
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)
additional to the standard, can be used to
form the basis of a checklist to assess the
suitability of cleanroom equipment.
References
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