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Good Cleanr Good Cleanr Good Cleanr Good Cleanr Good Cleanroom Practices oom Practices oom Practices

oom Practices oom Practices


a manual for cleanroom personnel
c k moorthy
good cleanroom practices
a manual for cleanroom personnel
good cleanroom practices
a manual for cleanroom personnel
c k moorthy
The frontiers of knowledge are
constantly changing, ever expanding.
As information becomes available,
changes in design approach,
procedures, equipment and their use
become necessary. The author and
publisher have, as far as it is possible,
taken care to ensure that the
information given in the text is both
accurate and current. However,
readers are strongly advised to confirm
that the information, especially with
regard to drug and device manufacture,
complies with current regulatory and
compendial expectations, legislations
and standards of practice.
Published by:
Center for GMP
509C NCL-Godavari
Pipeline Road
Jeedimetla PO
Hyderabad 500 055
eMail: ckm@cgxp.org; cgmp@vsnl.com
URL: www.cgxp.org
First Edition : September, 2007
Standard edition
Printed in India
Price: Rs 395.00
All rights reserved. No part of this work may be
copied, reproduced, adapted, abridged or
translated, stored in a retrieval system, or
transmitted in any form or by any means,
electronic, mechanical, photocopying, record-
ing or otherwise, without the prior written
permission of the publisher
dedication
V
oices in this book may be many; but the concerns and convictions
remain the same: you hold the key to the ultimate success of any
contamination control or GMP initiative.
This book is dedicated to you.
acknowledgement
A
s in all my previous compilations, here also, I have drawn
inspiration and material from the ideas and works of
extraordinarily gifted authors and speakers, far too numerous to
mention individually, and take this opportunity to record my sincere
appreciation and deep sense of indebtedness to every one of them.
Special mention, however, must be made of the following sources:
Biosafety in Microbiological and Biomedical Laboratories, CDC/NIH
4th edition
Selection and use of Biological Safety Cabinets, CDC/NIH 2nd edition
EUGGMP/WHO/USFDA/Schedule M guidelines
Dr W Whyte for his kind permission to reproduce sections from his
book Cleanroom Technology Design, Testing and Operation
published in 2001 by John Wiley and Sons (ISBN Number 0-471-
86842-6).
contents
1 contamination control 11
2 cleanroom 23
3 classification of air cleanliness 35
4 entry and exit of personnel 53
5 cleanroom disciplines 61
6 human interface in cleanrooms 71
7 laminar airflow 93
8 good biosafety practices 105
9 cGMP & you: personnel in drug and device manufacture 129
10 guidelines governing personnel in drug & device manufacture 137
11 good sanitation practices 187
C
ontaminants play an especially important role in the manufacture,
manipulation or repair of such items as semiconductors, space
vehicles, conventional and nuclear missiles, microbial cultures,
ball-bearings, parenterals, vaccines and human organs.
While it may be unusual to think of the human body as a product, or the
Operation Theatre as a factory, the same engineering principles of
microcontamination control apply. The control of infectious airborne
pathogenic organisms in hospital operating rooms and recovery wards
can be achieved in a manner identical to that used to protect against
airborne contaminants during pattern generation of semiconductor
devices, or during aseptic manipulations with thermolabile injectibles.
The risks of manufacture, of course, are different since the loss of a
human life has consequences beyond economics. But the technical
approaches to solving the problem remain similar.
contamination control
C K Moorthy
1 1
1 11
14 cleanroom operators manual
Contamination control is only a part of the larger Quality Assurance
Initiatives that aim to minimise the risk of producing a defective, and
maximise the probability of manufacturing a product "fit for use" or "fit
for purpose". By this token, contamination control is best described as
a set of systems, practices and procedures that aspire to minimise the
introduction of a contaminant into a product or process.
Contamination control can be compared to providing the highest level
of personal security to a VIP under threat. Depending on whether the
VIP is the President of the United States of America, or of Sri Lanka, or
of India, the group posing the threat differs. Once we know the identity
of the VIP, we are better placed not only to anticipate the sources of the
threat, but also to know more about their origin, locations, motives and
modus operandi.
The security steps we normally take are:
1 Isolate the VIP
2 Minimise his exposure, both in terms of duration and frequency
3 Seek and destroy or immobilise those threatening his safety
4 If his enemies are outside, we make it difficult for them to
penetrate the protective barriers
5 If they are already within, we flush them out
6 We monitor those in his immediate proximity
7 We advise the VIP not to antagonise anyone who may be around
him, friend today, and foe tomorrow (Don't generate enemies
within)
8 Stay vigilant and cope
In the context of contamination control, a product or process is what we
try to safeguard.
A contaminant is defined as any substance or energy that
produces an adverse effect on that product or process.
Such a classification is purely contextual, without bearing on its absolute
worth. Just as the enemy of one VIP may not necessarily be an enemy of
the next VIP, so too in contamination control. For example, most
processes tolerate normal levels of moisture. Except powder processing.
Hence, in the latter case, moisture assumes the role of a contaminant.
In a drug, a contaminant may not directly spoil the product or process.
However, on administration to the patient it may act in-vivo in different
ways:
15 contamination control
* No effect at all
* Cause physical occlusion
* Synergistically: where it enhances the effect of the active process
ingredient
* Antagonistically: where it competes with, changes or otherwise
inhibits the drug
* Independently: triggers its own independent pharmacological
activity
Contamination directly compromises the safety and quality of our
product, and hence a legitimate cGMP concern. Contamination control
measures will make more sense once we understand the nature of
contaminants and the contamination process.
We begin with classification of contaminants.
classification of contaminants
Regarded from the standpoint of the type of damage they do,
contaminants may be divided into subgroups:
Physical: Particles that cause damage by virtue of their physical
properties alone
Chemical: Organic chemicals such as oils, fats, waxes, fluxes, paints
and plastics may react chemically with a product and change
its properties. Gases induce contamination (like oxidation)
only in the gaseous phase. In contrast, vapours and mists
contaminate in the vapour phase; on condensation, in the
liquid phase (like oil films); and, on subsequent evaporation,
in the solid phase (residues).
ENERGY
SUBSTANCE
Physical Chemical Biologic
Dust
Dirt
Grit
Fibre
Lint
Fly ash
Organic
compounds
Inorganic salts
Acids, Bases
Condensates
Moisture, Vapour
Mist, Fume
Smoke
Bacteria
Fungus
Spore
Pollen
Virus
Human skin cells
Thermal
Light
Electromagnetic (EMI)
Electrostatic (ESD)
Radiation
Electrical (RF)
Table 1: Classification of contaminants
16 cleanroom operators manual
Biological: Microorganisms and endotoxins
Energy: Some products are thermolabile; others decompose on
prolonged exposure to sunlight
contaminant pathway
If you were to ask any agency that provides security to VIPs they will
tell you that the enemy may attempt a million times and fail; he needs to
succeed just once. In contrast, they must succeed each time. This is just
as true with contamination control.
On the flip side, the mere presence of a contaminant does not
automatically imply contamination. For contamination to occur, the
contaminant must first have its source; must then be transported and
reach the product site; must make contact with the product; and must be
retained by the product.
If this process of contamination, known as the contaminant pathway, is
broken at any stage, contamination does not occur.
For instance, if the source of the contaminant is absent; or, having a
source, it is unable to access the product; or, having somehow managed
to slip through, is prevented from making contact; or, even after having
Retention
Contact
Source
Transport
Figure 1: The contaminant pathway
17 contamination control
made contact, is not retained, or not allowed to be retained, contamination
does not take place, and the product is safe.
Contamination control may then be viewed as an exercise that aims to
break the contaminant pathway at one or more stages of the
contamination process.
sources of contaminants
Included contaminants emanate from raw materials and consumables;
fluidised contaminants from utilities; suspended contaminants from the
environment; settled contaminants from dust collecting surfaces; emitted
contaminants from machinery, moving parts and surfaces; shedded and
transferred contaminants from personnel. Cross-contamination occurs
when the active process ingredient of one product is carried forward to
the next drug product because of inadequate cleaning.
O Raw Materials, Components, Consumables
* Microflora
* Impurities
* Fibers, dust, cleaning residues and other particles
* Moisture
O Equipment
* Poor choice of materials of construction
* Improper or inadequate surface treatment
* Inadequate cleaning; cleaning residues
* Improper or inadequate maintenance
O Environment & Utilities
* Building materials and surface finishes
* Temperature & Humidity
* Light, radiation
* Air
- Microflora
- Fibers, dust and other particles
- Fumes, vapours and condensates
* Water
- Microflora and Endotoxins
- Fibers, dust and other particles
- Cleaning residues
18 cleanroom operators manual
* Gases & Compressed air
- Microflora and Endotoxins
- Oil droplets, dust and other particles
O Human
* Intrinsic contaminants
- Biologic Factory
* Extrinsic contaminants
- Importer of contaminants
- Transporter of contaminants
- Generator of contaminants
- Inducer of contamination
Figure 2: Sources of contaminants in cleanrooms
In fact, research into a large number of reported occurrences of
contamination in well-designed and maintained clean rooms reveals
that in 5% of the cases it was due to contaminated raw materials; in
10% through utilities and defective or soiled equipment, tools or
implements; in 5% due to faulty air filtration; and in 80% due to breaches
in the product-person interface.
Hence, contrary to popular belief, microcontamination control does not
begin and end with HEPA filters: it is only one of many concurrent
initiatives. Comprehensive microcontamination control requires a
program that effectively integrates and orchestrates planned offensive
measures on all four fronts. Pursuing one while ignoring others yields
sub-optimal results.
19 contamination control
Figure 3: An integrated approach to contamination control
I have personally seen many facilities where such "common sense" is
conspicuous by its absence. The User forces me through a commendable
decontamination entry regimen, only to leave me watch in amazement
the impunity with which the trolley boy "gate crashes" from the material
entry; double-doored and air locked. No decontamination protocols apply
to him, his trolley or their dirt-laden wheels, except on some neatly
typed SOP, stashed away in the recesses of a filing cabinet in the
Production Manager's Office.
master plan for contamination control
As mentioned at the outset, contamination control is much alike
protecting a VIP, and the steps outlined for security apply here.
A product or process is susceptible to contamination during manufacture,
assembly, testing, cleaning, transportation, storage, or even while being
used. Our objective is to minimise the risk of its being contaminated
along the way. We adopt a six-point strategy:
Identifying the contaminant
Our first exercise is in identifying the possible contaminants that threaten
the product or process. We can then design a contamination control
program that takes into account their characteristics and behavioural
pattern.
Anticipating the contaminant
Having identified the contaminants that are likely to compromise our
product or process, we focus on the possible sources from where they
could originate; and their mode of getting to the critical zone.
20 cleanroom operators manual
Preventing ingress
Preventing ingress of contaminants into the selected work area.
O Raw Materials, Components, Consumables
* Vendor qualification
* Limits on Impurities
* Primary and Secondary packaging
* Proper storage
* Proper sampling, testing and dispensing
O Equipment
* Appropriate choice of materials of construction
* Appropriate surface treatment
* Adequate cleaning; and cleaning validation
* Proper and timely maintenance
O Environment & Utilities
* Isolation of critical areas
* Appropriate materials of construction and surface finishes
* Entry restrictions and protocols
* Entry decontamination protocols
* Temperature & Humidity Control
* Air
- Air filtration
- Differential Pressure
- Airflow direction
- Airflow Velocity at sub-turbulent level
- Air Change Rate
- Task-specific air
cleanliness: a clean
air workstation or
tent in a cleanroom
* Water
-
Appropriate
treatment, storage and
distribution
Size
m
Dirty Normal
> 0.1 1 10
10
3 10
9
5 10
8
> 0.3 3 10
8
9 10
7
2 10
7
> 0.5 3 10
7
7 10
6
1 10
6
Number of Particles /m
3
in Outdoor Air
Clean
Table 2: Air quality
21 contamination control
* Gases & Compressed air
- Appropriate selection of system: oil-free compressor, piping
and accessories
- Appropriate in-line filtration
O Human
* Appropriate training
* Proper personal hygiene
* Proper gowns, gowning and decontamination
* Proper discipline and comportment
* High vigilance
Facilitating egress
Facilitate egress of suspended as well as settled contaminants from
within.
The air distribution system should be designed to displace contaminated
air to the exterior as directly and rapidly as possible. The principle of
Figure 4: Fortifying the work space
Outside environment
D
Cleanroom
C
B
A
X X
X XX
K K
K KK
L L
L LL
T T
T TT
22 cleanroom operators manual
Figure 5: Typical cleanroom design
dilution can be employed: clean air can be passed through the given
space in sufficient quantities to flush out as much of the contaminants
generated within the space, and thinning out the concentration of the rest.
An important corollary to control by dilution is an air distribution design
that maintains air velocity at sub-turbulent (LAF) levels to minimise
recirculating eddy currents.
An imaginative, effective and implementable sanitation scheme, closely
supervised and monitored is another method of getting settled
contaminants out of harms way. Surfaces that gather dust should be
avoided, or minimised where unavoidable; and all such surfaces should
be smooth and accessible for thorough cleaning.
Minimising internal generation
Minimise generation of contaminants within. We start by reducing the
number of operations, equipment, and personnel to the bare minimum.
What can be done outside, must be done outside; what can be outside,
should be outside; and who can be out side, should be outside.
23 contamination control
O Select class of air cleanliness
appropriate for the task
O Select location and layout optimising
flowpaths for men, material and process
o avoid loops in flowpaths
o isolate through barriers
o avoid direct / straight through
access
o stagger doorways
o no windows on external wall
o double-glazed view panels with
breathers
O Sustain overpressure along clean-to-
dirty axis, where not contraindicated
O Impose entry restrictions and thorough
decontamination procedures for men,
material and equipment
O Sustain overpressure along clean-to-
dirty axis, where not contraindicated
O Avoid surfaces that can accumulate
dust; where unavoidable, ensure easy
accessibility to clean and disinfect
O Implement comprehensive sanitation
plan
O Select material and equipment that
dont shed excessive particles or degas,
especially walls, floor and ceiling
O Establish sound maintenance for
upkeep of facility
O Operator training and discipline
O Good gowning
O Dilution of aerosol concentration by
dilution: increase in air change rate
O Controlled velocity airflow without
eddy currents to drag away suspended
contaminants from critical zone: LAF
O Reduce product exposure time and
exposure frequency
Basic Airborne Contamination Control Techniques
Coping with
residual
contaminants
Minimising
Generation
Facilitating Egress
Preventing Ingress
Table 3: Basic airborne contamination control techniques
What remains inside is subjected to careful control: the premises, the
utilities, the equipment, the process and the operators.
Coping with residual contaminants
The last of the techniques relates to coping with the residual
contaminants. Since deposition of suspended contaminants is a time
dependent phenomenon, reducing exposure frequency and exposure time
of sensitive products is an important form of control.
Controlled eddy-free displacement (LAF) of suspended contaminants,
directed away from the critical site is another powerful method used to
protect the product.
an introduction to the design of clean and
containment areas
Author W Whyte has kindly allowed the reproduction from his book
Cleanroom Technology Design, Testing and Operation published
in 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).
T
he cleanroom is a modern phenomenon. Although the roots of
cleanroom design and management go back more than 100 year
and are rooted in the control of infection in hospitals, the need
for a clean environment for industrial manufacturing is a requirement
of modern society. The use of cleanrooms is diverse and shown below is
a selection of products that are now being made in cleanrooms, or require
contamination control facilities.
It may be seen that the requirement for cleanrooms can be broadly divided
into two. The first area is that in which inanimate particles (dust) are a
problem and where their presence, even in submicron size, may prevent
a product functioning or reduce its useful life. The second group requires
the absence of microbe-carrying particles whose growth in the product
(or in a hospital patient) could lead to human infection. It may also be
seen that many of the examples given are recent innovations and this
list will certainly be added to in the future, there being a considerable
increase in the demand for these types of rooms.
2 2
2 22
26 cleanroom operators manual
some clean and containment room applications
Electronics: Computers, TV tubes, Flat screens, Magnetic tape
production
Semiconductors: Production of integrated circuits used in computer
memory and control. Micromechanics Gyroscopes, Miniature bearings,
Compact disc players
Optics: Lenses, Photographic film, Laser equipment
Biotechnology: Antibiotic production, Genetic engineering
Pharmacy: Sterile pharmaceuticals
Medical devices: Heart valves, Cardiac by-pass systems
Food and drink: Disease-free food and drink
Hospital: Immunodeficiency therapy, Isolation of contagious patients,
Operating rooms
The application of cleanrooms has increased and diversified. As well as
minimising the airborne contamination it may be necessary to contain
dangerous or toxic contamination within the room. This is done by
containment rooms.
Clean and containment rooms will be individually designed according
to their application, but there are a number of basic similarities and
design concepts that should be discussed before reading further chapters
of this book. These concepts consider the special requirements of
industries such as microelectronics, pharmaceuticals, medical devices
and biotechnology.
what is a cleanroom?
It is clear that a cleanroom is a room that is clean. However, a cleanroom
now has a special meaning and it is defined in Federal Standard 209E as:
A room in which the concentration of airborne particles is controlled
and which contains one or more clean zones.
and in ISO 14644-1:
A room in which the concentration of airborne particles is controlled,
and which is constructed and used in a manner to minimise the
introduction, generation, and retention of particles inside the room and
27 cleanrooms
in which other relevant parameters, e.g. temperature, humidity, and
pressure, are controlled as necessary.
classification of cleanrooms
Cleanrooms are classified by the cleanliness of their air. The method
most easily understood and universally applied is the one suggested in
versions of Federal Standard 209 (up to edition D). In this standard
the number of particles equal to and greater than 0.5 m is measured in
one cubic foot of air and this count is used to classify the room.
A classification of cleanrooms according to the older Federal Standard
209D is given in a simplified form in Table 1
Table 1: A simplified Federal Standard 209D classification of
cleanrooms
Fed Std 209D 1 10 100 1000 10000 100000
classification
No. of particles/ft
3
1 10 100 1000 10000 100000
> 0.5 m
This Federal Standard was superseded by a metric version (Federal
Standard 209E) which was published in 1992. However, because of its
simplicity and universal use, it will be many years before the older Federal
Standard 209D classification is forgotten. It is also likely that Federal
Standard 209D nomenclature will not be superseded by Federal Standard
209E but by the new International Organization for Standards (ISO)
standard 14644-1. (More of this in the next chapter.)
It should be appreciated that the airborne contamination level of
cleanroom is dependent on the particle-generating activities going on
in the room. If a room is empty, very low particle concentrations can be
achieved, these closely reflecting the quality of air supplied and hence
the removal efficiency of the high efficiency filter. If the room has
production equipment in it and operating, there will be a greater particle
concentration but the greatest concentration will occur when the room
is in full production. A classification of the room may therefore be carried
out when the room is:
as built: condition where the installation is complete with all services
connected and functioning but with no production equipment, materials,
or personnel present,
28 cleanroom operators manual
at rest: condition where the installation is complete with equipment
installed and operating in a manner agreed upon by the customer and
supplier, but with no personnel present,
operational: condition where the installation is functioning in the
specified manner, with the specified number of personnel present and
working in the manner agreed upon.
class of rooms required by different industries
The required standard of cleanliness of a room is dependent on the task
performed in it; the more susceptible the product is to contamination
the better the standard. The following list gives an indication of the
tasks carried out in different classifications of cleanrooms. These
suggested classifications are only an indication of what might be used
and care must be taken not to overdesign by providing cleaner than
necessary rooms as this has a big influence on cost.
possible cleanroom requirement for various tasks carried out
in cleanrooms
Class 1: These rooms are only used by integrated circuit manufacturers
manufacturing sub-micron geometries
Class 10: These rooms are used by semiconductor manufacturers
producing integrated circuits with line widths below 2 mm
Class 100: Used when a bacteria-free or particulate-free environment is
required in the manufacture of aseptically-produced injectable medicines.
Required for implant or transplant surgical operations. Isolation of
immunosuppressed patients, e.g. after bone marrow transplant operations
Class 1000: Manufacture of high quality optical equipment. Assembly
and testing of precision gyroscopes. Assembly of miniaturised bearings
Class 10 000: Assembly of precision hydraulic or pneumatic equipment,
servo-control valves, precision timing devices, high grade gearing
Class 100 000: General optical work, assembly of electronic components,
hydraulic and pneumatic assembly
types of clean areas
Clean areas can be divided into four main types. These are shown in a
diagrammatic form in Figure 1 and are as follows:
29 cleanrooms
Figure 1 Types of clean areas
Conventional. These cleanrooms are also known as turbulently-ventilated
or non-unidirectional flow and are distinguished by their method of air
supply. This is of the conventional type, the air being supplied by air
supply diffusers or filters in the ceiling.
Unidirectional flow. This was previously known as laminar flow. Clean
air is supplied from a bank of high efficiency filters and passes in a
unidirectional manner through the room.
Mixed flow. This type of cleanroom is conventionally ventilated but
where the product is exposed to contamination, a unidirectional flow
cabinet or workstation is used.
30 cleanroom operators manual
Isolators or microenvironment. Conventional design exposes the product
and focuses controls on all else. The Isolator design focuses on what is
most important: the immediate environment around the product, thus
rendering all other factors less critical.
These are used within a cleanroom to give the highest level of protection
against contamination. See Figure 2. As seen in Figure 3, the isolator is
shown to have a unidirectional supply of air but this may be a conventional
turbulent-flow type. Similarly, gauntlets are shown, but half suits are
also used.
conventionally ventilated cleanrooms
The general method of ventilation used in a simple conventionally
ventilated type of cleanroom is similar to that found in offices, shops,
etc. in that air is supplied by an air conditioning plant through diffusers
in the ceiling. However, a cleanroom differs from an ordinary ventilated
room in a number of ways:
Figure 2: Conventional cleanrooms vs Isolators
31 cleanrooms
Figure 3: Isolator featuring half-suits
1. Increased air supply: An office or shop will be supplied with sufficient
air to achieve comfort conditions; this may be in the region of 2 to 10 air
changes per hour. A typical conventionally ventilated cleanroom is likely
to have between 20 and 60 air changes per hour. This additional air
supply is mainly provided to dilute to an acceptable concentration the
contamination produced in the room.
2. High efficiency filters: A cleanroom uses filters much more efficient
than those used in offices etc. Cleanroom filters would normally be greater
than 99.97% efficient in removing particles greater than 0.3 m from
the room air supply. These filters are known as High Efficiency Particle
Air (HEPA) filters although Ultra Low Particle Air (ULPA) filters, which
have a higher efficiency, are used in microelectronic fabrication areas.
32 cleanroom operators manual
3. Terminal air filters: The high efficiency filters used in cleanrooms
are installed at the point of air discharge into the room. In air conditioning
systems used in offices, etc. the filters will be placed directly after the
ventilation plant but particles may be induced into the air supply ducts
or come off duct surfaces and hence pass into the room.
4. Room pressurisation and pass-through grilles: To ensure that air
does not pass from dirtier adjacent areas into the cleanroom, the
cleanroom is positively pressurised with respect to these dirtier areas.
This is done by extracting less air from the room than is supplied to it,
or by extracting the supplied air in adjacent areas. To achieve the correct
pressure and allow a designed movement of air from the cleanest to the
less clean rooms in a suite, pass-through grilles or dampers will usually
be seen at a low level on walls or doors.
Another indication that the room is a cleanroom is the type of surface
finish in a room. The room will be constructed of materials which do
not generate particles and are easy to clean. Surfaces will be constructed
so that they are accessible to cleaning and do not harbour dirt in cracks,
e.g. coved flooring and recessed lighting.
The airborne cleanliness of a conventionally ventilated cleanroom is
dependent on the amount and quality of air supplied to the room and the
efficiency of mixing of the air. Generally speaking, a cleanroom will
have sufficient air supply to achieve good mixing and the air quality of
the room will therefore only depend on the air supply quantity and quality.
It is important to understand that the cleanliness of a conventionally
ventilated cleanroom is dependent on the volume of air supplied per
unit of time and not the air change rate.
The cleanliness is also dependent on the generation of contamination
within the room. i.e. from machinery and individuals working in the
room. The more people in the cleanroom, the greater their activity and
the poorer their cleanroom garments the more airborne contamination
is generated. People moving about with poor cleanroom garments such
as smocks or laboratory coats will generate, on average, about 2 x 10
6
particles > 0.5 m/min, about 300 000 particles > 5.0 m/min, and
about 160 bacteria-carrying particles per minute. If people wear well
designed clothing (coverall, knee-length boots, hood, etc.) made from
tightly woven cloth the reduction of particles > 0.5 m, > 5.0 m and
bacteria-carrying particles will be about 50%, 88% and 92%, respectively.
Little information is available about the generation of particles from
machinery used in cleanrooms but this may account for hundreds to
millions of particles 0.5 m being dispersed per minute.
33 cleanrooms
If the efficiency of the supply filters can be assumed to be close to 100%
in removing the airborne contamination being considered, a rough
approximation of the likely airborne cleanliness of a conventionally
ventilated cleanroom (not a unidirectional flow one) can be achieved by
use of the following equation:
Airborne concentration = Number of particles (or bacteria) generated/min
(count/ft
3
or m
3
) Air volume supplied* (ft
3
or m
3
/min)
*including that from unidirectional flow work stations
Cleanrooms ventilated in this conventional turbulent manner may achieve
conditions as low as ISO 6 (Class 1000) during manufacturing but are
more likely to be ISO 7 (Class 10 000). To obtain cleaner rooms, greater
dilution of the particles generated is necessary and this can be achieved
by a unidirectional flow of air.
unidirectional airflow cleanrooms
Unidirectional airflow is used when low airborne concentrations of
particles of bacteria are required. This type of cleanroom was previously
known as laminar flow with a horizontal or vertical air flow at a uniform
speed of between 0.3 and 0.45 m/s (60 to 90 ft/min) and throughout the
entire air space.
The air velocity suggested is sufficient to remove relatively large particles
before they settle onto surfaces. Any contaminant generated into the air
can therefore be immediately removed by this flow of air, whereas the
conventional turbulently ventilated system relies on mixing and dilution
to remove contamination. In a theoretical situation in an empty room
with no obstructions to the airflow, contamination could be quickly
removed to the exhaust by air velocities much lower than those mentioned
above. However in a practical situation there are obstructions and people
moving about. Obstructions will cause the unidirectional flow to be turned
into turbulent flow and air vortexes to be established around the
obstructions. Movement of people will also turn unidirectional into
turbulent flow. Higher contamination concentrations will be established
in these turbulent areas. It is therefore necessary that the velocity is in
the region of 0.3 to 0.45 m/s (60 to 90 ft/min) so that the disrupted
unidirectional flow can be quickly reinstated and the contamination
around the obstructions be adequately diluted.
Unidirectional airflow is correctly defined in terms of air velocity, the
cleanliness of a unidirectional room being directly proportional to the
air velocity. Air changes per unit of time should not be used with a
34 cleanroom operators manual
unidirectional flow room as they are related to the volume of the room,
which generally has no effect on the performance of the system.
The air volumes supplied to unidirectional flow rooms are many times
(10-100) greater than those supplied to a conventionally ventilated room.
They are therefore very much more expensive in capital and running costs.
Unidirectional flow rooms are of two general types, namely horizontal
or vertical flow. In the horizontal system the air flow is wall-to-wall and
in the vertical system it flows from ceiling-to-ceiling.
In a typical vertical flow type of cleanroom, the air is supplied from a
complete bank of high efficiency filters in the roof and this flows vertically
through the room and out through open grilled flooring. Air in this
figure is shown to flow through the complete area of a floor but it is
common to find rooms in which the air returns through grilles which
are distributed about the floor. If the floor area is not too great, grilles
can alternatively be placed at a lower level in the walls. The exhaust air
is recirculated, mixed with some fresh make-up air, and supplied to the
room through the high efficiency filters in the room ceiling.
Most unidirectional cleanrooms are built in a vertical manner as particles
generated within the room will be quickly swept down and out of the
room. Less popular is the horizontal flow type of cleanroom.
This type of cleanroom is not so popular because any contamination
generated close to the filters will be swept down the room and could
contaminate work processes downwind. However as the area of a wall
in a room is usually much smaller than the ceiling the capital and running
costs are less. If the cleanroom can be arranged so that the most critical
operations are close to the supply filters and the dirtier ones at the exhaust
end, then this type of room can be successful.
mixed flow rooms
This type of room is a conventional flow room in which the critical
manufacturing operations are carried out within a higher quality of air
provided by a unidirectional flow system, e.g. a bench. This mixed type
of system is very popular as the best conditions are provided only where
they are needed and considerable cost savings are available for use in
this room, being one of the simplest and most effective methods of
controlling contamination. In this bench the operators contamination
is kept downwind of the critical process. Also available are a variety of
styles of vertical flow systems which may vary in size to encompass a
persons manipulations or large pieces of machinery.
35 cleanrooms
isolator or minienvironments
Hazardous work with toxic chemicals or dangerous bacteria has been
carried out for many years in glove boxes. Work on germ-free animals
has also been carried out for decades in plastic isolators which prevented
the entrance of micro-organisms. These contaminant-retaining and
contaminant-excluding systems do not principally depend on airflow
for isolation but walls of metal and plastic. This principle of isolation
clearly has excellent barrier properties and it has now been developed
for use in modern cleanroom technology. In the pharmaceutical
manufacturing area this technology is generally known as isolator or
barrier technology, whereas in the semiconductor industry it is generally
known as minienvironments.
Figure 3 shows the various components of an isolator. It may be seen
that there is a physical barrier to outside contamination, and personnel
either enter into half suits or use gauntlets to work at the clean processes
within the isolators. The air within the isolator is sterile and particle-
free having been filtered by high efficiency filters; this air is also used to
pressurise the system and prevent the ingress of outside contamination.
Figure 4: Rapid Transport Ports featuring - - doors
The containers and product cab enter and depart the isolator system
through a sterilising tunnel, pass through tunnel or docking transfer
device.
Another system, which is used in semiconductor manufacturing, is the
SMIF (Standard Mechanical Interface Format) system. In this system
silicon wafers are transported between machines in special containers
which prevent the wafers being contaminated by the air outside. These
containers, which contain the wafers, are slotted into the machine
interface, the wafers processed and then loaded onto another container
which can be taken to another machine and loaded into its interface.
W
e are now ready to specify the parameters for our clean room.
But when we say clean do we really mean clean? Prima facie,
clean implies absence of soil. Curiously we seldom use the
word in its literal sense. Intuitively we understand the term in its relative
sense. For example, a city is clean with plenty of clean parks, clean
buildings and clean roads. And your clean crockery on your clean dining
table in your clean home. Do we imply all are equally clean? No. The
degree of soil we subconsciously discount is contextual to each case.
That is why we would never set our buttered toast on the clean road, or
perform surgery in the clean park. So how clean is clean?
To translate this qualitative concept to a quantifiable parameter for
environment control, scientists measure the suspended contaminant
density, or number of suspended particles per unit volume. The lower
the contaminant density, the cleaner the environment.
classification of "air cleanliness"
C K Moorthy
3 3
3 33
38 cleanroom operators manual
We begin by determining or estimating the suspended contaminant
density in a given room or at the work point of interest. Typically this
lies in the range of 10 million (10
7
) to 100 billion (10
11
) per litre of
atmospheric air. Ideally we would like to get rid of all of them. But
that will cost money, and the proposition may not be financially
viable. Fortunately, this extreme level of cleanliness is not warranted.
Hence, we try to assess the maximum aerial contaminant density that
the process can be carried out at risk levels that are acceptable and cost-
effective: an environment "clean" enough for the intended purpose.
Statistics has
established that
airborne particle
profiles in clean,
semi-clean and
dirty
environments
were mathe-
matically pre-
dictable, and
equations could
be established by
which measure-
ment of the
number of any
one particle size
present in air
would provide
indirect estimate
of the number of
any other particle
size. If there were
less than 100,000
particles of size
0.5, or larger
per cubic foot of
air measured,
then it could be
assumed that the
number of 5
particles would
be less than 700
per cubic foot.
Size
m
Dirty Normal
> 0.1 1 10
10
3 10
9
5 10
8
> 0.3 3 10
8
9 10
7
2 10
7
> 0.5 3 10
7
7 10
6
1 10
6
Number of Particles /m
3
in Outdoor Air
Clean
Table 1: Air quality curves
39 classification of air cleanliness
ISO 14644-1
The ISO air cleanliness classification scheme is based on the formula:
Cn = 1O
N
(0. 1 /D)
2.08
.....(1)
Where
Cn = Maximum number concentration of particles per m
3
with diameter equal to or larger than the considered
particle diameter, rounded to the nearest whole
number, using no more than three significant digits
N = ISO classification number
D = Considered particle diameter in m
0.1 = a constant with the dimension m
Table 2: ISO 14644-1 airborne particulate cleanliness classes for
cleanrooms and clean zones.
Classification Maximum concentration limits (particles/m
3
of air) for particles
Number equal to and larger than the considered sizes shown below
(N) 0.1 0.2 0.3 0.5 1 5.0
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1 000 237 102 35 8
ISO 4 10 000 2 370 1 020 352 83
ISO 5 100 000 23 700 10 200 3 520 832 29
ISO 6 1 000 000 237 000 102 000 35 200 8 320 293
ISO 7 352 000 83 200 2 930
ISO 8 3 520 000 832 000 29 300
ISO 9 35 200 000 8 320 000 293 000
40 cleanroom operators manual
Note : Uncertainties related to the measurement process require that
concentration data with no more than three significant figures be used
in determining the classification level.
With the selection of 0.1 m as the reference particle diameter for air
cleanliness classification a very straightforward denomination scheme
results - thus overcoming elegantly the principal drawback of the metric
air cleanliness classes according to U.S. Federal Standard 209E. Simple,
single-digit class denominations now correspond with the traditional
classes of said standard: ISO 5, for example, replaces Class 100, and
ISO 8 substitutes Class 100 000.
The exponent 2.08 of the correlation between particle concentration and
particle diameter ensures the best possible co-incidence with the particle
concentrations according to U.S. Federal Standard 209E at that standards
reference particle diameter of 0.5 m. Thus, a harmonious connection
to previous generations of standards is assured.
Determinations for Micro and Macro Particles
In some situations, typically related to specific process requirements,
alternative levels of air cleanliness may have to be specified outside the
size range of particles applicable to classification. Descriptors have been
introduced for coping with such situations as follows:
the U descriptor for ultrafine particles below 0.1 m;
the M descriptor for particles above 5 m
The U descriptor is expressed in the format : (x : y) .....(2)
where :
x = the maximum permitted concentration of ultrafine particles,
expressed as the number of ultrafine particles per m
3
of air
y = the lower detection limit, i.e. the particle size in m at which
the applicable discrete particle counter - for example, a
condensation nucleus counter - is capable of detecting such
particles with 50 % counting efficiency
The M descriptor is expressed in the format : M (a;b);c.....(3)
where :
a = the maximum permitted concentration of macroparticles,
expressed as the number of macroparticles per m
3
of air
b = the equivalent diameter (or diameters) associated with the
specified method for measuring macroparticles
c = the specified method for measuring macroparticles
41 classification of air cleanliness
The concept of the U descriptor is not new - it already forms part of U.S.
Federal Standard 209E. On the other hand, the concept of the M
descriptor is new. In determining M descriptors, the difficulties of
sampling and assessing large particles has to be taken into consideration
as well as the fact that large particles are normally process -generated.
For these reasons the identification of the sampling device and evaluation
procedure should be addressed on an application-specific basis. Factors
such as the density, shape, volume and aerodynamic behaviour of the
particles need to be taken into account. For describing for instance, an
airborne macroparticle concentration of 1 000 particles/m
3
in the particle
size range of 10 to 20m using a cascade impactor for sampling and a
microscopic sizing and counting procedure for evaluation, the
designation would be : M (1 000; 10-20 m m) : cascade impactor
followed by microscopic sizing and counting
Under certain circumstances it may be necessary, to put special emphasis
on specific components of the total airborne particle population, such as
fibres. Fibres for instance, may be accounted for by supplementing the
M descriptor with a separate descriptor for fibres, having the format
Mfibre (a;b); c.
Cleanroom Testing to prove continued Compliance
At periodic intervals, cleanroom systems should be subjected to a formal
requalification procedure. The rules are established in another document
of the ISO series of cleanroom technology standards: ISO 14644-2.
Unlike the earlier years where specific values were specified for critical
parameters (for example, Air Velocity for Laminar Airflow should be
100 fpm etc) the current standard leaves fixing and determining
Table 3 : Strategic Testing (Required)
Schedule of Mandatory tests to demonstrate continuing compliance
Maximum
Test Parameter Class Time Interval Test Procedure
Particle Count Test <= ISO 5 6 Months ISO 14644-1
> ISO 5 12 Months Annex A
Air Pressure All Classes 12 Months ISO 14644-1
Difference Annex B5
Airflow All Classes 12 Months ISO 14644-1
Annex B4
42 cleanroom operators manual
parametric values entirely to be decided and mutually agreed by the
Buyer and Vendor.
ISO 14644-2 determines the type and frequency of testing required to
conform to the standard. Table 3 indicates which tests are mandatory
and Table 4 indicates which tests are optional.
Special Note :
1. Where the installation is equipped with facilities for continuous or
frequent monitoring of the airborne particulate concentrations and of
the differential pressure between rooms, the maximum time interval for
the normative tests may be extended to 24 months.
2. In the context of ISO 14644-2, frequent monitoring means that
measurements should be updated at specified intervals not exceeding
60 minutes during utilisation of the cleanroom, ie. in its operational
state.
According to this standard, this requalification should comprise at least
the following normative tests:
verification of the air cleanliness class;
verification of pressure differences between rooms;
a verification of the air velocity (for displacement airflow) or of
the airflow rate (for turbulent air-flow).
Other tests may optionally be included in the requalification programme
as agreed between customer and supplier such as:
Table 4: Strategic Testing (Optional)
Schedule of additional optional tests
Maximum
Test Parameter Class Time Interval Test Procedure
Installed Filter All Classes 24 Months ISO 14644-3
Leakage Annex B6
Containment All Classes 24 Months ISO 14644-3
Leakage Annex B4
Recovery All Classes 24 Months ISO 14644-3
Annex B13
Airflow All Classes 24 Months ISO 14644-3
Visualization Annex B7
43 classification of air cleanliness
a leakage or integrity test for the HEPA filters of the cleanroom
system;
a recovery test for cleanrooms with turbulent airflow;
a visualisation of the airflow in the cleanroom;
a containment leakage test for the cleanroom enclosure, i.e. its
walls and ceiling.
The test for demonstrating continued particle count compliance should
be performed at intervals not exceeding 6 months for cleanrooms of
ISO class 5 and below, and at intervals not exceeding 12 months for
cleanrooms of class 6 and above. This maximum interval of 12 months
also applies for the other normative compliance tests listed above. Where
the installation is equipped with facilities for continuous or frequent
monitoring, of the airborne particulate concentrations and of the
differential pressure between rooms, the maximum time interval for the
normative tests may be extended to 24 months. In the context of ISO
14644-2, frequent monitoring means that measurements should be
updated at specified intervals not exceeding 60 minutes during utilisation
of the cleanroom. i.e. in its operational state.
What is most baffling, however, is the fact that the standard should
catogorise a test as Optional and in the same breath specify a schedule
indicating the maximum time interval between tests. Perhaps it would
have been prudent to leave the frequency of testing to the discretion of
the User.
Reporting :
The results from testing cleanrooms for compliance with ISO 14644-1
shall be recorded and submitted as a comprehensive report which shall
include the following:
the name and address of the testing organisation, and the date on
which the test was performed;
the number and date of the standard according to which the test
was performed i.e. ISO 14644-1: 199x;
a clear indication of the physical location of the cleanroom tested
(including reference to adjacent areas if necessary), and the
indication of the co-ordinates of all sampling locations;
the specified ISO air cleanliness class, the corresponding
occupancy state(s), and the considered particle size(s);
details of the test method used, comprising also any specific
conditions relating to the test, or departures from the test method;
44 cleanroom operators manual
identification of the test instrument(s) and its (their) current
calibration certificate(s);
the test results, including particle concentration data for all
sampling location co-ordinates;
a statement of compliance or non-compliance with the specified
ISO air cleanliness class.
An important factor here would be evidence from the Testing
Organisation that they are deputing personnel who are qualified to carry
out the tests.
drug & device environmental requirements
Cleanroom technology did not originate from the drug or device industry:
nor did the standards and guidelines governing them. Over the past
four decades it has been, and continues to be, a semiconductor preserve.
Drug Regulators had long realised that these standards solved, at best,
only one part of their problem: particulates or non-viables. An equivalent
standard for microorganisms was clearly needed, and efforts were
required in this direction.
It has been established that the level of microbial contamination of aseptic
products is directly proportional to the aerial microbial concentration in
the room. Though no universal relationship has yet been established
between airborne contaminants and viable airborne contaminants, or
between airborne bacteria-laden particles and airborne inanimate
particles, there may be some situation-specific relationship.
ISO 14698, issued in three parts, recommends a system for bioaerosol
monitoring and control, but owing to the lack of consensus about what
microorganisms are acceptable for whom, and what their concentration
limits ought to be for which application, the standard stops short by
merely stating that the User should define the target levels and derive
the acceptable tolerance limits from that set point.
Both ISO 14644 and US Fed Std 209E base their tables on mathematical
formulae that follows the natural statistical distribution of suspended
particles. In stark contrast, the authors drug and device regulatory
guidance documents have made no such basis or claim. As a happy
accident, some values appear to be in close agreement with those
calculated from formulae advocated by ISO and USFed Std 209E.
ISO was seriously contemplating a change to International Standard
Units and cubic metres, so drug regulators too decided to stay in step.
45 classification of air cleanliness
They have not indicated how cubic metres of air samples are to be
measured when all currently available instrumentation are designed for
taking air samples at the rate of one cubic foot per minute only. What is
the User supposed to do? Run the counter for 35.4 minutes for each
sample? Most counter reset at the end of each minute. Most counters
are not designed for continuous monitoring, or even prolonged periods
of monitoring. Most users are not even aware of this inherent inadequacy.
Why did ISO choose the cubic metre? If they wanted International
Standard Units, then why not litre? The existing classification as
expounded in US Fed 209E was proving inadequate for the semiconductor
industry. The highest grade specified is Class 1, a quality of
environment in which you cannot produce Pentium VI. Hence they were
compelled to shift to a smaller reference particle size: 0.1 micron rather
than 0.5 micron. Also, at the pace at which the demand for cleaner and
cleaner space is growing, the contaminant density would have to be
expressed as particles per larger unit volume: one cubic metre rather
than just cubic foot. (Even the semiconductor industry is still at a loss
as to how to sample this larger volume, and the standard Cleanrooms
and Associated Controlled Environments, Part 3: Metrology and test
methods:14644-3 offers no answer either.)
EUGGMP/WHO/TGA/PIC/Schedule M: manufacture of sterile
medicinal products
Principle
The manufacture of sterile products is subject to special requirements in
order to minimise risks of microbiological contamination, and of
particulate and pyrogen contamination. Much depends on the skill,
training and attitudes of the personnel involved. Quality Assurance bears
a particularly great importance and this type of manufacture must strictly
follow carefully established and validated methods of preparation and
procedure. Sole reliance for sterility or other quality aspects must not be
placed on any terminal process or finished product test.
Note: This Annex does not lay down detailed methods for determining
the microbiological and particulate cleanliness of air, surfaces, etc.
Reference is made to other compendia such as the CEN/ISO Standards.
General
1. The manufacture of sterile products should be carried out in clean
areas, entry to which should be through airlocks for personnel and/or
for equipment and materials. Clean areas should be maintained to an
46 cleanroom operators manual
appropriate cleanliness standard and supplied with air which has passed
through filters of an appropriate efficiency.
2. The various operations of component preparation, product
preparation and filling should be carried out in separate areas within
the clean area. Manufacturing operations are divided into two categories;
firstly those where the product is terminally sterilised, and secondly
those which are conducted aseptically at some or all stages.
3. Clean areas for the manufacture of sterile products are classified
according to the required characteristics of the environment. Each
manufacturing operation requires an appropriate environmental
cleanliness level in the operational state in order to minimise the risks
of particulate or microbial contamination of the product or materials
being handled.
In order to meet in operation conditions these areas should be
designed to reach certain specified air-cleanliness levels in the at-
rest occupancy state.
The at-rest state is the condition where the installation is complete
with production equipment installed and operating but with no operating
personnel present. The in operation state is the condition where the
installation is functioning in the defined operating mode with the
specified number of personnel working.
For the manufacture of sterile medicinal products normally 4 grades
can be distinguished.
Grade A: The local zone for high risk operations, e.g. filling zone,
stopper bowls, open ampoules and vials, making aseptic connections.
Normally such conditions are provided by a laminar airflow
workstation. Laminar airflow systems should provide an
homogeneous air speed of 0.45 m/s +/- 20% (guidance value) at the
working position.
Grade B: In case of aseptic preparation and filling the background
environment for Grade A zone.
Grade C and D: Clean areas for carrying out less critical stages in the
manufacture of sterile products.
The airborne particulate classification for these grades is given in the
following table.
47 classification of air cleanliness
Notes:
(a) In order to reach the B, C and D air grades, the number of air
changes should be related to the size of the room and the
equipment and personnel present in the room. The air system
should be provided with appropriate filters such as HEPA for
grades A, B and C.
(b) The guidance given for the maximum permitted number of
particles in the at rest condition corresponds approximately to
the US Federal Standard 209 E and the ISO classifications as
follows:
grades A and B correspond with class 100, M 3.5, ISO 5; grade C
with class 10 000, M 5.5, ISO 7 and grade D with class 100 000,
M 6.5, ISO 8.
(c) The requirement and limit for this area will depend on the nature
of the operations carried out.
Examples of operations to be carried out in the various grades are given
in the table below (see also para.11 and 12)
The particulate conditions given in the table for the at-rest state should
be achieved in the unmanned state after a short clean up period of 15-
Table 5: Classification of air cleanliness
48 cleanroom operators manual
20 minutes (guidance value), after completion of operations. The
particulate conditions for grade A in operation given in the table should
be maintained in the zone immediately surrounding the product whenever
the product or open container is exposed to the environment. It is accepted
that it may not always be possible to demonstrate conformity with
particulate standards at the point of fill when filling is in progress, due
to the generation of particles or droplets from the product itself.
4. In order to control the particulate cleanliness of the various grades
in operation, the areas should be monitored.
5. In order to control the microbiological cleanliness of the various
grades in operation, the areas should be monitored. Where aseptic
operations are performed monitoring should be frequent using methods
such as settle plates, volumetric air and surface sampling (e.g. swabs
and contact plates). Sampling methods used in operation should not
interfere with zone protection. Results from monitoring should be
considered when reviewing batch documentation for finished product
release. Surfaces and personnel should be monitored after critical
operations.
Additional microbiological monitoring is also required outside
production operations, e.g. after validation of systems, cleaning and
sanitation.
Recommended limits for microbiological monitoring of clean areas in
operation:
Notes:
(a) These are average values
(b) Individual settle plates may be exposed for less than 4 hours
49 classification of air cleanliness
6. Appropriate alert and action limits should be set for the results of
particulate and microbiological monitoring. If these limits are exceeded
operating procedures should prescribe corrective action.
Blow/Fill/Seal Technology
10. Blow/fill/seal units are purpose built machines in which, in one
continuous operation, containers are formed from a thermoplastic
granulate, filled and then sealed, all by the one automatic machine.
Blow/fill/seal equipment used for aseptic production which is fitted with
an effective grade A air shower may be installed in at least a grade C
environment, provided that grade A/B clothing is used. The environment
should comply with the viable and non-viable limits at-rest and the viable
limit only when in operation. Blow/fill/seal equipment used for the
production of products for terminal sterilisation should be installed in
at least a grade D environment.
Because of this special technology particular attention should be paid to
at least the following: equipment design and qualification, validation
and reproducibility of cleaning-in-place and sterilisation-in-place,
background clean room environment in which the equipment is located,
operator training and clothing, and interventions in the critical zone of
the equipment including any aseptic assembly prior to the commencement
of filling.
Terminally sterilised products
11. Preparation of components and most products should be done in at
least a grade D environment in order to give low risk of microbial and
particulate contamination, suitable for filtration and sterilisation. Where
there is unusual risk to the product because of microbial contamination,
for example, because the product actively supports microbial growth or
must be held for a long period before sterilisation or is necessarily
processed not mainly in closed vessels, preparation should be done in a
grade C environment.
Filling of products for terminal sterilisation should be done in at least a
grade C environment.
Where the product is at unusual risk of contamination from the
environment, for example because the filling operation is slow or the
containers are wide-necked or are necessarily exposed for more than a
few seconds before sealing, the filling should be done in a grade A zone
with at least a grade C background.
50 cleanroom operators manual
Preparation and filling of ointments, creams, suspensions and emulsions
should generally be done in a grade C environment before terminal
sterilisation.
Aseptic preparation
12. Components after washing should be handled in at least a grade D
environment. Handling of sterile starting materials and components,
unless subjected to sterilisation or filtration through a micro-organism-
retaining filter later in the process, should be done in a grade A
environment with grade B background.
Preparation of solutions which are to be sterile filtered during the process
should be done in a grade C environment; if not filtered, the preparation
of materials and products should be done in a grade A environment with
a grade B background.
Handling and filling of aseptically prepared products should be done in
a grade A environment with a grade B background.
Transfer of partially closed containers, as used in freeze drying, should,
prior to the completion of stoppering, be done either in a grade A
environment with grade B background or in sealed transfer trays in a
grade B environment.
Preparation and filling of sterile ointments, creams, suspensions and
emulsions should be done in a grade A environment, with a grade B
background, when the product is exposed and is not subsequently filtered.
Premises
22. In clean areas, all exposed surfaces should be smooth, impervious
and unbroken in order to minimise the shedding or accumulation of
particles or micro-organisms and to permit the repeated application of
cleaning agents, and disinfectants where used.
23. To reduce accumulation of dust and to facilitate cleaning there should
be no uncleanable recesses and a minimum of projecting ledges, shelves,
cupboards and equipment. Doors should be designed to avoid those
uncleanable recesses; sliding doors may be undesirable for this reason.
24. False ceilings should be sealed to prevent contamination from the
space above them.
25. Pipes and ducts and other utilities should be installed so that they do
not create recesses, unsealed openings and surfaces which are difficult
to clean.
51 classification of air cleanliness
26. Sinks and drains should be prohibited in grade A/B areas used for
aseptic manufacture. In other areas air breaks should be fitted between
the machine or sink and the drains. Floor drains in lower grade
cleanrooms should be fitted with traps or water seals to prevent back-
flow.
27. Changing rooms should be designed as airlocks and used to provide
physical separation of the different stages of changing and so minimise
microbial and particulate contamination of protective clothing. They
should be flushed effectively with filtered air. The final stage of the
changing room should, in the at-rest state, be the same grade as the area
into which it leads. The use of separate changing rooms for entering
and leaving clean areas is sometimes desirable. In general hand washing
facilities should be provided only in the first stage of the changing rooms.
28. Both airlock doors should not be opened simultaneously. An
interlocking system or a visual and/or audible warning system should
be operated to prevent the opening of more than one door at a time.
29. A filtered air supply should maintain a positive pressure and an air
flow relative to surrounding areas of a lower grade under all operational
conditions and should flush the area effectively. Adjacent rooms of
different grades should have a pressure differential of 10-15 pascals
(guidance values). Particular attention should be paid to the protection
of the zone of greatest risk, that is, the immediate environment to which
a product and cleaned components which contact the product are exposed.
The various recommendations regarding air supplies and pressure
differentials may need to be modified where it becomes necessary to
contain some materials, e.g. pathogenic, highly toxic, radioactive or
live viral or bacterial materials or products. Decontamination of facilities
and treatment of air leaving a clean area may be necessary for some
operations.
30. It should be demonstrated that airflow patterns do not present a
contamination risk, e.g. care should be taken to ensure that airflows do
not distribute particles from a particle-generating person, operation or
machine to a zone of higher product risk.
31. A warning system should be provided to indicate failure in the air
supply. Indicators of pressure differences should be fitted between areas
where these differences are important. These pressure differences should
be recorded regularly or otherwise documented.
52 cleanroom operators manual
Equipment
32. A conveyor belt should not pass through a partition between a grade
A or B area and a processing area of lower air cleanliness, unless the
belt itself is continually sterilised (e.g. in a sterilising tunnel).
33. As far as practicable, equipment, fittings and services should be
designed and installed so that operations, maintenance and repairs can
be carried out outside the clean area. If sterilisation is required, it should
be carried out after complete reassembly wherever possible.
34. When equipment maintenance has been carried out within the clean
area, the area should be cleaned, disinfected and/or sterilised where
appropriate, before processing recommences if the required standards
of cleanliness and/or asepsis have not been maintained during the work.
35. Water treatment plants and distribution systems should be designed,
constructed and maintained so as to ensure a reliable source of water of
an appropriate quality. They should not be operated beyond their designed
capacity. Water for injections should be produced, stored and distributed
in a manner which prevents microbial growth, for example by constant
circulation at a temperature above 70C.
36. All equipment such as sterilisers, air handling and filtration systems,
air vent and gas filters, water treatment, generation, storage and
distribution systems should be subject to validation and planned
maintenance; their return to use should be approved.
Sanitation
37. The sanitation of clean areas is particularly important. They should
be cleaned thoroughly in accordance with a written programme. Where
disinfectants are used, more than one type should be employed.
Monitoring should be undertaken regularly in order to detect the
development of resistant strains.
38. Disinfectants and detergents should be monitored for microbial
contamination; dilutions should be kept in previously cleaned containers
and should only be stored for defined periods unless sterilised.
Disinfectants and detergents used in Grades A and B areas should be
sterile prior to use.
39. Fumigation of clean areas may be useful for reducing microbiological
contamination in inaccessible places.
53 classification of air cleanliness
WHO - airborne viable count
Schedule M - airborne viable count
Notes:
a. These are average values.
b. Individual settle plates may be exposed for not less than two hours
in Grade B, C and D areas and for not less than thirty minutes in
Grade A area.
USFDA: airborne viable & non-viable
a- All classifications based on data measured in the vicinity of
exposed materials/articles during periods of activity.
Grade Air sample Settle plates Contact plates Glove prints
(dia. 90 mm) (dia 55mm) (five fingers)
Cfu/m
3
Cfu/m
3
cfu per plate cfu per glove
A < 1 < 1 < 1 < 1
B 10 5 5 5
C 100 50 25 -
D 500 100 50 -
Air classifications
a
b- ISO 14644-1 designations provide uniform particle concentration
values for cleanrooms in multiple industries. An ISO 5 particle
concentration is equal to Class 100 and approximately equals EU
Grade A.
c- Values represent recommended levels of environmental quality.
You may find it appropriate to establish alternate microbiological
levels due to the nature of the operation.
d- The additional use of settling plates is optional.
e- Samples from Class 100 (ISO 5) environments should normally
yield no microbiological contaminants.
entry and exit of personnel
Author W Whyte has kindly allowed the reproduction from his book
Cleanroom Technology Design, Testing and Operation published
in 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).
P
eople can disperse millions of particles and thousands of microbe-
carrying particles from their skin and clothing. It is therefore
necessary for personnel working in a cleanroom to change into
clothing that minimises this dispersion.
Cleanroom clothing is made from fabrics that do not break up and lint;
they therefore disperse the minimum of fibres and particles. Cleanroom
clothing also acts as a filter against particles dispersed from the persons
skin and their indoor, or factory, clothing.
The type of cleanroom clothing used varies according to the type of
cleanroom. In cleanrooms where contamination control is very important,
personnel wear clothing that completely envelops them and prevent their
contamination being dispersed, i.e. a coverall, hood, facemask, knee-
length boots and gloves. In cleanrooms where contamination is not as
important, less enveloping clothing such as a smock, cap and shoe covers
may be quite sufficient.
4 4
4 44
56 cleanroom operators manual
Whatever the choice of clothing, garments will have to be donned prior
to entering the cleanroom, and they should be put on in such a way that
the outside of the clothing is not contaminated. This chapter describes
typical methods.
Some types of cleanroom garments are worn once before being thrown
away; others are sent for cleaning and processing after being used once.
However, garments are normally used more than once. It may therefore
be necessary to devise a storage method to ensure that a minimum of
contamination is deposited onto them. Possible methods are discussed
at the end of this chapter.
prior to arriving at the cleanroom
Poor personal cleanliness is not acceptable in a cleanroom. However it
is not clear how often personnel should bathe or shower, there being
little in the way of scientific investigations into this topic. Clearly a
shower would be necessary if someone has just had a haircut and is
likely to shed hair clippings. It is known that washing can remove the
natural skin oils and, in some individuals, the dispersion of skin and
skin bacteria can increase. People with dry skin may wish to use a skin
lotion to replace the lost skin oils.
Consideration should be given to what clothing is best worn below
cleanroom garments. Clothing made from artificial fibres, such as
polyester, are better than those made from wool and cotton, because
synthetic fabrics disperse much fewer particles and fibres. Close-woven
fabrics are also an advantage, as these are more effective in filtering and
controlling the particles and microbe-carrying particles dispersed from
the skin. This type of problem will be overcome if personnel are issued
with factory undergarments. These should be made from a fabric that
does not lint, and it should effectively filter particles dispersed from the
person.
Personnel should consider whether applying cosmetics, hair spray, nail
varnish, etc. at home is necessary, as these should be removed prior to
entering the cleanroom. They should also consider what rings, watches
and valuables they will bring to work, as they are likely to be removed
and stored.
changing into cleanroom garments
The best method of changing into cleanroom garments is one that
minimises contamination getting onto the outside of the garments. One
57 entry and exit of personnel
such method is described below. Some of the suggested procedures may
be unnecessary in poorer classes of cleanrooms, and further procedures
can be introduced in cleanrooms that manufacture products very
susceptible to contamination. It should also be noted that alternatives to
the proposed method are successfully used in existing cleanrooms, and
these are quite acceptable as long as they give a level of contamination
control appropriate to the standard of the cleanroom.
The design of clothing change areas is is normally divided into zones.
These may be rooms, or rooms divided by crossover benches. Change
areas can vary in design, but it is common to find them divided into
three zones:
1. Pre-change zone
2. Changing zone
3. Cleanroom entrance zone.
Personnel move through the zones in the following manner.
approaching the pre-change zone
Before starting to change into cleanroom clothing, it is best that personnel
blow their nose. It is impossible to do this correctly in a cleanroom, and
if this is done it will save an unnecessary trip out of the cleanroom.
They should also go to the toilet. If it is necessary to come out of the
cleanroom to go to the toilet, it is likely to entail changing out and back
into cleanroom clothing.
In cleanrooms where outdoor shoes are not removed, or effectively
covered, shoe cleaners should be used. Cleanroom shoe cleaners are
specially made to retain contamination dispersed from the shoe.
Sticky cleanroom mats or flooring are often used in the approach to the
change room. These are specially manufactured for use in cleanrooms.
There are two general types. One type is laminated from layers of thin
adhesive plastic film and the other from a thick resilient adhesive plastic.
Both work by removing dirt from the soles of footwear as personnel
walk over them. After a while they become soiled. In the case of the
plastic film version, the topmost layer is peeled off to expose a fresh
layer. In the case of the resilient plastic type the surface is washed.
If a laminated mat is used, shoes should be applied to a mat three times
to ensure the removal of practically all of the footwear contamination. If
the resilient-type cleanroom flooring is used it can cover a floor surface
58 cleanroom operators manual
area large enough to ensure that sufficient steps are placed on it to ensure
effective dirt removal. This is a minimum of three per foot i.e. six in all.
pre-change zone
Within the pre-change zone the following tasks may be carried out:
1. Personnel should remove sufficient street or factory clothes to feel
comfortable in the cleanroom. If the company provides dedicated
clothing to wear under the cleanroom garments, then all street
clothing should be removed and replaced with factory garments.
2. Watches and rings should be removed. They can harbour dirt,
produce chemical and particle contamination, and are liable to tear
gloves. Wedding rings that are smooth may be kept on if the ring (and
under the ring) is kept clean. Rings that are not smooth can be taped
over. Items such as cigarettes and lighters, wallets and other valuables
should be securely stored.
3. Remove cosmetics and, if required, apply a suitable skin
moisturiser. The composition of any moisturiser should be considered
to ensure that no chemicals used in the formulation cause
contamination problems in the product being manufactured.
4. Don a disposable bouffant hat, or hairnet. This ensures that hair
does not stick out from under the cleanroom hood.
5. Put on a beard cover, if appropriate.
6. Put on a pair of disposable footwear coverings, or change into
dedicated cleanroom shoes.
7. If a hand washing system is located in this area then wash the
hands, dry them and, if necessary, apply a suitable hand lotion.
However, it is probably best if hands are washed within the change
area just before the clean garments are put on (see below). If gloves
are used to put on cleanroom clothing, then hand washing can be
done here. In bioclean areas, it will be necessary to wash the hands in
a suitable skin disinfectant. Hands can be dried with a non-linting
towel or a hand drier. If a hand drier is used then the best type is one
that does not disturb the dirt on the floor.
8. Cross over from the pre-entry area into the change zone. The
demarcation between these two zones may be a door or a crossover
bench, or both. A sit-on transfer bench may be built across the zones
to ensure that personnel cannot walk round but must cross over it. If a
bench is used footwear should be attended to as it is crossed. If a
bench is not used, then a cleanroom mat or flooring should be used.
Personnel should stop at the mat and put their footwear three times to
59 entry and exit of personnel
the mat to make certain that it is clean and the minimum of
contamination is tracked into the next zone.
changing zone
The garments used in the cleanroom are put on in this area. Several
methods can be used but the following is suggested. This uses a method
assumes that a facemask, hood, coverall and overboots are used, but it
can be adapted for use with a cap, gown and overshoes. It requires that
the garments are put on from the top down.
1. The garments to be worn are selected. If a fresh garment is used,
then it should be checked for size and the packaging checked to
ensure that it is free from tears and faulty heat seals. The packaging is
then opened.
2. A facemask and hood (or cap) is put on. It appears to make little
difference whether the mask is put under, or over, the hood. Choose
which method is the most comfortable. If a hood is put on, the hair
must be tucked in and the studs (snaps) or ties at the back of the hood
adjusted for comfort.
3. If a hand washing system is installed in this area then the hands
should now be washed (and disinfected if required). This is possibly
the best time for personnel to wash their hands as clean garments will
now be handled and contaminated parts of the body, such as the hair
and face, should not be touched again.
4. Temporary gloves known as donning gloves are sometimes used
to prevent the outside of the cleanroom garment being contaminated.
Use of these gloves is confined to the higher quality of cleanroom.
These should, if required, be put on.
5. The coverall (or gown) should be removed from its packaging and
unfolded without touching the floor. It is sometimes possible to get the
cleanroom laundry to fold the garment in a way that will minimise
both the chance of the garment touching the floor and the outside
surface being contaminated by the personnels hands. If this is not
done, then the following can be considered.
If a coverall is used, it should be removed from its packing and allowed
to unfold without touching the floor. It should be unzipped and turned
so that the zip is to the side away from the person.
There are now several methods of putting on the garment to ensure that
it does not touch the floor. These are as follows:
60 cleanroom operators manual
The coverall can be gathered together at the 4 corners i.e. the two
wrists and the two ankles. It should then be possible to put first one
leg and then the other into the garment without the trouser legs
touching the floor.
The garment can be held in the inside at waist level, some of the
material gathered up and one leg and then the other put in to the
trouser legs. The top of the coverall can then be slipped over the
shoulders, or,
The left cuff and left zipper can be taken in the left hand and the
right zipper and right cuff taken in the right hand. The coverall can
then be gathered up at the waist and one leg placed into the garment,
and then the other leg placed into the other garment leg. By releasing
one cuff at a time, first one arm and then the other can be placed into
the garment.
The last two methods will work better if the trouser legs are folded back
on themselves so that they are shorter and less likely to touch the floor.
The garment should then be zipped all the way up to the top, ensuring
that all of the hood (if used) is tucked under the collar. A mirror is useful
at this stage. If the garment has press studs (snaps) at the ankles and
wrists, then these should be snapped shut.
cleanroom entrance zone
1. If a crossover bench is available, it should be crossed over now.
This bench is used to demarcate the slightly soiled changing-zone
from the cleaner entrance zone, and allows cleanroom footwear
(overshoes or overboots) to be correctly put on.
2. Personnel should sit on the bench. One leg should be raised, the
cleanroom footwear put on, the leg transferred over the bench and
placed on the floor of the entrance zone. Then the other leg should be
raised, the cleanroom footwear put on and the leg taken over the
bench. While still sitting on the bench, the legs of the cleanroom
garment and the footwear should be adjusted for comfort and security.
Personnel should now stand up.
3. If required, protective goggles can be put on. These are used not
only for safety reasons but to prevent eyelashes and eyebrow hair
falling onto the product.
4. The garments should be checked in a full-length mirror to see that
they are worn correctly. Check that the hood is tucked in and there are
no gaps between it and the coverall (or gown). Check that no hair can
be seen.
61 entry and exit of personnel
5. If donning gloves have been used they can be dispensed with now.
They can, however, be kept on and a pair of clean working gloves put
on top. Two pairs of gloves can be used as a precaution against
punctures, although sensitivity of touch is lost.
6. If deemed necessary, the hands can again be washed. Gloves can
also be washed. In a biocleanroom it is beneficial to decontaminate
the hands by applying an alcohol solution containing a skin
disinfectant. Apart from being more efficient, the use of an alcohol
solution overcomes the problem of having a washhand basin in the
room, with its attendant risk of microbial growth.
7. Low particle (and if required, sterile) working gloves should now
be put on, without the outside of them becoming contaminated. In
some cleanrooms this task is left until the personnel is within the
production cleanroom. If they are latex gloves, which are wrapped in
pairs with the cuffs rolled back (in the style used by surgeons), then
the gloves can be put on without being contaminated. In this case, the
first glove is taken out of the exposed package by gripping the fold of
the rolled-over cuff with the one hand and inserting the other hand
into it. Two fingers of the gloved hand are then passed under the
rolled-over cuff of the second glove and it is lifted from the package.
The hand is then put into the second glove, the fingers being slotted
into the correct fingers of the glove, and the cuff lifted over the cuff of
the cleanroom garment. It is now possible to pull back the cuff of the
first glove, making sure that it is completely over the garments cuff.
8. Most cleanroom gloves are not packed in a way that will allow
gloves to be put on without contaminating the glove surface. These
gloves must be gripped at the edge of the cuff and put on in a similar
way to that described above. Gloves packed in pairs will be
contaminated less than those packed in 50s or 100s, as it is difficult to
remove a glove from a large pack without contaminating those that
are left. If considered necessary, the gloves can now be washed or
disinfected.
9. Personnel may now proceed into the cleanroom. This may be over
a cleanroom mat.
exit changing procedures
When leaving a cleanroom, personnel will either (i) discard all their
garments and on re-entry use a new set of garments (this is normally
only employed in an aseptic pharmaceutical cleanroom), or (ii) discard
their disposable items, such as masks and gloves, but reuse their coverall,
smock, etc. on re-entry.
If a complete change of clothing is required on re-entry, then the
disposable items such as bouffant hats, gloves, facemask and disposable
overshoes are placed in a container for disposal. If the remainder of the
garments are not disposable then they should be placed in a separate
container for dispatch to the cleanroom laundry for processing.
If the garments are to be used again on re-entry, they should be removed
so that the outside of the garment is contaminated as little as possible.
The cleanroom footwear should be removed, one at a time, at a cross-
over bench, as each leg is taken over the bench. The coverall should
then be unzipped and removed using the hands within the garment to
remove it over the shoulder and down to the waist. In a sitting position,
one leg is now removed the garment. The empty arm and leg of the
garment should be held so that they do not touch the floor. The other leg
can now be removed. The facemask and hood can now be removed.
Garments to be used again on re-entry should be stored to prevent
contamination. This can be done in several ways, as follows:
Each item of clothing can be rolled up. In the case of cleanroom
footwear this should be done so that the dirty soles are to the outside.
The footwear can now be placed in separate pigeon holes and the
hood and coverall (or cap and gown) in another. If thought necessary,
the items of clothing can be placed into bags before being put into the
pigeon holes.
The hood (or cap) can be attached to the outside of the coverall (or
gown) by means of a snap (stud) and hung up, preferably in a cabinet.
The cleanroom footwear can be placed at the bottom of the cabinet. It
is best that their garments should not touch the wall, or each other. In
higher grade cleanrooms, clothing is often hung up in unidirectional
flow cabinets, specifically designed to ensure that garments are not
contaminated.
Garment bags can be used. These will have separate pockets for
the various clothing items and should be regularly laundered.
cleanroom disciplines
Author W Whyte has kindly allowed the reproduction from his book
Cleanroom Technology Design, Testing and Operation published
in 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).
C
leanroom personnel are a important source of cleanroom
contamination. Almost all micro-organisms found in a cleanroom
come from personnel, and they are also a major source of particles
and fibres. It is therefore necessary to ensure the minimum of
contamination is generated and transferred by personnel activities. By
observing certain disciplines, contamination of the product can be
minimised. These are discussed in this chapter.
When a cleanroom is about to be opened, management is faced with the
task of employing people to work in the room, and determining what
disciplines personnel (including maintenance and service technicians)
should adhere to within the cleanroom. It is hoped that this chapter will
assist in this task.
It should be noted that products manufactured in a cleanroom vary in
their sensitivity to contamination, and cleanroom disciplines should
reflect this. The information given in this chapter are options from which
5 5
5 55
64 cleanroom operators manual
the user can choose methods that best reflect the degree of risk associated
with their cleanroom.
people allowed into cleanrooms
People can, when walking, produce about 1 000 000 particles > 0.5 m
and several thousand microbe-carrying particles per minute. The more
people, the higher the dispersion within the cleanroom. It is therefore
important that the minimum of people, i.e. only the essential personnel
are allowed into cleanrooms, and management should ensure that this
is so.
Because many contamination problems are caused by lack of knowledge,
only people trained to work in a cleanroom should be allowed within
the cleanroom. Personnel should therefore be formally trained in the
various aspects of contamination control. Visitors should be discouraged
and only allowed in under the control of a supervisor; if a cleanroom is
designed with windows for visitors to look into the cleanroom, this will
usually suffice. Special care should be taken with service and maintenance
technicians, and their tools and materials; this is discussed at the end of
this chapter.
People who enter the cleanroom should not disperse significantly greater
amounts of contamination than the normal population. Given below are
examples of conditions that can cause more contamination than normal,
and may therefore be unacceptable. Acceptability will depend on the
risk, e.g. whether micro-organisms are a hazard, and whether the product
is highly susceptible to contamination or not. It will therefore be up to
management to decide which conditions are important.
The following suggestions contain criteria that can discriminate against
some personnel. It should be ensured that any discrimination is neither
illegal nor unfair. The list also contains a number of temporary
conditions. These are included as they may be a reason for temporarily
assigning personnel to a job outside the cleanroom.
Skin conditions where unusually large amounts of skin cells are
dispersed, such as dermatitis, sunburn or bad dandruff.
Respiratory conditions such as coughing or sneezing caused by
colds, flu or chronic lung disease.
In a biocleanroom, it may be necessary to screen personnel for the
carriage of micro-organisms that could grow in the product and cause
spoilage or disease. Their suitability for work in a cleanroom should
65 cleanroom disciplines
be considered with respect to the susceptibility of the product to
specific types of microbial growth.
People with allergic conditions, which cause sneezing, itching,
scratching, or a running nose, may not be suitable for employment in
a cleanroom. Sufferers from hay fever are likely to find relief in a
cleanroom because the air filtration system will filter out the allergens
responsible. Some people may be allergic to materials used in the
cleanroom, such as (a) garments made from polyester, (b) plastic or
latex gloves, (c) chemicals such as acids, solvents, cleaning agents
and disinfectants, and (d) products manufactured in the room, e.g.
antibiotics and hormones.
Depending on the contamination risk within the cleanroom, some
or all of the following suggestions should be brought to the attention
of the staff so that contamination within the room may be minimised:
Personnel should have a good level of personal hygiene. They
should shower regularly and keep dandruff at bay. They should wash
their hair after a haircut to prevent hair landing on the product. In the
case of dry skin, they should use skin lotion to replace skin oil that is
lacking; this should reduce dispersion.
Materials such as cosmetics, talcum powder, hair sprays, nail
polish, or similar materials are not normally allowed in a cleanrooms.
Anything added on to the body should generally be considered a
contaminant. Cosmetics are a particular problem in semiconductor
manufacturing as they contain a large amount of inorganic ions such
as titanium, iron, aluminium, calcium, barium, sodium and
magnesium. In the photographic industry, iron and iodine ions give
problems. Other industries, which do not have a problem with specific
chemicals, may still experience problems as each application will
deposit large numbers of particles (up to 10
9
for particles 0.5 mm)
on the skin. Some of these will detach in the cleanroom.
Watches and jewellery are normally not allowed in a cleanroom. If
jewellery is allowed, it must be under the clothing and gloves. Rings
can puncture gloves and harbour contamination under them.
Personnel may be reluctant, for sentimental reasons, to remove their
wedding or engagement rings. They may be allowed to keep them on
if the skin under the rings, as well as the rings, is washed. Where the
rings are liable to puncture the glove they should be taped over.
Smokers are said to produce more particles from their mouth than
the normal population and outgas chemicals from their body. It may
be necessary to ensure that they have not smoked for several hours
before entering the cleanroom. It has been reported that taking a drink
66 cleanroom operators manual
of water before entering the cleanroom reduces the number of
particles given off from the mouth.
personal items not allowed into the cleanroom
As a general rule, nothing should be allowed into the cleanroom that is
not required for production within the room. However, it is up to the
management of the cleanroom to decide what items could cause
contamination of the product. Items that should be considered for
inclusion in a list of prohibited items are:
food, drink, sweets and chewing gum
cans or bottles
smoking materials
radios, CD players, Walkmans, cell phones, pagers, etc.
newspapers, magazines, books and paper handkerchiefs
pencils and erasers
wallets, purses and other similar items.
disciplines within the cleanroom
Within a cleanroom, many rules-of-conduct must be followed to ensure
that products are not contaminated. The management must produce a
set of written procedures suitable for their room. It may be useful to
have these does and donts posted in the change or production area.
Commonly used procedures that may be adopted are given below. These
procedures do not consider the choice of cleanroom garments, masks,
gloves and similar clothing items.
air transfer
To ensure that air is not transferred from an area of high contamination
to one of lower contamination (e.g. the outside corridor to the production
room) the following disciplines should be adhered to:
1. Personnel must always come in and out of the cleanroom through
change areas. The change area is used not only to change clothing,
but as a buffer zone between the outer dirty corridor and the inner
clean production area. Personnel should not use any entrance, such as
an emergency exit, which leads directly from the production area to
the corridor; this will allow contamination to enter directly into the
cleanroom, and their garments may also become contaminated.
2. Doors should not be left open. If they are, air will be transferred
between the two adjoining areas because of general air turbulence as
67 cleanroom disciplines
well as air transfer caused by a temperature difference between the
two areas.
3. Doors should not be opened or closed quickly, or air will be
pumped from one area to the other.
4. Doors usually open inwards into the production room and are held
shut by the higher pressure. However, to aid the movement of
personnel who are carrying materials, some doors open outwards.
Doors should then be fitted with door-closing devices to ensure that
the doors are kept closed, and shut slowly to reduce the air transfer.
Doors without handles will assist in preventing contamination of
gloves.
5. When passing through the doors in an airlock, personnel should
ensure the first door is closed before going through the next one.
Electrical interlocks between entry and exit doors achieve this, but
care must be taken to ensure that there is no danger in the case of fire.
Indicator lights, which show if the doors are shut, are also used. Pass-
through hatches should be used in a similar way.
personnel behaviour
The following suggestions should be considered to ensure that personnel
do not contribute to the contamination within the room:
1. Silly behaviour should not be allowed. The generation of
contamination is proportional to activity. A motionless person can
generate about 100 000 particles >0.5 m/min. A person with head,
arms and body moving can generate about 1 000 000 particles &0.5
m/min. A person who is walking can generate about 5 000 000 particles
0.5 m/min. Personnel who move quickly passed products may cause a
disturbance of the air that leads to contamination.
Austins Index of contaminants shed by personnel: Particle dispersion in relation to movement
Activity Particles > 0.3 Viable contaminants
emitted per minute generated per minute
Standing or sitting without movement 100,000 750
Light head, hand & forearm movement 500,000 1,000
Moderate body and arm movement 1,000,000 1,500
Changing positions - sitting to standing 2,500,000 2,500
Slow walking 5,000,000 4,000
Moderate walking 7,500,000 8,000
Fast walking 10,000,000 15,000
Climbing stairs 10,000,000 15,000
Calisthenics > 15,000,000 30,000
Coughing > 15,000,000 > 30,000
Sneezing (excluding large droplets) > 30,000,000 > 50,000
68 cleanroom operators manual
2. Personnel should position themselves correctly with respect to the
product, so that contamination does not land on it. They should not
lean over the product in such a way that particles, fibres or microbe-
carrying particles, fall from personnel onto the product. If personnel
are working in a flow of unidirectional air, they should make sure that
they are not between the product and the source of the clean air, i.e.
the air filter. If they are, a shower of particles could deposit on the
product. Methods of working should be pre-planned to minimise this
type of contamination.
3. Consideration must be given as to how products are moved or
manipulated. No-touch techniques should be devised to prevent
contamination getting from the gloved hand onto the product.
Although gloves are worn in cleanrooms, they are still likely to be a
source of contamination (although a reduced one). An example of this
no touch technique is the use of long forceps rather than hands to
grip materials.
o Each cleanroom should have its own no-touch rules to ensure
that the product is not contaminated.
o Oil and skin particles would contaminate the wafer with
catastrophic results. If the wafer is held around the edge of the wafer
then contamination is reduced, but can still get onto the surface.
o Use of a glove will reduce contamination yet further, and this
technique is still used where the line widths are large and a lower
yield acceptable.
o In semiconductor facilities, wafers will be handled with a vacuum
wand which attaches itself to the back of the wafer Robotic
manipulation can also minimise contamination.
4. Personnel should not support material against their body.
Although they will be wearing cleanroom clothing, which is much
cleaner than indoor or factory clothing, it is not contamination free.
Particles, fibres and micro-organisms can be transferred onto the
items carried.
5. Personnel should not talk when working over the product, or
spittle from the mouth will pass round the imperfect seal between the
mask and the skin and contaminate the product. Talking, coughing or
sneezing can release contamination from the mask surface. If
personnel cough or sneeze, they must turn their head away from the
product. Masks are often replaced after sneezing. Masks must not be
worn below the nose but over the nose as large particles can be
released from the nose when snorting.
It is generally not good practice for personnel to touch cleanroom
69 cleanroom disciplines
surfaces. Although cleanroom surfaces are very much cleaner than
those outside the cleanroom, its surfaces, and that of the machinery in
the room, will have particles, fibres and bacteria on them. If personnel
touch their garments or mask, they also will pick up contamination on
their gloves, which may be transferred to the product. Hands grasped
together in front of the personnel, in the style of a hospital surgeon,
will help to ensure that they do not inadvertently touch surfaces.
6. Personal handkerchiefs should not be brought into cleanrooms.
These are clearly a major source of contamination and will transfer
particles and microbe-carrying particles into the air and onto gloves.
Noses should not be blown inside a cleanroom. The change area may
be an acceptable alternative.
7. Washing, or disinfection when required, of gloves during use
should be considered. Glove washing can be used in cleanrooms
where products are handled and there are particular difficulties in
keeping gloves clean. For example, in aseptic pharmaceutical
production areas, gloved hands are rinsed with a suitable disinfectant
(70% ethanol or iso-propanol) at regular intervals and prior to
starting a critical operation. Alcohols are particularly useful, as they
do not leave a residue on the glove.
handling materials
The following suggestions, which refer to the materials used in the
cleanroom, should be considered:
Cleanroom wipers that have low concentration of contamination
should be used. The exact type of wiper that is selected will depend on
the financial budget and what is being produced in the cleanroom. It
will also be necessary to decide how often a wipe should be used before
being discarded.
The movement of materials between the inside and outside of a
cleanroom should be minimised. Every time a product moves out of
the cleanroom there is a high possibility of it being contaminated in
the less-clean area, and this contamination being brought back when
it re-enters. It is best to store products in a suitable clean area within
the cleanroom, or in an adjoining clean area.
It is normal to find that great care has been taken to ensure that a
product is not contaminated during its manipulation stages. However,
after that, it can often be forgotten and left out in the cleanroom to
gather dust. Products that are susceptible to contamination should
therefore be kept in closed cabinets, containers, unidirectional flow
70 cleanroom operators manual
benches, or isolators. If the airflow in the cleanroom is unidirectional,
storage racks of the type that allow air to flow through are a good
choice. Materials should not be left standing on the floor.
Waste material should be collected frequently into easily identified
containers and removed frequently from the cleanroom.
Cleanrooms should be correctly cleaned (and disinfected if
required).
The cleanroom must be kept neat and tidy. If it is not tidy, it
cannot be kept clean.
maintenance and service personnel
Through lack of training or supervision, people who enter a cleanroom
to maintain or service machinery can be a considerable hazard. The
maintenance technician, unless instructed otherwise, will apply the same
techniques as they do outside the cleanroom. Service personnel from
outside firms may be completely untrained in cleanroom contamination
control techniques. The following is a list of procedures that should be
considered for maintenance and service personnel:
Maintenance and service technicians should only enter a
cleanroom with permission.
Maintenance and service technicians should be trained in
cleanroom techniques, or closely supervised when they are within the
cleanroom.
Technicians must wear the same, or equally efficient, cleanroom
clothing as cleanroom personnel, and use the same techniques to
change into cleanroom clothing when entering and exiting
cleanrooms. They should never enter the cleanrooms (especially at
weekends, or when no one else is around) without changing into
cleanroom clothing.
Technicians should ensure they remove dirty boiler suits, etc. and
wash their hands before changing into cleanroom clothing.
Tools that are used routinely for maintaining the cleanroom should
be cleaned (and sterilised, if required) and kept stored for sole used
within the cleanroom. Tools should be made from materials that do
not corrode. For example, stainless steel is much preferred to mild
steel tools , which may rust.
If a service engineer or contractor brings tools into the cleanroom
(especially those from outside the cleanroom organisation), then they
must be cleaned. A wipe-down with a cleanroom wiper moistened
with isopropyl alcohol (often 70%, in water) is a suitable method.
71 cleanroom disciplines
Only the tools or instruments needed within the room should be
selected, decontaminated, and put into a cleanroom compatible bag or
container. This has the advantage of leaving behind cases or
briefcases, with their associated scraps of paper, fluff etc., which are
potential sources of contamination; these should not be allowed into
the room.
Spare parts or items, like fluorescent light tubes, which have
wrappings, should have the wrappings removed outside the
manufacturing area and the parts wiped down.
Written methods should be kept for each activity, so that
contamination control techniques can be incorporated within a
specification. These should be adhered to.
Any instructions or drawings on non-cleanroom paper must not be
taken into the cleanroom. They can be photocopied onto cleanroom
paper, or laminated within plastic sheets, or placed in sealed plastic
bags.
Particle generating operations such as drilling holes, or repairing
ceilings and floors should be isolated from the rest of the area. A
localised extract or vacuum can also be used to remove any dust
generated.
Technicians should not bring any materials into a cleanroom that
are given on a list of contaminating material.
Technicians must tidy up when they are finished and ensure that the
area is then cleanroom cleaned by a person with suitable knowledge.
Only cleaning agents, materials and equipment that has been approved
for use in the cleanroom should be used.
human interface in cleanrooms
A
cleanroom is a special environment constructed at great cost,
operated and maintained at great expense, with the sole purpose
of insuring consistency in product quality and value and
minimising product contamination or failure. The best design, layout
and materials are worthless if the people working in the cleanroom do
not fully understand its significance or the whats and whys of its
operations.
Even in the best designed clean rooms microcontamination continues to
occur, and research studies on causes of such occurrences reveal that in
8 out of 10 cases failure can be traced to the humans in the environment.
It is common knowledge that contaminant level shoots up at
commencement of shift, and is directly proportional to the number of
people in the room. It drops only when activity ceases, and people exit.
With the employee brought into such sharp focus in the
microcontamination control process, training in good manufacturing
C K Moorthy
6 6
6 66
74 cleanroom operators manual
practices becomes one of the more important factors that influence the
quality and consistency of the finished product.
biologic factory
Humans may be viewed as biologic factories. They take in food, water
and air; generate energy; manufacture cells and other body parts for
growth, repair or replacement; and produce by-products and wastes,
just as in any common continuous processing plant.
Thus having a human in a cleanroom is in reality permitting a hi-tech
functioning mobile bioprocessing plant into your environment, complete
with its effluents. As part of our microcontamination control programme,
we begin by studying this factory from the cleanroom perspective.
The several layers of skin that cover the body are not monolithic films,
but an aggregate of millions of cells, each a microscopic fig leaf. These
cells die as a matter of course, and are constantly replenished. This
includes scalp flakes, or dandruff.
These dead cells are continually discarded. Unlike trees, which shed
leaves only in one season, our skin cells are shed every minute of every
living day and night. These cells are approximately 30 in length, 5
in width and less than 0.5 in thickness. The rate at which skin cells
are shed is influenced by the condition of the skin, its oil content, the
climate and the nature of activity. After shave lotions dissolve skin oils
and accelerate sloughing and flaking. Similarly, alcohols, while popular
Figure 1: Contaminant density profile


75 human interface in cleanrooms


as disinfectants, unless used with emollients like glycerol, tend to dissolve
the skin oils and aggravate shedding. Austin and others have carried
out extensive studies on this phenomenon and their results are
summarised here.
The different organisms present on the skin may be classified as transient
organisms (microorganisms which are deposited on and contaminate
the skin but do not multiply there), temporary residents (viable
contaminants that multiply on the skin and persist for short periods)
and resident organisms (microorganisms which colonise the deeper
crevices of the skin and hair follicles - 20% of skin bacteria are situated
deep within the skin, covered and protected by lipids and superficial
cornified epithelium, and are most inaccessible). The numbers and types
of bacteria on the skin differ considerably according to the body site
where they are found, or the sampling technique that may be employed.
In addition, individual variation in numbers is vast. This variation can
depend upon skin pH, fatty acids, age, condition, and the temperature
and humidity of the skin and environment. Some people may spread
bacteria more easily than others. Although the number of bacteria on
the skin of the hand is comparatively low, there is still a wide variation
from person to person. It is known that some individuals have
consistently high bacterial counts on their finger tips, while others have
Activity Particles > 0.3F
emitted
per minute*
Viable
contaminants
generated
per minute*
Standing or sitting without movement 100,000 750
Light head, hand & forearm movement 500,000 1,000
Moderate body and arm movement 1,000,000 1,500
Changing positions - sitting to standing 2,500,000 2,500
Slow walking 5,000,000 4,000
Moderate walking 7,500,000 8,000
Fast walking 10,000,000 15,000
Climbing stairs 10,000,000 15,000
Calisthenics $ 15,000,000 30,000
Coughing $ 15,000,000 $ 30,000
Sneezing (excluding large droplets) $ 30,000,000 $ 50,000
Austins Index of contaminants shed by personnel
* These figures refer not to contaminant density but to gross contaminant rate
Table 1: Austins contamination index
76 cleanroom operators manual
very low counts regardless of the method of hand washing or disinfectant
employed. Swabs are increasingly being taken from parts of the body
other than the conventional glove/finger prints. One organisation takes
swab samples from soles of operators' feet, abdomen, forearm and
forehead.
While it is generally agreed that the removal or killing of the transient
and temporarily resident flora is sufficient to prevent their transfer to
the product, any removal of resident flora is deemed a valuable additional
safeguard.
The body has glands all over, each producing its own substance. Oils,
sweat, saline, saliva, and wax are some of the substances so produced
that have the potential to contaminate the environment. We are familiar
with the oil stains that accompany our finger prints; each time we blink
we splash saline; when we open our mouths we spray droplets of saliva;
the sweat we generate passes through our clothes to a greater or lesser
extent, depending on the permeability of the fabric, by capillary action;
Site
Aerobic flora Anaerobic flora
Females Males
Forehead 2075 1225 8000 13500
Sternum 2125 165 50000 3500
Subclavicular area 350 130 18500 2275
Centre back 450 155 67500 7500
Shoulder 128 48 1025 1075
Deltoid area 118 65 57 127
Forearm 250 35 9 13
Palm 98 155 33 85
Lower axilla 500 92 14 12
Lumbar area 300 33 178 142
Periumblical area 850 175 55 80
Thigh upper front 325 140 9 35
Thigh lower front 350 67 14 16
Thigh back 325 82 4 5
Shin 190 77 7 8
Calf 173 20 2 5
Dorsum of foot 80 122 3 10
Sole 22750 675 10 4
Males
Human Bioprofile
Table 2: Human bioprofile
Females
77 human interface in cleanrooms
on evaporation of sweat the residual salts remain deposited on our skin
cells. Chlorides of sodium and potassium are routinely found on
analysing the contaminants in clean rooms.
Hair becomes statically charged on combing, and attracts dust. Oiled
hair retains the dust better than dry hair. Dry hair is brittle and breaks
easily. Hair also produces a protein called keratanin, which is released
into the environment.
Studies indicate that a man on an average breathes 16,000 quarts of air
per day, which converts to approximately 20 kg/day! And this aerosol is
exhaled from a distance as close as 20 to 40 cms from the sensitive work
piece. Inhalation disturbs the air pattern around the work area; exhalation
carries a mixture of gases, vapour, liquid droplets, mucous and, of course,
microorganisms. In particular, the exhaled air is rich with dust and
other allergens that the lung is anxious to be rid of, and such contaminants
are often thrown out with unusual force. Extreme examples are coughs
and sneezes.
Smokers breathe out more contaminants than nonsmokers, even several
hours after they have last smoked. Drinking water after smoking helps
slightly reduce the number exhaled.
Cuts, abrasions, wounds, rashes, allergies and boils; and topical
medicaments, dressings and plasters further aggravate the problem.
Other conditions requiring care and vigil are discharges from eyes, ears,
and nose; coughs, colds and sneezes; and, of course, menstrual periods.
Figure 2: Smokers exhalation
78 cleanroom operators manual
Data published in Ljungqvist and Reinmullers Ventilation and Airborne
Contamination Cleanrooms indicates that the total population of aerobic
bacteria on human skin is typically greater than 1.2 million/m
2
in the
head and neck region of both male and female subjects. The numbers of
organisms present on the hands and arms is typically in the range of
0.9-3 million/m
2
on healthy subjects. The numbers of viable anaerobes
are many times higher and consist primarily of Proprionibacterium
acnes.
A number of studies have been done on the release of total particulate by
humans in cleanroom clothing.
In the same publication referenced above, a study conducted by Takasago
Thermal Engineering found that a fully gowned person sitting in a
cleanroom would release about 15,000 particles per minute. A walking
individual, according to this study, releases roughly 157,000 total
particulates per minute.
In a study published by Reinmdller in 2001, it was reported that the
typical ratio between total particles > 0.5 and viable aerobic organisms
recovered is in the range of 600-7000 to 1.
Studies done on personnel clothed in new full coverage clean room gowns
found that these people release 600-1300 total particulates per hour in
the >0.5 size range and that among these were as many as 40 CFU of
viable aerobic organisms. These data are generally consistent with the
findings published by Dr William Whyte.
Reinmullers data also showed that as the gowns aged and were subjected
to washing and re-sterilization, both the number of total particulate and
the level of microbial contamination increased.
Not surprisingly, these studies indicate that there is also a correlation
between the amount of physical activity undertaken by personnel and
their strength as a source of contamination, or put another way the amount
of contamination they contribute to their surrounding environment.
Reinmuller also reported microbial contamination is strongly associated
with particulate, in the 0.5 size class. It has been widely assumed that
microorganisms in aseptic processing areas are associated with
particulate in the 5-10 size range.
If we consider from the work of Whyte, Reinmuller and others that it is
reasonable to consider that a typical, properly gowned cleanroom worker
will contribute 10-100 CFU of viable aerobic organisms to the
79 human interface in cleanrooms
environment per hour it is obvious that, given the high air exchange
and hence dilution rates used in todays cleanrooms that the total
recovered microbial concentration should be very low.
However, these data also clearly indicate that even our best cleanrooms
do not under any circumstance approach sterility.
In fact, it could be argued that they can only attain asepsis if we are
fortunate enough to have facilities staffed only by personnel who do not
release pathogens.
Body temperature is maintained at 37
0
C; but the skin temperature varies
from head to toe as can be demonstrated by thermographic techniques.
The average of these values is usually around 33
0
C. Since the cleanroom
is designed to operate within the range 22 - 24
0
C, the body surface is at
an average of about 10
0
C above its surroundings. This thermal gradient
triggers convective currents rising from floor level to above the head.
These currents disturb the airflow pattern in the room.
These are some of the intrinsic contaminants ushered in with every
human being who enters the cleanroom. Once we understand the body
and its danger zones, it is easier to devise ways and means to contain
the damage they can cause.
extrinsic contaminants
Not only do people produce contaminants, but they also serve as unwitting
carriers of contaminants that are extrinsic to them. Starting from the
water they wash with; the soaps they use; the towels and napkins; the
Figure 3: Convective air currents surround body
80 cleanroom operators manual
undergarments and street clothes; the cosmetics and makeup; jewellery
and personal effects - all these make their contributions to the
contaminant load carried by the individual. Analysis of the contaminants
found in clean rooms show compounds of zinc and magnesium and talc,
all originating from the talcum powders used by both men and women.
The dust and grit on the streets, the grime and soot in the air; the jostling
in crowds while they commute to work covers them all over with potential
contaminants. And since people are mobile, they carry these contaminants
with them wherever they go, leaving a trail along their path and place
in jeopardy whatever they handle or touch. Movement also causes
disturbance in the airflow field, and depending on how they move, they
cause turbulence and eddies in their wake of varying severity. The greater
the number of people in a room, the higher the contaminant level, and
greater the risk of product contamination.
Now that we know about the human microenvironment, and how humans
can be vectors of contaminants, we can devise ways and means to control,
if not altogether stop contamination from occurring.
The first regulation begins with ascertaining the bare minimum number
of people the cleanroom requires and setting the limit on the head count
in the room on this basis and declaring the area out of bounds for others.
In addition to restricting the entry into the cleanroom, there should be
further restrictions for accessing critical environments within the
cleanroom itself.


Figure 4: Contamination level inceases with people


81 human interface in cleanrooms
Decontamination procedures prior to entry should be clearly enunciated
and strictly enforced. Gowning procedures should be drawn up to suit
the requirements of the environment cleanliness aspired. Once finalised,
these procedures must be rigidly adhered to.
Since behaviour is so important, industrial engineering techniques of
time and motion study should be applied while drawing up the overall
personnel flow chart, with emphasis on reducing personnel movements
and body actions to minimal levels for optimal performance. The
operating procedures so arrived at should form the base for rigorous
training in operation skills imparted to employees.
selection of contamination control clothing
Anyone in the cleanroom business who wants an argument need only
mention the term garment. To many it is much like religion - they
already know what they believe, and no mere fact can ever change their
minds. We are assuming that there are at least some people who may be
interested in looking at the evidence and want to take a fresh look at the
parameters of concern. We cannot decide for you; but we can cover the
aspects to consider when a decision must be made.
The objective function of contamination control clothing is to serve as a
barrier between the human microenvironment and the cleanroom,
keeping particulates, skin flakes and the like from the operator from
escaping into the cleanroom environment. In effect the garment is a
filter. This garment/filter system must allow air and moisture to flow
through and carry off heat and moisture generated by the wearer. Ideally
a rubber bag or plastic suiting would be an excellent system for stopping
the contaminants, but would be a poor garment in any real-world
environment, and the final choice is often a trade off between the ideal
Class ISO 4 5 6 7 8
M #M2.5 M3.5 M4.5 M5.5 M6.5
E #10 100 1,000 10,000 100,000
Items Coverall Coverall Coverall Lab coat Lab coat
Hood Hood Hood Cap Cap
Mask Mask Mask
Boots Boots Overshoes Overshoes Overshoes
Gloves Gloves Gloves
Change Per entry Daily Daily 3/week 2/week
Table 3: Selection and use of cleanroom garments
82 cleanroom operators manual
and the practical, since the wearer s comfort is an important
consideration.
It is normally assumed that an effective filter must have a high pressure
drop, and therefore be uncomfortable. In fact, this is not the case.
Experiments show that the relationship between air filtration efficiency
and pressure drop is not necessarily always linear. What we want is a
reasonably good filter with a tolerably low pressure drop. At least one
of the synthetics, DACRON, offers these advantages, though the price
is high. But economising on gowns can prove costly beyond estimation:
and compromising on clothing quality can place your product and
reputation at high risk.
All the Guidelines for Good Manufacturing Practice speak with one
voice on the importance of good gowning practice.
The first consideration, therefore, is the choice of the fabric itself. The
important characteristics to look for are that it should not lint; it should
at least not generate static charges; should be fire-retardant if not
flameproof; and should be treated for water repellency and inhibition of
microbial growth.
antistatic, static dissipative and conductive fabrics
Some applications are more sensitive to static charge dissipation than
others, determined by the susceptibility of the product (microelectronic)
or the environment (vulnerable to explosions). These applications
demand conductive fabrics where electrically conductive fibres (carbon
filament or carbon treated polyamide filament) is woven together with
DACRON filaments resulting in strict electrostatic and particulate
protection without any external or chemical treatments. (The best
chemically treated fibres lose their conductive properties progressively
with each successive wash). Such fabrics effectively prevent electrostatic
surges by means of constant, rapid and controlled dissipation of charges
(positive or negative) through low level ionisation or corona discharge
to the atmosphere. A fabric is deemed to be antistatic if its surface
resistivity is 10
11
- 10
13
ohms per square centimetre; static dissipative in
the range 10
5
- 10
11
; and conductive in the range < 10
5.
Uniformly
distributed and controlled electrostatic discharge ensures cleaner fabric
surface, improves personal comfort and offers greater protection to the
product, environment and the operator.
Conductive fabrics are fully effective only when connected through
conductive wrist straps and controlled resistance to ground. Otherwise,
83 human interface in cleanrooms
they are only sub-optimally effective. Such fabrics are recommended
mainly where ESD or static induced fire and/or explosions are concerns.
what colour must you choose?
A cleanroom is also referred to as a white room; the clean-to-dirty
axis is also known as the white-to-black axis. Hence, white would be the
most appropriate choice of colour.
Other colours are in popular use. Many prefer other colours to hide
soil. This is not good cleanroom practice. The operator or supervisor
should be able to spot soiled garments and discard such garments.
Parameter Static Dissipative* Non-static
Composition 99.5% - 96% DACRON+ 100% DACRON 80d/150d
0.5% - 4% CARBON filament polymer yarn
filament polymer yarn in standard plain weave
Standard/Taffetta weave
Lint character non-linting non-linting
Weight 115 gms/sq m 70 - 135 gm/sq m
Weave 30 x 30/sq cm 30 x 25/sq cm
Break strength 25 Kg/25 mm width 25 Kg/25 mm width
Elongation 80% of rupture 80% of rupture
Resistivity 10
4
- 10
13
ohms/sq cm 1.3 x 10
15
ohms/sq cm
Voltage decay 90% in 10 - 25 secs 90% in < 60 secs
Static character Static Dissipative Non-static
Chemical Resists acid Resists acid
Permeability < 0.005 mps/sq ft < 0.005 mps/sq ft
< 1 CFM/sq ft < 1 CFM/sq ft
@ 25 mm wc @ 25 mm wc
Efficiency > 80% down to 0.5 > 80% down to 0.5
> 98% down to 5.0 > 98% down to 5.0
Durability 200 cycles 200 cycles
Taber abrasion 0.6% (unlaundered) 0.6% (unlaundered)
(% fibre loss)
* Fully effective only when connected through conductive wrist straps and controlled
resistance to ground. Otherwise, only sub-optimally effective. Recommended mainly where
ESD or static induced fire or explosion are concerns
Table 4: Cleanroom fabric characteristics
8
4
c
l
e
a
n
r
o
o
m

o
p
e
r
a
t
o
r
s


m
a
n
u
a
l


4. Ezee, or Genteel
5. Antistatic agent, Optical whitener, Fabric
softener (Carboxymethyl cellulose 5% v/v)
6. Class M6.5 (100,000) or better
1. Hyglo, Teepol, Clinitol, or CCl
4
2. Savlon, Dettol/Iteol, Hydrogen peroxide or
Peracetic acid
3. Perchloroethylene, Trichloroethylene or
Mineral turpentine

Sort & Group Prewash


Inspection
Repair Spotting &
Stain
Removal
1
Prewash
Antiseptic
2
1 2 3 4 5
Spin Dry Final Rinse
Liquid Additives
5
Rinse
Cold Water
Main Wash
Water 60
0
C
Liquid Detergent
4
Main Wash
Solvent
3
6 7 8 9 10
Press & Double
Wrap under
Class 100 LAF
Autoclave in
Sachet
Store in
Garment Cubicle
Issue
15 14 13 11 12
Figure 5: Washing soiled contamination control apparel
Air Dry under
Class 100
Laminar Airflow
(LAF)
6
85 human interface in cleanrooms
Some avoid white because it is so difficult to maintain. If the Navy
worldwide can use white and keep them sparkling, so can you.
Some use a variety of colours to distinguish among different departments
and product groups - maintenance, production, product A, product B
etc. But such distinctions can also be made with a small arm band or
shoulder stripe of a different colour, instead of having the entire garment
in that other colour.
The principal argument in favour of white is that it permits pre-wash
soak with bleach (NaOCl). This not only keeps it sparkling white, but
also acts as a strong anti-microbial treatment to reduce the bioburden.
Any subsequent autoclave sterilisation (as in drugs & device
manufacture) is rendered far more effective.
good cleanroom garment
tailoring practice
After you have
selected the fabric,
you decide on the
patterns that best suit
your needs, and
award the conversion
contract to an agency
that is familiar with
the special care required for
tailoring contamination control
clothing. Cut edges should be
sealed; stitching should be double-
seamed; tailoring should ensure
that no raw edges are exposed and
that there are no collection points
where dirt and lint can be
deposited and accumulated. As a
general rule, pockets and belts
must be avoided.
correct gowning
Errors in gowning are common,
and often negate the very purpose
of wearing contamination control
apparel. Exposing or improperly
Figure 7: Correct gowning
Figure 6:
Correct
tailoring
86 cleanroom operators manual
covering hair, face, moustaches and beards, wrists, street clothing, ankles
and street shoes should be scrupulously avoided. Even after gowning,
some contaminants do escape into the environment, but the numbers
are greatly reduced.
cleanroom laundry
To derive the maximum protection offered by contamination control
clothing, special care is needed in the manner, as well as the environment
in which it is washed, dried, pressed and packed. It is unfortunately
common to find cleanroom clothing sent out for laundering. It is
paradoxical: so much care is taken in selection and procurement of
these clothes; but little thought is spared to reflect on what is needed for
cleaning them after every use. The local laundry was not designed to
handle such garments, and the environment there is bound to be anything
but dust-free.
Orange Guide 2002 Annexure 1 Para 21 addresses this concern, and
strongly advocates the setting up of a dedicated in-house laundering
facility.
The complete procedure described here is for your guidance. Setting up
an in-house laundry, close to the main cleanroom, offers advantages you
Figure 8: Cleanroom laundry
87 human interface in cleanrooms
Figure 9: Good gowning sequence
cannot ignore. The cleanroom laundry air cleanliness level could be one
class lower than that being maintained in the processing area and the
regulations enforced there should apply to the laundry too.
After entry decontamination and gowning, we have one more device at
our disposal to minimise the probability of contamination: generate as
little as possible within the cleanroom. This demands good conduct
and strict discipline.
Posters explaining the Whats, Whys and Hows of Good Aseptic Practices
drawn up with imagination and wit and should be displayed at vantage
points to serve as constant reminders of the need for compliance and the
consequences of disregard.
good gowning practice
Garments should be worn correctly to serve the intended purpose. The
gowning procedure described here is intended to serve as a guide; you
88 cleanroom operators manual
Figure 10: Recommended gowning & degowning for sterile areas
should draw up your own gowning sequence by modifying this procedure
wherever necessary.
o Remove street footwear. Change into cleanroom footwear.
o Remove all street garments not necessary for warmth or modesty
89 human interface in cleanrooms
Figure 11: Recommended gowning & degowning for nonsterile areas
o Remove and safely store watches, rings, cigarettes, lighters,
jewellery, purse and other personal effects.
90 cleanroom operators manual
o Scrub down. Remove cosmetics, if any applied. Use appropriate
cleanroom grade detergent compatible with the disinfectants used
to remove physical contaminants.
o Washing of hands and forearms deserves special care. The under
surfaces of fingernails should be thoroughly cleaned with a soft
nylon brush, or when necessary, with a scraper.
o Wear gowning cap. This is optional at this point in the gowning
sequence. The purpose is to conceal the hair at an early stage, and
keep it covered thereafter.
o Enter change room. Installation of a good quality tacky mat at
entrance is recommended. If you are not sure of the quality, you
are better off without it. Even with a good tacky mat, research has
established that you need to walk a distance of 20 steps before you
have left behind 95% of your footborne debris. Having a standard
Welcome size tacky mat may not be as useful as imagined.
o Wear gowning gloves. This is also optional at this stage. The
objective is to avoid contact with washed bare hands. Select gloves
of proper style and size.
o Carefully put on the first glove, touching the outside of the glove
as little as possible. Then put on the second glove, taking care not
to touch anything other than cleanroom apparel.
o Obtain cleanroom apparel and accessories appropriate for your
task and prepare for donning.
o The first item to be worn is the legwear. Inspect the item for
damages and stains and once satisfied sit on the barrier stool, if
available, or on a chair or bench, and put on the first boot, taking
care to ensure that it does not touch the floor. Then swing the
clean foot over to the cleanroom side of the stool or bench. Put on
the second boot and swing over fully to the cleanroom side and
stand up.
o Next put on your head cover, if necessary over the cap already on.
Adjust to cover hair fully. Take care not to touch anything other
than the items of garments.
o Put on face mask, where applicable.
o Now prepare the coverall for wearing it. Inspect for tears and soil,
keeping it off the floor. Step into legs and then pull on the upper
half. Tuck the skirt of the hood inside the collar of the coverall or
coat. Close all fasteners at neck and wrists. Tuck legs of garment
into boots and refasten legwear till it is snug and comfortable.
91 human interface in cleanrooms
o Discard gowning gloves, if worn. Disinfect hands as per
procedure prescribed by your SOP. Put on working gloves using
the same technique and care described earlier for donning gloves.
Tuck cuffs of garment into gloves.
o Check that all leg, and arm openings are completely sealed with
gloves and boots.
o Do not adjust garment after donning working gloves. As a matter
of fact your gloved hand should now touch only your work related
objects and nothing else.
o Proceed through air shower and across another tacky mat to enter
the cleanroom.
hand decontamination and use of gloves
The wearing of rubber gloves is by itself an aseptic measure, minimizing
the risk of direct contact contamination of sterile equipment and
processes. However, some contamination can occur through torn gloves
or through invisible small holes that appear in about 20% of gloves
during use, and also through moisture on sleeves of cotton gowns. For
these reasons scrubbed operators should use an antiseptic skin
preparation.
Effective preparations are:
1. Certain detergent antiseptic solution containing, for example, 1%
Chlorhexidine or 1% Povidone Iodine applied vigorously to fingers,
hands, and forearms for 2-3 minutes with running water and no brush,
followed by rinsing and drying
2. 10 ml of 70% Ethanol or 60% Isopropanol containing Glycerol (1%)
and, for even greater antiseptic activity, Chlorhexidine (0.5%), but no
water. Rub vigorously on to fingers, hands and forearms until they are
dry.
Repeated use of these agents has a cumulative effect due partly to residues
of antiseptic left on the skin, which prevent the build-up of bacterial
flora on the gloved hand. A detergent must be used to remove physical
contaminants. The under surfaces of fingernails should be cleaned, when
necessary, with a scraper. Hands must be washed with an antiseptic
detergent preparation, and fresh gloves must be put on. If gloves are
sterilized and re-used they must be tested for holes by inflation
underwater. Rings should be removed before preparation of hands.
Use of brushes is generally discouraged, because they are in turn so
difficult to clean and disinfect. Besides, over enthusiastic scrubbing
92 cleanroom operators manual
can cause the skin oils to be removed to such an extent that it tends to
flake and slough off, emitting particles that may be or not carry transient
or resident microflora. The choice of detergent and antiseptic will
determine how effective your hand wash process is.
The objective should be clean and sanitise the skin before donning sterile
gloves, which acts as the final barrier. When hands are clean, the burden
on the gloves as protective gear diminishes.
good conduct in controlled environments
O Fully understand of contamination control techniques and realise
the enormous responsibility of working in a cleanroom.
O Pay attention to personal hygiene and clothing.
Figure 12: Bad conduct
93 human interface in cleanrooms
O Avoid unnecessary movements within the cleanroom
O When you must move, make it slow and rhythmic. Avoid
movements upstream of clean airflow.
O Avoid exiting the area until your next break period.
O Control any urge to indulge in nervous relief type mannerisms
such as scratching, rubbing hands, fastening and unfastening your
garment or twitching your face or legs.
O Smile. But avoid unnecessary conversation. If you must talk,
speak softly. Use intercom to communicate with those outside the
cleanroom.
O Horseplay, singing, humming, whistling, shouting, fun, frolic and
frivolity have their proper place: the cleanroom is not that place.
Figure 13: Good conduct
O If you have a point to argue, the cleanroom is not the place to do it in.
O Never eat, drink, chew or smoke in a cleanroom. If you are a
smoker, smoke outside and drink water before entering the
cleanroom.
O Insist on and use only cleanroom compatible stationery. If paper is
unavoidable, shield it in an acceptable wrapper and leave only a
window open for the area where you must write or enter data.
O Do not exchange items between clean and outside environments.
Any item coming in shall be subject to prescribed decontamination
procedures as laid down in your SOPs each time it enters or
reenters. Any item leaving should be decontaminated if so
required.
O If you are hurt or ill or otherwise indisposed, inform your
supervisor and abide by his decision.
O Air locks, specially those for equipment/material entry, should not
be occupied by cleanroom and outside personnel at the same point
in time.
O Keep products and components in covered containers, and avoid
exposing them to the environment unnecessarily.
O Open such trays or other containers only under LAF clean air
cover.
O Store containers along the side and downstream of the work piece,
not upstream. Avoid clutter at your work station. Keep it clean
and orderly.
O Place open dishes containing materials or work objects in the
unobstructed clean airflow zone. Similarly, fixtures for handling
the work piece should be in the unobstructed clean air path.
O Avoid bending over your products or components. Handle these
items with care, and hold either at the base or sides, depending on
how it is prescribed in your SOP.
O Never pick up and use any component that has accidentally fallen
to the floor.
O Insist on separate sets of tools, trolleys and other implements that
you may need in the cleanroom, and ensure that they remain there
and not sent out again. Follow the precept that what is not needed
should not be in the cleanroom; whatever is needed, shall not
leave the cleanroom.
O If you notice any abnormality, or are in doubt about something, or
have a suggestion for improvement, discuss it with your supervisor
at the first available opportunity.
L
aminar (or unidirectional) airflow as applied to industrial
cleanroom technology is defined as airflow in which the entire
mass of air within a confined space moves with uniform velocity
along parallel ( or non-intersecting) flow lines. The credit for
development of this technique for airborne contamination control is
generally attributed to Whitfield of Sandia Corporation, USA, who
termed it as a piston of clean air pushing out suspended contaminants
from the work environment.
In practice, achievement of true laminar airflow, as defined above, is
never possible. A suspended particle in space can move in any direction
- forward or backward; leftward or rightward; upward or downward.
However, when entrained in a laminar air stream, it moves predominantly
in one direction. In other words, its velocity along the direction of
airflow is substantially larger than any component of velocity in any
other direction. If the direction of flow is along the X-axis and the
velocity is U, then
laminar airflow
C K Moorthy
7 7
7 77
96 cleanroom operators manual
U
x
>> U
y
, U
z
Besides, true parallel flow is precluded by the practical necessity of
placing objects (including people) within the confined space. Although
any object so placed will cause discontinuities in the flow pattern, these
disturbed areas are swept out by the continuous flow of clean air.
Furthermore, air patterns tend to reestablish themselves within a distance
approximately equal to three to five times the equivalent diameter of the
object. The region immediately downstream of the obstructing object,
known as the wake zone, is at relatively low pressure (Bernoulli effect),
with strong turbulent currents, whose intensity decreases as we near the
point in space where the air pattern returns to normal. This entire zone
of low pressure is known as the cone of turbulence, where the apex of
the cone is at an approximate distance of 3 to 5 times the equivalent
diameter from the obstructing object (forming the base of the cone).
Behind each product or work piece placed in clean laminar airflow there
is such a cone; if the apex of the cone lies well inside the clean space,
the turbulent air, being clean, will not jeopardise the product; but if part
D
5D
Fig 2 Wake region disturbance & cone of turbulence
Fig 1 Unidirectional laminar airflow
x
o
y
U
X
constant
U
y
,

U
z
0
U
x
>>

U
y
,

U
z
97 laminar airflow
of the cone extends to contaminated space, the low pressures in the
wake will aspirate the contaminated air and increase the risk of product
contamination.
Suspended contaminants present in air when a laminar airflow system
is first turned on are propelled out of the cleanroom or work space in the
first pass, clearance being typically obtained within a few minutes due
to the high rate of air exchange, and at steady state the suspended
contaminant density is largely determined by that generated within the
room.
The air velocity in industrial laminar airflow installations is 0.3 to 0.6
mps (60 - 120 fpm), which is almost imperceptible, much less than the
force felt when walking at one mile per hour on a still day. Although
this velocity is very low, it is much higher than the rate at which
Air velocity in the laminar range is determined by Reynold's Number (N).
N = UD/
where is the fluid density, U is the flow speed, D is a characteristic length
and is the fluid viscosity.
Since both and are functions of temperature, the velocity range in
the laminar regime will vary with temperature too.
In typical cleanroom conditions, the mean value is 0.5 mps (100 fpm) with
a standard deviation of 0.065 mps (13 fpm), which translates to a total
range of 0.305 (61 fpm) to 0.695 mps (139 fpm). The ISO Standards allow
down to 0.2 mps (40 fpm); but the Orange Guide 2002 still insists on 0.45
mps +/- 0.1 mps (90 +/- 20 fpm). Schedule M permits Vertical Laminar
downflow velocity in the range (60 +/- 20 fpm).
Fig. 5.3
P
2
P
3
P
1
P
4
X
Y
U
1
U
2
U
3
U
4
O
U
1
=

U
2
= U
3
= U
4
P
1
=

P
2
= P
3
= P
4
98 cleanroom operators manual
suspended particles tend to settle. For example, a 10 sand particle
falls in still air at 1.5 fpm, and a bacteria (1) at less than an inch per
minute.
In other words, if the 10 sand particle were dropped in an industrial
horizontal laminar airflow installation, it would travel 20 horizontally
along direction of airflow while dropping less than 4 vertically. The
bacteria would have dropped less than a quarter of an inch over the
same distance. Laminar airflow, therefore, gives little opportunity to
the suspended contaminants it encounters to settle down and moves them
out along predetermined flow lines, away from vulnerable sites, passing
any point in space lying in its path once, and only once. If the suspended
contaminant, entrained upstream of the product, passes a critical site
without impinging or settling, it will never return to that site again. In
contrast, in turbulent airflow, the eddy currents present can, and often
do, allow a contaminant to return again and again.
However, the cost of a laminar airflow room is prohibitive, and most
designers rely on localised laminar airflow work stations at critical work
sites to protect against aerial contamination, and opt for the more
economical mixed flow or turbulent flow cleanrooms, where filtered air
is dispersed at multiple-terminals scattered in the ceiling.
Laminar airflow workstations are used for either or both of the following:
Product protection for operations involving materials that must be kept
sterile or free from unwanted ecological agents; and agent containment
for manipulations involving etiological agents, materials or procedures
requiring personnel protection, where the items in use must be confined
within the working area and not allowed to escape into the environment.
For selecting the pattern of airflow that best suits an application, the
primary consideration would be the nature of work being carried out on
the clean air work station. For optimum cleanliness, it is vital that the
flow of clean air across, on and around the product or process be
maintained at a maximum.
Horizontal flow systems offer maximum product protection, and are, by
far, the most effective form of contamination control. They call for the
least in operator discipline where the work activity involves physical
manipulation. Operators may bend their heads, or other parts of their
bodies over or around the work site without seriously jeopardising it.
The work table edge is deemed to be the boundary separating the clean
space from the contaminated environment, and care must be taken to
99 laminar airflow
ensure that the apex of any cone of
turbulence generated in the clean
space does not penetrate this boundary.
These systems, however, are
unsuitable for operations where toxic
fumes or vapours are encountered, or
for work with open vessels of
chemicals, solvents or powders, since
horizontal flow would raise vapour
levels in the room, increase solvent
drag-out and distribute powder
particles throughout the environment,
resulting in not only greater
contamination levels within, but also
enhanced risks of cross contamination
through operators who may be moving
from station to station.
In some cases, the production
equipment bulk may preclude parallel
horizontal flow across the work surface and cause eddies which could
negate the very purpose of a clean air bench. For such and other similar
applications, specially involving agent containment, a vertical downward
airflow configuration is more appropriate. Vertical downflow is also
favoured for procedures that do not
require eye-hand coordination, and for
equipment which is semiautomatic or
fully-automatic.
Horizontal LF systems are generally
fitted with a protective grille downstream
of the HEPA filter to prevent accidental
damage to the media as well as to serve
as a secondary plenum for pressure
stabilisation. Unfortunately, fine
particles that penetrate the filter often
impact on this grille, and over a period
of time a film or coating builds up behind
this grille, leading to the hazard of
intermittent emissions caused by
mechanical vibration or sudden
variations in airflow. (Had the fine
particles not been arrested, in all
Fig 4 Horizontal laminar flow
clean air work station
Fig 5 Vertical laminar
downflow clean air work
station
100 cleanroom operators manual
probability they may have just floated past the work site; but the
agglomeration on the incident face of the protective grille coughs up
much larger sized particles whose contaminating potential is much
enhanced.)
Unlike Horizontal LF, where airflow is unobstructed, the vertical
downward flow impinges directly on the work surface, which marks a
dead-end. Perforations on the work surface improves matters somewhat,
but it is still far from adequate. In the process, an envelope of air cushion
builds up over the surface, causing clean air entering the work space to
deviate towards the work station exit face much before it reaches the
work surface. Designs that feature partial or total exhaust, however,
have a better control over the airflow distribution within the work space.
Among the innovations in this design is the partial recirculatory system,
which sucks back up to 60% of the air from the work space through
return ducts terminating in slots along the periphery of the work surface.
Whenever work space air is exhausted from the room, there is partial
negative pressure with respect to the room at the work space. To prevent
room air from contaminating the product, designs provide for an air
curtain (high velocity sheath of air) along the entry face with perforations
on the work table edge, so that the air ingress is out of harms way.
Unlike fume exhaust chambers, clean air LF work stations do not allow
makeup air into the main work area. The table edge, for example, is
generally made to protrude outward slightly, so that the perforations on
the surface to draw in the makeup air is marginally outside the plane of
the air barrier.
Room air, being filtered and tempered, is too expensive to be cast out as
exhaust indiscriminately. To minimise the quantum so exhausted, a
design innovation termed add-air, or auxiliary air feed system, is
commonly employed, whereby a controlled amount of untempered air
from outside the clean environment (usually a corridor) is drawn in to
complement the air sucked in from the room. In this process, the exhaust
volume requirements are met; the work space is contained under negative
pressure; the product site is protected; and only the bare minimum
quantity of room air is used up.
Many design innovations in the laminar airflow pattern have been
introduced. Instead of having a piston of air moving with the same
constant velocity, the velocity profile could be graded, such that adjacent
streams are at marginally differing velocities, while retaining the entire
mass within acceptable LF limits (vary from 60 fpm to 120 fpm). This
101 laminar airflow
yields superior airstream integrity, specially
while confronting obstructing objects.
Air could be made to converge or focus on
the work site for enhanced dilution and
cleandown. Likewise, it could be diverging
to spread clean air and extend the clean zone
perimeter. While the latter two have air
streams that are not parallel, their velocity
is within the laminar range.
Radial airflow allows effective utilisation of
floor space by accommodating several
operators at the work table who do not get
into each others way. Inclined airflow
permits bringing the object or equipment to
be protected much closer to the filter.
In certain cases of containment, the product
aerosols must be kept away from the
operator. Powder weighing and dispensing
is a common application. To guarantee such
protection by isolation, reverse laminar
airflow techniques are employed.
The plenum is maintained under negative
pressure in some patented designs, such that
if a filter is ill-fitted or develops a leak in its
gasket, clean air from the work space is
sucked back through the gap in the filter
seating, rather than allow unfiltered air to
bypass the filter and contaminate the work
space.
Other improvements include incorporation of chemical adsorbent filters
for vapour, gas and odour removal; desiccants for moisture removal;
electronic intermediate filters for enhanced ultrafines capture and static
control; multispeed and variable speed motor-blowers or the more recent
smart motor-blower that automatically adjusts speed to compensate
for filter loading; and chilled water line complete with thermostat and
humidistat for temperature and humidity control.
The question of choice of material for bulkhead execution is often asked,
and the answer is coloured by the camp answering. In practice, it does
Converging airflow
Graded velocity LF
Conventional
univelocity LF
Fig 6 Laminar flow
variations
102 cleanroom operators manual
not really matter as long as the construction
is rugged, has a cleanroom grade surface
finish, can withstand normal rigours of
cleanroom sanitation chemicals and damps
noise and vibration to acceptable levels.
In some designs, like a clean air tent, the
sides are often enclosed with panels, While
such panels help isolate the interior, the
boundary layer separation of airflow at the
periphery causes aspiration of outside air
into the enclosure (Bernoulli effect). If the
design features an integral clean air barrier
all along the inner perimeter, such invading
aerosols can be contained.
Laminar airflow guarantees stability in the
parametric profiles (temperature, humidity
contaminant density and air velocity) along
its path. At the point where this ceases to
be the case, laminarity may be deemed to be
lost.
Before we close, let us emphasise that
laminarity relates to air velocity and not to
air cleanliness. We can have turbulent air
which is Class 100 clean; and true laminar
airflow of unclean air. To make double sure
that we want both, we say Class 100
Laminar Airflow.
Another advantage arising from such
unidirectional non-turbulent streamline flow
at uniform velocity is that parametric
gradients are not disturbed. They remain
stable. The points in space with identical
parametric values are referred to as being
isoparametric. For example, points in space
with identical contaminant density, or
number of particles per unit volume, are
known as isopleths. Laminar airflow may
be relied upon to guarantee stable isopleths.
As a corollary, when isopleths cease to be
stable, laminar airflow ceases to exist.
Radial univelocity LF
Diverging airflow
Inclined univelocity LF
Fig 7 More laminar flow
variations
Reverse LF
103 laminar airflow
Figure 9: Product protection
Improvement by airflow design
Figure 10: Disturbance of unidirectional airflow
Improvement by personnel behaviour
Interesting inputs on
unidirectional airflow from
ISO 14644-4
Figure 8: A Reverse HLAF
Containment Workstation for TB
sputum samplecollection
104 cleanroom operators manual
Figure 13: Disturbance of unidirectional airflow
Improvement by airflow concept
Figure 11: Disturbance of unidirectional airflow
Improvement by personnel behaviour
Figure 12: Disturbance of unidirectional airflow
Improvement by arrangement
105 laminar airflow
Figure 15: Personnel/environment/product protection
Figure 14: Passive & Active Systems
D
espite the 100+ years of our vaccine research, deveopment and
production traditions, there is still, in many organisations, at
both laboratory as well as shop floor, an alarming sense of
complacency, and apalling disregard for fundamentals of biosafety, due
either to incomplete or incorrect information, or to lack of comprehension
about the dangers involved in working with pathogenic organisms. The
reasons for this vary:
O Working with strains that induce the required immuno response,
but do not cause disease
O The organism is attenuated and lacks the virulence to cause
disease
O The concentration needed to induce disease is several orders of
magnitude higher than that which may be accidentally ingested
O The organism does not have any effect on adults
O The organism does not cause disease in humans
good biosafety practices
adapted with kind permission from the CDC/NIH 4th edition of
Biosafety in Microbiological and Biomedical Laboratories
8 8
8 88
108 cleanroom operators manual
These notions, widespread as they are, are disturbing, and something
that should cause deep concern. For example, Bordetella pertussis, a
human respiratory pathogen of worldwide distribution, is the causative
agent of whooping cough. The disease is typically a childhood illness;
however, the agent has increasingly been associated with adult illness.
Several outbreaks in health-care workers have been reported in the
literature. Adolescents and adults with atypical or undiagnosed disease
can serve as reservoirs of infection and transmit the organism to infants
and children. Eight cases of infection with B.pertussis in adults have
been documented at a large research institution. The individuals involved
did not work directly with the organism, but had access to common
laboratory spaces where the organism was manipulated. One case of
secondary transmission to a family member was documented. A similar
incident occurred at a large Midwestern university resulting in two
documented cases of laboratory-acquired infection and one documented
case of secondary transmission. Other laboratory-acquired infections with
B. pertuss is have been reported, as well as adult-to-adult transmission
in the workplace. Laboratory-acquired infections resulting from the
manipulation of clinical specimens or isolates have not been reported.
The attack rate of this airborne infection is influenced by intimacy and
frequency of exposure of susceptible individuals.
Genetic mutations, transgenic mutations and trans-species mutations
are all eminently plausible, and should not be discounted. It is well
recognised that virus in attenuated vaccine for birds can, after five
successive passages, can regain full virulence. Opportunistic pathogens
and compromised hosts are ubiquitous, and no precaution is too much
in our endeavours to provide biosafe working environs.
Though guidelines for biological production have been reproduced
elsewhere, the biosafety aspects of biohazardous operations are covered
here, drawing heavily from the guidelines and recommendations of
Center for Disease Control (CDC), USA; National Institute of Health
(NIH), USA and a host of other International Agencies concerned with
Biosafety in Medical and Biological Laboratories. As a consequence,
much of the material here is directed towards biosafe laboratories; but
the same principles also apply for manufacturing.
The reader is also cautioned about the differences in perception of risks
across countries for the same organism. For example, Foot and Mouth
Disease (FMD) is classified at Risk Level 2 in India; but at Risk Level 5
in Canada and elsewhere. Tuberculosis is routinely treated in India at
Level 2, while in this presentation where material has been borrowed
109 good biosafety practices
from USA and Canada, the risk is indicated at Level 3. What we
commonly refer to as P3 Facilities are described instead as P4 here.
biosafety
Microbiology laboratories and biological production centres are special,
often unique, work environments that may pose identifiable infectious
disease risks to persons in or near them.
Bacteria, viruses, fungi or other infectious agents are studied because
they may cause disease, they can help us understand the natural world,
and for many other reasons including the possibility of industrial
applications. Since many of the agents can be pathogenic to humans,
animals or other forms of life, their use poses risks which vary with
each agent and the way it is used. Biotech laboratories, therefore, are
special, often unique, work environments that may pose identifiable
infectious disease risks to persons in or near them.
Infections have been contracted in the laboratory and production areas
throughout the history of microbiology and immunology. As a result,
safety norms, standards and practices have been designed and developed
over the years to reduce to an acceptable level the risks inherent in the
use of dangerous materials. Stringent standards are set for hazardous
agents and less stringent ones for agents which cause only minor
problems. Safety standards are therefore compromises designed to allow
needed work to proceed without exposing those involved or others to
more than minimal risk.
Besides the attitudes and actions of those who work in these hazardous
environs determine their own safety, and that of their colleagues and of
the community. Facility, equipment and design can contribute to safety
only if they are used properly by people who are genuinely concerned
and knowledgeable about safety issues.
principles of biosafety
The term containment is used in describing safe methods for managing
infectious agents in the laboratory environment where they are being
handled or maintained. The purpose of containment is to reduce or
eliminate exposure of laboratory workers, other persons, and the outside
environment to potentially hazardous agents.
Primary containment, the protection of personnel and the immediate
laboratory environment from exposure to infectious agents, is provided
by both good microbiological technique and the use of appropriate safety
110 cleanroom operators manual
equipment. The use of vaccines may provide an increased level of personal
protection.
Secondary containment, the protection of the environment external to
the laboratory from exposure to infectious materials, is provided by a
combination of facility design and operational practices.
Therefore, the three elements of containment include laboratory practice
and technique, safety equipment, and facility design
laboratory practice and technique
The most important element of containment is strict adherence to
standard microbiological practices and techniques. Persons working with
infectious agents or potentially infected materials must be aware of
potential hazards, and must be trained and proficient in the practices
and techniques required for handling such material safely. The director
or person in charge of the laboratory is responsible for providing or
arranging for appropriate training of personnel.
Each laboratory should develop or adopt a biosafety or operations manual
which identifies the hazards that will or may be encountered, and which
specifies practices and procedures designed to minimize or eliminate
risks. Personnel should be advised of special hazards and should be
required to read and to follow the required practices and procedures. A
scientist trained and knowledgeable in appropriate laboratory techniques,
safety procedures, and hazards associated with handling infectious agents
must direct laboratory activities.
When standard laboratory practices are not sufficient to control the hazard
associated with a particular agent or laboratory procedure, additional
measures may be needed. The laboratory director is responsible for
selecting additional safety practices, which must be in keeping with the
hazard associated with the agent or procedure.
Laboratory personnel, safety practices, and techniques must be
supplemented by appropriate facility design and engineering features,
safety equipment, and management practices.
safety equipment ( primary barriers)
Safety equipment includes biological safety cabinets (BSCs), enclosed
containers, and other engineering controls designed to remove or
minimize exposures to hazardous biological materials. The biological
safety cabinet (BSC) is the principal device used to provide containment
111 good biosafety practices
of infectious splashes or aerosols generated by many microbiological
procedures.
Safety equipment also may include items for personal protection such
as gloves, coats, gowns, shoe covers, boots, respirators, face shields,
safety glasses, or goggles. Personal protective equipment is often used
in combination with biological safety cabinets and other devices which
contain the agents or materials being worked with.
facility design (secondary barrier)
The design of the facility is important in providing a barrier to protect
persons working inside and outside of the laboratory within the facility,
and to protect persons in the community from infectious agents which
may be accidentally released from the laboratory. Laboratory management
is responsible for providing facilities commensurate with the laboratorys
function and the recommended biosafety level for the agents being
manipulated.
The recommended secondary barrier is determined by the risk of
transmission of specific agents.
Secondary barriers in these laboratories will include separation of the
laboratory work area from public access, availability of a decontamination
facility (e.g., autoclave), and hand washing facilities. Design features
could include airconditioning, controlled access zones, airlocks at
laboratory entrances, or separate buildings or modules for isolation of
the laboratory.
biosafety levels
Four biosafety levels (BSLs) are described which consist of combinations
of laboratory practices and techniques, safety equipment, and laboratory
facilities. Each combination is specifically appropriate for the operations
performed, the documented or suspected routes of transmission of the
infectious agents, and for the laboratory function or activity.
The recommended biosafety level(s) for the organisms in Section VII
(Agent Summary Statements) represent those conditions under which
the agent can ordinarily be safely handled. The laboratory director is
specifically and primarily responsible for assessing risks and for
appropriately applying the recommended biosafety levels. Generally,
work with known agents should be conducted at the biosafety level
recommended in Section VII. When specific information is available to
suggest that virulence, pathogenicity, antibiotic resistance patterns,
112 cleanroom operators manual
vaccine and treatment availability, or other factors are significantly
altered, more (or less) stringent practices may be specified.
risk assessment
The potential for untoward events must be evaluated to reduce or
eliminate worker exposure to or release of infectious organisms. Through
the process of risk assessment, the work procedures are evaluated for
potential exposure to the microorganism.
The hierarchy of controls to prevent or minimize exposure to hazardous
materials includes engineering controls, administrative and procedural
controls, and work practices which may involve use of additional personal
protective equipment. Having a properly operating BSC available is an
effective engineering control; requiring its use is an administrative
control. Some suggested work practices and procedures associated with
working safely in a BSC are detailed here.
preparing for work within a class II BSC
Preparing a written checklist of materials necessary for a particular
activity and placing necessary materials in the BSC before beginning
work serves to minimize the number of arm-movement disruptions across
the fragile air barrier of the cabinet. The rapid movement of a workers
arms in a sweeping motion into and out of the cabinet will disrupt the
air curtain and may compromise the partial barrier containment provided
by the BSC. Moving arms in and out slowly, perpendicular to the face
opening of the cabinet, will reduce this risk. Other personnel activities
in the room (e.g., rapid movement, open/closing room doors, etc.) may
also disrupt the cabinet air barrier.
Laboratory coats should be worn buttoned over street clothing; latex
gloves are worn to provide hand protection. A solid front, back-closing
lab gown provides better protection of personal clothing than a traditional
lab coat. Gloves should be pulled over the knitted wrists of the gown,
rather than worn inside. Elasticized sleeves can also be worn to protect
the investigators wrists.
Before beginning work, the investigator should adjust the stool height
so that his/her face is above the front opening. Manipulation of materials
should be delayed for approximately one minute after placing the hands/
arms inside the cabinet. This allows the cabinet to stabilize and to air
sweep the hands and arms to remove surface microbial contaminants.
When the users arms rest flatly across the front grille, room air may
113 good biosafety practices
flow directly into the work area, rather than being drawn through the
front grille. Raising the arms slightly will alleviate this problem. The
front grille must not be blocked with research notes, discarded plastic
wrappers, pipetting devices, etc. All operations should be performed at
least four 4 inches from the front grille on the work surface.
Materials or equipment placed inside the cabinet may cause disruption
to the airflow, resulting in turbulence, possible cross-contamination, and/
or breach of containment. Extra supplies (e.g., additional gloves, culture
plates or flasks, culture media) should be stored outside the cabinet.
Only the materials and equipment required for the immediate work
should be placed in the BSC.
BSCs are designed to be operated 24 hours per day, and some
investigators find that continuous operation helps to control the
laboratorys level of dust and other airborne particulates. Although energy
conservation may suggest BSC operation only when needed, especially
if the cabinet is not used routinely, room air balance is an overriding
consideration. In some instances, room exhaust is balanced to include
air discharged through ducted BSCSs.
Cabinet blowers should be operated at least three to five minutes before
beginning work to allow the cabinet to purge. This purge will remove
any particulates in the cabinet. The work surface, the interior walls (not
including the supply filter diffuser), and the interior surface of the window
should be wiped with 70% ethanol (EtOH), a 1:100 dilution of household
bleach (i.e., 0.05% sodium hypochlorite), or other disinfectant as
determined by the investigator to meet the requirements of the particular
activity. When bleach is used, a second wiping with sterile water is
needed to remove the residual chlorine, which may eventually corrode
stainless steel surfaces. Wiping with non-sterile water may recontaminate
cabinet surfaces, a critical issue when sterility is essential (e.g.,
maintenance of cell cultures).
Similarly, the surfaces of all materials and containers placed into the
cabinet should be wiped with 70% ETOH to reduce the introduction of
contaminants to the cabinet environment. This simple step will reduce
introduction of mold spores and thereby minimize contamination of
cultures. Further reduction of microbial load on materials to be placed
or used in BSCs may be achieved by periodic decontamination of
incubators and refrigerators.
114 cleanroom operators manual
material placement inside the BSC
Plastic-backed absorbent toweling can be placed on the work surface
(but not on the front or rear grille openings). This toweling facilitates
routine cleanup and reduces splatter and aerosol formation during an
overt spill. It then can be folded and placed in an autoclavable biohazard
bag when work is completed.
Figure 1: Material placement inside the BSC
All materials should be placed as far back in the cabinet as practical,
toward the rear edge of the work surface and away from the front grille
of the cabinet.
Similarly, aerosol-generating equipment (e.g., vortex mixers, tabletop
centrifuges) should be placed toward the rear of the cabinet to take
advantage of the air split . Active work should flow from the clean to
contaminated area across the work surface. Bulky items such as biohazard
bags, discard pipette trays and suction collection flasks should be placed
to one side of the interior of the cabinet.
Certain common practices interfere with the operation of the BSC. The
autoclavable biohazard collection bag should not be taped to the outside
of the cabinet. Upright pipette collection containers should not be used
in BSCs nor placed on the floor outside the cabinet. The frequent inward/
outward movement needed to place objects in these containers is
disruptive to the integrity of the cabinet air barrier and can compromise
both personnel and product protection. Only horizontal pipette discard
trays containing an appropriate chemical disinfectant should be used
within the cabinet. Furthermore, potentially contaminated materials
should not be brought out of the cabinet until they have been surface
decontaminated. Alternatively, contaminated materials can be placed
115 good biosafety practices
into a closable container for transfer to an incubator, autoclave or for
other decontamination treatment.
operations within a class II BSC
Many common procedures conducted in BSCs may create splatter or
aerosols. Good microbiological techniques should always be used when
working in a biological safety cabinet. For example, techniques to reduce
splatter and aerosol generation will minimize the potential for personnel
exposure to infectious materials manipulated within the cabinet. Class
II cabinets are designed so that horizontally nebulized spores will be
captured by the downward flowing cabinet air within fourteen inches of
travel. Therefore, as a general rule of thumb, keeping clean materials at
least one foot away from aerosol-generating activities will minimize the
potential for cross-contamination.
The general work flow should be from clean to contaminated (dirty).
Materials and supplies should be placed in such a way as to limit the
movement of dirty items over clean ones.
Several measures can be taken to reduce the chance for cross-
contamination when working in a BSC. Opened tubes or bottles should
not be held in a vertical position. Investigators working with Petri dishes
and tissue culture plates should hold the lid above the open sterile surface
to minimize direct impaction of downward air. Bottle or tube caps should
not be placed on the toweling. Items should be recapped or covered as
soon as possible.
Open flames are not required in the near microbe-free environment of a
biological safety cabinet. On an open bench, flaming the neck of a culture
vessel will create an upward air current which prevents microorganisms
from falling into the tube or flask. An open flame in a BSC, however,
creates turbulence which disrupts the pattern of air supplied to the work
surface. When deemed absolutelv necessary, touch-plate microburners
equipped with a pilot light to provide a flame on demand mav be used.
Internal cabinet air disturbance and heat buildup will be minimized.
The burner must be turned off when work is completed. Small electric
furnaces are available for decontaminating bacteriological loops and
needles and are preferable to an open flame inside the BSC. Disposable
sterile loops can also be used.
Aspirator bottles or suction flasks should be connected to an overflow
collection flask containing appropriate disinfectant, and to an in-line
HEPA or equivalent filter.
116 cleanroom operators manual
Figure 2: Working with aspirator bottles and suction flasks
This combination will provide protection to the central building vacuum
system or vacuum pump, as well as to the personnel who service this
equipment. Inactivation of aspirated materials can be accomplished by
placing sufficient chemical decontamination solution into the flask to
kill the microorganisms as they are collected. Once inactivation occurs,
liquid materials can be disposed of appropriately as noninfectious waste.
Investigators must determine the appropriate method of decontaminating
materials that will be removed from the BSC at the conclusion of the
work. When chemical means are appropriate, suitable liquid disinfectant
should be placed into the discard pan before work begins. Items should
be introduced into the pan with minimum splatter, and allowed
appropriate contact time as per manufacturers instructions. Alternatively,
liquids can be autoclaved prior to disposal. Contaminated items should
be placed into a biohazard bag or discard tray inside the BSC. Water
should be added to the bag or tray prior to autoclaving.
When a steam autoclave is to be used, contaminated materials should be
placed into a biohazard bag or discard pan containing enough water to
ensure steam generation during the autoclave cycle. The bag should be
taped shut or the discard pan should be covered in the BSC prior to
removal to the autoclave. The bag should be transported and autoclaved
in a leakproof tray or pan.
surface decontamination
All containers and equipment should be surface decontaminated and
removed from the cabinet when work is completed. At the end of the
work day, the final surface decontamination of the cabinet should include
117 good biosafety practices
a wipe-down of the work surface, the cabinets sides and back, and the
interior of the glass. If necessary, the cabinet should also be monitored
for radioactivity and decontaminated when necessary. Investigators
should remove their gloves and gowns and wash their hands as the final
step in safe microbiological practices.
Small spills within the BSC can be handled immediately by removing
the contaminated absorbent paper toweling and placing it into the
biohazard bag. Any splatter onto items within the cabinet, as well as the
cabinet interior, should be immediately wiped with a towel dampened
with decontaminating solution. Gloves should be changed after the work
surface is decontaminated and before placing clean absorbent toweling
in the cabinet. Hands should be washed whenever gloves are changed or
removed.
Spills large enough to result in liquids flowing through the front or rear
grilles require more extensive decontamination. All items within the
cabinet should be surface decontaminated and removed. After ensuring
that the drain valve is closed, decontaminating solution can be poured
onto the work surface and through the grille(s) into the drain pan.
Twenty to thirty minutes is generally considered an appropriate contact
time for decontamination, but this varies with the disinfectant and the
microbiological agent. Manufacturers directions should be followed.
The spilled fluid and disinfectant solution on the work surface should
be absorbed with paper towels and discarded into a biohazard bag. The
drain pan should be emptied into a collection vessel containing
disinfectant. A flexible tube should be attached to the drain valve and be
of sufficient length to allow the open end to be submerged in the
disinfectant within the collection vessel. This procedure serves to
minimize aerosol generation. The drain pan should be flushed with water
and the drain tube removed.
Should the spilled liquid contain radioactive material, a similar procedure
can be followed. Radiation safety personnel should be contacted for
specific instructions.
gas decontamination
BSCs that have been used for work involving infectious materials must
be decontaminated before HEPA filters are changed or internal repair
work is done. Before a BSC is relocated, a risk assessment which
considers the agents manipulated within the BSC must be done to
determine the need for decontamination. The most common
118 cleanroom operators manual
decontamination method uses formaldehyde gas, although more recently
hydrogen peroxide vapor has been used successfully. This
environmentally benign vapor is useful in decontaminating HEPA filters,
isolation chambers and centrifuge enclosures.
facility and engineering requirements: secondary barriers
Whereas biological safety cabinets are considered to be the primary safety
barrier for manipulation of infectious materials, the laboratory room
itself is considered to be the secondary safety barrier. Inward directional
air flow is established exhausting a greater volume of air than is supplied
to a given laboratory and by drawing makeup air from the adjacent space.
This is optional at biosafety level 2 but must be maintained at BSL-3.
The air balance for the entire facility should be established and
maintained to ensure that air flow is from areas of least- to greater
contamination.
building exhaust
At BSL-3 and BSL-4, exhaust laboratory air must be directly exhausted
since it is considered potentially contaminated. This concept is referred
to as a dedicated single-pass exhaust system. The exhausted room air
can be HEPA-filtered when a high level of aerosol containment is needed,
which is always true at BSL-4 and is optional at BSL-3. When the
building exhaust system is used to vent a ducted BSC, the system must
have a sufficient capacity to maintain the exhaust flow if changes in the
static pressure within the system should occur. Otherwise, each cabinet
must have a dedicated exhaust system.
The room exhaust system should be sized to handle both the room and
all containment devices vented through the system. Adequate supply air
must be provided to ensure appropriate function of the exhaust system.
The facility engineer should be consulted before locating a new cabinet
requiring connection to the building exhaust system. Right angle bends,
long horizontal runs, and transitional connectors within the systems
will add to the demand on the exhaust fan. The building exhaust air
should be discharged away from supply air intakes, to prevent
entrainment of exhausted laboratory air back into the building air supply
system.
utility services
Utility services needed within a BSC must be planned carefully. Protection
of vacuum systems has already been addressed. Electrical outlets inside
119 good biosafety practices
the cabinet must be protected by ground fault circuit interrupters and
should be supplied by an independent circuit. When propane gas is
provided, a clearly marked emergency gas shut-off valve outside the
cabinet must be installed for fire safety. All nonelectrical utility services
should have exposed, accessible shut-off valves.
ultraviolet lamps
Ultraviolet (UV) lamps are not required in BSCs. If installed, UV lamps
must be cleaned weekly to remove any dust and dirt that may block the
germicidal effectiveness of the ultraviolet light. The lamps should be
checked periodically with a meter to ensure that the appropriate intensity
of UV light is being emitted. UV lamps must be turned off when the
room is occupied to protect eyes and skin from UV exposure, which can
burn the cornea and cause skin cancer.
BSC placement
Biological safety cabinets were developed as work stations to provide
personnel, product and environmental protection during the manipulation
of infectious microorganisms. Certain considerations must be met to
ensure maximum effectiveness of these primary barriers. Whenever
possible, a 12-inch clearance should be provided behind and on each
side of the cabinet to allow easy access for maintenance, and to ensure
that the air return to the laboratory is not hindered. A 12- to 14- inch
clearance above the cabinet may be required to provide for accurate air
velocity measurement across the exhaust filter surface with a
thermoanemometer and for exhaust filter changes. When the BSC is
hard-ducted or connected by a thimble unit to the ventilation system,
adequate space must be provided so that the configuration of the duct
work will not interfere with air flow. The thimble unit must provide
access to the exhaust filter for testing of the HEPA filter.
The ideal location for the biological safety cabinet is remote from the
entry (e.g., the rear of the laboratory away from traffic), since people
walking parallel to the face of a BSC can disrupt the air curtain. The air
curtain created at the front of the cabinet is quite fragile, amounting to
a nominal inward and downward velocity of 1 mph. Open windows, air
supply registers, or laboratory equipment that creates air movement (e.g.,
centrifuges, vacuum pumps) should not be located near the BSC.
Similarly, chemical fume hoods must not be located close to BSCs.
120 cleanroom operators manual
HEPA filters
HEPA filters, whether part of a building exhaust system or part of a
cabinet, will require replacement when they become so loaded that
sufficient air flow can no longer be maintained. Filters must be
decontaminated before removal. To contain the formaldehyde gas
typically used for microbiological decontamination, exhaust systems
containing HEPA filters require airtight dampers to be installed on both
the inlet and discharge side of the filter housing. This ensures
containment of the gas inside the filter housing during decontamination.
Figure 3: Bag-in/bag-out of contaminated HEPAs
Access panel ports in the filter housing also allow for performance testing
of the HEPA filter.
A bag-in/bag-out (BIBO) filter assembly can be used in situations where
HEPA filtration is necessary for operations involving biohazardous
materials and hazardous or toxic chemicals. This protects the technician
handling the filter as well as the environment. The BIBO system is used
when it is not possible to decontaminate the HEPA filters with
formaldehyde gas, or when hazardous toxic chemicals have been used
in the BSC. Note, however, that this requirement must be identified at
the time of purchase and installation; a BIBO assembly cannot be added
to a cabinet after-the-fact.
effective use of biological safety cabinets
Exposure to airborne microorganisms can result in infection of laboratory
workers or contamination of research materials. Biomedical engineering
and technology have provided safeguards, but these safeguards do not
prevent mistakes or human errors. Danger to personnel and to the success
of scientific investigation from carelessly or improperly used equipment
cannot be overly emphasized.
121 good biosafety practices
The Laminar Flow Biological Safety Cabinet, designed to prevent escape
of pathogens into the workers' environment and to bar contaminants
from the research work zone, is a key element to safe, successful
experimentation with biological materials. Escape of pathogens into the
workers' area is prevented by an air barrier at the front opening and the
cleaning action of the exhaust air filter. Inward flow of room air into
the front air intake grill creates the air barrier. The amount of air drawn
into the air intake grill and the amount of air exhausted through the
exhaust filter are equal. The exhaust filter removes airborne biological
contaminants which may be released in the cabinet. It does not remove
chemical or radiological contaminants.
Contamination of the work area inside the cabinet is prevented by the
cleaning action of the supply filters. Air flows through the cabinet work
area in a downward direction at a uniform velocity. The air continues to
be recirculated by the fan through the air flow plenum. Airborne
biological contaminants are removed by the filters as the air is returned
to the cabinet work area.
Certification and advance planning are of prime importance to safe
operation. Only qualified personnel using approved test methods and
equipment should provide performance certification at initial installation,
after maintenance, and on an annual basis thereafter. Certification is
also necessary after the cabinet has been moved and after filters have
been replaced. Many cabinets have gauges to indicate pressure differential
across the supply filters. If the filters must be replaced, the cabinet MUST
be decontaminated first. This is the responsibility of the researcher to
do or have done by a qualified contractor. Procedures must follow those
outlined in the National Sanitation Foundation Standard Number 49.
After decontamination, only qualified Site Support personnel should
replace filters. Fan speed must also be readjusted by qualified
maintenance technicians.
It is the responsibility of individual researchers and/or departments to
insure this process is accomplished at least annually.
In a survey performed by a cabinet manufacturer, 65 of 100 cabinets
failed to pass filtration system leak tests. The operators of these cabinets
were unaware of the malfunction. Maximum safety and full use of the
cabinet can be best achieved by adequate advanced planning. Ideally,
advanced planning should follow a procedural check list to anticipate
equipment, apparatus, media, order of events and the many other details
necessary for the completion of the assignment.
122 cleanroom operators manual
When planning is completed, start-up procedures may be initiated. There
are three start-up steps:
1 Turn on the lights
2 Check the air intake and exhaust grill to make sure they are
unobstructed
3 Turn on the fan
Allow the fan to operate a minimum of five minutes before manipulations
are begun in the cabinet. In addition, the following points should be
considered:
1 Some cabinets are equipped with ultraviolet light. These must be
turned off during the day while laboratory personnel are occupying
the room.
2 Hands and arms should be washed well with germicidal soap
before and after work in the cabinet.
3 Technicians are encouraged to wear long-sleeve gowns with knit
cuffs and rubber gloves. This minimizes the shedding of skin flora
into the work area and protects the hands and arms from
contamination by viable agents.
4 Interior surfaces of the work area should be disinfected by wiping
them thoroughly with 70% alcohol.
5 The cabinets should not be overloaded. Everything needed for the
complete procedure should be placed in the cabinet before starting
so that nothing passes in or out through the air barrier until the
procedure is completed.
6 Do not place anything over the front intake or rear exhaust grill in
units having a solid work surface.
7 As a general rule, keep equipment at least four inches inside the
cabinet window and perform transfer of viable materials as deeply
into the cabinet as possible.
8 After all materials have been placed in the cabinet, wait 2-3
minutes before beginning work. This will allow sufficient time for
the cabinet air to purge airborne contamination from the work
area.
9 Hold the activity in the room to a minimum. Unnecessary activity
may create disruptive air currents. The ideal location for a cabinet
is in a quiet end of the laboratory, removed fromdoorways, air
conditioning and heating vents. Opening and closing laboratory
doors can cause disruptive drafts that allow microorganisms to
penetrate the air barrier.
123 good biosafety practices
10 Schedule uninterrupted work periods. The movement of objects
including hands and arms causes turbulent air currents which
disrupt the air barrier and allow escape and entrance of airborne
contaminants.
11 Air turbulence caused by rotating laboratory equipment, such as a
small clinical centrifuge, disrupt airflow within the cabinet and at
the work opening. This is sufficient for contaminated air to escape
to the laboratory environment. If a centrifuge must be used in the
cabinet, do not perform other research activities in the cabinet
while the centrifuge is operating.
12 Normal laboratory contamination control procedures and aseptic
techniques are still necessary while working in the biological
safety cabinet.
13 Equipment in direct contact with the biological agent should not
be removed from the cabinet until enclosed or until the surface is
decontaminated. Trays of discarded pipettes and glassware must be
covered before removal from the cabinets.
14 If an accident occurs which spills or splatters the biological agent
in the work area, all surfaces in the cabinet must be surface
decontaminated before being removed.
15 Do not use a Bunsen Burner in a biological safety cabinet. The
flame causes turbulence in the air stream and the heat generated
may damage the HEPA filter. If a procedure requires the use of a
flame, a burner with a pilot light should be used. It should be
placed to the rear of the workspace where resulting air turbulence
will have a minimal effect.
16. Do not mouth pipette.
Following completion of the work, the following steps must be
performed:
1 Allow the cabinet to run 2-3 minutes with no activity. This will
allow sufficient time for cabinet airflow to purge airborne
contaminants from the work area;
2 Decontamination of the interior surfaces should be repeated after
removal of all materials, cultures, apparatus, etc. A careful check
of the work area should be made for spilled or splashed nutrients.
They may support fungus growth and result in spore liberation
that contaminates the protected work environment; and
3 Shut down by turning off the fan and lights. Use UV lights
according to manufacturer's recommendations.
4. Do not use the cabinet to store excess laboratory equipment.
124 cleanroom operators manual
bsc:faqs*
* Adapted from Labconco Biological Safety Cabinet Training Program,
Version 1.0, 3/91.
"I've got to use a Bunsen Burner in my biohazard cabinet..."
Using a Bunsen Burner in a biohazard cabinet compromises the
performance of the unit and may be dangerous. During operation, the
flame of a burner is very disruptive to the air flow patterns of the cabinet,
and may actually increase the dispersion of aerosols in the work area. In
addition, if the flame of the burner is too large, the excessive heat may
melt in adhesive holding the HEPA filter together or literally burn holes
in the filter media. (Yes, it does happen on a regular basis.) Finally, a
Bunsen Burner in a biological safety cabinet is just plain dangerous. An
unattended burner may blow out. If in a Type A or A/B3 cabinet, the
recirculating gas may reach explosive concentrations (that has also
happened on several occasions). Labconco recommends using alternative
methods such as electric incinerators, or disposable inoculating hoops,
for instance. The practice of flaming bottle mouths is unnecessary, as
the work area of a Biohazard Cabinet should be a sterile environment, if
used properly.
"I can use a biological safety cabinet just as if it were a fume hood..."
No. The biohazard cabinet and the chemical fume hood are two distinctly
different pieces of equipment and MUST be used differently. The fume
hood is designed to remove noxious or toxic fumes and aerosols away
from the operator. It should be constructed of materials that are inert to
a wide variety of chemical agents. The biohazard cabinet's primary
purpose is to protect the operator, environment, and often the product
from biohazardous contaminants. The biohazard cabinet and its HEPA
filters are constructed of materials that are inert to the chemicals used
in connection with biological research, but may be damaged by some of
the more corrosive chemicals commonly used in fume hoods. Don't try
to use a Biohazard Cabinet as a Fume Hood!
"If I work in a biohazard cabinet, I don't have to be as careful with
my technique..."
Wrong. The biohazard cabinet will provide personal and product
protection only if used properly. Aseptic technique must be practiced at
all times while working in a biohazard cabinet.
125 good biosafety practices
"I use the cabinet's UV light, so I don't need to decontaminate the
work area..."
Wrong. The UV light is only good as an adjunct, to minimize
contamination of the work area when the cabinet is not in use. Ultraviolet
light has virtually no penetrating power, and as such, will not kill
microbes protected by dust, dirt, or organic material. The best method
to prevent contamination in the cabinet is regular decontamination of
the work area surfaces, before and after the cabinet is used.
"Can I put a centrifuge in the biohazard cabinet?"
Large objects placed in the biohazard cabinet will impede the airflow
in the work area, reducing the efficiency of the cabinet. Electrical
appliances like centrifuges, blenders, etc., will often disrupt the airflow
around them due to their cooling fans. It is better to use a primary barrier
on the appliance (such as a sealed safety cup in the centrifuge) rather
than a biohazard cabinet to provide containment.
"There's nothing wrong with using the biohazard cabinet to store
material when not in use."
Yes there is. Storing chemicals and materials in the biohazard cabinet
make it more difficult to use when the need arises. If chemicals leak
while stored in the cabinet, the work area of the cabinet could be damaged.
Don't use the biohazard cabinet as a storage area.
"All biohazard cabinets should operate continuously, 24 hours-a-day."
Some applications of the biohazard cabinet require that the unit operate
continuously. When used to prepare cytotoxic drugs, for example, the
unit should operate continuously, to prevent toxic residue form migrating
out of the cabinet ductwork and into the laboratory. If the cabinet is not
used in such an application, there is no need to leave it operating
continuously. This will only reduce the life of the cabinet blower and
HEPA filters.
"If I leave my Type A cabinet running continuously, it will clean all
the air in the room to Class 100 conditions."
Not necessarily. Assuming you had an air-tight room, with no ventilation
system, an air-tight door seal, and no activity in it, then a recirculating
Type A cabinet might clean the room to Class 100 levels. This would
also unfortunately shorten the operating life of the motor and HEPA
filters (and heat up the room considerably). Regardless, as soon as the
126 cleanroom operators manual
operator opens the room door to enter, particulate-laden air will
contaminate the room, raising it far above Class 100 conditions.
"Is there any alternative to exhausting so much of costly tempered
room air?"
Yes. To ensure that the BSC is maintained at negative pressure with
respect to the room, you must draw room air at least sufficient to sustain
the face velocity at the specified level. This will work out to
approximately 20 to 35 cfm per linear foot of the workspace width. If
your cultures do not require any special temperature or RH control, then
you may draw untempered air from any adjacent room or corridor through
prefilters and make up your exhaust air volume. For example, if you are
using a Type II B3 BSC, it is designed for 30% exhaust, which works
out to throwing out 360 CFM. If you are able to sustain the face velocity
with 160 cfm drawn from the room, you may make up the balance 200
cfm required from an adjacent room. Do not draw air from outside the
building.
If the room in which you work is to be maintained at negative pressure
with respect to the outside environment, do not use the BSC exhaust
arrangement as the only means of achieving that condition. The room
should have its own separate exhaust system.
Exhaust air from BSCs and Biosafe facilities should not be connected to
the buildings general exhaust system. A separate dedicated exhaust
should be used.
Biosafe exhaust design should factor in such possibilities as power outage
and fan failure.
"Are the biological test methods different for different types of Class
II BSCs?"
Unfortunately, no. All four types of Class II BSCs are qualified using
the same microbiological test method described earlier. The User is
advised to devise more aggressive challenge methods, if deemed
necessary, appropriate to the application.
handling and disposal of waste
A. Biohazard waste
The following information regarding biohazard waste is being provided
to eliminate any misunderstandings about the requirements for proper
disposal of biohazard wastes.
127 good biosafety practices
Biohazard Wastes are discarded materials "that are biological agents or
conditions (as an infectious organism or unsecure laboratory condition)
that constitutes a hazard to man or his environment." This definition
includes "any and all substances which contain materials to which
organisms may cause injury or disease to man or his environment, but
which are not regulated as controlled industrial waste".
B. Infectious wastes include the following categories:
1 cultures and stocks of infectious agents and associated biologicals;
2 human blood and blood products,
3 pathological wastes,
4 contaminated sharps,
5 contaminated animal carcasses,
6 body parts, and bedding,
7 wastes from surgery, necropsy and other medical procedures,
laboratory wastes,
8 isolation wastes, unless determined to be non-infectious by the
infection control committee,
9 any other material and contaminated equipment which, in the
determination of the facility infection control staff, presents a
significant danger of infection because it is contaminated with, or
may reasonably be expected to be contaminated with, etiologic
agents.
C. Chemical wastes
Chemical Wastes subject to the requirements of biohazard waste
regulations include wastes from the following categories:
1 pharmaceutical wastes
2 laboratory reagents contaminated with infectious body fluids
3 all the disposable materials which have come into contact with
cytotoxic/antineoplastic agents during the preparation, handling,
and administration of such agents
4 other chemicals that may be contaminated by infectious agents, as
designated by experts at the point of generation of the waste.
D. Treated biohazard wastes
Treated Biohazard Wastes are all biohazard wastes that have been treated
by one of the following methods and rendered harmless and biologically
inert:
128 cleanroom operators manual
incineration in an approved incinerator,
steam sterilization at sufficient time and temperature to destroy
infectious agents in waste ("autoclaved"),
chemical disinfection where contact time, concentration, and
quantity of the chemical disinfectant are sufficient to destroy
infectious agents in the waste, and
any other method approved and generally recognized as effective.
E. Sharps
Sharps are used in animal or human patient care or treatment or in
medical research, or industrial laboratories, including:
hypodermic needles, syringes, (with or without the attached
needle)
pasteur pipettes
scalpel blades
suture needles
blood vials
needles with attached tubing
and culture dishes (regardless of presence of infectious agents).
other types of broken or unbroken glassware that were in contact
with infectious agents, such as used slides and cover slips.
The following guidelines should be followed for biohazard waste disposal:
1. If any infectious waste is also a chemical waste, call for assistance
with disposal AFTER disinfection. All waste of this type must be
non-human, non-infectious, and non-viable.
2. Biohazard wastes that are also radioactive shall be treated
according to requirements for both biohazard and radioactive
waste.
3. Untreated biohazard waste shall NEVER be disposed of in the
municipal solid waste stream. All laboratories shall evaluate their
waste stream to ensure that all biohazard wastes, including sharps
and syringes, are treated in a manner as described earlier before
disposal in the municipal waste stream.
4. Prior to any treatment all biohazard wastes, including those to be
incinerated, shall be enclosed in a puncture-proof, red
BIOHAZARD BAG that is marked with the universal biological
hazard symbol.
129 good biosafety practices
5. All sharps intended for disposal, whether contaminated or not,
shall be enclosed in a sharps container. Recapping needles is
dangerous and shall be avoided. Treat syringes as you would a
controlled substance. It is recommended that all unwanted
syringes be destroyed after disinfection but before disposal in the
solid waste stream. Destroying an infectious sharp or syringe
before disinfection could spread contamination. Special
consideration should also be given to the disposal of contaminated
pipettes.
6. After disinfection but before disposal in the municipal waste
stream, all treated biohazard wastes shall be enclosed in an
unmarked outer bag that is NOT red. Any biohazard waste that
has been treated as described above, packaged such that it is
clearly evident that the waste had been effectively treated AND
contains no chemical or radioactive waste is NOT subject to
regulation as biohazard waste and may be collected, transported,
and disposed of as MUNICIPAL WASTE.
F. Guidelines for disposal
1. If any infectious waste is also a chemical waste, call for assistance
with disposal after disinfection. Antineoplastic/cytotoxic agents
require special disposal.
2. Biomedical wastes that are also radioactive should be treated
according to requirements for both biomedical and radioactive
waste.
3. Prior to any treatment, all biomedical wastes, including those to be
incinerated, should be enclosed in a puncture-resistant, red
biohazard bag that is color-coded or labeled with the biological
hazard symbol.
4. All sharps intended for disposal, whether contaminated or not,
must be enclosed in a specially designed sharps container. Never
clip or recap needles before putting them in the sharps container.
The sharps container should be puncture-resistant, leak proof on
the sides and bottom, and color-coded or labeled with the
biohazard symbol. When selecting sharps containers, look for
special safety features such as lids that lock tight for safe disposal,
a container that can be sterilized by steam, gas, or chemicals, and
a clear top that would allow inspection. If sharps containers are
not specifically constructed to be autoclaved, the resulting mass of
melted plastic is extremely hazardous due to the needles that often
protrude.
5. Untreated biomedical waste is not to be disposed of in the
municipal waste stream. All biomedical waste, including sharps
and syringes, must be treated by incineration, steam sterilization,
or chemical disinfection before disposal in the municipal waste
stream.
6. After disinfection, but before disposal in the municipal waste
stream, all treated biomedical wastes should be enclosed in an
unmarked outer bag that is not red or labeled with the biohazard
symbol. Any biomedical waste that has been treated as described
above and packaged such that it is clearly evident that the waste
has been effectively treated, is not subject to regulation as
biomedical waste and may be collected, transported, and disposed
of as municipal waste.
why GMP?
When did you last pop a pill? Can you recall when you last administered
any medicine to your near and dear ones? Did it occur to you at that
time that the drug you were consuming or administering could be
adulterated or misbranded? Did you consider having it tested to verify
that the drug was indeed what the label claimed it was? No? Dont
worry. You are not alone. Everyone does exactly what you did. Some,
unfortunately, are no longer around to be counted.
Several patients at Davenport, Plymouth, UK paid for poorly sterilised
infusions with their lives. Nearer home in Kolar, scores of hypertensive
and hyperglycaemic patients died because their medicines were
inadvertently interchanged at the manufacturers end during packaging
and labeling. Little children on multivitamin courses developed severe
reactions because of cross-contamination with a systemic allergen
produced earlier in the same equipment train.
cGMP & you: personnel in drug and device
manufacture
C K Moorthy
9 9
9 99
132 cleanroom operators manual
Disasters like these are rare, which explains your own complacency and
blind trust in the pharmaceutical industry when you consumed your
pill; but, disturbingly, they are not uncommon. Contrary to what you
may have thought, drugs are not produced by infallible super humans in
outer space. Veterans in the industry certainly recall lapses they
themselves have witnessed over the years. Fortunately, most such
blunders are discovered or detected in time before they leave the factory
and reach the consumer.
Things seldom go horribly wrong all of a sudden. As Safety Engineers
will tell you, a series of near-mishaps if ignored will lead eventually to
some minor mishaps; and a series of minor mishaps will ultimately
culminate in a major mishap.
Some of the best lessons in GMP and sound scientific rationale have
come from lawyers! Justice Lentin, Justice Wolin and Mr C M Clothier
(who was later knighted for his efforts) to name a few.
the four areas of regulatory concern
Drug or device production has four, and just four, primary areas of
concern:
Contamination : Any substance or energy that adversely
affects drug performance
Goof ups : Errors of omission and commission of
human origin
Mix ups : Special case of human error through
gross negligence and carelessness
Process inconsistency : A process that is unstable and
unreliable
Current Good Manufacturing Practice (cGMP) endeavours to address
these issues. In some countries cGMP is merely a guideline; but in most
others it carries the weight of a law. Laws exist to safeguard some right
or value of a citizen, and cGMP is no different.
cGMP aspires to protect the following five core values (referred to as
SISPQ for short throughout this book):
Safety : The product remains free of any unexpected side effects
when used appropriately
Identity : The product is exactly what the label and related material
say it is; every material, component, significant piece of
equipment and operation is labeled and documented so
133 cGMP & you: personnel in drug and device manufacture
that lot histories can be accurately reconstructed from
start to finish
Strength : The concentration of the drug substance (for example,
weight/weight, weight/volume, or unit dose/volume
basis), and/or the potency, that is, the therapeutic activity
of the drug product as indicated by appropriate laboratory
tests or by adequately developed and controlled clinical
data (expressed, for example, in terms of units by
reference to a standard)
Purity : Absence of substances that produce adverse effects on
the product
Quality : Fitness for intended use
Contaminated LVPs caused the deaths at Davenport. Mr Clothier
discovered Klebsiella; Justice Lentin found fungus. Others have reported
roaches. A Mix up and consequent loss of Identity of the drugs led to
the deaths at Kolar.
you hold the key to GMP success
People hold the key to the success of any GMP initiative. If your
buildings, utilities and equipment are designed, installed, operated and
maintained in a validated state, what would you attribute defective
products, if any produced, to? People,of course.
If the raw materials and components come from qualified suppliers and
have been passed by QC, what would you attribute defective products,
if any produced, to? People,again.
A properly validated production process will not produce defectives.
What would you attribute defective products, if any produced, to? People.
Machines do not goof up. Machines do not mix up. Only people do.
On the other hand, your buildings, facilities and equipment cannot
function without people. Which is why I repeat that People, and only
people, determine the success or failure of GMP in your Plant. People
are the prime movers of any Organisation.
Two competitors on a level playing field, with identical premises,
facilities and equipment, and the same manufacturing process: what
makes one more successful than the other: the superiority of the formers
people.
134 cleanroom operators manual
failures traceable to personnel
particulate contamination: 80%
microbial contamination: 98%
human errors: 100%
It is commonly acknowledged that 60% of all product recalls world-
wide are traceable to human errors: marking & labelling errors;
packaging errors. A validated process fails commonly because of
weighing & dispensing errors; and non-adherence to SOPs.
importance of SOPs
GMP is the quality system guide that sets your Goals; but doesnt always
tell you how to achieve them.
Process development group, after exhaustive trials and errors, discovers
the path to achieving these goals - the Methods, if followed without
deviation, will produce a product of the desired quality. These methods
are formally transferred to production as Standard Operating Procedures
(SOPs).
Your records are the Proof that you have adhered to these SOPs, and
vindicate your commitment, sincerity and diligence in your work.
In other words, Goals, Methods and Proof reflect your GMP compliance.
resolving issues related to personnel
All types of contamination:
O High personal hygiene
O Decontamination before entry
O Good Gowning
O Hand wash & gloving
O Good conduct in process area
O Cautious, vigilant behaviour at the workplace
Product recalls: goof ups & mix ups
O Be fit for your job
O Stay fit for your job
O Be conscientious, alert and vigilant
O Have written SOPs for your jobs
O Strictly follow SOPs in your work
135 cGMP & you: personnel in drug and device manufacture
O When in doubt, dont guess: seek immediate help
O Document your work: cross-check and record
Process Control
O Have stable, capable process
O Validate the process
O Have written SOPs
O Strictly follow SOPs
O Document your work: cross-check and record
O Maintain state of control
Cross-check. Why? Because it is extremely likely that when you are
checking soemthing you do routinely, you may not always detect errors;
but when you are checking someone elses work, the mistake is more
readily noticed. The next time you fly, check the Captains instructions
to his crew: All ground staff to deplane; cabin-crew to arm all doors,
cross-check and report. Yes, cross-check.
the patient trusts you
I started this chapter asking you whether it had crossed your mind that
the pill you were giving your child could have been misbranded or
adulterated. No, it did not. Because you trusted the manufacturer,
because of his great reputation.
That is exactly what the patient you are serving is doing. He trusts you.
Any error on your side constitutes betrayal of that trust.
work as if the product is for you and your family
I am reminded of a story I once read about building a house.
An elderly carpenter was ready to retire. He told his employer-contractor
of his plans to leave the house-building business and live a more leisurely
life with his wife, enjoying his extended family. He would miss the
paycheck, but he needed to retire. They could get by.
The contractor was sorry to see his good worker go and asked if he
could build just one more house as a personal favor. The carpenter said
yes, but in time it was easy to see that his heart was not in his work. He
resorted to shoddy workmanship and used inferior materials. It was an
unfortunate way to end a dedicated career.
136 cleanroom operators manual
When the carpenter finished his work the employer came to inspect the
house. He handed the front-door key to the carpenter. This is your
house, he said, my gift to you.
The carpenter was shocked! What a shame! If he had only known he
was building his own house, he would have done it all so differently.
So it is with us. We build our lives, a day at a time, often putting less
than our best into the building. Then with a shock we realize we have to
live in the house we have built. If we could do it over, wed do it much
differently. But we cannot go back. You are the carpenter. Each day you
hammer a nail, place a board, or erect a wall. Life is a do-it-yourself
project, someone has said. Your attitudes and the choices you make
today, build the house you live in tomorrow. Build wisely!
Just imagine a situation where on a Saturday at 11:00 PM your child is
seriously ill. You call your family doctor in desperation only to find he
is out of station, due back only on Monday morning. But he gives you a
detailed home remedy to keep the situation under control until his return.
Would you prepare the home remedy yourself or leave it to your servant?
The product you are manufacturing could land up in your home: you or
members of your family may be consuming it. So manufacture wisely.
cGMP & you: a summary of points to consider
O The patient is unknown, in distress and in need of relief
O The patient trusts you and your product quality
O Product Quality is your responsibility
O Failure to adhere to GMP is betrayal of Patients trust
O Make the product for yourself: you could be the customer
O Look for ways to further improve your manufacturing practices
O SOPs define your Path for maintaining consistency in your
Product Quality
O Strict adherence to SOPs helps maintain your process in a state of
control
O Take pride in performing your job right the first time, every time,
all the time
O Good records are your Proof of Performance and vindication of
Responsibility
O Take GMP beyond regulatory compliance to a culture, a tradition
and your way of life
137 cGMP & you: personnel in drug and device manufacture
making GMP your culture
Observing Traffic Rules is a sign of civilisation comments a hoarding
in Egypt. Aim for the moon and you might still hit the tree tops,
quipped an old friend. These represent my sentiments.
We in India remove our footwear at the entrance; wash our hands before
and after a meal; bathe at least once a day. Women are advised to stay
isolated during their periods. No one has to tell us to do that; we do it by
sheer force of habit. Because it is our tradition, our culture. Such acts
are not so common or widespread in many parts of the world: they need
to be told. GMP is more compatible with our culture than with many
others. Make GMP your culture, and you will never have to worry about
compliance.
five golden rules of good documentation
Rule 1: Write what you do, exactly as you do; do what you write,
exactly as you write
Rule 2: Do not write what you do not do; do not do what you do not
write
Rule 3: If it is not written down, it didnt happen. Its just a rumour.
Rule 4: If it is not written down properly, it did not happen properly.
You can never be certain as to what actually happened
Rule 5: If the records are not correct, neither is the product
importance of good records
Good records represent Proof of Performance
Good records can vindicate your conscientiousness in your duty
Good records aid problem investigation
Good records can serve as a foundation upon which to base process
changes
Reliable records are important because they help
show how a process performed
identify drifts from nominal set points
prove sameness of successive batches
ten golden rules of GMP
The road to attaining a high level of cGMP is best summarised in these
ten golden rules:
1 Be fit for your job
2 Stay fit for your job
3 Have plant & machinery fit for intended use
4 Maintain the plant & machinery always fit for intended use
5 Have a stable, capable process
6 Validate your process
7 Have written operating procedures for your work
8 Follow the written operating procedures in your work
9 Cross check and report your data as you do it
10 Audit for continued conformance
I ask participants at my training programmes to write down what each
of them does in his or her job to protect and safeguard the core values of
GMP (SISPQ) ? And also, what would happen if they were not to observe
GMP requirements in their work?
If the above ten rules are followed, then cGMP will always translate to
mean Can Guarantee My Products!
management support
GMP responsibility spans the Organisation: GMP embraces all sections,
at all levels. Quality Responsibility and Accountability is a team effort,
not a policing effort. Much depends on the Management at the top. If
they are perceived to be committed, GMP will take root and blossom;
if, instead, it is only hype and lip service, employees will quickly follow
suit, and GMP will be reduced to a farce. Merely having Quality and
Production independent of each other will not help if the environment
is vitiated with business myopia, low ethics or high personnel insecurity.
The acid test on how committed the management is towards GMP is
in stress situations: how OOS test results are handled; how strictly
QC approval of starting materials prior to commencement of production
is implemented, specially when there are deadlines to be met; how aseptic
filling simulation failures are handled; how readily budgets from QA/
QC are approved, as compared to those from Marketing; how much
support in financial and other terms is extended for validation exercises;
whether QA is truly empowered or exists merely for effecting Quiet
Adjustments for regulatory expedience!
guidelines governing personnel in drug and
device manufacture
E
very guideline devotes a section to personnel. Some spell out
their expectations in greater detail than others. An attempt is
made here to present such expectations in a global context.
In a legal sense, a long list may be prepared indicating the sections, sub-
sections and paragraphs where personnel is referred to or alluded to,
directly or indirectly. This may be necessary for a prosecuting agency to
point out deficiencies. But we are interested here in a broad assessment
of the regulatory requirements, and place these in perspective.
Guidelines differ among themselves in their contents and relative
emphasis. Variances abound in perceptions among GMPs about
qualifications, QCs role and what constitutes adequate number of
personnel. USFDA singles out QC for GMP responsibility; EUGGMP
and TGA follow WHOs lead in expanding on the subject against a
Quality System backdrop and joint responsibility. Schedule M lies
somewhere between these extremes.
10 10
10 10 10
140 cleanroom operators manual
Sadly, none addresses the highly contentious, yet crucial, issues of an
employees responsibilities towards compliance, or advising management
about deviations or other problems, or suggesting improvements. Also,
there is no mention of what should the consequences be for non-adherence
or non-compliance at the individuals level.
While USFDA and Q7 have found it necessary to include consultants,
there is No mention of responsibilities, qualifications and track records
of vendors and sub-contractors.
WHO, European Community and Australia have paid special attention
to personnel requirements for biologicals.
We commence with each guidelines general expectations, and move
progressively to special requirements for different product groups,
ranging from bulk pharmaceuticals to sterile products, medical devices,
and biologicals.
Schedule M
1. Personnel
1.1The manufacture shall be conducted under the direct supervision of
competent technical staff with prescribed qualifications and practical
experience in the relevant dosage form and/or active pharmaceutical
products
1.2The head of the Quality Control Laboratory shall be independent of
the manufacturing unit. The testing shall be conducted under the direct
supervision of competent technical staff who shall be whole time
employees of the licensee.
1.3Personnel for Quality Assurance and Quality Control operations shall
be suitably qualified and experienced.
1.4Written duties of technical and Quality Control personnel shall be
laid and followed strictly.
1.5Number of personnel employed shall be adequate and in direct
proportion to the workload.
1.6The licensee shall ensure in accordance with a written instruction
that, all personnel in production area or into Quality control shall receive
training appropriate to the duties and responsibility assigned to them.
They shall be provided with regular in-service training.
141 guidelines governing personnel in drug and device manufacture
2. Health, clothing and sanitation of workers
2.1The personnel handling beta-lactum antibiotics shall be tested for
penicillin sensitivity before employment and those handling sex
hormones, cytotoxic substances and other potent drugs shall be
periodically examined for adverse effects. These personnel should be
moved out of these sections (except in dedicated facilities), by rotation,
as a health safeguard.
2.2Prior to employment, all personnel shall undergo medical
examination including eye examination and shall be free from
Tuberculosis, skin and other communicable or contagious diseases.
Thereafter, they should be medically examined periodically, at least once
a year. Records shall be maintained thereof shall provide the services of
a qualified physician for assessing the health status of personnel involved
in different activities.
2.3All persons, prior to and during employment, shall be trained in
practices which ensure personnel hygiene. A high level of personal
hygiene shall be observed by all those engaged in the manufacturing
processes. Instructions to this effect shall be displayed in change- rooms
and other strategic locations.
2.4No persons showing, at any time, apparent illness or open lesions
which may adversely affect the quality of products, shall be allowed to
handle starting materials, packaging materials, in - process materials,
and drug products until his condition is no longer judged to be a risk.
2.5All employees shall be instructed to report about their illness or
abnormal health condition to their immediate supervisor so that
appropriate action can be taken
2.6Direct contact shall be avoided between the unprotected hands of
personnel and raw materials, intermediate or finished, unpacked products
2.7All personnel shall wear clean body coverings appropriate to their
duties. Before entry into the manufacturing area, there shall be change
rooms separate, for each sex with adequate facilities for personal
cleanliness such as wash basin with running water, clean towels, hand
dryers, soaps, disinfectants etc. The change rooms shall be provided
with cabinets for the storage of personal belongings of the personnel.
2.8Smoking, eating, drinking, chewing or keeping plants, food, drink
and personal medicines shall not be permitted in production, laboratory,
storage and other areas where they might adversely influence the product
quality.
142 cleanroom operators manual
WHO
The role and position of the Authorized Person in the company
1. Authorised person as overall Quality Controller
The authorized person as the overall quality controller will be a member
of a team whose function includes the following major areas:
o implementation (and, when needed, establishment) of the quality
system;
o participation in the development of the companys quality manual;
o supervision of the regular internal audits or self-inspections;
o oversight of the quality control department;
o participation in external audit (vendor audit);
o participation in validation programmes.
Although authorized persons may not have line management
responsibility for many activities within this function (although they
should be involved in these activities as much as possible), they must be
aware of any changes that may affect compliance with technical or
regulatory requirements related to the quality of finished products. When
any aspect of the companys operations is not in accordance with GMP
guidelines or relevant legislation in force, the authorized person must
bring this to the attention of senior management. This duty should be
reflected in the authorized persons job description.
The availability of an authorized person should be a prerequisite for
issue of a manufacturing licence (authorization). The authorized person
(as well as persons responsible for production and quality control) must
be approved by the drug regulatory authority. The licence holder is obliged
to inform the drug regulatory authority, or other responsible authority
depending on national (regional) regulations, immediately if the
authorized person is replaced unexpectedly. Such provisions will assure
to a considerable degree the independence of the authorized person from
the management of the company in the fulfilment of his or her duties
even when under pressure to depart from professional and technical
standards.
As indicated in the GMP guidelines published by WHO, in certain
countries, depending on the national legislation or regulations, two
authorized persons are designated: one for production and another for
quality control. A company may have a complex structure, or operate at
several locations, or both, and sometimes a separate authorized person
143 guidelines governing personnel in drug and device manufacture
may be designated who is responsible for the manufacture of clinical
trial materials. Consequently it may be necessary to nominate several
authorized persons, one of them having the responsibilities of the overall
quality controller and the others responsible for site or branch operations.
The person authorizing batch release should be independent from
production activities.
The drug regulatory authority should approve the authorized person on
the basis of his or her professional curriculum vitae. Authorized persons
have duties not only to their employer but also to the competent authorities
such as the drug regulatory authority. They should establish good working
relations with inspectors and as far as possible provide information on
request during site inspections.
The authorized person depends upon many working colleagues for the
achievement of quality objectives, and may delegate some duties to
appropriately trained staff while remaining the overall quality controller.
It is therefore of paramount importance that he or she establish and
maintain a good working relationship with other persons in positions of
responsibility, especially those responsible for production and quality
control.
2. Implementation of the quality system
Authorized persons have a personal and professional responsibility for
ensuring that each batch of finished products has been manufactured in
accordance with the marketing authorization, GMP rules and all related
legal and administrative provisions. This does not necessarily mean that
they must have directly supervised all manufacturing and quality control
operations. They must be satisfied either directly or, more usually, by
proper operation of quality systems, that manufacturing and testing have
complied with all relevant requirements. Therefore it is recommended
that the manufacturer establishes and maintains a comprehensive quality
system, covering all aspects of GMP.
Useful reference material, in addition to rules and regulations on GMP,
may be found in the International Standards ISO 9000 family (9000
9004). These standards describe quality systems requirements that can
be used for external quality assurance purposes. The important element
of these documents is a quality manual, describing the quality policy
and objectives (commitment to quality) of the company, the
organizational structure, responsibilities and authorities, together with
a description of or references to documented quality system procedures.
144 cleanroom operators manual
Research and development activities and the transfer of results of the
developmental work to routine manufacture, including original product
design, formulation, processes development and validation, should
observe GMP principles as guidance. Batches produced for clinical trials
must follow applicable GMP. It is of vital importance that the quality of
routine production batches corresponds to a specification derived from
the composition of development batches. The quality and safety of a
pharmaceutical product depend on the application of appropriate
procedures, based on GMP, leading to a product within the recognized
specification. Standard procedures and recognized specifications cannot
be separated.
3. Routine duties of an authorized person
Before approving a batch for release the authorized person doing so
should always ensure that the following requirements have been met:
The marketing authorization and the manufacturing authorization
requirements for the product have been met for the batch
concerned.
The principles and guidelines of GMP, as laid down in the
guidelines published by WHO, have been followed.
The principal manufacturing and testing processes have been
validated, if different.
All the necessary checks and tests have been performed and
account taken of the production conditions and manufacturing
records.
Any planned changes or deviations in manufacturing or quality
control have been notified in accordance with a well-defined
reporting system before any product is released. Such changes may
need notification to and approval by the drug regulatory authority.
Any additional sampling, inspection, tests and checks have been
carried out or initiated, as appropriate, to cover planned changes
and deviations.
All necessary production and quality control documentation has
been completed and endorsed by supervisors trained in appropriate
disciplines.
Appropriate audits, self-inspections and spot-checks are being
carried out by experienced and trained staff.
Approval has been given by the head of the quality control
department.
145 guidelines governing personnel in drug and device manufacture
All relevant factors have been considered, including any not
specifically associated with the output batch directly under review
(e.g., subdivision of output batches from a common input, factors
associated with continuous production runs).
In certain circumstances the authorized person may be responsible for
the release of intermediates manufactured on contract.
4. Education and training
The pool of expertise drawn upon for candidates for the position of
authorized person may differ from country to country. The basic
qualifications of a scientific education and practical experience for key
personnel, including authorized persons, are outlined in the GMP
guidelines published by WHO (section 10, Personnel).
Additional requirements may include subjects such as principles of
quality assurance and GMP, principles of good laboratory practice as
applicable to research and development as well as to quality control,
detailed knowledge of the authorized/qualified persons duties and
responsibilities, of International Standards ISO 90009004 and
relationships with suppliers, principles and problems of formulation of
pharmaceutical preparations, pharmaceutical microbiology, and
principles and practice of sampling and testing of starting materials,
packaging components and finished dosage forms.
WHO: Other Personnel
10.1 Principle. The establishment and maintenance of a satisfactory
system of quality assurance and the correct manufacture and control of
pharmaceutical products and active ingredients rely upon people. For
this reason there must be sufficient qualified personnel to carry out all
the tasks for which the manufacturer is responsible. Individual
responsibilities should be clearly understood by the individuals concerned
and recorded as written descriptions. All personnel should be aware of
the principles of GMP that affect them.
General
10.2 The manufacturer should have an adequate number of personnel
with the necessary qualifications and practical experience. The
responsibilities placed on any one individual should not be so extensive
as to present any risk to quality.
10.3 The manufacturer should have an organization chart. All responsible
staff should have their specific duties recorded in written descriptions
146 cleanroom operators manual
and adequate authority to carry out their responsibilities. Their duties
may be delegated to designated deputies of a satisfactory qualification
level. There should be no gaps or unexplained overlaps in the
responsibilities of personnel concerned with the application of GMP.
10.4 All personnel should be aware of the principles of GMP that affect
them and receive initial and continuing training, including hygiene
instructions, relevant to their needs. All personnel should be motivated
to support the establishment and maintenance of high-quality standards.
10.5 Steps should be taken to prevent unauthorized people from entering
production, storage, and quality control areas. Personnel who do not
work in these areas should not use them as a passageway.
Key personnel
10.6 Key personnel include the head of production, the head of quality
control, the head of sales/distribution, and the authorized person(s).
Normally, key posts should be occupied by full-time personnel. The heads
of production and quality control should be independent of each other.
In large organizations, it may be necessary to delegate some of the
functions; however, the responsibility cannot be delegated.
10.7 Key personnel responsible for supervising the manufacture and
quality control of pharmaceutical products should possess the
qualifications of a scientific education and practical experience required
by national legislation. Their education should include the study of an
appropriate combination of (a) chemistry (analytical or organic) or
biochemistry, (b) chemical engineering, (c) microbiology, (d)
pharmaceutical sciences and technology, (e) pharmacology and
toxicology, (f) physiology, or (g) other related sciences. They should
also have adequate practical experience in the manufacture and quality
assurance of pharmaceutical products. In order to gain such experience,
a preparatory period may be required, during which they should exercise
their duties under professional guidance. The scientific education and
practical experience of experts should be such as to enable them to
exercise independent professional judgement, based on the application
of scientific principles and understanding to the practical problems
encountered in the manufacture and quality control of pharmaceutical
products.
10.8 The heads of the production and quality control departments
generally have some shared, or jointly exercised, responsibilities relating
to quality. These may include, depending on national regulations:
147 guidelines governing personnel in drug and device manufacture
(a) the authorization of written procedures and other documents,
including amendments;
(b) the monitoring and control of the manufacturing environment;
(c) plant hygiene;
(d) process validation and calibration of analytical apparatus;
(e) training, including the application and principles of quality
assurance;
(f) the approval and monitoring of suppliers of materials;
(g) the approval and monitoring of contract manufacturers;
(h) the designation and monitoring of storage conditions for materials
and products;
(i) the retention of records;
(j) the monitoring of compliance with GMP requirements;
(k) the inspection, investigation, and taking of samples, in order to
monitor factors that may affect product quality.
10.9 The head of the production department generally has the following
responsibilities:
(a) to ensure that products are produced and stored according to the
appropriate documentation in order to obtain the required quality;
(b) to approve the instructions relating to production operations,
including the in-process controls, and to ensure their strict
implementation;
(c) to ensure that the production records are evaluated and signed by a
designated person before they are made available to the quality
control department;
(d) to check the maintenance of the department, premises, and
equipment;
(e) to ensure that the appropriate process validations and calibrations
of control equipment are performed and recorded and the reports
made available;
(f) to ensure that the required initial and continuing training of
production personnel is carried out and adapted according to need.
10.10 The head of the quality control department generally has the
following responsibilities:
(a) to approve or reject starting materials, packaging materials, and
intermediate, bulk, and finished products;
(b) to evaluate batch records;
148 cleanroom operators manual
(c) to ensure that all necessary testing is carried out;
(d) to approve sampling instructions, specifications, test methods, and
other quality control procedures;
(e) to approve and monitor analyses carried out under contract;
(f) to check the maintenance of the department, premises and
equipment;
(g) to ensure that the appropriate validations, including those of
analytical procedures, and calibrations of control equipment are
done;
(h) to ensure that the required initial and continuing training of
quality control personnel is carried out and adapted according to
need.
Training
10.11 The manufacturer should provide training in accordance with a
written programme for all the personnel whose duties take them into
production areas or into control laboratories (including the technical,
maintenance, and cleaning personnel), and for other personnel whose
activities could affect the quality of the product.
10.12 Besides basic training on the theory and practice of GMP, newly
recruited personnel should receive training appropriate to the duties
assigned to them. Continuing training should also be given, and its
practical effectiveness should be periodically assessed. Training
programmes should be available, approved by the head of either
production or quality control, as appropriate. Training records should
be kept.
10.13 Personnel working in areas where contamination is a hazard, e.g.,
clean areas or areas where highly active, toxic, infectious, or sensitizing
materials are handled, should be given specific training.
10.14 The concept of quality assurance and all the measures capable of
improving its understanding and implementation should be fully
discussed during the training sessions.
10.15 Visitors or untrained personnel should preferably not be taken
into the production and quality control areas. If this is unavoidable,
they should be given information in advance, particularly about personal
hygiene and the prescribed protective clothing. They should be closely
supervised.
149 guidelines governing personnel in drug and device manufacture
Personal hygiene
10.16 All personnel, prior or and during employment, as appropriate,
should undergo health examinations. Personnel conducting visual
inspections should also undergo periodic eye examinations.
10.17 All personnel should be trained in the practices of personal hygiene.
A high level of personal hygiene should be observed by all those
concerned with manufacturing processes. In particular, personnel should
be instructed to wash their hands before entering production areas. Signs
to this effect should be posted and instructions observed.
10.18 Any person shown at any time to have an apparent illness or open
lesions that may adversely affect the quality of products should not be
allowed to handle starting materials, packaging materials, in-process
materials, or drug products until the condition is no longer judged to be
a risk.
10.19 All employees should be instructed and encouraged to report to
their immediate supervisor any conditions (relating to plant, equipment,
or personnel) that they consider may adversely affect the products.
10.20 Direct contact should be avoided between the operators hands
and starting materials, primary packaging materials, and intermediate
or bulk product.
10.21 To ensure protection of the product from contamination, personnel
should wear clean body coverings appropriate to the duties they perform,
including appropriate hair covering. Used clothes, if reusable, should
be stored in separate closed containers until properly laundered and, if
necessary, disinfected or sterilized.
10.22 Smoking, eating, drinking, chewing, and keeping plants, food,
drink, smoking material, and personal medicines should not be permitted
in production, laboratory, and storage areas or in any other areas where
they might adversely influence product quality.
10.23 Personal hygiene procedures including the use of protective
clothing should apply to all persons entering production areas, whether
they are temporary or full-time employees or non-employees - e.g.,
contractors employees, visitors, senior managers, and inspectors.
150 cleanroom operators manual
EUGGMP Chapter 2
Principle
The establishment and maintenance of a satisfactory system of quality
assurance and the correct manufacture of medicinal products relies upon
people. For this reason there must be sufficient qualified personnel to
carry out all the tasks which are the responsibility of the manufacturer.
Individual responsibilities should be clearly understood by the individuals
and recorded.
All personnel should be aware of the principles of Good Manufacturing
Practice that affect them and receive initial and continuing training,
including hygiene instructions, relevant to their needs.
General
2.1. The manufacturer should have an adequate number of personnel
with the necessary qualifications and practical experience. The
responsibilities placed on any one individual should not be so extensive
as to present any risk to Quality
2.2. The manufacturer must have an organisation chart. People in responsible
positions should have specific duties recorded in written job descriptions
and adequate authority to carry out their responsibilities. Their duties may
be delegated to designated deputies of a satisfactory qualification level. There
should be no gaps or unexplained overlaps in the responsibilities of those
personnel concerned with the application of Good Manufacturing Practice.
Key Personnel
2.3. Key Personnel includes the head of Production, the head of Quality
Control, and if at least one of these persons is not responsible for the
release of products the authorised person(s) designated for the purpose.
Normally key posts should be occupied by full-time personnel. The
heads of Production and Quality Control must be independent from each
other. In large organisations, it may be necessary to delegate some of
the functions listed in 2.5., 2.6. And 2.7.
2.4. ...
151 guidelines governing personnel in drug and device manufacture
2.5. The head of the Production Department generally has the following
responsibilities:
i. To ensure that products are produced and stored according to the
appropriate documentation in order to obtain the required quality;
ii. To approve the instructions relating to production operations and
to ensure their strict implementation;
iii. To ensure that the production records are evaluated and signed by
an authorised person before they are sent to the Quality Control
Department;
iv. To check the maintenance of his department, premises and
equipment;
v. To ensure that the appropriate validations are done;
vi. To ensure that the required initial and continuing training of his
department personnel is carried out and adapted according to
need.
2.6. The head of the Quality Control Department generally has the
following responsibilities:
i. To approve or reject, as he sees fit, starting materials, packaging
materials, and intermediate, bulk and finished products;
ii. To evaluate batch records;
iii. To ensure that all necessary testing is carried out;
iv. To approve specifications, sampling instructions, test methods and
other Quality Control procedures;
v. To approve and monitor any contract analysts;
vi. To check the maintenance of his department, premises and
equipment;
vii. To ensure that the appropriate validations are done;
viii.To ensure that the required initial and continuing training of his
department personnel is carried out and adapted according to
need.
2.7. The heads of Production and Quality Control generally have some
shared, or jointly exercised, responsibilities relating to quality. These
may include:
o The authorization of written procedures and other documents,
including amendments;
o The monitoring and control of the manufacturing environment;
o Plant hygiene;
152 cleanroom operators manual
o Process validation;
o Training;
o The approval and monitoring of suppliers of materials;
o The approval and monitoring of contract manufacturers;
o The designation and monitoring of storage conditions for
materials and products;
o The retention of records;
o The monitoring of compliance with the requirements of GMP;
o The inspection, investigation, and taking of samples, in order to
monitor factors which may affect product quality.
Training
2.8. The manufacturer should provide training for all the personnel whose
duties take them into production areas or into control laboratories
(including the technical, maintenance and cleaning personnel), and for
other personnel whose activities could affect the quality of the product.
2.9. Beside the basic training on the theory and practice of Good
Manufacturing Practice, newly recruited personnel should receive
training appropriate to the duties assigned to them. Continuing training
should also be given, and its practical effectiveness should be periodically
assessed. Training programmes should be available, approved by either
the head of Production or the head of Quality Control, as appropriate.
Training records should be kept.
2.10.Personnel working in areas where contamination is a hazard, e.g.
Clean areas or areas where highly active, toxic, infectious or sensitising
materials are handled, should be given specific training.
2.11.Visitors or untrained personnel should not be taken into the
production and Quality Control areas. If this is unavoidable, they should
be given information in advance, particularly about personal hygiene
and the prescribed protective clothing. They should be closely supervised.
2.12.The concept of Quality Assurance and all the measures capable of
improving its understanding and implementation should be fully
discussed during the training sessions.
Personal Hygiene
2.13. Detailed hygiene programmes should be established and adapted
to the different needs within the factory. They should include procedures
relating to the health, hygiene practices and clothing of personnel. These
153 guidelines governing personnel in drug and device manufacture
procedures should be understood and followed in a very strict way by
every person whose duties take him into the production and control
areas. Hygiene programmes should be promoted by management and
widely discussed during training sessions.
2.14. All personnel should receive medical examination upon
recruitment. It must be the manufacturers responsibility that there are
instructions ensuring that health conditions that can be of relevance to
the quality of products come to the manufacturers knowledge. After
the first medical examination, examinations should be carried out when
necessary for the work and personal health.
2.15. Steps should be taken to ensure as far as is practicable that no
person affected by an infectious disease or having open lesions on the
exposed surface of the body is engaged in the manufacture of medicinal
products.
2.16. Every person entering the manufacturing areas should wear
protective garments appropriate to the operations to be carried out.
2.17. Eating, drinking, chewing or smoking, or the storage of food,
drink, smoking materials or personal medication in the production and
storage areas should be prohibited. In general, any unhygienic practice
within the manufacturing areas or in any other area where the product
might be adversely affected, should be forbidden.
2.18. Direct contact should be avoided between the operators hands
and the exposed product as well as with any part of the equipment that
comes into contact with the products.
2.19. Personnel should be instructed to use the hand-washing facilities.
2.20.Any specific requirements for the manufacture of special groups of
products, for example sterile preparations, are covered in the Annexes.
USFDA CFR 211 Subpart B-Organization and Personnel
211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the responsibility
and authority to approve or reject all components, drug product
containers, closures, in-process materials, packaging material, labeling,
and drug products, and the authority to review production records to
assure that no errors have occurred or, if errors have occurred, that they
have been fully investigated. The quality control unit shall be responsible
154 cleanroom operators manual
for approving or rejecting drug products manufactured, processed,
packed, or held under contract by another company.
(b) Adequate laboratory facilities for the testing and approval (or
rejection) of components, drug product containers, closures, packaging
materials, in-process materials, and drug products shall be available to
the quality control unit.
(c) The quality control unit shall have the responsibility for approving
or rejecting all procedures or specifications impacting on the identity,
strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality control
unit shall be in writing; such written procedures shall be followed.
211.25 Personnel qualifications.
(a) Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, and experience,
or any combination thereof, to enable that person to perform the assigned
functions. Training shall be in the particular operations that the employee
performs and in current good manufacturing practice (including the
current good manufacturing practice regulations in this chapter and
written procedures required by these regulations) as they relate to the
employees functions. Training in current good manufacturing practice
shall be conducted by qualified individuals on a continuing basis and
with sufficient frequency to assure that employees remain familiar with
CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture, processing,
packing, or holding of a drug product shall have the education, training,
and experience, or any combination thereof, to perform assigned
functions in such a manner as to provide assurance that the drug product
has the safety, identity, strength, quality, and purity that it purports or is
represented to possess.
(c) There shall be an adequate number of qualified personnel to perform
and supervise the manufacture, processing, packing, or holding of each
drug product.
211.28 Personnel responsibilities.
(a) Personnel engaged in the manufacture, processing, packing, or
holding of a drug product shall wear clean clothing appropriate for the
duties they perform. Protective apparel, such as head, face, hand, and
155 guidelines governing personnel in drug and device manufacture
arm coverings, shall be worn as necessary to protect drug products from
contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter those
areas of the buildings and facilities designated as limited-access areas.
(d) Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions that
may adversely affect the safety or quality of drug products shall be
excluded from direct contact with components, drug product containers,
closures, in-process materials, and drug products until the condition is
corrected or determined by competent medical personnel not to jeopardize
the safety or quality of drug products. All personnel shall be instructed
to report to supervisory personnel any health conditions that may have
an adverse effect on drug products.
211.34 Consultants.
Consultants advising on the manufacture, processing, packing, or
holding of drug products shall have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for which
they are retained. Records shall be maintained stating the name, address,
and qualifications of any consultants and the type of service they provide.
Other sections in US FDA CFR 211 relating to Personnel
21 CFR 211.42(c) states, in part, that There shall be separate or defined
areas or such other control systems for the Firms operations as are
necessary to prevent contamination or mixups during the course of the
following Procedures: *** (10) Aseptic processing, which includes as
appropriate: *** (iv) A system for monitoring Environmental
conditions***.
21 CFR 211.113(b) states that Appropriate written procedures, designed
to prevent microbiological contamination of drug products purporting
to be sterile, shall be established and followed. Such procedures shall
include Validation of any sterilization process.
156 cleanroom operators manual
special mentions
Australian Code of GMP (TGA) Annex 13: Manufacture of
Investigational Medicinal Products
Personnel
4. Although it is likely that the number of staff involved will be small,
there should be separate people responsible for production and quality
control. All production operations should be carried out under control
of a clearly identified responsible person. Personnel involved in release
of investigational medicinal products should be appropriately trained
in quality systems, GMP and regulatory requirements specific to these
types of products. They must be independent of the staff responsible for
production.
Australian Code of GMP (TGA) Annex 8: Sampling of Starting and
Packaging Materials
Personnel
1. Personnel who take samples should receive initial and on-going regular
training in the disciplines relevant to correct sampling. This training
should include:
Sampling plans,
Written sampling procedures,
The techniques and equipment for sampling,
The risks of cross-contamination,
The precautions to be taken with regard to unstable and/or sterile
substances,
The importance of considering the visual appearance of materials,
containers and labels,
The importance of recording any unexpected or unusual
circumstances.
Australian Code of GMP (TGA) Annex 11: Computerised Systems
Personnel
1. It is essential that there is the closest co-operation between key
personnel and those involved with computer systems. Persons in
responsible positions should have the appropriate training for the
management and use of systems within
157 guidelines governing personnel in drug and device manufacture
Their field of responsibility which utilises computers. This should include
ensuring that appropriate expertise is available and used to provide advice
on aspects of design, validation, installation and operation of
computerised system.
active pharmaceutical ingredients
Q7A
A. Personnel Qualifications (3.1)
There should be an adequate number of personnel qualified by appropriate
education, training, and/or experience to perform and supervise the
manufacture of intermediates and APIs.
The responsibilities of all personnel engaged in the manufacture of
intermediates and APIs should be specified in writing.
Training should be regularly conducted by qualified individuals and
should cover, at a minimum, the particular operations that the employee
performs and GMP as it relates to the employees functions.
Records of training should be maintained. Training should be periodically
assessed.
B. Personnel Hygiene (3.2)
Personnel should practice good sanitation and health habits.
Personnel should wear clean clothing suitable for the manufacturing
activity with which they are involved and this clothing should be changed,
when appropriate. Additional protective apparel, such as head, face,
hand, and arm coverings, should be worn, when necessary, to protect
intermediates and APIs from contamination.
Personnel should avoid direct contact with intermediates or APIs.
Smoking, eating, drinking, chewing and the storage of food should be
restricted to certain designated areas separate from the manufacturing
areas.
Personnel suffering from an infectious disease or having open lesions
on the exposed surface of the body should not engage in activities that
could result in compromising the quality of APIs. Any person shown at
any time (either by medical examination or supervisory observation) to
158 cleanroom operators manual
have an apparent illness or open lesions should be excluded from activities
where the health condition could adversely affect the quality of the APIs
until the condition is corrected or qualified medical personnel determine
that the persons inclusion would not jeopardize the safety or quality of
the APIs.
C. Consultants (3.3)
Consultants advising on the manufacture and control of intermediates
or APIs should have sufficient education, training, and experience, or
any combination thereof, to advise on the subject for which they are
retained.
Records should be maintained stating the name, address, qualifications,
and type of service provided by these consultants.
WHO
18.7 Each firm should employ personnel with the necessary qualifications
and competence for the production and quality control of active
pharmaceutical ingredients. There should be an adequate number of
staff with appropriate education, technical knowledge, and practical
experience related to the job they perform.
18.8 The firm should have a defined organization represented in a chart.
Individual responsibilities should be laid down in written instructions,
to ensure that there are no gaps or overlaps. The responsibilities placed
on any one individual should not be so extensive as to incur any risk to
quality.
18.9 Staff at all levels should be adequately trained for the tasks and
responsibilities assigned to them.
18.10 Measures should be taken to ensure that no person affected by a
disease in a communicable form or having open lesions on the exposed
surface of the body is engaged in any production step involving direct
contact with the active pharmaceutical ingredients.
159 guidelines governing personnel in drug and device manufacture
sterile products
WHO
17.6 Only the minimum number of personnel required should be present
in clean areas; this is particularly important during aseptic processes.
Inspections and controls should be conducted from outside the areas as
far as possible.
17.7 All personnel (including those concerned with cleaning and
maintenance) employed in such areas should receive regular training in
disciplines relevant to the correct manufacture of sterile products,
including reference to hygiene and to the basic elements of microbiology.
When outside staff who have not received such training (e.g., building
or maintenance contractors) need to be brought in, particular care should
be taken over their supervision.
17.8 Staff who have been engaged in the processing of animal-tissue
materials or of cultures of microorganisms other than those used in the
current manufacturing process should not enter sterile-product areas
unless rigorous and clearly defined decontamination procedures have
been followed.
17.9 High standards of personal hygiene and cleanliness are essential,
and personnel involved in the manufacture of sterile preparations should
be instructed to report any condition that may cause the shedding of
abnormal numbers or types of contaminants; periodic health checks for
such conditions are desirable, Actions to be taken about personnel who
could be introducing undue microbiological hazard should be decided
by a designated competent person.
17.10 Outdoor clothing should not be brought into the clean areas, and
personnel entering the changing rooms should already be clad in standard
factory protective garments. Changing and washing should follow a
written procedure.
17.11 The clothing and its quality has to be adapted to the process and
the workplace, and worn in such a way as to protect the product from
contamination.
17.12 Wrist-watches and jewellery should not be worn in clean areas,
and cosmetics that can shed particles should not be used.
160 cleanroom operators manual
17.13 Clothing should be appropriate to the air grade of the area where
the personnel will be working. The description of clothing required for
each grade is given below.
Grade D: The hair and, where appropriate, beard should be covered.
Protective clothing and appropriate shoes or overshoes should be worn.
Appropriate measures should be taken to avoid any contamination
coming from outside the clean area.
Grade C: The hair and, where appropriate, beard should be covered. A
single or two-piece trouser suit, gathered at the wrists and with a high
neck, and appropriate shoes or overshoes should be worn. The clothing
should shed virtually no fibres or particulate matter.
Grade B: Headgear should totally enclose the hair and, where
appropriate, beard; it should be tucked into the neck of the suit; a face
mask should be worn to prevent the shedding of droplets; sterilized non-
powdered rubber or plastic gloves and sterilized or disinfected footwear
should be worn; trouser-bottoms should be tucked inside the footwear
and garment sleeves into the gloves. The protective clothing should shed
virtually no fibres or particulate matter and should retain particles shed
by the body.
17.14 For every worker in a grade B room, clean sterilized protective
garments should be provided at each work session, or at least once a day
if monitoring results justify it. Gloves should be regularly disinfected
during operations, and masks and gloves should be changed at least at
every working session. The use of disposable clothing may be necessary.
17.15 Clothing used in clean areas should be laundered or cleaned in
such a way that it does not gather additional particulate contaminants
that can later be shed. Separate laundry facilities for such clothing are
desirable. If fibres are damaged by inappropriate cleaning or sterilization
there may be an increased risk of shedding particles. Washing and
sterilization operations should follow standard operating procedures.
EUGGMP: Annex 1: Manufacture of Sterile Medicinal Products
13. Only the minimum number of personnel required should be present
in clean areas; this is particularly important during aseptic processing.
Inspections and controls should be conducted outside the clean areas as
far as possible.
14. All personnel (including those concerned with cleaning and
maintenance) employed in such areas should receive regular training in
161 guidelines governing personnel in drug and device manufacture
disciplines relevant to the correct manufacture of sterile products,
including reference to hygiene and to the basic elements of microbiology.
When outside staff who have not received such training (e.g. Building
or maintenance contractors) need to be brought in, particular care should
be taken over their instruction and supervision.
15. Staff who have been engaged in the processing of animal tissue
materials or of cultures of micro-organisms other than those used in the
current manufacturing process should not enter sterile-product areas
unless rigorous and clearly defined entry procedures have been followed.
16. High standards of personnel hygiene and cleanliness are essential.
Personnel involved in the manufacture of sterile preparations should be
instructed to report any condition which may cause the shedding of
abnormal numbers or types of contaminants; periodic health checks for
such conditions are desirable. Actions to be taken about personnel who
could be introducing undue microbiological hazard should be decided
by a designated competent person.
17. Changing and washing should follow a written procedure designed
to minimize contamination of clean area clothing or carry-through of
contaminants to the clean areas.
18. Wristwatches, make-up and jewellery should not be worn in clean
areas.
19. The clothing and its quality should be appropriate for the process
and the grade of the working area. It should be worn in such a way as to
protect the product from contamination. The description of clothing
required for each grade is given below:
Grade D: Hair and, where relevant, beard should be covered. A general
protective suit and appropriate shoes or overshoes should be worn.
Appropriate measures should be taken to avoid any contamination
coming from outside the clean area.
Grade C: Hair and, where relevant, beard and moustache should be
covered. A single or two-piece trouser suit, gathered at the wrists and
with high neck and appropriate shoes or overshoes should be worn.
They should shed virtually no fibres or particulate matter.
Grade A/B: Headgear should totally enclose hair and, where relevant,
beard and moustache; it should be tucked into the neck of the suit; a
face mask should be worn to prevent the shedding of droplets. Appropriate
sterilised, non-powdered rubber or plastic gloves and sterilised or
162 cleanroom operators manual
disinfected footwear should be worn. Trouser-bottoms should be tucked
inside the footwear and garment sleeves into the gloves. The protective
clothing should shed virtually no fibres or particulate matter and retain
particles shed by the body.
20. Outdoor clothing should not be brought into changing rooms leading
to grade B and C rooms. For every worker in a grade A/B area, clean
sterile (sterilised or adequately sanitised) protective garments should be
provided at each work session, or at least once a day if monitoring results
justify this. Gloves should be regularly disinfected during operations.
Masks and gloves should be changed at least at every working session.
21. Clean area clothing should be cleaned and handled in such a way
that it does not gather additional contaminants which can later be shed.
These operations should follow written procedures. Separate laundry
facilities for such clothing are desirable. Inappropriate treatment of
clothing will damage fibres and may increase the risk of shedding of
particles.
USFDA:
Guidance for Industry: Sterile Drug Products Produced by Aseptic
Processing - Current Good Manufacturing Practice
V. Personnel Training, Qualification & Monitoring
A well-designed aseptic process minimizes personnel intervention. As
operator activities increase in an aseptic processing operation, the risk
to finished product sterility also increases.
To ensure maintenance of product sterility, operators involved in aseptic
manipulations should adhere to the basic principles of aseptic technique
at all times. Appropriate training should be conducted before an
individual is permitted to enter the aseptic processing area and perform
operations. For example, such training should include aseptic technique,
cleanroom behavior, microbiology, hygiene, gowning, patient safety
hazards posed by a nonsterile drug product, and the specific written
procedures covering aseptic processing area operations.
After initial training, personnel should be updated regularly by an
ongoing training program. Supervisory personnel should routinely
evaluate each operators conformance to written procedures during actual
operations. Similarly, the quality control unit should provide regular
oversight of adherence to established, written procedures and basic aseptic
techniques during manufacturing operations.
163 guidelines governing personnel in drug and device manufacture
Some of these techniques aimed at maintaining sterility of sterile items
and surfaces include:
Contacting sterile materials only with sterile instruments
Sterile instruments (e.g., forceps) should always be used in the
handling of sterilized materials. Between uses, instruments should be
placed only in sterilized containers.
Instruments should be replaced as necessary throughout an operation.
After initial gowning, sterile gloves should be regularly sanitized to
minimize the risk of contamination.
Personnel should not directly contact sterile products, containers,
closures, or critical surfaces.
Moving slowly and deliberately
Rapid movements can create unacceptable turbulence in the critical
zone. Such movements disrupt the sterile field, presenting a challenge
beyond intended cleanroom design and control parameters. The
principle of slow, careful movement should be followed throughout
the cleanroom.
Keeping the entire body out of the path of unidirectional air
Unidirectional airflow design is used to protect sterile equipment
surfaces, container-closures, and product. Personnel should not
disrupt the path of unidirectional flow air in the aseptic processing
zone
Approaching a necessary manipulation in a manner that does not
compromise sterility of the product
To maintain sterility of nearby sterile materials, a proper aseptic
manipulation should be approached from the side and not above the
product (in vertical unidirectional flow operations). Also, an operator
should refrain from speaking when in direct proximity to an aseptic
processing line.
Maintaining Proper Gown Control
Prior to and throughout aseptic operations, an operator should not engage
in any activity that poses an unreasonable contamination risk to the
gown. Only personnel who have been qualified and appropriately gowned
should be permitted access to the aseptic processing area. An aseptic
processing area gown should provide a barrier between the body and
exposed sterilized materials and prevent contamination from particles
generated by, and microorganisms shed from, the body. Gowns should
164 cleanroom operators manual
be sterile and nonshedding and should cover the skin and hair (face-
masks, hoods, beard/moustache covers, protective goggles, elastic gloves,
cleanroom boots, and shoe overcovers are examples of common elements
of gowns).
Written procedures should detail the methods used to don each gown
component in an aseptic manner. An adequate barrier should be created
by the overlapping of gown components (e.g., gloves overlapping
sleeves). If an element of a gown is found to be torn or defective, it
should be changed immediately.
There should be an established program to regularly assess or audit
conformance of personnel to relevant aseptic manufacturing
requirements. An aseptic gowning qualification program should assess
the ability of a cleanroom operator to maintain the quality of the gown
after performance of gowning procedures. Gowning qualification should
include microbiological surface sampling of several locations on a gown
(e.g., glove fingers, facemask, forearm, chest, other sites).
Following an initial assessment of gowning, periodic requalification
should monitor various gowning locations over a suitable period to ensure
the consistent acceptability of aseptic gowning techniques. Semi-annual
or yearly requalification is sufficient for automated operations where
personnel involvement is minimized.
To protect exposed sterilized product, personnel should be expected to
maintain gown quality and strictly adhere to appropriate aseptic method.
Written procedures should adequately address circumstances under which
personnel should be retrained, requalified, or reassigned to other areas.
B. Laboratory Personnel
The basic principles of training, aseptic technique, and personnel
qualification in aseptic manufacturing also are applicable to those
performing aseptic sampling and microbiological laboratory analyses.
Processes and systems cannot be considered to be in control and
reproducible if the validity of data produced by the laboratory is in
question.
C. Monitoring Program
Personnel can significantly affect the quality of the environment in which
the sterile product is processed. A vigilant and responsive personnel
monitoring program should be established. Monitoring should be
accomplished by obtaining surface samples of each operators gloves on
165 guidelines governing personnel in drug and device manufacture
a daily basis, or in association with each batch. This sampling should be
accompanied by an appropriate sampling frequency for other strategically
selected locations of the gown.
The quality control unit should establish a more comprehensive
monitoring program for operators involved in operations which are
especially labor intensive (i.e., those requiring repeated or complex
aseptic manipulations).
Asepsis is fundamental to an aseptic processing operation. An ongoing
goal for manufacturing personnel in the aseptic processing room is to
maintain contamination-free gloves throughout operations. Sanitizing
gloves just prior to sampling is inappropriate because it can prevent
recovery of microorganisms that were present during an aseptic
manipulation. When operators exceed established levels or show an
adverse trend, an investigation should be conducted promptly. Follow-
up actions can include increased sampling, increased observation,
retraining, gowning requalification, and in certain instances,
reassignment of the individual to operations outside of the aseptic
processing area.
special sterile products
WHO
Guidelines on Good Manufacturing Practices for
radiopharmaceutical products
3. Personnel
3.1The manufacturing establishment, whether a hospital
radiopharmacy, centralized radiopharmacy, nuclear centre or
institution, industrial manufacturer or PET centre, and its personnel
should be under the control of a person who has a proven record of
academic achievement together with a demonstrated level of practical
expertise and experience in radiopharmacy and radiation hygiene.
Supporting academic and technical personnel should have the
necessary postgraduate or technical training and experience
appropriate to their function.
3.2 Personnel required to work in radioactive, clean and aseptic areas
should be selected with care, to ensure that they can be relied on to
observe the appropriate codes of practice and are not subject to any
disease or condition that could compromise the integrity of the product.
166 cleanroom operators manual
Health checks on personnel should be requested before employment
and periodically thereafter. Any changes in personal health status (e.g.
in haematology) may require the temporary exclusion of the person
from further radiation exposure.
3.3Only the minimum number of personnel required should be
present in clean and aseptic areas when work is in progress. Access to
these areas should be restricted during the preparation of
radiopharmaceuticals, kits or sterile set-ups. Inspection and control
procedures should be conducted from outside these areas as far as
possible.
3.4During the working day, personnel may pass between radioactive
and non-radioactive areas only if the safety rules of radiation control
(health physics control) are respected.
3.5The release of a batch may be approved only by a pharmacist or a
person with academic qualifications officially registered as a suitably
qualified person, and with appropriate experience in the manufacture
of radiopharmaceuticals.
3.6To ensure the safe manufacture of radiopharmaceuticals, personnel
should be trained in GMP, the safe handling of radioactive materials
and radiation safety procedures. They should also be required to take
periodic courses and receive training to keep abreast of the latest
developments in their fields.
3.7Training records should be maintained and periodic assessments
of the effectiveness of training programmes should be made.
3.8All personnel engaged in production, maintenance and testing
should follow the relevant guidelines for handling radioactive
products and be monitored for possible contamination and/or
irradiation exposure.
EUGGMP: Annex 3: Manufacture of Radiopharmaceuticals
1. All personnel (including those concerned with cleaning and
maintenance) employed in areas where radioactive products are
manufactured should receive additional training adapted to this class of
products. In particular, the personnel should be given detailed
information and appropriate training on radiation protection.
EUGGMP: Annex 6: Manufacture of Medicinal Gases
2. Personnel
2.1 The authorised person responsible for release of medicinal gases
should have a thorough knowledge of the production and control of
medicinal gases.
167 guidelines governing personnel in drug and device manufacture
2.2 All personnel involved in the manufacture of medicinal gases should
understand the GMP requirements relevant to medicinal gases and should
be aware of the critically important aspects and potential hazards for
patients from products in the form of medicinal gases.
biologicals
WHO Annex 2: Manufacture of Biological Products
3.1 The manufacturing establishment and its personnel shall be under
the authority of a person who has been trained in the techniques used in
manufacturing biological substances and who possesses the scientific
knowledge upon which the manufacture of these products is based. The
personnel shall include specialists with training appropriate to the
products made in the establishment.
3.2 Personnel required to work in clean and aseptic areas should be
selected with care, to ensure that they may be relied upon to observe the
appropriate codes of practice and are not subject to any disease or
condition that could compromise the integrity of the product
microbiologically or otherwise. High standards of personal hygiene and
cleanliness are essential. Staff should be instructed to report any
conditions (e.g. Diarrhoea, coughs, colds, infected skin or hair, wounds,
fever of unknown origin) that may cause the shedding of abnormal
numbers or types of organisms into the working environment. Health
checks on personnel for such conditions should be required before
employment and periodically thereafter. Any changes in health status
that could adversely affect the quality of the product shall preclude the
person concerned from working in the production area.
3.3 Only the minimum number of personnel required should be present
in clean and aseptic areas when work is in progress. Inspection and
control procedures should be conducted from outside these areas as far
as possible.
3.4 During the working day, personnel shall not pass from areas where
live microorganisms or animals are handled to premises where other
products or organisms are handled unless clearly defined
decontamination measures, including a change of clothing and shoes,
are followed. Persons not concerned with the production process should
168 cleanroom operators manual
not enter the production area except for essential purposes, and in that
case they shall be supplied with sterile protective clothing.
3.5 The staff engaged in the manufacturing process should be separate
from the staff responsible for animal care.
3.6 The names and qualifications of those responsible for approving lot
processing records (protocols) should be registered with the national
control authority.
3.7 To ensure the manufacture of high-quality products, personnel should
be trained in good manufacturing and laboratory practices in appropriate
fields such as bacteriology, virology, biometry, chemistry, medicine,
immunology and veterinary medicine.
3.8 Training records should be maintained and periodic assessments of
the effectiveness of training programmes should be made.
3.9 All personnel engaged in production, maintenance, testing and
animal care (and inspectors) should be vaccinated with appropriate
vaccines and, where appropriate, be submitted to regular testing for
evidence of active tuberculosis. Apart from the obvious problem of
exposure of staff to infectious agents, potent toxins or allergens, it is
necessary to avoid the risk of contamination of a production batch with
these agents.
3.10 Where BCG vaccines are being manufactured, access to production
areas shall be restricted to staff who are carefully monitored by regular
health checks. In the case of manufacture of products derived from human
blood or plasma, vaccination of workers against hepatitis B is
recommended.
EUGGMP: Annex 2: Manufacture of Biological Medicinal Products
For Human Use
1. All personnel (including those concerned with cleaning, maintenance
or quality control) employed in areas where biological medicinal products
are manufactured should receive additional training specific to the
products
Manufactured and to their work. Personnel should be given relevant
information and training in hygiene and microbiology.
2. Persons responsible for production and quality control should have
an adequate background in relevant scientific disciplines, such as
bacteriology, biology, biometry, chemistry, medicine, pharmacy,
169 guidelines governing personnel in drug and device manufacture
pharmacology, virology, immunology and veterinary medicine, together
with sufficient practical experience to enable them to exercise their
management function for the process concerned.
3. The immunological status of personnel may have to be taken into
consideration for product safety. All personnel engaged in production,
maintenance, testing and animal care (and inspectors) should be
vaccinated where necessary with appropriate specific vaccines and have
regular health checks. Apart from the obvious problem of exposure of
staff to infectious agents, potent toxins or allergens, it is necessary to
avoid the risk of contamination of a production
Batch with infectious agents. Visitors should generally be excluded from
production areas.
4. Any changes in the immunological status of personnel which could
adversely affect the quality of the product should preclude work in the
production area. Production of BCG vaccine and tuberculin products
should be restricted to staff who are carefully monitored by regular checks
of immunological status or chest X-ray.
5. In the course of a working day, personnel should not pass from areas
where exposure to live organisms or animals is possible to areas where
other products or different organisms are handled. If such passage is
unavoidable, clearly
Defined decontamination measures, including change of clothing and
shoes and, where necessary, showering should be followed by staff
involved in any such production.
Australian Code of GMP (TGA)
Human Blood and Tissues: Section 2
Personnel and Training
Rationale
200 The establishment and maintenance of a satisfactory system of
quality assurance and the correct manufacture of product relies
upon people. For this reason there must be competent personnel
to carry out all tasks in accordance with documented procedures.
General
201 Areas of responsibility and lines of authority of key personnel
should be identifiable on an organisational chart.
170 cleanroom operators manual
202 The names and job descriptions of key personnel must be
documented.
203 Personnel must be shown to be competent in their assigned duties.
204 Key personnel must have adequate authority to discharge their
responsibilities. Suitable persons should be deputised to carry
out the duties and functions of key personnel in their absence.
205 There should be no unexplained or conflicting overlaps in the
responsibilities of those concerned with GMP. The responsibilities
placed upon any one person should not compromise the effective
execution of assigned duties.
206 The key personnel, responsible for managing and supervising
manufacture, quality assurance and quality control, must have
the necessary competencies to ensure that blood or tissues meet
the required standards and specifications consistently.
Training
207 Learning and development programs must be developed in
accordance with identified needs. Programs should be documented
and include on-going training and refresher training.
208 Personnel must be made aware of the principles of GMP relevant
to their duties.
209 There should be a formal mechanism for determining the
competency of the workplace trainer and assessor to deliver
training and assess the competency of the trainee.
210 For personnel at sites remote from the licensed site, who undertake
a step in manufacture, (such as at tissue retrieval), there must be
documentation to demonstrate that the work practice(s)
undertaken are under the control of, and acceptable to, the licensed
site.
211 All personnel must be shown to have undergone learning and
development for the documented procedure relevant to the work
practice being performed. There must be records to show that all
personnel have acknowledged subsequent changes to a
procedure(s).
171 guidelines governing personnel in drug and device manufacture
212 Learning and development related to sanitation and personal
hygiene should be included in staff learning and development
programs.
Records
213 Records must demonstrate that each staff member is trained for
the work practices they are authorised to perform. The records
should include the following:
the learning and development program set up to meet
individual needs;
the timeframe required to complete the program; and
assessment and any action taken if expected competence
was not achieved.
214 Personnel must not be permitted to sign or initial a document
unless they have been trained and assessed as competent in the
work practices associated with the signature, and in the
significance of the signature.
215 A register of staff signatures and initials must be maintained.
Entries should be updated at regular stated intervals and the
previous records archived.
personnel:faqs
Questions & Answers on the new Australian Code of GMP for
Medicinal Products Version 4 - 17 December 2002
Personnel (Chapter 2)
5. What does necessary qualifications mean in clause 2.1?
In the absence of a definition in the 2002 Australian Code of GMP, the
TGA will continue to reference the meaning as specified in clauses 301
and 305 of the1990 Australian Code of GMP. In the absence of relevant
formal qualifications the company will be requested to provide
justification based on risk, noting the nature of the product and
complexity of the operation.
6. What are training requirements for personnel (clauses 2.8-2.12)?
It is expected that training be carried out by persons with relevant
training, qualifications and experience in the subject matter and should
172 cleanroom operators manual
preferably be themselves trained as trainers. Training (and records
thereof) should be given to people affected in all circumstances where
significant change occurs in the quality management system, e.g. when
SOPs or methods are changed. This requirement should be reflected in
procedures.
There are a number of people who have a direct bearing on quality
outcomes. These include contractors, consultants and casual employees.
Appropriate training should be provided.
7. What are language requirements for personnel?
Manufacturers should define language requirements or standards and
ensure personnel are proficient in regard that language for their allocated
tasks, particularly in relation to documenting and recording. Procedures
employed to overcome identifiable deficiencies should be documented.
USFDA 21 CFR Part 820: Medical devices: Quality System
Regulation
820.25 Personnel.
(a) General. Each manufacturer shall have sufficient personnel with the
necessary education, background, training, and experience to assure that
all activities required by this part are correctly performed.
(b) Training. Each manufacturer shall establish procedures for identifying
training needs and ensure that all personnel are trained to adequately
perform their assigned responsibilities. Training shall be documented.
(1) As part of their training, personnel shall be made aware of device
defects which may occur from the improper performance of their specific
jobs.
(2) Personnel who perform verification and validation activities shall
be made aware of defects and errors that may be encountered as part of
their job functions.
820.70 Production and process controls.
(d) Personnel. Each manufacturer shall establish and maintain
requirements for the health, cleanliness, personal practices, and clothing
of personnel if contact between such personnel and product or
environment could reasonably be expected to have an adverse effect on
product quality. The manufacturer shall ensure that maintenance and
other personnel who are required to work temporarily under special
173 guidelines governing personnel in drug and device manufacture
environmental conditions are appropriately trained or supervised by a
trained individual.
820.75 Process validation.
(b)(1) Each manufacturer shall ensure that validated processes are
performed by qualified individual(s)
quality system regulation for devices (qsr 820)
Establishing a quality system should be an integrated and universal effort.
A total quality systems approach should be designed to satisfy the
particular quality, safety, and performance needs of a specific
manufacturer, product, and user-market. Employees play a vital role in
achieving these objectives.
Obviously, employees need to be aware of the details of the quality system
and how to meet them. The Quality System (QS) regulation supports
these goals by requiring that a manufacturer have sufficient qualified
personnel and by requiring quality awareness training for personnel
[820.25(a)]. Management with executive responsibility shall ensure their
quality policy is understood, implemented, and maintained at all levels
of the organization. This should be accomplished by supplying sufficient
resources, training, responsibility, and authority to all managing
personnel that will enable them to perform their tasks.
Personnel involved in design, manufacturing, quality assurance, auditing,
complaint processing, servicing, etc., should be properly trained, both
by education and experience. No matter how effective quality assurance
and production systems are as concepts, people still play the major role
in designing and producing a quality product. Lack of training as
reflected in instances of negligence, poor operating techniques, or the
inability of employees to discharge their functions properly can lead
to defective products and, sometimes, to regulatory or liability problems.
Employee attitude is the most important personnel factor that can assure
an effective quality system. By management setting an excellent example
and through effective training, quality consciousness should be developed
in every employee. Each person should be made aware of the importance
of his or her individual contributions in the overall effort to achieve an
acceptable level of quality.
The role of management in this vital awareness effort cannot be passive
management should be diligent in looking for factors that indicate a
need for employee training [820.25(b)]. A quality system should include
174 cleanroom operators manual
an ongoing formal program for training all personnel. All personnel
should be made aware that product quality is not solely the responsibility
of management or any other single group. Quality is the responsibility
of every employee any employee can generate a quality problem
through ignorance of their job requirements or negligence.
FDA Observations
It is not unusual for FDA investigators to conduct factory inspections
and observe employees who are clearly unaware of situations that can
result in poor device quality. These employees obviously have not been
properly instructed on what activities or conditions will directly cause
defective devices or that can lead to mixups, contamination, or other
problems that can cause non-conforming devices. For example, an
improperly maintained piece of manufacturing equipment may eventually
have disastrous consequences on finished devices. Therefore, the
employee charged with maintaining the equipment, as well as the
operator of the equipment, should be made aware of conditions that
reflect a need for maintenance.
FDA investigators have observed employees: smoking near or sweeping
dust into open processing tanks where the smoke and dust would destroy
the usefulness of the device; blowing smoke or sweeping dust onto devices
to be sterilized; handling delicate devices while wearing rings or other
jewelry; wearing gloves with holes or rubbing their nose and continuing
to handle devices that need to comply with bioburden requirements;
wearing cleanroom clothing into uncontrolled areas; and other poor
practices such as leaving windows or doors open in controlled
environmental areas.
FDA investigators were advised by management that it is the
manufacturers policy not to allow the above situations to occur. The
implementation of this policy is questionable. Are these employees
originally and then periodically reminded of the reason: for not smoking,
eating, and wearing rings; and for personal cleanliness, and other
employee requirements? People respond better when they know why
they are allowed or not allowed to do certain activities - not just being
told that it is company policy.
Device GMP Requirements
The QS regulation requires in section 820.25 that each manufacturer
shall have sufficient personnel with the necessary education, background,
training, and experience to assure that all activities required by this part
175 guidelines governing personnel in drug and device manufacture
are correctly performed. [The requirement for sufficient trained personnel
is also covered by resource requirements in 820.20(b)(2) as follows.
Each manufacturer shall provide adequate resources, including the
assignment of trained personnel, for management, performance of work,
and assessment activities, including internal quality audits, to meet the
requirements of this part.]
Each manufacturer shall establish procedures for identifying training
needs and ensure that all personnel are trained to adequately perform
their assigned responsibilities. Training shall be documented. As part
of their training, personnel shall be made aware of device defects which
may occur from the improper performance of their specific jobs. [In
addition to training, personnel also have to be notified if they are
responsible for nonconforming product. The intent is to prevent or reduce
nonconforming product.
Each manufacturer shall establish and maintain procedures to control
product that does not conform to specified requirements [820.90(a)].
The procedures shall address the identification, documentation,
evaluation, segregation, and disposition of nonconforming product. The
evaluation of nonconformance shall include a determination of the need
for an investigation and notification of the persons or organizations
responsible for the nonconformance. The evaluation and any
investigation shall be documented. Personnel who perform verification
and validation shall be made aware of defects and errors that may be
encountered as part of their job functions. There are also personnel
requirements in 820.70(d) and 820.75(b)(1) as follows.
Each manufacturer shall establish and maintain requirements for the
health, cleanliness, personal practices, and clothing of personnel if
contact between such personnel and product or environment could
reasonably be expected to have an adverse effect on product quality. The
manufacturers shall ensure that maintenance and other personnel who
are required to work temporarily under special environmental conditions
are appropriately trained or supervised by a trained individual.
Each manufacturer shall ensure that validated processes are performed
by qualified individual(s) [870.75(b)(1)].
Employee Selection
As the first step in meeting GMP personnel requirements, manufacturers
should select or hire appropriate employees for the tasks to be performed.
The initial selection of employees for a specific job is made based on a
176 cleanroom operators manual
combination of education, experience, personal habits, interests, etc.
For example, education alone is not a good indicator of whether a recent
graduate with a scientific degree can design a product.
New employees should be informed that they are working in a regulated
industry and should be initially trained to perform their specific jobs
and be made aware of any defects or problems that may occur from:
o improper performance of their assigned tasks;
o using incorrect tools or incorrect use of a tool;
o poor hygiene, poor health, or smoking or eating on the job;
o poor work habits or being in the wrong location; and
o other detrimental factors.
Production Personnel
Section 820.70(d) requires that personnel in contact with a device or its
environment shall be clean, healthy, and suitably attired where lack of
cleanliness, good health, or suitable attire could adversely affect the
device. Personnel who, by medical examination or supervisory
observation, appear to have a condition which could adversely affect the
device should be excluded from affected operations until the adverse
condition is corrected. Personnel should be instructed to report such
conditions to their supervisor. Such actions by management could create
problems unless employees are instructed about work practices and
requirements when they are hired or initially assigned to the task in an
environmentally controlled area.
If eating, drinking, or smoking could have an adverse affect on the
devices fitness for use, then employees should be informed that these
activities are to be done only in designated areas.
Employees need to be informed why certain personnel and work practices
are required. Basic instructions about invisible microorganisms and
particulates will make the company requirements much more meaningful.
People respond better when they know why they are allowed or not
allowed to do certain activities rather than just being told it is company
policy.
Some factors that should be considered when teaching employees about
working in a controlled environment include:
o proper attire and dressing anteroom;
o controlled use of, and entry into, controlled areas;
177 guidelines governing personnel in drug and device manufacture
o minimizing body movements;
o locating the body and hands with respect to product and airflow;
o prohibiting eating, drinking, smoking, or gum chewing;
o reducing of coughing, sneezing and other objectionable health
related conditions;
o preventing use of lead pencils and certain cosmetics;
o bathing and hand washing requirements;
o preventing or controlling the cutting, tearing or storage of
cardboard, paper, debris, etc.;
o eliminating electrostatic charges by selection of clothing,
grounding, etc.;
o ensuring cleanliness of raw materials, components and tools; etc.
o using correct furniture and eliminating use of extra furniture;
o regulating the storage of tools, glassware and containers;
o cleaning the room and production equipment per written procedure;
and
o cleaning of work surfaces and chairs.
Technical Personnel
The manufacturer should assure that they have sufficient properly trained
personnel, or programs to train technical personnel, to design, validate,
develop processes, and produce the new or modified device.
Scientific and technical personnel usually need training in:
o regulatory requirements;
o company documentation systems;
o verification and validation techniques;
o consensus standards;
o human factors;
o labeling;
o safety;
o reliability;
o producibility; and,
o other peripheral design topics.
New design personnel may be introduced to manufacturing methods
and producibility issues by being assigned to various manufacturing areas
before starting their design activities. The resulting knowledge and
178 cleanroom operators manual
experience is as valuable as their technical education remember that
the ultimate objective of a design and manufacturing operation is to
produce a safe and effective device.
In another valuable training technique, manufacturing personnel are
assigned to assist development personnel in verifying components, and
assembling and verifying subassemblies and prototype devices.
These training techniques:
o improve communications and technology transfer between the
various departments;
o help meet the interface requirements in 820.30(b), Design and
Development Planning;
o help promote concurrent engineering;
o help research and development personnel understand that the goal is
to produce a device not just design a device;
o achieve advance training for manufacturing personnel about a
forthcoming design;
o reduce production problems by improving the producibility of the
device based on the expertise and input of the manufacturing
personnel into the design of the device; and
o reduce production problems based on the expertise and input of the
device design personnel into the design of processes and production
tools, jigs, molds, in-house standards, and test methods.
All of these are important and valuable side benefits to these simple
cross-training techniques. Such training should be documented.
Process Validation Personnel
The above discussion for technical personnel also applies to technical
employees that perform process validation. After the processes are
validated, these technical personnel should use their expertise and
experience to develop training methods or help train production
employees on how to monitor, control, and operate validated processes.
Section 820.75(b) requires a manufacturer to establish and maintain
procedures for monitoring and control of process parameters for validated
processes to ensure that specified requirements continue to be met.
Further, 820.75(b)(1) requires that validated processes be performed by
qualified individuals. Obviously, operators that are trained to operate
each specific validated process are needed to meet these requirements.
179 guidelines governing personnel in drug and device manufacture
During the development and validation of a process, planning for
eventual maintenance can reduce or prevent confusion during emergency
repairs. An emergency could lead to improper repairs, such as use of a
wrong replacement part. Therefore, the installation qualification should
include a review of pertinent training requirements, maintenance
procedures, repair parts lists, and calibration of measuring equipment.
Quality Assurance Personnel
QA or product acceptance employees shall meet the GMP personnel
requirements for manufacturing employees AND shall be made aware
of defects and errors likely to be found in nonconforming components
and devices. Usually, it is easier and more effective to teach all of the
GMP personnel requirements to all appropriate employees.
Production or QA personnel performing quality assurance or acceptance
functions should :
o Maintain requirements for health, cleanliness, and clothing
standards which will prevent an adverse effect on product quality.
o Adequately train and/or supervise temporary personnel working in
special environmental conditions.
The production department shall have sufficient personnel with the
necessary education, background, training, and experience to assure that
all production activities are correctly performed. Employees are selected
and/or trained for their assigned tasks. These tasks may be janitorial,
receiving, pulling parts, production, labeling, acceptance test and
inspection, packaging, painting, welding, mixing, specific technical tests,
etc.
To meet this requirement, each manufacturer shall establish procedures
for identifying training needs and ensure that all personnel are trained
to adequately perform their assigned responsibilities.
As part of their training, personnel shall be made aware of device defects
which may occur from the improper performance of their specific jobs.
Employees should be informed that they may need to be qualified or
certified to perform certain tasks such as welding, operating a validated
process or working in controlled areas. Likewise, employees need to be
told that where necessary, they will be informed about improper
performance of their assign tasks with the intent of improving their
performance and reducing the likelihood of producing nonconforming
product. Where necessary, employees should be certified to perform
180 cleanroom operators manual
manufacturing or quality acceptance procedures where a high degree of
specialized skill is required. Training shall be documented.
Complaint Handling
It is a good idea for most of the company personnel to receive basic
training in complaint handling techniques. Appropriate employees such
as receptionists, salespersons, representatives, secretaries, service
personnel, and other employees who talk with users should receive
training on their responsibilities in regard to complaint handling
requirements in section 820.198. If these employees receive a device
complaint, they need to know they have a responsibility to report it to
the company person(s) assigned to handle complaints.
Likewise, importers and distributors should be made aware of the
complaint requirements, and they should be requested to forward
complaints to the manufacturer.
Management
Proper job performance by employees as required by the QS regulation
dictates that management have a good knowledge of the QS regulation
and resulting quality system. Therefore, management should also have
appropriate education, training, and experience. As part of their review
of the quality system, management should make certain that adequate
how to do documentation is available to employees.
Proper job performance should be supported by correct and complete
quality system and device master records. These records should be written
in such a manner that the intended employees can understand and
properly use them.
Management should show their commitment to training by providing a
training room such as a cafeteria and training equipment such as
chalkboards, flip charts, video cameras, VCRs, television monitors, slide
projectors, overhead projectors, screens, workbooks, etc.
Training Methods
Training for employees may be achieved by many methods such as:
o device regulatory and GMP seminars;
o individual consultations with managers, consultants, FDA
personnel, etc.;
o on-the-job training with appropriate instructors;
181 guidelines governing personnel in drug and device manufacture
o cross-training details between R&D and production;
o video tapes and movies;
o slide shows with an appropriate instructor;
o reading GMP/QA manuals and textbooks; and
o formal college QA courses.
To meet GMP requirements, all training should be documented as noted
above.
Training Indicators
A proactive approach to training is required by 820.25(b) where each
manufacturer is required to establish procedures for identifying training
needs. Thus, management should diligently look for factors that indicate
a need for additional training or retraining. Some of these training
indicators are:
o verification failures due to basic problems,
! post-submission technical and labeling information required by
ODE for 510(k) submissions,
o validation problems due to routine problems,
o excessive design transfer problems or delays,
o inadequate device master record,
o excessive device defects,
o excessive process equipment or line down-time,
o improper labeling or packaging,
o employee confusion,
o employees ignoring environmental control requirements,
o process or sterilization failures,
o incorrect ordering or shipment information,
o customer complaints, and
o excessive or basic items on a FDA list of observations.
This information is derived from management observations, analysis of
device history records, analysis of complaint records, quality assurance
audits, etc.
Audits
As management performs their daily activities they are aware of the
obvious aspects of personnel workmanship and work practices. However,
182 cleanroom operators manual
to make sure that all aspects, obvious, hidden, or subtle, of the required
quality system exist and are operating correctly, the QS regulation in
820.20(b) requires planned and periodic audits of the quality system.
This audit covers:
o noting personnel practices in areas being audited,
o looking for training indicators as listed above, and
o whether the company approach to training programs is proactive.
The audit also includes an inspection and review of training:
o programs and content,
o facilities,
o equipment, and
o records.
A report should be made of each quality audit, including any reaudits(s)
of deficient matters such as incorrect performance of work, lack of
training, failure to update training, the training program not being
proactive for all of the personnel that receive complaints, part of the
training equipment is not functioning, on-the-job training not adequately
supervised or documented, etc. Audit reports that cover training activities
and personnel practices should be reviewed by management responsible
for these factors in their department. Corrective actions for deficient
training and personnel practices shall be taken where necessary (820.22).
183 guidelines governing personnel in drug and device manufacture
sample procedures (SOPs)
C O M P A N Y L O G O Page 1 of 2
Title Employee Training SOP Number
Prepared by Date Prepared
Approved by Date Rev
ECN Notes
Policy - Employees shall be trained as needed to perform their assigned
tasks and shall be made aware that we produce medical devices in
accordance with various regulations and standards.
Scope - This procedure applies to all employees.
Hiring - The education, background, training, and experience of
prospective employees shall be considered with respect to the
requirements of the job to be filled.
Responsibility - Managers are responsible for assuring that the
employees assigned to them are trained or otherwise qualified for the
assigned jobs. Before assigning an employee for the first time to a new
job, managers shall check their training to verify that the employee has
been trained or qualified for the new job.
The QA department is responsible for training facilities, equipment,
and supplies.
Training - All inexperienced employees shall be trained to perform their
assigned jobs. On-the-job training shall be monitored closely by a
supervisor. All employees shall be made aware of design and/or
production defects, visible and invisible, in the device, labeling, and
packaging that may occur from the improper performance of their jobs
and defects that they should look for and detect. Our cleanliness
(environmental control) and safety procedures shall be explained to all
employees.
Quality Assurance Employees - QA or product acceptance employees
shall receive the training noted above and shall be made aware of errors
and defects, visible and invisible, likely to be encountered as part of
their quality assurance functions.
Customer Complaints - Receptionists, managers, representatives,
salespersons, and other employees likely to receive complaints are trained
in complaint handling procedures applicable to their functions.
184 cleanroom operators manual
Change Control - All employees are to be advised that they are to perform
their jobs as instructed or as covered by standard operating procedures
(SOPs). They are NOT allowed to change cleaning, compounding,
processing, testing, packaging, labeling, or tasks covered by SOPs until
the change is approved according to our change control SOP.
Documentation - All classroom and on-the-job training shall be
documented by the supervisor and trainer of the employee on the form
as shown on sheet 2. A separate form for each employee with a record of
their training shall be filed and shall be updated at the end of each
training session.
185 guidelines governing personnel in drug and device manufacture
cleanroom and workstation procedure
This procedure is divided into general requirements, non-laminar airflow
clean rooms, and workstations, laminar airflow clean rooms and
workstations, and clean room personnel rules. The first part of this
procedure contains useful information for any area of a plant were
moderate control is needed to reduce particulate contamination. The
level of control needed increases as the procedure goes from non-laminar
airflow to laminar airflow. The final section contains additional
requirements for personnel working in a clean room.
PROCEDURE TITLE: Clean Room and Work Station Procedure
No.___ Rev.___
Prepared by___________ App by_____ Date________
A. General Requirements
1. No eating, drinking, smoking, or chewing gum.
2. Specified garments must be worn when entering and inside the clean
area. These shall be stored in the anteroom and not worn in non-clean
areas.
3. Only approved clean room paper shall be allowed in the area.
4. Use only ballpoint pens (fine point preferred).
5. Rouge, lipstick, eye shadow, eyebrow pencil, mascara, and false
eyelashes shall not be worn by any worker while in any clean area.
6. No cosmetics of any kind are to be applied or removed in the clean
area.
7. Skin lotions or lanolin-base soaps are in the restrooms for employees
to use to guard against flaking due to dry skin.
8. Solvent contact with the bare skin should be avoided, as most solvents
will remove the natural skin oils and cause excessive skin flaking.
9. The use of paper or fabric towels is not recommended washrooms
should have electrically powered, warm-air dryers.
10. Approved pliers, tweezers or lint-free gloves must be used to handle
manufacturing materials, components, or finished devices.
186 cleanroom operators manual
11. Do not touch with gloves or finger cots any covered or uncovered
part of the body, or any item or surface that has not been thoroughly
cleaned.
12. All containers, racks, jigs, fixtures, and tools should be cleaned to
the same level of cleanliness specified for the device being processed.
B. Non-laminar Airflow Cleanrooms and Workstations
1. Garments shall be pocket-less, lint-free coveralls, with snug fitting
fasteners at the neck, wrist, and ankles.
2. Lint-free caps must be worn and must completely cover the hair and
head except for the eyes, nose, mouth, and chin.
3. Shoes shall be cleaned and covered with a non-shedding boot-type
cover or changed to approved clean room footwear. If special footwear
is provided, it shall not be worn outside the clean room and dressing
room.
4. Janitorial services shall be performed only by adequately trained and
supervised personnel, each of whom must be properly garbed.
5. All equipment to be brought into the clean room shall be qualified for
clean room use and first be thoroughly cleaned. Use only equipment
that will minimize the generation of contaminants.
6. Traffic into and within the clean room shall be restricted to authorized
and properly garbed personnel, and unnecessary movements by these
personnel shall be minimized.
C. Laminar Airflow Clean Rooms and Work Stations
1. Garments may vary with the operation being performed, but the
minimum garment shall be a pocketless, lint-free smock which extends
to at least 15 inches below the work surface. The collar and cuffs shall
have fasteners.
2. Head covering shall be worn, and shall completely cover the hair. If
the operation requires the wearer to lean over the work, or move into the
airstream between the filter bank and the work piece, the front, sides,
and rear neck areas of the head shall also be covered.
3. Shoe covers are not necessary for vertical or horizontal laminar airflow
facilities except when the work is being performed less than 24 inches
from the floor.
187 guidelines governing personnel in drug and device manufacture
4. A face mask may be needed if an operator has a cold, or if the nose
and mouth must be brought very close to the work piece for work on
miniature components or devices. Check with your supervisor for
instructions.
D. Clean Room Personnel Rules
Personnel will be asked to cooperate in maintaining a low contaminant
emission rate by observing the following rules.
1. Bathe at night, instead of in the morning, to allow the build-up of
normal body oils which reduces skin shedding. Also, use skin lotions.
2. Wear clean, unstarched, low-shedding garments.
3. Where appropriate, shave daily and be clean shaven or wear
appropriate hair covering.
4. Avoid touching, rubbing, and scratching exposed areas of the body.
5. Exercise extra care to rid the hands of normal residue from home
duties such as starching, baking, plastering, wallpapering, painting,
concrete work, carpentering or other particulate generating activity.
6. Request duty outside the or away from the clean room area when you
have a cold or other viral or bacterial infection.
G
ood Sanitation and Housekeeping Practices are an important
element of GMP, and goes a long way in maintaining a high
state of control in a properly validated manufacturing
environment. Sanitation comprises both cleaning and disinfection, and
in the following sections we shall discuss each separately.
cleaning
The purpose of cleaning is to remove soil, any substance that is not an
integral part of a structure, or designed to assist in function. This
objective may be modified by practicality and cost, and should be achieved
without shortening the life of the item, interfering with its function, or
increasing the risk of contamination. Any item after cleaning should
have fewer rather than more contaminants on it. Contaminated water,
soiled mops or wipes often increase the number of viable and nonviable
contaminants on a surface. The source of soil may be particles deposited
good sanitation practices
C K Moorthy
11 11
11 11 11
190 cleanroom operators manual
from the air or transferred by direct contact from hands, equipment or
implements.
Soil removal is not merely to prevent it from contaminating a product,
though it is certainly the single most important objective in the context
of aseptic zones. Soil can obliterate identification marks, warnings or
instructions on equipment; corrode, abrade or react chemically with a
surface; block channels, interfere with valves, or the flow of liquids,
gases or electric current; encourage insects, pests or growth of
microorganisms; form an insulating shield that obstructs penetration of
heat or chemicals, specially during sterilisation or disinfection; and can
generally reduce the confidence in the facilitys ability to deliver quality
products.
Cleanroom/Aseptic zone cleaning
Cleanroom/Aseptic zone cleaning is a specialised task, which requires
trained staff that will keep to detailed schedules, and often requires
equipment, methods and materials not used in other situations. Why?
Because soil in aseptic zones can potentiate product contamination. To
add to our difficulties, the bulk of the contaminants encountered in aseptic
zones are invisible. How do you clean what you cannot see?
If we have gravel or river sand soiling our clothes, we merely shake it
off, or brush it off. But if red mud or talcum powder gets on our clothes,
we find it more difficult to dislodge it. Washing with water usually
solves the problem. If some paint or blood stain soils our clothes it
takes more than soap and water to remove the stains.
This is because particles, like gravel, in the size range above 20 do not
bond strongly with the surface they are in contact, and can be removed
by conventional methods employing simple brushing or detergents and
water. This is primary or gross cleaning.
Particles, like fine mud or talc, in the size range of 0.1 to 20 are
influenced by considerations like polarity and surface tension, and require
coaxing with surfactants (surface acting agents) for removal. This
constitutes secondary or precision cleaning.
Particles, like stains, in the size range below 0.1 bond aggressively
through forces of intermolecular attraction, and can be persuaded to
loosen their grip only by strong solvents. This is tertiary cleaning or
cleansing.
191 good sanitation practices
Analogies from our day-to-day cleaning experiences: gross cleaning
while dusting, sweeping and wiping; moderate precision cleaning while
bathing, washing clothes and polishing articles; and tertiary cleaning
while removing stains.
Whether it is an aseptic zone floor or ceiling, work surface or component,
equipment or tool, it is necessary that we identify the nature of the
contaminant and choose a cleaning technique appropriate for that task.
Methods of cleaning
Two basic methods of cleaning are used: dry and wet. Dry methods rely
on mechanical action to loosen and remove larger objects and particulate
soil, but do not remove stains and are unsuitable for wet, oily or greasy
surfaces. Wet cleaning employs detergent solutions, surfactants and
solvents to loosen and resuspend or dissolve adherent soil.
Cleaning should not end up as an exercise in redistribution of settled
contaminants. For example, sweeping with brooms increases suspended
contaminant density by 700%! Dust attracting mops cause an increase
of 30%; wet scrubbing machines by 3%. Vacuum cleaning without
filtered exhaust increases the count by 25%; if fitted with a HEPA exhaust,
it causes a decrease in the count by 20%. The effect varies with the
make of equipment and manner of use.
Hazards while cleaning
Cleaning should not be undertaken while the aseptic zone is in operation;
if unavoidable, first cover all susceptible sites and open vessels and allow
at least 15 minutes for dispersed contaminants to settle out of harms
way before re-exposing them. Though dispersal of contaminants into
the air is less likely with wet cleaning, the solutions become contaminated
quickly; splashes are common, and aerosol droplets can travel far and
wide to contaminate. Wet methods require proper drying out after the
cleaning process; otherwise they bring in their own store of problems
like accelerated microbial growth, corrosion and chemical attacks, and
slippery floors. Besides, if a detergent or soap is used for cleaning, it is
important to consider the difficulty that may arise with build up of
residues, which must be deemed as yet another type of soil.
Detergents and their residues
A common problem associated with detergents is its composition.
Suppliers do not provide specific data on composition, which makes it
difficult to evaluate residues. Unlike product residues, where tolerance
192 cleanroom operators manual
levels for residual concentration are often laid down and accepted, there
are no corresponding acceptance limits for detergent residues, since
detergents are not part of the manufacturing process and are added only
to facilitate the cleaning process. If the detergent is not easily removable,
a different, more suitable detergent should be selected.
When in doubt, deem it dirty
Some areas, by the nature of the function carried out there, may be heavily
contaminated. While every effort is made to keep these areas as clean
as possible, it is often more prudent to deem them as contaminated and
take necessary precautions, rather than adopt expensive ineffective
measures and then ignore the risk.
Setting up a staging area
There would be much less to clean down inside the aseptic zone if we
were to make sure that all men and materials are sent in thoroughly
cleaned. It is good practice to set up a staging area just outside the
aseptic zone for carrying out final gross clean down prior to entry. If
the equipment or component is manufactured under clean conditions;
and if every item entering the aseptic zone is sent double-wrapped, so
that the outer jacket serves as a dust cover and can be stripped in the
staging area, the decontamination work load is reduced and the whole
process becomes more effective.
In fact, aseptic zone practices are being increasingly adopted by
cleanroom contractors while setting up an aseptic processing zone.
Cleanroom Construction Protocol requires immediate pick up of spills;
vacuuming while drilling; providing temporary curtains around site
where dust generating operations are being carried out to avoid dispersal
and spread of debris. Such techniques reduce the start up contaminant
load, resulting in faster clean down on commissioning.
Drawing up a cleaning programme
The first important step is to appoint a Sanitation Team. Routine cleaning
should be carried out as part of an agreed programme with detailed
agreed schedules and procedures. Regimen drawn up for the facility
should be given preference where it conflicts with the manufacturers
instructions, but it is always a good idea to read the instructions first
and clarify discrepancies. Alternate methods or materials should not be
used unless authorised. Cleaning products should not be mixed unless
known to be compatible. Soaps and detergents may often reduce the
effectiveness of disinfectants; some products may react dangerously. For
193 good sanitation practices
example, soap neutralises quarternary ammonium compounds (like
Savlon) and acid cleaners react on exposure to hypo chlorites (bleach)
to release chlorine. Surface deterioration is often attributable to
inappropriate cleaning. Not all commonly used cleaning techniques
have been introduced as properly planned, coordinated and adequately
researched programmes, and it is reasonable to check methods, which
do not appear to be soundly based. It is part of the job of the
contamination control team to liaise with other disciplines in evaluating
the need for changes in existing procedures and programmes related to
contamination risk.
Waste management
The programme must provide for management of wastes. Waste includes
spillage, defective packaging materials, containers and products.
Estimates should be made of waste, both quantities and characteristics
at various points in the manufacturing process and means of collection
and disposal provided. The wastes must be effectively separated from
the process stream to provide positive assurance that the product will
not be contaminated. Disposal means, whether waste containers, dust
collection equipment, vacuum collectors or even separate sewage system,
should be clearly marked.
To illustrate the need to identify and separate waste streams, consider
the liquid waste discharge from a pharmaceutical facility. The rest room,
lavatory, and kitchen waste, known as domestic sanitary sewage, is one
type; rinse water from process areas, tank drainage from compounding
areas and laboratory wastes, known as industrial waste, is the other
type. While the former may be directly discharged into a sanitary sewage
system, the latter may require some pretreatment prior to discharge. To
facilitate the streams, most production facilities have multiple sewage
systems. This need to separate the two types of liquid waste streams is
intended for the protection of the municipal sewage treatment system
and facility.
Internally, the separation of process waste from domestic waste is
necessary to help maintain the controlled conditions in the aseptic zone.
If all liquid wastes were discharged via a single system, any blockage or
overflow condition in that system could cause a overflow of one type of
waste into the other, and domestic waste may find its way into the
production area, introducing an unacceptable and indeterminate bacterial
contamination. To preclude the possibility of this condition,
pharmaceutical facilities have separate domestic and process waste
194 cleanroom operators manual
systems, which do not connect with the plant, and are equipped to prevent
backflow of waste into the facility.
Control of the waste disposal problem then involves a three-element
system: solid waste disposal; liquid waste disposal; and airborne waste
(dust) collection and disposal. For each ingredient or item of waste,
thought must be given to:
What is to be collected?
What quantities are expected?
How must the waste be moved through and out of the area to
prevent accumulation and possible contamination?
How must the material be disposed off: municipal sewage, landfill
or incineration?
Organising for cleaning
Effective cleaning of both physical facility and equipment is enhanced
by facility design details, which reduce bacterial growth areas, minimise
contaminant collection points and improve surface cleanability. Beyond
design details, broader consideration must be given for the space and
utility needs of cleaning.
Cleaning equipment
Cleaning equipment must be controlled like all other equipment entering
controlled environments. It must be cleaned, sanitised and, where
necessary, sterilised if for ultra clean use. After use, the equipment
must be removed from the controlled area for storage and cleaning prior
to reuse. The equipment required will depend on individual needs but
may include buckets, mops, sponges, spray guns, brushes and vacuum
hoses. Areas must be provided adjacent to the controlled environment
where cleaning equipment can be cleaned and stored without subjecting
it to potential contamination.
Utility requirements
Utility needs for aseptic zone cleaning are unique. Both sewage drains
and non-aseptic water supplies are contamination potentials to be
avoided. Use of Water for Injection or DM/DI filtered water eliminates
the potential water contamination. After cleaning, the wastewater may
be picked up by mops, which may redistribute contamination rather
than remove it. One alternate approach is to spray the cleaning solution
onto the surface and remove it by a central vacuum collection system.
The vacuum connections are sanitised as part of the area cleaning activity
195 good sanitation practices
to prevent contamination of the clean environment. Although this
method is effective, the vacuum piping must be planned and installed in
the walls of the facility during construction.
Cleaning auxiliary areas
Auxiliary areas are those places upstream of the controlled environment
in which packaging components, and processing equipment are cleaned
and sterilised, and in which chemicals are blended into clean bulk
formulations.
The ceiling, lighting fixtures (inside and outside), sprinkler heads and
air supply vents are thoroughly washed with a microbicidal detergent
solution and cloth. Burned-out bulbs are replaced with new ones that
have been similarly wiped. Then walls, including baseboards, doors,
doorframes and air return vents are thoroughly washed.
Following this, all horizontal surfaces, fixtures, equipment and furniture
are washed and wiped. Accessible floor areas and cover bases are
vacuumed and machine scrubbed, with a final wipe with clean water.
Cleaning the critical zone
The controlled environment in which the critical process is carried out
is cleaned using the procedures outlined for auxiliary areas. One
significant difference to be borne in mind is that there are no drains
provided in a controlled environment, since they are a potential source
of contaminants. Liquid spills in controlled environs should be removed
with a wet/dry vacuum fitted with a HEPA exhaust, followed by a damp
wipe down with microbicidal detergent solution.
Cleaning service areas
For purposes of definition, a service area includes offices, rest rooms,
storage rooms, mechanical support rooms, lockers and rooms downstream
of the controlled processes.
The ceilings are wiped down with a microbicidal detergent solution using
a sponge or cloth. The sprinkler heads are dusted with a soft-bristled
brush and light diffusers are cleaned using detergent solution. Where
drapes are unavoidable, a vacuum cleaner equipped with a brush tool is
used. The air supply and return vents are washed with a degreasing
microbicidal detergent solution and sponge. A microbicidal detergent
solution is used to wipe down the walls, door and partitions. The cloth
or sponge employed in such operations must always be of a non-shedding
196 cleanroom operators manual
type to reduce particulation. The windows are washed with a suitable
window cleaner. Accessible areas of office furniture and other
miscellaneous equipment are damp wiped using a microbicidal detergent
solution and cloth.
Rest rooms are especially hard to clean and require great care. Sinks
and bowls and related plumbing hardware are washed with a microbicidal
detergent and cloth. The interior surfaces of all bowls are cleaned with
hydrochloric acid.
In mechanical support rooms, lockers and storage rooms, accessible floor
areas and cover bases are vacuumed and then machine scrubbed. The
floor is then rinsed with clean water. The floor drains and drinking
fountain drains are flushed with a microbicidal detergent solution.
Equipment cleaning
Equipment cleaning, like facility cleaning, requires consideration during
planning stages. It lends itself to a central operation, at least for closely
allied production areas, but cannot be located in such a way that travel
through non-controlled areas is required. Equipment cleaning involves
not only the process machinery but also all associated auxiliaries like
pumps, hoses, pipes, fittings and filters. The cleaning may involve
disassembly, removal of product residue, reassembly, integrity testing,
sterilisation and storage. The area should be separate from, but adjacent
to the clean production area, and will probably function at irregular
hours. An adequate supply of water, including pure water, steam,
compressed air, nitrogen, is typically required. If equipment is to be
used aseptically, provision must be made for sterilisation prior to use.
Preparation, like planning, is a vital part of the manufacturing process.
Preparation of equipment entails the cleaning, sanitising, assembling,
and in many cases, sterilising and/or depyrogenation of equipment, which
may include items as diverse as tanks, mixers, process equipment, transfer
lines and the work area in general. The proper cleaning of all equipment
that comes in contact with the product is particularly critical. Concern
must be demonstrated for general cleanliness as well as for the equipment
and area, so that one must be sure that the area and equipment are free
from cross-contamination from products processed just previously, or
those being processed nearby.
The first step in maintaining clean equipment is the practice of ordinary
good housekeeping practices. Orderliness and cleanliness are pre-
requisites for proper aseptic zone operation. Equipment should never
197 good sanitation practices
be put away dirty. Cleaning up as soon as possible after an operation has
been completed is good practice. Dirty equipment can supply the
contaminants, both viable and nonviable, to compromise other portions
of the facility. Nothing substitutes for good nonabrasive scrubbing with
microbicidal detergent solution followed by wipe down with clean water.
Because some equipment are complex, chemical tests are often employed
to detect residual detergents in the rinse water, and rinsing is continued
until the level is below maximum acceptable limits. Where possible,
drying should be under LAF cover; and storage must be under lint-free
wraps in a clean, dry area.
Microbial purity of water for cleaning should meet PHS standards with
not more than 500 CFU/ml. Final rinse is recommended with pure
water at a temperature of 80
o
C with not more than 100CFU/ml.
Drawing up a cleaning programme
o Cleaning should be introduced as a properly planned, coordinated
and adequately researched programme
o Choose a cleaning technique appropriate for the intended task
o Microbial purity of water for cleaning should meet PHS standards,
not more than 500 CFU/ml. Final rinse is recommended with
pure water (WFI grade) containing not more than 100 CFU/ml at a
temperature of 80
o
C.
o Because some equipment are very complex, chemical tests may be
required to monitor residual detergents in the rinse water, and
rinsing continued until the level falls below maximum acceptable
limits. Where possible, drying should be under LAF cover.
o The sanitation programme must take into account waste
management
What is to be collected
What quantities are expected
How must the waste be moved through and out of the area to
prevent accumulation and possible contamination
How must the material be disposed off: municipal sewage,
landfill or incineration
Good cleaning practice: a summary
It is recommended practice to first demarcate and grade your
controlled environment, so that sanitation stringency increases
towards the core locations. This is called zoning. On a floor map
of the aseptic zone different areas are coloured differently, coded to
198 cleanroom operators manual
signify the sanitation stringency prescribed for each. Red is
usually reserved for the most critical sites, while green is
forbidden, since no area anywhere in or around an aseptic zone
can be deemed safe.
Check that all cleaning agents and implements are aseptic zone
grade: cleanable, sterilisable and non-contaminating. It is also
important to evaluate some other key parameters and
characteristics like surface tension, polarity and pH; their
solubility, stability and reactivity, including corrosiveness; their
efficiency as surfactants; their propensity to leave residues; and
most importantly, the recommended use dilution and temperature.
Prepare a fresh cleaning solution, accurately diluted for each task.
Make up only the quantity required in a clean, dry container.
Freshly drawn tap water is usually suitable for peripheral areas.
Very hard water will precipitate soaps and neutralise some
disinfectants. For aseptic processing zones use WFI grade water.
Hot water cleans better than cold. But at temperatures above 65
o
C
it coagulates proteins, and organic stains, if any, will then be more
difficult to remove.
Use of two buckets mounted firmly on a trolley, one for fresh
solution and the other for rinsing is common practice; use of three
buckets, one marked dirty where the soiled solution is drained, a
second marked rinse and last marked clean would be an even more
effective procedure.
Brushes, mops and wipes should be dry and clean before use.
Apply the cleaning solution evenly to all of the surfaces. Do not
apply more fluid than necessary onto a surface. This avoids waste,
seepage into cracks, shrinkage of surface materials, and difficulties
of subsequent removal.
Always clean down from ceiling, walls to floor, from the farthest
point to nearest, with gentle, steady, unidirectional strokes. This
holds for both wet as well as dry wiping, where the stroke length
should not be more than 400 mm. (When dry wiping, expose a
fresh, clean surface for each stroke).
Rinse off cleaning solutions when practical, and change contents
frequently to prevent buildup of soil in the solution, which will
lead to recontamination.
Allow sufficient time for cleaning solutions to penetrate the soil on
the surface. However, do bear in mind that strong acid or alkaline
cleaning agents can damage surfaces if left in contact too long.
199 good sanitation practices
Dispose off used cleaning solution in the manner prescribed by
your SOP in the designated area. Do not empty into washbasins or
work area sinks.
Remove any fluid trapped in channels or elsewhere, and dry the
cleaned surface as thoroughly as possible.
Remove cleaning equipment, accessories and implements from the
aseptic zone as soon as the cleaning process is completed. Clean
them as per methods laid down in your SOP, dry them and store
them in the designated location. If the equipment is faulty, report
it promptly to your supervisor.
Wash hands before carrying out any other duties.
Some tips for cleaning personnel
Rule Number 1
Cleaning or decontamination agents should never be mixed unless
specified in the SOP. Many products have been ruined by chemical
cleansers that were mixed and wrongly applied to equipment with
the result that an insoluble residue was left which was then
transferred to the product. In some cases mixing can be dangerous
to the operator.
Rule Number 2
Cleaning should be done by working from the top downwards. The
lower the surface, the dirtier the surface. The further away from
the HEPA filters in the ceiling the greater the surface soiling, so
working should always be away from the filters outwards and
downwards. Product containers and closures as well as other
unused materials should be removed at this point.
Rule Number 3
Always use fresh filtered cleaning agents.
Rule Number 4
Always clean cleaning equipment.
Rule Number 5
Never add soil to the cleanroom when cleaning it.
Rule Number 6
Always work TOP TO BOTTOM; FARTHEST TO NEAREST
A checklist for cleaning personnel
1 Check and review the Standard Operating Procedure
2 Gather all supplies, checking to make certain that they are clean
200 cleanroom operators manual
3 Place all supplies in the air-lock or pass-through
4 Change into prescribed clothing following laid-down procedures
for scrub-up and gowning
5 Prepare cleaning solutions ensuring accurate measures
6 Enter the process area and move supplies to the area to be cleaned
7 Remove unused components and raw materials
8 Disassemble equipment requiring re-processing and remove it to
the re-processing area or air-lock
9 Begin the cleaning process by removing gross soils
10 Clean equipment by working from the top down to the floor.
NEVER WORK UPWARDS!
11 Clean ceilings, walls and floors
12 Remove cleaning materials from the area and place cleaning
equipment in the air-lock when all tasks have been completed. Do
not remove process area specific items such as vacuum cleaners,
but make sure that they are cleaned and emptied using the correct
SOPs
13 Clean the air locks
14 Clean the outside areas
List of Dos
1 Hands, fingernails and face to be clean at all times
2 Proper protective clothing to be worn correctly at all times
3 Wear gloves or finger-cots as required
4 Always clean and disinfect spectacles before entering the process
area
5 Keep all parts and tools at the workstation as clean and orderly as
possible
6 Always use tool racks provided. These must never be wooden
7 Keep surplus parts in appropriate containers
8 Make certain that parts are clean before assembling
9 Always work on a clean surface and never on cloth or paper towel
that can transfer contaminants to equipment or the work piece
10. Always report any changes In environmental conditions
List of Donts
1 Never comb hair in the process area
2 Never wear or apply cosmetics in the process area
201 good sanitation practices
3 Never wear finger polish or nail varnish
4 Dont wear jewellery in the process area
5 Dont eat or chew gum in the process area
6 Dont smoke in the process area
7 Avoid nervous habits such as scratching and rubbing hands
together
8 Dont wear soiled or ordinary street clothes in the process area
9. Dont leave exposed components on the workbench or area
10 Dont walk about unnecessarily and be cautious when approaching
someone else
Disinfection
Present practice is far from satisfactory in the use of disinfectants. Every
institution often has a different disinfection programme, and the choice
of disinfectants for similar purposes varies considerably. A wide range
of disinfectants is used, some of which are clearly unsuited for the purpose
for which they are employed. In dispensing solutions, members of staff
apparently rely upon such measures as a tablespoonful to a bucket, until
it looks enough and depending on the smell. The important principle of
strong enough for long enough is generally overlooked. Too often,
their abuse leads to a dangerous notion of security.
Antiseptics, disinfectants and germicides
Terms like antiseptics, disinfectants and germicides are often used
interchangeably without drawing distinctions. While all three have
antimicrobial action, antiseptics are intended for clinical use, while
disinfectants are for use on inanimate objects. The term germicide is all
embracing to mean fungicide, bactericide, sporicide and viricide. As
mentioned earlier, though some chemical agents are effective against
all varieties of microbial flora, there is a general tendency to dismiss
disinfectants as being useful only against vegetative bacteria and lipid
viruses.
Planned disinfection
Floor cleaning mops, wipes, baths, bath mops and brushes, washbowls,
nail brushes and communal jars containing antiseptics and soap are
confirmed sources of contamination and microbes. Antimicrobial
chemicals must be properly applied if they are to be of service. Each
facility should adopt a properly planned programme on the kind and
concentrations of disinfectants to be used for particular purposes, a system
202 cleanroom operators manual
of supervision to ensure that the staff are implementing this programme
and a system of in-use tests to be made on samples of the disinfectant
solutions actually being used in the different areas to ascertain and
confirm that they are at the correct concentration and retain adequate
activity.
Application methods
Disinfectants may be applied using a variety of methods, as dictated by
their nature and the surface to be treated. Agents prepared as liquids
may be applied by:
Spraying is convenient for small to medium size surfaces. However,
diluted agents should not be stored in a spray bottle for long periods of
time. Time of storage is dependent upon the chemical stability of the
agent and the potential for the applicator to become a reservoir for
resistant organisms.
Wiping is effective for small to medium size surfaces. Wiping combines
the chemical activity of the agent and the physical removal of organisms
or soil by abrasion. Wipes should be clean and non-particulating.
Mopping is appropriate for large environmental surfaces and is
accomplished by one of three techniques:
Damp mopping: A clean mop of suitable design is dipped into the agent
and squeezed out. The mopped surface remains wet for some time.
Wet mopping: Two buckets of decontaminating solution are prepared
according to labeled instructions. A liberal amount of solution from one
bucket is applied to the surface; and the mop is then rinsed and squeezed
out in the second bucket.
Flood and vacuum: A liberal amount of disinfectant solution is applied
to the surface, and after a prescribed time of contact the excess is wet
vacuumed from the surface.
Submersion in solutions of chemical agents may be effective for
decontaminating small surfaces or equipment. Surface cleanliness is a
significant parameter in the effectiveness of this method. The activity
of some agents like glutaraldehyde are enhanced when used thus in
ultrasonic baths.
Fogging is used for disinfecting rooms and their contents. A solution of
an appropriate agent is aerosolised in mist form using a revolving
dispenser or other suitable device.. The success of this procedure depends
203 good sanitation practices
upon covering all surfaces with a fine layer of solution. This success
could later translate into a problem if there are insoluble residues, or the
film stubbornly adheres to the surface making thorough cleaning difficult.
Fumigation where the chemical agent is applied in a gaseous state,
concentrated in enclosed areas either at ambient pressure or under
vacuum pressure.
Selection of agents
For daily routine disinfection selection should favour those that are
convenient, safe and non-noxious. The more potent, noxious or toxic
agents should be reserved for use on a less frequent basis (weekly or
monthly) or when advised due to an increase in the baseline microbial
level, presence of unique (i.e. sporeformers) or pathogenic
microorganisms, or occurrence of atypical operational circumstances.
Use of different types of disinfectants on a rotational basis is practised
by many companies, although there is no published data in the literature
that indicates that the use of a single disinfectant agent, consistent with
label instructions, will lead to so-called microbial resistance. If
disinfectants are to be rotated there are pitfalls to be avoided, because
not all disinfectants are compatible with one another.
Cost is a relevant factor when choosing disinfectants. Those designed
for special purposes may be both unsuitable and too expensive for use as
general environmental disinfectants. To be used safely on human tissue
a disinfectant would have to be non-toxic, non-allergenic, non-corrosive
and have a neutral pH. These properties are expensive to achieve and
are usually obtained at the expense of other desirable properties like
range of action.
Drawing up a disinfection programme
1. List all purposes for which disinfectants are used, then check all
requisitions and orders to ensure list is complete.
2. Eliminate use of chemical disinfectants when an alternative can be
reasonably employed. For example, when heat is an option choose
sterilisation; or when thorough cleaning alone is adequate; or
when disposable items can be economically used. This should
then leave few remaining uses for disinfectant fluids.
3. Select the smallest number of disinfectants possible for the
remaining uses.
204 cleanroom operators manual
Formaldehyde
Conditions: Humidity 60% to 80%
Temperature Low, approx. 18
o
C
Additives: Inhibit polymerisation 10% methyl alcohol
Inhibit corrosion 2 % Borax
Neutralisation Ammonia in shallow tray
Fumigation of Rooms
Gaseous/Fumes per 1000 cft 150g KMnO
4
+ 280 ml formalin
Boiling/fogging per 1000 cft 500 ml formalin + 1000 ml water
Fumigation of Cabinets
Boiling formalin per cft 2 ml
Vaporise paraformaldehyde per cft 0.3 g
Surface disinfection 1:10 formalin
Hydrogen peroxide
Additives Silver nitrate
Antimony nitrate
60% IPA
General use 2 - 10% in distilled water / 60% IPA
Fumigation: By fogging 20 % H
2
O
2
in distilled water
Surface disinfection 5 - 10% H
2
O
2
in distilled water
Water decontaminatlon 100 ppm H
2
O
2
+

2 ml Formalin
Virus inactivation 50% H
2
O
2
Virosil
Fumigation: By fogging per 1000 cft 200 ml in 800 ml of
distilled water
Surface disinfection 5% in distilled water
Media for isolation
Plate count agar for bacterial solution
Potato dextrose agar/ Sabroud's agar for fungal isolation
Table 1: Summary of disinfection practices
Summary of disinfection practices
205 good sanitation practices
Antiseptic .................... Y ...... N....... N ....... N ...... Y....... Y ....... Y ...... Y....... N ....... Y ...... N
Disinfectant ................ Y ...... Y....... Y ....... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... Y
Germicide ................... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... N....... N ....... N ...... Y
Additives .................... Y ...... Y....... N ....... N ...... Y....... N ....... Y ...... N....... N ....... N ...... N
Concentration (%w/v) 2 .... 2-8 ........ 1 ..... 10 ..... 70 ........ 2 ........ 2 ....... 5 ........ 2 ........ 5 ....... 2
Fungi ........................... E ...... G........ P ....... F ....... E....... G
GPC ............................. E ....... E....... E ....... E ....... E....... E ....... E ....... E....... E ....... G ....... E
GNB ............................ E ....... E....... E ....... E ....... E....... G ....... E ...... G........ F ....... P ....... E
Spores ......................... E ...... G....... E ....... G ....... P....... G ....... P ....... P........ P ....... P ....... P
Lipid virus .................. E ....... E....... E ....... E ....... E....... G ....... G ...... G....... G ....... F ....... E
Nonlipid virus ............ E ....... E....... E ....... G ...... V....... G ....... P ....... P........ P ....... P ...... V
Human tissue .............. N ...... N....... N ....... N ...... Y....... Y ....... Y ...... Y....... N ....... N ...... N
Hands & feet .............. Y ...... N....... N ....... N ...... Y....... Y ....... Y ...... Y....... N ....... N ...... N
Environment air ......... N ...... Y....... N ....... N ...... N....... N ....... N ...... N....... N ....... N ...... N
Contact parts .............. Y ...... N....... Y ....... Y ...... Y....... N ....... N ...... N....... N ....... N ...... N
Work surface .............. Y ...... N....... Y ....... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... N
Equipment surface ..... Y ...... N....... Y ....... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... N
Glassware ................... Y ...... Y....... Y ....... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... N
Culture spills .............. Y ...... Y....... Y ....... Y ...... Y....... N ....... N ...... N....... N ....... N ...... N
Walls & Ceiling ......... Y ...... Y....... Y ....... Y ...... Y....... Y ....... Y ...... Y....... N ....... N ...... N
Floor ............................ Y ...... N....... N ....... N ...... N....... Y ....... Y ...... Y....... N ....... N ...... Y
Sinks ........................... Y ...... N....... Y ....... Y ...... N....... Y ....... Y ...... Y....... N ....... N ...... N
Toilet ........................... N ...... N....... N ....... N ...... N....... N ....... N ...... N....... N ....... N ...... Y
Hard water .................. N ...... N....... N ....... N ...... N....... N ....... Y ...... N....... N ....... N ...... N
Anionic soap .............. N ...... N....... N ....... N ...... N....... N ....... N ...... Y....... N ....... N ...... N
Cationic detergent ...... N ...... N....... Y ....... Y ...... N....... N ....... N ...... N....... N ....... N ...... Y
Cork ............................ N ...... N....... N ....... N ...... N....... N ....... Y ...... Y....... N ....... N ...... N
Organic matter ........... N ...... Y....... Y ....... Y ...... Y....... N ....... Y ...... Y....... Y ....... Y ...... N
Proteins ....................... Y ...... Y....... Y ....... Y ...... Y....... N ....... Y ...... Y....... Y ....... Y ...... N
Shelf life > 1 week ..... N ...... Y....... N ....... N ...... Y....... Y ....... Y ...... Y....... Y ....... Y ...... Y
Corrosive .................... Y ...... Y....... Y ....... Y ...... Y....... Y ....... N ...... N....... N ....... N ...... N
Attacks plastics .......... Y ...... N....... N ....... Y ...... Y....... Y ....... N ...... N....... N ....... N ...... Y
Stains ........................... Y ...... N....... N ....... Y ...... N....... Y ....... N ...... N....... N ....... Y ...... Y
Residues ...................... N ...... Y....... N ....... N ...... N....... N ....... N ...... N....... N ....... Y ...... Y
Irritate skin/eye/nose . Y ...... Y....... Y ....... Y ...... N....... N ....... N ...... N....... Y ....... Y ...... Y
Toxic ........................... Y ...... Y....... Y ....... Y ...... N....... N ....... N ...... N....... N ....... Y ...... Y
Safe handling ............. N ...... N....... Y ....... Y ...... Y....... N ....... N ...... N....... N ....... N ...... Y
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Properties and proper use of common disinfectants
T
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Table 2: Properties and proper use of common disinfectants
206 cleanroom operators manual
4. Arrange for distribution of selected disinfectants at correct use
dilution, or provide apparatus for accurate measurements at point
of use.
5. Make sure that every potential User of disinfectants receives
adequate instructions on correct usage. These should include:
- The correct disinfectant concentration to be used for each task
- Substances that will react with, neutralise or otherwise interfere
with the disinfectant
- The shelf life at the concentration supplied; the type of container
and closure to be used; and the frequency with which the solution
must be changed in use.
- Personal safety instructions: should gloves be worn? How to open
and mix safely? What to do in case product comes in contact with
skin or eye?
6. The programme should be monitored to ensure that it is, and
continues to be, effective. Periodic in-use tests, assays and
estimations of concentration are recommended.
Good disinfection practice: a summary
The general principles are summarised here to serve as a guideline for
the sanitation team. First decide on the type of disinfection programme.
This requires consultation among the Microbiologist, Pharmacist and
the User. Demand for disinfectants may come from many departments.
There are also many sources of supply. All requests should be approved
by the contamination control team, who can check whether they are
appropriate and in conformity with the overall programme.
List all purposes for which disinfectants are used, then check all
requisitions and orders to ensure list is complete.
Eliminate use of chemical disinfectants when an alternative can be
reasonably employed. For example, when heat is an option choose
sterilisation; or when thorough cleaning alone is adequate; or
when disposable items can be economically used. This should
then leave few remaining uses for disinfectant fluids.
Select the smallest number of disinfectants possible for the
remaining uses.
Arrange for distribution of selected disinfectants at correct use
dilution, or provide apparatus for accurate measurements at point
of use.
Make sure that every potential User of disinfectants receives
adequate instructions on correct usage. These should include:
207 good sanitation practices
The correct disinfectant concentration to be used for each task
Substances that will react with, neutralise or otherwise interfere
with the disinfectant
The shelf life at the concentration supplied; the type of container
and closure to be used; and the frequency with which the solution
must be changed in use.
Personal safety instructions: should gloves be worn? How to open
and mix safely? What to do in case product comes in contact with
skin or eye?
The programme should be monitored to ensure that it is, and
continues to be, effective. Periodic in-use tests, assays and
estimations of concentration are recommended.