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Good Cleanroom Practices PDF
Good Cleanroom Practices PDF
com
c k moorthy
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Published by:
Standard edition
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.
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.
contents
1 contamination control 11
2 cleanroom 23
5 cleanroom disciplines 61
7 laminar airflow 93
contamination control
C K Moorthy
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.
contamination control 15
* 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.
classification of contaminants
SUBSTANCE
ENERGY
Physical Chemical Biologic
Dust Organic Bacteria Thermal
Dirt compounds Fungus Light
Grit Inorganic salts Spore Electromagnetic (EMI)
Fibre Acids, Bases Pollen Electrostatic (ESD)
Lint Condensates Virus Radiation
Fly ash Moisture, Vapour Human skin cells Electrical (RF)
Mist, Fume
Smoke
Table 1: Classification of contaminants
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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.
Transport Contact
Source
Retention
contamination control 17
sources of contaminants
contamination control 19
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
3
Number of Particles /m in Outdoor Air - Task-specific air
Size
cleanliness: a clean
Dirty Normal Clean air workstation or
µm
“tent” in a cleanroom
> 0.1 1 × 1010 3 × 109 5 × 108
* Water
8 7 7
> 0.3 3 × 10 9 × 10 2 × 10 -
Appropriate
> 0.5 3 × 107 7 × 106 1 × 106 treatment, storage and
distribution
Table 2: Air quality
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contamination control 21
D Outside environment
K X Cleanroom
LT
contamination control 23
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.
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what is a cleanroom?
cleanrooms 27
classification of cleanrooms
Clean areas can be divided into four main types. These are shown in a
diagrammatic form in Figure 1 and are as follows:
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cleanrooms 29
cleanrooms 31
cleanrooms 33
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.
cleanrooms 35
isolator or minienvironments
The containers and product cab enter and depart the isolator system
through a sterilising tunnel, pass through tunnel or docking transfer
device.
C K Moorthy
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?
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
Number of Particles /m3 in Outdoor Air
particles of size
Size 0.5µ, or larger
Dirty Normal Clean
µm per cubic foot of
air measured,
> 0.1 1 × 1010 3 × 109 5 × 108 then it could be
assumed that the
> 0.3 3 × 108 9 × 107 2 × 107 number of 5µ
particles would
> 0.5 3 × 107 7 × 106 1 × 106 be less than 700
per cubic foot.
Table 1: Air quality curves
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ISO 14644-1
(N) µ
0.1µ µ
0.2µ µ
0.3µ µ
0.5µ 1µ µ
5.0µ
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
With the selection of 0.1 µm 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 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/m3 in the particle
size range of 10 to 20µm 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”
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
Special Note :
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;
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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.
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.
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.)
Principle
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.
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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-
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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
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.
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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 70°C.
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
B 10 5 5 5
C 100 50 25 -
D 500 100 50 -
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.
Air classificationsa
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 person’s
skin and their indoor, or factory, clothing.
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.
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.
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
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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 personnel’s 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:
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· 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.
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 garment’s 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.
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.
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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.
the user can choose methods that best reflect the degree of risk associated
with their cleanroom.
People can, when walking, produce about 1 000 000 particles > 0.5 µm
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.
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.
cleanroom disciplines 65
air transfer
cleanroom disciplines 67
personnel behaviour
Activity µ
Particles > 0.3µ 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
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cleanroom disciplines 69
handling materials
cleanroom disciplines 71
C K Moorthy
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.
practices becomes one of the more important factors that influence the
quality and consistency of the finished product.
biologic factory
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 30µ in length, 5µ
in width and less than 0.5µ 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
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Human Bioprofile
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;
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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 >0.5µ 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.
Reinmuller’s 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.
environment per hour it is obvious that, given the high air exchange
and hence dilution rates used in today’s 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.
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
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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.
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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
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.
* 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
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.
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84
Figure 5: Washing soiled contamination control apparel
1 2 3 4 5
Sort & Group Prewash Repair Spotting & Prewash
Inspection Stain Antiseptic2
Removal1
10 9 8 7 6
Spin Dry Final Rinse Rinse Main Wash Main Wash
Liquid Additives5 Cold Water Water 60 0C Solvent3
Liquid Detergent4
11 12 13 14 15
Air Dry under
correct gowning
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
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.
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.
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.
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.
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.
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laminar airflow
C K Moorthy
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.
Ux >> Uy , Uz
UX ≈ constant
Uy , U z ≈ 0
Ux >> Uy, Uz
o x
Fig 1 Unidirectional laminar airflow
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.
5D
laminar airflow 97
N = ρUD/µ
U1
P1
U2
P2
U3
P3
U4
P4
X U1 = U2 = U 3 = U 4
O P1 = P2 = P 3 = P 4
Fig. 5.3
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Laminar airflow workstations are used for either or both of the following:
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.
laminar airflow 99
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.)
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 harm’s 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.
Interesting inputs on
unidirectional airflow from
ISO 14644-4
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
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biosafety
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
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.
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.
biosafety levels
risk assessment
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 user’s arms rest flatly across the front grille, room air may
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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.
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.
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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
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surface decontamination
a wipe-down of the work surface, the cabinet’s 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.
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.
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
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building exhaust
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
ultraviolet lamps
BSC placement
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.
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HEPA filters
Access panel ports in the filter housing also allow for performance testing
of the HEPA filter.
bsc:faqs*
"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!
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.
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.
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.
Exhaust air from BSCs and Biosafe facilities should not be connected to
the building’s general exhaust system. A separate dedicated exhaust
should be used.
"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.
A. Biohazard waste
Treated Biohazard Wastes are all biohazard wastes that have been treated
by one of the following methods and rendered harmless and biologically
inert:
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C K Moorthy
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? Don’t
worry. You are not alone. Everyone does exactly what you did. Some,
unfortunately, are no longer around to be counted.
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.
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.
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
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.
Machines do not goof up. Machines do not mix up. Only people do.
importance of SOPs
GMP is the quality system guide that sets your Goals; but doesn’t always
tell you how to achieve them.
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.
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.
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.
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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.”
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, we’d 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!
The product you are manufacturing could land up in your home: you or
members of your family may be consuming it. So manufacture wisely.
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.
If the above ten rules are followed, then cGMP will always translate to
mean Can Guarantee My Products!
management support
10
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.
Schedule M
1. Personnel
WHO
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.
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).
General
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.
10.12 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.
10.14 The concept of quality assurance and all the measures capable of
improving its understanding and implementation should be fully
discussed during the training sessions.
Personal hygiene
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.
EUGGMP Chapter 2
Principle
General
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. ...
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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;
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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.
Personal Hygiene
(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
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(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.
§ 211.34 Consultants.
special mentions
Personnel
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
Q7A
C. Consultants (3.3)
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.
18.9 Staff at all levels should be adequately trained for the tasks and
responsibilities assigned to them.
sterile products
WHO
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.
17.13 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.
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.
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 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
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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:
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.
B. Laboratory Personnel
C. Monitoring Program
WHO
3. Personnel
3.1 The 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.
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biologicals
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
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not enter the production area except for essential purposes, and in that
case they shall be supplied with sterile protective clothing.
3.6 The names and qualifications of those responsible for approving lot
processing records (protocols) should be registered with the national
control authority.
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
Rationale
General
Training
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.
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.
personnel:faqs
Personnel (Chapter 2)
(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.
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.
FDA Observations
Employee Selection
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.
Complaint Handling
Management
Training Methods
Training Indicators
Audits
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.
C O M PAN Y LO 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.
Change Control - All employees are to be advised that they are to perform
their jobs as instructed or as covered by standard operating procedures
(SOP’s). They are NOT allowed to change cleaning, compounding,
processing, testing, packaging, labeling, or tasks covered by SOP’s until
the change is approved according to our change control SOP.
A. General Requirements
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.
8. Solvent contact with the bare skin should be avoided, as most solvents
will remove the natural skin oils and cause excessive skin flaking.
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.
2. Lint-free caps must be worn and must completely cover the hair and
head except for the eyes, nose, mouth, and chin.
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.
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.
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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.
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11
C K Moorthy
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
This is because particles, like gravel, in the size range above 20µ 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 0.1µ to 20µ 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 0.1µ 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.
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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.
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.
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.
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.
Waste management
systems, which do not connect with the plant, and are equipped to prevent
backflow of waste into the facility.
Cleaning equipment
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
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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.
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
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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.
Equipment cleaning
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 oC 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 oC.
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
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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
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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
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Application methods
Damp mopping: A clean mop of suitable design is dipped into the agent
and squeezed out. The mopped surface remains wet for some time.
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.
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.
Formaldehyde
Conditions: Humidity 60% to 80%
Temperature Low, approx. 18oC
Additives: Inhibit polymerisation 10% methyl alcohol
Inhibit corrosion 2 % Borax
Neutralisation Ammonia in shallow tray
Fumigation of Rooms
Gaseous/Fumes per 1000 cft 150g KMnO4 + 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 % H2O2 in distilled water
Surface disinfection 5 - 10% H2O2 in distilled water
Water decontaminatlon 100 ppm H2O2 + 2 ml Formalin
Virus inactivation 50% H2O2
Virosil
Fumigation: By fogging per 1000 cft 200 ml in 800 ml of
distilled water
Surface disinfection 5% in distilled water
Formaldehyde gas
Glutaraldehyde
Peracetic acid
Alcohol ethyl
Metallic salts
Chlorxylenol
Hypochlorite
Iodophors
Phenolics
QACs
H2O 2
Antiseptic .................... Y ...... N ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... N ....... Y ...... N
TYPE
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
USE
Concentration (%w/v) 2 .... 2-8 ........ 1 ..... 10 ..... 70 ........ 2 ........ 2 ....... 5 ........ 2 ........ 5 ....... 2
Fungi ........................... E ...... G ........ P ....... F ....... E ....... G
ACTIVITY
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
SUITABLE APPLICATIONS
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
CHARACTERISTICS INACTIVATED
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