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Good Cleanroom Practices

A manual for cleanroom personnel

c k moorthy G ood C leanroom P ractices A manual for cleanroom personnel c k moorthy

Published by:

Center for GMP 509C NCL-Godavari Pipeline Road Jeedimetla PO Hyderabad 500 055 URL:

First Edition : September, 2007

Standard edition

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.

Dedication D edication V oices in this book may be many; but the concerns and convictions

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.


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-



1 contamination control


2 cleanroom


3 classification of air cleanliness


4 entry and exit of personnel


5 cleanroom disciplines


6 human interface in cleanrooms


7 laminar airflow


8 good biosafety practices


9 cGMP & you: personnel in drug and device manufacture


10 guidelines governing personnel in drug & device manufacture


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.

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.


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:

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:


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).

Particles that cause damage by virtue of their physical










Bacteria Fungus Spore Pollen Virus Human skin cells

Thermal Light Electromagnetic (EMI) Electrostatic (ESD) Radiation Electrical (RF)




Inorganic salts


Acids, Bases



Fly ash

Moisture, Vapour

Mist, Fume



Table 1: Classification of contaminants


cleanroom operators’ manual

Biological: Microorganisms and endotoxins


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

Transport Contact Retention Source
Transport Contact Retention Source
Transport Contact


Transport Contact Retention Source


Figure 1: The contaminant pathway

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


next drug product because of inadequate cleaning.


Raw Materials, Components, Consumables

* Microflora

* Impurities

* Fibers, dust, cleaning residues and other particles

* Moisture



* Poor choice of materials of construction

* Improper or inadequate surface treatment

* Inadequate cleaning; cleaning residues

* Improper or inadequate maintenance


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


* Gases & Compressed air

cleanroom operators’ manual

- Microflora and Endotoxins

- Oil droplets, dust and other particles



* 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


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.

contamination control contamination control 19 Figure 3: An integrated approach to contamination control I have personally


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

We can then design a contamination control

the product or process.

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.


cleanroom operators’ manual

Preventing ingress

Preventing ingress of contaminants into the selected work area.


Raw Materials, Components, Consumables

* Vendor qualification

* Limits on Impurities

* Primary and Secondary packaging

* Proper storage

* Proper sampling, testing and dispensing



* Appropriate choice of materials of construction

* Appropriate surface treatment

* Adequate cleaning; and cleaning validation

* Proper and timely maintenance


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


Number of Particles /m 3 in Outdoor Air

- Task-specific air




a clean





air workstation or “tent” in a cleanroom

> 0.1


× 10 10


× 10 9


× 10 8




> 0.3


× 10 8


× 10 7


× 10 7





> 0.5


× 10 7


× 10 6


× 10 6

treatment, storage and




Table 2: Air quality

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 D Outside environment C B A KKKKK XXXXX Cleanroom LLLLL TTTTT
Facilitating egress
Outside environment

Figure 4: Fortifying the work space

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


cleanroom operators’ manual 22 cleanroom operators’ manual Figure 5: Typical cleanroom design dilution can be employed: clean

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 harm’s 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.

contamination control


What remains inside is subjected to careful control: the premises, the utilities, the equipment, the process and the operators.

Coping with residual contaminants

Basic Airborne Contamination Control Techniques

Preventing Ingress


Select class of air cleanliness

appropriate for the task


Select location and layout optimising flowpaths for men, material and process


avoid loops in flowpaths


isolate through barriers


avoid direct / straight through access


stagger doorways


no windows on external wall


double-glazed view panels with breathers


Sustain overpressure along clean-to- dirty axis, where not contraindicated


Impose entry restrictions and thorough decontamination procedures for men, material and equipment

Facilitating Egress


Sustain overpressure along clean-to-

dirty axis, where not contraindicated


Avoid surfaces that can accumulate dust; where unavoidable, ensure easy accessibility to clean and disinfect


Implement comprehensive sanitation




Select material and equipment that don’t shed excessive particles or degas, especially walls, floor and ceiling



Establish sound maintenance for upkeep of facility


Operator training and discipline


Good gowning

Coping with


Dilution of aerosol concentration by dilution: increase in air change rate




Controlled velocity airflow without eddy currents to drag away suspended contaminants from critical zone: LAF


Reduce product exposure time and exposure frequency

Table 3: Basic airborne contamination control techniques

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.


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



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 classification

1 10





No. of particles/ft 3 > 0.5 m

1 10





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,


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 29 Figure 1 Types of clean areas Conventional . These cleanrooms are also known

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.


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.

the product, thus rendering all other factors less critical. Figure 2: Conventional cleanrooms vs Isolators These

Figure 2: Conventional cleanrooms vs Isolators

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:


31 cleanrooms 31 Figure 3: Isolator featuring half-suits 1. Increased air supply: An office or shop

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.


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 µm/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 µm, > 5.0 µm 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 ³ 0.5 µm being dispersed per minute.



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


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 operator’s 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 person’s manipulations or large pieces of machinery.


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.

the system and prevent the ingress of outside contamination. Figure 4: Rapid Transport Ports featuring -

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.


classification of "air cleanliness"

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?

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.


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.

of 5 particles would be less than 700 per cubic foot.   Number of Particles /m

Number of Particles /m 3 in Outdoor Air







> 0.1


× 10 10


× 10 9


× 10 8

> 0.3


× 10 8


× 10 7


× 10 7

> 0.5


× 10 7


× 10 6


× 10 6

Table 1: Air quality curves

classification of air cleanliness

ISO 14644-1


classification of air cleanliness ISO 14644-1 39 Classification   Maximum concentration limits



Maximum concentration limits (particles/m 3 of air) for particles equal to and larger than the considered sizes shown below


























10 000

2 370

1 020




100 000

23 700

10 200







000 000

237 000

102 000








352 000

83 200

2 930



520 000

832 000

29 300



200 000


320 000

293 000

Table 2: ISO 14644-1 airborne particulate cleanliness classes for cleanrooms and clean zones.

The ISO air cleanliness classification scheme is based on the formula:



1O N (0. 1 /D) 2.08





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



ISO classification number



Considered particle diameter in m



a constant with the dimension m


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 standard’s 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)”

where :

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”

where :

x =



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



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 20 m 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

Test Parameter


Maximum Time Interval Test Procedure

Particle Count Test

<= ISO 5 > ISO 5 All Classes

6 Months

ISO 14644-1

12 Months

Annex A

Air Pressure

12 Months

ISO 14644-1


Annex B5


All Classes

12 Months

ISO 14644-1


Annex B4


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).

Table 4: Strategic Testing (Optional)

Schedule of additional optional tests




Test Parameter


Time Interval

Test Procedure

Installed Filter

All Classes



ISO 14644-3



Annex B6


All Classes



ISO 14644-3



Annex B4


All Classes



ISO 14644-3


Annex B13


All Classes



ISO 14644-3



Annex B7

Other tests may optionally be included in the requalification programme as agreed between customer and supplier such as:

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;


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.

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.)


medicinal products


manufacture of sterile

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.


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



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.

classification of air cleanliness

47 classification of air cleanliness 47 Table 5: Classification of air cleanliness Notes: (a) In

Table 5: Classification of air cleanliness




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.


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,


6.5, ISO 8.


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-

the table for the “at-rest” state should be achieved in the unmanned state after a short


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:


monitoring of clean areas in operation: Notes: (a) These are average values (b) Individual settle plates

(a) These are average values (b) Individual settle plates may be exposed for less than 4 hours

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.


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.


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.

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.


cleanroom operators’ manual


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.


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.

classification of air cleanliness

WHO - airborne viable count


of air cleanliness WHO - airborne viable count 53 Schedule M - airborne viable count Grade

Schedule M - airborne viable count


Air sample

Settle plates (dia. 90 mm) Cfu/m 3

Contact plates (dia 55mm) cfu per plate

Glove prints (five fingers) cfu per glove

Cfu/m 3


< 1

< 1

< 1

< 1

















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

in Grade A area. USFDA: airborne viable & non-viable Air classifications a a- All classifications based

Air classifications a

a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.

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.


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.

Values represent recommended levels of environmental quality.


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 person’s 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.


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

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


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

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 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:


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.

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 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.

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


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

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 ³ 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


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 don’ts’ 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

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.

Austin’s Index of contaminants shed by personnel: Particle dispersion in relation to movement

Viable contaminants


Particles > 0.3

emitted per minute generated per minute

Standing or sitting without movement



Light head, hand & forearm movement



Moderate body and arm movement



Changing positions - sitting to standing



Slow walking



Moderate walking



Fast walking



Climbing stairs




> 15,000,000



> 15,000,000

> 30,000

Sneezing (excluding large droplets)



> 50,000


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

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


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


· 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.

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


· 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 66666 human interface in cleanrooms C K Moorthy A cleanroom is a special environment constructed

C K Moorthy

66666 human interface in cleanrooms C K Moorthy A cleanroom is a special environment constructed at
66666 human interface in cleanrooms C K Moorthy A cleanroom is a special environment constructed at

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


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.

wastes, just as in any common continuous processing plant. Figure 1: Contaminant density profile Thus having

Figure 1:

Contaminant density profile

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

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.

Austin’s Index of contaminants shed by personnel


Particles > 0.3F emitted per minute*





per minute*

Standing or sitting without movement Light head, hand & forearm movement Moderate body and arm movement Changing positions - sitting to standing Slow walking Moderate walking Fast walking Climbing stairs Calisthenics Coughing Sneezing (excluding large droplets)

















$ 15,000,000


$ 15,000,000

$ 30,000

$ 30,000,000

$ 50,000

* These figures refer not to contaminant density but to gross contaminant rate

Table 1:

Austin’s contamination index

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


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.


Human Bioprofile



Aerobic flora

Anaerobic flora





Forehead Sternum Subclavicular area Centre back Shoulder Deltoid area Forearm Palm Lower axilla Lumbar area Periumblical area Thigh upper front Thigh lower front Thigh back Shin Calf Dorsum of foot Sole









































































Table 2:

Human bioprofile

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;

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.

from eyes, ears, and nose; coughs, colds and sneezes; and, of course, menstrual periods. Figure 2:

Figure 2:

Smokers’ exhalation


cleanroom operators’ manual

Data published in Ljungqvist and Reinmuller’s 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.

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.

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

human interface in cleanrooms


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.

Figure 3: Convective air currents surround body
Figure 3:
Convective air currents surround body

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

Starting from the

water they wash with; the soaps they use; the towels and napkins; the

carriers of contaminants that are extrinsic to them.


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

in the airflow field, and depending on how they move, they Figure 4: Contamination level inceases

Figure 4:

Contamination level inceases with people

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.

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

Class ISO






















Lab coat

Lab coat


















Per entry





Table 3:

Selection and use of cleanroom garments

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


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,

human interface in cleanrooms




Static Dissipative*





99.5% - 96% DACRON+ 0.5% - 4% CARBON filament polymer yarn Standard/Taffetta weave non-linting

100% DACRON 80d/150d filament polymer yarn in standard plain weave

Lint character




gms/sq m


- 135 gm/sq m



x 30/sq cm


x 25/sq cm

Break strength


Kg/25 mm width


Kg/25 mm width


80% of rupture

80% of rupture



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



Resists acid

Resists acid



0.005 mps/sq ft


0.005 mps/sq ft


1 CFM/sq ft @ 25 mm wc

> 80% down to 0.5


1 CFM/sq ft @ 25 mm wc

> 80% down to 0.5



> 98% down to 5.0

> 98% down to 5.0







Taber abrasion (% fibre loss)

0.6% (unlaundered)

0.6% (unlaundered)


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

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.

Many prefer other colours to “hide”

soil. This is not good cleanroom practice.

should be able to spot soiled garments and discard such garments.

Other colours are in popular use.

The operator or supervisor


cleanroom operators’ manual

Figure 5: Washing soiled contamination control apparel

12 3

Sort & Group







4 5


Removal 1

Spotting &


Antiseptic 2

7 6

Spin Dry

Final Rinse


Main Wash

Main Wash

Liquid Additives 5

Cold Water

Water 60 0 C Liquid Detergent 4

Solvent 3


Air Dry under Class 100 Laminar Airflow (LAF) 6

12 13

14 15

Press & Double

Autoclave in

Store in



Wrap under Class 100 LAF




1. Hyglo, Teepol, Clinitol, or CCl

2. Savlon, Dettol/Iteol, Hydrogen peroxide or Peracetic acid

3. Perchloroethylene, Trichloroethylene or Mineral turpentine


4. Ezee, or Genteel

5. Antistatic agent, Optical whitener, Fabric softener (Carboxymethyl cellulose 5% v/v)

6. Class M6.5 (100,000) or better

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

more effective. good cleanroom garment tailoring practice Figure 6: Correct tailoring After you have selected the

Figure 6:



garment tailoring practice Figure 6: Correct tailoring After you have selected the fabric, you decide on

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