good cleanroom practices_a manual for cleanroom personnel

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1 Basics of contamination control 2 Introduction to 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 11 Good sanitation practices in cleanrooms

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  • Good CleanrGood CleanrGood CleanrGood CleanrGood Cleanroom Practicesoom Practicesoom Practicesoom Practicesoom Practices

    a manual for cleanroom personnel

    c k moorthy

  • good cleanroom practices

    a manual for cleanroom personnel

  • good cleanroom practices

    a manual for cleanroom personnel

    c k moorthy

  • The frontiers of knowledge areconstantly changing, ever expanding.As information becomes available,changes in design approach,procedures, equipment and their usebecome necessary. The author andpublisher have, as far as it is possible,taken care to ensure that theinformation given in the text is bothaccurate and current. However,readers are strongly advised to confirmthat the information, especially withregard to drug and device manufacture,complies with current regulatory andcompendial expectations, legislationsand standards of practice.

    Published by:

    Center for GMP509C NCL-GodavariPipeline RoadJeedimetla POHyderabad 500 055eMail: [email protected]; [email protected]: www.cgxp.org

    First Edition : September, 2007

    Standard edition

    Printed in India

    Price: Rs 395.00

    All rights reserved. No part of this work may becopied, reproduced, adapted, abridged ortranslated, stored in a retrieval system, ortransmitted in any form or by any means,electronic, mechanical, photocopying, record-ing or otherwise, without the prior writtenpermission of the publisher

  • dedication

    Voices in this book may be many; but the concerns and convictionsremain the same: you hold the key to the ultimate success of anycontamination control or GMP initiative.This book is dedicated to you.

  • acknowledgement

    As in all my previous compilations, here also, I have drawninspiration and material from the ideas and works ofextraordinarily gifted authors and speakers, far too numerous tomention individually, and take this opportunity to record my sincereappreciation 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/NIH4th editionSelection and use of Biological Safety Cabinets, CDC/NIH 2nd editionEUGGMP/WHO/USFDA/Schedule M guidelinesDr W Whyte for his kind permission to reproduce sections from hisbook Cleanroom Technology Design, Testing and Operationpublished in 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).

  • contents

    1 contamination control 11

    2 cleanroom 23

    3 classification of air cleanliness 35

    4 entry and exit of personnel 53

    5 cleanroom disciplines 61

    6 human interface in cleanrooms 71

    7 laminar airflow 93

    8 good biosafety practices 105

    9 cGMP & you: personnel in drug and device manufacture 129

    10 guidelines governing personnel in drug & device manufacture 137

    11 good sanitation practices 187

  • Contaminants play an especially important role in the manufacture,manipulation or repair of such items as semiconductors, spacevehicles, 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 theOperation Theatre as a factory, the same engineering principles ofmicrocontamination control apply. The control of infectious airbornepathogenic organisms in hospital operating rooms and recovery wardscan be achieved in a manner identical to that used to protect againstairborne contaminants during pattern generation of semiconductordevices, or during aseptic manipulations with thermolabile injectibles.The risks of manufacture, of course, are different since the loss of ahuman life has consequences beyond economics. But the technicalapproaches to solving the problem remain similar.

    contamination control

    C K Moorthy

    11111

  • 14 cleanroom operators manual

    Contamination control is only a part of the larger Quality AssuranceInitiatives that aim to minimise the risk of producing a defective, andmaximise the probability of manufacturing a product "fit for use" or "fitfor purpose". By this token, contamination control is best described asa set of systems, practices and procedures that aspire to minimise theintroduction of a contaminant into a product or process.

    Contamination control can be compared to providing the highest levelof personal security to a VIP under threat. Depending on whether theVIP is the President of the United States of America, or of Sri Lanka, orof India, the group posing the threat differs. Once we know the identityof the VIP, we are better placed not only to anticipate the sources of thethreat, but also to know more about their origin, locations, motives andmodus operandi.

    The security steps we normally take are:

    1 Isolate the VIP2 Minimise his exposure, both in terms of duration and frequency3 Seek and destroy or immobilise those threatening his safety4 If his enemies are outside, we make it difficult for them to

    penetrate the protective barriers5 If they are already within, we flush them out6 We monitor those in his immediate proximity7 We advise the VIP not to antagonise anyone who may be around

    him, friend today, and foe tomorrow (Don't generate enemieswithin)

    8 Stay vigilant and cope

    In the context of contamination control, a product or process is what wetry to safeguard.

    A contaminant is defined as any substance or energy thatproduces an adverse effect on that product or process.

    Such a classification is purely contextual, without bearing on its absoluteworth. Just as the enemy of one VIP may not necessarily be an enemy ofthe next VIP, so too in contamination control. For example, mostprocesses 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 differentways:

  • 15contamination 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 ourproduct, and hence a legitimate cGMP concern. Contamination controlmeasures will make more sense once we understand the nature ofcontaminants and the contamination process.

    We begin with classification of contaminants.

    classification of contaminants

    Regarded from the standpoint of the type of damage they do,contaminants may be divided into subgroups:

    Physical: Particles that cause damage by virtue of their physicalproperties alone

    Chemical: Organic chemicals such as oils, fats, waxes, fluxes, paintsand plastics may react chemically with a product and changeits properties. Gases induce contamination (like oxidation)only in the gaseous phase. In contrast, vapours and mistscontaminate in the vapour phase; on condensation, in theliquid phase (like oil films); and, on subsequent evaporation,in the solid phase (residues).

    ENERGYSUBSTANCE

    Physical Chemical BiologicDustDirtGrit

    FibreLint

    Fly ash

    Organiccompounds

    Inorganic saltsAcids, BasesCondensates

    Moisture, VapourMist, Fume

    Smoke

    BacteriaFungusSporePollenVirus

    Human skin cells

    ThermalLight

    Electromagnetic (EMI)Electrostatic (ESD)

    RadiationElectrical (RF)

    Table 1: Classification of contaminants

  • 16 cleanroom operators manual

    Biological: Microorganisms and endotoxinsEnergy: 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 willtell you that the enemy may attempt a million times and fail; he needs tosucceed just once. In contrast, they must succeed each time. This is justas true with contamination control.

    On the flip side, the mere presence of a contaminant does notautomatically imply contamination. For contamination to occur, thecontaminant must first have its source; must then be transported andreach the product site; must make contact with the product; and must beretained by the product.

    If this process of contamination, known as the contaminant pathway, isbroken at any stage, contamination does not occur.

    For instance, if the source of the contaminant is absent; or, having asource, it is unable to access the product; or, having somehow managedto slip through, is prevented from making contact; or, even after having

    Retention

    Contact

    Source

    Transport

    Figure 1: The contaminant pathway

  • 17contamination control

    made contact, is not retained, or not allowed to be retained, contaminationdoes not take place, and the product is safe.

    Contamination control may then be viewed as an exercise that aims tobreak the contaminant pathway at one or more stages of thecontamination process.

    sources of contaminants

    Included contaminants emanate from raw materials and consumables;fluidised contaminants from utilities; suspended contaminants from theenvironment; settled contaminants from dust collecting surfaces; emittedcontaminants from machinery, moving parts and surfaces; shedded andtransferred contaminants from personnel. Cross-contamination occurswhen the active process ingredient of one product is carried forward tothe next drug product because of inadequate cleaning.

    O Raw Materials, Components, Consumables* Microflora* Impurities* Fibers, dust, cleaning residues and other particles* Moisture

    O Equipment* Poor choice of materials of construction* Improper or inadequate surface treatment* Inadequate cleaning; cleaning residues* Improper or inadequate maintenance

    O Environment & Utilities* Building materials and surface finishes* Temperature & Humidity* Light, radiation* Air

    - Microflora- Fibers, dust and other particles- Fumes, vapours and condensates

    * Water- Microflora and Endotoxins- Fibers, dust and other particles- Cleaning residues

  • 18 cleanroom operators manual

    * Gases & Compressed air- Microflora and Endotoxins- Oil droplets, dust and other particles

    O Human* Intrinsic contaminants

    - Biologic Factory* Extrinsic contaminants

    - Importer of contaminants- Transporter of contaminants- Generator of contaminants- Inducer of contamination

    Figure 2: Sources of contaminants in cleanrooms

    In fact, research into a large number of reported occurrences ofcontamination in well-designed and maintained clean rooms revealsthat in 5% of the cases it was due to contaminated raw materials; in10% through utilities and defective or soiled equipment, tools orimplements; in 5% due to faulty air filtration; and in 80% due to breachesin the product-person interface.Hence, contrary to popular belief, microcontamination control does notbegin and end with HEPA filters: it is only one of many concurrentinitiatives. Comprehensive microcontamination control requires aprogram that effectively integrates and orchestrates planned offensivemeasures on all four fronts. Pursuing one while ignoring others yieldssub-optimal results.

  • 19contamination control

    Figure 3: An integrated approach to contamination control

    I have personally seen many facilities where such "common sense" isconspicuous by its absence. The User forces me through a commendabledecontamination entry regimen, only to leave me watch in amazementthe impunity with which the trolley boy "gate crashes" from the materialentry; double-doored and air locked. No decontamination protocols applyto him, his trolley or their dirt-laden wheels, except on some neatlytyped SOP, stashed away in the recesses of a filing cabinet in theProduction Manager's Office.

    master plan for contamination control

    As mentioned at the outset, contamination control is much alikeprotecting 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 beingused. Our objective is to minimise the risk of its being contaminatedalong the way. We adopt a six-point strategy:

    Identifying the contaminant

    Our first exercise is in identifying the possible contaminants that threatenthe product or process. We can then design a contamination controlprogram that takes into account their characteristics and behaviouralpattern.

    Anticipating the contaminant

    Having identified the contaminants that are likely to compromise ourproduct or process, we focus on the possible sources from where theycould originate; and their mode of getting to the critical zone.

  • 20 cleanroom operators manual

    Preventing ingress

    Preventing ingress of contaminants into the selected work area.O Raw Materials, Components, Consumables

    * Vendor qualification* Limits on Impurities* Primary and Secondary packaging* Proper storage* Proper sampling, testing and dispensing

    O Equipment* Appropriate choice of materials of construction* Appropriate surface treatment* Adequate cleaning; and cleaning validation* Proper and timely maintenance

    O Environment & Utilities* Isolation of critical areas* Appropriate materials of construction and surface finishes* Entry restrictions and protocols* Entry decontamination protocols* Temperature & Humidity Control* Air

    - Air filtration- Differential Pressure- Airflow direction- Airflow Velocity at sub-turbulent level

    - Air Change Rate- Task-specific aircleanliness: a cleanair workstation ortent in a cleanroom

    * Water-

    Appropriatetreatment, storage anddistribution

    Size

    mDirty Normal

    > 0.1 1 1010 3 109 5 108

    > 0.3 3 108 9 107 2 107

    > 0.5 3 107 7 106 1 106

    Number of Particles /m3 in Outdoor Air

    Clean

    Table 2: Air quality

  • 21contamination control

    * Gases & Compressed air- Appropriate selection of system: oil-free compressor, piping

    and accessories- Appropriate in-line filtration

    O Human* Appropriate training* Proper personal hygiene* Proper gowns, gowning and decontamination* Proper discipline and comportment* High vigilance

    Facilitating egress

    Facilitate egress of suspended as well as settled contaminants fromwithin.

    The air distribution system should be designed to displace contaminatedair to the exterior as directly and rapidly as possible. The principle of

    Figure 4: Fortifying the work space

    Outside environmentD

    Cleanroom

    C

    B

    A

    XXXXXKKKKK LLLLL TTTTT

  • 22 cleanroom operators manual

    Figure 5: Typical cleanroom designdilution can be employed: clean air can be passed through the givenspace in sufficient quantities to flush out as much of the contaminantsgenerated within the space, and thinning out the concentration of the rest.

    An important corollary to control by dilution is an air distribution designthat maintains air velocity at sub-turbulent (LAF) levels to minimiserecirculating eddy currents.

    An imaginative, effective and implementable sanitation scheme, closelysupervised and monitored is another method of getting settledcontaminants out of harms way. Surfaces that gather dust should beavoided, or minimised where unavoidable; and all such surfaces shouldbe smooth and accessible for thorough cleaning.

    Minimising internal generation

    Minimise generation of contaminants within. We start by reducing thenumber 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.

  • 23contamination control

    O Select class of air cleanlinessappropriate for the task

    O Select location and layout optimisingflowpaths for men, material and processo avoid loops in flowpathso isolate through barrierso avoid direct / straight through

    accesso stagger doorwayso no windows on external wallo double-glazed view panels with

    breathersO Sustain overpressure along clean-to-

    dirty axis, where not contraindicatedO Impose entry restrictions and thorough

    decontamination procedures for men,material and equipment

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

    O Avoid surfaces that can accumulatedust; where unavoidable, ensure easyaccessibility to clean and disinfect

    O Implement comprehensive sanitationplan

    O Select material and equipment thatdont shed excessive particles or degas,especially walls, floor and ceiling

    O Establish sound maintenance forupkeep of facility

    O Operator training and disciplineO Good gowning

    O Dilution of aerosol concentration bydilution: increase in air change rate

    O Controlled velocity airflow withouteddy currents to drag away suspendedcontaminants from critical zone: LAF

    O Reduce product exposure time andexposure frequency

    Basic Airborne Contamination Control Techniques

    Coping withresidual

    contaminants

    MinimisingGeneration

    Facilitating Egress

    Preventing Ingress

    Table 3: Basic airborne contamination control techniques

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

    Coping with residual contaminants

  • The last of the techniques relates to coping with the residualcontaminants. Since deposition of suspended contaminants is a timedependent phenomenon, reducing exposure frequency and exposure timeof 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 toprotect the product.

  • an introduction to the design of clean andcontainment areas

    Author W Whyte has kindly allowed the reproduction from his bookCleanroom Technology Design, Testing and Operation publishedin 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).

    The cleanroom is a modern phenomenon. Although the roots ofcleanroom design and management go back more than 100 yearand are rooted in the control of infection in hospitals, the needfor a clean environment for industrial manufacturing is a requirementof modern society. The use of cleanrooms is diverse and shown below isa selection of products that are now being made in cleanrooms, or requirecontamination control facilities.

    It may be seen that the requirement for cleanrooms can be broadly dividedinto two. The first area is that in which inanimate particles (dust) are aproblem and where their presence, even in submicron size, may preventa product functioning or reduce its useful life. The second group requiresthe absence of microbe-carrying particles whose growth in the product(or in a hospital patient) could lead to human infection. It may also beseen that many of the examples given are recent innovations and thislist will certainly be added to in the future, there being a considerableincrease in the demand for these types of rooms.

    22222

  • 26 cleanroom operators manual

    some clean and containment room applications

    Electronics: Computers, TV tubes, Flat screens, Magnetic tapeproduction

    Semiconductors: Production of integrated circuits used in computermemory 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 asminimising the airborne contamination it may be necessary to containdangerous or toxic contamination within the room. This is done bycontainment rooms.

    Clean and containment rooms will be individually designed accordingto their application, but there are a number of basic similarities anddesign concepts that should be discussed before reading further chaptersof this book. These concepts consider the special requirements ofindustries such as microelectronics, pharmaceuticals, medical devicesand biotechnology.

    what is a cleanroom?

    It is clear that a cleanroom is a room that is clean. However, a cleanroomnow has a special meaning and it is defined in Federal Standard 209E as:

    A room in which the concentration of airborne particles is controlledand 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 theintroduction, generation, and retention of particles inside the room and

  • 27cleanrooms

    in which other relevant parameters, e.g. temperature, humidity, andpressure, are controlled as necessary.

    classification of cleanrooms

    Cleanrooms are classified by the cleanliness of their air. The methodmost easily understood and universally applied is the one suggested inversions of Federal Standard 209 (up to edition D). In this standardthe number of particles equal to and greater than 0.5 m is measured inone cubic foot of air and this count is used to classify the room.

    A classification of cleanrooms according to the older Federal Standard209D is given in a simplified form in Table 1Table 1: A simplified Federal Standard 209D classification of

    cleanrooms

    Fed Std 209D 1 10 100 1000 10000 100000classificationNo. of particles/ft3 1 10 100 1000 10000 100000> 0.5 m

    This Federal Standard was superseded by a metric version (FederalStandard 209E) which was published in 1992. However, because of itssimplicity and universal use, it will be many years before the older FederalStandard 209D classification is forgotten. It is also likely that FederalStandard 209D nomenclature will not be superseded by Federal Standard209E 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 ofcleanroom is dependent on the particle-generating activities going onin the room. If a room is empty, very low particle concentrations can beachieved, these closely reflecting the quality of air supplied and hencethe removal efficiency of the high efficiency filter. If the room hasproduction equipment in it and operating, there will be a greater particleconcentration but the greatest concentration will occur when the roomis in full production. A classification of the room may therefore be carriedout when the room is:

    as built: condition where the installation is complete with all servicesconnected and functioning but with no production equipment, materials,or personnel present,

  • 28 cleanroom operators manual

    at rest: condition where the installation is complete with equipmentinstalled and operating in a manner agreed upon by the customer andsupplier, but with no personnel present,

    operational: condition where the installation is functioning in thespecified manner, with the specified number of personnel present andworking in the manner agreed upon.

    class of rooms required by different industries

    The required standard of cleanliness of a room is dependent on the taskperformed in it; the more susceptible the product is to contaminationthe better the standard. The following list gives an indication of thetasks carried out in different classifications of cleanrooms. Thesesuggested classifications are only an indication of what might be usedand care must be taken not to overdesign by providing cleaner thannecessary rooms as this has a big influence on cost.

    possible cleanroom requirement for various tasks carried outin cleanrooms

    Class 1: These rooms are only used by integrated circuit manufacturersmanufacturing sub-micron geometries

    Class 10: These rooms are used by semiconductor manufacturersproducing integrated circuits with line widths below 2 mm

    Class 100: Used when a bacteria-free or particulate-free environment isrequired in the manufacture of aseptically-produced injectable medicines.Required for implant or transplant surgical operations. Isolation ofimmunosuppressed patients, e.g. after bone marrow transplant operations

    Class 1000: Manufacture of high quality optical equipment. Assemblyand 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 adiagrammatic form in Figure 1 and are as follows:

  • 29cleanrooms

    Figure 1 Types of clean areas

    Conventional. These cleanrooms are also known as turbulently-ventilatedor non-unidirectional flow and are distinguished by their method of airsupply. This is of the conventional type, the air being supplied by airsupply diffusers or filters in the ceiling.

    Unidirectional flow. This was previously known as laminar flow. Cleanair is supplied from a bank of high efficiency filters and passes in aunidirectional manner through the room.

    Mixed flow. This type of cleanroom is conventionally ventilated butwhere the product is exposed to contamination, a unidirectional flowcabinet or workstation is used.

  • 30 cleanroom operators manual

    Isolators or microenvironment. Conventional design exposes the productand focuses controls on all else. The Isolator design focuses on what ismost important: the immediate environment around the product, thusrendering all other factors less critical.

    These are used within a cleanroom to give the highest level of protectionagainst contamination. See Figure 2. As seen in Figure 3, the isolator isshown to have a unidirectional supply of air but this may be a conventionalturbulent-flow type. Similarly, gauntlets are shown, but half suits arealso used.

    conventionally ventilated cleanrooms

    The general method of ventilation used in a simple conventionallyventilated type of cleanroom is similar to that found in offices, shops,etc. in that air is supplied by an air conditioning plant through diffusersin the ceiling. However, a cleanroom differs from an ordinary ventilatedroom in a number of ways:

    Figure 2: Conventional cleanrooms vs Isolators

  • 31cleanrooms

    Figure 3: Isolator featuring half-suits1. Increased air supply: An office or shop will be supplied with sufficientair to achieve comfort conditions; this may be in the region of 2 to 10 airchanges per hour. A typical conventionally ventilated cleanroom is likelyto have between 20 and 60 air changes per hour. This additional airsupply is mainly provided to dilute to an acceptable concentration thecontamination produced in the room.

    2. High efficiency filters: A cleanroom uses filters much more efficientthan those used in offices etc. Cleanroom filters would normally be greaterthan 99.97% efficient in removing particles greater than 0.3 m fromthe room air supply. These filters are known as High Efficiency ParticleAir (HEPA) filters although Ultra Low Particle Air (ULPA) filters, whichhave a higher efficiency, are used in microelectronic fabrication areas.

  • 32 cleanroom operators manual

    3. Terminal air filters: The high efficiency filters used in cleanroomsare installed at the point of air discharge into the room. In air conditioningsystems used in offices, etc. the filters will be placed directly after theventilation plant but particles may be induced into the air supply ductsor come off duct surfaces and hence pass into the room.

    4. Room pressurisation and pass-through grilles: To ensure that airdoes not pass from dirtier adjacent areas into the cleanroom, thecleanroom 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 correctpressure and allow a designed movement of air from the cleanest to theless clean rooms in a suite, pass-through grilles or dampers will usuallybe seen at a low level on walls or doors.

    Another indication that the room is a cleanroom is the type of surfacefinish in a room. The room will be constructed of materials which donot generate particles and are easy to clean. Surfaces will be constructedso 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 isdependent on the amount and quality of air supplied to the room and theefficiency of mixing of the air. Generally speaking, a cleanroom willhave sufficient air supply to achieve good mixing and the air quality ofthe room will therefore only depend on the air supply quantity and quality.It is important to understand that the cleanliness of a conventionallyventilated cleanroom is dependent on the volume of air supplied perunit of time and not the air change rate.

    The cleanliness is also dependent on the generation of contaminationwithin the room. i.e. from machinery and individuals working in theroom. The more people in the cleanroom, the greater their activity andthe poorer their cleanroom garments the more airborne contaminationis generated. People moving about with poor cleanroom garments suchas smocks or laboratory coats will generate, on average, about 2 x 106particles > 0.5 m/min, about 300 000 particles > 5.0 m/min, andabout 160 bacteria-carrying particles per minute. If people wear welldesigned clothing (coverall, knee-length boots, hood, etc.) made fromtightly woven cloth the reduction of particles > 0.5 m, > 5.0 m andbacteria-carrying particles will be about 50%, 88% and 92%, respectively.Little information is available about the generation of particles frommachinery used in cleanrooms but this may account for hundreds tomillions of particles 0.5 m being dispersed per minute.

  • 33cleanrooms

    If the efficiency of the supply filters can be assumed to be close to 100%in removing the airborne contamination being considered, a roughapproximation of the likely airborne cleanliness of a conventionallyventilated cleanroom (not a unidirectional flow one) can be achieved byuse of the following equation:

    Airborne concentration = Number of particles (or bacteria) generated/min(count/ft3 or m3) Air volume supplied* (ft3 or m3/min)

    *including that from unidirectional flow work stationsCleanrooms ventilated in this conventional turbulent manner may achieveconditions as low as ISO 6 (Class 1000) during manufacturing but aremore likely to be ISO 7 (Class 10 000). To obtain cleaner rooms, greaterdilution of the particles generated is necessary and this can be achievedby a unidirectional flow of air.

    unidirectional airflow cleanrooms

    Unidirectional airflow is used when low airborne concentrations ofparticles of bacteria are required. This type of cleanroom was previouslyknown as laminar flow with a horizontal or vertical air flow at a uniformspeed of between 0.3 and 0.45 m/s (60 to 90 ft/min) and throughout theentire air space.

    The air velocity suggested is sufficient to remove relatively large particlesbefore they settle onto surfaces. Any contaminant generated into the aircan therefore be immediately removed by this flow of air, whereas theconventional turbulently ventilated system relies on mixing and dilutionto remove contamination. In a theoretical situation in an empty roomwith no obstructions to the airflow, contamination could be quicklyremoved to the exhaust by air velocities much lower than those mentionedabove. However in a practical situation there are obstructions and peoplemoving about. Obstructions will cause the unidirectional flow to be turnedinto turbulent flow and air vortexes to be established around theobstructions. Movement of people will also turn unidirectional intoturbulent flow. Higher contamination concentrations will be establishedin these turbulent areas. It is therefore necessary that the velocity is inthe region of 0.3 to 0.45 m/s (60 to 90 ft/min) so that the disruptedunidirectional flow can be quickly reinstated and the contaminationaround the obstructions be adequately diluted.

    Unidirectional airflow is correctly defined in terms of air velocity, thecleanliness of a unidirectional room being directly proportional to theair velocity. Air changes per unit of time should not be used with a

  • 34 cleanroom operators manual

    unidirectional flow room as they are related to the volume of the room,which generally has no effect on the performance of the system.

    The air volumes supplied to unidirectional flow rooms are many times(10-100) greater than those supplied to a conventionally ventilated room.They are therefore very much more expensive in capital and running costs.

    Unidirectional flow rooms are of two general types, namely horizontalor vertical flow. In the horizontal system the air flow is wall-to-wall andin the vertical system it flows from ceiling-to-ceiling.

    In a typical vertical flow type of cleanroom, the air is supplied from acomplete bank of high efficiency filters in the roof and this flows verticallythrough the room and out through open grilled flooring. Air in thisfigure is shown to flow through the complete area of a floor but it iscommon to find rooms in which the air returns through grilles whichare distributed about the floor. If the floor area is not too great, grillescan alternatively be placed at a lower level in the walls. The exhaust airis recirculated, mixed with some fresh make-up air, and supplied to theroom through the high efficiency filters in the room ceiling.

    Most unidirectional cleanrooms are built in a vertical manner as particlesgenerated within the room will be quickly swept down and out of theroom. Less popular is the horizontal flow type of cleanroom.

    This type of cleanroom is not so popular because any contaminationgenerated close to the filters will be swept down the room and couldcontaminate work processes downwind. However as the area of a wallin a room is usually much smaller than the ceiling the capital and runningcosts are less. If the cleanroom can be arranged so that the most criticaloperations are close to the supply filters and the dirtier ones at the exhaustend, then this type of room can be successful.

    mixed flow rooms

    This type of room is a conventional flow room in which the criticalmanufacturing operations are carried out within a higher quality of airprovided by a unidirectional flow system, e.g. a bench. This mixed typeof system is very popular as the best conditions are provided only wherethey are needed and considerable cost savings are available for use inthis room, being one of the simplest and most effective methods ofcontrolling contamination. In this bench the operators contaminationis kept downwind of the critical process. Also available are a variety ofstyles of vertical flow systems which may vary in size to encompass apersons manipulations or large pieces of machinery.

  • 35cleanrooms

    isolator or minienvironments

    Hazardous work with toxic chemicals or dangerous bacteria has beencarried out for many years in glove boxes. Work on germ-free animalshas also been carried out for decades in plastic isolators which preventedthe entrance of micro-organisms. These contaminant-retaining andcontaminant-excluding systems do not principally depend on airflowfor isolation but walls of metal and plastic. This principle of isolationclearly has excellent barrier properties and it has now been developedfor use in modern cleanroom technology. In the pharmaceuticalmanufacturing area this technology is generally known as isolator orbarrier technology, whereas in the semiconductor industry it is generallyknown as minienvironments.

    Figure 3 shows the various components of an isolator. It may be seenthat there is a physical barrier to outside contamination, and personneleither enter into half suits or use gauntlets to work at the clean processeswithin the isolators. The air within the isolator is sterile and particle-free having been filtered by high efficiency filters; this air is also used topressurise the system and prevent the ingress of outside contamination.

    Figure 4: Rapid Transport Ports featuring - - doors

  • The containers and product cab enter and depart the isolator systemthrough a sterilising tunnel, pass through tunnel or docking transferdevice.

    Another system, which is used in semiconductor manufacturing, is theSMIF (Standard Mechanical Interface Format) system. In this systemsilicon wafers are transported between machines in special containerswhich prevent the wafers being contaminated by the air outside. Thesecontainers, which contain the wafers, are slotted into the machineinterface, the wafers processed and then loaded onto another containerwhich can be taken to another machine and loaded into its interface.

  • We 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 theword in its literal sense. Intuitively we understand the term in its relativesense. For example, a city is clean with plenty of clean parks, cleanbuildings and clean roads. And your clean crockery on your clean diningtable in your clean home. Do we imply all are equally clean? No. Thedegree of soil we subconsciously discount is contextual to each case.That is why we would never set our buttered toast on the clean road, orperform surgery in the clean park. So how clean is clean?

    To translate this qualitative concept to a quantifiable parameter forenvironment control, scientists measure the suspended contaminantdensity, or number of suspended particles per unit volume. The lowerthe contaminant density, the cleaner the environment.

    classification of "air cleanliness"

    C K Moorthy

    33333

  • 38 cleanroom operators manual

    We begin by determining or estimating the suspended contaminantdensity in a given room or at the work point of interest. Typically thislies in the range of 10 million (107) to 100 billion (1011) per litre ofatmospheric air. Ideally we would like to get rid of all of them. Butthat will cost money, and the proposition may not be financiallyviable. Fortunately, this extreme level of cleanliness is not warranted.Hence, we try to assess the maximum aerial contaminant density thatthe process can be carried out at risk levels that are acceptable and cost-effective: an environment "clean" enough for the intended purpose.

    Statistics hasestablished thatairborne particleprofiles in clean,semi-clean anddirtyenvironmentswere mathe-matically pre-dictable, andequations couldbe established bywhich measure-ment of thenumber of anyone particle sizepresent in airwould provideindirect estimateof the number ofany other particlesize. If there wereless than 100,000particles of size0.5, or largerper cubic foot ofair measured,then it could beassumed that thenumber of 5particles wouldbe less than 700per cubic foot.

    Size

    mDirty Normal

    > 0.1 1 1010 3 109 5 108

    > 0.3 3 108 9 107 2 107

    > 0.5 3 107 7 106 1 106

    Number of Particles /m3 in Outdoor Air

    Clean

    Table 1: Air quality curves

  • 39classification of air cleanliness

    ISO 14644-1

    The ISO air cleanliness classification scheme is based on the formula:Cn = 1ON (0. 1 /D)2.08 .....(1)

    WhereCn = Maximum number concentration of particles per m3

    with diameter equal to or larger than the consideredparticle diameter, rounded to the nearest wholenumber, using no more than three significant digits

    N = ISO classification numberD = Considered particle diameter in m0.1 = a constant with the dimension m

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

    Classification Maximum concentration limits (particles/m3 of air) for particlesNumber equal to and larger than the considered sizes shown below

    (N) 0.1 0.2 0.3 0.5 1 5.0

    ISO 1 10 2ISO 2 100 24 10 4ISO 3 1 000 237 102 35 8ISO 4 10 000 2 370 1 020 352 83ISO 5 100 000 23 700 10 200 3 520 832 29ISO 6 1 000 000 237 000 102 000 35 200 8 320 293ISO 7 352 000 83 200 2 930ISO 8 3 520 000 832 000 29 300ISO 9 35 200 000 8 320 000 293 000

  • 40 cleanroom operators manual

    Note : Uncertainties related to the measurement process require thatconcentration data with no more than three significant figures be usedin determining the classification level.

    With the selection of 0.1 m as the reference particle diameter for aircleanliness classification a very straightforward denomination schemeresults - thus overcoming elegantly the principal drawback of the metricair cleanliness classes according to U.S. Federal Standard 209E. Simple,single-digit class denominations now correspond with the traditionalclasses of said standard: ISO 5, for example, replaces Class 100, andISO 8 substitutes Class 100 000.

    The exponent 2.08 of the correlation between particle concentration andparticle diameter ensures the best possible co-incidence with the particleconcentrations according to U.S. Federal Standard 209E at that standardsreference particle diameter of 0.5 m. Thus, a harmonious connectionto 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 thesize range of particles applicable to classification. Descriptors have beenintroduced for coping with such situations as follows:

    the U descriptor for ultrafine particles below 0.1 m; the M descriptor for particles above 5 m

    The U descriptor is expressed in the format : (x : y) .....(2)where :x = the maximum permitted concentration of ultrafine particles,

    expressed as the number of ultrafine particles per m3 of airy = the lower detection limit, i.e. the particle size in m at which

    the applicable discrete particle counter - for example, acondensation nucleus counter - is capable of detecting suchparticles with 50 % counting efficiency

    The M descriptor is expressed in the format : M (a;b);c .....(3)where :a = the maximum permitted concentration of macroparticles,

    expressed as the number of macroparticles per m3of airb = the equivalent diameter (or diameters) associated with the

    specified method for measuring macroparticlesc = the specified method for measuring macroparticles

  • 41classification 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 Mdescriptor is new. In determining M descriptors, the difficulties ofsampling and assessing large particles has to be taken into considerationas well as the fact that large particles are normally process -generated.For these reasons the identification of the sampling device and evaluationprocedure should be addressed on an application-specific basis. Factorssuch as the density, shape, volume and aerodynamic behaviour of theparticles need to be taken into account. For describing for instance, anairborne macroparticle concentration of 1 000 particles/m3 in the particlesize range of 10 to 20m using a cascade impactor for sampling and amicroscopic sizing and counting procedure for evaluation, thedesignation would be : M (1 000; 10-20 m m) : cascade impactorfollowed by microscopic sizing and counting

    Under certain circumstances it may be necessary, to put special emphasison specific components of the total airborne particle population, such asfibres. Fibres for instance, may be accounted for by supplementing theM descriptor with a separate descriptor for fibres, having the formatMfibre (a;b); c.Cleanroom Testing to prove continued Compliance

    At periodic intervals, cleanroom systems should be subjected to a formalrequalification procedure. The rules are established in another documentof the ISO series of cleanroom technology standards: ISO 14644-2.

    Unlike the earlier years where specific values were specified for criticalparameters (for example, Air Velocity for Laminar Airflow should be100 fpm etc) the current standard leaves fixing and determining

    Table 3 : Strategic Testing (Required)Schedule of Mandatory tests to demonstrate continuing compliance

    MaximumTest Parameter Class Time Interval Test Procedure

    Particle Count Test ISO 5 12 Months Annex A

    Air Pressure All Classes 12 Months ISO 14644-1Difference Annex B5Airflow All Classes 12 Months ISO 14644-1

    Annex B4

  • 42 cleanroom operators manual

    parametric values entirely to be decided and mutually agreed by theBuyer and Vendor.

    ISO 14644-2 determines the type and frequency of testing required toconform to the standard. Table 3 indicates which tests are mandatoryand Table 4 indicates which tests are optional.

    Special Note :

    1. Where the installation is equipped with facilities for continuous orfrequent monitoring of the airborne particulate concentrations and ofthe differential pressure between rooms, the maximum time interval forthe normative tests may be extended to 24 months.

    2. In the context of ISO 14644-2, frequent monitoring means thatmeasurements should be updated at specified intervals not exceeding60 minutes during utilisation of the cleanroom, ie. in its operationalstate.

    According to this standard, this requalification should comprise at leastthe following normative tests:

    verification of the air cleanliness class; verification of pressure differences between rooms; a verification of the air velocity (for displacement airflow) or of

    the airflow rate (for turbulent air-flow).

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

    Table 4: Strategic Testing (Optional)Schedule of additional optional tests

    MaximumTest Parameter Class Time Interval Test ProcedureInstalled Filter All Classes 24 Months ISO 14644-3Leakage Annex B6Containment All Classes 24 Months ISO 14644-3Leakage Annex B4Recovery All Classes 24 Months ISO 14644-3

    Annex B13Airflow All Classes 24 Months ISO 14644-3Visualization Annex B7

  • 43classification of air cleanliness

    a leakage or integrity test for the HEPA filters of the cleanroomsystem;

    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 shouldbe performed at intervals not exceeding 6 months for cleanrooms ofISO class 5 and below, and at intervals not exceeding 12 months forcleanrooms of class 6 and above. This maximum interval of 12 monthsalso applies for the other normative compliance tests listed above. Wherethe installation is equipped with facilities for continuous or frequentmonitoring, of the airborne particulate concentrations and of thedifferential pressure between rooms, the maximum time interval for thenormative tests may be extended to 24 months. In the context of ISO14644-2, frequent monitoring means that measurements should beupdated at specified intervals not exceeding 60 minutes during utilisationof the cleanroom. i.e. in its operational state.

    What is most baffling, however, is the fact that the standard shouldcatogorise a test as Optional and in the same breath specify a scheduleindicating the maximum time interval between tests. Perhaps it wouldhave been prudent to leave the frequency of testing to the discretion ofthe User.

    Reporting :

    The results from testing cleanrooms for compliance with ISO 14644-1shall be recorded and submitted as a comprehensive report which shallinclude the following:

    the name and address of the testing organisation, and the date onwhich the test was performed;

    the number and date of the standard according to which the testwas 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 theindication of the co-ordinates of all sampling locations;

    the specified ISO air cleanliness class, the correspondingoccupancy state(s), and the considered particle size(s);

    details of the test method used, comprising also any specificconditions relating to the test, or departures from the test method;

  • 44 cleanroom operators manual

    identification of the test instrument(s) and its (their) currentcalibration certificate(s);

    the test results, including particle concentration data for allsampling location co-ordinates;

    a statement of compliance or non-compliance with the specifiedISO air cleanliness class.

    An important factor here would be evidence from the TestingOrganisation that they are deputing personnel who are qualified to carryout 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 pastfour 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 equivalentstandard for microorganisms was clearly needed, and efforts wererequired in this direction.

    It has been established that the level of microbial contamination of asepticproducts is directly proportional to the aerial microbial concentration inthe room. Though no universal relationship has yet been establishedbetween airborne contaminants and viable airborne contaminants, orbetween airborne bacteria-laden particles and airborne inanimateparticles, there may be some situation-specific relationship.

    ISO 14698, issued in three parts, recommends a system for bioaerosolmonitoring and control, but owing to the lack of consensus about whatmicroorganisms are acceptable for whom, and what their concentrationlimits ought to be for which application, the standard stops short bymerely stating that the User should define the target levels and derivethe acceptable tolerance limits from that set point.

    Both ISO 14644 and US Fed Std 209E base their tables on mathematicalformulae that follows the natural statistical distribution of suspendedparticles. In stark contrast, the authors drug and device regulatoryguidance documents have made no such basis or claim. As a happyaccident, some values appear to be in close agreement with thosecalculated from formulae advocated by ISO and USFed Std 209E.

    ISO was seriously contemplating a change to International StandardUnits and cubic metres, so drug regulators too decided to stay in step.

  • 45classification of air cleanliness

    They have not indicated how cubic metres of air samples are to bemeasured when all currently available instrumentation are designed fortaking air samples at the rate of one cubic foot per minute only. What isthe User supposed to do? Run the counter for 35.4 minutes for eachsample? Most counter reset at the end of each minute. Most countersare not designed for continuous monitoring, or even prolonged periodsof monitoring. Most users are not even aware of this inherent inadequacy.

    Why did ISO choose the cubic metre? If they wanted InternationalStandard Units, then why not litre? The existing classification asexpounded in US Fed 209E was proving inadequate for the semiconductorindustry. The highest grade specified is Class 1, a quality ofenvironment in which you cannot produce Pentium VI. Hence they werecompelled to shift to a smaller reference particle size: 0.1 micron ratherthan 0.5 micron. Also, at the pace at which the demand for cleaner andcleaner space is growing, the contaminant density would have to beexpressed as particles per larger unit volume: one cubic metre ratherthan just cubic foot. (Even the semiconductor industry is still at a lossas to how to sample this larger volume, and the standard Cleanroomsand Associated Controlled Environments, Part 3: Metrology and testmethods:14644-3 offers no answer either.)

    EUGGMP/WHO/TGA/PIC/Schedule M: manufacture of sterilemedicinal products

    Principle

    The manufacture of sterile products is subject to special requirements inorder to minimise risks of microbiological contamination, and ofparticulate and pyrogen contamination. Much depends on the skill,training and attitudes of the personnel involved. Quality Assurance bearsa particularly great importance and this type of manufacture must strictlyfollow carefully established and validated methods of preparation andprocedure. Sole reliance for sterility or other quality aspects must not beplaced on any terminal process or finished product test.

    Note: This Annex does not lay down detailed methods for determiningthe microbiological and particulate cleanliness of air, surfaces, etc.Reference is made to other compendia such as the CEN/ISO Standards.

    General

    1. The manufacture of sterile products should be carried out in cleanareas, entry to which should be through airlocks for personnel and/orfor equipment and materials. Clean areas should be maintained to an

  • 46 cleanroom operators manual

    appropriate cleanliness standard and supplied with air which has passedthrough filters of an appropriate efficiency.

    2. The various operations of component preparation, productpreparation and filling should be carried out in separate areas withinthe clean area. Manufacturing operations are divided into two categories;firstly those where the product is terminally sterilised, and secondlythose which are conducted aseptically at some or all stages.

    3. Clean areas for the manufacture of sterile products are classifiedaccording to the required characteristics of the environment. Eachmanufacturing operation requires an appropriate environmentalcleanliness level in the operational state in order to minimise the risksof particulate or microbial contamination of the product or materialsbeing handled.

    In order to meet in operation conditions these areas should bedesigned to reach certain specified air-cleanliness levels in the at-rest occupancy state.

    The at-rest state is the condition where the installation is completewith production equipment installed and operating but with no operatingpersonnel present. The in operation state is the condition where theinstallation is functioning in the defined operating mode with thespecified number of personnel working.

    For the manufacture of sterile medicinal products normally 4 gradescan 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 airflowworkstation. Laminar airflow systems should provide anhomogeneous air speed of 0.45 m/s +/- 20% (guidance value) at theworking position.Grade B: In case of aseptic preparation and filling the backgroundenvironment for Grade A zone.Grade C and D: Clean areas for carrying out less critical stages in themanufacture of sterile products.The airborne particulate classification for these grades is given in thefollowing table.

  • 47classification of air cleanliness

    Notes:(a) In order to reach the B, C and D air grades, the number of air

    changes should be related to the size of the room and theequipment and personnel present in the room. The air systemshould be provided with appropriate filters such as HEPA forgrades A, B and C.

    (b) The guidance given for the maximum permitted number ofparticles in the at rest condition corresponds approximately tothe US Federal Standard 209 E and the ISO classifications asfollows:grades A and B correspond with class 100, M 3.5, ISO 5; grade Cwith class 10 000, M 5.5, ISO 7 and grade D with class 100 000,M 6.5, ISO 8.

    (c) The requirement and limit for this area will depend on the natureof the operations carried out.

    Examples of operations to be carried out in the various grades are givenin the table below (see also para.11 and 12)The particulate conditions given in the table for the at-rest state shouldbe achieved in the unmanned state after a short clean up period of 15-

    Table 5: Classification of air cleanliness

  • 48 cleanroom operators manual

    20 minutes (guidance value), after completion of operations. Theparticulate conditions for grade A in operation given in the table shouldbe maintained in the zone immediately surrounding the product wheneverthe product or open container is exposed to the environment. It is acceptedthat it may not always be possible to demonstrate conformity withparticulate standards at the point of fill when filling is in progress, dueto the generation of particles or droplets from the product itself.

    4. In order to control the particulate cleanliness of the various gradesin operation, the areas should be monitored.

    5. In order to control the microbiological cleanliness of the variousgrades in operation, the areas should be monitored. Where asepticoperations are performed monitoring should be frequent using methodssuch as settle plates, volumetric air and surface sampling (e.g. swabsand contact plates). Sampling methods used in operation should notinterfere with zone protection. Results from monitoring should beconsidered when reviewing batch documentation for finished productrelease. Surfaces and personnel should be monitored after criticaloperations.

    Additional microbiological monitoring is also required outsideproduction operations, e.g. after validation of systems, cleaning andsanitation.

    Recommended limits for microbiological monitoring of clean areas inoperation:Notes:

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

  • 49classification of air cleanliness

    6. Appropriate alert and action limits should be set for the results ofparticulate and microbiological monitoring. If these limits are exceededoperating procedures should prescribe corrective action.

    Blow/Fill/Seal Technology

    10. Blow/fill/seal units are purpose built machines in which, in onecontinuous operation, containers are formed from a thermoplasticgranulate, filled and then sealed, all by the one automatic machine.

    Blow/fill/seal equipment used for aseptic production which is fitted withan effective grade A air shower may be installed in at least a grade Cenvironment, provided that grade A/B clothing is used. The environmentshould comply with the viable and non-viable limits at-rest and the viablelimit only when in operation. Blow/fill/seal equipment used for theproduction of products for terminal sterilisation should be installed inat least a grade D environment.

    Because of this special technology particular attention should be paid toat least the following: equipment design and qualification, validationand 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 ofthe equipment including any aseptic assembly prior to the commencementof filling.

    Terminally sterilised products

    11. Preparation of components and most products should be done in atleast a grade D environment in order to give low risk of microbial andparticulate contamination, suitable for filtration and sterilisation. Wherethere is unusual risk to the product because of microbial contamination,for example, because the product actively supports microbial growth ormust be held for a long period before sterilisation or is necessarilyprocessed not mainly in closed vessels, preparation should be done in agrade C environment.

    Filling of products for terminal sterilisation should be done in at least agrade C environment.

    Where the product is at unusual risk of contamination from theenvironment, for example because the filling operation is slow or thecontainers are wide-necked or are necessarily exposed for more than afew seconds before sealing, the filling should be done in a grade A zonewith at least a grade C background.

  • 50 cleanroom operators manual

    Preparation and filling of ointments, creams, suspensions and emulsionsshould generally be done in a grade C environment before terminalsterilisation.

    Aseptic preparation

    12. Components after washing should be handled in at least a grade Denvironment. 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 Aenvironment with grade B background.

    Preparation of solutions which are to be sterile filtered during the processshould be done in a grade C environment; if not filtered, the preparationof materials and products should be done in a grade A environment witha grade B background.

    Handling and filling of aseptically prepared products should be done ina 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 Aenvironment with grade B background or in sealed transfer trays in agrade B environment.

    Preparation and filling of sterile ointments, creams, suspensions andemulsions should be done in a grade A environment, with a grade Bbackground, when the product is exposed and is not subsequently filtered.

    Premises

    22. In clean areas, all exposed surfaces should be smooth, imperviousand unbroken in order to minimise the shedding or accumulation ofparticles or micro-organisms and to permit the repeated application ofcleaning agents, and disinfectants where used.

    23. To reduce accumulation of dust and to facilitate cleaning there shouldbe no uncleanable recesses and a minimum of projecting ledges, shelves,cupboards and equipment. Doors should be designed to avoid thoseuncleanable recesses; sliding doors may be undesirable for this reason.

    24. False ceilings should be sealed to prevent contamination from thespace above them.

    25. Pipes and ducts and other utilities should be installed so that they donot create recesses, unsealed openings and surfaces which are difficultto clean.

  • 51classification of air cleanliness

    26. Sinks and drains should be prohibited in grade A/B areas used foraseptic manufacture. In other areas air breaks should be fitted betweenthe machine or sink and the drains. Floor drains in lower gradecleanrooms should be fitted with traps or water seals to prevent back-flow.

    27. Changing rooms should be designed as airlocks and used to providephysical separation of the different stages of changing and so minimisemicrobial and particulate contamination of protective clothing. Theyshould be flushed effectively with filtered air. The final stage of thechanging room should, in the at-rest state, be the same grade as the areainto which it leads. The use of separate changing rooms for enteringand leaving clean areas is sometimes desirable. In general hand washingfacilities should be provided only in the first stage of the changing rooms.

    28. Both airlock doors should not be opened simultaneously. Aninterlocking system or a visual and/or audible warning system shouldbe 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 airflow relative to surrounding areas of a lower grade under all operationalconditions and should flush the area effectively. Adjacent rooms ofdifferent grades should have a pressure differential of 10-15 pascals(guidance values). Particular attention should be paid to the protectionof the zone of greatest risk, that is, the immediate environment to whicha product and cleaned components which contact the product are exposed.The various recommendations regarding air supplies and pressuredifferentials may need to be modified where it becomes necessary tocontain some materials, e.g. pathogenic, highly toxic, radioactive orlive viral or bacterial materials or products. Decontamination of facilitiesand treatment of air leaving a clean area may be necessary for someoperations.

    30. It should be demonstrated that airflow patterns do not present acontamination risk, e.g. care should be taken to ensure that airflows donot distribute particles from a particle-generating person, operation ormachine to a zone of higher product risk.

    31. A warning system should be provided to indicate failure in the airsupply. Indicators of pressure differences should be fitted between areaswhere these differences are important. These pressure differences shouldbe recorded regularly or otherwise documented.

  • 52 cleanroom operators manual

    Equipment

    32. A conveyor belt should not pass through a partition between a gradeA or B area and a processing area of lower air cleanliness, unless thebelt itself is continually sterilised (e.g. in a sterilising tunnel).33. As far as practicable, equipment, fittings and services should bedesigned and installed so that operations, maintenance and repairs canbe carried out outside the clean area. If sterilisation is required, it shouldbe carried out after complete reassembly wherever possible.

    34. When equipment maintenance has been carried out within the cleanarea, the area should be cleaned, disinfected and/or sterilised whereappropriate, before processing recommences if the required standardsof 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 ofan appropriate quality. They should not be operated beyond their designedcapacity. Water for injections should be produced, stored and distributedin a manner which prevents microbial growth, for example by constantcirculation at a temperature above 70C.

    36. All equipment such as sterilisers, air handling and filtration systems,air vent and gas filters, water treatment, generation, storage anddistribution systems should be subject to validation and plannedmaintenance; their return to use should be approved.

    Sanitation

    37. The sanitation of clean areas is particularly important. They shouldbe cleaned thoroughly in accordance with a written programme. Wheredisinfectants are used, more than one type should be employed.Monitoring should be undertaken regularly in order to detect thedevelopment of resistant strains.

    38. Disinfectants and detergents should be monitored for microbialcontamination; dilutions should be kept in previously cleaned containersand should only be stored for defined periods unless sterilised.Disinfectants and detergents used in Grades A and B areas should besterile prior to use.

    39. Fumigation of clean areas may be useful for reducing microbiologicalcontamination in inaccessible places.

  • 53classification of air cleanliness

    WHO - airborne viable count

    Schedule M - airborne viable count

    Notes:a. These are average values.b. Individual settle plates may be exposed for not less than two hours

    in Grade B, C and D areas and for not less than thirty minutes inGrade A area.

    USFDA: airborne viable & non-viable

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

    Grade Air sample Settle plates Contact plates Glove prints(dia. 90 mm) (dia 55mm) (five fingers)

    Cfu/m3 Cfu/m3 cfu per plate cfu per glove

    A < 1 < 1 < 1 < 1

    B 10 5 5 5

    C 100 50 25 -

    D 500 100 50 -

    Air classificationsa

  • b- ISO 14644-1 designations provide uniform particle concentrationvalues for cleanrooms in multiple industries. An ISO 5 particleconcentration is equal to Class 100 and approximately equals EUGrade A.c- Values represent recommended levels of environmental quality.You may find it appropriate to establish alternate microbiologicallevels 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 normallyyield no microbiological contaminants.

  • entry and exit of personnel

    Author W Whyte has kindly allowed the reproduction from his bookCleanroom Technology Design, Testing and Operation publishedin 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).

    People can disperse millions of particles and thousands of microbe-carrying particles from their skin and clothing. It is thereforenecessary for personnel working in a cleanroom to change intoclothing 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. Cleanroomclothing also acts as a filter against particles dispersed from the personsskin and their indoor, or factory, clothing.

    The type of cleanroom clothing used varies according to the type ofcleanroom. In cleanrooms where contamination control is very important,personnel wear clothing that completely envelops them and prevent theircontamination being dispersed, i.e. a coverall, hood, facemask, knee-length boots and gloves. In cleanrooms where contamination is not asimportant, less enveloping clothing such as a smock, cap and shoe coversmay be quite sufficient.

    44444

  • 56 cleanroom operators manual

    Whatever the choice of clothing, garments will have to be donned priorto entering the cleanroom, and they should be put on in such a way thatthe outside of the clothing is not contaminated. This chapter describestypical methods.

    Some types of cleanroom garments are worn once before being thrownaway; others are sent for cleaning and processing after being used once.However, garments are normally used more than once. It may thereforebe necessary to devise a storage method to ensure that a minimum ofcontamination is deposited onto them. Possible methods are discussedat the end of this chapter.

    prior to arriving at the cleanroom

    Poor personal cleanliness is not acceptable in a cleanroom. However itis not clear how often personnel should bathe or shower, there beinglittle in the way of scientific investigations into this topic. Clearly ashower would be necessary if someone has just had a haircut and islikely to shed hair clippings. It is known that washing can remove thenatural skin oils and, in some individuals, the dispersion of skin andskin bacteria can increase. People with dry skin may wish to use a skinlotion to replace the lost skin oils.

    Consideration should be given to what clothing is best worn belowcleanroom garments. Clothing made from artificial fibres, such aspolyester, are better than those made from wool and cotton, becausesynthetic fabrics disperse much fewer particles and fibres. Close-wovenfabrics are also an advantage, as these are more effective in filtering andcontrolling the particles and microbe-carrying particles dispersed fromthe skin. This type of problem will be overcome if personnel are issuedwith factory undergarments. These should be made from a fabric thatdoes not lint, and it should effectively filter particles dispersed from theperson.

    Personnel should consider whether applying cosmetics, hair spray, nailvarnish, etc. at home is necessary, as these should be removed prior toentering the cleanroom. They should also consider what rings, watchesand valuables they will bring to work, as they are likely to be removedand stored.

    changing into cleanroom garments

    The best method of changing into cleanroom garments is one thatminimises contamination getting onto the outside of the garments. One

  • 57entry and exit of personnel

    such method is described below. Some of the suggested procedures maybe unnecessary in poorer classes of cleanrooms, and further procedurescan be introduced in cleanrooms that manufacture products verysusceptible to contamination. It should also be noted that alternatives tothe proposed method are successfully used in existing cleanrooms, andthese are quite acceptable as long as they give a level of contaminationcontrol 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. Changeareas can vary in design, but it is common to find them divided intothree zones:

    1. Pre-change zone2. Changing zone3. 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 personnelblow their nose. It is impossible to do this correctly in a cleanroom, andif 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 thecleanroom to go to the toilet, it is likely to entail changing out and backinto cleanroom clothing.

    In cleanrooms where outdoor shoes are not removed, or effectivelycovered, shoe cleaners should be used. Cleanroom shoe cleaners arespecially made to retain contamination dispersed from the shoe.

    Sticky cleanroom mats or flooring are often used in the approach to thechange room. These are specially manufactured for use in cleanrooms.There are two general types. One type is laminated from layers of thinadhesive plastic film and the other from a thick resilient adhesive plastic.Both work by removing dirt from the soles of footwear as personnelwalk over them. After a while they become soiled. In the case of theplastic film version, the topmost layer is peeled off to expose a freshlayer. 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 timesto ensure the removal of practically all of the footwear contamination. Ifthe resilient-type cleanroom flooring is used it can cover a floor surface

  • 58 cleanroom operators manual

    area large enough to ensure that sufficient steps are placed on it to ensureeffective 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 feelcomfortable in the cleanroom. If the company provides dedicatedclothing to wear under the cleanroom garments, then all streetclothing 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 teargloves. Wedding rings that are smooth may be kept on if the ring (andunder the ring) is kept clean. Rings that are not smooth can be tapedover. Items such as cigarettes and lighters, wallets and other valuablesshould be securely stored.3. Remove cosmetics and, if required, apply a suitable skinmoisturiser. The composition of any moisturiser should be consideredto ensure that no chemicals used in the formulation causecontamination problems in the product being manufactured.4. Don a disposable bouffant hat, or hairnet. This ensures that hairdoes 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 intodedicated cleanroom shoes.7. If a hand washing system is located in this area then wash thehands, dry them and, if necessary, apply a suitable hand lotion.However, it is probably best if hands are washed within the changearea just before the clean garments are put on (see below). If glovesare used to put on cleanroom clothing, then hand washing can bedone here. In bioclean areas, it will be necessary to wash the hands ina suitable skin disinfectant. Hands can be dried with a non-lintingtowel or a hand drier. If a hand drier is used then the best type is onethat does not disturb the dirt on the floor.8. Cross over from the pre-entry area into the change zone. Thedemarcation between these two zones may be a door or a crossoverbench, or both. A sit-on transfer bench may be built across the zonesto ensure that personnel cannot walk round but must cross over it. If abench is used footwear should be attended to as it is crossed. If abench 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

  • 59entry and exit of personnel

    the mat to make certain that it is clean and the minimum ofcontamination is tracked into the next zone.

    changing zone

    The garments used in the cleanroom are put on in this area. Severalmethods can be used but the following is suggested. This uses a methodassumes that a facemask, hood, coverall and overboots are used, but itcan be adapted for use with a cap, gown and overshoes. It requires thatthe 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 toensure that it is free from tears and faulty heat seals. The packaging isthen opened.2. A facemask and hood (or cap) is put on. It appears to make littledifference whether the mask is put under, or over, the hood. Choosewhich method is the most comfortable. If a hood is put on, the hairmust be tucked in and the studs (snaps) or ties at the back of the hoodadjusted for comfort.3. If a hand washing system is installed in this area then the handsshould now be washed (and disinfected if required). This is possiblythe best time for personnel to wash their hands as clean garments willnow be handled and contaminated parts of the body, such as the hairand face, should not be touched again.4. Temporary gloves known as donning gloves are sometimes usedto 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 andunfolded without touching the floor. It is sometimes possible to get thecleanroom laundry to fold the garment in a way that will minimiseboth the chance of the garment touching the floor and the outsidesurface being contaminated by the personnels hands. If this is notdone, then the following can be considered.

    If a coverall is used, it should be removed from its packing and allowedto unfold without touching the floor. It should be unzipped and turnedso that the zip is to the side away from the person.

    There are now several methods of putting on the garment to ensure thatit does not touch the floor. These are as follows:

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    The coverall can be gathered together at the 4 corners i.e. the twowrists and the two ankles. It should then be possible to put first oneleg and then the other into the garment without the trouser legstouching the floor. The garment can be held in the inside at waist level, some of thematerial gathered up and one leg and then the other put in to thetrouser legs. The top of the coverall can then be slipped over theshoulders, or, The left cuff and left zipper can be taken in the left hand and theright zipper and right cuff taken in the right hand. The coverall canthen 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 releasingone cuff at a time, first one arm and then the other can be placed intothe garment.

    The last two methods will work better if the trouser legs are folded backon 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, ensuringthat all of the hood (if used) is tucked under the collar. A mirror is usefulat this stage. If the garment has press studs (snaps) at the ankles andwrists, then these should be snapped shut.

    cleanroom entrance zone1. If a crossover bench is available, it should be crossed over now.This bench is used to demarcate the slightly soiled changing-zonefrom 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, thecleanroom footwear put on, the leg transferred over the bench andplaced on the floor of the entrance zone. Then the other leg should beraised, the cleanroom footwear put on and the leg taken over thebench. While still sitting on the bench, the legs of the cleanroomgarment 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 notonly for safety reasons but to prevent eyelashes and eyebrow hairfalling onto the product.4. The garments should be checked in a full-length mirror to see thatthey are worn correctly. Check that the hood is tucked in and there areno gaps between it and the coverall (or gown). Check that no hair canbe seen.

  • 61entry 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 puton top. Two pairs of gloves can be used as a precaution againstpunctures, although sensitivity of touch is lost.6. If deemed necessary, the hands can again be washed. Gloves canalso be washed. In a biocleanroom it is beneficial to decontaminatethe hands by applying an alcohol solution containing a skindisinfectant. Apart from being more efficient, the use of an alcoholsolution overcomes the problem of having a washhand basin in theroom, with its attendant risk of microbial growth.7. Low particle (and if required, sterile) working gloves should nowbe put on, without the outside of them becoming contaminated. Insome cleanrooms this task is left until the personnel is within theproduction cleanroom. If they are latex gloves, which are wrapped inpairs with the cuffs rolled back (in the style used by surgeons), thenthe gloves can be put on without being contaminated. In this case, thefirst glove is taken out of the exposed package by gripping the fold ofthe rolled-over cuff with the one hand and inserting the other handinto it. Two fingers of the gloved hand are then passed under therolled-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 slottedinto the correct fingers of the glove, and the cuff lifted over the cuff ofthe cleanroom garment. It is now possible to pull back the cuff of thefirst glove, making sure that it is completely over the garments cuff.8. Most cleanroom gloves are not packed in a way that will allowgloves to be put on without contaminating the glove surface. Thesegloves must be gripped at the edge of the cuff and put on in a similarway to that described above. Gloves packed in pairs will becontaminated less than those packed in 50s or 100s, as it is difficult toremove a glove from a large pack without contaminating those thatare left. If considered necessary, the gloves can now be washed ordisinfected.9. Personnel may now proceed into the cleanroom. This may be overa cleanroom mat.

    exit changing procedures

    When leaving a cleanroom, personnel will either (i) discard all theirgarments and on re-entry use a new set of garments (this is normallyonly employed in an aseptic pharmaceutical cleanroom), or (ii) discardtheir 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 thedisposable items such as bouffant hats, gloves, facemask and disposableovershoes are placed in a container for disposal. If the remainder of thegarments are not disposable then they should be placed in a separatecontainer for dispatch to the cleanroom laundry for processing.

    If the garments are to be used again on re-entry, they should be removedso 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 shouldthen be unzipped and removed using the hands within the garment toremove 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 thegarment should be held so that they do not touch the floor. The other legcan now be removed. The facemask and hood can now be removed.

    Garments to be used again on re-entry should be stored to preventcontamination. This can be done in several ways, as follows:

    Each item of clothing can be rolled up. In the case of cleanroomfootwear this should be done so that the dirty soles are to the outside.The footwear can now be placed in separate pigeon holes and thehood and coverall (or cap and gown) in another. If thought necessary,the items of clothing can be placed into bags before being put into thepigeon holes. The hood (or cap) can be attached to the outside of the coverall (orgown) 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. Itis best that their garments should not touch the wall, or each other. Inhigher grade cleanrooms, clothing is often hung up in unidirectionalflow cabinets, specifically designed to ensure that garments are notcontaminated. Garment bags can be used. These will have separate pockets forthe various clothing items and should be regularly laundered.

  • cleanroom disciplines

    Author W Whyte has kindly allowed the reproduction from his bookCleanroom Technology Design, Testing and Operation publishedin 2001 by John Wiley and Sons (ISBN Number 0-471-86842-6).

    Cleanroom personnel are a important source of cleanroomcontamination. Almost all micro-organisms found in a cleanroomcome from personnel, and they are also a major source of particlesand fibres. It is therefore necessary to ensure the minimum ofcontamination is generated and transferred by personnel activities. Byobserving certain disciplines, contamination of the product can beminimised. These are discussed in this chapter.

    When a cleanroom is about to be opened, management is faced with thetask of employing people to work in the room, and determining whatdisciplines personnel (including maintenance and service technicians)should adhere to within the cleanroom. It is hoped that this chapter willassist in this task.

    It should be noted that products manufactured in a cleanroom vary intheir sensitivity to contamination, and cleanroom disciplines shouldreflect this. The information given in this chapter are options from which

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    the user can choose methods that best reflect the degree of risk associatedwith their cleanroom.

    people allowed into cleanrooms

    People can, when walking, produce about 1 000 000 particles > 0.5 mand several thousand microbe-carrying particles per minute. The morepeople, the higher the dispersion within the cleanroom. It is thereforeimportant that the minimum of people, i.e. only the essential personnelare allowed into cleanrooms, and management should ensure that thisis so.

    Because many contamination problems are caused by lack of knowledge,only people trained to work in a cleanroom should be allowed withinthe cleanroom. Personnel should therefore be formally trained in thevarious aspects of contamination control. Visitors should be discouragedand only allowed in under the control of a supervisor; if a cleanroom isdesigned with windows for visitors to look into the cleanroom, this willusually suffice.