Good Cleanroom Practices

Good Cleanr oom Practices Cleanroom

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

Published by: Center for GMP 509C NCL-Godavari Pipeline Road Jeedimetla PO Hyderabad 500 055 eMail: [email protected]; [email protected] URL: www.cgxp.org

First Edition : September, 2007 Standard edition Printed in India Price: Rs 395.00

All rights reserved. No part of this work may be copied, reproduced, adapted, abridged or translated, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher

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

V

oices in this book may be many; but the concerns and convictions remain the same: you hold the key to the ultimate success of any contamination control or GMP initiative.

This book is dedicated to you.

acknowledgement

A

s in all my previous compilations, here also, I have drawn inspiration and material from the ideas and works of extraordinarily gifted authors and speakers, far too numerous to mention individually, and take this opportunity to record my sincere appreciation and deep sense of indebtedness to every one of them. Special mention, however, must be made of the following sources: Biosafety in Microbiological and Biomedical Laboratories, CDC/NIH 4th edition Selection and use of Biological Safety Cabinets, CDC/NIH 2nd edition EUGGMP/WHO/USFDA/Schedule M guidelines Dr W Whyte for his kind permission to reproduce sections from his book ‘Cleanroom Technology – Design, Testing and Operation’ published in 2001 by John Wiley and Sons (ISBN Number 0-47186842-6).

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

1 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

14

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 2 3 4 5 6 7

8

Isolate the VIP Minimise his exposure, both in terms of duration and frequency Seek and destroy or immobilise those threatening his safety If his enemies are outside, we make it difficult for them to penetrate the protective barriers If they are already within, we flush them out We monitor those in his immediate proximity We advise the VIP not to antagonise anyone who may be around him, friend today, and foe tomorrow (Don't generate enemies within) 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

15

* No effect at all * Cause physical occlusion * Synergistically: where it enhances the effect of the active process ingredient * Antagonistically: where it competes with, changes or otherwise inhibits the drug * Independently: triggers its own independent pharmacological activity Contamination directly compromises the safety and quality of our product, and hence a legitimate cGMP concern. Contamination control measures will make more sense once we understand the nature of contaminants and the contamination process. We begin with classification of contaminants. classification of contaminants Regarded from the standpoint of the ‘type’ of damage they do, contaminants may be divided into subgroups: Physical:

Particles that cause damage by virtue of their physical properties alone Chemical: Organic chemicals such as oils, fats, waxes, fluxes, paints and plastics may react chemically with a product and change its properties. Gases induce contamination (like oxidation) only in the gaseous phase. In contrast, vapours and mists contaminate in the vapour phase; on condensation, in the liquid phase (like oil films); and, on subsequent evaporation, in the solid phase (residues). SUBSTANCE ENERGY Physical Dust Dirt Grit Fibre Lint Fly ash

Chemical

Biologic

Organic Bacteria Thermal compounds Fungus Light Inorganic salts Spore Electromagnetic (EMI) Acids, Bases Pollen Electrostatic (ESD) Condensates Virus Radiation Moisture, Vapour Human skin cells Electrical (RF) Mist, Fume Smoke Table 1: Classification of contaminants

cleanroom operators’ manual

16

Biological: Microorganisms and endotoxins Energy: Some products are thermolabile; others decompose on prolonged exposure to sunlight contaminant pathway If you were to ask any agency that provides security to VIPs they will tell you that the enemy may attempt a million times and fail; he needs to succeed just once. In contrast, they must succeed each time. This is just as true with contamination control. On the flip side, the mere presence of a contaminant does not automatically imply contamination. For contamination to occur, the contaminant must first have its source; must then be transported and reach the product site; must make contact with the product; and must be retained by the product. If this process of contamination, known as the contaminant pathway, is broken at any stage, contamination does not occur. For instance, if the source of the contaminant is absent; or, having a source, it is unable to access the product; or, having somehow managed to slip through, is prevented from making contact; or, even after having

Transport

Contact

Source

Retention

Figure 1: The contaminant pathway

contamination control

17

made contact, is not retained, or not allowed to be retained, contamination does not take place, and the product is safe. Contamination control may then be viewed as an exercise that aims to break the contaminant pathway at one or more stages of the contamination process. sources of contaminants Included contaminants emanate from raw materials and consumables; fluidised contaminants from utilities; suspended contaminants from the environment; settled contaminants from dust collecting surfaces; emitted contaminants from machinery, moving parts and surfaces; shedded and transferred contaminants from personnel. Cross-contamination occurs when the active process ingredient of one product is carried forward to the next drug product because of inadequate cleaning. O Raw Materials, Components, Consumables * Microflora * Impurities * Fibers, dust, cleaning residues and other particles * Moisture O Equipment * Poor choice of materials of construction * Improper or inadequate surface treatment * Inadequate cleaning; cleaning residues * Improper or inadequate maintenance O Environment & Utilities * Building materials and surface finishes * Temperature & Humidity * Light, radiation * Air - Microflora - Fibers, dust and other particles - Fumes, vapours and condensates * Water - Microflora and Endotoxins - Fibers, dust and other particles - Cleaning residues

18

cleanroom operators’ manual

* Gases & Compressed air - Microflora and Endotoxins - Oil droplets, dust and other particles O Human * Intrinsic contaminants - Biologic Factory * Extrinsic contaminants - Importer of contaminants - Transporter of contaminants - Generator of contaminants - Inducer of contamination

Figure 2: Sources of contaminants in cleanrooms

In fact, research into a large number of reported occurrences of contamination in well-designed and maintained clean rooms reveals that in 5% of the cases it was due to contaminated raw materials; in 10% through utilities and defective or soiled equipment, tools or implements; in 5% due to faulty air filtration; and in 80% due to breaches in the product-person interface. Hence, contrary to popular belief, microcontamination control does not begin and end with HEPA filters: it is only one of many concurrent initiatives. Comprehensive microcontamination control requires a program that effectively integrates and orchestrates planned offensive measures on all four fronts. Pursuing one while ignoring others yields sub-optimal results.

contamination control

19

Figure 3: An integrated approach to contamination control

I have personally seen many facilities where such "common sense" is conspicuous by its absence. The User forces me through a commendable decontamination entry regimen, only to leave me watch in amazement the impunity with which the trolley boy "gate crashes" from the material entry; double-doored and air locked. No decontamination protocols apply to him, his trolley or their dirt-laden wheels, except on some neatly typed SOP, stashed away in the recesses of a filing cabinet in the Production Manager's Office. master plan for contamination control As mentioned at the outset, contamination control is much alike protecting a VIP, and the steps outlined for security apply here. A product or process is susceptible to contamination during manufacture, assembly, testing, cleaning, transportation, storage, or even while being used. Our objective is to minimise the risk of its being contaminated along the way. We adopt a six-point strategy: Identifying the contaminant Our first exercise is in identifying the possible contaminants that threaten the product or process. We can then design a contamination control program that takes into account their characteristics and behavioural pattern. Anticipating the contaminant Having identified the contaminants that are likely to compromise our product or process, we focus on the possible sources from where they could originate; and their mode of getting to the critical zone.

cleanroom operators’ manual

20

Preventing ingress Preventing ingress of contaminants into the selected work area. O Raw Materials, Components, Consumables * Vendor qualification * Limits on Impurities * Primary and Secondary packaging * Proper storage * Proper sampling, testing and dispensing O Equipment * Appropriate choice of materials of construction * Appropriate surface treatment * Adequate cleaning; and cleaning validation * Proper and timely maintenance O Environment & Utilities * Isolation of critical areas * Appropriate materials of construction and surface finishes * Entry restrictions and protocols * Entry decontamination protocols * Temperature & Humidity Control * Air - Air filtration - Differential Pressure - Airflow direction - Airflow Velocity at sub-turbulent level - Air Change Rate 3 - Task-specific air Number of Particles /m in Outdoor Air cleanliness: a clean Size Clean Dirty Normal air workstation or µm “tent” in a cleanroom > 0.1

1 × 1010

3 × 109

5 × 108

7

7

*

8

> 0.3

3 × 10

> 0.5

3 × 107

9 × 10

7 × 106

Table 2: Air quality

2 × 10

1 × 106

Water Appropriate treatment, storage and distribution

contamination control

21

* 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

K

X

Cleanroom

LT

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

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

23

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

O O

O O

Facilitating Egress

O O O

Minimising Generation

O O O O

Coping with residual contaminants

O O O

Select class of air cleanliness appropriate for the task Select location and layout optimising flowpaths for men, material and process o avoid loops in flowpaths o isolate through barriers o avoid direct / straight through access o stagger doorways o no windows on external wall o double-glazed view panels with breathers Sustain overpressure along clean-todirty axis, where not contraindicated Impose entry restrictions and thorough decontamination procedures for men, material and equipment Sustain overpressure along clean-todirty axis, where not contraindicated Avoid surfaces that can accumulate dust; where unavoidable, ensure easy accessibility to clean and disinfect Implement comprehensive sanitation plan 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 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.

2 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

26

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

cleanrooms

27

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 µm 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 No. of particles/ft3 > 0.5 µm

1

10

100

1000 10000 100000

1

10

100

1000 10000 100000

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

28

· 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:

cleanrooms

29

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

30

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.

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:

cleanrooms

31

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 µm from the room air supply. These filters are known as High Efficiency Particle Air (HEPA) filters although Ultra Low Particle Air (ULPA) filters, which have a higher efficiency, are used in microelectronic fabrication areas.

32

cleanroom operators’ manual

3. Terminal air filters: The high efficiency filters used in cleanrooms are installed at the point of air discharge into the room. In air conditioning systems used in offices, etc. the filters will be placed directly after the ventilation plant but particles may be induced into the air supply ducts or come off duct surfaces and hence pass into the room. 4. Room pressurisation and pass-through grilles: To ensure that air does not pass from dirtier adjacent areas into the cleanroom, the cleanroom is positively pressurised with respect to these dirtier areas. This is done by extracting less air from the room than is supplied to it, or by extracting the supplied air in adjacent areas. To achieve the correct pressure and allow a designed movement of air from the cleanest to the less clean rooms in a suite, pass-through grilles or dampers will usually be seen at a low level on walls or doors. Another indication that the room is a cleanroom is the type of surface finish in a room. The room will be constructed of materials which do not generate particles and are easy to clean. Surfaces will be constructed so that they are accessible to cleaning and do not harbour dirt in cracks, e.g. coved flooring and recessed lighting. The airborne cleanliness of a conventionally ventilated cleanroom is dependent on the amount and quality of air supplied to the room and the efficiency of mixing of the air. Generally speaking, a cleanroom will have sufficient air supply to achieve good mixing and the air quality of the room will therefore only depend on the air supply quantity and quality. It is important to understand that the cleanliness of a conventionally ventilated cleanroom is dependent on the volume of air supplied per unit of time and not the air change rate. The cleanliness is also dependent on the generation of contamination within the room. i.e. from machinery and individuals working in the room. The more people in the cleanroom, the greater their activity and the poorer their cleanroom garments the more airborne contamination is generated. People moving about with poor cleanroom garments such as smocks or laboratory coats will generate, on average, about 2 x 106 particles > 0.5 µm/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.

cleanrooms

33

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/ft3 or m3) Air volume supplied* (ft3 or m3/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

34

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.

cleanrooms

35

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 particlefree having been filtered by high efficiency filters; this air is also used to pressurise the system and prevent the ingress of outside contamination.

Figure 4: Rapid Transport Ports featuring - α− β β- 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.

3 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

38

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 (107) to 100 billion (1011) 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 costeffective: an environment "clean" enough for the intended purpose.

Number of Particles /m3 in Outdoor Air Size µm

Dirty

Normal

Clean

> 0.1

1 × 1010

3 × 109

5 × 108

> 0.3

3 × 108

9 × 107

2 × 107

> 0.5

3 × 107

7 × 106

1 × 106

Table 1: Air quality curves

Statistics has established that airborne particle profiles in clean, semi-clean and dirty environments were mathematically predictable, and equations could be established by which measurement 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 0.5µ, or larger per cubic foot of air measured, then it could be assumed that the number of 5µ particles would be less than 700 per cubic foot.

classification of air cleanliness

39

ISO 14644-1

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

Classification Number

(N)

0.1µ µ

0.2µ µ

0.3µ µ

0.5µ µ

1µ

5.0µ µ

ISO 1

10

2

ISO 2

100

24

10

4

ISO 3

1 000

237

102

35

8

ISO 4

10 000

2 370

1 020

352

83

ISO 5

100 000

23 700

10 200

3 520

832

ISO 6

1 000 000 237 000 102 000

35 200

8 320

293

ISO 7

352 000

83 200

2 930

ISO 8

3 520 000

832 000

29 300

ISO 9

35 200 000

8 320 000

293 000

29

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: .....(1) Cn = 1ON (0. 1 /D)2.08 Where Cn = Maximum number concentration of particles per m3 with diameter equal to or larger than the considered particle diameter, rounded to the nearest whole number, using no more than three significant digits N = ISO classification number D = Considered particle diameter in µm 0.1 = a constant with the dimension µm

cleanroom operators’ manual

40

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 µm as the reference particle diameter for air cleanliness classification a very straightforward denomination scheme results - thus overcoming elegantly the principal drawback of the metric air cleanliness classes according to U.S. Federal Standard 209E. Simple, single-digit class denominations now correspond with the traditional classes of said standard: ISO 5, for example, replaces Class 100, and ISO 8 substitutes Class 100 000. The 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 µm. 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 µm; • the M descriptor for particles above 5 µm The U descriptor is expressed in the format : “(x : y)” .....(2) where : x = y =

the maximum permitted concentration of ultrafine particles, expressed as the number of ultrafine particles per m3 of air the lower detection limit, i.e. the particle size in µm at which the applicable discrete particle counter - for example, a condensation nucleus counter - is capable of detecting such particles with 50 % counting efficiency

The M descriptor is expressed in the format : “M (a;b);c” .....(3) where : a = b = c =

the maximum permitted concentration of macroparticles, expressed as the number of macroparticles per m3of air the equivalent diameter (or diameters) associated with the specified method for measuring macroparticles the specified method for measuring macroparticles

classification of air cleanliness

41

The concept of the U descriptor is not new - it already forms part of U.S. Federal Standard 209E. On the other hand, the concept of the M descriptor is new. In determining M descriptors, the difficulties of sampling and assessing large particles has to be taken into consideration as well as the fact that large particles are normally process -generated. For these reasons the identification of the sampling device and evaluation procedure should be addressed on an application-specific basis. Factors such as the density, shape, volume and aerodynamic behaviour of the particles need to be taken into account. For describing for instance, an airborne macroparticle concentration of 1 000 particles/m3 in the particle size range of 10 to 20µm using a cascade impactor for sampling and a microscopic sizing and counting procedure for evaluation, the designation would be : “M (1 000; 10-20 m m) : cascade impactor followed by microscopic sizing and counting” Under certain circumstances it may be necessary, to put special emphasis on specific components of the total airborne particle population, such as fibres. Fibres for instance, may be accounted for by supplementing the M descriptor with a separate descriptor for fibres, having the format “Mfibre (a;b); c”. Cleanroom Testing to prove continued Compliance At periodic intervals, cleanroom systems should be subjected to a formal requalification procedure. The rules are established in another document of the ISO series of cleanroom technology standards: ISO 14644-2. Unlike the earlier years where specific values were specified for critical parameters (for example, Air Velocity for Laminar Airflow should be 100 fpm etc) the current standard leaves fixing and determining Table 3 : Strategic Testing (Required)

Schedule of Mandatory tests to demonstrate continuing compliance Maximum Test Parameter Class Time Interval Test Procedure Particle Count Test Air Pressure Difference Airflow

<= ISO 5 > ISO 5 All Classes

6 Months 12 Months 12 Months

All Classes

12 Months

ISO 14644-1 Annex A ISO 14644-1 Annex B5 ISO 14644-1 Annex B4

cleanroom operators’ manual

42

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 Maximum Test Parameter Class Time Interval Installed Filter All Classes 24 Months Leakage Containment All Classes 24 Months Leakage Recovery All Classes 24 Months Airflow Visualization

All Classes

24 Months

Test Procedure ISO 14644-3 Annex B6 ISO 14644-3 Annex B4 ISO 14644-3 Annex B13 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

• • • •

43

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

44

• • •

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

45

They have not indicated how cubic metres of air samples are to be measured when all currently available instrumentation are designed for taking air samples at the rate of one cubic foot per minute only. What is the User supposed to do? Run the counter for 35.4 minutes for each sample? Most counter reset at the end of each minute. Most counters are not designed for “continuous” monitoring, or even prolonged periods of monitoring. Most users are not even aware of this inherent inadequacy. Why did ISO choose the “cubic metre”? If they wanted International Standard Units, then why not “litre”? The existing classification as expounded in US Fed 209E was proving inadequate for the semiconductor industry. The highest grade specified is “Class 1”, a quality of environment in which you cannot produce Pentium VI. Hence they were compelled to shift to a smaller reference particle size: 0.1 micron rather than 0.5 micron. Also, at the pace at which the demand for cleaner and cleaner space is growing, the contaminant density would have to be expressed as particles per larger unit volume: one cubic metre rather than just cubic foot. (Even the semiconductor industry is still at a loss as to how to sample this larger volume, and the standard Cleanrooms and Associated Controlled Environments, Part 3: Metrology and test methods:14644-3 offers no answer either.) EUGGMP/WHO/TGA/PIC/Schedule M: manufacture of sterile medicinal products Principle The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance bears a particularly great importance and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test. Note: This Annex does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces, etc. Reference is made to other compendia such as the CEN/ISO Standards. General 1. The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an

46

cleanroom operators’ manual

appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. 2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages. 3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled. In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “atrest” 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

Table 5: Classification of air cleanliness

Notes: (a) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grades A, B and C. (b) The guidance given for the maximum permitted number of particles in the “at rest” condition corresponds approximately to the US Federal Standard 209 E and the ISO classifications as follows: grades A and B correspond with class 100, M 3.5, ISO 5; grade C with class 10 000, M 5.5, ISO 7 and grade D with class 100 000, M 6.5, ISO 8. (c) The requirement and limit for this area will depend on the nature of the operations carried out. Examples of operations to be carried out in the various grades are given in the table below (see also para.11 and 12) The particulate conditions given in the table for the “at-rest” state should be achieved in the unmanned state after a short “clean up” period of 15-

48

cleanroom operators’ manual

20 minutes (guidance value), after completion of operations. The particulate conditions for grade A in operation given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself. 4. In order to control the particulate cleanliness of the various grades in operation, the areas should be monitored. 5. In order to control the microbiological cleanliness of the various grades in operation, the areas should be monitored. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitation. Recommended limits for microbiological monitoring of clean areas in operation: Notes:

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

classification of air cleanliness

49

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

50

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-organismretaining filter later in the process, should be done in a grade A environment with grade B background. Preparation of solutions which are to be sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background. Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B background. Transfer of partially closed containers, as used in freeze drying, should, prior to the completion of stoppering, be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment. Preparation and filling of sterile ointments, creams, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered. Premises 22. In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimise the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used. 23. To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason. 24. False ceilings should be sealed to prevent contamination from the space above them. 25. Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.

classification of air cleanliness

51

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 backflow. 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

52

Equipment 32. A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel). 33. As far as practicable, equipment, fittings and services should be designed and installed so that operations, maintenance and repairs can be carried out outside the clean area. If sterilisation is required, it should be carried out after complete reassembly wherever possible. 34. When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work. 35. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C. 36. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved. Sanitation 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

53

WHO - airborne viable count

Schedule M - airborne viable count Grade

Air sample Cfu/m3

Settle plates (dia. 90 mm) Cfu/m3

Contact plates (dia 55mm) cfu per plate

Glove prints (five fingers) cfu per glove

A

<1

<1

<1

<1

B

10

5

5

5

C

100

50

25

-

D

500

100

50

-

Notes: a. These are average values. b. Individual settle plates may be exposed for not less than two hours in Grade B, C and D areas and for not less than thirty minutes in Grade A area. USFDA: airborne viable & non-viable

Air classificationsa

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. c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological levels due to the nature of the operation. d- The additional use of settling plates is optional. e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

4 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 microbecarrying 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, kneelength 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

56

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

57

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

58

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

59

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

60

· 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

61

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 crossover 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.

5 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

64

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 µm and several thousand microbe-carrying particles per minute. The more people, the higher the dispersion within the cleanroom. It is therefore important that the minimum of people, i.e. only the essential personnel are allowed into cleanrooms, and management should ensure that this is so. 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

65

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 109 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

66

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

67

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. Passthrough 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 µm/min. A person with head, arms and body moving can generate about 1 000 000 particles & 0.5 µm/min. A person who is walking can generate about 5 000 000 particles 0.5 µm/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 Activity

Particles > 0.3µ µ emitted per minute

Viable contaminants 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 Calisthenics Coughing Sneezing (excluding large droplets)

100,000 500,000 1,000,000 2,500,000 5,000,000 7,500,000 10,000,000 10,000,000 > 15,000,000 > 15,000,000 > 30,000,000

750 1,000 1,500 2,500 4,000 8,000 15,000 15,000 30,000 > 30,000 > 50,000

68

cleanroom operators’ manual

2. Personnel should position themselves correctly with respect to the product, so that contamination does not land on it. They should not lean over the product in such a way that particles, fibres or microbecarrying 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

69

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

70

benches, or isolators. If the airflow in the cleanroom is unidirectional, storage racks of the type that allow air to flow through are a good choice. Materials should not be left standing on the floor. · Waste material should be collected frequently into easily identified containers and removed frequently from the cleanroom. · Cleanrooms should be correctly cleaned (and disinfected if required). · The cleanroom must be kept neat and tidy. If it is not tidy, it cannot be kept clean. maintenance and service personnel Through lack of training or supervision, people who enter a cleanroom to maintain or service machinery can be a considerable hazard. The maintenance technician, unless instructed otherwise, will apply the same techniques as they do outside the cleanroom. Service personnel from outside firms may be completely untrained in cleanroom contamination control techniques. The following is a list of procedures that should be considered for maintenance and service personnel: · Maintenance and service technicians should only enter a cleanroom with permission. · Maintenance and service technicians should be trained in cleanroom techniques, or closely supervised when they are within the cleanroom. · Technicians must wear the same, or equally efficient, cleanroom clothing as cleanroom personnel, and use the same techniques to change into cleanroom clothing when entering and exiting cleanrooms. They should never enter the cleanrooms (especially at weekends, or when no one else is around) without changing into cleanroom clothing. · Technicians should ensure they remove dirty boiler suits, etc. and wash their hands before changing into cleanroom clothing. · Tools that are used routinely for maintaining the cleanroom should be cleaned (and sterilised, if required) and kept stored for sole used within the cleanroom. Tools should be made from materials that do not corrode. For example, stainless steel is much preferred to mild steel tools , which may rust. · If a service engineer or contractor brings tools into the cleanroom (especially those from outside the cleanroom organisation), then they must be cleaned. A wipe-down with a cleanroom wiper moistened with isopropyl alcohol (often 70%, in water) is a suitable method.

cleanroom disciplines

71

Only the tools or instruments needed within the room should be selected, decontaminated, and put into a cleanroom compatible bag or container. This has the advantage of leaving behind cases or briefcases, with their associated scraps of paper, fluff etc., which are potential sources of contamination; these should not be allowed into the room. · Spare parts or items, like fluorescent light tubes, which have wrappings, should have the wrappings removed outside the manufacturing area and the parts wiped down. · Written methods should be kept for each activity, so that contamination control techniques can be incorporated within a specification. These should be adhered to. · Any instructions or drawings on non-cleanroom paper must not be taken into the cleanroom. They can be photocopied onto cleanroom paper, or laminated within plastic sheets, or placed in sealed plastic bags. · Particle generating operations such as drilling holes, or repairing ceilings and floors should be isolated from the rest of the area. A localised extract or vacuum can also be used to remove any dust generated. · Technicians should not bring any materials into a cleanroom that are given on a list of ‘contaminating material’. Technicians must tidy up when they are finished and ensure that the area is then ‘cleanroom cleaned’ by a person with suitable knowledge. Only cleaning agents, materials and equipment that has been approved for use in the cleanroom should be used.

6 human interface in cleanrooms

C K Moorthy

A

cleanroom is a special environment constructed at great cost, operated and maintained at great expense, with the sole purpose of insuring consistency in product quality and value and minimising product contamination or failure. The best design, layout and materials are worthless if the people working in the cleanroom do not fully understand its significance or the whats and whys of its operations. 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

74

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.

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 30µ in length, 5µ in width and less than 0.5µ in thickness. The rate at which skin cells are shed is influenced by the condition of the skin, its oil content, the climate and the nature of activity. After shave lotions dissolve skin oils and accelerate sloughing and flaking. Similarly, alcohols, while popular

human interface in cleanrooms

75

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 Activity

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)

Particles > 0.3F Viable emitted contaminants per minute* generated per minute* 100,000 500,000 1,000,000 2,500,000 5,000,000 7,500,000 10,000,000 10,000,000 $ 15,000,000 $ 15,000,000 $ 30,000,000

750 1,000 1,500 2,500 4,000 8,000 15,000 15,000 30,000 $ 30,000 $ 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

76

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 Site

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

Males

2075 2125 350 450 128 118 250 98 500 300 850 325 350 325 190 173 80 22750

Anaerobic flora

Females

Males

Females

1225 165 130 155 48 65 35 155 92 33 175 140 67 82 77 20 122 675

8000 50000 18500 67500 1025 57 9 33 14 178 55 9 14 4 7 2 3 10

13500 3500 2275 7500 1075 127 13 85 12 142 80 35 16 5 8 5 10 4

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

77

on evaporation of sweat the residual salts remain deposited on our skin cells. Chlorides of sodium and potassium are routinely found on analysing the contaminants in clean rooms. Hair becomes statically charged on combing, and attracts dust. Oiled hair retains the dust better than dry hair. Dry hair is brittle and breaks easily. Hair also produces a protein called keratanin, which is released into the environment. Studies indicate that a man on an average breathes 16,000 quarts of air per day, which converts to approximately 20 kg/day! And this aerosol is exhaled from a distance as close as 20 to 40 cms from the sensitive work piece. Inhalation disturbs the air pattern around the work area; exhalation carries a mixture of gases, vapour, liquid droplets, mucous and, of course, microorganisms. In particular, the exhaled air is rich with dust and other allergens that the lung is anxious to be rid of, and such contaminants are often thrown out with unusual force. Extreme examples are coughs and sneezes. Smokers breathe out more contaminants than nonsmokers, even several hours after they have last smoked. Drinking water after smoking helps slightly reduce the number exhaled. Cuts, abrasions, wounds, rashes, allergies and boils; and topical medicaments, dressings and plasters further aggravate the problem. Other conditions requiring care and vigil are discharges from eyes, ears, and nose; coughs, colds and sneezes; and, of course, menstrual periods.

Figure 2: Smokers’ exhalation

78

cleanroom operators’ manual

Data published in Ljungqvist and 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/m2 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/m2 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 > 0.5µ 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 >0.5µ size range and that among these were as many as 40 CFU of viable aerobic organisms. These data are generally consistent with the findings published by Dr William Whyte. Reinmuller’s data also showed that as the gowns aged and were subjected to washing and re-sterilization, both the number of total particulate and the level of microbial contamination increased. 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 0.5µ size class. It has been widely assumed that microorganisms in aseptic processing areas are associated with particulate in the 5-10µ 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

79

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

Body temperature is maintained at 37 0C; 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 0C. Since the cleanroom is designed to operate within the range 22 - 24 0C, the body surface is at an average of about 10 0C above its surroundings. This thermal gradient triggers convective currents rising from floor level to above the head. These currents disturb the airflow pattern in the room. These are some of the intrinsic contaminants ushered in with every human being who enters the cleanroom. Once we understand the body and its danger zones, it is easier to devise ways and means to contain the damage they can cause. extrinsic contaminants Not only do people produce contaminants, but they also serve as unwitting carriers of contaminants that are extrinsic to them. Starting from the water they wash with; the soaps they use; the towels and napkins; the

80

cleanroom operators’ manual

undergarments and street clothes; the cosmetics and makeup; jewellery and personal effects - all these make their contributions to the contaminant load carried by the individual. Analysis of the contaminants found in clean rooms show compounds of zinc and magnesium and talc, all originating from the talcum powders used by both men and women. The dust and grit on the streets, the grime and soot in the air; the jostling in crowds while they commute to work covers them all over with potential contaminants. And since people are mobile, they carry these contaminants with them wherever they go, leaving a trail along their path and place in jeopardy whatever they handle or touch. Movement also causes disturbance in the airflow field, and depending on how they move, they

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

81

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 4 M #M2.5 E #10

5 M3.5 100

6 M4.5 1,000

7 M5.5 10,000

8 M6.5 100,000

Items

Coverall Hood Mask Boots Gloves

Coverall Hood Mask Boots Gloves

Coverall Hood Mask Overshoes Gloves

Lab coat Cap

Lab coat Cap

Overshoes

Overshoes

Per entry

Daily

Daily

3/week

2/week

Change

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

82

cleanroom operators’ manual

and the practical, since the wearer ’s comfort is an important consideration. It is normally assumed that an effective filter must have a high pressure drop, and therefore be uncomfortable. In fact, this is not the case. Experiments show that the relationship between air filtration efficiency and pressure drop is not necessarily always linear. What we want is a reasonably good filter with a tolerably low pressure drop. At least one of the synthetics, DACRON, offers these advantages, though the price is high. But economising on gowns can prove costly beyond estimation: and compromising on clothing quality can place your product and reputation at high risk. All the Guidelines for Good Manufacturing Practice speak with one voice on the importance of good gowning practice. The first consideration, therefore, is the choice of the fabric itself. The important characteristics to look for are that it should not lint; it should at least not generate static charges; should be fire-retardant if not flameproof; and should be treated for water repellency and inhibition of microbial growth. antistatic, static dissipative and conductive fabrics Some applications are more sensitive to static charge dissipation than others, determined by the susceptibility of the product (microelectronic) or the environment (vulnerable to explosions). These applications demand conductive fabrics where electrically conductive fibres (carbon filament or carbon treated polyamide filament) is woven together with DACRON filaments resulting in strict electrostatic and particulate protection without any external or chemical treatments. (The best chemically treated fibres lose their conductive properties progressively with each successive wash). Such fabrics effectively prevent electrostatic surges by means of constant, rapid and controlled dissipation of charges (positive or negative) through low level ionisation or corona discharge to the atmosphere. A fabric is deemed to be antistatic if its surface resistivity is 1011 - 1013 ohms per square centimetre; static dissipative in the range 105 - 1011; and conductive in the range < 105. 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

83

Parameter

Static Dissipative*

Non-static

Composition

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

Lint character

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

Weight

115 gms/sq m

70 - 135 gm/sq m

Weave

30 x 30/sq cm

30 x 25/sq cm

Break strength

25 Kg/25 mm width

25 Kg/25 mm width

Elongation

80% of rupture

80% of rupture

Resistivity

104 - 1013ohms/sq cm

1.3 x 1015 ohms/sq cm

Voltage decay

90% in 10 - 25 secs

90% in < 60 secs

Static character

Static Dissipative

Non-static

Chemical

Resists acid

Resists acid

Permeability

< 0.005 mps/sq ft < 1 CFM/sq ft @ 25 mm wc

< 0.005 mps/sq ft < 1 CFM/sq ft @ 25 mm wc

Efficiency

> 80% down to 0.5 µ > 98% down to 5.0 µ

> 80% down to 0.5 µ > 98% down to 5.0 µ

Durability

200 cycles

200 cycles

Taber abrasion (% fibre loss)

0.6% (unlaundered)

0.6% (unlaundered)

non-linting

* 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. Other colours are in popular use. Many prefer other colours to “hide” soil. This is not good cleanroom practice. The operator or supervisor should be able to spot soiled garments and discard such garments.

84

Figure 5: Washing soiled contamination control apparel

1 Sort & Group

2 Prewash Inspection

3

4

5

Repair

Spotting & Stain Removal1

Prewash Antiseptic2

9

8

7

6

Final Rinse Liquid Additives5

Rinse Cold Water

Main Wash Water 60 0C Liquid Detergent4

Main Wash Solvent3

11

12

13

14

15

Air Dry under Class 100 Laminar Airflow (LAF)6

Press & Double Wrap under Class 100 LAF

Autoclave in Sachet

Store in Garment Cubicle

Issue

1. 2. 3.

Hyglo, Teepol, Clinitol, or CCl4 Savlon, Dettol/Iteol, Hydrogen peroxide or Peracetic acid Perchloroethylene, Trichloroethylene or Mineral turpentine

4. 5. 6.

Ezee, or Genteel Antistatic agent, Optical whitener, Fabric softener (Carboxymethyl cellulose 5% v/v) Class M6.5 (100,000) or better

cleanroom operators’ manual

10 Spin Dry

human interface in cleanrooms

85

Some avoid white because it is so difficult to maintain. If the Navy worldwide can use white and keep them sparkling, so can you. Some use a variety of colours to distinguish among different departments and product groups - maintenance, production, product A, product B etc. But such distinctions can also be made with a small arm band or shoulder stripe of a different colour, instead of having the entire garment in that other colour. The principal argument in favour of white is that it permits pre-wash soak with “bleach” (NaOCl). This not only keeps it sparkling white, but also acts as a strong anti-microbial treatment to reduce the bioburden. Any subsequent autoclave sterilisation (as in drugs & device manufacture) is rendered far more effective. good cleanroom garment tailoring practice After you have selected the fabric, you decide on the patterns that best suit your needs, and Figure 6: award the conversion Correct contract to an agency tailoring that is familiar with the special care required for tailoring contamination control clothing. Cut edges should be sealed; stitching should be doubleseamed; 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

cleanroom operators’ manual

86

covering hair, face, moustaches and beards, wrists, street clothing, ankles and street shoes should be scrupulously avoided. Even after gowning, some contaminants do escape into the environment, but the numbers are greatly reduced. cleanroom laundry To derive the maximum protection offered by contamination control clothing, special care is needed in the manner, as well as the environment in which it is washed, dried, pressed and packed. It is unfortunately common to find cleanroom clothing sent out for laundering. It is paradoxical: so much care is taken in selection and procurement of

Figure 8: Cleanroom laundry

these clothes; but little thought is spared to reflect on what is needed for cleaning them after every use. The local laundry was not designed to handle such garments, and the environment there is bound to be anything but dust-free. Orange Guide 2002 Annexure 1 Para 21 addresses this concern, and strongly advocates the setting up of a dedicated in-house laundering facility. The complete procedure described here is for your guidance. Setting up an in-house laundry, close to the main cleanroom, offers advantages you

human interface in cleanrooms

87

cannot ignore. The cleanroom laundry air cleanliness level could be one class lower than that being maintained in the processing area and the regulations enforced there should apply to the laundry too. After entry decontamination and gowning, we have one more device at our disposal to minimise the probability of contamination: generate as little as possible within the cleanroom. This demands good conduct and strict discipline. Posters explaining the Whats, Whys and Hows of Good Aseptic Practices drawn up with imagination and wit and should be displayed at vantage points to serve as constant reminders of the need for compliance and the consequences of disregard. good gowning practice Garments should be worn correctly to serve the intended purpose. The gowning procedure described here is intended to serve as a guide; you

Figure 9: Good gowning sequence

88

cleanroom operators’ manual

Figure 10: Recommended gowning & degowning for sterile areas

should draw up your own gowning sequence by modifying this procedure wherever necessary. o Remove street footwear. Change into cleanroom footwear. o Remove all street garments not necessary for warmth or modesty

human interface in cleanrooms

89

Figure 11: Recommended gowning & degowning for nonsterile areas

o Remove and safely store watches, rings, cigarettes, lighters, jewellery, purse and other personal effects.

90

cleanroom operators’ manual

o Scrub down. Remove cosmetics, if any applied. Use appropriate cleanroom grade detergent compatible with the disinfectants used to remove physical contaminants. o Washing of hands and forearms deserves special care. The under surfaces of fingernails should be thoroughly cleaned with a soft nylon brush, or when necessary, with a scraper. o Wear gowning cap. This is optional at this point in the gowning sequence. The purpose is to conceal the hair at an early stage, and keep it covered thereafter. o Enter change room. Installation of a good quality “tacky” mat at entrance is recommended. If you are not sure of the quality, you are better off without it. Even with a good tacky mat, research has established that you need to walk a distance of 20 steps before you have left behind 95% of your footborne debris. Having a standard “Welcome” size tacky mat may not be as useful as imagined. o Wear gowning gloves. This is also optional at this stage. The objective is to avoid contact with washed bare hands. Select gloves of proper style and size. o Carefully put on the first glove, touching the outside of the glove as little as possible. Then put on the second glove, taking care not to touch anything other than cleanroom apparel. o Obtain cleanroom apparel and accessories appropriate for your task and prepare for donning. o The first item to be worn is the legwear. Inspect the item for damages and stains and once satisfied sit on the “barrier” stool, if available, or on a chair or bench, and put on the first boot, taking care to ensure that it does not touch the floor. Then swing the clean foot over to the cleanroom side of the stool or bench. Put on the second boot and swing over fully to the cleanroom side and stand up. o Next put on your head cover, if necessary over the cap already on. Adjust to cover hair fully. Take care not to touch anything other than the items of garments. o Put on face mask, where applicable. o Now prepare the coverall for wearing it. Inspect for tears and soil, keeping it off the floor. Step into legs and then pull on the upper half. Tuck the skirt of the hood inside the collar of the coverall or coat. Close all fasteners at neck and wrists. Tuck legs of garment into boots and refasten legwear till it is snug and comfortable.

human interface in cleanrooms

91

o Discard gowning gloves, if worn. Disinfect hands as per procedure prescribed by your SOP. Put on working gloves using the same technique and care described earlier for donning gloves. Tuck cuffs of garment into gloves. o Check that all leg, and arm openings are completely sealed with gloves and boots. o Do not adjust garment after donning working gloves. As a matter of fact your gloved hand should now touch only your work related objects and nothing else. o Proceed through air shower and across another tacky mat to enter the cleanroom. hand decontamination and use of gloves The wearing of rubber gloves is by itself an aseptic measure, minimizing the risk of direct contact contamination of sterile equipment and processes. However, some contamination can occur through torn gloves or through invisible small holes that appear in about 20% of gloves during use, and also through moisture on sleeves of cotton gowns. For these reasons scrubbed operators should use an antiseptic skin preparation. Effective preparations are: 1. Certain detergent antiseptic solution containing, for example, 1% Chlorhexidine or 1% Povidone Iodine applied vigorously to fingers, hands, and forearms for 2-3 minutes with running water and no brush, followed by rinsing and drying 2. 10 ml of 70% Ethanol or 60% Isopropanol containing Glycerol (1%) and, for even greater antiseptic activity, Chlorhexidine (0.5%), but no water. Rub vigorously on to fingers, hands and forearms until they are dry. Repeated use of these agents has a cumulative effect due partly to residues of antiseptic left on the skin, which prevent the build-up of bacterial flora on the gloved hand. A detergent must be used to remove physical contaminants. The under surfaces of fingernails should be cleaned, when necessary, with a scraper. Hands must be washed with an antiseptic detergent preparation, and fresh gloves must be put on. If gloves are sterilized and re-used they must be tested for holes by inflation underwater. Rings should be removed before preparation of hands. Use of brushes is generally discouraged, because they are in turn so difficult to clean and disinfect. Besides, over enthusiastic scrubbing

cleanroom operators’ manual

92

can cause the skin oils to be removed to such an extent that it tends to flake and slough off, emitting particles that may be or not carry transient or resident microflora. The choice of detergent and antiseptic will determine how effective your hand wash process is. The objective should be clean and sanitise the skin before donning sterile gloves, which acts as the final barrier. When hands are clean, the burden on the gloves as protective gear diminishes. good conduct in controlled environments O Fully understand of contamination control techniques and realise the enormous responsibility of working in a cleanroom. O Pay attention to personal hygiene and clothing.

Figure 12: Bad conduct

human interface in cleanrooms

93

O Avoid unnecessary movements within the cleanroom O When you must move, make it slow and rhythmic. Avoid movements upstream of clean airflow. O Avoid exiting the area until your next break period. O Control any urge to indulge in nervous relief type mannerisms such as scratching, rubbing hands, fastening and unfastening your garment or twitching your face or legs. O Smile. But avoid unnecessary conversation. If you must talk, speak softly. Use intercom to communicate with those outside the cleanroom. O Horseplay, singing, humming, whistling, shouting, fun, frolic and frivolity have their proper place: the cleanroom is not that place.

Figure 13: Good conduct

O If you have a point to argue, the cleanroom is not the place to do it in. O Never eat, drink, chew or smoke in a cleanroom. If you are a smoker, smoke outside and drink water before entering the cleanroom. O Insist on and use only cleanroom compatible stationery. If paper is unavoidable, shield it in an acceptable wrapper and leave only a window open for the area where you must write or enter data. O Do not exchange items between clean and outside environments. Any item coming in shall be subject to prescribed decontamination procedures as laid down in your SOPs each time it enters or reenters. Any item leaving should be decontaminated if so required. O If you are hurt or ill or otherwise indisposed, inform your supervisor and abide by his decision. O Air locks, specially those for equipment/material entry, should not be occupied by cleanroom and outside personnel at the same point in time. O Keep products and components in covered containers, and avoid exposing them to the environment unnecessarily. O Open such trays or other containers only under LAF clean air cover. O Store containers along the side and downstream of the work piece, not upstream. Avoid clutter at your work station. Keep it clean and orderly. O Place open dishes containing materials or work objects in the unobstructed clean airflow zone. Similarly, fixtures for handling the work piece should be in the unobstructed clean air path. O Avoid bending over your products or components. Handle these items with care, and hold either at the base or sides, depending on how it is prescribed in your SOP. O Never pick up and use any component that has accidentally fallen to the floor. O Insist on separate sets of tools, trolleys and other implements that you may need in the cleanroom, and ensure that they remain there and not sent out again. Follow the precept that what is not needed should not be in the cleanroom; whatever is needed, shall not leave the cleanroom. O If you notice any abnormality, or are in doubt about something, or have a suggestion for improvement, discuss it with your supervisor at the first available opportunity.

7 laminar airflow

C K Moorthy

L

aminar (or unidirectional) airflow as applied to industrial cleanroom technology is defined as airflow in which the entire mass of air within a confined space moves with uniform velocity along parallel ( or non-intersecting) flow lines. The credit for development of this technique for airborne contamination control is generally attributed to Whitfield of Sandia Corporation, USA, who termed it as “a piston of clean air” pushing out suspended contaminants from the work environment. In practice, achievement of true laminar airflow, as defined above, is never possible. A suspended particle in space can move in any direction - forward or backward; leftward or rightward; upward or downward. However, when entrained in a laminar air stream, it moves predominantly in one direction. In other words, its velocity along the direction of airflow is substantially larger than any component of velocity in any other direction. If the direction of flow is along the X-axis and the velocity is U, then

cleanroom operators’ manual

96

Ux >> Uy , Uz y

UX ≈ constant Uy , U z ≈ 0 Ux >> Uy, Uz o

x

Fig 1 Unidirectional laminar airflow Besides, true parallel flow is precluded by the practical necessity of placing objects (including people) within the confined space. Although any object so placed will cause discontinuities in the flow pattern, these disturbed areas are swept out by the continuous flow of clean air. Furthermore, air patterns tend to reestablish themselves within a distance approximately equal to three to five times the equivalent diameter of the object. The region immediately downstream of the obstructing object, known as the wake zone, is at relatively low pressure (Bernoulli effect), with strong turbulent currents, whose intensity decreases as we near the point in space where the air pattern returns to normal. This entire zone of low pressure is known as the cone of turbulence, where the apex of the cone is at an approximate distance of 3 to 5 times the equivalent diameter from the obstructing object (forming the base of the cone).

D

5D Fig 2 Wake region disturbance & cone of turbulence Behind each product or work piece placed in clean laminar airflow there is such a cone; if the apex of the cone lies well inside the clean space, the turbulent air, being clean, will not jeopardise the product; but if part

laminar airflow

97

Air velocity in the laminar range is determined by Reynold's Number (N). N

=

ρUD/µ

where ρ is the fluid density, U is the flow speed, D is a characteristic length and µ is the fluid viscosity. Since both ρ and µ are functions of temperature, the velocity range in the laminar regime will vary with temperature too. In typical cleanroom conditions, the mean value is 0.5 mps (100 fpm) with a standard deviation of 0.065 mps (13 fpm), which translates to a total range of 0.305 (61 fpm) to 0.695 mps (139 fpm). The ISO Standards allow down to 0.2 mps (40 fpm); but the Orange Guide 2002 still insists on 0.45 mps +/- 0.1 mps (90 +/- 20 fpm). Schedule M permits Vertical Laminar downflow velocity in the range (60 +/- 20 fpm).

of the cone extends to contaminated space, the low pressures in the wake will aspirate the contaminated air and increase the risk of product contamination. Suspended contaminants present in air when a laminar airflow system is first turned on are propelled out of the cleanroom or work space in the first pass, clearance being typically obtained within a few minutes due to the high rate of air exchange, and at steady state the suspended contaminant density is largely determined by that generated within the room. The air velocity in industrial laminar airflow installations is 0.3 to 0.6 mps (60 - 120 fpm), which is almost imperceptible, much less than the force felt when walking at one mile per hour on a still day. Although this velocity is very low, it is much higher than the rate at which Y U1 P1

U2

P2

U3

P3

U4

O

P4

X

U1 = U2 = U 3 = U 4 P1 = P2 = P 3 = P 4

Fig. 5.3

98

cleanroom operators’ manual

suspended particles tend to settle. For example, a 10µ sand particle falls in still air at 1.5 fpm, and a bacteria (1µ) at less than an inch per minute. In other words, if the 10µ sand particle were dropped in an industrial horizontal laminar airflow installation, it would travel 20’ horizontally along direction of airflow while dropping less than 4” vertically. The bacteria would have dropped less than a quarter of an inch over the same distance. Laminar airflow, therefore, gives little opportunity to the suspended contaminants it encounters to settle down and moves them out along predetermined flow lines, away from vulnerable sites, passing any point in space lying in its path once, and only once. If the suspended contaminant, entrained upstream of the product, passes a critical site without impinging or settling, it will never return to that site again. In contrast, in turbulent airflow, the eddy currents present can, and often do, allow a contaminant to return again and again. However, the cost of a laminar airflow room is prohibitive, and most designers rely on localised laminar airflow work stations at critical work sites to protect against aerial contamination, and opt for the more economical mixed flow or turbulent flow cleanrooms, where filtered air is dispersed at multiple-terminals scattered in the ceiling. Laminar airflow workstations are used for either or both of the following: Product protection for operations involving materials that must be kept sterile or free from unwanted ecological agents; and agent containment for manipulations involving etiological agents, materials or procedures requiring personnel protection, where the items in use must be confined within the working area and not allowed to escape into the environment. For selecting the pattern of airflow that best suits an application, the primary consideration would be the nature of work being carried out on the clean air work station. For optimum cleanliness, it is vital that the flow of clean air across, on and around the product or process be maintained at a maximum. Horizontal flow systems offer maximum product protection, and are, by far, the most effective form of contamination control. They call for the least in operator discipline where the work activity involves physical manipulation. Operators may bend their heads, or other parts of their bodies over or around the work site without seriously jeopardising it. The work table edge is deemed to be the boundary separating the clean space from the contaminated environment, and care must be taken to

laminar airflow

99

ensure that the apex of any cone of turbulence generated in the clean space does not penetrate this boundary. These systems, however, are unsuitable for operations where toxic fumes or vapours are encountered, or for work with open vessels of chemicals, solvents or powders, since horizontal flow would raise vapour levels in the room, increase solvent drag-out and distribute powder particles throughout the environment, resulting in not only greater contamination levels within, but also enhanced risks of cross contamination through operators who may be moving from station to station. Fig 4 Horizontal laminar flow clean air work station

In some cases, the production equipment bulk may preclude parallel horizontal flow across the work surface and cause eddies which could negate the very purpose of a clean air bench. For such and other similar applications, specially involving agent containment, a vertical downward airflow configuration is more appropriate. Vertical downflow is also favoured for procedures that do not require eye-hand coordination, and for equipment which is semiautomatic or fully-automatic.

Fig 5 Vertical laminar downflow clean air work station

Horizontal LF systems are generally fitted with a protective grille downstream of the HEPA filter to prevent accidental damage to the media as well as to serve as a secondary plenum for pressure stabilisation. Unfortunately, fine particles that penetrate the filter often impact on this grille, and over a period of time a film or coating builds up behind this grille, leading to the hazard of intermittent emissions caused by mechanical vibration or sudden variations in airflow. (Had the fine particles not been arrested, in all

100

cleanroom operators’ manual

probability they may have just floated past the work site; but the agglomeration on the incident face of the protective grille coughs up much larger sized particles whose contaminating potential is much enhanced.) Unlike Horizontal LF, where airflow is unobstructed, the vertical downward flow impinges directly on the work surface, which marks a dead-end. Perforations on the work surface improves matters somewhat, but it is still far from adequate. In the process, an envelope of air cushion builds up over the surface, causing clean air entering the work space to deviate towards the work station exit face much before it reaches the work surface. Designs that feature partial or total exhaust, however, have a better control over the airflow distribution within the work space. Among the innovations in this design is the partial recirculatory system, which sucks back up to 60% of the air from the work space through return ducts terminating in slots along the periphery of the work surface. Whenever work space air is exhausted from the room, there is partial negative pressure with respect to the room at the work space. To prevent room air from contaminating the product, designs provide for an air curtain (high velocity sheath of air) along the entry face with perforations on the work table edge, so that the air ingress is out of harm’s way. Unlike fume exhaust chambers, clean air LF work stations do not allow makeup air into the main work area. The table edge, for example, is generally made to protrude outward slightly, so that the perforations on the surface to draw in the makeup air is marginally outside the plane of the air barrier. Room air, being filtered and tempered, is too expensive to be cast out as exhaust indiscriminately. To minimise the quantum so exhausted, a design innovation termed add-air, or auxiliary air feed system, is commonly employed, whereby a controlled amount of untempered air from outside the clean environment (usually a corridor) is drawn in to complement the air sucked in from the room. In this process, the exhaust volume requirements are met; the work space is contained under negative pressure; the product site is protected; and only the bare minimum quantity of room air is used up. Many design innovations in the laminar airflow pattern have been introduced. Instead of having a piston of air moving with the same constant velocity, the velocity profile could be graded, such that adjacent streams are at marginally differing velocities, while retaining the entire mass within acceptable LF limits (vary from 60 fpm to 120 fpm). This

laminar airflow

Conventional univelocity LF

101

yields superior airstream integrity, specially while confronting obstructing objects. Air could be made to converge or focus on the work site for enhanced dilution and cleandown. Likewise, it could be diverging to spread clean air and extend the clean zone perimeter. While the latter two have air streams that are not parallel, their velocity is within the laminar range.

Graded velocity LF

Converging airflow

Fig 6 Laminar flow variations

Radial airflow allows effective utilisation of floor space by accommodating several operators at the work table who do not get into each other’s way. Inclined airflow permits bringing the object or equipment to be protected much closer to the filter. In certain cases of containment, the product aerosols must be kept away from the operator. Powder weighing and dispensing is a common application. To guarantee such protection by isolation, reverse laminar airflow techniques are employed. The plenum is maintained under negative pressure in some patented designs, such that if a filter is ill-fitted or develops a leak in its gasket, clean air from the work space is sucked back through the gap in the filter seating, rather than allow unfiltered air to bypass the filter and contaminate the work space.

Other improvements include incorporation of chemical adsorbent filters for vapour, gas and odour removal; desiccants for moisture removal; electronic intermediate filters for enhanced ultrafines capture and static control; multispeed and variable speed motor-blowers or the more recent “smart” motor-blower that automatically adjusts speed to compensate for filter loading; and chilled water line complete with thermostat and humidistat for temperature and humidity control. The question of choice of material for bulkhead execution is often asked, and the answer is coloured by the camp answering. In practice, it does

cleanroom operators’ manual

102

Diverging airflow

Inclined univelocity LF

Radial univelocity LF

not really matter as long as the construction is rugged, has a cleanroom grade surface finish, can withstand normal rigours of cleanroom sanitation chemicals and damps noise and vibration to acceptable levels. In some designs, like a clean air tent, the sides are often enclosed with panels, While such panels help isolate the interior, the boundary layer separation of airflow at the periphery causes aspiration of outside air into the enclosure (Bernoulli effect). If the design features an integral clean air barrier all along the inner perimeter, such invading aerosols can be contained. Laminar airflow guarantees stability in the parametric profiles (temperature, humidity contaminant density and air velocity) along its path. At the point where this ceases to be the case, laminarity may be deemed to be lost. Before we close, let us emphasise that laminarity relates to air velocity and not to air cleanliness. We can have turbulent air which is Class 100 clean; and true laminar airflow of unclean air. To make double sure that we want both, we say Class 100 Laminar Airflow.

Reverse LF

Fig 7 More laminar flow variations

Another advantage arising from such unidirectional non-turbulent streamline flow at uniform velocity is that parametric gradients are not disturbed. They remain stable. The points in space with identical parametric values are referred to as being isoparametric. For example, points in space with identical contaminant density, or number of particles per unit volume, are known as isopleths. Laminar airflow may be relied upon to guarantee stable isopleths. As a corollary, when isopleths cease to be stable, laminar airflow ceases to exist.

laminar airflow

103

Figure 8: A Reverse HLAF Containment Workstation for TB sputum samplecollection

Interesting inputs on unidirectional airflow from ISO 14644-4

Figure 9: Product protection Improvement by airflow design

Figure 10: Disturbance of unidirectional airflow Improvement by personnel behaviour

104

cleanroom operators’ manual

Figure 11: Disturbance of unidirectional airflow Improvement by personnel behaviour

Figure 12: Disturbance of unidirectional airflow Improvement by arrangement

Figure 13: Disturbance of unidirectional airflow Improvement by airflow concept

laminar airflow

105

Figure 14: Passive & Active Systems

Figure 15: Personnel/environment/product protection

8 good biosafety practices

adapted with kind permission from the CDC/NIH 4th edition of Biosafety in Microbiological and Biomedical Laboratories

D

espite the 100+ years of our vaccine research, deveopment and production traditions, there is still, in many organisations, at both laboratory as well as shop floor, an alarming sense of complacency, and apalling disregard for fundamentals of biosafety, due either to incomplete or incorrect information, or to lack of comprehension about the dangers involved in working with pathogenic organisms. The reasons for this vary: O Working with strains that induce the required immuno response, but do not cause disease O The organism is attenuated and lacks the virulence to cause disease O The concentration needed to induce disease is several orders of magnitude higher than that which may be accidentally ingested O The organism does not have any effect on adults O The organism does not cause disease in humans

108

cleanroom operators’ manual

These notions, widespread as they are, are disturbing, and something that should cause deep concern. For example, Bordetella pertussis, a human respiratory pathogen of worldwide distribution, is the causative agent of whooping cough. The disease is typically a childhood illness; however, the agent has increasingly been associated with adult illness. Several outbreaks in health-care workers have been reported in the literature. Adolescents and adults with atypical or undiagnosed disease can serve as reservoirs of infection and transmit the organism to infants and children. Eight cases of infection with B.pertussis in adults have been documented at a large research institution. The individuals involved did not work directly with the organism, but had access to common laboratory spaces where the organism was manipulated. One case of secondary transmission to a family member was documented. A similar incident occurred at a large Midwestern university resulting in two documented cases of laboratory-acquired infection and one documented case of secondary transmission. Other laboratory-acquired infections with B. pertuss is have been reported, as well as adult-to-adult transmission in the workplace. Laboratory-acquired infections resulting from the manipulation of clinical specimens or isolates have not been reported. The attack rate of this airborne infection is influenced by intimacy and frequency of exposure of susceptible individuals. Genetic mutations, transgenic mutations and trans-species mutations are all eminently plausible, and should not be discounted. It is well recognised that virus in attenuated vaccine for birds can, after five successive passages, can regain full virulence. Opportunistic pathogens and compromised hosts are ubiquitous, and no precaution is too much in our endeavours to provide biosafe working environs. Though guidelines for biological production have been reproduced elsewhere, the biosafety aspects of biohazardous operations are covered here, drawing heavily from the guidelines and recommendations of Center for Disease Control (CDC), USA; National Institute of Health (NIH), USA and a host of other International Agencies concerned with Biosafety in Medical and Biological Laboratories. As a consequence, much of the material here is directed towards biosafe laboratories; but the same principles also apply for manufacturing. The reader is also cautioned about the differences in perception of risks across countries for the same organism. For example, Foot and Mouth Disease (FMD) is classified at Risk Level 2 in India; but at Risk Level 5 in Canada and elsewhere. Tuberculosis is routinely treated in India at Level 2, while in this presentation where material has been borrowed

good biosafety practices

109

from USA and Canada, the risk is indicated at Level 3. What we commonly refer to as P3 Facilities are described instead as P4 here. biosafety Microbiology laboratories and biological production centres are special, often unique, work environments that may pose identifiable infectious disease risks to persons in or near them. Bacteria, viruses, fungi or other infectious agents are studied because they may cause disease, they can help us understand the natural world, and for many other reasons including the possibility of industrial applications. Since many of the agents can be pathogenic to humans, animals or other forms of life, their use poses risks which vary with each agent and the way it is used. Biotech laboratories, therefore, are special, often unique, work environments that may pose identifiable infectious disease risks to persons in or near them. Infections have been contracted in the laboratory and production areas throughout the history of microbiology and immunology. As a result, safety norms, standards and practices have been designed and developed over the years to reduce to an acceptable level the risks inherent in the use of dangerous materials. Stringent standards are set for hazardous agents and less stringent ones for agents which cause only minor problems. Safety standards are therefore compromises designed to allow needed work to proceed without exposing those involved or others to more than minimal risk. Besides the attitudes and actions of those who work in these hazardous environs determine their own safety, and that of their colleagues and of the community. Facility, equipment and design can contribute to safety only if they are used properly by people who are genuinely concerned and knowledgeable about safety issues. principles of biosafety The term “containment” is used in describing safe methods for managing infectious agents in the laboratory environment where they are being handled or maintained. The purpose of containment is to reduce or eliminate exposure of laboratory workers, other persons, and the outside environment to potentially hazardous agents. Primary containment, the protection of personnel and the immediate laboratory environment from exposure to infectious agents, is provided by both good microbiological technique and the use of appropriate safety

cleanroom operators’ manual

110

equipment. The use of vaccines may provide an increased level of personal protection. Secondary containment, the protection of the environment external to the laboratory from exposure to infectious materials, is provided by a combination of facility design and operational practices. Therefore, the three elements of containment include laboratory practice and technique, safety equipment, and facility design laboratory practice and technique The most important element of containment is strict adherence to standard microbiological practices and techniques. Persons working with infectious agents or potentially infected materials must be aware of potential hazards, and must be trained and proficient in the practices and techniques required for handling such material safely. The director or person in charge of the laboratory is responsible for providing or arranging for appropriate training of personnel. Each laboratory should develop or adopt a biosafety or operations manual which identifies the hazards that will or may be encountered, and which specifies practices and procedures designed to minimize or eliminate risks. Personnel should be advised of special hazards and should be required to read and to follow the required practices and procedures. A scientist trained and knowledgeable in appropriate laboratory techniques, safety procedures, and hazards associated with handling infectious agents must direct laboratory activities. When standard laboratory practices are not sufficient to control the hazard associated with a particular agent or laboratory procedure, additional measures may be needed. The laboratory director is responsible for selecting additional safety practices, which must be in keeping with the hazard associated with the agent or procedure. Laboratory personnel, safety practices, and techniques must be supplemented by appropriate facility design and engineering features, safety equipment, and management practices. safety equipment ( primary barriers) Safety equipment includes biological safety cabinets (BSCs), enclosed containers, and other engineering controls designed to remove or minimize exposures to hazardous biological materials. The biological safety cabinet (BSC) is the principal device used to provide containment

good biosafety practices

111

of infectious splashes or aerosols generated by many microbiological procedures. Safety equipment also may include items for personal protection such as gloves, coats, gowns, shoe covers, boots, respirators, face shields, safety glasses, or goggles. Personal protective equipment is often used in combination with biological safety cabinets and other devices which contain the agents or materials being worked with. facility design (secondary barrier) The design of the facility is important in providing a barrier to protect persons working inside and outside of the laboratory within the facility, and to protect persons in the community from infectious agents which may be accidentally released from the laboratory. Laboratory management is responsible for providing facilities commensurate with the laboratory’s function and the recommended biosafety level for the agents being manipulated. The recommended secondary barrier is determined by the risk of transmission of specific agents. Secondary barriers in these laboratories will include separation of the laboratory work area from public access, availability of a decontamination facility (e.g., autoclave), and hand washing facilities. Design features could include airconditioning, controlled access zones, airlocks at laboratory entrances, or separate buildings or modules for isolation of the laboratory. biosafety levels Four biosafety levels (BSLs) are described which consist of combinations of laboratory practices and techniques, safety equipment, and laboratory facilities. Each combination is specifically appropriate for the operations performed, the documented or suspected routes of transmission of the infectious agents, and for the laboratory function or activity. The recommended biosafety level(s) for the organisms in Section VII (Agent Summary Statements) represent those conditions under which the agent can ordinarily be safely handled. The laboratory director is specifically and primarily responsible for assessing risks and for appropriately applying the recommended biosafety levels. Generally, work with known agents should be conducted at the biosafety level recommended in Section VII. When specific information is available to suggest that virulence, pathogenicity, antibiotic resistance patterns,

cleanroom operators’ manual

112

vaccine and treatment availability, or other factors are significantly altered, more (or less) stringent practices may be specified. risk assessment The potential for untoward events must be evaluated to reduce or eliminate worker exposure to or release of infectious organisms. Through the process of risk assessment, the work procedures are evaluated for potential exposure to the microorganism. The hierarchy of controls to prevent or minimize exposure to hazardous materials includes engineering controls, administrative and procedural controls, and work practices which may involve use of additional personal protective equipment. Having a properly operating BSC available is an effective engineering control; requiring its use is an administrative control. Some suggested work practices and procedures associated with working safely in a BSC are detailed here. preparing for work within a class II BSC Preparing a written checklist of materials necessary for a particular activity and placing necessary materials in the BSC before beginning work serves to minimize the number of arm-movement disruptions across the fragile air barrier of the cabinet. The rapid movement of a worker’s arms in a sweeping motion into and out of the cabinet will disrupt the air curtain and may compromise the partial barrier containment provided by the BSC. Moving arms in and out slowly, perpendicular to the face opening of the cabinet, will reduce this risk. Other personnel activities in the room (e.g., rapid movement, open/closing room doors, etc.) may also disrupt the cabinet air barrier. Laboratory coats should be worn buttoned over street clothing; latex gloves are worn to provide hand protection. A solid front, back-closing lab gown provides better protection of personal clothing than a traditional lab coat. Gloves should be pulled over the knitted wrists of the gown, rather than worn inside. Elasticized sleeves can also be worn to protect the investigator’s wrists. Before beginning work, the investigator should adjust the stool height so that his/her face is above the front opening. Manipulation of materials should be delayed for approximately one minute after placing the hands/ arms inside the cabinet. This allows the cabinet to stabilize and to “air sweep” the hands and arms to remove surface microbial contaminants. When the user’s arms rest flatly across the front grille, room air may

good biosafety practices

113

flow directly into the work area, rather than being drawn through the front grille. Raising the arms slightly will alleviate this problem. The front grille must not be blocked with research notes, discarded plastic wrappers, pipetting devices, etc. All operations should be performed at least four “4” inches from the front grille on the work surface. Materials or equipment placed inside the cabinet may cause disruption to the airflow, resulting in turbulence, possible cross-contamination, and/ or breach of containment. Extra supplies (e.g., additional gloves, culture plates or flasks, culture media) should be stored outside the cabinet. Only the materials and equipment required for the immediate work should be placed in the BSC. BSCs are designed to be operated 24 hours per day, and some investigators find that continuous operation helps to control the laboratory’s level of dust and other airborne particulates. Although energy conservation may suggest BSC operation only when needed, especially if the cabinet is not used routinely, room air balance is an overriding consideration. In some instances, room exhaust is balanced to include air discharged through ducted BSCSs. Cabinet blowers should be operated at least three to five minutes before beginning work to allow the cabinet to “ purge”. This purge will remove any particulates in the cabinet. The work surface, the interior walls (not including the supply filter diffuser), and the interior surface of the window should be wiped with 70% ethanol (EtOH), a 1:100 dilution of household bleach (i.e., 0.05% sodium hypochlorite), or other disinfectant as determined by the investigator to meet the requirements of the particular activity. When bleach is used, a second wiping with sterile water is needed to remove the residual chlorine, which may eventually corrode stainless steel surfaces. Wiping with non-sterile water may recontaminate cabinet surfaces, a critical issue when sterility is essential (e.g., maintenance of cell cultures). Similarly, the surfaces of all materials and containers placed into the cabinet should be wiped with 70% ETOH to reduce the introduction of contaminants to the cabinet environment. This simple step will reduce introduction of mold spores and thereby minimize contamination of cultures. Further reduction of microbial load on materials to be placed or used in BSCs may be achieved by periodic decontamination of incubators and refrigerators.

cleanroom operators’ manual

114

material placement inside the BSC Plastic-backed absorbent toweling can be placed on the work surface (but not on the front or rear grille openings). This toweling facilitates routine cleanup and reduces splatter and aerosol formation during an overt spill. It then can be folded and placed in an autoclavable biohazard bag when work is completed.

Figure 1: Material placement inside the BSC

All materials should be placed as far back in the cabinet as practical, toward the rear edge of the work surface and away from the front grille of the cabinet. Similarly, aerosol-generating equipment (e.g., vortex mixers, tabletop centrifuges) should be placed toward the rear of the cabinet to take advantage of the air split . Active work should flow from the clean to contaminated area across the work surface. Bulky items such as biohazard bags, discard pipette trays and suction collection flasks should be placed to one side of the interior of the cabinet. Certain common practices interfere with the operation of the BSC. The autoclavable biohazard collection bag should not be taped to the outside of the cabinet. Upright pipette collection containers should not be used in BSCs nor placed on the floor outside the cabinet. The frequent inward/ outward movement needed to place objects in these containers is disruptive to the integrity of the cabinet air barrier and can compromise both personnel and product protection. Only horizontal pipette discard trays containing an appropriate chemical disinfectant should be used within the cabinet. Furthermore, potentially contaminated materials should not be brought out of the cabinet until they have been surface decontaminated. Alternatively, contaminated materials can be placed

good biosafety practices

115

into a closable container for transfer to an incubator, autoclave or for other decontamination treatment. operations within a class II BSC Many common procedures conducted in BSCs may create splatter or aerosols. Good microbiological techniques should always be used when working in a biological safety cabinet. For example, techniques to reduce splatter and aerosol generation will minimize the potential for personnel exposure to infectious materials manipulated within the cabinet. Class II cabinets are designed so that horizontally nebulized spores will be captured by the downward flowing cabinet air within fourteen inches of travel. Therefore, as a general rule of thumb, keeping clean materials at least one foot away from aerosol-generating activities will minimize the potential for cross-contamination. The general work flow should be from “clean to contaminated (dirty)”. Materials and supplies should be placed in such a way as to limit the movement of “dirty” items over “clean” ones. Several measures can be taken to reduce the chance for crosscontamination when working in a BSC. Opened tubes or bottles should not be held in a vertical position. Investigators working with Petri dishes and tissue culture plates should hold the lid above the open sterile surface to minimize direct impaction of downward air. Bottle or tube caps should not be placed on the toweling. Items should be recapped or covered as soon as possible. Open flames are not required in the near microbe-free environment of a biological safety cabinet. On an open bench, flaming the neck of a culture vessel will create an upward air current which prevents microorganisms from falling into the tube or flask. An open flame in a BSC, however, creates turbulence which disrupts the pattern of air supplied to the work surface. When deemed absolutelv necessary, touch-plate microburners equipped with a pilot light to provide a flame on demand mav be used. Internal cabinet air disturbance and heat buildup will be minimized. The burner must be turned off when work is completed. Small electric “furnaces” are available for decontaminating bacteriological loops and needles and are preferable to an open flame inside the BSC. Disposable sterile loops can also be used. Aspirator bottles or suction flasks should be connected to an overflow collection flask containing appropriate disinfectant, and to an in-line HEPA or equivalent filter.

cleanroom operators’ manual

116

Figure 2: Working with aspirator bottles and suction flasks

This combination will provide protection to the central building vacuum system or vacuum pump, as well as to the personnel who service this equipment. Inactivation of aspirated materials can be accomplished by placing sufficient chemical decontamination solution into the flask to kill the microorganisms as they are collected. Once inactivation occurs, liquid materials can be disposed of appropriately as noninfectious waste. Investigators must determine the appropriate method of decontaminating materials that will be removed from the BSC at the conclusion of the work. When chemical means are appropriate, suitable liquid disinfectant should be placed into the discard pan before work begins. Items should be introduced into the pan with minimum splatter, and allowed appropriate contact time as per manufacturer’s instructions. Alternatively, liquids can be autoclaved prior to disposal. Contaminated items should be placed into a biohazard bag or discard tray inside the BSC. Water should be added to the bag or tray prior to autoclaving. When a steam autoclave is to be used, contaminated materials should be placed into a biohazard bag or discard pan containing enough water to ensure steam generation during the autoclave cycle. The bag should be taped shut or the discard pan should be covered in the BSC prior to removal to the autoclave. The bag should be transported and autoclaved in a leakproof tray or pan. surface decontamination All containers and equipment should be surface decontaminated and removed from the cabinet when work is completed. At the end of the work day, the final surface decontamination of the cabinet should include

good biosafety practices

117

a wipe-down of the work surface, the cabinet’s sides and back, and the interior of the glass. If necessary, the cabinet should also be monitored for radioactivity and decontaminated when necessary. Investigators should remove their gloves and gowns and wash their hands as the final step in safe microbiological practices. Small spills within the BSC can be handled immediately by removing the contaminated absorbent paper toweling and placing it into the biohazard bag. Any splatter onto items within the cabinet, as well as the cabinet interior, should be immediately wiped with a towel dampened with decontaminating solution. Gloves should be changed after the work surface is decontaminated and before placing clean absorbent toweling in the cabinet. Hands should be washed whenever gloves are changed or removed. Spills large enough to result in liquids flowing through the front or rear grilles require more extensive decontamination. All items within the cabinet should be surface decontaminated and removed. After ensuring that the drain valve is closed, decontaminating solution can be poured onto the work surface and through the grille(s) into the drain pan. Twenty to thirty minutes is generally considered an appropriate contact time for decontamination, but this varies with the disinfectant and the microbiological agent. Manufacturer’s directions should be followed. The spilled fluid and disinfectant solution on the work surface should be absorbed with paper towels and discarded into a biohazard bag. The drain pan should be emptied into a collection vessel containing disinfectant. A flexible tube should be attached to the drain valve and be of sufficient length to allow the open end to be submerged in the disinfectant within the collection vessel. This procedure serves to minimize aerosol generation. The drain pan should be flushed with water and the drain tube removed. Should the spilled liquid contain radioactive material, a similar procedure can be followed. Radiation safety personnel should be contacted for specific instructions. gas decontamination BSCs that have been used for work involving infectious materials must be decontaminated before HEPA filters are changed or internal repair work is done. Before a BSC is relocated, a risk assessment which considers the agents manipulated within the BSC must be done to determine the need for decontamination. The most common

cleanroom operators’ manual

118

decontamination method uses formaldehyde gas, although more recently hydrogen peroxide vapor has been used successfully. This environmentally benign vapor is useful in decontaminating HEPA filters, isolation chambers and centrifuge enclosures. facility and engineering requirements: secondary barriers Whereas biological safety cabinets are considered to be the primary safety barrier for manipulation of infectious materials, the laboratory room itself is considered to be the secondary safety barrier. Inward directional air flow is established exhausting a greater volume of air than is supplied to a given laboratory and by drawing makeup air from the adjacent space. This is optional at biosafety level 2 but must be maintained at BSL-3. The air balance for the entire facility should be established and maintained to ensure that air flow is from areas of least- to greater contamination. building exhaust At BSL-3 and BSL-4, exhaust laboratory air must be directly exhausted since it is considered potentially contaminated. This concept is referred to as a dedicated single-pass exhaust system. The exhausted room air can be HEPA-filtered when a high level of aerosol containment is needed, which is always true at BSL-4 and is optional at BSL-3. When the building exhaust system is used to vent a ducted BSC, the system must have a sufficient capacity to maintain the exhaust flow if changes in the static pressure within the system should occur. Otherwise, each cabinet must have a dedicated exhaust system. The room exhaust system should be sized to handle both the room and all containment devices vented through the system. Adequate supply air must be provided to ensure appropriate function of the exhaust system. The facility engineer should be consulted before locating a new cabinet requiring connection to the building exhaust system. Right angle bends, long horizontal runs, and transitional connectors within the systems will add to the demand on the exhaust fan. The building exhaust air should be discharged away from supply air intakes, to prevent entrainment of exhausted laboratory air back into the building air supply system. utility services Utility services needed within a BSC must be planned carefully. Protection of vacuum systems has already been addressed. Electrical outlets inside

good biosafety practices

119

the cabinet must be protected by ground fault circuit interrupters and should be supplied by an independent circuit. When propane gas is provided, a clearly marked emergency gas shut-off valve outside the cabinet must be installed for fire safety. All nonelectrical utility services should have exposed, accessible shut-off valves. ultraviolet lamps Ultraviolet (UV) lamps are not required in BSCs. If installed, UV lamps must be cleaned weekly to remove any dust and dirt that may block the germicidal effectiveness of the ultraviolet light. The lamps should be checked periodically with a meter to ensure that the appropriate intensity of UV light is being emitted. UV lamps must be turned off when the room is occupied to protect eyes and skin from UV exposure, which can burn the cornea and cause skin cancer. BSC placement Biological safety cabinets were developed as work stations to provide personnel, product and environmental protection during the manipulation of infectious microorganisms. Certain considerations must be met to ensure maximum effectiveness of these primary barriers. Whenever possible, a 12-inch clearance should be provided behind and on each side of the cabinet to allow easy access for maintenance, and to ensure that the air return to the laboratory is not hindered. A 12- to 14- inch clearance above the cabinet may be required to provide for accurate air velocity measurement across the exhaust filter surface with a thermoanemometer and for exhaust filter changes. When the BSC is hard-ducted or connected by a thimble unit to the ventilation system, adequate space must be provided so that the configuration of the duct work will not interfere with air flow. The thimble unit must provide access to the exhaust filter for testing of the HEPA filter. The ideal location for the biological safety cabinet is remote from the entry (e.g., the rear of the laboratory away from traffic), since people walking parallel to the face of a BSC can disrupt the air curtain. The air curtain created at the front of the cabinet is quite fragile, amounting to a nominal inward and downward velocity of 1 mph. Open windows, air supply registers, or laboratory equipment that creates air movement (e.g., centrifuges, vacuum pumps) should not be located near the BSC. Similarly, chemical fume hoods must not be located close to BSCs.

cleanroom operators’ manual

120

HEPA filters HEPA filters, whether part of a building exhaust system or part of a cabinet, will require replacement when they become so loaded that sufficient air flow can no longer be maintained. Filters must be decontaminated before removal. To contain the formaldehyde gas typically used for microbiological decontamination, exhaust systems containing HEPA filters require airtight dampers to be installed on both the inlet and discharge side of the filter housing. This ensures containment of the gas inside the filter housing during decontamination.

Figure 3: Bag-in/bag-out of contaminated HEPAs

Access panel ports in the filter housing also allow for performance testing of the HEPA filter. A bag-in/bag-out (BIBO) filter assembly can be used in situations where HEPA filtration is necessary for operations involving biohazardous materials and hazardous or toxic chemicals. This protects the technician handling the filter as well as the environment. The BIBO system is used when it is not possible to decontaminate the HEPA filters with formaldehyde gas, or when hazardous toxic chemicals have been used in the BSC. Note, however, that this requirement must be identified at the time of purchase and installation; a BIBO assembly cannot be added to a cabinet after-the-fact. effective use of biological safety cabinets Exposure to airborne microorganisms can result in infection of laboratory workers or contamination of research materials. Biomedical engineering and technology have provided safeguards, but these safeguards do not prevent mistakes or human errors. Danger to personnel and to the success of scientific investigation from carelessly or improperly used equipment cannot be overly emphasized.

good biosafety practices

121

The Laminar Flow Biological Safety Cabinet, designed to prevent escape of pathogens into the workers' environment and to bar contaminants from the research work zone, is a key element to safe, successful experimentation with biological materials. Escape of pathogens into the workers' area is prevented by an air barrier at the front opening and the cleaning action of the exhaust air filter. Inward flow of room air into the front air intake grill creates the air barrier. The amount of air drawn into the air intake grill and the amount of air exhausted through the exhaust filter are equal. The exhaust filter removes airborne biological contaminants which may be released in the cabinet. It does not remove chemical or radiological contaminants. Contamination of the work area inside the cabinet is prevented by the cleaning action of the supply filters. Air flows through the cabinet work area in a downward direction at a uniform velocity. The air continues to be recirculated by the fan through the air flow plenum. Airborne biological contaminants are removed by the filters as the air is returned to the cabinet work area. Certification and advance planning are of prime importance to safe operation. Only qualified personnel using approved test methods and equipment should provide performance certification at initial installation, after maintenance, and on an annual basis thereafter. Certification is also necessary after the cabinet has been moved and after filters have been replaced. Many cabinets have gauges to indicate pressure differential across the supply filters. If the filters must be replaced, the cabinet MUST be decontaminated first. This is the responsibility of the researcher to do or have done by a qualified contractor. Procedures must follow those outlined in the National Sanitation Foundation Standard Number 49. After decontamination, only qualified Site Support personnel should replace filters. Fan speed must also be readjusted by qualified maintenance technicians. It is the responsibility of individual researchers and/or departments to insure this process is accomplished at least annually. In a survey performed by a cabinet manufacturer, 65 of 100 cabinets failed to pass filtration system leak tests. The operators of these cabinets were unaware of the malfunction. Maximum safety and full use of the cabinet can be best achieved by adequate advanced planning. Ideally, advanced planning should follow a procedural check list to anticipate equipment, apparatus, media, order of events and the many other details necessary for the completion of the assignment.

122

cleanroom operators’ manual

When planning is completed, start-up procedures may be initiated. There are three start-up steps: 1 Turn on the lights 2 Check the air intake and exhaust grill to make sure they are unobstructed 3 Turn on the fan Allow the fan to operate a minimum of five minutes before manipulations are begun in the cabinet. In addition, the following points should be considered: 1 Some cabinets are equipped with ultraviolet light. These must be turned off during the day while laboratory personnel are occupying the room. 2 Hands and arms should be washed well with germicidal soap before and after work in the cabinet. 3 Technicians are encouraged to wear long-sleeve gowns with knit cuffs and rubber gloves. This minimizes the shedding of skin flora into the work area and protects the hands and arms from contamination by viable agents. 4 Interior surfaces of the work area should be disinfected by wiping them thoroughly with 70% alcohol. 5 The cabinets should not be overloaded. Everything needed for the complete procedure should be placed in the cabinet before starting so that nothing passes in or out through the air barrier until the procedure is completed. 6 Do not place anything over the front intake or rear exhaust grill in units having a solid work surface. 7 As a general rule, keep equipment at least four inches inside the cabinet window and perform transfer of viable materials as deeply into the cabinet as possible. 8 After all materials have been placed in the cabinet, wait 2-3 minutes before beginning work. This will allow sufficient time for the cabinet air to purge airborne contamination from the work area. 9 Hold the activity in the room to a minimum. Unnecessary activity may create disruptive air currents. The ideal location for a cabinet is in a quiet end of the laboratory, removed fromdoorways, air conditioning and heating vents. Opening and closing laboratory doors can cause disruptive drafts that allow microorganisms to penetrate the air barrier.

good biosafety practices

123

10 Schedule uninterrupted work periods. The movement of objects including hands and arms causes turbulent air currents which disrupt the air barrier and allow escape and entrance of airborne contaminants. 11 Air turbulence caused by rotating laboratory equipment, such as a small clinical centrifuge, disrupt airflow within the cabinet and at the work opening. This is sufficient for contaminated air to escape to the laboratory environment. If a centrifuge must be used in the cabinet, do not perform other research activities in the cabinet while the centrifuge is operating. 12 Normal laboratory contamination control procedures and aseptic techniques are still necessary while working in the biological safety cabinet. 13 Equipment in direct contact with the biological agent should not be removed from the cabinet until enclosed or until the surface is decontaminated. Trays of discarded pipettes and glassware must be covered before removal from the cabinets. 14 If an accident occurs which spills or splatters the biological agent in the work area, all surfaces in the cabinet must be surface decontaminated before being removed. 15 Do not use a Bunsen Burner in a biological safety cabinet. The flame causes turbulence in the air stream and the heat generated may damage the HEPA filter. If a procedure requires the use of a flame, a burner with a pilot light should be used. It should be placed to the rear of the workspace where resulting air turbulence will have a minimal effect. 16. Do not mouth pipette. Following completion of the work, the following steps must be performed: 1 Allow the cabinet to run 2-3 minutes with no activity. This will allow sufficient time for cabinet airflow to purge airborne contaminants from the work area; 2 Decontamination of the interior surfaces should be repeated after removal of all materials, cultures, apparatus, etc. A careful check of the work area should be made for spilled or splashed nutrients. They may support fungus growth and result in spore liberation that contaminates the protected work environment; and 3 Shut down by turning off the fan and lights. Use UV lights according to manufacturer's recommendations. 4. Do not use the cabinet to store excess laboratory equipment.

cleanroom operators’ manual

124

bsc:faqs* * Adapted from Labconco Biological Safety Cabinet Training Program, Version 1.0, 3/91. "I've got to use a Bunsen Burner in my biohazard cabinet..." Using a Bunsen Burner in a biohazard cabinet compromises the performance of the unit and may be dangerous. During operation, the flame of a burner is very disruptive to the air flow patterns of the cabinet, and may actually increase the dispersion of aerosols in the work area. In addition, if the flame of the burner is too large, the excessive heat may melt in adhesive holding the HEPA filter together or literally burn holes in the filter media. (Yes, it does happen on a regular basis.) Finally, a Bunsen Burner in a biological safety cabinet is just plain dangerous. An unattended burner may blow out. If in a Type A or A/B3 cabinet, the recirculating gas may reach explosive concentrations (that has also happened on several occasions). Labconco recommends using alternative methods such as electric incinerators, or disposable inoculating hoops, for instance. The practice of flaming bottle mouths is unnecessary, as the work area of a Biohazard Cabinet should be a sterile environment, if used properly. "I can use a biological safety cabinet just as if it were a fume hood..." No. The biohazard cabinet and the chemical fume hood are two distinctly different pieces of equipment and MUST be used differently. The fume hood is designed to remove noxious or toxic fumes and aerosols away from the operator. It should be constructed of materials that are inert to a wide variety of chemical agents. The biohazard cabinet's primary purpose is to protect the operator, environment, and often the product from biohazardous contaminants. The biohazard cabinet and its HEPA filters are constructed of materials that are inert to the chemicals used in connection with biological research, but may be damaged by some of the more corrosive chemicals commonly used in fume hoods. Don't try to use a Biohazard Cabinet as a Fume Hood! "If I work in a biohazard cabinet, I don't have to be as careful with my technique..." Wrong. The biohazard cabinet will provide personal and product protection only if used properly. Aseptic technique must be practiced at all times while working in a biohazard cabinet.

good biosafety practices

125

"I use the cabinet's UV light, so I don't need to decontaminate the work area..." Wrong. The UV light is only good as an adjunct, to minimize contamination of the work area when the cabinet is not in use. Ultraviolet light has virtually no penetrating power, and as such, will not kill microbes protected by dust, dirt, or organic material. The best method to prevent contamination in the cabinet is regular decontamination of the work area surfaces, before and after the cabinet is used. "Can I put a centrifuge in the biohazard cabinet?" Large objects placed in the biohazard cabinet will impede the airflow in the work area, reducing the efficiency of the cabinet. Electrical appliances like centrifuges, blenders, etc., will often disrupt the airflow around them due to their cooling fans. It is better to use a primary barrier on the appliance (such as a sealed safety cup in the centrifuge) rather than a biohazard cabinet to provide containment. "There's nothing wrong with using the biohazard cabinet to store material when not in use." Yes there is. Storing chemicals and materials in the biohazard cabinet make it more difficult to use when the need arises. If chemicals leak while stored in the cabinet, the work area of the cabinet could be damaged. Don't use the biohazard cabinet as a storage area. "All biohazard cabinets should operate continuously, 24 hours-a-day." Some applications of the biohazard cabinet require that the unit operate continuously. When used to prepare cytotoxic drugs, for example, the unit should operate continuously, to prevent toxic residue form migrating out of the cabinet ductwork and into the laboratory. If the cabinet is not used in such an application, there is no need to leave it operating continuously. This will only reduce the life of the cabinet blower and HEPA filters. "If I leave my Type A cabinet running continuously, it will clean all the air in the room to Class 100 conditions." Not necessarily. Assuming you had an air-tight room, with no ventilation system, an air-tight door seal, and no activity in it, then a recirculating Type A cabinet might clean the room to Class 100 levels. This would also unfortunately shorten the operating life of the motor and HEPA filters (and heat up the room considerably). Regardless, as soon as the

cleanroom operators’ manual

126

operator opens the room door to enter, particulate-laden air will contaminate the room, raising it far above Class 100 conditions. "Is there any alternative to exhausting so much of costly tempered room air?" Yes. To ensure that the BSC is maintained at negative pressure with respect to the room, you must draw room air at least sufficient to sustain the face velocity at the specified level. This will work out to approximately 20 to 35 cfm per linear foot of the workspace width. If your cultures do not require any special temperature or RH control, then you may draw untempered air from any adjacent room or corridor through prefilters and make up your exhaust air volume. For example, if you are using a Type II B3 BSC, it is designed for 30% exhaust, which works out to throwing out 360 CFM. If you are able to sustain the face velocity with 160 cfm drawn from the room, you may make up the balance 200 cfm required from an adjacent room. Do not draw air from outside the building. If the room in which you work is to be maintained at negative pressure with respect to the outside environment, do not use the BSC exhaust arrangement as the only means of achieving that condition. The room should have its own separate exhaust system. Exhaust air from BSCs and Biosafe facilities should not be connected to the building’s general exhaust system. A separate dedicated exhaust should be used. Biosafe exhaust design should factor in such possibilities as power outage and fan failure. "Are the biological test methods different for different types of Class II BSCs?" Unfortunately, no. All four types of Class II BSCs are qualified using the same microbiological test method described earlier. The User is advised to devise more aggressive challenge methods, if deemed necessary, appropriate to the application. handling and disposal of waste A. Biohazard waste The following information regarding biohazard waste is being provided to eliminate any misunderstandings about the requirements for proper disposal of biohazard wastes.

good biosafety practices

127

Biohazard Wastes are discarded materials "that are biological agents or conditions (as an infectious organism or unsecure laboratory condition) that constitutes a hazard to man or his environment." This definition includes "any and all substances which contain materials to which organisms may cause injury or disease to man or his environment, but which are not regulated as controlled industrial waste". B. Infectious wastes include the following categories: 1 2 3 4 5 6 7

cultures and stocks of infectious agents and associated biologicals; human blood and blood products, pathological wastes, contaminated sharps, contaminated animal carcasses, body parts, and bedding, wastes from surgery, necropsy and other medical procedures, laboratory wastes, 8 isolation wastes, unless determined to be non-infectious by the infection control committee, 9 any other material and contaminated equipment which, in the determination of the facility infection control staff, presents a significant danger of infection because it is contaminated with, or may reasonably be expected to be contaminated with, etiologic agents. C. Chemical wastes Chemical Wastes subject to the requirements of biohazard waste regulations include wastes from the following categories: 1 pharmaceutical wastes 2 laboratory reagents contaminated with infectious body fluids 3 all the disposable materials which have come into contact with cytotoxic/antineoplastic agents during the preparation, handling, and administration of such agents 4 other chemicals that may be contaminated by infectious agents, as designated by experts at the point of generation of the waste. D. Treated biohazard wastes Treated Biohazard Wastes are all biohazard wastes that have been treated by one of the following methods and rendered harmless and biologically inert:

cleanroom operators’ manual

128

• • •

•

incineration in an approved incinerator, steam sterilization at sufficient time and temperature to destroy infectious agents in waste ("autoclaved"), chemical disinfection where contact time, concentration, and quantity of the chemical disinfectant are sufficient to destroy infectious agents in the waste, and any other method approved and generally recognized as effective.

E. Sharps Sharps are used in animal or human patient care or treatment or in medical research, or industrial laboratories, including: • • • • • • • •

hypodermic needles, syringes, (with or without the attached needle) pasteur pipettes scalpel blades suture needles blood vials needles with attached tubing and culture dishes (regardless of presence of infectious agents). other types of broken or unbroken glassware that were in contact with infectious agents, such as used slides and cover slips.

The following guidelines should be followed for biohazard waste disposal: 1. If any infectious waste is also a chemical waste, call for assistance with disposal AFTER disinfection. All waste of this type must be non-human, non-infectious, and non-viable. 2. Biohazard wastes that are also radioactive shall be treated according to requirements for both biohazard and radioactive waste. 3. Untreated biohazard waste shall NEVER be disposed of in the municipal solid waste stream. All laboratories shall evaluate their waste stream to ensure that all biohazard wastes, including sharps and syringes, are treated in a manner as described earlier before disposal in the municipal waste stream. 4. Prior to any treatment all biohazard wastes, including those to be incinerated, shall be enclosed in a puncture-proof, red BIOHAZARD BAG that is marked with the universal biological hazard symbol.

good biosafety practices

129

5. All sharps intended for disposal, whether contaminated or not, shall be enclosed in a sharps container. Recapping needles is dangerous and shall be avoided. Treat syringes as you would a controlled substance. It is recommended that all unwanted syringes be destroyed after disinfection but before disposal in the solid waste stream. Destroying an infectious sharp or syringe before disinfection could spread contamination. Special consideration should also be given to the disposal of contaminated pipettes. 6. After disinfection but before disposal in the municipal waste stream, all treated biohazard wastes shall be enclosed in an unmarked outer bag that is NOT red. Any biohazard waste that has been treated as described above, packaged such that it is clearly evident that the waste had been effectively treated AND contains no chemical or radioactive waste is NOT subject to regulation as biohazard waste and may be collected, transported, and disposed of as MUNICIPAL WASTE. F. Guidelines for disposal 1. If any infectious waste is also a chemical waste, call for assistance with disposal after disinfection. Antineoplastic/cytotoxic agents require special disposal. 2. Biomedical wastes that are also radioactive should be treated according to requirements for both biomedical and radioactive waste. 3. Prior to any treatment, all biomedical wastes, including those to be incinerated, should be enclosed in a puncture-resistant, red biohazard bag that is color-coded or labeled with the biological hazard symbol. 4. All sharps intended for disposal, whether contaminated or not, must be enclosed in a specially designed sharps container. Never clip or recap needles before putting them in the sharps container. The sharps container should be puncture-resistant, leak proof on the sides and bottom, and color-coded or labeled with the biohazard symbol. When selecting sharps containers, look for special safety features such as lids that lock tight for safe disposal, a container that can be sterilized by steam, gas, or chemicals, and a clear top that would allow inspection. If sharps containers are not specifically constructed to be autoclaved, the resulting mass of melted plastic is extremely hazardous due to the needles that often protrude.

5. Untreated biomedical waste is not to be disposed of in the municipal waste stream. All biomedical waste, including sharps and syringes, must be treated by incineration, steam sterilization, or chemical disinfection before disposal in the municipal waste stream. 6. After disinfection, but before disposal in the municipal waste stream, all treated biomedical wastes should be enclosed in an unmarked outer bag that is not red or labeled with the biohazard symbol. Any biomedical waste that has been treated as described above and packaged such that it is clearly evident that the waste has been effectively treated, is not subject to regulation as biomedical waste and may be collected, transported, and disposed of as municipal waste.

9 cGMP & you: personnel in drug and device manufacture

C K Moorthy

why GMP? When did you last pop a pill? Can you recall when you last administered any medicine to your near and dear ones? Did it occur to you at that time that the drug you were consuming or administering could be adulterated or misbranded? Did you consider having it tested to verify that the drug was indeed what the label claimed it was? No? Don’t worry. You are not alone. Everyone does exactly what you did. Some, unfortunately, are no longer around to be counted. Several patients at Davenport, Plymouth, UK paid for poorly sterilised infusions with their lives. Nearer home in Kolar, scores of hypertensive and hyperglycaemic patients died because their medicines were inadvertently interchanged at the manufacturer’s end during packaging and labeling. Little children on multivitamin courses developed severe reactions because of cross-contamination with a systemic allergen produced earlier in the same equipment train.

cleanroom operators’ manual

132

Disasters like these are rare, which explains your own complacency and blind trust in the pharmaceutical industry when you consumed your pill; but, disturbingly, they are not uncommon. Contrary to what you may have thought, drugs are not produced by infallible super humans in outer space. Veterans in the industry certainly recall lapses they themselves have witnessed over the years. Fortunately, most such blunders are discovered or detected in time before they leave the factory and reach the consumer. Things seldom go horribly wrong all of a sudden. As Safety Engineers will tell you, a series of near-mishaps if ignored will lead eventually to some minor mishaps; and a series of minor mishaps will ultimately culminate in a major mishap. Some of the best lessons in GMP and sound scientific rationale have come from lawyers! Justice Lentin, Justice Wolin and Mr C M Clothier (who was later knighted for his efforts) to name a few. the four areas of regulatory concern Drug or device production has four, and just four, primary areas of concern: Contamination

:

Goof ups

:

Mix ups

:

Process inconsistency

:

Any substance or energy that adversely affects drug performance Errors of omission and commission of human origin Special case of human error through gross negligence and carelessness A process that is unstable and unreliable

Current Good Manufacturing Practice (cGMP) endeavours to address these issues. In some countries cGMP is merely a guideline; but in most others it carries the weight of a law. Laws exist to safeguard some right or value of a citizen, and cGMP is no different. cGMP aspires to protect the following five core values (referred to as SISPQ for short throughout this book): Safety

:

Identity :

The product remains free of any unexpected side effects when used appropriately The product is exactly what the label and related material say it is; every material, component, significant piece of equipment and operation is labeled and documented so

cGMP & you: personnel in drug and device manufacture

Strength :

Purity

:

Quality :

133

that lot histories can be accurately reconstructed from start to finish The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard) Absence of substances that produce adverse effects on the product Fitness for intended use

Contaminated LVPs caused the deaths at Davenport. Mr Clothier discovered Klebsiella; Justice Lentin found fungus. Others have reported roaches. A Mix up and consequent loss of Identity of the drugs led to the deaths at Kolar. you hold the key to GMP success People hold the key to the success of any GMP initiative. If your buildings, utilities and equipment are designed, installed, operated and maintained in a validated state, what would you attribute defective products, if any produced, to? People,of course. If the raw materials and components come from qualified suppliers and have been passed by QC, what would you attribute defective products, if any produced, to? People,again. A properly validated production process will not produce defectives. What would you attribute defective products, if any produced, to? People. Machines do not goof up. Machines do not mix up. Only people do. On the other hand, your buildings, facilities and equipment cannot function without people. Which is why I repeat that People, and only people, determine the success or failure of GMP in your Plant. People are the prime movers of any Organisation. Two competitors on a level playing field, with identical premises, facilities and equipment, and the same manufacturing process: what makes one more successful than the other: the superiority of the former’s people.

cleanroom operators’ manual

134

failures traceable to personnel particulate contamination: microbial contamination: human errors:

80% 98% 100%

It is commonly acknowledged that 60% of all product recalls worldwide are traceable to human errors: marking & labelling errors; packaging errors. A validated process fails commonly because of weighing & dispensing errors; and non-adherence to SOPs. importance of SOPs GMP is the quality system guide that sets your Goals; but doesn’t always tell you how to achieve them. Process development group, after exhaustive trials and errors, discovers the path to achieving these goals - the Methods, if followed without deviation, will produce a product of the desired quality. These methods are formally transferred to production as Standard Operating Procedures (SOPs). Your records are the Proof that you have adhered to these SOPs, and vindicate your commitment, sincerity and diligence in your work. In other words, Goals, Methods and Proof reflect your GMP compliance. resolving issues related to personnel All types of contamination: O High personal hygiene O Decontamination before entry O Good Gowning O Hand wash & gloving O Good conduct in process area O Cautious, vigilant behaviour at the workplace Product recalls: goof ups & mix ups O Be “fit” for your job O Stay “fit” for your job O Be conscientious, alert and vigilant O Have written SOPs for your jobs O Strictly follow SOPs in your work

cGMP & you: personnel in drug and device manufacture

135

O When in doubt, don’t guess: seek immediate help O Document your work: cross-check and record Process Control O Have stable, capable process O Validate the process O Have written SOPs O Strictly follow SOPs O Document your work: cross-check and record O Maintain state of control Cross-check. Why? Because it is extremely likely that when you are checking soemthing you do routinely, you may not always detect errors; but when you are checking someone else’s work, the mistake is more readily noticed. The next time you fly, check the Captain’s instructions to his crew: “ All ground staff to deplane; cabin-crew to arm all doors, cross-check and report.” Yes, cross-check. the patient trusts you I started this chapter asking you whether it had crossed your mind that the pill you were giving your child could have been misbranded or adulterated. No, it did not. Because you trusted the manufacturer, because of his great reputation. That is exactly what the patient you are serving is doing. He trusts you. Any error on your side constitutes betrayal of that trust. work as if the product is for you and your family I am reminded of a story I once read about building a house. An elderly carpenter was ready to retire. He told his employer-contractor of his plans to leave the house-building business and live a more leisurely life with his wife, enjoying his extended family. He would miss the paycheck, but he needed to retire. They could get by. The contractor was sorry to see his good worker go and asked if he could build just one more house as a personal favor. The carpenter said yes, but in time it was easy to see that his heart was not in his work. He resorted to shoddy workmanship and used inferior materials. It was an unfortunate way to end a dedicated career.

cleanroom operators’ manual

136

When the carpenter finished his work the employer came to inspect the house. He handed the front-door key to the carpenter. “This is your house,” he said, “my gift to you.” The carpenter was shocked! What a shame! If he had only known he was building his own house, he would have done it all so differently. So it is with us. We build our lives, a day at a time, often putting less than our best into the building. Then with a shock we realize we have to live in the house we have built. If we could do it over, we’d do it much differently. But we cannot go back. You are the carpenter. Each day you hammer a nail, place a board, or erect a wall. “Life is a do-it-yourself project,” someone has said. Your attitudes and the choices you make today, build the “house” you live in tomorrow. Build wisely! Just imagine a situation where on a Saturday at 11:00 PM your child is seriously ill. You call your family doctor in desperation only to find he is out of station, due back only on Monday morning. But he gives you a detailed home remedy to keep the situation under control until his return. Would you prepare the home remedy yourself or leave it to your servant? The product you are manufacturing could land up in your home: you or members of your family may be consuming it. So manufacture wisely. cGMP & you: a summary of points to consider O O O O O O O O O O O

The patient is unknown, in distress and in need of relief The patient trusts you and your product quality Product Quality is your responsibility Failure to adhere to GMP is betrayal of Patients’ trust Make the product for yourself: you could be the customer Look for ways to further improve your manufacturing practices SOPs define your Path for maintaining consistency in your Product Quality Strict adherence to SOPs helps maintain your process in a state of control Take pride in performing your job right the first time, every time, all the time Good records are your Proof of Performance and vindication of Responsibility Take GMP beyond regulatory compliance to a culture, a tradition and your way of life

cGMP & you: personnel in drug and device manufacture

137

making GMP your culture “Observing Traffic Rules is a sign of civilisation” comments a hoarding in Egypt. “Aim for the moon and you might still hit the tree tops”, quipped an old friend. These represent my sentiments. We in India remove our footwear at the entrance; wash our hands before and after a meal; bathe at least once a day. Women are advised to stay isolated during their periods. No one has to tell us to do that; we do it by sheer force of habit. Because it is our tradition, our culture. Such acts are not so common or widespread in many parts of the world: they need to be told. GMP is more compatible with our culture than with many others’. Make GMP your culture, and you will never have to worry about compliance. five golden rules of good documentation Rule 1: Write what you do, exactly as you do; do what you write, exactly as you write Rule 2: Do not write what you do not do; do not do what you do not write Rule 3: If it is not written down, it didn’t happen. It’s just a rumour. Rule 4: If it is not written down properly, it did not happen properly. You can never be certain as to what actually happened Rule 5: If the records are not correct, neither is the product importance of good records • Good records represent Proof of Performance • Good records can vindicate your conscientiousness in your duty • Good records aid problem investigation • Good records can serve as a foundation upon which to base process changes • Reliable records are important because they help – show how a process performed – identify drifts from nominal set points – prove “sameness” of successive batches

ten golden rules of GMP The road to attaining a high level of cGMP is best summarised in these ten golden rules: 1 2 3 4 5 6 7 8 9 10

Be “fit” for your job Stay “fit” for your job Have plant & machinery “fit” for intended use Maintain the plant & machinery always “fit” for intended use Have a stable, capable process Validate your process Have written operating procedures for your work Follow the written operating procedures in your work Cross check and report your data as you do it Audit for continued conformance

I ask participants at my training programmes to write down what each of them does in his or her job to protect and safeguard the core values of GMP (SISPQ) ? And also, what would happen if they were not to observe GMP requirements in their work? If the above ten rules are followed, then cGMP will always translate to mean Can Guarantee My Products! management support GMP responsibility spans the Organisation: GMP embraces all sections, at all levels. Quality Responsibility and Accountability is a team effort, not a policing effort. Much depends on the Management at the top. If they are perceived to be committed, GMP will take root and blossom; if, instead, it is only hype and lip service, employees will quickly follow suit, and GMP will be reduced to a farce. Merely having Quality and Production “independent” of each other will not help if the environment is vitiated with business myopia, low ethics or high personnel insecurity. The “acid test” on how committed the management is towards GMP is in “stress” situations: how OOS test results are handled; how strictly QC approval of starting materials prior to commencement of production is implemented, specially when there are deadlines to be met; how aseptic filling simulation failures are handled; how readily budgets from QA/ QC are approved, as compared to those from Marketing; how much support in financial and other terms is extended for validation exercises; whether QA is truly empowered or exists merely for effecting “Quiet Adjustments” for regulatory expedience!

10 guidelines governing personnel in drug and device manufacture

E

very guideline devotes a section to personnel. Some spell out their expectations in greater detail than others. An attempt is made here to present such expectations in a global context.

In a legal sense, a long list may be prepared indicating the sections, subsections and paragraphs where “personnel” is referred to or alluded to, directly or indirectly. This may be necessary for a prosecuting agency to point out “deficiencies”. But we are interested here in a broad assessment of the regulatory requirements, and place these in perspective. Guidelines differ among themselves in their contents and relative emphasis. Variances abound in perceptions among GMPs about “qualifications”, QC’s role and what constitutes “adequate” number of personnel. USFDA singles out QC for GMP responsibility; EUGGMP and TGA follow WHO’s lead in expanding on the subject against a Quality System backdrop and joint responsibility. Schedule M lies somewhere between these extremes.

cleanroom operators’ manual

140

Sadly, none addresses the highly contentious, yet crucial, issues of an employee’s responsibilities towards compliance, or advising management about deviations or other problems, or suggesting improvements. Also, there is no mention of what should the consequences be for non-adherence or non-compliance at the individual’s level. While USFDA and Q7 have found it necessary to include “consultants”, there is No mention of responsibilities, qualifications and track records of vendors and sub-contractors. WHO, European Community and Australia have paid special attention to personnel requirements for biologicals. We commence with each guideline’s “general” expectations, and move progressively to “special” requirements for different product groups, ranging from bulk pharmaceuticals to sterile products, medical devices, and biologicals. Schedule M 1. Personnel 1.1 The manufacture shall be conducted under the direct supervision of competent technical staff with prescribed qualifications and practical experience in the relevant dosage form and/or active pharmaceutical products 1.2 The head of the Quality Control Laboratory shall be independent of the manufacturing unit. The testing shall be conducted under the direct supervision of competent technical staff who shall be whole time employees of the licensee. 1.3 Personnel for Quality Assurance and Quality Control operations shall be suitably qualified and experienced. 1.4 Written duties of technical and Quality Control personnel shall be laid and followed strictly. 1.5 Number of personnel employed shall be adequate and in direct proportion to the workload. 1.6 The licensee shall ensure in accordance with a written instruction that, all personnel in production area or into Quality control shall receive training appropriate to the duties and responsibility assigned to them. They shall be provided with regular in-service training.

guidelines governing personnel in drug and device manufacture

141

2. Health, clothing and sanitation of workers 2.1 The personnel handling beta-lactum antibiotics shall be tested for penicillin sensitivity before employment and those handling sex hormones, cytotoxic substances and other potent drugs shall be periodically examined for adverse effects. These personnel should be moved out of these sections (except in dedicated facilities), by rotation, as a health safeguard. 2.2 Prior to employment, all personnel shall undergo medical examination including eye examination and shall be free from Tuberculosis, skin and other communicable or contagious diseases. Thereafter, they should be medically examined periodically, at least once a year. Records shall be maintained thereof shall provide the services of a qualified physician for assessing the health status of personnel involved in different activities. 2.3 All persons, prior to and during employment, shall be trained in practices which ensure personnel hygiene. A high level of personal hygiene shall be observed by all those engaged in the manufacturing processes. Instructions to this effect shall be displayed in change- rooms and other strategic locations. 2.4 No persons showing, at any time, apparent illness or open lesions which may adversely affect the quality of products, shall be allowed to handle starting materials, packaging materials, in - process materials, and drug products until his condition is no longer judged to be a risk. 2.5 All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken 2.6 Direct contact shall be avoided between the unprotected hands of personnel and raw materials, intermediate or finished, unpacked products 2.7 All personnel shall wear clean body coverings appropriate to their duties. Before entry into the manufacturing area, there shall be change rooms separate, for each sex with adequate facilities for personal cleanliness such as wash basin with running water, clean towels, hand dryers, soaps, disinfectants etc. The change rooms shall be provided with cabinets for the storage of personal belongings of the personnel. 2.8 Smoking, eating, drinking, chewing or keeping plants, food, drink and personal medicines shall not be permitted in production, laboratory, storage and other areas where they might adversely influence the product quality.

cleanroom operators’ manual

142

WHO The role and position of the Authorized Person in the company 1. Authorised person as overall Quality Controller The authorized person as the overall quality controller will be a member of a team whose function includes the following major areas: o implementation (and, when needed, establishment) of the quality system; o participation in the development of the company’s quality manual; o supervision of the regular internal audits or self-inspections; o oversight of the quality control department; o participation in external audit (vendor audit); o participation in validation programmes. Although authorized persons may not have line management responsibility for many activities within this function (although they should be involved in these activities as much as possible), they must be aware of any changes that may affect compliance with technical or regulatory requirements related to the quality of finished products. When any aspect of the company’s operations is not in accordance with GMP guidelines or relevant legislation in force, the authorized person must bring this to the attention of senior management. This duty should be reflected in the authorized person’s job description. The availability of an authorized person should be a prerequisite for issue of a manufacturing licence (authorization). The authorized person (as well as persons responsible for production and quality control) must be approved by the drug regulatory authority. The licence holder is obliged to inform the drug regulatory authority, or other responsible authority depending on national (regional) regulations, immediately if the authorized person is replaced unexpectedly. Such provisions will assure to a considerable degree the independence of the authorized person from the management of the company in the fulfilment of his or her duties even when under pressure to depart from professional and technical standards. As indicated in the GMP guidelines published by WHO, in certain countries, depending on the national legislation or regulations, two authorized persons are designated: one for production and another for quality control. A company may have a complex structure, or operate at several locations, or both, and sometimes a separate authorized person

guidelines governing personnel in drug and device manufacture

143

may be designated who is responsible for the manufacture of clinical trial materials. Consequently it may be necessary to nominate several authorized persons, one of them having the responsibilities of the overall quality controller and the others responsible for site or branch operations. The person authorizing batch release should be independent from production activities. The drug regulatory authority should approve the authorized person on the basis of his or her professional curriculum vitae. Authorized persons have duties not only to their employer but also to the competent authorities such as the drug regulatory authority. They should establish good working relations with inspectors and as far as possible provide information on request during site inspections. The authorized person depends upon many working colleagues for the achievement of quality objectives, and may delegate some duties to appropriately trained staff while remaining the overall quality controller. It is therefore of paramount importance that he or she establish and maintain a good working relationship with other persons in positions of responsibility, especially those responsible for production and quality control. 2. Implementation of the quality system Authorized persons have a personal and professional responsibility for ensuring that each batch of finished products has been manufactured in accordance with the marketing authorization, GMP rules and all related legal and administrative provisions. This does not necessarily mean that they must have directly supervised all manufacturing and quality control operations. They must be satisfied either directly or, more usually, by proper operation of quality systems, that manufacturing and testing have complied with all relevant requirements. Therefore it is recommended that the manufacturer establishes and maintains a comprehensive quality system, covering all aspects of GMP. Useful reference material, in addition to rules and regulations on GMP, may be found in the International Standards ISO 9000 family (9000– 9004). These standards describe quality systems requirements that can be used for external quality assurance purposes. The important element of these documents is a quality manual, describing the quality policy and objectives (commitment to quality) of the company, the organizational structure, responsibilities and authorities, together with a description of or references to documented quality system procedures.

cleanroom operators’ manual

144

Research and development activities and the transfer of results of the developmental work to routine manufacture, including original product design, formulation, processes development and validation, should observe GMP principles as guidance. Batches produced for clinical trials must follow applicable GMP. It is of vital importance that the quality of routine production batches corresponds to a specification derived from the composition of development batches. The quality and safety of a pharmaceutical product depend on the application of appropriate procedures, based on GMP, leading to a product within the recognized specification. Standard procedures and recognized specifications cannot be separated. 3. Routine duties of an authorized person Before approving a batch for release the authorized person doing so should always ensure that the following requirements have been met: •

• • •

•

•

•

• •

The marketing authorization and the manufacturing authorization requirements for the product have been met for the batch concerned. The principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed. The principal manufacturing and testing processes have been validated, if different. All the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records. Any planned changes or deviations in manufacturing or quality control have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification to and approval by the drug regulatory authority. Any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations. All necessary production and quality control documentation has been completed and endorsed by supervisors trained in appropriate disciplines. Appropriate audits, self-inspections and spot-checks are being carried out by experienced and trained staff. Approval has been given by the head of the quality control department.

guidelines governing personnel in drug and device manufacture

•

145

All relevant factors have been considered, including any not specifically associated with the output batch directly under review (e.g., subdivision of output batches from a common input, factors associated with continuous production runs).

In certain circumstances the authorized person may be responsible for the release of intermediates manufactured on contract. 4. Education and training The pool of expertise drawn upon for candidates for the position of authorized person may differ from country to country. The basic qualifications of a scientific education and practical experience for key personnel, including authorized persons, are outlined in the GMP guidelines published by WHO (section 10, Personnel). Additional requirements may include subjects such as principles of quality assurance and GMP, principles of good laboratory practice as applicable to research and development as well as to quality control, detailed knowledge of the authorized/qualified person’s duties and responsibilities, of International Standards ISO 9000–9004 and relationships with suppliers, principles and problems of formulation of pharmaceutical preparations, pharmaceutical microbiology, and principles and practice of sampling and testing of starting materials, packaging components and finished dosage forms. WHO: Other Personnel 10.1 Principle. The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly understood by the individuals concerned and recorded as written descriptions. All personnel should be aware of the principles of GMP that affect them. General 10.2 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality. 10.3 The manufacturer should have an organization chart. All responsible staff should have their specific duties recorded in written descriptions

cleanroom operators’ manual

146

and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. 10.4 All personnel should be aware of the principles of GMP that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs. All personnel should be motivated to support the establishment and maintenance of high-quality standards. 10.5 Steps should be taken to prevent unauthorized people from entering production, storage, and quality control areas. Personnel who do not work in these areas should not use them as a passageway. Key personnel 10.6 Key personnel include the head of production, the head of quality control, the head of sales/distribution, and the authorized person(s). Normally, key posts should be occupied by full-time personnel. The heads of production and quality control should be independent of each other. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated. 10.7 Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. Their education should include the study of an appropriate combination of (a) chemistry (analytical or organic) or biochemistry, (b) chemical engineering, (c) microbiology, (d) pharmaceutical sciences and technology, (e) pharmacology and toxicology, (f) physiology, or (g) other related sciences. They should also have adequate practical experience in the manufacture and quality assurance of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they should exercise their duties under professional guidance. The scientific education and practical experience of experts should be such as to enable them to exercise independent professional judgement, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and quality control of pharmaceutical products. 10.8 The heads of the production and quality control departments generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, depending on national regulations:

guidelines governing personnel in drug and device manufacture

147

(a) the authorization of written procedures and other documents, including amendments; (b) the monitoring and control of the manufacturing environment; (c) plant hygiene; (d) process validation and calibration of analytical apparatus; (e) training, including the application and principles of quality assurance; (f) the approval and monitoring of suppliers of materials; (g) the approval and monitoring of contract manufacturers; (h) the designation and monitoring of storage conditions for materials and products; (i) the retention of records; (j) the monitoring of compliance with GMP requirements; (k) the inspection, investigation, and taking of samples, in order to monitor factors that may affect product quality. 10.9 The head of the production department generally has the following responsibilities: (a) to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; (b) to approve the instructions relating to production operations, including the in-process controls, and to ensure their strict implementation; (c) to ensure that the production records are evaluated and signed by a designated person before they are made available to the quality control department; (d) to check the maintenance of the department, premises, and equipment; (e) to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available; (f) to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need. 10.10 The head of the quality control department generally has the following responsibilities: (a) to approve or reject starting materials, packaging materials, and intermediate, bulk, and finished products; (b) to evaluate batch records;

cleanroom operators’ manual

148

(c) to ensure that all necessary testing is carried out; (d) to approve sampling instructions, specifications, test methods, and other quality control procedures; (e) to approve and monitor analyses carried out under contract; (f) to check the maintenance of the department, premises and equipment; (g) to ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are done; (h) to ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need. Training 10.11 The manufacturer should provide training in accordance with a written programme for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product. 10.12 Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by the head of either production or quality control, as appropriate. Training records should be kept. 10.13 Personnel working in areas where contamination is a hazard, e.g., clean areas or areas where highly active, toxic, infectious, or sensitizing materials are handled, should be given specific training. 10.14 The concept of quality assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions. 10.15 Visitors or untrained personnel should preferably not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.

guidelines governing personnel in drug and device manufacture

149

Personal hygiene 10.16 All personnel, prior or and during employment, as appropriate, should undergo health examinations. Personnel conducting visual inspections should also undergo periodic eye examinations. 10.17 All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production areas. Signs to this effect should be posted and instructions observed. 10.18 Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials, or drug products until the condition is no longer judged to be a risk. 10.19 All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment, or personnel) that they consider may adversely affect the products. 10.20 Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials, and intermediate or bulk product. 10.21 To ensure protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized. 10.22 Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material, and personal medicines should not be permitted in production, laboratory, and storage areas or in any other areas where they might adversely influence product quality. 10.23 Personal hygiene procedures including the use of protective clothing should apply to all persons entering production areas, whether they are temporary or full-time employees or non-employees - e.g., contractors’ employees, visitors, senior managers, and inspectors.

cleanroom operators’ manual

150

EUGGMP Chapter 2 Principle The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs. General 2.1. The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to Quality 2.2. The manufacturer must have an organisation chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice. Key Personnel 2.3. Key Personnel includes the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the authorised person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.5., 2.6. And 2.7. 2.4. ...

guidelines governing personnel in drug and device manufacture

151

2.5. The head of the Production Department generally has the following responsibilities: i. To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; ii. To approve the instructions relating to production operations and to ensure their strict implementation; iii. To ensure that the production records are evaluated and signed by an authorised person before they are sent to the Quality Control Department; iv. To check the maintenance of his department, premises and equipment; v. To ensure that the appropriate validations are done; vi. To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. 2.6. The head of the Quality Control Department generally has the following responsibilities: i. To approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk and finished products; ii. To evaluate batch records; iii. To ensure that all necessary testing is carried out; iv. To approve specifications, sampling instructions, test methods and other Quality Control procedures; v. To approve and monitor any contract analysts; vi. To check the maintenance of his department, premises and equipment; vii.To ensure that the appropriate validations are done; viii.To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. 2.7. The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include: o The authorization of written procedures and other documents, including amendments; o The monitoring and control of the manufacturing environment; o Plant hygiene;

cleanroom operators’ manual

152

o o o o o

Process validation; Training; The approval and monitoring of suppliers of materials; The approval and monitoring of contract manufacturers; The designation and monitoring of storage conditions for materials and products; o The retention of records; o The monitoring of compliance with the requirements of GMP; o The inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality. Training 2.8. The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product. 2.9. Beside the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept. 2.10.Personnel working in areas where contamination is a hazard, e.g. Clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, should be given specific training. 2.11.Visitors or untrained personnel should not be taken into the production and Quality Control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised. 2.12.The concept of Quality Assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions. Personal Hygiene 2.13. Detailed hygiene programmes should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These

guidelines governing personnel in drug and device manufacture

153

procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programmes should be promoted by management and widely discussed during training sessions. 2.14. All personnel should receive medical examination upon recruitment. It must be the manufacturer’s responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the manufacturer’s knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health. 2.15. Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products. 2.16. Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. 2.17. Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden. 2.18. Direct contact should be avoided between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the products. 2.19. Personnel should be instructed to use the hand-washing facilities. 2.20.Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the Annexes. USFDA CFR 211 Subpart B-Organization and Personnel § 211.22 Responsibilities of quality control unit. (a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible

cleanroom operators’ manual

154

for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company. (b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit. (c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product. (d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed. § 211.25 Personnel qualifications. (a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. (b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess. (c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product. § 211.28 Personnel responsibilities. (a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and

guidelines governing personnel in drug and device manufacture

155

arm coverings, shall be worn as necessary to protect drug products from contamination. (b) Personnel shall practice good sanitation and health habits. (c) Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas. (d) Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products. § 211.34 Consultants. Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide. Other sections in US FDA CFR 211 relating to Personnel 21 CFR 211.42(c) states, in part, that “There shall be separate or defined areas or such other control systems for the Firm’s operations as are necessary to prevent contamination or mixups during the course of the following Procedures: *** (10) Aseptic processing, which includes as appropriate: *** (iv) A system for monitoring Environmental conditions***.” 21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include Validation of any sterilization process.”

cleanroom operators’ manual

156

special mentions Australian Code of GMP (TGA) Annex 13: Manufacture of Investigational Medicinal Products Personnel 4. Although it is likely that the number of staff involved will be small, there should be separate people responsible for production and quality control. All production operations should be carried out under control of a clearly identified responsible person. Personnel involved in release of investigational medicinal products should be appropriately trained in quality systems, GMP and regulatory requirements specific to these types of products. They must be independent of the staff responsible for production. Australian Code of GMP (TGA) Annex 8: Sampling of Starting and Packaging Materials Personnel 1. Personnel who take samples should receive initial and on-going regular training in the disciplines relevant to correct sampling. This training should include: · · · · · · ·

Sampling plans, Written sampling procedures, The techniques and equipment for sampling, The risks of cross-contamination, The precautions to be taken with regard to unstable and/or sterile substances, The importance of considering the visual appearance of materials, containers and labels, The importance of recording any unexpected or unusual circumstances.

Australian Code of GMP (TGA) Annex 11: Computerised Systems Personnel 1. It is essential that there is the closest co-operation between key personnel and those involved with computer systems. Persons in responsible positions should have the appropriate training for the management and use of systems within

guidelines governing personnel in drug and device manufacture

157

Their field of responsibility which utilises computers. This should include ensuring that appropriate expertise is available and used to provide advice on aspects of design, validation, installation and operation of computerised system.

active pharmaceutical ingredients Q7A A. Personnel Qualifications (3.1) There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs. The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing. Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee’s functions. Records of training should be maintained. Training should be periodically assessed. B. Personnel Hygiene (3.2) Personnel should practice good sanitation and health habits. Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination. Personnel should avoid direct contact with intermediates or APIs. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to

cleanroom operators’ manual

158

have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person’s inclusion would not jeopardize the safety or quality of the APIs. C. Consultants (3.3) Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants. WHO 18.7 Each firm should employ personnel with the necessary qualifications and competence for the production and quality control of active pharmaceutical ingredients. There should be an adequate number of staff with appropriate education, technical knowledge, and practical experience related to the job they perform. 18.8 The firm should have a defined organization represented in a chart. Individual responsibilities should be laid down in written instructions, to ensure that there are no gaps or overlaps. The responsibilities placed on any one individual should not be so extensive as to incur any risk to quality. 18.9 Staff at all levels should be adequately trained for the tasks and responsibilities assigned to them. 18.10 Measures should be taken to ensure that no person affected by a disease in a communicable form or having open lesions on the exposed surface of the body is engaged in any production step involving direct contact with the active pharmaceutical ingredients.

guidelines governing personnel in drug and device manufacture

159

sterile products WHO 17.6 Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processes. Inspections and controls should be conducted from outside the areas as far as possible. 17.7 All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products, including reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g., building or maintenance contractors) need to be brought in, particular care should be taken over their supervision. 17.8 Staff who have been engaged in the processing of animal-tissue materials or of cultures of microorganisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined decontamination procedures have been followed. 17.9 High standards of personal hygiene and cleanliness are essential, and personnel involved in the manufacture of sterile preparations should be instructed to report any condition that may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable, Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person. 17.10 Outdoor clothing should not be brought into the clean areas, and personnel entering the changing rooms should already be clad in standard factory protective garments. Changing and washing should follow a written procedure. 17.11 The clothing and its quality has to be adapted to the process and the workplace, and worn in such a way as to protect the product from contamination. 17.12 Wrist-watches and jewellery should not be worn in clean areas, and cosmetics that can shed particles should not be used.

160

cleanroom operators’ manual

17.13 Clothing should be appropriate to the air grade of the area where the personnel will be working. The description of clothing required for each grade is given below. Grade D: The hair and, where appropriate, beard should be covered. Protective clothing and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. Grade C: The hair and, where appropriate, beard should be covered. A single or two-piece trouser suit, gathered at the wrists and with a high neck, and appropriate shoes or overshoes should be worn. The clothing should shed virtually no fibres or particulate matter. Grade B: Headgear should totally enclose the hair and, where appropriate, beard; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets; sterilized nonpowdered rubber or plastic gloves and sterilized or disinfected footwear should be worn; trouser-bottoms should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and should retain particles shed by the body. 17.14 For every worker in a grade B room, clean sterilized protective garments should be provided at each work session, or at least once a day if monitoring results justify it. Gloves should be regularly disinfected during operations, and masks and gloves should be changed at least at every working session. The use of disposable clothing may be necessary. 17.15 Clothing used in clean areas should be laundered or cleaned in such a way that it does not gather additional particulate contaminants that can later be shed. Separate laundry facilities for such clothing are desirable. If fibres are damaged by inappropriate cleaning or sterilization there may be an increased risk of shedding particles. Washing and sterilization operations should follow standard operating procedures. EUGGMP: Annex 1: Manufacture of Sterile Medicinal Products 13. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic processing. Inspections and controls should be conducted outside the clean areas as far as possible. 14. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in

guidelines governing personnel in drug and device manufacture

161

disciplines relevant to the correct manufacture of sterile products, including reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. Building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision. 15. Staff who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed. 16. High standards of personnel hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be taken about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person. 17. Changing and washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. 18. Wristwatches, make-up and jewellery should not be worn in clean areas. 19. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. The description of clothing required for each grade is given below: Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. Grade C: Hair and, where relevant, beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter. Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or

cleanroom operators’ manual

162

disinfected footwear should be worn. Trouser-bottoms should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body. 20. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session, or at least once a day if monitoring results justify this. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least at every working session. 21. Clean area clothing should be cleaned and handled in such a way that it does not gather additional contaminants which can later be shed. These operations should follow written procedures. Separate laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage fibres and may increase the risk of shedding of particles. USFDA: Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice V. Personnel Training, Qualification & Monitoring A well-designed aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, operators involved in aseptic manipulations should adhere to the basic principles of aseptic technique at all times. Appropriate training should be conducted before an individual is permitted to enter the aseptic processing area and perform operations. For example, such training should include aseptic technique, cleanroom behavior, microbiology, hygiene, gowning, patient safety hazards posed by a nonsterile drug product, and the specific written procedures covering aseptic processing area operations. After initial training, personnel should be updated regularly by an ongoing training program. Supervisory personnel should routinely evaluate each operator’s conformance to written procedures during actual operations. Similarly, the quality control unit should provide regular oversight of adherence to established, written procedures and basic aseptic techniques during manufacturing operations.

guidelines governing personnel in drug and device manufacture

163

Some of these techniques aimed at maintaining sterility of sterile items and surfaces include: • Contacting sterile materials only with sterile instruments Sterile instruments (e.g., forceps) should always be used in the handling of sterilized materials. Between uses, instruments should be placed only in sterilized containers. Instruments should be replaced as necessary throughout an operation. After initial gowning, sterile gloves should be regularly sanitized to minimize the risk of contamination. Personnel should not directly contact sterile products, containers, closures, or critical surfaces. • Moving slowly and deliberately Rapid movements can create unacceptable turbulence in the critical zone. Such movements disrupt the sterile field, presenting a challenge beyond intended cleanroom design and control parameters. The principle of slow, careful movement should be followed throughout the cleanroom. • Keeping the entire body out of the path of unidirectional air Unidirectional airflow design is used to protect sterile equipment surfaces, container-closures, and product. Personnel should not disrupt the path of unidirectional flow air in the aseptic processing zone • Approaching a necessary manipulation in a manner that does not compromise sterility of the product To maintain sterility of nearby sterile materials, a proper aseptic manipulation should be approached from the side and not above the product (in vertical unidirectional flow operations). Also, an operator should refrain from speaking when in direct proximity to an aseptic processing line. Maintaining Proper Gown Control Prior to and throughout aseptic operations, an operator should not engage in any activity that poses an unreasonable contamination risk to the gown. Only personnel who have been qualified and appropriately gowned should be permitted access to the aseptic processing area. An aseptic processing area gown should provide a barrier between the body and exposed sterilized materials and prevent contamination from particles generated by, and microorganisms shed from, the body. Gowns should

cleanroom operators’ manual

164

be sterile and nonshedding and should cover the skin and hair (facemasks, hoods, beard/moustache covers, protective goggles, elastic gloves, cleanroom boots, and shoe overcovers are examples of common elements of gowns). Written procedures should detail the methods used to don each gown component in an aseptic manner. An adequate barrier should be created by the overlapping of gown components (e.g., gloves overlapping sleeves). If an element of a gown is found to be torn or defective, it should be changed immediately. There should be an established program to regularly assess or audit conformance of personnel to relevant aseptic manufacturing requirements. An aseptic gowning qualification program should assess the ability of a cleanroom operator to maintain the quality of the gown after performance of gowning procedures. Gowning qualification should include microbiological surface sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest, other sites). Following an initial assessment of gowning, periodic requalification should monitor various gowning locations over a suitable period to ensure the consistent acceptability of aseptic gowning techniques. Semi-annual or yearly requalification is sufficient for automated operations where personnel involvement is minimized. To protect exposed sterilized product, personnel should be expected to maintain gown quality and strictly adhere to appropriate aseptic method. Written procedures should adequately address circumstances under which personnel should be retrained, requalified, or reassigned to other areas. B. Laboratory Personnel The basic principles of training, aseptic technique, and personnel qualification in aseptic manufacturing also are applicable to those performing aseptic sampling and microbiological laboratory analyses. Processes and systems cannot be considered to be in control and reproducible if the validity of data produced by the laboratory is in question. C. Monitoring Program Personnel can significantly affect the quality of the environment in which the sterile product is processed. A vigilant and responsive personnel monitoring program should be established. Monitoring should be accomplished by obtaining surface samples of each operator’s gloves on

guidelines governing personnel in drug and device manufacture

165

a daily basis, or in association with each batch. This sampling should be accompanied by an appropriate sampling frequency for other strategically selected locations of the gown. The quality control unit should establish a more comprehensive monitoring program for operators involved in operations which are especially labor intensive (i.e., those requiring repeated or complex aseptic manipulations). Asepsis is fundamental to an aseptic processing operation. An ongoing goal for manufacturing personnel in the aseptic processing room is to maintain contamination-free gloves throughout operations. Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation. When operators exceed established levels or show an adverse trend, an investigation should be conducted promptly. Followup actions can include increased sampling, increased observation, retraining, gowning requalification, and in certain instances, reassignment of the individual to operations outside of the aseptic processing area.

special sterile products WHO Guidelines on Good Manufacturing radiopharmaceutical products

Practices

for

3. Personnel 3.1 The manufacturing establishment, whether a hospital radiopharmacy, centralized radiopharmacy, nuclear centre or institution, industrial manufacturer or PET centre, and its personnel should be under the control of a person who has a proven record of academic achievement together with a demonstrated level of practical expertise and experience in radiopharmacy and radiation hygiene. Supporting academic and technical personnel should have the necessary postgraduate or technical training and experience appropriate to their function. 3.2 Personnel required to work in radioactive, clean and aseptic areas should be selected with care, to ensure that they can be relied on to observe the appropriate codes of practice and are not subject to any disease or condition that could compromise the integrity of the product.

cleanroom operators’ manual

166

Health checks on personnel should be requested before employment and periodically thereafter. Any changes in personal health status (e.g. in haematology) may require the temporary exclusion of the person from further radiation exposure. 3.3 Only the minimum number of personnel required should be present in clean and aseptic areas when work is in progress. Access to these areas should be restricted during the preparation of radiopharmaceuticals, kits or sterile set-ups. Inspection and control procedures should be conducted from outside these areas as far as possible. 3.4 During the working day, personnel may pass between radioactive and non-radioactive areas only if the safety rules of radiation control (health physics control) are respected. 3.5 The release of a batch may be approved only by a pharmacist or a person with academic qualifications officially registered as a suitably qualified person, and with appropriate experience in the manufacture of radiopharmaceuticals. 3.6 To ensure the safe manufacture of radiopharmaceuticals, personnel should be trained in GMP, the safe handling of radioactive materials and radiation safety procedures. They should also be required to take periodic courses and receive training to keep abreast of the latest developments in their fields. 3.7 Training records should be maintained and periodic assessments of the effectiveness of training programmes should be made. 3.8 All personnel engaged in production, maintenance and testing should follow the relevant guidelines for handling radioactive products and be monitored for possible contamination and/or irradiation exposure. EUGGMP: Annex 3: Manufacture of Radiopharmaceuticals 1. All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive products are manufactured should receive additional training adapted to this class of products. In particular, the personnel should be given detailed information and appropriate training on radiation protection. EUGGMP: Annex 6: Manufacture of Medicinal Gases 2. Personnel 2.1 The authorised person responsible for release of medicinal gases should have a thorough knowledge of the production and control of medicinal gases.

guidelines governing personnel in drug and device manufacture

167

2.2 All personnel involved in the manufacture of medicinal gases should understand the GMP requirements relevant to medicinal gases and should be aware of the critically important aspects and potential hazards for patients from products in the form of medicinal gases.

biologicals WHO Annex 2: Manufacture of Biological Products 3.1 The manufacturing establishment and its personnel shall be under the authority of a person who has been trained in the techniques used in manufacturing biological substances and who possesses the scientific knowledge upon which the manufacture of these products is based. The personnel shall include specialists with training appropriate to the products made in the establishment. 3.2 Personnel required to work in clean and aseptic areas should be selected with care, to ensure that they may be relied upon to observe the appropriate codes of practice and are not subject to any disease or condition that could compromise the integrity of the product microbiologically or otherwise. High standards of personal hygiene and cleanliness are essential. Staff should be instructed to report any conditions (e.g. Diarrhoea, coughs, colds, infected skin or hair, wounds, fever of unknown origin) that may cause the shedding of abnormal numbers or types of organisms into the working environment. Health checks on personnel for such conditions should be required before employment and periodically thereafter. Any changes in health status that could adversely affect the quality of the product shall preclude the person concerned from working in the production area. 3.3 Only the minimum number of personnel required should be present in clean and aseptic areas when work is in progress. Inspection and control procedures should be conducted from outside these areas as far as possible. 3.4 During the working day, personnel shall not pass from areas where live microorganisms or animals are handled to premises where other products or organisms are handled unless clearly defined decontamination measures, including a change of clothing and shoes, are followed. Persons not concerned with the production process should

168

cleanroom operators’ manual

not enter the production area except for essential purposes, and in that case they shall be supplied with sterile protective clothing. 3.5 The staff engaged in the manufacturing process should be separate from the staff responsible for animal care. 3.6 The names and qualifications of those responsible for approving lot processing records (protocols) should be registered with the national control authority. 3.7 To ensure the manufacture of high-quality products, personnel should be trained in good manufacturing and laboratory practices in appropriate fields such as bacteriology, virology, biometry, chemistry, medicine, immunology and veterinary medicine. 3.8 Training records should be maintained and periodic assessments of the effectiveness of training programmes should be made. 3.9 All personnel engaged in production, maintenance, testing and animal care (and inspectors) should be vaccinated with appropriate vaccines and, where appropriate, be submitted to regular testing for evidence of active tuberculosis. Apart from the obvious problem of exposure of staff to infectious agents, potent toxins or allergens, it is necessary to avoid the risk of contamination of a production batch with these agents. 3.10 Where BCG vaccines are being manufactured, access to production areas shall be restricted to staff who are carefully monitored by regular health checks. In the case of manufacture of products derived from human blood or plasma, vaccination of workers against hepatitis B is recommended. EUGGMP: Annex 2: Manufacture of Biological Medicinal Products For Human Use 1. All personnel (including those concerned with cleaning, maintenance or quality control) employed in areas where biological medicinal products are manufactured should receive additional training specific to the products Manufactured and to their work. Personnel should be given relevant information and training in hygiene and microbiology. 2. Persons responsible for production and quality control should have an adequate background in relevant scientific disciplines, such as bacteriology, biology, biometry, chemistry, medicine, pharmacy,

guidelines governing personnel in drug and device manufacture

169

pharmacology, virology, immunology and veterinary medicine, together with sufficient practical experience to enable them to exercise their management function for the process concerned. 3. The immunological status of personnel may have to be taken into consideration for product safety. All personnel engaged in production, maintenance, testing and animal care (and inspectors) should be vaccinated where necessary with appropriate specific vaccines and have regular health checks. Apart from the obvious problem of exposure of staff to infectious agents, potent toxins or allergens, it is necessary to avoid the risk of contamination of a production Batch with infectious agents. Visitors should generally be excluded from production areas. 4. Any changes in the immunological status of personnel which could adversely affect the quality of the product should preclude work in the production area. Production of BCG vaccine and tuberculin products should be restricted to staff who are carefully monitored by regular checks of immunological status or chest X-ray. 5. In the course of a working day, personnel should not pass from areas where exposure to live organisms or animals is possible to areas where other products or different organisms are handled. If such passage is unavoidable, clearly Defined decontamination measures, including change of clothing and shoes and, where necessary, showering should be followed by staff involved in any such production. Australian Code of GMP (TGA) Human Blood and Tissues: Section 2 Personnel and Training Rationale 200

The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of product relies upon people. For this reason there must be competent personnel to carry out all tasks in accordance with documented procedures.

General 201

Areas of responsibility and lines of authority of key personnel should be identifiable on an organisational chart.

cleanroom operators’ manual

170

202

The names and job descriptions of key personnel must be documented.

203

Personnel must be shown to be competent in their assigned duties.

204

Key personnel must have adequate authority to discharge their responsibilities. Suitable persons should be deputised to carry out the duties and functions of key personnel in their absence.

205

There should be no unexplained or conflicting overlaps in the responsibilities of those concerned with GMP. The responsibilities placed upon any one person should not compromise the effective execution of assigned duties.

206

The key personnel, responsible for managing and supervising manufacture, quality assurance and quality control, must have the necessary competencies to ensure that blood or tissues meet the required standards and specifications consistently.

Training 207

Learning and development programs must be developed in accordance with identified needs. Programs should be documented and include on-going training and refresher training.

208

Personnel must be made aware of the principles of GMP relevant to their duties.

209

There should be a formal mechanism for determining the competency of the workplace trainer and assessor to deliver training and assess the competency of the trainee.

210

For personnel at sites remote from the licensed site, who undertake a step in manufacture, (such as at tissue retrieval), there must be documentation to demonstrate that the work practice(s) undertaken are under the control of, and acceptable to, the licensed site.

211

All personnel must be shown to have undergone learning and development for the documented procedure relevant to the work practice being performed. There must be records to show that all personnel have acknowledged subsequent changes to a procedure(s).

guidelines governing personnel in drug and device manufacture

212

171

Learning and development related to sanitation and personal hygiene should be included in staff learning and development programs.

Records 213

Records must demonstrate that each staff member is trained for the work practices they are authorised to perform. The records should include the following: · · ·

the learning and development program set up to meet individual needs; the timeframe required to complete the program; and assessment and any action taken if expected competence was not achieved.

214

Personnel must not be permitted to sign or initial a document unless they have been trained and assessed as competent in the work practices associated with the signature, and in the significance of the signature.

215

A register of staff signatures and initials must be maintained. Entries should be updated at regular stated intervals and the previous records archived.

personnel:faqs Questions & Answers on the new Australian Code of GMP for Medicinal Products Version 4 - 17 December 2002 Personnel (Chapter 2) 5. What does “necessary qualifications” mean in clause 2.1? In the absence of a definition in the 2002 Australian Code of GMP, the TGA will continue to reference the meaning as specified in clauses 301 and 305 of the1990 Australian Code of GMP. In the absence of relevant formal qualifications the company will be requested to provide justification based on risk, noting the nature of the product and complexity of the operation. 6. What are training requirements for personnel (clauses 2.8-2.12)? It is expected that training be carried out by persons with relevant training, qualifications and experience in the subject matter and should

cleanroom operators’ manual

172

preferably be themselves trained as trainers. Training (and records thereof) should be given to people affected in all circumstances where significant change occurs in the quality management system, e.g. when SOPs or methods are changed. This requirement should be reflected in procedures. There are a number of people who have a direct bearing on quality outcomes. These include contractors, consultants and casual employees. Appropriate training should be provided. 7. What are language requirements for personnel? Manufacturers should define language requirements or standards and ensure personnel are proficient in regard that language for their allocated tasks, particularly in relation to documenting and recording. Procedures employed to overcome identifiable deficiencies should be documented. USFDA 21 CFR Part 820: Medical devices: Quality System Regulation § 820.25 Personnel. (a) General. Each manufacturer shall have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by this part are correctly performed. (b) Training. Each manufacturer shall establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities. Training shall be documented. (1) As part of their training, personnel shall be made aware of device defects which may occur from the improper performance of their specific jobs. (2) Personnel who perform verification and validation activities shall be made aware of defects and errors that may be encountered as part of their job functions. § 820.70 Production and process controls. (d) Personnel. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special

guidelines governing personnel in drug and device manufacture

173

environmental conditions are appropriately trained or supervised by a trained individual. § 820.75 Process validation. (b)(1) Each manufacturer shall ensure that validated processes are performed by qualified individual(s) quality system regulation for devices (qsr 820) Establishing a quality system should be an integrated and universal effort. A total quality systems approach should be designed to satisfy the particular quality, safety, and performance needs of a specific manufacturer, product, and user-market. Employees play a vital role in achieving these objectives. Obviously, employees need to be aware of the details of the quality system and how to meet them. The Quality System (QS) regulation supports these goals by requiring that a manufacturer have sufficient qualified personnel and by requiring quality awareness training for personnel [820.25(a)]. Management with executive responsibility shall ensure their quality policy is understood, implemented, and maintained at all levels of the organization. This should be accomplished by supplying sufficient resources, training, responsibility, and authority to all managing personnel that will enable them to perform their tasks. Personnel involved in design, manufacturing, quality assurance, auditing, complaint processing, servicing, etc., should be properly trained, both by education and experience. No matter how effective quality assurance and production systems are as concepts, people still play the major role in designing and producing a quality product. Lack of training — as reflected in instances of negligence, poor operating techniques, or the inability of employees to discharge their functions properly — can lead to defective products and, sometimes, to regulatory or liability problems. Employee attitude is the most important personnel factor that can assure an effective quality system. By management setting an excellent example and through effective training, quality consciousness should be developed in every employee. Each person should be made aware of the importance of his or her individual contributions in the overall effort to achieve an acceptable level of quality. The role of management in this vital awareness effort cannot be passive — management should be diligent in looking for factors that indicate a need for employee training [820.25(b)]. A quality system should include

cleanroom operators’ manual

174

an ongoing formal program for training all personnel. All personnel should be made aware that product quality is not solely the responsibility of management or any other single group. Quality is the responsibility of every employee — any employee can generate a quality problem through ignorance of their job requirements or negligence. FDA Observations It is not unusual for FDA investigators to conduct factory inspections and observe employees who are clearly unaware of situations that can result in poor device quality. These employees obviously have not been properly instructed on what activities or conditions will directly cause defective devices or that can lead to mixups, contamination, or other problems that can cause non-conforming devices. For example, an improperly maintained piece of manufacturing equipment may eventually have disastrous consequences on finished devices. Therefore, the employee charged with maintaining the equipment, as well as the operator of the equipment, should be made aware of conditions that reflect a need for maintenance. FDA investigators have observed employees: smoking near or sweeping dust into open processing tanks where the smoke and dust would destroy the usefulness of the device; blowing smoke or sweeping dust onto devices to be sterilized; handling delicate devices while wearing rings or other jewelry; wearing gloves with holes or rubbing their nose and continuing to handle devices that need to comply with bioburden requirements; wearing cleanroom clothing into uncontrolled areas; and other poor practices such as leaving windows or doors open in controlled environmental areas. FDA investigators were advised by management that it is the manufacturer’s policy not to allow the above situations to occur. The implementation of this policy is questionable. Are these employees originally and then periodically reminded of the reason: for not smoking, eating, and wearing rings; and for personal cleanliness, and other employee requirements? People respond better when they know why they are allowed or not allowed to do certain activities - not just being told that it is company policy. Device GMP Requirements The QS regulation requires in section 820.25 that each manufacturer shall have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by this part

guidelines governing personnel in drug and device manufacture

175

are correctly performed. [The requirement for sufficient trained personnel is also covered by resource requirements in 820.20(b)(2) as follows. Each manufacturer shall provide adequate resources, including the assignment of trained personnel, for management, performance of work, and assessment activities, including internal quality audits, to meet the requirements of this part.] Each manufacturer shall establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities. Training shall be documented. As part of their training, personnel shall be made aware of device defects which may occur from the improper performance of their specific jobs. [In addition to training, personnel also have to be notified if they are responsible for nonconforming product. The intent is to prevent or reduce nonconforming product. Each manufacturer shall establish and maintain procedures to control product that does not conform to specified requirements [820.90(a)]. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation of nonconformance shall include a determination of the need for an investigation and notification of the persons or organizations responsible for the nonconformance. The evaluation and any investigation shall be documented. Personnel who perform verification and validation shall be made aware of defects and errors that may be encountered as part of their job functions. There are also personnel requirements in 820.70(d) and 820.75(b)(1) as follows. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. The manufacturers shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual. Each manufacturer shall ensure that validated processes are performed by qualified individual(s) [870.75(b)(1)]. Employee Selection As the first step in meeting GMP personnel requirements, manufacturers should select or hire appropriate employees for the tasks to be performed. The initial selection of employees for a specific job is made based on a

cleanroom operators’ manual

176

combination of education, experience, personal habits, interests, etc. For example, education alone is not a good indicator of whether a recent graduate with a scientific degree can design a product. New employees should be informed that they are working in a regulated industry and should be initially trained to perform their specific jobs and be made aware of any defects or problems that may occur from: o improper performance of their assigned tasks; o using incorrect tools or incorrect use of a tool; o poor hygiene, poor health, or smoking or eating on the job; o poor work habits or being in the wrong location; and o other detrimental factors. Production Personnel Section 820.70(d) requires that personnel in contact with a device or its environment shall be clean, healthy, and suitably attired where lack of cleanliness, good health, or suitable attire could adversely affect the device. Personnel who, by medical examination or supervisory observation, appear to have a condition which could adversely affect the device should be excluded from affected operations until the adverse condition is corrected. Personnel should be instructed to report such conditions to their supervisor. Such actions by management could create problems unless employees are instructed about work practices and requirements when they are hired or initially assigned to the task in an environmentally controlled area. If eating, drinking, or smoking could have an adverse affect on the devices’ fitness for use, then employees should be informed that these activities are to be done only in designated areas. Employees need to be informed why certain personnel and work practices are required. Basic instructions about invisible microorganisms and particulates will make the company requirements much more meaningful. People respond better when they know why they are allowed or not allowed to do certain activities rather than just being told it is company policy. Some factors that should be considered when teaching employees about working in a controlled environment include: o proper attire and dressing anteroom; o controlled use of, and entry into, controlled areas;

guidelines governing personnel in drug and device manufacture

177

o minimizing body movements; o locating the body and hands with respect to product and airflow; o prohibiting eating, drinking, smoking, or gum chewing; o reducing of coughing, sneezing and other objectionable health related conditions; o preventing use of lead pencils and certain cosmetics; o bathing and hand washing requirements; o preventing or controlling the cutting, tearing or storage of cardboard, paper, debris, etc.; o eliminating electrostatic charges by selection of clothing, grounding, etc.; o ensuring cleanliness of raw materials, components and tools; etc. o using correct furniture and eliminating use of extra furniture; o regulating the storage of tools, glassware and containers; o cleaning the room and production equipment per written procedure; and o cleaning of work surfaces and chairs. Technical Personnel The manufacturer should assure that they have sufficient properly trained personnel, or programs to train technical personnel, to design, validate, develop processes, and produce the new or modified device. Scientific and technical personnel usually need training in: o regulatory requirements; o company documentation systems; o verification and validation techniques; o consensus standards; o human factors; o labeling; o safety; o reliability; o producibility; and, o other peripheral design topics. New design personnel may be introduced to manufacturing methods and producibility issues by being assigned to various manufacturing areas before starting their design activities. The resulting knowledge and

cleanroom operators’ manual

178

experience is as valuable as their technical education — remember that the ultimate objective of a design and manufacturing operation is to produce a safe and effective device. In another valuable training technique, manufacturing personnel are assigned to assist development personnel in verifying components, and assembling and verifying subassemblies and prototype devices. These training techniques: o improve communications and technology transfer between the various departments; o help meet the interface requirements in 820.30(b), Design and Development Planning; o help promote concurrent engineering; o help research and development personnel understand that the goal is to produce a device — not just design a device; o achieve advance training for manufacturing personnel about a forthcoming design; o reduce production problems by improving the producibility of the device based on the expertise and input of the manufacturing personnel into the design of the device; and o reduce production problems based on the expertise and input of the device design personnel into the design of processes and production tools, jigs, molds, in-house standards, and test methods. All of these are important and valuable side benefits to these simple cross-training techniques. Such training should be documented. Process Validation Personnel The above discussion for technical personnel also applies to technical employees that perform process validation. After the processes are validated, these technical personnel should use their expertise and experience to develop training methods or help train production employees on how to monitor, control, and operate validated processes. Section 820.75(b) requires a manufacturer to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that specified requirements continue to be met. Further, 820.75(b)(1) requires that validated processes be performed by qualified individuals. Obviously, operators that are trained to operate each specific validated process are needed to meet these requirements.

guidelines governing personnel in drug and device manufacture

179

During the development and validation of a process, planning for eventual maintenance can reduce or prevent confusion during emergency repairs. An emergency could lead to improper repairs, such as use of a wrong replacement part. Therefore, the installation qualification should include a review of pertinent training requirements, maintenance procedures, repair parts lists, and calibration of measuring equipment. Quality Assurance Personnel QA or product acceptance employees shall meet the GMP personnel requirements for manufacturing employees AND shall be made aware of defects and errors likely to be found in nonconforming components and devices. Usually, it is easier and more effective to teach all of the GMP personnel requirements to all appropriate employees. Production or QA personnel performing quality assurance or acceptance functions should : o Maintain requirements for health, cleanliness, and clothing standards which will prevent an adverse effect on product quality. o Adequately train and/or supervise temporary personnel working in special environmental conditions. The production department shall have sufficient personnel with the necessary education, background, training, and experience to assure that all production activities are correctly performed. Employees are selected and/or trained for their assigned tasks. These tasks may be janitorial, receiving, pulling parts, production, labeling, acceptance test and inspection, packaging, painting, welding, mixing, specific technical tests, etc. To meet this requirement, each manufacturer shall establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities. As part of their training, personnel shall be made aware of device defects which may occur from the improper performance of their specific jobs. Employees should be informed that they may need to be qualified or certified to perform certain tasks such as welding, operating a validated process or working in controlled areas. Likewise, employees need to be told that where necessary, they will be informed about improper performance of their assign tasks with the intent of improving their performance and reducing the likelihood of producing nonconforming product. Where necessary, employees should be certified to perform

cleanroom operators’ manual

180

manufacturing or quality acceptance procedures where a high degree of specialized skill is required. Training shall be documented. Complaint Handling It is a good idea for most of the company personnel to receive basic training in complaint handling techniques. Appropriate employees such as receptionists, salespersons, representatives, secretaries, service personnel, and other employees who talk with users should receive training on their responsibilities in regard to complaint handling requirements in section 820.198. If these employees receive a device complaint, they need to know they have a responsibility to report it to the company person(s) assigned to handle complaints. Likewise, importers and distributors should be made aware of the complaint requirements, and they should be requested to forward complaints to the manufacturer. Management Proper job performance by employees as required by the QS regulation dictates that management have a good knowledge of the QS regulation and resulting quality system. Therefore, management should also have appropriate education, training, and experience. As part of their review of the quality system, management should make certain that adequate “how to do” documentation is available to employees. Proper job performance should be supported by correct and complete quality system and device master records. These records should be written in such a manner that the intended employees can understand and properly use them. Management should show their commitment to training by providing a training room such as a cafeteria and training equipment such as chalkboards, flip charts, video cameras, VCRs, television monitors, slide projectors, overhead projectors, screens, workbooks, etc. Training Methods Training for employees may be achieved by many methods such as: o device regulatory and GMP seminars; o individual consultations with managers, consultants, FDA personnel, etc.; o on-the-job training with appropriate instructors;

guidelines governing personnel in drug and device manufacture

181

o cross-training details between R&D and production; o video tapes and movies; o slide shows with an appropriate instructor; o reading GMP/QA manuals and textbooks; and o formal college QA courses. To meet GMP requirements, all training should be documented as noted above. Training Indicators A proactive approach to training is required by 820.25(b) where each manufacturer is required to establish procedures for identifying training needs. Thus, management should diligently look for factors that indicate a need for additional training or retraining. Some of these training indicators are: o verification failures due to basic problems, ! post-submission technical and labeling information required by ODE for 510(k) submissions, o validation problems due to routine problems, o excessive design transfer problems or delays, o inadequate device master record, o excessive device defects, o excessive process equipment or line down-time, o improper labeling or packaging, o employee confusion, o employees ignoring environmental control requirements, o process or sterilization failures, o incorrect ordering or shipment information, o customer complaints, and o excessive or basic items on a FDA list of observations. This information is derived from management observations, analysis of device history records, analysis of complaint records, quality assurance audits, etc. Audits As management performs their daily activities they are aware of the obvious aspects of personnel workmanship and work practices. However,

cleanroom operators’ manual

182

to make sure that all aspects, obvious, hidden, or subtle, of the required quality system exist and are operating correctly, the QS regulation in 820.20(b) requires planned and periodic audits of the quality system. This audit covers: o noting personnel practices in areas being audited, o looking for training indicators as listed above, and o whether the company approach to training programs is proactive. The audit also includes an inspection and review of training: o o o o

programs and content, facilities, equipment, and records.

A report should be made of each quality audit, including any reaudits(s) of deficient matters such as incorrect performance of work, lack of training, failure to update training, the training program not being proactive for all of the personnel that receive complaints, part of the training equipment is not functioning, on-the-job training not adequately supervised or documented, etc. Audit reports that cover training activities and personnel practices should be reviewed by management responsible for these factors in their department. Corrective actions for deficient training and personnel practices shall be taken where necessary (820.22).

guidelines governing personnel in drug and device manufacture

183

sample procedures (SOPs) C O M PAN Y LO G O Title Employee Training Prepared by Approved by ECN Notes

Page 1 of 2 SOP Number Date Prepared Date Rev

Policy - Employees shall be trained as needed to perform their assigned tasks and shall be made aware that we produce medical devices in accordance with various regulations and standards. Scope - This procedure applies to all employees. Hiring - The education, background, training, and experience of prospective employees shall be considered with respect to the requirements of the job to be filled. Responsibility - Managers are responsible for assuring that the employees assigned to them are trained or otherwise qualified for the assigned jobs. Before assigning an employee for the first time to a new job, managers shall check their training to verify that the employee has been trained or qualified for the new job. The QA department is responsible for training facilities, equipment, and supplies. Training - All inexperienced employees shall be trained to perform their assigned jobs. On-the-job training shall be monitored closely by a supervisor. All employees shall be made aware of design and/or production defects, visible and invisible, in the device, labeling, and packaging that may occur from the improper performance of their jobs and defects that they should look for and detect. Our cleanliness (environmental control) and safety procedures shall be explained to all employees. Quality Assurance Employees - QA or product acceptance employees shall receive the training noted above and shall be made aware of errors and defects, visible and invisible, likely to be encountered as part of their quality assurance functions. Customer Complaints - Receptionists, managers, representatives, salespersons, and other employees likely to receive complaints are trained in complaint handling procedures applicable to their functions.

184

cleanroom operators’ manual

Change Control - All employees are to be advised that they are to perform their jobs as instructed or as covered by standard operating procedures (SOP’s). They are NOT allowed to change cleaning, compounding, processing, testing, packaging, labeling, or tasks covered by SOP’s until the change is approved according to our change control SOP. Documentation - All classroom and on-the-job training shall be documented by the supervisor and trainer of the employee on the form as shown on sheet 2. A separate form for each employee with a record of their training shall be filed and shall be updated at the end of each training session.

guidelines governing personnel in drug and device manufacture

185

cleanroom and workstation procedure This procedure is divided into general requirements, non-laminar airflow clean rooms, and workstations, laminar airflow clean rooms and workstations, and clean room personnel rules. The first part of this procedure contains useful information for any area of a plant were moderate control is needed to reduce particulate contamination. The level of control needed increases as the procedure goes from non-laminar airflow to laminar airflow. The final section contains additional requirements for personnel working in a clean room. PROCEDURE TITLE: Clean Room and Work Station Procedure No.___ Rev.___ Prepared by___________ App by_____

Date________

A. General Requirements 1. No eating, drinking, smoking, or chewing gum. 2. Specified garments must be worn when entering and inside the clean area. These shall be stored in the anteroom and not worn in non-clean areas. 3. Only approved clean room paper shall be allowed in the area. 4. Use only ballpoint pens (fine point preferred). 5. Rouge, lipstick, eye shadow, eyebrow pencil, mascara, and false eyelashes shall not be worn by any worker while in any clean area. 6. No cosmetics of any kind are to be applied or removed in the clean area. 7. Skin lotions or lanolin-base soaps are in the restrooms for employees to use to guard against flaking due to dry skin. 8. Solvent contact with the bare skin should be avoided, as most solvents will remove the natural skin oils and cause excessive skin flaking. 9. The use of paper or fabric towels is not recommended — washrooms should have electrically powered, warm-air dryers. 10. Approved pliers, tweezers or lint-free gloves must be used to handle manufacturing materials, components, or finished devices.

186

cleanroom operators’ manual

11. Do not touch with gloves or finger cots any covered or uncovered part of the body, or any item or surface that has not been thoroughly cleaned. 12. All containers, racks, jigs, fixtures, and tools should be cleaned to the same level of cleanliness specified for the device being processed. B. Non-laminar Airflow Cleanrooms and Workstations 1. Garments shall be pocket-less, lint-free coveralls, with snug fitting fasteners at the neck, wrist, and ankles. 2. Lint-free caps must be worn and must completely cover the hair and head except for the eyes, nose, mouth, and chin. 3. Shoes shall be cleaned and covered with a non-shedding boot-type cover or changed to approved clean room footwear. If special footwear is provided, it shall not be worn outside the clean room and dressing room. 4. Janitorial services shall be performed only by adequately trained and supervised personnel, each of whom must be properly garbed. 5. All equipment to be brought into the clean room shall be qualified for clean room use and first be thoroughly cleaned. Use only equipment that will minimize the generation of contaminants. 6. Traffic into and within the clean room shall be restricted to authorized and properly garbed personnel, and unnecessary movements by these personnel shall be minimized. C. Laminar Airflow Clean Rooms and Work Stations 1. Garments may vary with the operation being performed, but the minimum garment shall be a pocketless, lint-free smock which extends to at least 15 inches below the work surface. The collar and cuffs shall have fasteners. 2. Head covering shall be worn, and shall completely cover the hair. If the operation requires the wearer to lean over the work, or move into the airstream between the filter bank and the work piece, the front, sides, and rear neck areas of the head shall also be covered. 3. Shoe covers are not necessary for vertical or horizontal laminar airflow facilities except when the work is being performed less than 24 inches from the floor.

guidelines governing personnel in drug and device manufacture

187

4. A face mask may be needed if an operator has a cold, or if the nose and mouth must be brought very close to the work piece for work on miniature components or devices. Check with your supervisor for instructions. D. Clean Room Personnel Rules Personnel will be asked to cooperate in maintaining a low contaminant emission rate by observing the following rules. 1. Bathe at night, instead of in the morning, to allow the build-up of normal body oils which reduces skin shedding. Also, use skin lotions. 2. Wear clean, unstarched, low-shedding garments. 3. Where appropriate, shave daily and be clean shaven or wear appropriate hair covering. 4. Avoid touching, rubbing, and scratching exposed areas of the body. 5. Exercise extra care to rid the hands of normal residue from home duties such as starching, baking, plastering, wallpapering, painting, concrete work, carpentering or other particulate generating activity. 6. Request duty outside the or away from the clean room area when you have a cold or other viral or bacterial infection.

11 good sanitation practices

C K Moorthy

G

ood Sanitation and Housekeeping Practices are an important element of GMP, and goes a long way in maintaining a high state of control in a properly validated manufacturing environment. Sanitation comprises both cleaning and disinfection, and in the following sections we shall discuss each separately. cleaning The purpose of cleaning is to remove soil, any substance that is not an integral part of a structure, or designed to assist in function. This objective may be modified by practicality and cost, and should be achieved without shortening the life of the item, interfering with its function, or increasing the risk of contamination. Any item after cleaning should have fewer rather than more contaminants on it. Contaminated water, soiled mops or wipes often increase the number of viable and nonviable contaminants on a surface. The source of soil may be particles deposited

cleanroom operators’ manual

190

from the air or transferred by direct contact from hands, equipment or implements. Soil removal is not merely to prevent it from contaminating a product, though it is certainly the single most important objective in the context of aseptic zones. Soil can obliterate identification marks, warnings or instructions on equipment; corrode, abrade or react chemically with a surface; block channels, interfere with valves, or the flow of liquids, gases or electric current; encourage insects, pests or growth of microorganisms; form an insulating shield that obstructs penetration of heat or chemicals, specially during sterilisation or disinfection; and can generally reduce the confidence in the facility’s ability to deliver quality products. Cleanroom/Aseptic zone cleaning Cleanroom/Aseptic zone cleaning is a specialised task, which requires trained staff that will keep to detailed schedules, and often requires equipment, methods and materials not used in other situations. Why? Because soil in aseptic zones can potentiate product contamination. To add to our difficulties, the bulk of the contaminants encountered in aseptic zones are invisible. How do you clean what you cannot see? If we have gravel or river sand soiling our clothes, we merely shake it off, or brush it off. But if red mud or talcum powder gets on our clothes, we find it more difficult to dislodge it. Washing with water usually solves the problem. If some paint or blood stain soils our clothes it takes more than soap and water to remove the stains. This is because particles, like gravel, in the size range above 20µ do not bond strongly with the surface they are in contact, and can be removed by conventional methods employing simple brushing or detergents and water. This is primary or gross cleaning. Particles, like fine mud or talc, in the size range of 0.1µ to 20µ are influenced by considerations like polarity and surface tension, and require coaxing with surfactants (surface acting agents) for removal. This constitutes secondary or precision cleaning. Particles, like stains, in the size range below 0.1µ bond aggressively through forces of intermolecular attraction, and can be persuaded to loosen their grip only by strong solvents. This is tertiary cleaning or cleansing.

good sanitation practices

191

Analogies from our day-to-day cleaning experiences: gross cleaning while dusting, sweeping and wiping; moderate precision cleaning while bathing, washing clothes and polishing articles; and tertiary cleaning while removing stains. Whether it is an aseptic zone floor or ceiling, work surface or component, equipment or tool, it is necessary that we identify the nature of the contaminant and choose a cleaning technique appropriate for that task. Methods of cleaning Two basic methods of cleaning are used: dry and wet. Dry methods rely on mechanical action to loosen and remove larger objects and particulate soil, but do not remove stains and are unsuitable for wet, oily or greasy surfaces. Wet cleaning employs detergent solutions, surfactants and solvents to loosen and resuspend or dissolve adherent soil. Cleaning should not end up as an exercise in redistribution of settled contaminants. For example, sweeping with brooms increases suspended contaminant density by 700%! Dust attracting mops cause an increase of 30%; wet scrubbing machines by 3%. Vacuum cleaning without filtered exhaust increases the count by 25%; if fitted with a HEPA exhaust, it causes a decrease in the count by 20%. The effect varies with the make of equipment and manner of use. Hazards while cleaning Cleaning should not be undertaken while the aseptic zone is in operation; if unavoidable, first cover all susceptible sites and open vessels and allow at least 15 minutes for dispersed contaminants to settle out of harm’s way before re-exposing them. Though dispersal of contaminants into the air is less likely with wet cleaning, the solutions become contaminated quickly; splashes are common, and aerosol droplets can travel far and wide to contaminate. Wet methods require proper drying out after the cleaning process; otherwise they bring in their own store of problems like accelerated microbial growth, corrosion and chemical attacks, and slippery floors. Besides, if a detergent or soap is used for cleaning, it is important to consider the difficulty that may arise with build up of residues, which must be deemed as yet another type of soil. Detergents and their residues A common problem associated with detergents is its composition. Suppliers do not provide specific data on composition, which makes it difficult to evaluate residues. Unlike product residues, where tolerance

cleanroom operators’ manual

192

levels for residual concentration are often laid down and accepted, there are no corresponding acceptance limits for detergent residues, since detergents are not part of the manufacturing process and are added only to facilitate the cleaning process. If the detergent is not easily removable, a different, more suitable detergent should be selected. When in doubt, deem it dirty Some areas, by the nature of the function carried out there, may be heavily contaminated. While every effort is made to keep these areas as clean as possible, it is often more prudent to deem them as contaminated and take necessary precautions, rather than adopt expensive ineffective measures and then ignore the risk. Setting up a staging area There would be much less to clean down inside the aseptic zone if we were to make sure that all men and materials are sent in thoroughly cleaned. It is good practice to set up a staging area just outside the aseptic zone for carrying out final gross clean down prior to entry. If the equipment or component is manufactured under clean conditions; and if every item entering the aseptic zone is sent double-wrapped, so that the outer jacket serves as a dust cover and can be stripped in the staging area, the decontamination work load is reduced and the whole process becomes more effective. In fact, aseptic zone practices are being increasingly adopted by cleanroom contractors while setting up an aseptic processing zone. Cleanroom Construction Protocol requires immediate pick up of spills; vacuuming while drilling; providing temporary curtains around site where dust generating operations are being carried out to avoid dispersal and spread of debris. Such techniques reduce the start up contaminant load, resulting in faster clean down on commissioning. Drawing up a cleaning programme The first important step is to appoint a Sanitation Team. Routine cleaning should be carried out as part of an agreed programme with detailed agreed schedules and procedures. Regimen drawn up for the facility should be given preference where it conflicts with the manufacturer’s instructions, but it is always a good idea to read the instructions first and clarify discrepancies. Alternate methods or materials should not be used unless authorised. Cleaning products should not be mixed unless known to be compatible. Soaps and detergents may often reduce the effectiveness of disinfectants; some products may react dangerously. For

good sanitation practices

193

example, soap neutralises quarternary ammonium compounds (like Savlon) and acid cleaners react on exposure to hypo chlorites (bleach) to release chlorine. Surface deterioration is often attributable to inappropriate cleaning. Not all commonly used cleaning techniques have been introduced as properly planned, coordinated and adequately researched programmes, and it is reasonable to check methods, which do not appear to be soundly based. It is part of the job of the contamination control team to liaise with other disciplines in evaluating the need for changes in existing procedures and programmes related to contamination risk. Waste management The programme must provide for management of wastes. Waste includes spillage, defective packaging materials, containers and products. Estimates should be made of waste, both quantities and characteristics at various points in the manufacturing process and means of collection and disposal provided. The wastes must be effectively separated from the process stream to provide positive assurance that the product will not be contaminated. Disposal means, whether waste containers, dust collection equipment, vacuum collectors or even separate sewage system, should be clearly marked. To illustrate the need to identify and separate waste streams, consider the liquid waste discharge from a pharmaceutical facility. The rest room, lavatory, and kitchen waste, known as domestic sanitary sewage, is one type; rinse water from process areas, tank drainage from compounding areas and laboratory wastes, known as industrial waste, is the other type. While the former may be directly discharged into a sanitary sewage system, the latter may require some pretreatment prior to discharge. To facilitate the streams, most production facilities have multiple sewage systems. This need to separate the two types of liquid waste streams is intended for the protection of the municipal sewage treatment system and facility. Internally, the separation of process waste from domestic waste is necessary to help maintain the controlled conditions in the aseptic zone. If all liquid wastes were discharged via a single system, any blockage or overflow condition in that system could cause a overflow of one type of waste into the other, and domestic waste may find its way into the production area, introducing an unacceptable and indeterminate bacterial contamination. To preclude the possibility of this condition, pharmaceutical facilities have separate domestic and process waste

cleanroom operators’ manual

194

systems, which do not connect with the plant, and are equipped to prevent backflow of waste into the facility. Control of the waste disposal problem then involves a three-element system: solid waste disposal; liquid waste disposal; and airborne waste (dust) collection and disposal. For each ingredient or item of waste, thought must be given to: What is to be collected? What quantities are expected? How must the waste be moved through and out of the area to prevent accumulation and possible contamination? How must the material be disposed off: municipal sewage, landfill or incineration? Organising for cleaning Effective cleaning of both physical facility and equipment is enhanced by facility design details, which reduce bacterial growth areas, minimise contaminant collection points and improve surface cleanability. Beyond design details, broader consideration must be given for the space and utility needs of cleaning. Cleaning equipment Cleaning equipment must be controlled like all other equipment entering controlled environments. It must be cleaned, sanitised and, where necessary, sterilised if for ultra clean use. After use, the equipment must be removed from the controlled area for storage and cleaning prior to reuse. The equipment required will depend on individual needs but may include buckets, mops, sponges, spray guns, brushes and vacuum hoses. Areas must be provided adjacent to the controlled environment where cleaning equipment can be cleaned and stored without subjecting it to potential contamination. Utility requirements Utility needs for aseptic zone cleaning are unique. Both sewage drains and non-aseptic water supplies are contamination potentials to be avoided. Use of Water for Injection or DM/DI filtered water eliminates the potential water contamination. After cleaning, the wastewater may be picked up by mops, which may redistribute contamination rather than remove it. One alternate approach is to spray the cleaning solution onto the surface and remove it by a central vacuum collection system. The vacuum connections are sanitised as part of the area cleaning activity

good sanitation practices

195

to prevent contamination of the clean environment. Although this method is effective, the vacuum piping must be planned and installed in the walls of the facility during construction. Cleaning auxiliary areas Auxiliary areas are those places upstream of the controlled environment in which packaging components, and processing equipment are cleaned and sterilised, and in which chemicals are blended into clean bulk formulations. The ceiling, lighting fixtures (inside and outside), sprinkler heads and air supply vents are thoroughly washed with a microbicidal detergent solution and cloth. Burned-out bulbs are replaced with new ones that have been similarly wiped. Then walls, including baseboards, doors, doorframes and air return vents are thoroughly washed. Following this, all horizontal surfaces, fixtures, equipment and furniture are washed and wiped. Accessible floor areas and cover bases are vacuumed and machine scrubbed, with a final wipe with clean water. Cleaning the critical zone The controlled environment in which the critical process is carried out is cleaned using the procedures outlined for auxiliary areas. One significant difference to be borne in mind is that there are no drains provided in a controlled environment, since they are a potential source of contaminants. Liquid spills in controlled environs should be removed with a wet/dry vacuum fitted with a HEPA exhaust, followed by a damp wipe down with microbicidal detergent solution. Cleaning service areas For purposes of definition, a service area includes offices, rest rooms, storage rooms, mechanical support rooms, lockers and rooms downstream of the controlled processes. The ceilings are wiped down with a microbicidal detergent solution using a sponge or cloth. The sprinkler heads are dusted with a soft-bristled brush and light diffusers are cleaned using detergent solution. Where drapes are unavoidable, a vacuum cleaner equipped with a brush tool is used. The air supply and return vents are washed with a degreasing microbicidal detergent solution and sponge. A microbicidal detergent solution is used to wipe down the walls, door and partitions. The cloth or sponge employed in such operations must always be of a non-shedding

cleanroom operators’ manual

196

type to reduce particulation. The windows are washed with a suitable window cleaner. Accessible areas of office furniture and other miscellaneous equipment are damp wiped using a microbicidal detergent solution and cloth. Rest rooms are especially hard to clean and require great care. Sinks and bowls and related plumbing hardware are washed with a microbicidal detergent and cloth. The interior surfaces of all bowls are cleaned with hydrochloric acid. In mechanical support rooms, lockers and storage rooms, accessible floor areas and cover bases are vacuumed and then machine scrubbed. The floor is then rinsed with clean water. The floor drains and drinking fountain drains are flushed with a microbicidal detergent solution. Equipment cleaning Equipment cleaning, like facility cleaning, requires consideration during planning stages. It lends itself to a central operation, at least for closely allied production areas, but cannot be located in such a way that travel through non-controlled areas is required. Equipment cleaning involves not only the process machinery but also all associated auxiliaries like pumps, hoses, pipes, fittings and filters. The cleaning may involve disassembly, removal of product residue, reassembly, integrity testing, sterilisation and storage. The area should be separate from, but adjacent to the clean production area, and will probably function at irregular hours. An adequate supply of water, including pure water, steam, compressed air, nitrogen, is typically required. If equipment is to be used aseptically, provision must be made for sterilisation prior to use. Preparation, like planning, is a vital part of the manufacturing process. Preparation of equipment entails the cleaning, sanitising, assembling, and in many cases, sterilising and/or depyrogenation of equipment, which may include items as diverse as tanks, mixers, process equipment, transfer lines and the work area in general. The proper cleaning of all equipment that comes in contact with the product is particularly critical. Concern must be demonstrated for general cleanliness as well as for the equipment and area, so that one must be sure that the area and equipment are free from cross-contamination from products processed just previously, or those being processed nearby. The first step in maintaining clean equipment is the practice of ordinary good housekeeping practices. Orderliness and cleanliness are prerequisites for proper aseptic zone operation. Equipment should never

good sanitation practices

197

be put away dirty. Cleaning up as soon as possible after an operation has been completed is good practice. Dirty equipment can supply the contaminants, both viable and nonviable, to compromise other portions of the facility. Nothing substitutes for good nonabrasive scrubbing with microbicidal detergent solution followed by wipe down with clean water. Because some equipment are complex, chemical tests are often employed to detect residual detergents in the rinse water, and rinsing is continued until the level is below maximum acceptable limits. Where possible, drying should be under LAF cover; and storage must be under lint-free wraps in a clean, dry area. Microbial purity of water for cleaning should meet PHS standards with not more than 500 CFU/ml. Final rinse is recommended with pure water at a temperature of 80 oC with not more than 100CFU/ml. Drawing up a cleaning programme o Cleaning should be introduced as a properly planned, coordinated and adequately researched programme o Choose a cleaning technique appropriate for the intended task o Microbial purity of water for cleaning should meet PHS standards, not more than 500 CFU/ml. Final rinse is recommended with pure water (WFI grade) containing not more than 100 CFU/ml at a temperature of 80 oC. o Because some equipment are very complex, chemical tests may be required to monitor residual detergents in the rinse water, and rinsing continued until the level falls below maximum acceptable limits. Where possible, drying should be under LAF cover. o The sanitation programme must take into account waste management • What is to be collected • What quantities are expected • How must the waste be moved through and out of the area to prevent accumulation and possible contamination • How must the material be disposed off: municipal sewage, landfill or incineration Good cleaning practice: a summary • It is recommended practice to first demarcate and grade your controlled environment, so that sanitation stringency increases towards the core locations. This is called zoning. On a floor map of the aseptic zone different areas are coloured differently, coded to

cleanroom operators’ manual

198

•

•

•

•

•

•

•

signify the sanitation stringency prescribed for each. Red is usually reserved for the most critical sites, while green is forbidden, since no area anywhere in or around an aseptic zone can be deemed safe. Check that all cleaning agents and implements are aseptic zone grade: cleanable, sterilisable and non-contaminating. It is also important to evaluate some other key parameters and characteristics like surface tension, polarity and pH; their solubility, stability and reactivity, including corrosiveness; their efficiency as surfactants; their propensity to leave residues; and most importantly, the recommended use dilution and temperature. Prepare a fresh cleaning solution, accurately diluted for each task. Make up only the quantity required in a clean, dry container. Freshly drawn tap water is usually suitable for peripheral areas. Very hard water will precipitate soaps and neutralise some disinfectants. For aseptic processing zones use WFI grade water. Hot water cleans better than cold. But at temperatures above 65 oC it coagulates proteins, and organic stains, if any, will then be more difficult to remove. Use of two buckets mounted firmly on a trolley, one for fresh solution and the other for rinsing is common practice; use of three buckets, one marked dirty where the soiled solution is drained, a second marked rinse and last marked clean would be an even more effective procedure. Brushes, mops and wipes should be dry and clean before use. Apply the cleaning solution evenly to all of the surfaces. Do not apply more fluid than necessary onto a surface. This avoids waste, seepage into cracks, shrinkage of surface materials, and difficulties of subsequent removal. Always clean down from ceiling, walls to floor, from the farthest point to nearest, with gentle, steady, unidirectional strokes. This holds for both wet as well as dry wiping, where the stroke length should not be more than 400 mm. (When dry wiping, expose a fresh, clean surface for each stroke). Rinse off cleaning solutions when practical, and change contents frequently to prevent buildup of soil in the solution, which will lead to recontamination. Allow sufficient time for cleaning solutions to penetrate the soil on the surface. However, do bear in mind that strong acid or alkaline cleaning agents can damage surfaces if left in contact too long.

good sanitation practices

•

• •

•

199

Dispose off used cleaning solution in the manner prescribed by your SOP in the designated area. Do not empty into washbasins or work area sinks. Remove any fluid trapped in channels or elsewhere, and dry the cleaned surface as thoroughly as possible. Remove cleaning equipment, accessories and implements from the aseptic zone as soon as the cleaning process is completed. Clean them as per methods laid down in your SOP, dry them and store them in the designated location. If the equipment is faulty, report it promptly to your supervisor. Wash hands before carrying out any other duties.

Some tips for cleaning personnel Rule Number 1 Cleaning or decontamination agents should never be mixed unless specified in the SOP. Many products have been ruined by chemical cleansers that were mixed and wrongly applied to equipment with the result that an insoluble residue was left which was then transferred to the product. In some cases mixing can be dangerous to the operator. Rule Number 2 Cleaning should be done by working from the top downwards. The lower the surface, the dirtier the surface. The further away from the HEPA filters in the ceiling the greater the surface soiling, so working should always be away from the filters outwards and downwards. Product containers and closures as well as other unused materials should be removed at this point. Rule Number 3 Always use fresh filtered cleaning agents. Rule Number 4 Always clean cleaning equipment. Rule Number 5 Never add soil to the cleanroom when cleaning it. Rule Number 6 Always work TOP TO BOTTOM; FARTHEST TO NEAREST A checklist for cleaning personnel 1 Check and review the Standard Operating Procedure 2 Gather all supplies, checking to make certain that they are clean

cleanroom operators’ manual

200

3 Place all supplies in the air-lock or pass-through 4 Change into prescribed clothing following laid-down procedures for scrub-up and gowning 5 Prepare cleaning solutions ensuring accurate measures 6 Enter the process area and move supplies to the area to be cleaned 7 Remove unused components and raw materials 8 Disassemble equipment requiring re-processing and remove it to the re-processing area or air-lock 9 Begin the cleaning process by removing gross soils 10 Clean equipment by working from the top down to the floor. NEVER WORK UPWARDS! 11 Clean ceilings, walls and floors 12 Remove cleaning materials from the area and place cleaning equipment in the air-lock when all tasks have been completed. Do not remove process area specific items such as vacuum cleaners, but make sure that they are cleaned and emptied using the correct SOP’s 13 Clean the air locks 14 Clean the outside areas List of Do’s 1 2 3 4

Hands, fingernails and face to be clean at all times Proper protective clothing to be worn correctly at all times Wear gloves or finger-cots as required Always clean and disinfect spectacles before entering the process area 5 Keep all parts and tools at the workstation as clean and orderly as possible 6 Always use tool racks provided. These must never be wooden 7 Keep surplus parts in appropriate containers 8 Make certain that parts are clean before assembling 9 Always work on a clean surface and never on cloth or paper towel that can transfer contaminants to equipment or the work piece 10. Always report any changes In environmental conditions List of Don’ts 1 Never comb hair in the process area 2 Never wear or apply cosmetics in the process area

good sanitation practices

201

3 4 5 6 7

Never wear finger polish or nail varnish Don’t wear jewellery in the process area Don’t eat or chew gum in the process area Don’t smoke in the process area Avoid nervous habits such as scratching and rubbing hands together 8 Don’t wear soiled or ordinary street clothes in the process area 9. Don’t leave exposed components on the workbench or area 10 Don’t walk about unnecessarily and be cautious when approaching someone else Disinfection Present practice is far from satisfactory in the use of disinfectants. Every institution often has a different disinfection programme, and the choice of disinfectants for similar purposes varies considerably. A wide range of disinfectants is used, some of which are clearly unsuited for the purpose for which they are employed. In dispensing solutions, members of staff apparently rely upon such measures as a tablespoonful to a bucket, until it looks enough and depending on the smell. The important principle of strong enough for long enough is generally overlooked. Too often, their abuse leads to a dangerous notion of security. Antiseptics, disinfectants and germicides Terms like antiseptics, disinfectants and germicides are often used interchangeably without drawing distinctions. While all three have antimicrobial action, antiseptics are intended for clinical use, while disinfectants are for use on inanimate objects. The term germicide is all embracing to mean fungicide, bactericide, sporicide and viricide. As mentioned earlier, though some chemical agents are effective against all varieties of microbial flora, there is a general tendency to dismiss disinfectants as being useful only against vegetative bacteria and lipid viruses. Planned disinfection Floor cleaning mops, wipes, baths, bath mops and brushes, washbowls, nail brushes and communal jars containing antiseptics and soap are confirmed sources of contamination and microbes. Antimicrobial chemicals must be properly applied if they are to be of service. Each facility should adopt a properly planned programme on the kind and concentrations of disinfectants to be used for particular purposes, a system

cleanroom operators’ manual

202

of supervision to ensure that the staff are implementing this programme and a system of in-use tests to be made on samples of the disinfectant solutions actually being used in the different areas to ascertain and confirm that they are at the correct concentration and retain adequate activity. Application methods Disinfectants may be applied using a variety of methods, as dictated by their nature and the surface to be treated. Agents prepared as liquids may be applied by: Spraying is convenient for small to medium size surfaces. However, diluted agents should not be stored in a spray bottle for long periods of time. Time of storage is dependent upon the chemical stability of the agent and the potential for the applicator to become a reservoir for resistant organisms. Wiping is effective for small to medium size surfaces. Wiping combines the chemical activity of the agent and the physical removal of organisms or soil by abrasion. Wipes should be clean and non-particulating. Mopping is appropriate for large environmental surfaces and is accomplished by one of three techniques: Damp mopping: A clean mop of suitable design is dipped into the agent and squeezed out. The mopped surface remains wet for some time. Wet mopping: Two buckets of decontaminating solution are prepared according to labeled instructions. A liberal amount of solution from one bucket is applied to the surface; and the mop is then rinsed and squeezed out in the second bucket. Flood and vacuum: A liberal amount of disinfectant solution is applied to the surface, and after a prescribed time of contact the excess is wet vacuumed from the surface. Submersion in solutions of chemical agents may be effective for decontaminating small surfaces or equipment. Surface cleanliness is a significant parameter in the effectiveness of this method. The activity of some agents like glutaraldehyde are enhanced when used thus in ultrasonic baths. Fogging is used for disinfecting rooms and their contents. A solution of an appropriate agent is aerosolised in mist form using a revolving dispenser or other suitable device.. The success of this procedure depends

good sanitation practices

203

upon covering all surfaces with a fine layer of solution. This success could later translate into a problem if there are insoluble residues, or the film stubbornly adheres to the surface making thorough cleaning difficult. Fumigation where the chemical agent is applied in a gaseous state, concentrated in enclosed areas either at ambient pressure or under vacuum pressure. Selection of agents For daily routine disinfection selection should favour those that are convenient, safe and non-noxious. The more potent, noxious or toxic agents should be reserved for use on a less frequent basis (weekly or monthly) or when advised due to an increase in the baseline microbial level, presence of unique (i.e. sporeformers) or pathogenic microorganisms, or occurrence of atypical operational circumstances. Use of different types of disinfectants on a rotational basis is practised by many companies, although there is no published data in the literature that indicates that the use of a single disinfectant agent, consistent with label instructions, will lead to so-called microbial resistance. If disinfectants are to be rotated there are pitfalls to be avoided, because not all disinfectants are compatible with one another. Cost is a relevant factor when choosing disinfectants. Those designed for special purposes may be both unsuitable and too expensive for use as general environmental disinfectants. To be used safely on human tissue a disinfectant would have to be non-toxic, non-allergenic, non-corrosive and have a neutral pH. These properties are expensive to achieve and are usually obtained at the expense of other desirable properties like range of action. Drawing up a disinfection programme 1. List all purposes for which disinfectants are used, then check all requisitions and orders to ensure list is complete. 2. Eliminate use of chemical disinfectants when an alternative can be reasonably employed. For example, when heat is an option choose sterilisation; or when thorough cleaning alone is adequate; or when disposable items can be economically used. This should then leave few remaining uses for disinfectant fluids. 3. Select the smallest number of disinfectants possible for the remaining uses.

204

cleanroom operators’ manual

Summary of disinfection practices

Formaldehyde Conditions: Humidity 60% to 80% Temperature Low, approx. 18oC Additives: Inhibit polymerisation 10% methyl alcohol Inhibit corrosion 2 % Borax Neutralisation Ammonia in shallow tray Fumigation of Rooms Gaseous/Fumes per 1000 cft 150g KMnO4 + 280 ml formalin Boiling/fogging per 1000 cft 500 ml formalin + 1000 ml water Fumigation of Cabinets Boiling formalin per cft 2 ml Vaporise paraformaldehyde per cft 0.3 g Surface disinfection 1:10 formalin Hydrogen peroxide Additives Silver nitrate Antimony nitrate 60% IPA General use 2 - 10% in distilled water / 60% IPA Fumigation: By fogging 20 % H2O2 in distilled water Surface disinfection 5 - 10% H2O2 in distilled water Water decontaminatlon 100 ppm H2O2 + 2 ml Formalin Virus inactivation 50% H2O2 Virosil Fumigation: By fogging per 1000 cft 200 ml in 800 ml of distilled water Surface disinfection 5% in distilled water Media for isolation Plate count agar for bacterial solution Potato dextrose agar/ Sabroud's agar for fungal isolation Table 1: Summary of disinfection practices

good sanitation practices

205

Phenolics

Metallic salts

Peracetic acid

QACs

Chlorxylenol

Iodophors

Alcohol ethyl

H2O 2

ACTIVITY

Hypochlorite

USE

Additives .................... Y ...... Y ....... N ....... N ...... Y ....... N ....... Y ...... N ....... N ....... N ...... N Concentration (%w/v) 2 .... 2-8 ........ 1 ..... 10 ..... 70 ........ 2 ........ 2 ....... 5 ........ 2 ........ 5 ....... 2 Fungi ........................... E ...... G ........ P ....... F ....... E ....... G GPC ............................. E ....... E ....... E ....... E ....... E ....... E ....... E ....... E ....... E ....... G ....... E GNB ............................ E ....... E ....... E ....... E ....... E ....... G ....... E ...... G ........ F ....... P ....... E Spores ......................... E ...... G ....... E ....... G ....... P ....... G ....... P ....... P ........ P ....... P ....... P Lipid virus .................. E ....... E ....... E ....... E ....... E ....... G ....... G ...... G ....... G ....... F ....... E Nonlipid virus ............ E ....... E ....... E ....... G ...... V ....... G ....... P ....... P ........ P ....... P ...... V

SUITABLE APPLICATIONS

Formaldehyde gas

TYPE

Antiseptic .................... Y ...... N ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... N ....... Y ...... N Disinfectant ................ Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... N ...... Y Germicide ................... Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... N ...... N ....... N ....... N ...... Y

Human tissue .............. N ...... Hands & feet .............. Y ...... Environment air ......... N ...... Contact parts .............. Y ...... Work surface .............. Y ...... Equipment surface ..... Y ...... Glassware ................... Y ...... Culture spills .............. Y ...... Walls & Ceiling ......... Y ...... Floor ............................ Y ...... Sinks ........................... Y ...... Toilet ........................... N ......

N ....... N ....... N ...... N ....... N ....... N ...... Y ....... N ....... N ...... N ....... Y ....... Y ...... N ....... Y ....... Y ...... N ....... Y ....... Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... N ....... N ....... N ...... N ....... Y ....... Y ...... N ....... N ....... N ......

Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... N ....... N ....... N ...... Y ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... Y ....... N ....... N ...... Y ....... Y ....... Y ...... N ....... Y ....... Y ...... N ....... Y ....... Y ...... N ....... N ....... N ......

Y ....... N ....... N ...... Y ....... N ....... N ...... N ....... N ....... N ...... N ....... N ....... N ...... Y ....... Y ....... N ...... Y ....... Y ....... N ...... Y ....... Y ....... N ...... N ....... N ....... N ...... Y ....... N ....... N ...... Y ....... N ....... N ...... Y ....... N ....... N ...... N ....... N ....... N ......

N N N N N N N N N Y N Y

CHARACTERISTICS INACTIVATED

Glutaraldehyde

Properties and proper use of common disinfectants

Hard water .................. N ...... Anionic soap .............. N ...... Cationic detergent ...... N ...... Cork ............................ N ...... Organic matter ........... N ...... Proteins ....................... Y ......

N ....... N ....... N ...... N ....... N ....... N ...... N ....... Y ....... Y ...... N ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ......

N ....... N ....... Y ...... N ....... N ....... N ...... N ....... N ....... N ...... N ....... N ....... Y ...... Y ....... N ....... Y ...... Y ....... N ....... Y ......

N ....... N ....... N ...... Y ....... N ....... N ...... N ....... N ....... N ...... Y ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ......

N N Y N N N

Shelf life > 1 week ..... N ...... Corrosive .................... Y ...... Attacks plastics .......... Y ...... Stains ........................... Y ...... Residues ...................... N ...... Irritate skin/eye/nose . Y ...... Toxic ........................... Y ...... Safe handling ............. N ......

Y ....... N ....... N ...... Y ....... Y ....... Y ...... N ....... N ....... Y ...... N ....... N ....... Y ...... Y ....... N ....... N ...... Y ....... Y ....... Y ...... Y ....... Y ....... Y ...... N ....... Y ....... Y ......

Y ....... Y ....... Y ...... Y ....... Y ....... N ...... Y ....... Y ....... N ...... N ....... Y ....... N ...... N ....... N ....... N ...... N ....... N ....... N ...... N ....... N ....... N ...... Y ....... N ....... N ......

Y ....... Y ....... Y ...... N ....... N ....... N ...... N ....... N ....... N ...... N ....... N ....... Y ...... N ....... N ....... Y ...... N ....... Y ....... Y ...... N ....... N ....... Y ...... N ....... N ....... N ......

Y N Y Y Y Y Y Y

Table 2: Properties and proper use of common disinfectants

cleanroom operators’ manual

206

4. Arrange for distribution of selected disinfectants at correct use dilution, or provide apparatus for accurate measurements at point of use. 5. Make sure that every potential User of disinfectants receives adequate instructions on correct usage. These should include: - The correct disinfectant concentration to be used for each task - Substances that will react with, neutralise or otherwise interfere with the disinfectant - The shelf life at the concentration supplied; the type of container and closure to be used; and the frequency with which the solution must be changed in use. - Personal safety instructions: should gloves be worn? How to open and mix safely? What to do in case product comes in contact with skin or eye? 6. The programme should be monitored to ensure that it is, and continues to be, effective. Periodic in-use tests, assays and estimations of concentration are recommended. Good disinfection practice: a summary The general principles are summarised here to serve as a guideline for the sanitation team. First decide on the type of disinfection programme. This requires consultation among the Microbiologist, Pharmacist and the User. Demand for disinfectants may come from many departments. There are also many sources of supply. All requests should be approved by the contamination control team, who can check whether they are appropriate and in conformity with the overall programme. • •

• •

•

List all purposes for which disinfectants are used, then check all requisitions and orders to ensure list is complete. Eliminate use of chemical disinfectants when an alternative can be reasonably employed. For example, when heat is an option choose sterilisation; or when thorough cleaning alone is adequate; or when disposable items can be economically used. This should then leave few remaining uses for disinfectant fluids. Select the smallest number of disinfectants possible for the remaining uses. Arrange for distribution of selected disinfectants at correct use dilution, or provide apparatus for accurate measurements at point of use. Make sure that every potential User of disinfectants receives adequate instructions on correct usage. These should include:

good sanitation practices

• • •

•

•

207

The correct disinfectant concentration to be used for each task Substances that will react with, neutralise or otherwise interfere with the disinfectant The shelf life at the concentration supplied; the type of container and closure to be used; and the frequency with which the solution must be changed in use. Personal safety instructions: should gloves be worn? How to open and mix safely? What to do in case product comes in contact with skin or eye? The programme should be monitored to ensure that it is, and continues to be, effective. Periodic in-use tests, assays and estimations of concentration are recommended.