clean area
TRANSCRIPT
Clean Room Technology
Clean room
A clean room can be defined as an environment where the supply, distribution and filtration of clean air and the material of construction are regulated to meet the appropriate cleanliness levels required and defined by the governing authorities to execute a validatible clean room.
Sources of contamination
Possible sources of contamination are – 1. Atmosphere 2. Operator 3. Raw materials 4. Equipment
1. AtmosphereAtmosphere is invariably heavily contaminatedwith particles and microorganisms.
a) Contaminants in outside air Originate from soil and carry soil organisms
including-1.Bacteria spores (Bacillus spp, Clostrium spp)2.Mould spores (Penicillium, Mucour, Aspergilius)3.Yeasts 4.Micrococci
b. Contaminants in indoor air 1.Originate from human body and clothing’s-2.Bacteria spores on human skin
(Staphylococcus spp, Streptococcus spp)3.These will also occur in droplets expelled
out into the air from respiratory tract by talking, coughing, sneezing etc.
2. Operator (Most risky factor)The skin, hair and clothing of the operator are potent sources of particulate and microbial contamination. Organisms found on the skin and transmitted on the skin particles are –StaphylococcusDiphtheroidsLipophillic yeastsDermatophytic fungi
3. Raw materials1.drugs which are obtained from natural sourcesExample:Plant source – saprophytic bacteria, yeast,
moulds;Animal source –pathogenic bacteria / spores.2.packaging materials and closures contaminate
specially the parenteral solutions.3.Pigments: Salmonella4.Starches: Coliforms5.Gums: Actinomyces6.Water – prime source of particulate
contamination
4. Equipment
during their preparation and processing
they may generate dustsfrom atmosphere, particles and droplets
may be sedimented on to the internal and external surface of equipment.
Typical system for supplying clean air
1.Intake of fresh air2.Prefiltration3.Temperature adjustment4.Humidification5.Final filtration
1. Intake of fresh airAs most of the pathogen-containing dust particles are found at street level or ground level, so air should be collected as possible as from upper level.2. PrefiltrationThis consists of a coarse filtration-to remove large particlesto protect the main filter3. Temperature adjustmentThe air is passed over coils through which steam or refrigerant is circulated to permit thermostatic control of the air temperature.
4. HumidificationThe air is passed through a fine atomizedspray of demineralized water to increase thehumidity to an acceptable level. Drying of air is achieved by-
• passing it over the beds of desiccant• condensing the vapour in a cooling unit
5. Final filtrationIt is achieved by using a “High Efficiency Particulate Air” (HEPA) filter, positioned at oras close as the inlet to the room.
Types of clean room (On flow)
There are two basic types of clean room; these are identified by the method of ventilation, namely the non-unidirectional type (sometimes called conventional turbulent) and the more effective unidirectional type (sometimes called laminar flow). The unidirectional type can be divided into cross flow and down flow.
Non-unidirectional clean rooms (Fig. 1) have a ventilation supply system similar to that found in offices and shops where ceiling diffusers supply filtered, conditioned air which mixes and dilutes the contaminated room air.
Clean room ventilation differs because –the air filters are of a high efficiency and
installed in a terminal position in the supply ducts
the air supply to the room is much greater than that needed for comfort
the clean room is at a higher pressure than adjacent areas to ensure that contamination does not move from a less clean area to a cleaner one.
Unidirectional clean rooms are ventilated through a complete ceiling or wall of high efficiency filters. The velocity is usually about 0.30 m/s in down flow rooms and 0.45 m/s in cross flow.
Mixed flow systems (Fig. 3) are used in most pharmaceutical applications. The ventilation of the background room area is non unidirectional whereas in the critical area, where the product is open to contamination, airflow is unidirectional. There has, however, been a trend towards protecting the critical area with isolators. Isolators (Fig, 4) give almost complete protection from room contamination as they are positively pressurized with air supplied through high efficiency air filters. The operator works outside the system using glove ports to make contact with the containers and the filling and sealing machinery.
Table : Federal Standard 209E Airborne Particulate Cleanliness Classes
The British Standard
British Standard 5295:1989
Whole number ISO airborne particulate cleanliness classesClass maximum' number of particles In each cubic meter equal to or greater than the
specified size
0.1µm 0.2µm 0.3µm 0.5µm 1µm 5µm
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1000 237 102 35 8
ISO 4 10000 2370 1020 352 83
ISO 5 100000 23700 10200 3520 832 29
ISO 6 1000000 237000 102000 35200 8320 293
ISO 7 352000 83200 2930
ISO 8 3520000 832000 29300
ISO 9 35200000 8320000 293000
Pharmaceutical Clean Room ClassificationEU GGMP
Types of filters
For air filtration there are two types of air filters are used. They are-
1.Fibrous filters,2.HEPA (High Efficiency Particulate Air)
filters.
HEPA filter
High efficiency particulate air (HEPA) filters are essential to the correct performance of a clean room. Composed of various fibers (mainly glass) bonded with resin or acrylic binders. Filter consists of a continuous sheet of filtration material, placed between each pleat and sealed into rigid metal frame. They are capable to remove 99.99% ofparticles < 1 µm. Its filter efficiency is ≥ 99.97% of particles as small as 0.3µm.
New generations of ultrahigh efficiency filters are now available. This can retent 99.99% of particles at 0.1 µm level.
These are—Ultra-retention particle filters (UPLA)Very Efficient Particle Air (VEPA) filters
HVAC system for manufacturing premisesWhat is HVAC
It is the abbreviated form of - Heating, Ventilating, and Air Conditioning, which is a system, which provides conditioned air by providing Heating Cooling & Ventilation System. The parameters of HVAC include the following:
TemperatureRelative HumidityAir ClassRoom to room Pressure GradientAir QualitySound level.
Recommended limit of the above HVAC Parameters are mentioned below
Temperature: 20±5ºC Relative Humidity: It is recommended to
maintain RH within 50±5 % in all manufacturing areas, unless there is any specific recommendation for any special operation. For example, for Effervescent product manufacturing it is recommended to maintain the relative humidity around 20%.
Air Class: As per International standards; i.e. Federal standards, ISO standards; British standards etc.
Pressure Gradient: It should be maintain relatively negative unless there is any special requirements. E.g. For sterile areas.
Air Quality: It should be Dust and Odor free
Sound level: It should be maintain with in 20 db.
Various components of a typical HVAC system are as follows
Air Handling unit (AHU)Condensing UnitChillerCentrifugal PumpsCooling TowerDucting & AccessoriesDiffuserReturn GrillDehumidifierAir FiltersDust ExtractorWet Scrubber for Odor control Internal lining of ducts to control the noise level.
Cleaning and disinfecting
Daily cleaning should take place immediately after the work shift ends and involves cleaning of all work surfaces and floors.
More thorough cleaning of the room should be arranged on a Weekly basis. This involves fumigation of the room with formaldehyde vapor at high relative humidity for a 12hour period
Cleaning materials should be selected to be compatible with the surfaces being cleaned and should not cause corrosion or leave a residue
Suitable cleaning agents are the alkaline detergents and nonionic and ionic surfactants.
Sodium hypochloride and organochlorine compounds at concentrations of 50— 100 parts per million free chlorine,
quaternary ammonium compounds at 0.1—0.2%,
70%ethanol or isopropanol, and 1% w/v formaldehyde solution are all
suitable disinfectants for use on work surfaces in clean areas
Cetritmide or chlorhexidine in 70% alcohol are suitable for use as skin disinfectants.
Personnel : The Key Factor in Clean Room Operations
“People are the largest single source of contamination”
Personnel contribute markedly to product contamination by releasing inert and viable particles in a continuous shower of material.
The following lists a few of the categories into which these contaminants may be classified:
Skin flakes and scales Fragments of human hair Droplets of moisture from breathing and
coughing Cosmetics, Including hair spray and heavy use
of aerosol deodorants Lint and starch particles from washable fabricsFibers and frayed particles of wool, cashmere,
or similar loose-weave fabrics.
Particulate Contamination by personnel:
People are continuously shedding skin cells. Each adult loses approximately 6 to 14 g of
dead skin/ day.Each person loses a complete layer of skin
about every 4 days.Humans create contamination problems that
are bacterial, chemical, and particulate innature.The particles are highly insoluble, extremely
fragile, and resistant to heat.
Microbial Contamination by personnel:The microbial contaminants that are shed are associated with the skin scales and are indigenous to the particular person. These organisms are referred to as resident organisms. Microorganisms can also be transferred to and from objects which the operator has touched or handled. These are called transient organisms since they are carried from one location to another by all personnel touching these surfaces
Table: Contamination Indices
Characteristics of Clean Room EmployeesPersonnel with skin and/or upper respiratory
diseases should be excluded from the clean room operations.
Persons with allergies to synthetic fabrics or solvents used in the operation should also be eliminated from this critical area.
Persons suffering from eczema or other scale conditions, hives, or similar problems should not be permitted to work in the clean room.
People considered heavy smokers are likely to demonstrate-periods of excessive coughing, which emits large numbers of bacteria from the oral cavity, and they may wish to enter and exit the clean room more frequently than nonsmokers.
Personnel Practices and Proceduresa) Practices Related to GowningAll personnel entering the clean room must be familiar with
the established gowning procedureHands and fingernails must be scrubbed thoroughly with
the disinfectant soap provided before entering the clean room.
Hands should be dried with the hot air dryer. The use of paper or fabric towels in the clean area is forbidden.
Skin lotions or lanolin base soaps should be provided for employees to tighten the skin and guard against epidermal scale.
Eyeglasses must be washed and dried with lint-free tissue.Special procedures must be observed in utilizing air locks
and air showers when present.
Shoes must be covered with nonshedding booties or changed to approved clean room footwear. Approved clean room garments must be worn.
The hood must be tucked completely inside the uniform, and the uniform zippered securely to the neck.
If any part of the clean room uniform becomes damaged, torn, or soiled during routine operations, the employee must return to the gowning area and replace the damaged part
Normally, no dean room garment may be used a second time without beingrewashed and resterilized.
All hair is to be completely covered at all times.Personnel should avoid reaching under the hood or other
parts of the garment with gloved hand.Coveralls are not to be unzipped in the clean room.
No skin is to be exposed between the gloved hand and coveralls.
If they become contaminated, gloves must be rinsed in the disinfectant solution provided.
Cosmetics are not to be worn or applied in the clean room. This includes rouge, lipstick, facial powder, eye shadow and eyebrow pencil, mascara, eyeliner, false eyelashes, fingernail polish, hair spray, and the heavy use of an aerosol deodorant.
No jewelry (i.e., large rings, necklaces, earrings, lockets, watches, bracelets) is to be worn in the clean room.
Valuable items such as wallets may be carried into the clean room in the company supplied uniform pockets, provided that they are not removed inside the clean room.
Personal items such as keys, coins, cigarettes, matches, pencils, handkerchiefs, - watches, tissues, and combs should not be carried into the clean
b) Clean Room ProceduresBefore entering any clean environment, personnel
should understand the responsibilities of their position and know aseptic techniques.
Traffic into and within the clean room should be restricted to authorized personnel
Movement in the clean room should be slow and rhythmic.
Once inside the clean room, personnel should remain until the break or lunch Period.
Nervous relief-type mannerisms such as head scratching or rubbing hands, face, or parts of the body must be consciously avoided.
Loud, unnecessary talk through the mask should be avoided. Laughing. Whistling, singing, and shouting increase the number of bacteria emitted from the mouth.
Horseplay is strictly forbidden in the clean room
No eating of food, chewing of gum or tobacco, or smoking is permitted in the clean area.
No pencils or erasers should be used in the clean room. Ball point pens and magic markers are suggested
Paper in any form (except that produced expressly for clean room operations) is not allowed in the clean facility. When it is necessary that paper forms be used, the form should be shielded with a clean plastic covering that has a window exposing the area on which the operator is to write.
No one who is physically ill, especially with a stomach or respiratory disorder/may enter All verbal communication with people outside the clean area should be accomplished through the use of an intercom or telephone.
Paper, pens, keys, and so on, must not be passed from the nonclean to the clean area or vice versa.
Air locks are used as a barrier to the ingress of unclean air from the critical area, and as a passageway for equipment to be brought into and removed from the clean facility.
All vials, bottles, and ampuls must be handled in covered trays.
Trays containing product containers should be opened only under a laminar airflow device.
Personnel should not reach over or lean over open vials on the line.
Personnel should keep their hands away from vial openings. Vials should be handled from the bottom.
Glassware and stoppers generate particulates and must be handled with care
Components that have fallen onto the floor must not be picked up and used
Testing Of Clean and Aseptic Rooms:a)Commissioning tests:
British Standard 5295 lists the tests and procedures which should be used to commission a clean or aseptic room.
Final filter installation test: This is done to demonstrate that the filter is not damaged and that the filter mounting frame does not leak at the gasket flange or the connection to the ducting.
Induction leak test: This test demonstrates that particles cannot enter the room from leaks in construction joints or by back-streaming from openings.
_Filter efficiency test: Aerosol photometers and the generation and detection of DOP smoke or sodium chloride crystals are usually used for these tests.
Particulate contamination control test: This is used to demonstrate that the number and size distribution of particles in the clean room air do not exceed the levels specified for the particular class of room. Microscopic techniques and direct reading light scattering photometers are used in this type of test.
Air pressure test: This test determines the differential pressure between the clean area and adjacent areas. This is usually measured using a sensitive manometer.
Temperature and humidity tests: Measurements are usually made with a sling psychrometer, repeat readings being taken after 30 seconds' whirling of the instrument until stable wet and dry bulb temperatures are obtained.
Air flow tests : Air flow within ducts can be measured with a pitot tube and manometer. Air change rates can be demonstrated by tracer gas decay rate or
Noise level tests : British Standard stipulates a maximum level of 65 dB
Lighting test: The quality of the general illumination within the area and also at the work bench is measured using a portable photoelectric photometer. Recommended lighting levels at the work surface are <300 lux (28 ft candles) for the British Standard and 100— 150 ft candles (1076 – 1614 lux) for the US Standard.
Microbiological tests :Settle plates Agar contact plates and swabsProcess simulation testsSterility tests
Monitoring test: Air pressure, temperature, and humidity measurements
should be recorded continuously.Particulate contamination should be determined daily for
aseptic (Class 1) rooms and weekly for clean (Class 2) rooms
Tests for air flow velocity and uniformity should be carried out at 3-monthly intervals.
Tests for filter efficiency should be conducted yearly. Tests should also be repeated after repairs or maintenance
Settle plates, agar contact plates and swabs, and sterility tests should be carried out during each work shift.
It is recommended that process simulation tests should be conducted at 3- monthly intervals.