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PharmaConsultation
Blog
A blog site for pharma GMP discussion
tuned at each point of use to their individual quality classification. This involves treatment with
different filter types depending on the compressed air quality requirements at each outlet. This is the
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B: water
C: total oil content (in
Each point of use in a pharmaceutical facility should have a quality designation consisting of a set of
specifications based on the requirements of that point of use. These can be related back to the ISO
8573-1 classes with the following nomenclature - ISO 8573-1:2010 Class A.B.C. For instance, a
clean room compressed air use point may be designated as ISO 8573-1:2010 Class 1.2.1. This
designation states that the solid particulate specification (A) would match Class 1 purity (NMT 20,000
particles LE 0.5 microns / m3). Water Content (B) would match Class 2 purity (LE 40 deg.C.
dewpoint and no liquid water). Total Oil Content (C) would match Class 1 purity (NMT 0.01 mg/m3).
Solid Particulate
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Particulates found in compressed air come from the ambient intake air (dirt, soot, bacteria, etc.) and
the compressing system (compressor and piping distribution system) itself. It is important that new
piping is thoroughly cleaned after installation to remove dirt, metal oxides and other particulate.
Older piping can be a source of built-up pipe scale (salts) and metal oxide (rust) particulate.
Industrial ambient intake air may contain as many as 150 million particles per cubic meter. 80% of
these particles are less than 10 microns in diameter. Bacteria, pollen and fungal spores can be less
than 2 microns in size. When this ambient air is compressed to 160 psi or higher, the particulate
concentration increases substantially. A typical compressed air intake filter has a porosity of 4 10
microns at a 95% efficiency. Coalescing filters with a rating of 0.01 to 5 microns are placed prior to
the dessicant dryer. A compressed air particulate filter with a rating of 1 to 3 microns is typically
placed immediately after the dessicant dryer. For aseptic operations in the clean room, a point-ofuse sterilizing cartridge filter at a porosity of 0.2 microns is used. This filter is sterilized prior to
use using steam sterilizer or SIP technology. The sterilized filter must be integrity tested and
replaced on a periodic basis. For non-sterile pharma manufacturing locations, point-of-use nonsterile filters with a 0.2 micron porosity are often utilized.
Non-viable particulate testing is performed by attaching a laser particle counter to a suitable access
point on the compressed air distribution system. A high pressure diffuser attachment to the nonviable particulate tester is required to reduce the line air pressure to atmospheric levels for proper
measurement and to avoid damage to the testing instrument. The laser counter provides an
instantaneous differential count of particles by size range.
The FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing cGMP
states: A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological
and particle quality after filtration should be equal to or better than that of the air in the environment
into which the gas is introduced. This is saying that for pharmaceutical clean rooms, the
specification for non-viable particle count at compressed air use points should align with the
environmental classification of the room that the compressed air is supplying.
FDA Air Classification Guidance: Particulate Air Action Levels
Class 100 (ISO 5) Environments: 3520 particles / m3 GE 0.5uM
Class 1000 (ISO 6) Environments: 35,200 particles / m3 GE 0.5 uM
Class 10,000 (ISO 7) Environments: 352,000 particles / m3 GE 0.5 uM
Class 100,000 (ISO 8) Environments: 3,520,000 particles / m3 GE 0.5 uM
Water Content
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Daltons Law states that in any mixture of gases, the total pressure of the gas is the the sum of the
partial pressures of the component gases. The major components of air are nitrogen, oxygen and
water vapor. The total atmospheric pressure of air is composed of the partial pressures of these
three gases. The concentrations, and therefore the partial pressures, of nitrogen and oxygen remain
fairly constant. Water vapor concentration, however, is highly variable and must be measured to be
determined. The water vapor partial pressure (and concentration) is directly correlated to
temperature. At 20 deg. C. (68 deg. F.) air is considered saturated with water vapor at a partial
pressure of 23.5 mbar. If more water vapor is added at this partial pressure, the excess water will
condense into liquid.
This phenomenon can be utilized to provide a means of measuring the water vapor concentration of
an air sample. Air is passed over a temperature controlled surface. The temperature of the surface
is cooled until condensation forms. This temperature is called the Dew Point of the air and can be
correlated with the corresponding saturation vapor pressure (or water vapor concentration) of the air.
Pressure Dew Point refers to the dew point temperature of a gas under pressure. This is important
when measuring compressed air because increasing the pressure of a gas increases the dew point
temperature of the gas. As an example, air at an atmospheric pressure of 1013.3 mbar may have a
measured dew point of -10 deg. C. If the air is compressed, and the total pressure of the air is
doubled to 2026.6 mbar, the partial pressure of water vapor is also doubled (according to Daltons
Law) and the new pressure dew point is -1 deg. C.
Why is the dew point of compressed air important in the pharmaceutical industry? The risks
associated with letting dewpoint levels go unchecked can include equipment failure, and
condensation in the process lines, This condensation can produce rusting and corrosion in the
piping which can flake off and contaminate the downstream environment. In addition, the
combination of water condensate and warm compressed air provides the ideal environment for
microbial growth and the subsequent contamination of both environment and product at the use
point. The water can be considered a contaminant in itself to certain products that may react and
degrade with moisture contact.
Compressed air systems for the pharmaceutical industry typically use a dessicant drying system
(heated or heatless) installed after the compressor. These systems can absorb residual water vapor
from the compressed air stream and can reduce the dew point to 40 deg. C. and drier if
required. Dessicant dryers only remove water vapor and must have water aerosols and liquid water
removed using coalescing filters prior to treatment. A maximum 40 deg. C. is the recommended
dew point target for Quality Class 2 in the ISO8573.1 standard. This may be too dry for some
pharmaceutical applications as it may dessicate and deactivate the product (certain biologicals). For
these applications, -20 deg. C. (Quality Class 3) may be more suitable.
The dew point of a compressed air system can be measured by using a fixed mount
instrument located at the supply side after the dryer and at various points of use throughout the
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distribution system. These measuring devices can provide local display, alarm relay and datalogging
capabilities. Portable dew point measuring devices are useful for quality audits, verifying dryer
performance, and checking the calibration of the fixed mount units. There are two major types of
technology used in dew point measuring devices: the condensation mirror type and the metallic
oxide or polymer capacitive sensor type. Each have advantages and disadvantages depending on
the target dewpoint level, accuracy requirements, and the relative cost.
Total Oil Content
21 CFR 820.70 (e) states that each manufacturer shall establish and maintain procedures to
prevent contamination of equipment or product by substances that could reasonably be expected to
have an adverse effect on product quality. This GMP regulation applies to any oil vapor, aerosol or
liquid that may be present in compressed air. Sources of oil in compressed air may originate from
the intake ambient air (vehicle exhaust, industrial pollution, etc.) or from the compressor
itself. Typically, oil-free compressors are utilized by the pharmaceutical industry. These
compressors use either rotary-screw or centrifugal technologies. However, even when using an oilfree compressor, small amounts of hydrocarbon may still be present in the intake air and the
distribution system itself.
The majority of oil in compressed air can be removed by incorporating a pair of coalescing filters
downstream of the compressor and prior to the dessicant dryer. These filters remove residual
aerosol / liquid oil and water as well as particulate from the compressed air . Liquid waste is
channelled from the filter cartridge to an automatic drain as rapidly as it enters the filter. Often, the
coalescing filters are followed by an activated carbon filter which can further remove trace odors and
oil vapor from the compressed air.
In the pharmaceutical industry, compressed air should have as low an oil content as possible. ISO
8573-1:2010 specifies a maximum 0.01 mg / m3 as its Class 1 quality level for this contaminent.
This is a typical specification for critical use points in a pharmaceutical facility. Manufacturers are
now offering oil-free compressors which claim 0 mg/m3 oil content (ISO 8573-1:2010 Class 0). Keep
in mind, achieving this specification is dependent on the systems auxiliary filters to remove any
hydrocarbon content present in the ambient intake air.
The oil content of compressed air is measured by using a hydrocarbon specific Drager tube. The
tube is hooked up to the compressed air line and compressed air is run through the tube for a
specified time. The oil level is visually obtained after the mixing of the contained sulfuric acid with
the oil creates a color change in the Drager tube.
Bioburden
As has been stated, it is important to periodically measure the bioburden or microbial load of
pharmaceutical compressed air as the opportunity exists for microbial contamination of the system.
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Bioburden measurement of compressed air is usually accomplished by the use of a Slit to Agar or
STA sampling instrument. At the sampling site, the compressed air pressure is reduced by means of
a built-in or external regulator. This is attached to a flow meter which adjusts the flow rate of the
sampled air to a suitable rate (example: 1 cu. ft. per minute). The STA sampler uses a rotating petri
dish containing a suitable agar (usually Tryptic Soy Agar) to capture the flowing air through a slit.
Any microorganisms in the air flow will impinge on the agar and the resulting colonies can be
counted after incubation. The microbial count of the compressed air can be calculated as X CFU per
cubic meter.
The FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing cGMP
states: A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological
and particle quality after filtration should be equal to or better than that of the air in the environment
into which the gas is introduced. This is saying that for pharmaceutical clean rooms, the
specification for microbiological count at compressed air use points should align with the
environmental classification of the room that the compressed air is supplying.
FDA Air Classification Guidance: Microbiological Air Action Levels
Class 100 (ISO 5) Environment: 1 CFU/m3
Class 1000 (ISO 6) Environment: 7 CFU/m3
Class 10,000 (ISO 7) Environment: 10 CFU/m3
Class 100,000 (ISO 8) Environment: 100 CFU/m3
Bioburden Monitoring Frequency
The following frequency is suggested for monitoring compressed air clean room use points for
microbiological testing:
Class 100 (ISO 5): Once per shift
Class 1000 (ISO 6): Once per day
Class 10,000 (ISO 7): Once per week
Class 100,000 (ISO 8): Once per month
Particulate / Water / Oil Content Monitoring Frequency
It is suggested that the compressor output location and all use points in the compressed air system
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be monitored for particulate, water and oil content at least once per month. Many pharmaceutical
companies have continuous, automated monitoring of dew point (water content) at all locations
because of its importance for the proper maintenance of the system.
Compressed Air is a very powerful and useful utility that is critical to the overall high quality
environment required by the pharmaceutical industry. Routine testing and maintenance of a
facilitys compressed air system to the appropriate standard is important to assure the high quality of
the compressed air, the equipment, and ultimately the finished pharma product.
dinesh
on October 26, 2013 at 7:41 pm said:
http://pharmaconsultation.com/blog/pharmaceutical-compressed-air-quality-gmp-requ... 25-06-2014