Compressed Air

Pharmaceutical Compressed Air – Quality GMP Requirements

by Roger Cowan 1/31/2012

Compressed air for pharmaceutical use is considered a critical utility as many of its applicationsinvolve direct contact with the pharmaceutical product. For example, compressed air is frequently used to de-dust and spray coat tablets. It is also used to over-pressurize mixing and holding tanksand to pressurize liquid product through filters and fill lines. Finally, automated production lines use compressed air to operate control valves and pneumatic cylinders. Exhaust air from these components could contaminate the local environment and consequently the end product.

Therefore, the compressed air system must be properly designed and built from the outset. The subsequent initial validation testing and the ongoing monitoring of compressed air is vital to assuring both the quality and safety of the pharmaceutical product. Compressed air is often overlooked as a potential source of clean room and product contamination.

A pharma quality compressed air system typically consists of a compressor and after-cooler, air receiver storage tank, particulate filter(s), coalescing filter(s), a dessicant air dryer(s), a pipeline distribution system, and various point-of-use filters including sterilizing filters for aseptic operations. The compressor is typically an on-demand, oil-free type. Compressed air discharged from the compressor is hot and loaded with water vapor. The compressed air enters an after-cooler unitwhich cools the air resulting in condensation of air moisture and hydrocarbon vapors which are then drained through automated drain valves.

It is recommended that the compressed air is treated for major contaminant reduction to a “general purpose” quality level prior to entry into the distribution system. The compressed air is then fine 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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The pharmaceutical industry does not currently have a specific guideline or regulation for compressed air that details specific quality requirements, sampling frequency or sampling locations. The FDA recognizes that the ”one size fits all” axiom does not apply to compressed air standards. Each facility has unique quality requirements based on the product type as well as the various environments and machinery being served within that facility. The quality standards for apharmaceutical facility are best defined as a composite set of specifications that are site-specific based upon the point-of-use requirements. FDA/EU GMP Guidances, USP/EP and ISO 8573 air standards are common sources from which to draw input as to these specifications.

ISO 8573-1:2010 is an important international standard that provides specifications for a variety of compressed air purity classes. ISO 8573-1:2010 recognizes three classifications of contamination in compressed air. These are:

A: solid particulate B: watercontent C: total oil content (in aerosol,vapor and liquid forms)

Each of these three contaminant classifications have 11 quality classes which are specified in the following table:

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



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-of-use 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 non-sterile 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 non-viable 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 aninstantaneous differential count of particles by size range.

The FDA Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – cGMPstates: “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



Dalton’s 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 andwater 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 willcondense 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 Dalton’s 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 formicrobial 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 ifrequired. 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 somepharmaceutical 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



distribution system. These measuring devices can provide local display, alarm relay and dataloggingcapabilities. 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 metallicoxide 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 compressoritself. Typically, oil-free compressors are utilized by the pharmaceutical industry. These compressors use either rotary-screw or centrifugal technologies. However, even when using an oil-free compressor, small amounts of hydrocarbon may still be present in the intake air and thedistribution 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 residualaerosol / 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 it’s 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 system’s 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.



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 petridish 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 – cGMPstates: “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, thespecification 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



ONE THOUGHT ON “PHARMACEUTICAL COMPRESSED AIR – QUALITY GMP REQUIREMENTS”

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 afacility’s 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.

dineshon October 26, 2013 at 7:41 pm said:

What,s about the sterility of compressed air used for flushing during sterile manufacturing.



Compressed Air

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