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Microbial monitoring of compressed gases used in pharmaceutical manufacturing

Compressed gases are used in a lot of different steps during pharmaceutical manufacturing:

  • compressed air in direct contact with products to clean, aerate, or;
  • process gases in fluid pumps that take products through the production and filling processes;
  • gases such as nitrogen or argon, can also be used for blanketing or to spray or coat a product.

The risks associated with the use of these gases, depend on the amount and type of product contact and based on this risk assessment, a suitable monitoring plan should be in place. The latest draft of Annex 1, Manufacture of Sterile Medicinal Products (EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines), introduced the concept of a contamination control strategy which limits particulate and microbial contamination and promotes process understanding, which means a thorough understanding of potential sources of contamination, regular trend analysis is performed, ensuring appropriate critical quality attributes of high-risk utilities and gases and other high-risk utilities that come in direct contact with the product or primary container are of appropriate chemical, particulate and microbial quality.

 

Specifically, actions should be taken to ensure the sterility of process gases, including filtration through a sterilizing filter at the point where the gas is used in production, and sterilization of any subsequent piping or tubing. Filtration should be part of batch standards, with certification guaranteed before release. Integrity testing should be performed for both critical and non-critical gas filters. Although reference to compressed air sampling is made within EU and FDA GMP’s, ISO 8573 sets out the general approach and requirements for compressed gases. ISO 8573 is the group of international standards relating to the quality (or purity) of compressed air. The standard consists of nine separate parts, with part 1 specifying the quality requirements of the compressed air and parts 2 – 9 specifying the methods of testing for a range of contaminants and provide valuable information to the interested party or analytical laboratory. The frequency of testing and limits (criteria) should be based on a risk assessment of the activities and should be often enough to enable meaningful trends to be assessed.

Compressed gas and air systems normally represent unsuitable environment for microbial growth, nevertheless microbial survival is possible, if there are nutrients available. More often the source is adventitious contamination. Sources of contamination include source of the air of gas (oil, dirt, dust and moisture, microorganisms), piping distribution systems (rust, pipe scale, mineral deposits, bacteria), bacterial retentive filter and sample valve.

Analysing micro burden data at point of use outlets throughout compressed air pipeline systems at a given time, acts as a window of observation into the control of the facility. Maintaining control means proper preventative maintenance, microbial monitoring scheduling and risk assessment must be appropriate for the industry being monitored. Once the compressed air microbial monitoring plan is approved, a sampling procedure that provides the company with the results suitable to its limits and specifications needs to be established. This requires the use of a procedure that accurately measures and samples a specific volume of air for microbial burden analysis inside the tested compressed air system. Compressed air sampling should form part of an environmental monitoring program, along with cleanroom assessments.