Introduction
This guidance provides recommendations when developing specifications for the design of Direct Impact Compressed Air, Pressure Swing Adsorption (PSA) and Cryogenic Nitrogen Systems used in the manufacture of Active Pharmaceutical Ingredients (APIs) and Drug Products (DPs).
It is desirable that the quality of the compressed air and nitrogen is assured through adequate design, appropriate controls (e.g. change control, procedures), and routine maintenance of the system. If these controls are in place, direct-impact compressed air and nitrogen systems typically do not require analytical testing to be conducted. Routine release testing (e.g. identification testing) of vendor supplied compressed air or nitrogen shipments may still be needed for release of these incoming raw materials. This release testing is outside the scope of this guidance. The development of specifications for compressed air and nitrogen systems is typically conducted during the engineering design phase of the system, with documented verification of the systems’ suitability for intended use conducted during commissioning and qualification.
The scope of this guidance is applicable to systems that have direct impact on product quality (e.g. product contact). Indirect and no impact systems are outside the scope of this guidance. If it is determined that testing of a system is necessary, the limits for the testing should be suitable for the intended use of the gas. Commonly used limits and references for test methods are include in Table 1.
It does not include recommendations for the location, frequency or number of samples for this testing. These considerations may depend upon the results of a risk assessment to target the sampling commensurate with the risk.
A system level impact assessment is performed to determine which systems are considered direct impact. Examples of applications that are often considered direct impact may include:
- Air used to spray tablet coatings.
- Air and nitrogen used to dry product, product contact equipment surfaces, vials or ampoules.
- Air and nitrogen used to clean and dry product-contact equipment surfaces.
- Air and Nitrogen used to suspend API during micronizing or milling steps.
- Nitrogen used to blanket API vessels.
System Control Considerations
It is desirable that the assurance of quality of the air or nitrogen is controlled through adequate engineered design, operation and maintenance of the system. If this is accomplished, compressed air and nitrogen systems typically do not require routine analytical testing to be conducted. If testing of the system has been determined to be necessary (e.g. due to invasive maintenance work), then the recommendations below and in Table 1 may be considered.
Viable and Non-viable Particulates
Viable and non-viable particulate level requirements are typically controlled through adequate system design and utilization of critical use-point filtration and maintenance. Compressed air and nitrogen systems are typically designed, controlled and maintained in a dry state, therefore significantly reducing the risk of microbial growth. Filter selection is dependant on the intended use of the compressed air or nitrogen and the particulate requirements defined during the system design phase.
Particulate levels of compressed air or nitrogen used in aseptic or sterile applications are controlled using sterilizing-grade (0.22µm, micro-retentive) point of use filters. Due to the criticality of application, these filters are typically integrity tested before and after use.
Particulate removal for compressed air or nitrogen used in non-sterile applications is often conducted using either critical point of use or supply-line particulate filters. These are typically in the range of 0.45-5.0µm pore-size. While integrity testing of filters used in non-sterile applications is not required, a filter inspection and replacement schedule (e.g. every 6-12 months) is typically established.
Where particulate filters are not located at the critical point of use, it is important to consider the potential for particulate contamination of the system to occur during maintenance activities, conducted down-stream of the supply-particulate filters to the actual use point(s). In these cases, the distribution piping downstream of the installed supply-line filter may have particulate testing performed prior to the system being used for production use. It is recommended that filters be located as close as is practical to the intended critical point of use.
Moisture Content
If moisture content testing is determined to be necessary, limits for moisture may include applicable EP pharmacopoeia limits. 5 Moisture levels are typically controlled via adequate system design, operation and maintenance. They are typically monitored continuously using on-line instrumentation and associated alarms. For air and nitrogen systems where the level of moisture is considered critical, the instrumentation and alarms associated with the monitoring of moisture levels are commissioned and qualified.
Oil-mist & Hydrocarbons (as part of Oil-Mist)
Oil-mist within compressed air and nitrogen systems is typically controlled by using oil-free compressors. Some compressors are ‘oil-free’ but there may still be components within the compressor that utilize oil. Removal of oil-mist from these systems is performed through the use of coalescing filters located in the distribution system. Where these design controls are in place, oil-mist is not expected to be present in the system and no routine testing or monitoring is therefore recommended.
Nitrogen System Purity
Purity of nitrogen generated on-site using PSA systems is typically monitored through the use of on-line continuous oxygen and moisture-content monitoring with associated alarms.
Other Potential Contaminants
During the design and construction phases consider other potential contaminants, such as cutting oils or cleaning agents used in system construction or subsequent maintenance activities. A risk-assessment can be conducted to assess the likelihood of other contaminants being present and to assist with the elimination of their sources, or development of a testing strategy if necessary.
| Potential Contaminant | Method of Control | Specification |
| Viable Particu1ates | Maintaining a very low dew point (e.g. 400C) thereby keeping the system dry.
Point of Use teri1izing-grade filter(s) (0.22µm hydrophobic micro-retentive), including integrity testing where required |
Not needed where:
– Sterile point of use filters are in place and these filters are on a prescribed maintenance program. – For non-steri1e manufacturing where the system has been maintained dry, or – There are no product requirements |
| Non Viable Particu1ates | Particulate Filters (0.45 – 5.0 µm) as close to the critical point of use as
possible. |
Not needed if adequate filters are in place (e.g. point of use) and these
filters are on a prescribed maintenance program. Per ISO 14644 or comparable EU Standards for room class/grade design |
| Moisture | Through system design (e.g. use of appropriate dryers, continuous monitoring and alarms) | Not more than 67 ppm v/v.
Dew Point in the range of -4 to -94°F (-20 to -700C) @ 1 bar Atmospheric absolute |
| Oil-Mist | Coalescing Oil Filters (with 2 µm pore size to limit carryover to less than 1 PPM) | Not needed if oil free
Systems and components are used. Less than 1 PPM |
| N2 Purity | Through system design (e.g. Continuous monitoring and alarms) | Depends on intended use.
Commonly used limits are per USP/EP. |