Operating And Maintaining Pharmaceutical Gas Distribution Systems

By Fritz Röder, GMP Compliance Adviser

Pharmaceutical gases are used during the manufacture of medicines. In contrast to medical gases, these are not medicinal products. While the requirements for the production of medical gases are clearly regulated in Annex 6 of the EU GMP guidelines, pharmaceutical manufacturers are confronted with the situation that they must define the requirements themselves when using pharmaceutical gases, depending on the intended use of the gas.

This is not always easy and is completely different from other high-purity media. In the case of water quality, the standard monographs of the relevant countries are usually followed, making it relatively easy to obtain the correct specification. However, this approach is not recommended for gases, especially compressed air systems, in order to avoid unnecessarily high specifications. Instead, the quality parameters are put together on a risk-based basis.

Due to the various potential uses for pharmaceutical gases, a wide selection of gas qualities is commercially available. Because guidelines and ordinances are of little help, the selection of a suitable gas quality by the manufacturer of medicinal products is a major challenge.

If a gas is used in the manufacturing process and comes into direct contact with the product, the stringent cGMP requirements must be met. These gases are categorized as "gases with product contact". One example is the use of nitrogen to make the finished medicinal product inert (unless otherwise stated in the dossier of the finished product). Classifying a gas as a "gas with product contact" makes it much easier to define its specifications later.

The organization of pharmaceutical gases into different gas categories also means that there are quite different installation options for gas distribution systems. The most important distinguishing features of these gas distribution systems are the quality of the gas, the tightness of the system, and the scope of the documentation.

Operation Of Gas Distribution Systems

The requirements for GMP-compliant systems (e. g., ventilation systems) also apply to the operation of a gas distribution system. This means that quality assurance measures must be implemented, and the corresponding documentation must be created.

Quality assurance measures include:

• proper instruction and training of operating personnel,
• comprehensive system documentation,
• comprehensive monitoring of the system,
• clear instructions on which events must be reported when, to whom, and in what way, and
• recording of all events in the system logbook.

Maintenance Of Gas Distribution Systems

Servicing and maintenance must be conducted on a regular basis, i.e., at least once a year. Maintenance work may not affect the quality of the gas. To guarantee this, maintenance personnel must be professionally trained and instructed. The training should be regulated in an SOP.

The maintenance of a gas distribution system should include the following:

• inspection of compressor equipment in compressed air systems,
• inspection of mechanical components, e. g., dryers, steam traps, etc.,
• filter replacement,
• integrity testing of sterile filters,
• calibration of monitoring equipment,
• comprehensive gas analysis at a point of use and at the supply unit in accordance with the specifications, and
• leak testing.

After the system has been serviced, it can be taken for granted that the pipeline system has been exposed to the ambient air. To prevent the risk of contamination through humidity, the ISPE recommends flushing steel pipelines with a dry gas (minus 70 degrees C) for 2 hours. Polytetrafluorethylene (PTFE) or copper pipelines should be flushed for 4 hours because both materials are more hygroscopic. The gas analysis should be carried out after flushing at selected critical points to ensure that the quality of the gas is consistent.

Monitoring Of Gas Distribution Systems

To maintain and verify the quality of the gas supply, continuous measurement and monitoring of quality-related parameters is an established practice.

The following parameters should be continuously monitored and documented in a gas distribution system:

• humidity,
• pressure,
• oil content, and
• flow rate.

The following should be tested at regular intervals (at least once a year):

• particles,
• leak tightness,
• microorganisms,
• residual oxygen (in the case of nitrogen from on-site facilities), and
• specific requirements (depending on the gas type).

Online measurement technology is available to monitor residual moisture, particles, and oil content. This gives operators significantly better control over their process. Online oil and residual moisture measurement devices are usually not used excessively. Therefore, it is worthwhile installing such systems for business reasons alone, especially when expensive pharmaceuticals are produced in the plant.

Microorganisms, particles, and oil-content are the most important parameters from a pharmaceutical viewpoint. Measurement of them is described briefly below.

Determination Of Microbiological Contamination In Gases

Recommendations for determining the microorganisms in pressurized gases can be found in EN ISO 14698-1 and ISO 8537-7. The fundamental problem with sampling gases is that the measurement must be carried out at system pressure; otherwise, the microorganisms will be destroyed. In principle, the microorganisms "burst" if the pressure drops too quickly during sampling (similar to what happens to a diver who surfaces too quickly). If the microorganisms die unexpectedly, a "false negative" result is obtained in the analysis, i.e., the result is lower than the actual concentration in the gas system. To prevent this, samples are taken using a sampling system.

The sampling system takes the gas from a line at production system pressure and feeds it through a membrane filter. This is a special filter for microbiological testing of compressed gases. The measuring system works automatically so that appropriate sample volumes are taken. After sampling, the membrane filter is incubated in the laboratory and evaluated.

Another way of carrying out microbiological measurements is to take samples using an active air sampler and a diffuser. The diffuser is used to reduce the pressure of the gas before it flows across the intake opening of the active air sampler. The agar strip from the air sampler is then evaluated in the laboratory.

Although measurement using an active air sampler and diffuser is not recommended, the method is used in the industry. The disadvantage of the system is that the gas pressure is reduced in the diffuser. This results in the destruction of microorganisms, which means the measurement can be distorted. It is also necessary to ensure that the volume flow for testing comes from the point of use and is not contaminated by false air. If a terminal sterile filter is installed, it must be determined in advance whether the sample is to be taken before or after the filter. Both options provide useful information. Depending on this decision, a sampling valve must also be installed at the appropriate point.

Measurement of particle concentration in gases

Measurement is carried out using an optical scattered light particle counter. It is important when selecting a particle counter that the particle size range of the counter covers the particle sizes being monitored. Samples can be taken directly from a pipe or from a point of use. The methods differ with regard to the measurement connections and the use of a so-called diffuser.

There are now some excellent compact sampling systems on the market that only require connection to a particle counter. As previously mentioned, online devices are also available and useful. These provide a permanent data source and continuous quality monitoring.

Measurement of hydrocarbon vapors in gases

Hydrocarbon vapors are monitored by continuous sampling of the gas flowing through the pipeline. The sample is transported to the sensor through a riser. The level of hydrocarbon vapor is measured in the sensor by a photoionization detector (PID). The resulting electrical signal is amplified and evaluated. The number of samples and the measurement sampling device correspond to the requirements of ISO 8573. In accordance with ISO 8573-1:2010, the measuring range includes compressed air class 1.

In practice, however, it has been demonstrated that class 1 is close to the limit of quantification (LOQ) for the oil content. Furthermore, this measurement technology only records oil vapors. Nevertheless, the liquid oil components should be fully separated by the treatment technology.

In practice, it is rarely necessary to specify compressed air quality as class 1. Most applications require class 2. The monograph in the Ph. Eur. only specifies class 1, too. One possible exception could be the fermentation of biological agents. The active bacteria (species- and process-dependent) could react sensitively to residual oil contents. In most other cases, class 2 should suffice in terms of the oil content, which also makes things much easier in practice in terms of measurement technology.

As well as using a PID device, it is also possible to analyze the oil content offline using Dräger-Tubes, which are then sent away for external analysis using gas chromatography.

An online measuring device that continuously measures and records the oil content makes a significant contribution to the quality assurance of the gas distribution system. This is particularly true when oil-lubricated compressors are used.

This article is an excerpt from GMP knowledge contained in the online portal GMP Compliance Adviser, which provides in-depth information about GMP best practices and regulations with a focus on Europe but also referring to the U.S., Japan, and many more (PIC/S, ICH, WHO, etc.).

About The Author:

Fritz Röder is  a director and site account engineer in the pharmaceutical industry. He is a recognized expert in the field of water and ultrapure media technology. In addition to this specialization, he looks back on a wide range of experience in the GMP environment. He is also a member of the EDQM working group for water, the ISPE Steering Committee on water and steam and the Parenteral Drug Association.