10/11 March 2020
In many cases, gaseous media used such as compressed air contact the product. They are thus quality relevant, and in particular, of course, in the case of sterile products. However, in the pharmacopoeias they are specified relatively inaccurate compared to the pharmaceutical water qualities. Parameters and limits have to be defined by pharmaceutical users themselves.
There are always mistakes, because requirements are phrased inaccurately. A "classic" specification is "sterile compressed air" without considering the impact on the pipeline network and the necessary sterilization of the entire system. A second "classic" is the requirement "oil-free" for compressed air - without setting a reasonable limit value in mg/m³.
One specification, as for pharmaceutical water, is comprised in the European Pharmacopoeia.
However, these requirements are valid only if the gas has been legally classified as a medicinal product or as a medical device. The specifications relating to the medicinal product are valid e.g. when patients in the hospital are ventilated with air because then the gas is fed directly to the patient. To adopt the specification in the pharmacopoeia unseen in the specification for a compressed air system for the production of medicinal products can lead to unnecessarily expensive and inefficient designs. Details of the monograph in the European Pharmacopoeia for 'Medical Air' are discussed below.
With regard to oil the European Pharmacopoeia comprises the specification:
"Oil: maximum 0.1mg/m³, determined using an oil detector tube (...), when an oil lubricated compressor is used for the production."
These oil detector tubes are not optimal to use. The minimum detectable value is 0.1 mg/m³ and the colour change of the sulfuric acid absorber is very difficult to detect. In the "small print", it is often required to know the type of the oil and to use a specific tube for the different oils. A reasonable preventive determination of a warning value of about 0.05 mg/m³ of an unknown oil is thus impossible. Today many pharmaceutical companies with oil-critical processes use on-line measuring devices for the oil content in compressed air. The devices work similarly to the TOC measurement in the water: Hydrocarbons are oxidized to CO2 and measured as CO2. However, in the European Pharmacopoeia it is not clearly defined what oil is exactly: oil aerosols, oil vapor, or whether all hydrocarbons in the air are to be regarded as oil. The above phrasing in the European Pharmacopoeia also strengthens the erroneous belief that oil reaches the compressed air only via the compressor. Theoretically, a new oil-free compressor can be connected to an old oiled pipe network according to the above mentioned specifications - and still one does not have to measure. In practice, there are drug productions that exceed 0.1mg/m³ because a leakage spray is used in the vicinity of the air intake of the compressor or the emergency diesel generator is being tested - or because of the traffic jam on a nearby highway.
For the test conditions for the water content there are also particular characterstics (maximum 67ppm V/V for compressed gas cylinders or max. 870ppm V/V for compressed air generated by the compressor).
The USP (the US Pharmacopoeia) handle the testing of water or oil content quite easily: the so-called mirror test is required. In this case, one lets the gas flow against a clean surface and checks whether oil streaks or water droplets form there. This technologically rather simple requirement of the US colleagues should remind us Europeans to define the limits and the evaluation of excesses with a sense of proportion.
A further possible compressed air specification is the ISO 8573-1 from the year 2010. For pharmaceutical applications a specification according to class 2 is often useful. However, caution is required with respect to particles, since this standard stipulates that no particles larger than 5 µm may be contained in classes 1-5. Typical stainless steel pipe systems in the pharmaceutical industry with central filters directly downstream of the production plant do not fulfil this requirement. These compressed air networks are operated at flow velocities up to 80 m/s. Pressure reducers and valves can also discharge particles. The limits for particles should therefore be determined based on the clean room classes themselves.
For classes A and B, a 0.2 µm point of use filter must ensure the sterility and the required reduction of the particle load for inflowing compressed air. Pneumatic valves seated in such a clean room must then typically also be supplied with this filtered air quality.
Microbiological limit values are missing for the compressed air both in the pharmacopoeia and in the ISO 8573. Here it is also recommended to define the limits based on the clean room classes in which the compressed air is used, e.g. for class C the max. permissible 100KBE/m³ from Annex 1.