The Importance Of Filter Testing

How important is filter testing in the pharma industry?

Filtration in the pharmaceutical industry covers a wide range of applications from powder processing to liquid purification, such as saline or dextrose solutions. In the case of the former, the advantage of good filtration processes mainly lies in recovering valuable drugs, which can cost in excess of $1 million per kilogram. The advantage here is purely commercial.

Graham Rideal

For intravenous products, however, good filtration is a matter of life and death; a simple internet search on recalled drugs reveals particulate contaminants from the clearly visible, such as glass fragments, wood fibres and mould, to the invisible, and potentially lethal, bacteriological contamination.

The primary test of a filter begins with the filter medium itself to ensure it is fit for purpose. Thereafter the filter system must be tested in situ. Failure can occur in the filter medium or in the sealing arrangement when assembled.

Porosity

One of the simplest methods of comparing filter media is to test porosity either by air or water flow under prescribed conditions. Lower flow rates or higher back pressures indicate better filter performance.

Bubble point

The flow rate method is refined in the so-called bubble point test. Here, the filter is saturated with a liquid and then a gas (usually air) is pressurised from below. As the pressure increases, the air finds the single largest pore, which is blown out, forming a bubble on the surface: the bubble point. The Washburn equation is then applied to convert the applied pressure into the diameter of the pore.

Porometry

Porometry takes the bubble point one step further by continuing the pressurisation of the filter beyond the bubble point. Successively smaller pores are blown clear by the air pressure until the smallest pore is finally evacuated. The applied pressure versus flow rate profile can then be interpolated to provide complete pore size distribution.

Challenge testing

Challenge testing, as the name implies, involves challenging the surface of a filter with actual particles, which could be solid or liquids such as oil mists. Particle sizes are measured upstream and downstream of the filter. The maximum size particle passing reflects the largest pore, while the reduction in concentration determines the efficiency of the filter.

Although conceptually easy to understand, challenge testing can give varying results depending on the particles used and the method of measurement. Irregular-shaped particles have a number of dimensions determined by their shape, so it is important to specify the method of particle size analysis. Furthermore, the method of measuring particle concentration can give different results; averaging by volume, for example, will give a completely different result compared with a number average.

How should a filter test method be chosen?

Selecting an appropriate methodology for testing filter performance depends very much on the application of the filter. For non-critical applications where a simple quality assurance test is required, a basic porosity or bubble point test may be all that is required. For example, in the manufacture of syringe and water filters or in belt filters for product collection, the maximum pore size or the effective cut point of the filter medium is often the process control parameter.

If a comprehensive analysis of the poresize distribution in a filter is needed (e.g., dialysis membranes or air vents in bodily fluid aerosol traps used in theatre, then a porometer has to be used. However, because the pore sizes obtained are derived theoretically, they do not necessarily correspond to the true geometric size of the pores. There may also be variations from instrument to instrument, and operator to operator.

Nevertheless, the porometer is one of the most powerful tools in filter testing because it can measure pores from the sub-micron level to several hundred microns. Another advantage is that the test is nondestructive. As the pore structure is only invaded by an easily cleanable liquid, the actual filter used in the test can be reused in the final filter application.

So long as care is taken in particle selection and the statistics of measurement, challenge testing is one of the most robust methods of filter testing. If spherical particles are used and analysed by microscopy, where any out-of-shape particles can be eliminated, it is the most unambiguous test of them all. A particle either passes or is trapped by the filter and its size can be traced back to international standards of length. The range of measurement is restricted only by the particles available, so measurements could go down to a few nanometres using gold sols.

Generally speaking, challenge testing is restricted to measuring the cut points or maximum pore sizes, although new developments can provide pore size distributions in some cases. The measurement technique is called the 'near mesh' method where the spherical particles become lodged in the pores during the challenge test. When released by tapping or ultrasonic energy, the diameters of the 'near mesh' microspheres reflect the diameters of the filter pores.

In critical applications, challenge testing is the method of choice. However, unlike porometry, the actual filters used in the test cannot be used in the final application because of particle contamination.

What developments do you expect to see in the future?

We now seem to be living in the nanotechnology generation where science is moving to smaller and smaller sizes. Filtration is no exception and there are already several filters available that use nano fibres, which, when used in syringe filters, can turn black Indian ink into pure water with a gentle press of the thumb (see nanofibre filtration now being offered by many filter media manufacturers).

Where as material science was once the predominant technology, chemistry is becoming the predominant discipline as molecular cages are built, rather like nano-lobster traps, to selectively remove contaminants or harvest valuable nano products. This exciting new technology known as Metal Organic Frameworks or MOFs, chemically constructs links or cages around a pore that are reduced in thickness to that of a single chemical bond of sub-nano proportions. As a consequence, these structures have the highest known surface areas, typically up to 6000 m² /g. Put into perspective, this is equivalent to having the surface area of six football pitches packed under the nail of your little finger!

At such small sizes, porometry would not be appropriate because of the small pore size and the physical structure of the filter, which is usually in powder form. The only filter testing method available in these instances is challenge testing. Particle size analysis then becomes of paramount importance. However, there are now 'new kids on the block' rising to meet the challenge, such as ultra-high speed analytical centrifuges and nanoparticle tracking devices.

In the case of the analytical centrifuge running at up to 24000 rpm (CPS Disc centrifuge), a 'line start' technique is used, rather like a 100 m sprint. The sedimentation is followed optically as the larger particles sediment faster and so arrive at the finishing line before the smaller ones.

In the nanotracking method (NanoSight) individual nano particles scintillate light as they are illuminated by a laser in a liquid. Rather like floating dust particles scintillate a beam of sunlight in a room. This Brownian motion can then be tracked by microscopy and the diffusion rates used to calculate particle size.

In both of these methods, particle sizes distributions down to a few nanometres can be measured. The technologies are being used in the study of gold sols in the treatment of cancer and rheumatoid arthritis.

However, in the MOF porous structures, even these methods fall short and either transmission electron microscopy or calculations from chemical bonds must be used to determine the pore sizes. At the moment, this exciting technology is something of a 'solution looking for a problem', but there is no doubt that the most significant applications in the future will be found in the pharmaceutical industry, most likely as highly specific catalysts in producing new active ingredients.

Dr Graham Rideal is CEO, Whitehouse Scientific and Science Correspondent for The Filtration Society.