Elements of Sterile Medicine Manufacturing – HEPA Filtration
What is a HEPA Filter
HEPA stands for High Efficiency Particulate Air. It is a standard originally defined and developed by the U.S. Department of Energy during the 1940s as part of their efforts to contain the spread of particles and contamination resulting from development work with Nuclear materials and radioactive fallout.
To meet the HEPA standard, the filter must remove 99.97% or more of all particles which are 0.3 microns (micrometers) in diameter. In other words, for every 10,000 particles that are 0.3 microns in diameter, only three of them pass through.
How are they made?
HEPA filters are composed of a mat of randomly arranged fibres formed into a continuous sheet that is pleated and folded within a supporting frame with plastic or metal separators and a surrounding frame.
The fibres are typically composed of polypropylene or fiberglass with diameters between 0.5 and 2.0 microns.
This mat of random fibres create a narrow and convoluted pathway through which air passes.
How do they function?
Three key mechanisms enable a HEPA to function over a range of particulate sizes:
1) IMPACT. When the largest particles are passing through this pathway, the fibres behave like a kitchen sieve which physically block the passage of the particle.
2) INTERCEPTION. When smaller particles pass with air, as the air twist and turns, the smaller particles cannot keep the same motion of air up and they collide with the fibres. This effect increases with diminishing fibre separation and higher air flow velocity.
3) DIFFUSION. The smallest particles (Particles below 0.3µm) have very little inertia due to their low mass and they move around the air molecules in Brownian motion (drunken walk). Because of their movement, they end up crashing into the fibres.
Key factors affecting a filter function and performance are fibre diameter, filter thickness, and face velocity. The air space between HEPA filter fibres is typically much greater than 0.3 μm. It is often possible to see through an effective and functioning HEPA filter.
Diffusion predominates below the 0.xn--1m-99b diameter particle size, whilst impaction and interception predominate above 0.xn--4m-99b. In between, near the most penetrating particle size (MPPS) 0.xn--21m-yyc, both diffusion and interception are comparatively inefficient. Because this is the weakest point in the filter's performance, the HEPA specifications use the retention of particles near this size (0.3μm) to classify the filter.
HEPA filters are typically pleated to maximise the effective surface area of the filter. This permits the filter to function for the maximum period of time (as the accumulated material is spread over more filter) and it minimises the pressure at any single point in the membrane.
Limitations of HEPA Filtration
HEPA filters have limitations that must be accommodated for their effective use.
1) No gas filtration. HEPA filters are designed to arrest very fine particles effectively, but they do not filter out gasses and odour molecules. Circumstances requiring filtration of volatile organic compounds, chemical vapours, or odours call for the use of an activated carbon (charcoal) or other type of filter instead of or in addition to a HEPA filter.
2) Filter blockage. Due to how they work HEPA filters are prone to a gradual accumulation of material which will reduce the velocity of air flowing through them. This will cause a reducing in the air changes per hour in the area immediately beyond the filter which may pose other risks to the product being filled or manufactured. If a filter is significantly blocked and air pressure pre filter rises relative to the pressure posy filer and in extreme circumstances this may also cause the filter to fail.
3) Mechanical integrity. The filter material itself is quite easily damaged and must be protected from any impacts or other physical damage. It should not get saturated with water. Particular care must be paid to sealing the filter around the frame to ensure air does not bypass the filter and defeat its purpose.
A HEPA filter can used in conjunction with a pre-filter to extend the usage life of the more expensive HEPA filter. In such setup, the first stage in the filtration process is made up of a pre-filter which removes most of the larger particles from the air. The second stage high-quality HEPA filter removes the finer particles that escape from the pre-filter. This is common in pharmaceutical air handling units.
Filter Classification
The following table shows the various classes for high efficiency filters in accordance with EN 1822 and ISO 29463.
Although there are not different types of HEPA – as filters either meet or fail the HEPA standard – there are different levels of HEPA efficiency. This is in addition to the above standard and is used to further compare and categorize HEPA filters amongst each other.
HEPA H13-H14 are within the highest tier of air filter and are considered medical grade quality. Whereas H10-H12 filters only trap 85-99.5% of all particles that are 0.3 microns in diameter, HEPA H13 and H14 trap 99.95% and 99.995% of such particles, respectively.
When do you change/replace HEPA filters?
User of HEPA filters should maintain a rationale that is based on a risk assessment for the frequency of filter testing and change out. An exact guidance figure in terms of a maximum duration of use for HEPA filters in months, cannot be found in the relevant GMP guidelines.
Obviously – in terms of continued function – the filter has to be free of leaks. This is verified by qualification and regularly performed leak tests as per ISO 14644-3, which are mandatory for sterile facilities.
According to the PIC/S technical interpretation of the Annex 1 (PIC/S PI 032-2), leak tests are to be performed every six months in A/B zones and every twelve months in C/D zones. The FDA Aseptic Guide demands a regular inspection. Leaks may be repaired; those repaired areas may only take up 0.5% of the filter surface per filter.
An observation of damage should instigate an investigation and risk assessment and may be captured as a deviation.
From a practical viewpoint, one could say that the maximum duration of use depends directly on the pressure drop. Changing the filters only makes sense if the pressure drop gets too high for the performance of the ventilation system or if the cost of energy demand lies above the cost of a filter change. The filters do have to pass the leak tests (see above), of course. Users will often build up evidence of pressure drop increase with time to develop pre-emptive replacement strategies.
