Filtration in blow-fill-seal applications

Emma Bartin and Philip Blosse from Pall take a look at BFS applications and how filtration is important in their use in the pharmaceutical industry

Blow-fill-seal (BFS) or form-fill-seal (FFS) machines are widely used in the pharmaceutical industry to fill and package predominantly ophthalmic and parenteral products, into the final dosage form. During the process the packaging for the final dosage form is made by extruding a plastic parison into a mould to form a container. The product is aseptically filled into the container, which is then sealed.

The filtration requirements for BFS machines are similar to those for other aseptic filling processes where terminal sterilisation by heat cannot be used. The product must be sterile filtered before being aseptically packaged.

Sterile filtered compressed air is used to move product from a holding tank to the filling machine and also to blow air into the parison and to supply the air shower around the filling area. Sterile vent filters are required on storage tanks. Steam used to steam-in-place (SIP) the BFS machine is usually filtered.

BFS systems have some significant differences from conventional cleanroom filling processes and can directly affect the filter selection and validation.

These differences include automated processes where SIP is used. It can be stressful to filters as there is the potential for high differential pressures across the filter at high temperature. Some modern filters designed specifically for SIP applications can withstand differential pressures up to 1 bar at 125°C, where other filters may have a maximum differential pressure of only 300 mbar (30 kPa).

In some blow-fill-seal applications product filters may be used continuously for several days and in some cases over a week. Process specific validation should reflect these long process times.

sterile filtered

Although this practice is becoming less common due to concerns about batch- to-batch contamination, some BFS processes re-use liquid filters over several batches. In this case, they should be validated to show that final product quality is assured.

The product is sterile filtered into a holding vessel within the BFS machine and, for a second time between the holding vessel and the filling head, figure 1. Both sets of filters must be validated.

The majority of products that are filled and packaged using BFS technology are aqueous based and will be filtered using a hydrophilic 0.2mm sterilising grade membrane filter.

Products containing low concentrations of preservative or proteins should use liquid filters with low adsorption properties.

Diminutive bacteria may be found in low nutrient solutions or under special product conditions and may penetrate 0.2mm filters. Longer process times may also increase the occurrence of diminutive species. Some BFS operators are choosing to use 0.1mm rated filters to eliminate the risk of filter penetration.

core validation

A sanitary filter housing is important, especially in liquid applications. Product contact surfaces should have no threads and should be electropolished to a surface finish no greater than 0.4mm Ra.

Filter manufacturers will provide core validation for their products, but both EU and US GMP require that process specific validation be carried out.

For process specific validation of bacterial removal the filter is challenged with specific bacteria under process conditions. If the product is bactericidal, there are established methods for managing a bacterial challenge test under these conditions.

integrity testing

The flow rate through the filter just before the filling head is usually intermittent.

Typically, it may have a 10 second flow time, then 60 seconds static.

This flow pattern should also be replicated as far as possible during the bacterial challenge validation. Compatibility, extractables and adsorption validation should also be completed.

Integrity testing of the liquid filters is usually carried out on-line in BFS processes either before or after sterilisation of the filter. European GMP recommends that the filter is tested after sterilisation. Product wet integrity test values, whether for a Forward Flow or Bubble Point test can simplify the integrity test on line because alternative wetting fluids do not have to be removed before filtration.

Hydrophobic PTFE membranes are typically used for gas and vent applications as they provide high strength during SIP and can be easily integrity tested using the water intrusion test. Filters are usually replaced on a time basis or when the maximum cumulative steam life has been reached, typically 165 hours.

Filter manufacturers will supply core validation for air filters and this is usually considered sufficient.

Housing design is particularly important during SIP of hydrophobic filters as incomplete drainage of condensate can blind the filter. Ideally, the drain valve should be at the lowest point on the upstream side of the filter system to allow condensate to drain freely.

Integrity testing of the hydrophobic filters may be performed on-line or off-line. The water intrusion test avoids the use of isopropyl alcohol (IPA) or other low surface tension solvents.

effective sterilisation

When testing on-line, air filters may be difficult to access and an automated water intrusion test system, which fills the housing with water and drains it after the test may be of use.

Steam used in steam-in-place applications must be dry, saturated and of good purity to avoid damage to filters and to ensure effective sterilisation. Porous, sintered stainless steel filters with a gas rating of 1mm or finer are usually used.

In conclusion, blow-fill-seal machines have been used in pharmaceutical manufacturing since the 1960s and filters are an integral part of the process. Careful filter selection and validation ensures the sterility and quality of the final product.