Filtration aids aseptic processing

A number of new filtration technologies are being introduced to make aseptic systems easier to manage and to increase security. Keith Wickert from Pall Life Sciences discusses the use of filtration in aseptic production

Although regulatory authorities favour terminal sterilisation, as it is viewed as a more reliable technique for obtaining sterile product, there are many active ingredients and many dosage forms where terminal sterilisation would result in damage to the final product.

Many of the regulators' concerns are related to the operator-dependent, manual activities associated with aseptic processing. These include the assembly of critical equipment, the sterilisation of equipment, connecting sterilised equipment together (aseptic connections) and equipment cleaning.

A number of recent developments have been designed to make the operation of an aseptic processing system easier to manage and can also help to increase the assurance of obtaining a sterile product.

product sterilisation

The most common technique used to sterilise products manufactured by aseptic processing is filtration. The use of sterilising grade filters is a well-established technique and it can be supported by significant process-specific validation activities. In recent years the design of filter systems has been evolving to improve ease of use and security.

Traditional cartridge/housing systems consist of a polymeric filter cartridge installed in a stainless steel housing. The filter cartridge is often used to process a single batch and is then replaced with a new filter.

However, the stainless steel housing is re-used and needs to be dismantled, cleaned, reassembled and re-sterilised before it can be used again. All of these operations are usually manual tasks so it is difficult to ensure that they are carried out in a reproducible manner and hard to validate properly.

Fully disposable filter capsules consisting of a filter permanently bonded into a plastic casing are increasingly used as an alternative to reusable stainless steel housings. These devices minimise many of the operator-dependent activities.

Cleaning is eliminated and the supplier assembles the filters, typically using automated equipment and they also involve operators who are experts in filter manufacturing techniques.

This technology has in the past had its limitations with respect to sterilisation techniques and the size of units available. Both of these issues have been addressed.

Although most disposable filters can be autoclaved or in some cases gamma-sterilised, they cannot be steam-sterilised` in place (SIP) and therefore need to be installed aseptically.

The need to make an aseptic connection introduces a risk of compromising the security of the process. This problem is being addressed by the introduction of in-situ steam sterilisable capsule filters.

steam-sterilisable filters

This is a new development consisting of a fully disposable filter. The Novasip filter assembly is unique in being steam-sterilisable in place. It is made from a special engineering plastic, polyetherimide, that is robust enough to withstand the temperatures and pressures of dynamic steam sterilisation, but is also suitable for biopharmaceutical applications. The product is supported by extensive validation documentation that includes studies on biological compatibility and extractables.

Other benefits seen from this type of filter are that it provides a much lower installation cost than a similar sized housing system, and it removes all of the cleaning and maintenance issues associated with filter housings.

Figure 1 shows the reduction in the number of process steps that can be achieved by using a disposable SIP filter compared with the typical housing-based system. The potential savings in time and labour costs are also significant. A timesaving of 45-60 mins should be possible in many cases; this can be even higher if extensive flushing is required to remove traces of hazardous materials. These costs are additional to the initial costs of cleaning validation and any periodic re-validation costs.

Disposable filters have been available for a number of years, but until recently have been available only in sizes suitable for small to medium scale processes. This is changing as products such as Kleenpak Nova filters are introduced. These capsules incorporate a standard 25cm (10in) long filter unit, which is identical to the units used in stainless steel filter housings for large-scale processes. This allows disposable filters of up to 75cm in length to be supplied.

Two major benefits arise from this. First, it expands significantly the range of capsules available. Pleated filters can now be supplied in disposable formats with surface areas as small as 200cm² and as large as 24,000cm², as prefilters, sterilising grade filters and virus removal filters. They can be used in a much wider range of process applications and with product batch sizes of several thousands of litres.

γ–sterilised

Second, as the filtration unit is identical to the unit used widely in stainless steel housings, the requalification required to switch from a reusable filtration system, that needs cleaning and reassembly for each use, to a fully disposable unit is minimal. In many cases this is limited to verification that the new unit can be sterilised effectively.

The use of pre-sterilised disposable bag/filter combinations, i.e. laminated plastic bags complete with filters, connecting tubing and couplers, is being investigated by a wide range of pharmaceutical manufacturers. These assemblies are supplied pre-sterilised by gamma irradiation and can be used as a fully disposable sterile processing system.

In the biotechnology industry especially, gamma-sterilised plastic bags have been used as disposable containers for raw materials and intermediate products. This concept is being developed further, as many biotechnology producers are now looking to use fully disposable processing systems throughout the process and other types of pharmaceutical manufacturers are adopting the technology.

This technology has the benefit of avoiding the need to make an aseptic connection between the filter and downstream container. The whole system is then disposed of after use, thereby minimising cleaning and operator exposure.

However, it is less attractive where processes may vary and a great degree of flexibility is required, for example in development laboratories or contract manufacturing. In these areas disposable filters and containers can be used, but they are often purchased as separate items to allow 'mix and match'. This provides the flexibility required, avoids the cleaning and assembly issues, but does result in the need for aseptic connections and the associated risk. This risk is being significantly reduced by the development of aseptic connection devices (ACD).

extensive studies

The ACD is a disposable unit that allows the integral connection of two previously sterilised pathways without the risk of operator related contamination.

The device consists of a male and female part where each of the ports is protected with a hydrophobic strip. The two ends can be locked together; making a joint that is effectively permanent. Then the two strips can be peeled away simultaneously bringing two sterile faces together. As the two ends are firmly locked together, this avoids the risk of introducing contamination.

The security offered by the system has been qualified by extensive studies using bacterial spores as a contaminant. The units are supplied suitable for sterilisation by gamma irradiation or by autoclave and so can be incorporated into a range of equipment, not just disposable containers and filters.

There have been a number of recent developments that are designed to make the operation of an aseptic processing system easier to manage and can help to increase the assurance of obtaining a sterile product. Technology such as disposable filters, disposable containers and ACDs can also increase flexibility, eliminate cleaning issues and can reduce operational costs.

Hollow fibre outclass pleated membranes

Fibercor, Minntech's industrial filtration and separation business, designs, manufactures and markets a growing line of high-purity fluid filters, cleaning and disinfecting solutions and filtration housings and accessories. FiberFlo hollow fibre cartridge, capsule and vent filters, as well as degas modules, are used in pharmaceutical manufacturing and laboratory settings worldwide to remove bacteria and pyrogens from solutions. The entire Fiberflo product line is integrity testable and pore sizes are certified by a latex bead challenge. Pore size control and membrane asymmetry allows its hollow fibre filters to reject all 0.45, 0.2, 0.1 or 0.05mm beads, whereas pleated membranes pass significant quantities of these. This unique pore size control and membrane structure enable the Fiberflo to remove fine particles, bacteria, pyrogens and endotoxins. These bead challenge test results demonstrate that Minntech has a differentiated product compared with the traditional pleated membrane filters. T+1 800 328 3345
F +1 763 553 3387
fibercorinfo@minntech.com

Fundamental thickness control

STAWAG Biotech, based in Schlieren, Switzerland, has introduced Fundastop II, which controls cake thickness on the company's Funda filter discs. The Fundastop II guarantees exact control of the cake thickness on the filter discs: when the desired thickness is reached, it gives a signal that interrupts the product feed. The subsequent steps in the process – e.g. draining, washing, drying and discharge – are then started automatically. For full automatic and therefore economic operation, the filter shave to be equipped with the Fundastop II, which observes the height of the cake on the filter plates. spoon-like sensor A filter cake is formed on filter cloth or screen during filtration. The growing filter cake is observed periodically by a spoon-like sensor, which is activated by a magnetic drive. The growing cake limits the sensor movement. A reference point is set before start of filtration. The difference between the reference point and the actual status is converted in a 4-20 mA signal. This output signal can be used to control the filtration process or to keep the operator informed about the height of the cake on the filter discs. T +41 1730 4434
F +41 730 4628
staweg.biotech@funda.ch

Prosep expands facilities with purpose-built warehouse

Prosep Filter Systems has opened its purpose-built premises in Elland, West Yorkshire. The warehousing and office facility will enable the company to treble stockholding capacity and maintain its target of delivering 90% of all orders from stock. Prosep was appointed exclusive regional distributor for Parker Process Filtration Division in 1996, and since that time has expanded sales of the Parker range of high performance liquid filtration products. In 2001 Prosep became its largest European distributor for process filtration products. The company supplies a wide range of products, including filter cartridges, bag filters and strainers for process liquid applications, gas filters, air conditioning products, air filters and specialist filters for hospital/medical applications. For more than 17 years the company has been meeting the needs of chemical and pharmaceutical, food and beverage, petrochemical and semi-conductor markets by supplying quality products, technical expertise and customer service. T +44 1422 377367
F +44 1422 377369
www.prosep.co.uk