Recent Developments in Aseptic Processing

Aseptic production is a demanding process that requires specialist techniques and receives significant regulatory attention. A number of new technologies are being introduced to make it easier to manage aseptic systems and to increase security. Keith Wickert of Pall Life Sciences explains

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: -

  • Assembly of critical equipment
  • Sterilisation of equipment
  • Connecting sterilised equipment together (aseptic connections)
  • Equipment cleaning
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. 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 are usually manual tasks so it is difficult to ensure that these operations are carried out in a reproducible manner and difficult 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 filters are assembled by the supplier typically using automated equipment and involving operators who are experts in filter manufacturing techniques. This technology has in the past had its limitations with respect to sterilisation techniques and size of units available. Both of these issues have been addressed now. 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 CAPSULE FILTERS This is a new development consisting of a fully disposable filter. The 'Pall' '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. The flow chart shows the reduction in the number of process steps that can be achieved by using a disposable SIP filter compared to the typical housing-based system. The potential savings in time and labour costs are also significant. A timesaving of 45 – 60 minutes 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. Benefits of disposable systems Housing/Cartridge System Disposable Filter System Large Scale Disposable Filters Disposable filters have been available for a number of years, but until recently have only been available in sizes suitable for small to medium scale processes. This is changing as products such as 'Kleenpak' Nova filters are introduced. Kleenpak Nova capsules incorporate a standard 25cm (10") 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. This has two major benefits. Firstly, 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 24,000 cm², as prefilters, sterilising grade filters and virus removal filters. They can therefore be used in a much wider range of process applications and with product batch sizes of several thousands of litres. Secondly, 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. DISPOSABLE STERILE PROCESSING SYSTEMS The use of pre-sterilised disposable bag/filter combinations, i.e. laminated plastic bag(s) 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. This technology is less attractive where processes may vary and a great degree of flexibility is required e.g. 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 an Aseptic Connection Device by Pall Life Sciences. ASEPTIC CONNECTION DEVICE The Aseptic Connection Device 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 so can be incorporated into range of equipment, not just disposable containers and filters. CONCLUSIONS 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 Aseptic Connection Devices can also increase flexibility, eliminate cleaning issues and can reduce operational costs.

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