Filtrate, integrate ... consolidate

Single-use, disposable products are in use throughout our daily lives. From nappies to contact lenses, disposable products are convenient, cost effective and save us time.

Disposable products are also being used increasingly by the biopharmaceutical industry in the manufacturing process to improve the speed and safety of drug development and delivery. This article will explore the applications where disposable equipment can be used, the different types of disposable equipment available now and the benefits of using it compared to traditional stainless steel, hard piped systems.

Disposable equipment Disposable equipment can save time and cost in the manufacturing process from drug development to full scale production. New proposals on amendments to EU directive 91/256/EEC will require GMP compliance for investigational new drugs, which means validation has to be done early in the development process. Pre-sterilised, disposable products can save valuable time, which would otherwise be spent on cleaning and sterilisation validation at this critical stage. Scaleable filters and systems which use the same materials of construction minimises further validation when progressing onto pilot plant and full production scale. Disposable products are suitable for a wide range of fluids commonly used in the biopharmaceutical industry, including media (serum and non-serum containing as well as special formulations), buffers, reagents, sanitising agents, cell harvest fluid, intermediate and final products.¹ Integrated, single-use filtration systems are comprised of disposable bags and capsule filters connected with tubing, clamps, adapters and connection devices. The bag, which forms the heart of the system is used as a substitute for stainless steel and glass containers which have been traditionally used by the pharmaceutical industry for fluid filtration. The bag is fully flexible and self venting. For small volumes (50mL to 50L), two-dimensional pillow-type bags are available, while in larger applications (100L to 2,500L) three-dimensional bags are used. When filled with fluid, the bags should be supported and a tray can be used for smaller sized bags, while square aluminium or stainless steel tanks can be used to support the larger ones. The polymeric bags are made from advanced films which are ideally formulated to meet process requirements. Disposable filter assemblies consisting of a filter cartridge supplied ready sealed in a plastic housing have been available for several years and correspond to the traditional stainless steel filter housing and filter elements. Capsule filters are now available in a variety of sizes from syringe filters to 30in (75cm) long capsules from a range of industry suppliers. Prefilters, sterilising and virus filters are all available as disposable assemblies. Capsules can also be manifolded together to provide large scale filtration systems; for example, a prefilter, sterilising filter and virus filter can be connected together to meet all filtration requirements. Disposable tangential flow filtration cassettes are also now available, along with disposable chromatography membranes. Suitability of the bag and filter capsule are critical to realising the benefits of these systems. A single-use filtration system must be scaleable to meet biopharmaceutical companies' changing needs as they move from discovery to pilot and eventually to production. A wide variety of bag and capsule options are available to ensure the most appropriate and economical system is used. It is also important that the materials of construction are the same, ranging from the smallest to the largest system, to get reproducible results. This saves time and simplifies design and development. Although the disposable bag and filter are the main components of the system, tubing must be used to connect the filter to the bag and the system to other parts of the bioprocess. Platinum cured silicone tubing is used in many biopharmaceutical applications. It has fewer leachable constituents than alternatives (e.g. peroxide cured silicone tubing) and also has smoother internal surfaces, which mean there is less chance of losing the proteins contained in many biopharmaceutical fluids through adhesion to the tubing surface. The most critical connections are aseptic connections between two sterilised components e.g. a disposable, gamma sterilised bag and filter system and another part of the system which has been steam sterilised. Aseptic connections are often performed in a laminar flow HEPA-filtered air hood with the components to be connected protected by a porous wrap. Other techniques involve quick-connectors and tubing welders. A disposable unit is now available for performing aseptic connections, which allows the user to make a connection of two previously sterilised pathways in seconds without the need for a laminar flow hood or tubing welder. The device consists of a male and female part where each of the ports is protected by a hydrophobic strip. During connection, the two ends are locked together, forming a joint which is effectively permanent. The two strips are peeled away simultaneously bringing the two sterile faces together. An inner plunger tube is pushed through the protected connection and into the female side of the device to complete the new sterile pathway. The units are supplied suitable for gamma irradiation or autoclave sterilisation and so can be incorporated into a range of equipment. Disposable systems can be gamma irradiated to sterilise them; gamma irradiation has been found to be a predictable, consistent and safe sterilisation method. It is important to consider the choice of materials, as gamma irradiation can degrade certain polymers, resulting in elevated extractables or (in the worst cases) even destroying the polymers. Because of this, bags must use films which are gamma stable. Tubing materials recommended for gamma exposure include silicone and most PVC tubings. The capsule filter's gamma-irradiation suitability must also be considered. Hydrophilic polyvinylidene fluoride, hydrophilic polyethersulfone and amphoteric nylon filter media are proven to be gamma-irradiation tolerant. • Cleaning and cleaning validation Disposable products can be supplied pre-sterilised by gamma radiation and are thrown away after use. Traditional stainless steel systems require validation of the cleaning cycle after use to document that all traces of product have been removed from the system. Costly cleaning validation must, in some cases, be performed on a regular basis, for example, every three years. In addition, stainless steel hard piped systems and glass containers are costly to clean and sterilise on a batch by batch basis and may need specialised equipment. • Safety considerations Because a fully integrated, single-use system including the filter, bag, tubing and other components is manufactured and sterilised as one, it eliminates the contamination and other risks associated with aseptic connections during filling. In traditional stainless steel filter housing and cartridge systems, the filters must be installed into the housings at the production site and there is a risk that the filter may be damaged during installation. Disposable filter capsules are sold as a system and the seal between the filter and plastic housing is made at the manufacturing stage, eliminating this risk. • Operator safety Single-use filtration systems also ensure that operators do not come in contact with cleaning solutions, cytotoxic fluids or buffers with extreme pH levels. • Validation of sterilisation cycles Unlike disposable systems sterilised by gamma irradiation, stainless steel systems are steam sterilised, which can introduce production time delays and requires validation and maintenance of the sterilisation system. • Reduction in time and cost of drug development Disposable systems save time in drug development, eliminating the time required for validation documentation of cleaning, maintenance and sterilisation. In addition, when disposable systems or filters are used during the initial stages of development, the validation process can be simplified during scale-up since the materials of construction are often the same. • Reduction in process time and costs Time is saved directly in the process since there is no cleaning and no sterilisation required for the bag, filter and associated system components. Furthermore, because the filter, bag and tubing are pre-assembled, the time required for traditional aseptic connections is eliminated. The initial set-up time to make an aseptic connection in a laminar flow hood can take approximately 10 to 15 minutes and each connection thereafter can take at least three minutes. These connections can also be difficult to make in cramped environments. Aseptic connections made using the new disposable aseptic connection device can offer significant time savings over traditional aseptic connection techniques. • Translucent housings and bags Unlike stainless steel systems, single-use systems designed with translucent materials can show process fluids in the bag, tubing and capsule filters. The ability to see the fluid enables operators to easily check fluid levels and flow, as well as spot fluid discoloration and air pockets immediately. Disposable products offer significant savings in both cost and time by eliminating the need for cleaning and steam-in-place validation, and offering user-friendly features such as translucent housings. Considerable cost savings can be realised at each phase of scale-up by replacing stainless steel, hard-piped systems with single-use systems.² As single-use products gain wider acceptance in the biopharmaceutical industry, the integration of complementary disposable products will increase to provide safer, more efficient processing solutions.³