The primary goal of membrane filtration in pharmaceutical processing is to remove viable microorganisms from the filtrate. The reliable separation of microorganisms by direct interception is the foundation of the production of sterile products by aseptic processing. This sterilization by filtration is of primary interest for solutions that for one reason or another cannot be heat-sterilized, but is also of interest for products that are heat-sterilized.
In bioprocessing, the end products are generally denatured by heat sterilization, making final sterilization by filtration a necessity. Sterilizing-grade filtration is also used throughout the process to keep the bioburden low. The controlled growth of the cell line and overall efficiency of each process step is critical. The uncontrolled presence and growth of foreign microorganisms will have detrimental effects on the process.
For products that can be heat-sterilized, sterile filtration has a place as well. Low bioburden levels must be maintained during the production of parenteral products through the process to maintain endotoxin levels within acceptable limits.
The process solution, once sterilized by filtration, must be maintained in a sterile state. Traditionally, this has been accomplished through the use of sterilized stainless steel filter housings, piping, and process vessels. For smaller process volumes, the filter housing, piping, and vessel may be autoclaved in one piece. By necessity, the assembly itself is not sealed during autoclaving. The system must be open to allow steam to reach all the internal surfaces that must be sterilized. Proper wrapping and handling, perhaps under aseptic conditions, is required to maintain the sterility of the system after removal from the autoclave.
Larger assemblies may be autoclaved as individual components. These components must then be assembled without compromising sterility before use. Still larger assemblies are typically steamed-in-place to sterilize the fluid path prior to use.
Of course, the autoclave or steam-in-place (SIP) cycle for each component must be validated to sterilize the component. Additionally, the cleaning of each component to remove product residue to prevent batch-to-batch cross contamination must be performed between each batch. The effectiveness of the cleaning and rinsing procedures to remove product and cleaning residues must be validated, monitored, and periodically revalidated.
Single-use products enhance the function of sterile filtration by making it easier to filter, maintain sterility, and reduce cross-contamination rises.
The earliest examples of single-use products for filtration date back at least 25 years to the introduction of small-scale filter capsules by many manufacturers. These filter capsules incorporated a plastic filter housing and filter cartridge into a one-piece disposable unit. Capsules were typically fitted into an assembly that was autoclaved before use. Alternatively, capsules that are delivered presterilized from the manufacturer may be used directly out of the package, with the user attaching them under aseptic conditions. Encapsulated filters are now widely available from small scale to full-scale process volumes. Encapsulated 10-, 20-, and 30-in. cartridges may be ganged together to provide single-use filter trains for very large volumes.
In development since the late 1980s, single-use sterile bags were introduced to replace rigid glass, plastic or stainless steel containers for small-volume storage and transport of biological solutions and growth media. Originally, blood and IV solution bags were adapted for process use. As these products have matured, specially designed films, fittings, and assemblies have come into use.
The combined use of filter capsules and sterile bags followed soon after, with processors performing aseptic connections of presterilized filters to presterilized bags. A natural progression soon followed, in which manufacturers of bags provided services to allow customer-supplied filters to be attached to the bags at the time of manufacture, with the whole assembly sterilized by gamma irradiation. Early applications of single-use technology included cell culture media and buffer filtration and storage. The filter and bag assemblies used for these early applications were of very basic design, simply attaching a filter capsule to a standard bag design. As applications have grown, custom-designed custom filter and bag assemblies have become commonplace.
Drivers of single-use systems
The rapid progression of disposable bioprocessing systems has been fundamentally driven by divergent groups within bioprocess companies. While each of these groups has possessed a unique set of drivers, the totality of the impact on a manufacturer's ability to efficiently and safely deliver drug products is what has ultimately moved the industry.
From an operational standpoint it has become clear that disposable bioprocessing systems can enhance production throughput and reduce production risk. The operational benefits derived from disposables can vary from processor to processor, however the most widely cited have been:
* elimination of CIP/SIP cycles associated with stainless housings and containers;
* elimination of autoclave cycles associated with small-volume containers and fluid processing systems;
* reduction in cross-contamination rates associated with reusable fluid processing systems;
* reduction in production downtime associated with stainless component cleaning;
* elimination o f utility bottlenecks caused by steam and water supply constraints.
Financially, disposable systems have translated into a reduction in cost of goods sold. Cost reductions have been well quantified by drug manufacturers and disposable suppliers alike. Again, benefits vary between drug manufacturers. The most widely cited are:
* reduction in direct material costs for CIP/SIP water, steam, and acid;
* reduction in direct labor costs involved in conducting CIP/SIP operations; * reduction in utility costs associated with the generation of dean steam and purified water;
* reduction in lost product write-off costs resulting in contamination;
* reduction in ongoing maintenance costs associated with stainless steel equipment;
* reduction in ongoing validation costs associated with reusable vessels.
Strategically, disposable systems offer a range of benefits to executive management teams. Facilities incorporating disposable systems require less capital investment in steam and chemical lines and equipment. A reduction in piping and hardware provides a corresponding reduction in the overall facility size requirement. Disposable systems can be scaled more rapidly than stainless systems, thereby speeding time to market. Disposable systems also offer enhanced process flexibility, a critical factor for many companies given the inherent uncertainty in product approvals.
The future of single-use systems
Within the past year or so, major suppliers of sterilizing-grade filters have announced alliances or partnerships with suppliers of fluid-handling bags. In turn, suppliers of fluid-handling bags have alliances with technology companies that enhance bag utility and functionality. The sum of these relationships is the development of services and systems that further the operational, economic, and strategic impact already created by the upfront integration of filters with bags. These new and developing services and systems range from the basic to the complex, but all ultimately have the potential to provide value to a bioprocess company.
Beginning with the basics, at least one filter manufacturer now has an established stock of capsule filters at its bag partner's facility. The filter/bag assembly is purchased as a unit with a single purchase order, resulting in a streamlined purchasing process and delivery of a custom sterile assembly in as few as 2-3 weeks. This company also carries off-the-shelf filter/bag assemblies for customers that need next-day delivery.
Moving ahead in the scale of complexity, the recent development of a number of connective technologies now allow the aseptic or sterile connection of filter/bag assemblies to stainless or other disposable systems. These connection devices are completely disposable and have extensive validation data associated with them. The result is the elimination of laminar hood connections, and the ability to apply disposable technology in areas of the plant that were previously not disposable candidates.