Faster processing, improved quality assurance, and simplified cleaning validation are critical factors fueling the impetus towards disposable systems for pharmaceuticals and biopharmaceuticals processing. While the concept of a completely disposable manufacturing process would have been considered utopian a few years ago, today it is just another shift in the manufacturing paradigm. New aseptic processing initiatives by FDA have spurred greater interest in disposable processing systems as a way to minimize opportunities for product cross-contamination and to aid in compliance.
Disposable Systems Eclipse Stainless Steel
The elimination of cleaning and cleaning validation is a significant benefit of disposable processing. Cleaning process equipment consumes time and valuable operator resources. Cleaning chemicals require suitable handling systems for the delivery and disposal of the fluids. Care must also be taken to use these chemicals in the appropriate concentrations to ensure that they perform their specified function. In addition, proper handling techniques are needed to ensure that the system is properly cleaned and that the operators are protected from contact with potentially hazardous cleaning fluids.
During the cleaning of stainless steel systems the filter housings are typically dismantled prior to cleaning. Following cleaning, stainless steel hard-piped systems must be rinsed with a suitable amount of water to ensure that the residual cleaning fluid is removed. For some applications, the cost of the cleaning operation increases when water for injection (WFI) is required for the system flush. Following each cleaning and flushing, the systems must be re-assembled and re-sterilized, which adds further time to the operation as well as increases labor costs.
Perhaps the most critical element of cleaning is validation of the process. Complicated cleaning processes are cumbersome to document, and it is even harder to prove that traces of the cleaning chemicals have been removed. Instead of having to prove that the cleaning has been effective, disposable systems are used one time and discarded. Gaps in cleaning validation documentation can cause regulatory scrutiny, and in the worst case, production of new or existing products is delayed. Failure to execute specified cleaning standard operating procedures (SOPs) are a non-compliance. For example, in the case of caustic solutions (often used for cleaning), if the concentration of the caustic is incorrect or if the temperature of the cleaning fluid used is not at the SOP-specified temperature, the validity of the cleaning process may be questioned.
Disposable systems also offer drug developers an alternative in terms of sterilization. While stainless steel systems are confined to steam sterilization processes, either autoclave or steam-in-place (SIP), disposable systems can be purchased pre-sterilized by gamma irradiation. Existing steam sterilization processes can also be used for the disposable capsule filters. Most capsule filters can be subjected to sterilization by autoclave, and some capsules (which have suitable materials of construction) can also be subjected to SIP.
Disposable products that are supplied pre-sterilized by gamma irradiation eliminate the need for sterilization and sterilization validation procedures and can reduce the maintenance of sterilization equipment. The user can essentially remove the product from its package and install it in the process. The disposable product supplier provides validation documentation. While the cost of sterilization by gamma irradiation is comparable to that of traditional steam sterilization methods, the gamma irradiation process reduces labor, and circumvents many of the potential issues associated with in-house steam sterilization. For example, if condensate has not been properly drained from a filter that has been steamed in place, the filter membrane could become wet out. The bubble point of the membrane must be exceeded to expel the fluid from the pores and allow steam penetration. This situation could lead to an extended steam cycle, or in the worst case, damage the filter due to excessive pressure in the forward direction, if an increased pressure is used to expel fluid at an elevated temperature.
Disposable products have a growing presence in filtration, purification and separation applications used to make a wide range of biopharmaceuticals, such as vaccines, monoclonal antibodies, and patient specific treatments. Small-scale tangential flow filters (TFF), direct flow filters (DFF) of all sizes, and membrane chromatography units are available for use in single-use systems. In addition, these capsules can be assembled with bioprocessing bags, tubing, valves or clamps, and connection devices to form fully integrated single-use filtration systems. Disposable filters can also be manifolded together to maximize processing capacity.
Disposable products are available in a range of sizes, making them ideal for use at every stage of drug development, from discovery to production. Single-use products that use the same materials of construction minimize re-validation requirements as a new process is scaled up.
The tubing used in these systems is usually clear and the capsule filters are typically designed with clear or translucent housings. This design feature allows operators to observe fluid levels and flow, as well as to detect fluid discoloration and air pockets, thereby enabling problems to be immediately identified and addressed.
High-growth biotechnology companies, large pharmaceutical companies and contract manufacturers stand to gain significant speed, safety and cost saving benefits from using disposable systems.
A disposable processing approach is especially cost-effective and efficient for start-up biotech companies that do not have hard-piped processing systems already in place. As many biotech start-ups have not fully defined their operating parameters, single-use products can save them from making premature investments in capital equipment. In a market where funding can be scarce, single-use products provide an effective cost and labor saving strategy. In addition, the timeliness of making a batch for clinical trials can be crucial for the timeline of development, and disposable systems can be assembled much faster than a comparable hard piped system. For these reasons, the trend towards building a disposable infrastructure from the ground up is building momentum in this sector.
Large pharmaceutical companies have a slightly different motivation for incorporating disposable systems into their drug processes. Cost, capacity and compliance issues are the deciding factors in this sector. The time and labor spent to dismantle, clean, and re-sterilize stainless steel products is performed at considerable cost to large pharmaceutical companies. Time required to meet the FDA’s stringent requirement for documentation on cleaning and cleaning validation procedures is eliminated as the systems are intended for single use. Expansion of an existing process can be more cost-effective with a shorter timeline for the expansion if disposable system components are used. A further benefit for pharmaceutical companies is that it is possible to change an existing filtration process to a disposable process train thus eliminating cleaning and cleaning validation as well as system assembly requirements. This is a viable option since the filters used in stainless steel housings and the filter capsules use the same materials of construction, thus avoiding extensive re-validation.
Single-use products help contract manufacturers reduce cross-contamination risks, upfront equipment costs, space requirements, and complicated cleaning and cleaning validation procedures. This increases profit margin, enhances safety, and reduces compliance concerns, enabling pharmaceutical and biotech product manufacturers and contract manufacturing facilities to be more competitive in a growing market.
With multiple connection points required in disposable processing operations, the connection method has considerable influence over the speed and safety of the whole process. Current methods include quick connectors, which require assembly under a laminar flow hood and tubing welders that mandate the use of a welding device.
The key to streamlining aseptic connections is to reduce the total number of steps needed to complete the process. Despite the name “quick connector,” it can take up to 18 minutes to make a connection with such a device. This is due to the fact that operations must be performed under a laminar flow hood, which generally requires 15 - 20 minutes to set up, or in a laminar flow environment, which may or may not be readily accessible, depending upon the layout of the facility. By contrast, a connection can be made anywhere in the facility in seconds with a new connector (Pall Kleenpak™ connector) (Table 1) because it does not require the use of a laminar flow environment, or any other capital equipment. Beyond the time required to set up and make the connection, laminar flow hoods are costly, require maintenance, and take up precious space in a cramped environment.
A connector that requires only a few simple hand movements reduces the risks of operator error. With operation of equipment, such as a laminar flow hood or tubing welder, comes increased opportunity for incorrect usage. For example, laminar flow hoods require the use of HEPA filters and these filters are changed-out on a schedule and tested. If a HEPA filter fails the post use test, then all connections between the change out period are at risk of contamination. The need to maintain and document maintenance for these types of equipment give drug developers further reason to take a simpler approach to aseptic connections. Both tubing welders and laminar flow hoods also require validation, adding to the number of steps involved in the connection process, and ultimately slowing down development.
Disposable Processing Benefits as They Relate to Filters
Available for direct flow filtration (DFF) and tangential flow filtration (TFF) applications, disposable filters demonstrate strong cost and time savings over their stainless steel counterparts by eliminating the need to assemble, clean and validate cleaning of the units (Table 2). Like single-use aseptic connectors, disposable filters can also be supplied pre-sterilized by gamma irradiation, avoiding the need for SIP or autoclave sterilization processes.
Ease of scalability provides long-term economic justification for the use of disposable filter systems. By using filters that are made of the same materials of construction, process volumes can be scaled from 100 ml at the bench stage, to thousands of liters at production scale with minimal re-validation. Single-use filters can also be manifolded together to increase processing volume without necessarily increasing the filter size as a further means of simplifying scale-up. A smaller footprint, which is characteristic of single-use systems, maximizes limited space in facilities to increase manufacturing capacity.
Assembled Single-Use Systems Maximize Benefits
The benefits of single-use system components increase when they are assembled together. A typical single-use filtration system combines multiple filter elements, bioprocessing bags, clamps, tubing and connection devices to form a fully integrated, pre-sterilized solution for filtration applications. The drug product manufacturer receives a fully assembled, pre-sterilized filtration system. This not only saves assembly, cleaning and sterilization time, but it also significantly reduces the chances for operator error.
The entire single-use filtration system can be gamma irradiated prior to delivery to the biopharmaceutical manufacturing site. These filtration systems are offered in a range of sizes, so that corresponding filters and bags are available for every stage of development. This ensures that the most appropriate and economical disposable filter scheme is used. By using the same materials of construction, these systems also ensure reproducible results during scale up. Together, thesefactors can streamline drug development to increase manufacturing capacity, while meeting validation requirements.
Factors Driving Change in the Drug Development Arena
Ongoing globalization, revolutionary technological breakthroughs, and government regulation and deregulation, have consistently impacted the pharmaceutical industry landscape in recent years. The overriding concerns of the biotechnology and pharmaceutical industries are regulatory and compliance issues, insufficient manufacturing capacity, and addressing the economic challenges of producing niche drugs and therapies.
Disposable systems reduce possibilities for non-compliance as related to system validation and cleaning issues. They improve the economic feasibility of producing niche drugs by enabling faster, more cost-effective product changeovers. Disposable systems ease the manufacturing capacity crunch by simplifying scale-up, eliminating process steps maximizing throughput, and speeding product changeovers. All this streamlines manufacturing and allows the manufacturers to respond nimbly to the dynamic marketplace.