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The biotechnology and pharmaceutical industries have some overriding concerns, namely regulatory and compliance issues, insufficient manufacturing capacity, and the economic challenges of producing niche drugs and therapies.
The biotechnology and pharmaceutical industries have some overriding concerns, namely regulatory and compliance issues, insufficient manufacturing capacity, and the economic challenges of producing niche drugs and therapies. Disposable systems can favorably impact the last item and provide some relief to the others as well.
Disposable systems improve the economic feasibility of producing niche drugs by enabling faster and cost-effective product changeovers. Manufacturing capacity is gained by simplifying scale up, eliminating process steps, and maximizing throughput. Because these systems are sterile and remain sterile, positive regulatory reviews are facilitated. Any technology this good surely deserves a closer look, and that is what follows.
Manufacturing costs generally make up 18% to 20% of a pharmaceutical company's operating costs (1). Maximizing productivity from manufacturing assets is critical in terms of maintaining a sustainable competitive advantage. This requires fast turnaround and cleaning procedures, especially when operating multi-product facilities and minimizing shutdown time for modification and maintenance. Of course, optimizing product recovery presents an additional opportunity to favorably impact costs. We will show that to maximize overall process efficiency, a holistic approach is needed from the outset, whereby downstream processing is directly matched with bioreactor performance.
A wide range of biopharmaceuticals such as vaccines, monoclonal antibodies, and patient-specific treatments are already being made with disposable products in certain filtration, purification, and separation applications. Small-scale tangential flow filters (TFF), direct-flow filters (DFF) of all sizes, and membrane chromatography units are available and adapted for single-use systems. In addition, capsules can be bundled 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.
Figure 1. A single-use aseptic connector between flexible tubings requires no laminar flow hood or specialized equipment.
Disposable products are available in a range of sizes, making them ideal for use in every stage of drug development. Single-use products composed of the same materials of construction minimize re-validation requirements when 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 identified immediately and isolated from the rest of the process (if required).
High-growth biotechnology companies, large pharmaceutical companies, and contract manufacturers stand to gain significant speed, safety, and cost-saving benefits by 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.
When funding is scarce, single-use products can provide an effective cost- and labor-saving strategy. Additionally, the timeliness of making a batch for clinical trials can be crucial for the development timeline, and disposable systems can be assembled much faster that a comparable hard-piped system.
Large pharmaceutical companies have a different motive for incorporating disposable systems into their drug processes. Cost, capacity, and compliance issues are the deciding factors. The time and labor spent to dismantle, clean, and re-sterilize stainless steel products is a considerable cost to large pharmaceutical companies. The time required to meet FDA's increasing calls for documentation of cleaning and cleaning validation procedures can be significantly reduced. Expansion of an existing process can be more cost-effective and faster 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 in order to reap the benefits of reduced cleaning, validation, and assembly requirements. This is a viable option since the same materials of construction are used for the filters formerly in stainless steel housings. As a result, extensive re-validation is generally not required.
Table 1. Comparison of set-up times between a single-use cartridge filter and a stainless steel housing.
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 them to be more competitive in a growing market.
The benefits of disposable processing can be profound. Disposable processing could increase the profitability of niche therapies and drugs, thereby making treatments for rare or unusual illnesses and diseases more readily available.
Conversion from stainless steel equipment to disposable filtration systems avoids the complexities normally associated with adopting new processing methods by virtue of the fact that both designs use the same filter. The point of differentiation -- the filter housing -- does not influence the outcome of the filtration. In addition, disposable capsule filters now are available in larger sizes and can be used to replace 10-, 20-, or 30-inch filters in parallel or serial arrangements.
All disposable products are sterilized with gamma radiation or steam-sterilized and aseptically bagged at the supplier's factory. That is the reason that wet chemicals are not used at the manufacturing site and explains the savings we discuss below. Instead of having to prove that cleaning has been effective, disposable systems are used one time and discarded. Additionally, gamma radiation has a short half-life, so residual radioactivity is not an issue.
Table 2. Comparison of buffer and cleaning chemical volumes between a traditional column and a membrane chromatography capsule.
The elimination of cleaning and cleaning validation is a significant benefit of disposable processing. Having to clean process equipment consumes time and valuable operator resources. Corrosive and environmentally unfriendly cleaning chemicals require suitable handling systems for the delivery and disposal of the fluids. Care must be taken to ensure that concentrations of cleaning chemicals are correct so they perform their specified function. In addition, proper handling techniques are needed to ensure a system is properly cleaned and operators are protected from contact with potentially hazardous cleaning fluids.
Stainless steel or glass systems usually must be dismantled prior to cleaning. After the cleaning process, the systems must be rinsed with a suitable amount of water to ensure that the residual cleaning fluid is removed. For some applications, highly treated, more expensive water, such as water for injection, is required for the system flush. Following each cleaning and flushing, the systems are then re-assembled and re-sterilized, which adds further time to the operation as well as increased labor costs.
Perhaps the most critical element of cleaning is validation of the process. Complicated cleaning processes are difficult to document, and even harder to prove that trace chemicals have been removed. 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) can also cause concern. For example, caustic solutions are 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. Stainless steel systems are confined to steam-sterilization processes, either autoclave or steam-in-place (SIP). However, disposable systems give drug developers the option to purchase systems pre-sterilized through 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 drug developers to perform 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 their process. The 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 spares drug developers 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, to filter damage due to excessive pressure in the forward direction, if an increased pressure is used to expel fluid at an elevated temperature.
Table 3. Comparison of process time required for a traditional column and a membrane chromatography capsule.
Connection points between flexible tubings are another area in which disposability has unique advantages. To replace stainless steel systems that generally require the use of a laminar flow hood, there is available a new single-use aseptic connector (2). A key benefit is that the new connector does not require the use of a laminar flow hood or any specialized equipment. We illustrate one version in Figure 1.
When multiple connection points are required in disposable process operation, the connection method has considerable influence over the speed and safety of the whole process. The methods that will be obsolete include quick connectors, which require assembly under a laminar flow hood and tubing welders, which require 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 to 20 minutes of set-up time. A laminar flow environment may not be readily accessible, depending upon the layout of the facility. By contrast, using the aseptic connection device, the connection can be made anywhere in the facility because there is no requirement for a laminar flow hood, or any other capital equipment. Beyond the time required to set up and make the connection, laminar flow hoods are costly 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. Auxiliary equipment, such as a laminar flow hood or tubing welder, increases the opportunity for error. 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 made since the last change out might be contaminated. The need to maintain and document maintenance auxiliary equipment gives drug developers further reason to use a simpler approach to aseptic connections. Both tubing welders and laminar flow hoods require validation, adding paperwork to the steps involved in the connection process, and ultimately slowing development.
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. We do a sample calculation in Table 1. Like single-use aseptic connection devices, disposable filters can also be supplied pre-sterilized by gamma irradiation, avoiding the need for SIP or autoclave sterilization processes. Both of these steaming processes raise the risk of filter damage during installation. For example, during SIP operations, filters may be damaged due to reverse pressurization.
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 up 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.
Prefabricated assemblies of components should offer great benefits. Say a drug manufacturer orders a single-use filtration system. A typical one combines multiple filter elements, bioprocessing bags, clamps, tubing, and connection devices to form a fully integrated, pre-sterilized solution for filtration applications. This is delivered fully assembled and pre-sterilized. 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 currently 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.
The introduction of membrane chromatography in a single-use format is indicative of the industry's drive towards disposable processing. Previously limited to large stainless steel, glass, or acrylic columns, chromatography applications can now be performed using membranes with high dynamic capacity. Ion-exchange chromatography membranes are used for DNA, virus, and host-cell protein removal as well as purification of gene therapy vectors. Whereas a traditional resin-bead chromatography column needs cleaning and regeneration, membrane chromatography avoids the maintenance, labor, and time-associated with these cleaning and validation operations. For example, a 1 L disposable chromatography capsule can be used for a DNA removal application requiring a 50 L resin column (3).
Traditional resin-based columns can require large volumes of buffers for regeneration and cleaning. Table 2 provides a comparison of the volume of buffer required for a resin-based column and a disposable, membrane-based column.
Warner estimates the average cost of buffers and cleaning chemicals at $4/L. The traditional column requires 1,335 liters more than the membrane chromatography capsule for a single process run of $5,340 or more. In addition to the buffer and cleaning chemical costs, cleaning validation and labor are required, which increases the cost of the traditional column in comparison to the membrane chromatography capsule.
Even more interesting is a velocity factor. A traditional 50 L column flows at approximately 5 L/min whereas a 1 L membrane chromatography column flows at 50 L/min. Table 3 shows a comparison of the time required for each process step. The labor savings for the membrane chromatography column is estimated at $1,005 per operation.
Like disposable filters, the design of membrane chromatography units provides for linear scale up to minimize revalidation issues. A small footprint is also advantageous in an environment where multiple drugs are competing for development space.
In today's price-sensitive environment, cost-of-goods is a major factor in determining market penetration and potential access to new areas of opportunity. The traditional sequential mode of "design-build-validate" project management that was the mainstay of the last century is now a suicidal strategy. Companies do not want to build a "greenfield" plant dedicated to a single product. The norm is the multi-purpose/multi-product plant design. The modular approach using disposables can improve production efficiency and product quality, while simultaneously reducing the number of individual entities that require management. Twin drivers are fueling a trend to "disposable processing." One is the need for shorter process cycles starting in development and continuing into production. The other is a quality assurance requirement for straightforward and simplified cleaning. The concept of a completely disposable manufacturing process, which would have been considered utopian a few years ago, is today just another shift in the manufacturing paradigm. It is helping manufacturers to produce more drugs in less time and to respond nimbly to a dynamic marketplace.
(1) Bergsten, C., "Collaborative Approaches Streamline Capital Project Delivery,"
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(2) Haughney, H. and Aranha, H., "A Novel Aseptic Connection Device: Considerations for Use in Aseptic Processing of Pharmaceuticals," Pharm. Technol., 27(s5), Aseptic Processing Supplement, 16–21 (May 2003).
(3) Warner, T. and Nochumson, S., "Rethinking the Economics of Chromatography," BioPharm Int. 16(1), 58–60 (January 2003). BPI