Disposable Components Enable a New Approach to Biopharmaceutical Manufacturing

Developing biopharmaceuticals is an expensive business involving a great deal of uncertainty. The pressures during drug development are considerable. Increasing speed-to-clinic and market and controlling costs while maintaining a high level of product quality are critical aspects of a successful drug development program. Whether outsourced or built in-house, clinical and commercial manufacturing capacity is a key strategic asset in such a program. This article examines how the emerging field of single-use, disposable components can help to improve manufacturing operations with regard to speed, cost, and quality.

Although disposable components are beginning to see more use in industry, the vast majority of bioprocess equipment in manufacturing facilities is fabricated from stainless steel. Stainless steel is the material of choice due to its relatively high chemical resistance to most bioprocess buffers and the ability to electropolish it, which reduces surfaces that can harbor microbes and facilitates sanitary operations. The amount of stainless steel in a typical biomanufacturing plant is impressive. Seed and production bioreactors, media and buffer prep tanks, large chromatography columns, tangential flow filtration devices, and holding tanks for water for injection (WFI) and purified water are all typically fabricated from stainless steel. These units may have their own steel piping within each skid. In addition, each unit operation requires pipes, pumps, transfer panels, and connectors to make transfers from the preceding unit operation to the next step in the process, as well as piping and connections for media and buffer transfer and clean-in-place (CIP) and steam-in-place (SIP) operations. It is no surprise that the move by many companies to build large-capacity cell culture facilities has been dubbed the "stainless steel arms race."

The complexity of these systems adds significantly to the capital investment required to develop biopharmaceuticals and to the overall cost of biomanufacturing facilities. A pilot facility with 100-L capacity may cost roughly $10 million to construct, equip, and launch. A large pilot or small commercial facility with a 1,000-L capacity may cost roughly $40 million, and plants with capacity between 10,000 and 20,000 L may cost in excess of $100 million. As a rule of thumb, the expense of validation accounts for 10 to 20% of the cost of a plant. The complexity of such plants also translates into long construction timelines and makes capacity expansion and reconfiguring operations for a new product or process difficult.

Advantages of Disposables

Disposable components are currently available for most lab- and pilot-scale bioprocess operations (Table 1) and offer many advantages which can help reduce the complexity of constructing and operating a biopharmaceutical facility.

Table 1. Disposable components for biomanufacturing

Cleaning. One of the greatest advantages of disposable components is that they are supplied clean and ready to use and are not used for subsequent operations. This eliminates the requirement for cleaning operations and the utilities that support them and simplifies engineering and validation requirements. These components also provide an opportunity to improve product quality by completely eliminating the possibility of batch-to-batch or product-to-product cross contamination.

Sterilization. Most disposable components are also provided presterilized (usually by gamma irradiation). As with cleaning, this eliminates operations and simplifies engineering, validation, and utility requirements for unit operation.

Engineering. The design of disposable components already includes some of the engineering required to run a given unit operation and eliminates requirements for cleaning and sterilization. As a result, the engineering requirements for the reusable hardware component may be reduced. For example, membrane absorber capsules eliminate column packing and associated equipment; disposable tubing avoids concerns with weld quality, piping slope, and elimination of dead-legs; and doing away with CIP and SIP eliminates the need for associated piping, valves and controls, and pressure-rating of vessels.

Equipment installation time. Disposable components reduce or eliminate the need to fabricate stainless steel equipment, which often involves long lead times. The elimination of cleaning and sterilization and reduction of engineering complexity also help to reduce delivery and installation timelines.

Utility requirement. Because disposable components do not require cleaning and sterilization, CIP skids and purified and WFI water and steam generation demands can be decreased. To make a significant impact on utilities, a large number of unit operations or key operations with high demand must use disposable components. For example, replacing buffer hold tanks with bioprocess bags may reduce CIP requirements enough to justify reducing the number or size of CIP skids necessary to handle cleaning of the reusable equipment.

Validation. Elimination of cleaning and sterilization requirements and reduction of engineering complexity also reduces the complexity and scope of validation. Fewer reusable components must be tracked in installation qualifications, and extensive studies to validate sterilization and cleaning can be eliminated entirely.

Space. Incorporating disposable components into facility design may lead to more efficient use of space. Bioprocess containers are collapsible and can be easily removed after use. This can significantly reduce the space required for buffer tank "farms." Finished manufacturing space is usually the most expensive per square foot, so using it more efficiently can reduce costs. Even if buffer tanks are located in unfinished "gray space," reducing the square footage required for a facility can result in a degree of cost savings. Moreover, disposables also allow unit operations to be more rapidly reconfigured for a new process by removing the limitations of hard piping and stationary tanks.

Labor. Using components that are provided clean and presterilized effectively outsources the cost of cleaning and sterilization. If the demand for cleaning and sterilization is significantly reduced, the labor required to support these operations can also fall. Set-up and turnaround time for disposable components is typically comparable to or shorter than the time required for set-up and turnaround of reusable equipment. Labor may be impacted in other areas as well (Table 2).

Table 2. Impact of disposables on labor

Quality. Cleaning validation confirms the reduction of process-related materials to acceptable levels on the product-contact surfaces of process equipment. The use of disposables takes this one step further by removing the possibility that residual material from a previous batch will be carried over into the next batch and by eliminating the chance of confusion in tracking reusable components that are not cleaned in place. Further, the use of presterilized tubing and tubing welders or similar sterile tubing connectors makes it easier to operate steps as closed, sterile operations, even where sanitary operations may be acceptable. This can reduce the chance of rejecting a batch due to unacceptable bioburden levels or the presence of "objectionable" pathogenic organisms - a problem which can occur even in validated commercial facilities.

Disadvantages of Disposables

Despite the many advantages of using disposable components, there are several disadvantages.

Cost per batch. Disposable components are used only once, so a new component must be purchased for each batch, resulting in a higher cost of materials per batch. Filter capsules, for example, are generally more expensive than cartridges because they require additional materials and additional effort to manufacture, and bioprocess bags used for buffers will be a recurring cost per batch whereas a buffer tank is a one-time cost.

Dependence on vendors. Using disposable components increases a biomanufacturer's dependence on its vendors, increasing the risk that a critical component may not be available when needed. The vendor must be able to assure a consistent supply of quality components (in terms of cleanliness, sterility, and batch-to-batch performance).

Material compatibility. Disposable components may not be appropriate for use with some process buffers, and extractables from these components must be evaluated. The industry is moving toward a common strategy for assessing extractables. Many vendors can provide packages of extractables data for their materials, and a risk-based approach to assessing extractables has been proposed. ¹ An in-depth report characterizing the type of extractables from a wide range of polymers also was published recently.²

Waste. After use, disposable components become waste and may need to be treated as biohazard waste. Removal of biohazard waste is typically contracted out to a specialized company which removes the waste and incinerates it. This is both an additional cost and an environmental concern. Although incineration avoids the generation of large volumes of solid waste, it may impact air quality. As the use of disposables increases, this is an issue industry should examine more closely.

Disposable components also have limitations. Disposable components cannot replace some unit operations, including many chromatography chemistries, and many of the small-scale components that are available may not be available or feasible for large-scale use. Additionally, components may not be suitable for harsh chemicals or extreme temperatures.

Economics

Using disposable components does not eliminate the need for reusable equipment entirely. Membrane adsorber chromatography and tangential flow filtration (TFF) capsules still require pumps, valves and pressure gauges, and large bioprocess bags require a tank or frame to support them. The capital cost for a step using disposable components is usually significantly lower, however, because hardware requirements are minimized. Disposables can also decrease demand on utilities and the scope of engineering and validation, further reducing the cost of constructing a biopharmaceutical plant. Elimination of cleaning and sterilization requirements and reduction of maintenance and validation can lead to labor savings.

However, since these potential savings are offset by the increased cost-per-batch of the disposable components themselves, including waste removal, it is not immediately apparent how much cost savings disposables really provide.

A few studies have attempted to answer this question. One examined the use of bioprocess bags in place of buffer tanks, focusing on the impact on equipment, labor, and materials at the 2000-L scale.³ This study concluded that replacing buffer tanks with bioprocess bags reduced capital equipment, utility demand, and labor, resulting in an overall cost of goods savings of 8%. Another study, using a model constructed in collaboration with BioPharm Services, extrapolated the probable cost of disposables for larger scales - 100 L, 1,000 L and 10,000 L - in cell culture operations, downstream operations, and hold tanks for buffer, media, and product.⁴ This model indicated that replacing product-hold tanks with bioprocess bags could result in a cost savings of 11 to 14% and that disposable cell culture equipment could save in excess of 20% if cell culture capacity and turnaround time were rate limiting. Downstream processing using disposables resulted in a small cost savings at the 100-L scale, a small cost disadvantage at the 1,000-L scale, and a major disadvantage at the 10,000-L scale. A hypothetical process using disposable components for all unit operations appeared to be advantageous at the 100-L scale and practical at the 1,000-L scale. Savings were largely due to decreased cost of capital equipment and secondarily to the reduction in labor and infrastructure required to support it.

Although this study was a cursory and theoretical examination of the economics of disposables at pilot and commercial scale, and it made assumptions about disposables technology that has not yet been developed, it shows the potential impact that disposables may have on large-scale biomanufacturing. The lower fixed costs from reduced capital, in combination with the advantages of flexibility, shorter lead times for capacity expansion and the potential to improve quality, leads to the question: How far away is a fully disposable biomanufacturing process?

Application

The answer to this question is a function of scale. A fully disposable process is practical with currently available technology at the 10-L scale. This may have utility in the development of cell-based therapies, viral vectors, and personalized medicines, as well as the early development of recombinant protein biotherapeutics.

A proof-of-concept, disposable, closed monoclonal antibody process has been demonstrated at the 10-L scale, and most elements of this process were scaled to a 100-L bioreactor process.⁵ Most of the disposable components used in this process could be scaled up to 1,000-L scale. While the selection of disposable components that can be applied practically to a 10,000-L scale MAb process are quite limited, disposables technology is moving in that direction. The major filter manufacturers now offer 30-inch disposable filter capsules, and even larger capsules are available as custom orders. Aditionally, HyClone recently fabricated a 10,000-L bioprocess bag as part of a commercial-scale media and buffer mixing system.

FlexMax: A Novel Platform

Recent advances in disposable components have allowed the development of a new bioprocessing platform. The FlexMax platform used at Xcellerex integrates three recent technologies - disposables, electronic batch records and process automation, and barrier isolation - to create an alternative to the traditional stainless steel biomanufacturing facility.

With FlexMax, each unit operation is enclosed in a portable, closed environment module, similar in concept to an isolator. This effectively shrinks the cleanroom of a traditional facility down around the unit operation while removing the operator - the greatest source of contamination - from the environment. The extensive use of disposable components eliminates the need for CIP and SIP operations, minimizing the fluid transfer lines and manipulations required. The elimination of required utilities is significant - most modules require only power and data connections to support manufacturing operations. The use of electronic batch records and process automation reduces the number of manual operations and the opportunity for operator error.

This manufacturing platform has been used to produce GMP MAbs for a clinical trial. In order to initiate the trial on time, manufacturing needed to begin in the summer of 2002, but no contract manufacturing capacity was available until the following year. Beginning in January 2002, a 100-L FlexMax platform was designed; constructed; integrated with process equipment, automation, and controls; and validated. In May, the completed systems were moved into a 600 ft² clean room and revalidated using abbreviated protocols. GMP manufacture began in early June, enabling the trial to start on schedule. The platform was constructed in under six months from design to validation, and the capital cost was 50% less than a traditional facility.

Disposable components for biomanufacturing have the potential to significantly reduce capital costs and plant complexity, increase the speed of capacity expansion, improve flexibility for new processes, and improve product quality. These advantages are available today for processes up to 100 L, and many components are available for larger scales. As technology continues to advance, expect to see disposable components playing an increasingly important role in large-scale biomanufacturing.

References

1. Bennan J, Bing F, Boone H, Fernandez J, Seely B, van Deinse H, Miller D. Evaluation of extractables from product-contact surfaces.

BioPharm International

2002;15(12):22-34.

2. Jenke D. Extractable/leachable substances from plastic materials used as pharmaceutical product containers/devices. PDA Journal 2002; 56(6):332-370.

3. Sinclair A, Monge M. Quantitative economic evaluation of single use disposables in bioprocessing. Pharmaceutical Engineering, 2002; 22(3): 20-34.

4. Hodge G. Economics of disposable process components for the manufacture of monoclonal antibodies. IBC: Antibody Production and Downstream Processing Conference; 2002 September 24; London, England.

5. Hodge G. Use of disposable bioprocess equipment for antibody production. Waterside Conference; 2002 May 20; Savannah, Georgia.