May 1, 2017 (Vol. 37, No. 9)
Surendra Balekai Senior Global Product Manager Thermo Fisher Scientific
Modular Facilities with Single-Use Technologies Effectively Solve Demands of the Market
Use of modular facilities will be of significant interest to the biopharmaceutical industry in a few years, and single-use technologies will be vital to this manufacturing transformation.
The biopharmaceutical industry has experienced tremendous change within the few decades of its existence. Further evolution is expected in the coming years as greater speed to market at lower cost becomes ever more imperative. To make this possible, flexibility in smaller footprints will be achieved through the adoption of continuous processing in modular facilities that extensively employ single-use technologies.
Time Is of the Essence
Whether biopharmaceutical companies are producing innovative products or biosimilars, they face intense pressure to be the first to market. In the era of value-based medicine, new biologic drugs must offer a significant advantage over existing medicines. MarketsandMarkets predicts that the value of the biosimilars market will increase at a compound annual growth rate (CAGR) of 26.3%, from $3.39 billion in 2016 to $10.9 billion in 2021.1 Biosimilars that receive first approval will typically capture the greatest market share among many competitors.
Any mechanisms that can reduce the time to market, including reduction of time for construction of commercial manufacturing facilities, are being pursued. Reducing cost while accelerating development and commercialization is also a growing expectation.
Additionally, risk must be managed. For a biologic drug candidate undergoing clinical trials, the likelihood of success is low. At any given phase, a limited number of clinical manufacturing batches (typically 5–10) will be required depending on the patient population and dosage level. To reduce risk at this stage, it is essential to minimize any investment in infrastructure.
The shift to personalized medicine, including the development of drugs targeting smaller patient populations, combined with the desire of many governments for local manufacturing, is also creating the need for smaller, flexible, multiproduct manufacturing plants that can be replicated in multiple locations around the world.
The Modular Solution
Modular facilities with single-use technologies are increasingly seen as an effective solution for meeting these changing needs in the biopharmaceutical industry. These facilities require the construction of only very basic infrastructure—a foundation and pillars. The walls, ceiling, and utilities are prefabricated and shipped to the site for installation within the basic framework. As a result, it takes as little as 50% of the time to build a modular vs. a stainless-steel plant, depending on the size and specifications. In general, modular facilities are operational within 18–24 months, compared to 30–36 months for traditional stainless-steel plants.2
Given these benefits, the use of modular facilities is expected to increase in the next three to five years by both branded biologics manufacturers and biopharmaceutical contract manufacturing organizations (CMOs). Access to modular facilities may, however, negatively impact the CMO market; with modular facilities, it is possible to quickly replicate the same manufacturing infrastructure in multiple locations.
One factor currently limiting the widespread adoption of modular biofacilities is the lack of infrastructure for easily transporting the facility components to locations away from sea coasts. There is work to be done to establish the appropriate capabilities throughout the world, which should take place over the next several years.
Hand in Hand
Modular facilities would not offer the time and cost benefits they do without the deployment of single-use technologies. In fact, the use of stainless-steel equipment would defeat the purpose of moving to a modular design. Facilities based on stainless-steel equipment have a much larger footprint; they require robust, fixed supports and walls; and the utility requirements are much greater. Single-use systems come presterilized, eliminating the need for cleaning and sterilization and the associated costs.
The cost per gram to produce a monoclonal antibody (mAb) in a single-use facility is approximately $175 compared to $225 in a stainless-steel plant.3 Overall operating costs are lower by approximately 20%: for a 2,000 L bioreactor capacity, an investment of ~$20 million is required for a single-use facility vs. $25 million for a stainless-steel plant.4
Amgen’s single-use facility provides an example of the potential time savings provided by disposable technology. The company implemented single-use technologies across its process flow, with the period from the start of construction to the facility opening lasting less than 24 months.5
Today, most upstream and downstream unit operations in a biopharmaceutical plant can be performed in single-use equipment. Most drug manufacturers are interested in moving toward the “factory of the future” in which a single-use platform is employed for media preparation and storage, cell culture, harvesting, and most downstream bioprocesses including buffer preparation and storage, intermediate and final product storage, filtration, viral inactivation, freeze/thaw applications, and long-term product storage.
Only chromatography and ultra- and diafiltration currently remain challenging, and single-use equipment suppliers are making significant progress toward the development of cost-effective solutions for these applications being made by single-use equipment suppliers.
In modular facilities, single-use technologies also provide the flexibility needed for the safe production of multiple products. Cross-contamination issues are dramatically reduced or eliminated with the use of disposable equipment. In addition, the wide selection of single-use equipment options allows for customization and optimization of individual processes by each end user.
It is recommended wherever possible that one single-use film platform be selected for use in single-use facilities. This approach helps reduce the work, time, and cost required for validation of multiple films for different single-use unit operations.
Biopharmaceutical manufacturers are increasingly realizing the benefits of single-use technologies in commercial production applications in both existing and new facilities. Advances in the cell-culture field, including improvements in media, feed supplements, and cell lines, have led to titers nearly 10 times those observed just a decade ago. As a result, large 10,000–20,000 L stainless-steel bioreactors are no longer needed; often one or multiples of 2,000 L bioreactors are sufficient.
As an ultimate consequence, the adoption of single-use technologies for commercial biomanufacturing has been facilitated, and biologics producers are benefiting from smaller production footprints, lower operating costs, and reduced capital expenditures.
Recent advances in single-use technologies have focused on downstream unit operations, and further developments will be forthcoming over the next several years. For instance, there is significant interest in improving disposable inline buffer dilution systems to allow for a reduction of the number of large vessels required during downstream processing. A shift from home-built systems to specially designed transfer assemblies to connect different unit operations is also occurring. In addition, adoption of disposable technologies for fill-finish operations has picked up in recent years.
The use of disposable technologies for the manufacture of next-generation therapies, including cell and gene therapies and other personalized medicines, will be a big driver of innovation going forward. Single-use systems have been widely adopted for small-scale production of these advanced medicines; as they continue to have success in clinical trials, it is expected that further development of disposable technologies will be crucial to their successful commercialization.
There are some aspects of single-use technologies that require further attention, such as disposable sensors. Single-use equipment manufacturers are working hard to develop solutions that will allow real-time monitoring for optimization of bioprocesses. Examples include developing sensor technologies for the online measurement of cell mass and glucose concentration and the determination of other metabolites during cell culture. Some of these technologies are available, but their reliability has yet to be accepted by the industry.
Standardization of single-use equipment components remains an issue as well. Industry groups such as the biopharmaceutical industry association BPOG (BioPhorum Operations Group) and the single-use supplier group BPSA (Bio-Process Systems Alliance) are working to develop potential solutions. However, because every bioprocess is unique with its own individual requirements, one standard set of equipment is not sufficient, and customization will always be necessary. Intellectual property concerns must also be addressed. Given the difficulties that must be overcome, progress on this issue is expected within the next three to five years.
Standardization of quality expectations would also be very beneficial for the single-use industry. Currently many different groups, including BPSA, BPOG, the American Society of Mechanical Engineers (ASME), and others, have each published their own quality guidelines for single-use systems. Unfortunately, at the present time, there is no concerted industry effort to address this issue.
Finally, biopharmaceutical manufacturers with existing stainless-steel manufacturing plants are faced with the challenge of developing hybrid facilities that maximize the benefits of both their existing equipment and single-use technologies. Single-use suppliers must work closely with end users to help identify solutions that incorporate new disposable equipment with existing stainless-steel infrastructure to provide the optimal cost and time benefits.
Adoption of single-use technologies for commercial manufacturing of biologics is the first stage of recent, major innovation in the biopharmaceutical industry. It has enabled both the development of modular facilities and movement toward the natural second stage of evolution in innovation—the implementation of continuous processing.
Although initially resistant to the concept of continuous pharmaceutical manufacturing, the U.S. Food and Drug Administration (FDA) now strongly encourages its implementation due to the numerous benefits it provides in terms of quality improvements, reduced environmental impact, and potential cost and time savings.6 This second stage of innovation involves a radical shift for the biopharmaceutical industry that will take some time but will ultimately transform bioprocessing. Real progress on this front is expected in the next three to five years.