White Paper

The Advent Of Single-Use Technology: Moving Forward

Source: Pall Life Sciences - BioPharmaceuticals
Mario Phillips

By Mario Philips, President, Single-Use Technologies at Pall Life Sciences

For more than three decades, novel biologics, including monoclonal antibodies, immunotherapies, vaccines and therapeutic proteins, have transformed the pharmaceutical and therapeutic landscapes. Yet as patent expirations on many of these biological blockbusters come to fruition, there is significant competition coming from biosimilars; this is expected to continue leading into 2020. [1,2] The resulting increases in demand for more specialized drug products—including vaccines and cell therapies—in the development pipeline has drastically spiked demand for manufacturing capacity.

Traditionally, the manufacturing of biopharmaceutical products—which involves multiple steps in upstream production and downstream purification—remained relatively inflexible. Facilities would be hard-piped and space consuming, with large stainless steel bioreactors and storage tanks to hold intermediates and buffers. [3] Over the past decade, however, single-use innovations have disrupted the old way of doing things and are now coming full circle for biopharmaceutical manufacturing.

Where traditional production facilities relied on expensive fixed equipment, single-use systems offer flexible and cost-effective technologies that can be introduced and used across the manufacturing process. No time is spent cleaning and sanitizing the bioreactors. And without the reusable parts to clean, there are no chemicals, water, steam or other utilities used. Nor is there chance of cross contamination between batches, because single-use technologies come in a sterile, ready-to-use format. All of this results in lower manufacturing operation and maintenance costs.

With recent technical advances making end-to-end single-use manufacturing possible, the quest for innovation and increased efficiencies has become the vanguard of manufacturers adopting single-use systems for biopharmaceutical production.

Changing Needs

Health systems around the world are demanding increased volumes of drugs at decreased prices. Not surprisingly, this means that manufacturers are looking for the most innovative ways to reduce their capital investments, without sacrificing production rates. As the industry shifts away from blockbuster drugs that served a very large number of patients to a multitude of drugs that serve a smaller volume of customers, manufacturers need facilities that can produce more than one product, offering flexibility and scalability.

Single-use systems answer this need by drastically slashing capital costs for new builds and even offering cost reductions for retrofitting existing biopharmaceutical manufacturing facilities. While significantly varying and subject to the individual needs of the manufacturer, based on mid-priced equipment, these capital equipment costs are generally estimated to be 30%-50% of the budgeted facility costs. [4]

Also important to note is that a single-use facility can easily develop multiple products in one location. Once a batch is produced, the process is complete; new sterile bags and a reactor are then brought in to start producing the next agent. There is also less need for such critical utilities as water-for-injection clean steam, and process hold vessels (intermediate product hold, media hold and buffer hold), further increasing the flexibility and reducing costs, without sacrificing product quality or safety. [4,5]

Market Penetration

The greatest market penetration of single-use technologies has been in the US and Europe, mainly for process development and clinical manufacturing. However going forward emerging economies will be an explosive growth market for SUT. In the emerging countries the biopharmaceutical industry is less established and thus more open to new technology. An Indian vaccine company, for instance, has likely not invested in stainless steel so they have no legacy or past history with this technology.

Similar to how China moved directly to mobile phones because of a lack of a landline infrastructure, many drug development companies in emerging markets are less likely to invest in traditional stainless steel solutions. Rather, these markets want to invest in the more flexible and faster to market technology when developing new vaccines and molecules.

Globally, about 80% of all drugs currently on the market are still made in stainless steel, and only 20% have converted to single use. But some predictions are that in the next five years, upward of 50% of drugs will be produced using single-use technology.

Significant Innovation

Single-use products first entered the marketplace about a decade ago; since then, numerous applications have become available. As an original pioneer in this industry, ATMI LifeSciences has remained focused on how these technologies can improve biopharmaceutical processes.

Most traditional commercial products show expression levels between 0.2-3.0 g/L in stainless steel. When single-use technologies first came to market, it followed that those technologies should have the same expression levels. But innovators like ATMI LifeSciences thought differently; they wanted to simultaneously improve and intensify the process. Instead of remaining at status quo, they wondered if this expression level could perhaps be increased to, e.g., 10 g/L.

Driven by finding more effective methods of production, ATMI LifeSciences innovated new solutions for customers to change their approach to the process; ATMI has continually improved upon it with technologies like the Integrity® iCELLis® bioreactor for vaccine manufacturing and the Integrity® Xpansion® bioreactor for cell therapies.

Traditionally, labor-intensive manual processes are generally based on either two-dimensional (2-D) systems including polystyrene T-flasks, roller bottles and multitray-stacked system or microcarrier-based processes for biopharmaceutical (vaccine) production. While these systems have benefits, they also have drawbacks. Two-dimensional systems are relatively easy to implement, but scale-up raises major issues of size (footprint), capital outlay, and due to a large number of “open” operations, increased contamination risk.

Switching to a single-use technology like ATMI’s Xpansion Multiplate (2-D) Bioreactor not only simplifies the process of adherent stem cell expansion, it reduces the need for labor and space during production by replacing a large number of traditional cell stacks ATMI’s technology. The system, designed to enable adherent cell growth in the same conditions and surfaces as in T-flasks, enables production of large amounts of cells. Innovations like this dramatically cut costs by eliminating the need for a large investment to build a facility that supports the traditional development process.

ATMI LifeSciences was able to do the same for vaccine development with the iCELLis single-use bioreactor, eliminating all manual operations, cutting down on the space needed, and intensifying the process to make it more efficient.

The fixed-bed design of the iCELLis system is especially designed for process intensification. In only 25L of volume, the technology offers up to 500m/2 growth area. Compared with multitray-stacked systems and roller bottles, this represents a huge reduction in volumes, one iCELLis 25L reactor replaces 3,000 roller bottles. But in addition to volume reduction, the iCELLis system also enables higher specific productivity and tackles problems inherent to classical fixed-bed systems such as lack of scalability, insufficient or limited oxygenation and the presence of metabolite gradients. [6]

In all cases, the customer benefits from the significant cost savings, improved safety and reduced contamination netted by closing the process with single-use innovations. There is a also time savings on the regulatory front compared with traditional methods as there is no longer the need to perform and validate each step to obtain regulatory approval.

Increasing Adoption

Another important catalyst for the strong adoption rate of single-use systems stems is the ability to implement this strategy at a number of different points along the production process. While there are still some limitations with large-scale production, as the technology has evolved, single-use systems have translated into areas such as mixing, purification, formulation and even filling.

While specific numbers are not available at the this time, and individual reports may differ, the overall consensus is that switching to single-use from stainless steel yields about a 50% reduction of capital and a 30-40% impact on the cost of goods sold.

The trend toward a wider variety of lower volume production of biosimilars expected after the “demise” of the “blockbuster” is rapidly changing the market, and drug manufacturers are looking for new ways to find success in the today’s market and that of the future. Innovative single-use technologies allow manufacturers to realize great advances in biopharmaceutical production, whether expanding an existing facility or building a new one.

ATMI, Integrity, iCELLis and Xpansion are trademarks or registered trademarks of Advanced Technology Materials, Inc. in the U.S., other countries or both.

References:

[1] Sheppard A., Iervolino A. Biosimilars: about to leap? 10th EGA International Symposium on Biosimilar Medicines. 2012 April 19: London.

[2] Gal R. Biosimilars: Reviewing US Law and US/EU Patents; Bottom Up Model Suggests 12 Products and $7-$8B Market by 2020. Bernstein Research. 26 May 2011.

[3] Abhinav A. S., Gottschalk U. Single-use disposable technologies for biopharmaceutical manufacturing. Trends in Biotechnology 3 (31), 2013: 147-154.

[4] Langer E.S., Ranck J. The ROI Case: Economic justification for Disposables in Biopharmaceutical manufacturing. BioProcess International Supplement (10), 2005; 46-50.

[5] Sandstrom C., Schmidt B. Facility-Design Considerations for the Use of Disposable Bags. BioProcess International Supplement (10), 2005: 56-60.

[6] Pörtner R., Barradas P. O.B.J. Cultivation of mammalian cells in fixed-bed reactors. Anim. Cell Biotechnol. Methods Protocols (24), 2007: 353-369.

Pall Life Sciences - BioPharmaceuticals