The Game Changer

Single-use technologies are coming of age and joining other driving forces to reshape the landscape of biopharmaceutical industry. This innovation has created new platforms for bioprocessing, offering competitive advantages and tremendous opportunities to current biomanufacturers. Moreover, the increasing acceptance of disposable systems with proven success will help enable niche products and bring emergent players to the market.

The Age of Stainless Steel

The discovery of DNA structure in the middle of the 20th century led to numerous breakthroughs in biological science and inspired a generation of entrepreneurs. The 1980s and 1990s saw a booming biotech industry with all eyes on bringing biologic products to market. As with small-molecule drugs, biologic development faces challenges in long development cycles, low success rates, and high costs. According to Tufts, it was estimated to take about $1.2 billion to commercialize a single biologic drug in 2008 (1).

Several additional barriers of entry are unique to biologics. The first is a scientific barrier. Fundamental understanding of the characteristics of a given biomolecule contributing to its clinical efficacy and immunogenicity is crucial to selecting a drug candidate early on. Although much progress has been made here, we still have an incomplete picture of critical quality attributes (CQAs) due to the complexity of proteins and biological functionalities.

The second barrier is technological. The ability to design, construct, and express a large molecule effectively in a biological system is essential to producing commercial quantity of biologic materials. Phage-display and Xeno-mouse technologies contributed to the rapid success of monoclonal antibody (MAb) commercialization. In addition, a broad array of expression systems from Escherichia coli to yeast and mammalian cells such as Chinese hamster ovary (CHO) and baby hamster kidney (BHK) cells provides viable platforms of biological hosts for protein synthesis.

The third barrier is related to manufacturing. Although fermentation technology can be traced back to the dawn of civilization, mammalian cell culture technology — the expression system preferred for most known therapeutic proteins with desirable glycosylation patterns — is relatively new. It took two decades of trials and tribulations to bring cell culture from a bench technique at milligram scales to industrial production at kilogram scales. The era of biopharmaceuticals is manifested in the capability of producing large quantities of biologics in stainless steel bioreactors. Today those large-scale stirred-tank bioreactors (usually >10,000 L in scale) represent modern mammalian cell culture technology, a major workhorse of biopharmaceutical industry. Many blockbuster biologics — such as Enbrel etanercept from Immunex Corporation, Avastin bevacizumab from Genentech (Roche), and Humira adalimumab from Abbott Laboratories — are produced using large-scale bioreactors.

The Birth and Adoption of Disposables

As the biopharmaceutical industry bathed in its successes using large-scale bioreactor technology, a “disruptive” innovation was under development in parallel. Interestingly, the first single-use Wave bioreactor in 1996 coincided with the highest ever number of biotechnology drugs approved in one year between 1982 and 2007 (2). Vijay Singh, the inventor and founder of Wave Biotech, has recounted the journey of the bioreactor’s creation and reminisced:

Predicting the future is always dangerous. Who could have predicted in 1996 that a bag could be used as a bioreactor and would replace tank bioreactors costing five times as much? While better designs will evolve, the intrinsic simplicity of the Wave bioreactor will ensure it remains a useful device for many applications in the years to come. (3)

Single-use bioreactors have since evolved beyond the wave-based design and been adopted both for research purposes and GMP production. Moreover, single-use technologies such as disposable filters, flexible containers, membranes, sampling devices, and chromatography columns have penetrated into almost every unit operation in bioprocessing.

The Nobel-Prize–winning physicist Max Planck once said, “An important scientific innovation rarely makes its way by gradually winning over and converting its opponents. What does happen is that its opponents gradually die out and the growing generation is familiarized with the idea from the start.” What has been achieved by the single-use technologies is contrary to Planck’s proclamation because of three important factors: timing, context, and promise.

The final decade of 20th century was an exciting era for biotech industry. Buoyed by the triumph of products in the market, the industry attracted enthusiastic support from investors. Between 1996 and 2000, there were 156 biotech initial public offerings (IPOs) in all, with 45 in 1996 and 66 in 2000 (4). That influx of cash fueled innovation, leading to more clinical trials, BLAs, and product approvals. But the inherent uncertainty of drug development did not diminish. To bring biological products to clinics and eventually to market, companies must ensure that manufacturing capacity is in place to meet supply requirements.

Many biotech companies with no manufacturing facilities or with insufficient capacity to support clinical trials and product launches face a dilemma of whether and/or when to build a new facility. Building one requires significant up-front capital investment long before a drug candidate demonstrates clinical efficacy. To some companies, that presents an investment risk and a strategic choice regarding whether to invest limited resources in a manufacturing facility or research and development. For others, it is not an option if they have insufficient financial means to build their own facilities. Despite progress made in large-scale cell culture technology, the sophistication and operating complexity of large-scale GMP facilities are quite demanding, and require an experienced workforce for successful project execution. Single-use technologies were born to address the challenges of construction, operation, and maintenance of conventional facilities.

One promise of disposables is the cost benefit derived from improved efficiency. Capital investment including validation cost for facilities with single-use technologies is typically a magnitude lower than for traditional facilities with stainless steel equipment. Because the consumable portion of the equipment (e.g., tank liners and filters) is generally presterilized, ready to use, and disposable after use, there is no need to perform cleaning/sterilization activities. That reduces energy and labor costs. Change-over and equipment set-up are much simpler and quicker, and overall production cycle times are shorter. In addition, the cost of consumables associated with single-use technologies is a function of production volume, which allows it to fluctuate with production demand instead of being a fixed cost.

Another promise of disposables is their ease of operation. Compared with traditional equipment, less manipulation is required to set up and operate a single-use system. This allows fewer opportunities for error. Most such systems strive for simplicity and are operator- and maintenance-friendly. Training manufacturing operators and maintenance staff becomes less burdensome and time-consuming.

Another advantage of single-use technologies is their portability. The floor-plan layout of a disposables-based facility can be changed much more easily than that of a traditional facility. Different process requirements can be easily addressed by moving equipment into or out of a production suite. Because of the disposable nature of single-use systems, contamination is less of a concern (especially cross-contamination for multihost, multiproduct facilities).

What single-use technologies bring to the table has struck a chord. They were first accepted by process development and production groups for toxicology studies and early stage clinical trials. As commercially available systems become more robust and reliable, disposables have been incorporated into process platforms by many biomanufacturers, and more commercial production facilities now use these technologies as an integral part of their manufacturing processes and their efficiency and productivity improvement tools.

Remaining Challenges: Although single-use technologies have delivered success in development laboratories and GMP production suites, challenges and improvement opportunities yet remain. For example, concerns with extractables and leachables have not been fully addressed. System integrity issues could lead to contaminations or loss of product. Product quality consistency, lot-to-lot variability, and the single sourcing of raw materials — although not unique to single-use technologies — have presented some challenges especially in GMP environments. And the cost of consumables will become a growing concern as these technologies are integrated into more unit operations with significantly increased use. Nevertheless, with the right applications, the benefits of single-use technologies outweigh related concerns. In under 10 years, these technologies have grown tremendously by attracting end users for all the reasons mentioned above.

Transforming Biomanufacturing

Biopharmaceutical products have exhibited strong growth over the past decade. Biologics now account for 7.5% of all drugs on the market and ~10% of the total expenditure for marketed drugs, and their use is growing at >20% per year. Biological drug candidates constitute 32% of all pipeline research programs. In addition, biologics are administered in life-saving or end-stage applications 74% more than chemically derived pharmaceuticals (5).

Market and Reimbursement Realities: However, the biopharmaceutical industry is facing some unprecedented challenges. Because many biologics are indicated to treat chronic deceases such as rheumatoid arthritis, multiple sclerosis, and chronic kidney failure, their dosing schedules can last for years at higher expense than small-molecule pharmaceuticals. With growing healthcare costs, particularly in the United States (where such costs will rise from 17% in 2008 to 20% of gross domestic product by 2017), pressure from the public, payers, and governments to provide low-cost medicines is on the rise, and controlling healthcare costs has becomes a top national imperative (6). In the future, the basis of payment for medicine will shift from prescriptions to performance and outcomes. Furthermore, cost/benefit ratios and demonstrated values will be required for new drug approvals (7).

Like pharmaceutical companies in general, the biopharmaceutical industry has suffered a pipeline “dry spell” in recent years, with fewer blockbusters on the horizon. It seems unfair to simply put the blame on R&D productivity because scientific breakthroughs are hard to obtain, and many drug candidates based on identified and validated targets have already been commercialized. As we continue to gain better understanding of diseases at the genetic and molecular level, personalized and precision medicines that target specific patient populations will emerge and drive the growth of biologics. Although such products are unlikely to become individual blockbusters with high-volume demand, with more of them being developed and commercialized, they will occupy a greater portion of market share and manufacturing capacity. Along with healthcare cost control, patent expirations, and a regulation pathway for biosimilars being established, the biopharmaceutical marketplace is expected to become more competitive and volatile.

Supply Chain Complexity: As the global economy continues to shape this industry, its supply chain will become increasingly complex owing to the progressive trend of partnerships, outsourcing, and offshoring. External forces from healthcare and regulatory dynamics, fluctuating market conditions, and (lack of) predictability will converge with the internal forces of cost pressure, supply chain management, and advancement of process technologies. Together these driving forces will require the biopharmaceutical industry to reexamine its current manufacturing capacity, capability, and geographical locations — potentially leading to rationalization and optimization of manufacturing networks for meeting future process and production requirements.

The Value of Flexibility

Future biomanufacturing will need to be flexible to handle multiple products, different production volumes for each product, and rapid changes in market demand at lower cost. However, many of today’s facilities are built to supply blockbuster-like products with high volume and steady demand. The fixed configuration is usually product or process specific. Introducing new products into such facilities often requires modifications that can be expensive with long lead times. It is especially challenging to scale production up or down to market demand as both directions incur financial consequences, either with significant capital investment or facility charges for idle capacity. As cell culture technology continues to push titers to 5 g/L and even 10 g/L, many facilities with “six-pack”–like designs based on 1–2 g/L titers will find themselves being caught in the shift of production bottlenecks with excessive cell culture capacity and constrained recovery and purification capacity.

To anticipate future needs, biomanufacturing facilities need to move away from large-scale, stick-built fixed configurations to mobile “warehouse” designs that will be less expensive and easier to build. Because of projected increases in cell culture titers, the size of bioreactors are likely to be middle-scale. Clean spaces will be optimized and can be easily expanded and contracted. Interiors will be highly configurable, with utility panels and portable equipment to accommodate product mixes and different production volumes. This has offered a center stage for single-use technologies as a new manufacturing platform.

For example, a single-use bioreactor fits well with the required scale for production. With lower capital investment, ease of operations and portability, it is likely to replace stainless steel stirred-tank bioreactors. Flexible containers will come with presterilized assemblies such as ports, filters, and sensors for storage of buffer and product intermediates. Buffers or media can be prepared in bags for mid-scale operations, which can be further simplified with predispensed chemicals. These applications will enable closed processing in most unit operations. Because of the nature of “single-use,” product and process change-over will be measured in hours instead of days as required in conventional facilities.

A bioprocess facility with that mobile warehouse design and single-use applications will offer several competitive advantages for biomanufacturing. First of all, it enables “just-in-time” manufacturing for responding to demand variability and minimizing inventory levels while meeting clinical and commercial supply requirements. Quick construction and set up is particularly advantageous for vaccine production in response to pandemic or bioterrorist threats at desirable geographical locations. Because capital investment is relatively lower than for conventional facilities (and operations are also simpler with applications of single-use technologies), lower fixed costs and less labor will be required to maintain and operate new facilities. Although the cost of consumables is likely to be higher, it corresponds to production volumes as a variable cost. There will also be energy savings due to overall reduction of cleaning activities. So total costs are likely to be lower, especially for small-volume production.

A second advantage is a significant reduction in the cost of change-over and alleviation of concerns over cross-contamination for multiproduct manufacturing facilities. Third, the new approach potentially reduces the hurdle of product and process comparability. With conventional facilities, materials for toxicology and early phase clinical studies are typically made at pilot scale, then materials for late-phase clinical trials are produced at large commercial manufacturing scale. Product and process comparability must be demonstrated as each product moves along through different development stages. In a mobile warehouse facility using disposables, it is possible to choose a certain scale for production through the entire development cycle. With easily expandable space and portable equipment, a process can be scaled “out” with multiple trains at the same scale instead of being scaled “up” to larger equipment, reducing or eliminating costs from comparability work and concerns of process scalability and comparability.

Implications of the Paradigm Shift

After decades of industrializing biologics production in facilities designed for dedicated products with fixed stainless steel equipment, the increasing application of single-use technologies signals a paradigm shift for biomanufacturing. Application of single-use technologies has changed the world of biomanufacturing profoundly, not only because it may bring benefits to the existing manufacturers but also because it may lower the cost of entry for newcomers. CMOs, manufacturers of biosimilars, and new players from emerging markets may seek the same advantages of single-use technologies and compete effectively in the global market.

As biomanufacturers depend more on single-use technologies, the relationship between suppliers and their customers will evolve. Biomanufacturers must acknowledge the critical role suppliers play in their value chain. Partnership and close collaboration between suppliers and manufacturers (and suppliers with each other) will intensify. Codevelopment and codesign activities are likely to increase. The debate over customization and standardization will continue, as will its influence on supply reliability and pricing. Environmental sustainability will become a common goal and must be jointly tackled by both suppliers and biomanufacturers.

Heavily invested in conventional facilities, current biomanufacturers also face challenges to bring these innovations in-house. It can be financially and technologically daunting to introduce single-use technologies to a facility with fixed stainless steel tanks and bioreactors. History has shown how innovations were stifled due to previous investment in old technologies and the impending cost of implementing new ones. Biomanufacturers must make a strategic decision, no matter how painful it may be, to rationalize their current facilities based on capacity, functionality, technology, geographical location, and future projections of process and supply requirements — and if needed, to build new facilities to augment existing production networks.

Single-use technologies will continue to play a key role in shaping the future of the biopharmaceutical industry. As technologies continue to evolve, new applications will emerge and in turn further stimulate technological development and innovation. Reducing cost of goods manufactured (COGM) will make biotherapeutics, especially personalized medicines, more accessible to patients while allowing companies to generate profit and continue investing in drug discovery and development. Growth of the biopharmaceutical industry will positively affect health care in our society and dramatically improve the lives of world populations.

REFERENCES

1.) 2008.Outlook 2008, Tufts Center for the Study of Drug Development, Boston.

2.) 2009. BioWorld Snapshots: Biotechnology Products on the Markets Since 1982, BioWorld Today, Atlanta.

3.) Singh, V. 2005. The Wave Bioreactor Story, Wave Biotech LLC, Somerset.

4.) Burrill, GS. 2010.Biotech IPOs Completed 1996–2009, Burrill & Company, San Francisco.

5.) Harris, M. 2009. The Billion-Plus Blockbusters: The Top 25 Biotech Drugs. BioWorld Today www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=51907.

6.) 2009.Facts on Health Care Costs, National Coalition on Health Care, Washington.

7.) 2007.Beyond Borders Global Biotechnology Report 2007, Ernst & Young, Zurich/Boston.