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.