Introduction
In recent years, the application of single-use technologies in the bioprocessing industry has become more widely adopted, even while a longstanding demand for stainless steel, reusable devices in large scale production continues mostly unabated. This growth, documented in our 16th Annual Report of BioManufacturing1, shows that over the past 13 years single-use bioreactors, and mixing systems, grew by 59 percentage points, 55 points, respectively.
On an annual basis, the growth rate of adoption of single-use “Bioreactors” continues to run at around 11% this year. However, as more facilities use them, growth in adoption of single-use devices has necessarily slowed down as market saturation is reached. For many, probably most, of these product classes, reported slow growth rates likely reflect their already relatively widespread adoption, particularly the simpler and/or less expensive products, such as “Sampling systems” and “Bags”.
Many of these products had already achieved relatively high adoption. For example, disposable media bags were among the very first single use products. In contrast, some new(er) single-use equipment, such as membrane adsorbers and perfusion and tangential flow filtration devices, continue to have low adoption rates. As we reach market saturation for single-use systems being used for pre-commercial applications, it will take greater regulatory acceptance (more commercial product approvals) for plastics usage and/or more approvals of single-use manufactured commercial products to allow this market to capture more significant market share and sales growth at larger commercial scales.
Adoption by Application in Biomanufacturing
We compare adoption rates, and percent of the industry using SUS devices, by stage of manufacture, and see logical variations. For example, SUS bioreactors are used by 71.2% of the industry in process development, but only 36% in commercial production. Yet over 55% use single-use sampling systems in clinical or commercial production, versus only 28% in R&D. This reflects the relative benefits of using disposable, versus reusable devices within the process stream. When it is cheaper to clean and validate big equipment, such as a large-scale bioreactor, than it is to purchase a single-use device, the industry is making these logical decisions.
Because virtually any new technology will be evaluated for new pipeline products (not existing manufacturing processes), we also expect to see more single-use adoption at smaller scale (process development and clinical scale).
As the Report details, single-use equipment, at pre-commercial scales, has moved to a position of dominance over stainless steel systems, particularly earlier stage, and upstream. While there remains limited use of single-use systems for commercial manufacturing, this is starting to change as more new products being developed using single-use systems move through the development pipeline. Developers are gradually focusing on single-use systems for more flexible commercial manufacturing. Costs of non-blockbuster scale commercial manufacturing using single-use systems are now considered competitive with stainless steel systems. Further, as regulators continue to gain familiarity with the safety profiles and materials used in these devices, product manufacturers are seeing accelerating rates of approvals, and SUS adoption. As this move toward commercial scale occurs, the market for single-use devices can be expected to increase significantly. This includes more scaling-out using multiple process lines anchored by the large single-use 1,000-2,000 (and greater) liter bioreactors rather than scaling-up using one or several larger stainless steel bioreactor-based process lines.
Application of Single-Use Technology: Single-Use Products Dominate in Almost All Stages of R&D Manufacture
According to our annual data, SUS devices have engaged almost every aspect of the bioprocessing industry. In fact, we estimate that at clinical or process development scale, nearly 85% of operations substantially use some SUS devices. In Fig 2, we see that disposable filter cartridges, for example, are used by 85.6% of respondents, while nearly 80% use some scale of disposable bioreactors.
CMOs and Biotherapeutic Developers’ Different Goals
In the study, we also compare contract manufacturing organizations (CMOs) use of SUS devices. Paramount among CMOs is a need for more flexible production capacity and fast campaign change-overs. Moreover, they must make more products more rapidly at varying scales, since compared to biotherapeutic developers they possess a relative lack of legacy production systems, thus they tend to use more diverse types of single-use components and systems. Thus, we find greater penetration for SUS devices, and more rapid uptake of new SUS technologies among CMOs.
An important difference exists in business management philosophy between CMOs, with their ever-changing processing lines and facilities, and the more stable product developers for bioprocessing equipment and facilities. For the product developers, a facility can be considered a long-term investment and corporate assets. But CMOs execute more development and manufacturing projects with smaller footprint requirements to generate higher revenue, compared to biotherapeutic developers who have far fewer products, who take their time, refining processes with a dedicated operational staff to manage the production facilities, and likely do not share many of the same concerns as CMOs.
Reasons for Adoption of Single-Use Systems
The overwhelming acceptance and the rapid transition to disposable technologies is brought about by a number of factors. In our studies, we have measured the reasons for over a decade, and one of the most significant drivers is the constant improving and redesigning of the devices, making disposables more useable, more effective (fewer contamination risks, lower cleaning and validation costs), and more acceptable to regulators (better leachable and extractable data and profiles).
Indeed, the most frequently cited reason for moving to disposables is the elimination of cleaning requirements, a time consuming and expensive proposition. For many companies the high consumables cost of disposables can pale in comparison to the costs incurred from cleaning, especially taking into account the cost of monster volumes of very expensive purified water necessitated by the cleaning process.
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There are still many reasons to holdout on the decision to jump to disposables. The high cost of consumables continues to be a major factor in the decision not to adopt SUS technologies. This is followed by concern over leachables and extractables which could create regulatory problems.
Although the possibility of loss of product through breakage of bags was cited as a significant concern, manufacturers claim that recent improvements to strengthen the bags has obviated this issue. Yet the fear persists because the risks of even a minor leak or puncture could mean the loss of an entire batch of product, potentially worth millions.
Another interesting facet of the debate rests with the comparison of US and European companies’ responses. Excessive cost was a major concern and a more significant factor among Europeans as compared to American companies. Overall, U.S. respondents appear to be fixated on practical constraints and limitations – not only high costs, but also regulatory issues, and budgets.
As the industry continues to evolve, advances on the upstream end, in media and cell lines that provide greatly improved protein yields, and these improvements generate changes in design and utilization of single-use devices. In more recent years, with higher upstream productivity, required capacity can often be achieved using equipment with a tenth of the capacity compared to just a decade or two ago. This translates to a 2,000 L SUS bioreactor now being able to do the job formerly done by 2 x 10,000 L stainless steel bioreactors. Single use bioreactors and other equipment are now fully viable and cost-effective options (up to the 1,000-2,000 L scale, with some suppliers offering even greater capacity).
These advances mean that system complexity can be reduced, shortening lead-time to get a facility or process line up and running. Further, utilities, space, and labor requirements are also reduced with single-use versus comparable size stainless steel process lines. Because there is much less chance for cross product contamination with single-use, related quality and regulatory concerns are diminished.
The improvements in SUS devices have important long range implications, as many new biopharmaceutical start-ups and small to medium companies, including new entrants worldwide, are now able to spend much less initial capital to quickly advance new products through the proof of concept stage and beyond.
Downstream Improvements
Although many suppliers have innovative single-use downstream technologies in the works, most have not yet been commercialized, so this area may be perceived as a final frontier.
Major problems involve chromatography, which lacks single-use systems. Although single campaign pre-packed reusable/recycled chromatography columns are seeing rapid adoption, these are not truly single-use. Protein A resin is a traditional component of antibody purification protocols, and at present, few cost-effective alternatives are available. With a price tag of $12,000 per liter or more, it can make up 30% of the total cost of Mab production and purification. Many are seeking alternatives, but so far few have met with more than limited success. Because of the remarkable efficacy of Protein A, many antibody purification companies are willing to overcome sticker shock and live with its high price. But there can be little doubt that an alternative with a lower price, the same robust performance, and equivalent regulatory acceptance would be greeted with excitement.
A significant trend today is the availability of pre-packed chromatography columns, including delivery and pick-up for recycling, permitting “plug-and play” convenience, and adaptable for single-use mode, depending on the application and unit cost. These devices offer a number of well-recognized features, including eliminating the work of packing and testing, along with standardized sizing, packing, shelf storage, and rapid delivery of custom columns.
Emerging Trends and Greener Bioprocessing Through Disposables
Looking to emerging trends, the 16th Annual Report stresses the rise of modular bioproduction systems, especially for major biopharmaceutical manufacturers. For example, Pfizer is constructing a fully modular plant in China and GE and G-Con are manufacturing single-use equipment installed within a portable self-enclosed modular unit. True single-use modular bioprocessing units are especially relevant to biodefense and epidemic vaccines manufacturing, where needs for rapid manufacturing responses are dire and transitory.
The Report also reviews the need for environmentally friendly solutions where the vendors are also responsible for recycling. Although the biotech industry is a minor contributor to the overall burden of industrial pollution, some manufacturers have taken a more aggressive role in confronting this intractable issue. It is noteworthy that accounting studies comparing disposables with multiple use stainless operations show that disposables can actually be “greener” due to the burden of cleaning; this is exacerbated by the fact that the current trend is to have stricter requirements for cleaning, which leads to more complex and expensive cleaning cycles, and more complex, time-consuming, and expensive validation. This adds another, albeit complicated dimension to the advantages of disposables.
References:
- 16th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2019, www.bioplanassociates.com/16th
About the Authors
K. John Morrow Jr, Ph.D., is a long-time collaborator with BioPlan Associates, Inc. He is president of Newport Biotech Consultants since 2005. He has published numerous articles in the trade press and peer reviewed academic journals. [email protected], +1 513-237-3303, www.newportbiotech.com.
Eric S. Langer is the President and Managing Partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing fi rm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing,” and many other industry reports. [email protected], +1 301-921-5979, www.bioplanassociates.com.
Survey Methodology: The 2019 Sixteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 221 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 24 countries. The methodology also included 120 direct suppliers of materials, services, and equipment to this industry. This year’s study covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time and assesses differences in the major markets in the U.S. and Europe.