Biopharmaceutical manufacturing directly supports the $240 billion biologics industry, and small improvements in costs of manufacturing can result in very significant savings. However, unlike other industries, where adoption of new technologies are often quickly embraced, in bioprocessing, change evolves slowly. This is due to a few factors, but one of the largest is the intense regulation of the industry. Manufacturers and contract manufacturing organizations (CMOs) must gain regulatory approval for any change in technology or process. Therefore, change is slow to happen because once a manufacturing process has been established and approved, the costs of change are significant, and incentives to change are limited.
Despite the onerous regulatory and testing burdens facing manufacturers who seek innovation and process improvements, change does happen. New technologies are developed, and the industry moves forward, albeit slowly. One such change over the past 20 years has been the adoption of Single-Use System (SUS) and disposables. In recent years, we have seen fewer blockbuster drugs, more biologics having higher potency that require smaller production volumes, advances of biosimilars targeting smaller markets, and ongoing incremental improvements in production yields and efficiencies that create production operations at much smaller scales. This has permitted the use of single-use devices, such as plastic bioreactors, mixing systems, and containers that are now dominating clinical production, and are moving toward commercial operations.
Having adaptable equipment and flexible facilities that can manufacture multiple biopharmaceutical products at once, or in tandem, rather than a single drug that will carry a company for many quarters to come, is now a standard of the bioprocessing industry.
Single-use and disposable devices are being used for a range of applications including upstream production, mixing, filtration, purification, fill-finish, and storage, among others. These systems provide faster change-overs and reduced times for production. BioPlan Associates has surveyed global biopharmaceutical manufacturers and CMOs to gain insight into current and future trends in the industry. In BioPlan’s 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, we asked 227 bioprocessing decision-makers where they are using SUS and disposables, and the critical factors, trends and hurdles being seen in adoption.
How Common are Single-Use Devices?
The most common single use devices are basic tubing, disposable filter cartridges, and connectors and clamps. Although we do note that these devices must meet exceptionally high standards for quality, and performance, nearly 90% of respondents to our survey indicated they are using these products at some scale. In fact, these devices are reaching market saturation, at least at clinical scale. At the bottom of the ‘adoption’ list are perfusion devices, membrane adsorbers, and disposable chromatography devices. These are at the lower end of usage ranges because they tend to be newer; given the slow adoption rates in this industry, they are still moving up on the growth curve. While many devices were tracking around a healthy 13% annual growth rate last year, the more saturated devices were showing only single-digit growth. As more facilities use them, growth in adoption of single-use devices necessarily slows as market saturation is reached. For many, probably most of these product classes, slow usage growth rates likely reflect their relatively widespread adoption prior to our collecting these data, particularly the simpler and/or less-expensive products, such as “Sampling systems” and “Media bags, purchased dry”. Many of these products achieved relatively high adoption in earlier years. For example, disposable media bags were among the very first single-use products, with single-use filters common even before this.
In contrast, some new(er) single use equipment, such as membrane adsorbers and perfusion/tangential flow filtration devices, simply are newer and continue to have relatively low adoption rates. As we reach a market saturation point for single-use pre-commercial applications, it will take greater regulatory acceptance (commercial product approvals) for plastics usage and/or more approvals of single-use manufactured commercial biologics to allow this market to capture more significant market shares and growth in sales.
In our study, we evaluated the growth (change) in disposables applications over the past 11 years (See Figure 2), in terms of the difference in percentage facilities actually implementing disposable applications. This year, “Bioreactors” percentages continued to grow rapidly, up from 21% in 2006 to 80.3% adoption; a 59.3% point difference. “Mixing Systems” also saw a large point difference this year, 58.4%, from a point difference of 50.8% in 2016. “Perfusion devices” reported 35.9% growth this year, up from 33.1% in 2016. Other areas have grown at faster rates this year, than reported in 2016, again reflecting either slower and/or earlier adoption and associated higher baseline usage rates (e.g., exemplified by the areas with the least growth – “Media bags (wet)”, “Media bags (dry)” both long used in bioprocessing – and “Disposable chromatography” with a high initial baseline).
Figure 1. Usage of Disposables in Biopharmaceutical manufacturing, any Stage of R&D or Manufacture (Selected Data) Figure 2. Selected Devices-11-Year Percentage-Point Change in First-Usage of Disposables, 2006-2017 The average annual growth rate (CAGR) for some of these devices between 2006 and 2017 has been relatively high, around 13% for mixing systems, membrane adsorbers, and bioreactors. Other more common devices that have seen less average growth due to the fact that these were already in steady use when BioPlan began collecting data in 2006. In addition, some other single-use equipment may be showing slower growth today, such as perfusion/tangential flow filtration devices, because there is more regulatory approval required to allow these devices to reach market saturation.
Process Scales Where SUS and Disposables are Being Used
We looked at commercial production, scaleup/clinical production, process development, and early R&D. By far, disposables are being more widely used in scale-up/clinical production and process development than commercial production. In scale-up/clinical production-scale, adoption rates for nearly every type of single-use product is over 70%, with several areas over 80%. In contrast, disposable chromatography, for example, is used by only 20% at commercial scale. This is not unexpected, since devices like larger scale SUS chromatography are not (yet) available, and membrane adsorbers have not yet entered mainstream commercial markets.
Reasons for Adopting Single-Use Technology And Disposables
Study participants cited reducing capital investment in facilities and equipment as the most critical reason for increasing disposable use. This was cited by 27.7% of respondents, an almost 50% increase over that response in 2016. This is likely due to the fact that manufacturers are continuing to focus on productivity, efficiency, and short-term cost savings and therefore see a decrease in facility costs as a good way to accomplish these goals. The next most critical reasons cited for adopting SUS were to eliminate cleaning requirements (15.2%), faster campaign turnaround time (8.9%), decrease risk of cross-contamination (8%), and flexibility of a modular approach (7.1%).
We also asked the most critical reason for not increasing disposable use. The number one listed reason was the high cost of disposables, cited by 23.4% of respondents. The fact that cost issues have risen to the top is indicative of how SUS device manufacturers have generally begun to resolve concerns of the past, including breakage, and leachables and extractables, both of which have taken the top spots in prior years.
When Will Facilities Be Using 100% Fully Disposable Technology?
A majority of industry experts, 64.9%, either said they ‘strongly agree’ or ‘agree’ that there will be a 100% fully disposable facility in operation in 5 years. This is up from 57.2% of respondents last year. It’s likely these facilities would be new and using devices like single-use upstream bioreactors and downstream disposable chromatography and filtration systems. Nearly two-thirds of respondents (65.7%) said they anticipated their own facility’s cGMP clinical/commercial operations would be substantially using single-use devices in five years. This response keeps going up, from 51.8% in 2016 and 49.1% in 2015.
Figure 3. Single-use / Disposable Device Adoption Factors Conclusions
Single-use systems, which are being used at clinical scale for well over 80% of bioprocessing operations, will continue to be adopted by biomanufacturers and CMOs at larger commercial scale as pipeline products being produced in SUS are approved, and move into commercial production. Because most single-use disposable systems are already being used in scale up/clinical production, much of the future growth will come from the growth of larger commercial scales, increasing market growth of SUS since these are much costlier systems to implement. As the industry matures, vendors are creating improved disposable technologies to differentiate themselves from competitors. This bodes well for manufacturers and CMOs as it will drive down prices and increase competition.
Disposable processing equipment is now being considered increasingly for more strategic reasons, such as reduction in overall costs, and improved productivity. The ‘tactical’ reasons such as reductions in cleaning and validation requirements and in crosscontamination events are still important decision factors, but are being seen as relatively less critical.
As better upstream productivity in recent years has required lower and/or less frequent dosing, and production requirements can be made at a tenth of the scale from a decade ago, more production lines can be specified at single-use scales. At this scale, e.g., 2,000L or less, disposable bioreactors are viable and cost-effective. Further, some facilities, such as CMC Biologics in Bothell, WA, and Copenhagen Denmark are chaining multiple 2000 liter bioreactors to create up to 12,000L batch sizes. Thus, further reducing the need for large stainless steel tankage.
Complete single-use upstream processes can compete with larger commercial-scale manufacturing in cost. And now, suppliers and innovators are turning to downstream processing single-use systems to find cost-effective and efficient solutions. Even facilities with conventional steel facilities are creating hybrids with SUS to optimally incorporate disposables for production.
As regulatory agencies become more comfortable with the performance of SUS, the industry will see a wider adoption at commercial scale. This will result in the market for SUS rapidly growing far past its current size. The availability of current SUS has benefited new biopharmaceutical start-ups in particular, allowing them to spend much less capital and quickly advance the development of new products. Single-use systems may therefore increase the competition within the biopharmaceutical manufacturing industry as a whole, allowing smaller and medium-sized companies to gain a quick foothold, whereas in the past, they would have been prevented from doing so by huge up-front facilities costs.
References
- 14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates, Inc. April 2017, www.bioplanassociates.com
Author Biography
Eric S. Langer is President and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm 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]301-921-5979. www. bioplanassociates.com
Survey Methodology: The 2017 Fourteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 227 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 25 countries. The methodology also included over 131 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 world’s major markets in the U.S. and Europe.