The embracement of single-use applications by the biopharmaceutical industry is no secret. They now dominate clinical scale manufacturing, and as the pipeline of new products advances, are now moving into mainstream commercial bioproduction. However attitudes differ on which disposable applications are most important. For example, biotherapeutic developers and contract manufacturing organizations (CMOs) approach the question of single-use equipment from different perspectives. CMOs have fewer fixed ‘legacy’ stainless steel systems, and they can pass on the direct costs of bioproduction to their clients, so they tend to adopt singleuse technologies more rapidly. In addition, CMOs work in a competitive environment, and their ability to adopt new technologies that will provide higher yield, more productivity, less contamination, and all at lower costs, mean they tend to be more willing to evaluate and employ newer systems in their operations.
In BioPlan Associates’ 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production [1], we surveyed more than 300 developers and CMOs to gain a comprehensive look at the state of the single-use market today. Our results indicate that the market is growing quickly, but that each group of respondents has a different set of perspectives shaping their single-use strategies.
Most Popular Products
We measured 15 of the most common single-use devices and evaluated differences in usage among biomanufacturers and CMOs (the study also evaluates US/EU and Rest-of-World usage). Not unexpectedly, we found 100% of CMOs and 90.7% of biotherapeutic developers use disposable filter cartridges, the most common application for each set of respondents.
Figure 1. Selected Devices: Usage of Disposables in Biopharmaceutical Manufacturing; Biotherapeutic Developers vs. CMO
Beyond that, we discovered different priorities. For example, among CMOs, bioreactors, buffer containers, and media bags (purchased dry) tied for the second spot, used by 85.7% of respondents, with waste containers and tubing for disposable applications tied for the fifth position, at 78.6% of respondents.
Overall, CMOs demonstrated higher adoption in 9 of the 15 disposable applications we identified. Some of the biggest discrepancies we found were for the following applications:
- Depth filters (88.4% of biotherapeutic developers vs. 64.3% of CMOs);
- Bioreactors (76.7% of developers vs. 85.7% of CMOs);
- Sampling systems (79.1% of developers vs. 64.3% of CMOs);
- Waste containers (57% of developers vs. 78.6% of CMOs); and
- Disposable chromatography devices (48.8% vs. 57.1%).
Unsurprisingly, CMOs, with their need for more flexible production capacity and fast campaign change-overs, along with their relative lack of legacy production systems, tend to be more frequent users of disposable components and systems. It is interesting to see that CMOs also report greater adoption of complex single-use devices such as bioreactors, mixing systems, and membrane adsorbers. Last year, both groups were relatively on par in usage of these complex devices, with developers on the whole reporting slightly greater penetration.
CMOs appear to have leapfrogged the biotherapeutic developers on account of greater penetration. For example, while both CMOs and developers last year reported 76.5% adoption of bioreactors, this year that figure has risen to 85.7% of CMOs, while staying constant for developers. The same pattern is true for mixing systems and membrane adsorbers.
Budgets for Disposable Products
Not only are CMOs increasingly turning to disposable bioreactors, they are also spending hefty amounts for them. On a per-facility basis, we found this year that CMOs outspent biotherapeutic developers on bioreactors by a slight margin, $185,000 compared to $165,862/facility.
While that’s only about a 12% difference, it’s notable because in each of the other 13 disposable products we identified, developers reported spending more on a per facility basis, sometimes by a large degree.
Some of the areas in which we found significant gaps in per-facility spending between CMOs and developers included:
- Disposable filter cartridges, where developers out-spent CMOs by 630%;
- Depth filters, where developers out-spent CMOs by 260%;
- Media bags, purchased dry, where developers out spent CMOs by 354%
- Tangential flow filtration devices, where developers out spent CMOs 450%.
These gaps are expected, given that CMOs may tend to be working on smaller scale or clinical scale projects versus commercial scale projects at the biotherapeutic developers.
However, these results are an interesting departure from last year’s findings, in which CMOs reported spending more than developers in almost all of the disposable components. This may be an indication of the penetration that single-use devices are making in larger scale bioprocessing. We do note that the data can be quite noisy – in that relatively few very expensive purchases can skew the results.
New Product Development
While CMOs are taking up single-use bioreactors in greater numbers this year and spending more on them than their developer counterparts, their thirst for new and more innovative products appears to have cooled considerably. Whereas last year, disposable bioreactors were cited as a new product development area of interest by about twice the proportion of CMOs as developers (56% vs. 27.7%), this year interest is about equal at one-third of respondents in each group (33.3% and 34.1%, respectively).
Figure 2. New Product Development Areas of Interest, Biotherapeutic Developers vs. CMOs
By contrast, CMO interest in disposable purification product innovation rose from 40% last year to 61.1% this year, while the increase was more muted for developers (from 27.1% to 30.2% this year).
CMOs this year again expressed more interest than developers in disposable controller innovation (16.7% versus 9.5%), but in a reversal from last year, reported less interest in new product development for disposable bags connectors (38.9% versus 44%) and disposable probes and sensors (27.8% versus 41.3%).
Why Increase Use of Disposables?
As part of our study, we identified reasons for the trend toward increased use of disposable and single-use system components. As a general theme, we found that the reasons biopharmaceutical manufacturers and CMOs gave for potentially increasing their usage of disposables have stayed relatively consistent from the past few years. This may reflect a maturation of this segment. As the industry becomes more aware of the attributes and benefits of disposable usage and as the use of disposables increases, decision-makers’ needs and specific reasons for increasing usage continue to level out. Factors associated with cost are likely to continue to fluctuate with the changing economic situation.
Overall, the top 3 reasons given by respondents (CMOs and developers combined) for increasing their use of disposables remain the same from last year:
- Decreasing risk of product cross-contamination;
- Reducing time to get facility up and running; and
- Eliminating cleaning requirements.
The rankings of those attributes have changed from last year, but as in prior years, they remain quite clearly the top reasons. We also see CMOs more likely to agree with a range of reasons for increasing use than biotherapeutic developers. This can possibly be tied back to higher adoption rates among CMOs, or simply be a reflection of greater enthusiasm for these products. Either way, CMOs and developers rank the 25 attributes we identified fairly differently. Among CMOs, the top “very important” reason for increasing use of disposables was “Decreasing risk of cross-contamination” (75%). This was in contrast to biotherapeutic developers’ top reason: “Reducing time to get facility up and running” (43.2%).
CMOs and developers are expected to differ on the primary benefits of using disposable devices, but it’s nonetheless informative to understand their perspectives, as they have contrasting infrastructure requirements, (which is why biotherapeutic developers are relatively more concerned with time and capital investment in facilities).
What’s Holding Back Further Adoption of Disposables?
It stands to reason that biodevelopers and CMOs, with their different business models and resulting concerns, also have different concerns about the adoption of disposables. When we asked respondents to indicate the factors that may restrict their use of disposables, a leading 81.8% of CMOs agreed or strongly agreed that they did not want to become vendordependent (single-source issues), closely followed by the 80% who were concerned about limited scalability over a broad range (such as 2L to 2,000L). Scalability concerns for CMOs are up significantly this year, from just 35.7% last year. The scalability of disposable reactors is a critical tool for late phase/commercial lot production and process characterization increasing focus on this issue this year may be due to perceived or actual penetration of single-use products in late-stage manufacturing.
Beyond those top two factors, CMOs also point to concerns with:
- Breakage of bags and loss production material (72.7%),
- Leachables and extractables (66.7%),
- Already having invested in equipment for their current systems (63.6%), and
- High cost of non-disposable equipment (housing, controllers – also 63.6%)
Fixed, stainless steel equipment is a concern for CMOs because this is not a pass-through cost for them, and therefore impacts their profit margins. Biotherapeutic developers share those concerns, to be sure, but to different degrees. Among developers, top concerns included:
- Leachables and extractables, cited by 81.3%
- Breakage of bags and loss of production (73.6%)
- Material incompatibility with process fluids (69.3%)
- Single-source issues (66.2%).
Remarkably, the most frequently-cited issues affecting CMOs are related to supply and implementation, rather than to quality or direct cost concerns. That speaks to the focus placed by CMOs on producing the biologic in a time-effective manner, whereas end-users usually support the product beyond its production alone. Vendors are making efforts to put in place significant quality systems and testing strategies to minimize customer losses, which could ease quality concerns. But as disposable technology matures, there is an increasing concern about single vendor dependency, which needs to be addressed using back-up vendor substitution, which takes time and investment
Single Most Critical Reason for Restricting Use
When we asked both groups of respondents to identify the single most critical reason for not increasing the use of disposable technologies this year, we found broader agreement between both parties.
While L&E did not make the top of the list for CMOs when we asked them to identify the factors of concern, it leapt to the top of the list when we asked them to narrow down their concerns to a single area, and by a significant margin at that. In fact, a whopping 65% of CMOs named this as their most important reason for not increasing use of disposables.
Concern over L&E might also be a reflection of the transition of disposable products into later phases of clinical development over the last few years. L&E requires comprehensive studies to quantify and define control strategies for these impurities, which might vary from vendor to vendor. Having uniformity and consistency of quality standards and data from vendors will assist in mitigating the customer’s concern. Notably, CMOs indicate more concerns with costs than do biodevelopers: 10% said that the high cost of disposables was their single greatest concern, versus 4.3% of developers. However, the fact that 10% or fewer in each group felt cost was their biggest concern points to the relevance and value of single technologies to this industry.
Summary
Data from our study clearly indicates that single-use applications remain very important among both CMOs and biotherapeutic developers, but that their different business models contribute to significant variances in their perceptions of these products.
Many CMOs are concerned with time and cost-effectiveness of the products, though when it comes down to it, they are ready to pay for their favored products, such as disposable bioreactors. Many of the study results point to a shift within the market, whereby both CMOs and biodevelopers are increasingly focusing on benefits – and concerns – that are more apparent with the further adoption of these devices in the later stages of biomanufacturing.
In general, as cost concerns are not the top factor restricting further adoption of disposables, we can expect that penetration of these devices will continue to increase both amongst CMOs and biodevelopers. In addition, as leachables and extractables guidance for testing is established, particularly at commercial scale, the industry will feel even more comfortable with introducing these applications in the later stages of biomanufacturing
References
- 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2013, Rockville, MD www. bioplanassociates.com/10th
Survey Methodology: The 2013 Tenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from over 300 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 29 countries. The methodology also included over 180 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.
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. He can be reached via e-mail at [email protected] or by phone at 301-921-5979. www.bioplanassociates.com