Demand for Innovation: Disposable Devices Top the List in 2011

Source: 8th Annual Report and Survey of Biopharmaceutical Manufacturing, April 2011, BioPlan Associates, Inc. www.bioplanassociates.com We also evaluated the trend in demands for new products from vendors, and found some significant shifts. Interest in better innovation in disposable, single-use devices for measuring and monitoring (probes, sensors, etc) jumped from 29.3% of respondents in 2010 to 37.0% this year. Relatively few of these products are currently available and there are often issues regarding ports and how to pass disposable sensors through bioreactors and other vessels and their bag liners. Meanwhile, improved disposable purification products, which led all areas this year at 37.9% of respondents, showed modest growth from last year’s 34.9%. While this was the area where users most desired improved single-use products, the result was not a surprise. Improvements in upstream manufacturing have greatly enhanced yields in recent years, largely as a result of improved cell lines and expression systems. However, downstream purification processes have scarcely changed and are increasingly the limiting factor in commercial-scale biopharmaceutical manufacture. Also, purification, including chromatography columns and media, with different steps and equipment, can be time-consuming and expensive. Interest in disposable bags, connectors, and other such products modestly decreased from 2010 (36.5% this year, compared to 38.9% in 2010), but remains high on the list of desired innovations. Possible innovations such as unitary (single-piece) molded plastic bioreactors could offer advantages, including in performance and reduced costs, over adding expensive plastic bags/liners to expensive stainless steel bioreactors and other containers. However, the predominant single-use paradigm continues to be adding multi-layer plastic laminate bags/ liners to what are essentially classic-design stainless steel bioreactors, mixers and other fluid containers. Many of the key vendors are committed to this approach, and some have recently invested in costly bag-making manufacturing facilities. These companies will be dedicated to current product lines and this paradigm for years to come. The problem with this approach, along with a host of other current single-use equipment designs, is that they curb opportunities for innovation and new product introductions. Once initiated, vendors are effectively unable to significantly upgrade existing product lines. Furthermore, incremental product upgrades risk seriously distressing their existing customers, particularly if current products are phased out. Indeed, bioprocessing product changes require considerable expense and work, including modification of regulatory filings, SOPs and training, and perhaps most discouragingly, potentially requiring another round of validation testing. The approximately $100,000 price tag for testing of devices with significant product contact (required for approvals) stands as a major deterrent. Interest in assays grew significantly this year, from 24.5% of respondents in 2010 to 31.1%, in line with a trend expectation from the industry, which sees more and more automated assays being implemented to achieve higher quality and consistency.[1]  However, some of last year’s key new product areas declined in interest among respondents. These include: chromatography products (37% down to 30%) and process development, both downstream and upstream (35% to 27% and 25% to 19%, respectively). This lessening of concern for new bioreactor products may be related to the emergence of some interesting innovations, which have sparked recognitions such as PBS Biotech’s recent honoring as Business of the Year by Pacific Coast Business Times. In particular, small scale single use bioreactors, with traditional impeller designs like NBS or Millipore’s, have begun to fill some of the gaps in the disposable bioreactor market. This is an example whereby the available “bag design” bioreactors did not meet customers’ needs, and a creative alternative emerged. In some business models and specific situations, small scale bioreactors will replace bag design. Even so, according to Robert Repetto, Director of Technology and Innovation at Pfizer, “it will not revolutionize the bioreactor market, as its scope is too limited to be disruptive to the industry.”[1] Additional areas of general interest to respondents, both this year and last, where increased attention to new product development was desired, include:

• Online monitoring and control
• Improved quality and consistency of materials 
• Energy efficiency 
• Quality control and consistency 
• Reliability/robustness of analytical equipment 
• Instrument accuracy and reliability.

CMOs vs Biotherapeutic DevelopersWe measured the differences in demand for new, better products between biotherapeutic developers and CMOs, and found some significant variances. A considerably larger percent (57%) of CMOs want better disposable devices such as probes and sensors, almost 23 percentage points higher than biotherapeutic developers. Whereas, in the previous year, CMOs saw disposable products: bioreactors and purification as the most significant areas of interest, this year chromatography was on par with purification as the second leading area. It also was notably more sought after by CMOs than biodevelopers, by a margin of over 10%. Biomanufacturers continue to be more interested in assay development (33% vs 21%). However their interest in analytical development only produced a 2% difference in comparison to CMOs. Services (validation and process development) were of significantly greater interest to biomanufacturers than CMOs. This is not unexpected, since CMOs have many more product campaigns in process, and typically must have competent staff available. Biomanufacturers were also slightly more interested in cell culture media, which is a reversal from last year, when CMOs expressed a slightly larger interest in this area. At the bottom of the list, we found that not a single CMO sought new product developments for stainless steel.Regional PreferencesThe study also compares the differences between respondents in the US to those in Western Europe and the “Rest of World.” In this analysis, we found some noteworthy divergences in opinion. For example, more US biomanufacturers are expecting vendors to provide new products in areas such as disposable product: probes, sensors, controllers, instrumentation, and reagents and supplements. Meanwhile, Western European biomanufacturers and CMOs are substantially more interested in seeing solutions in chromatography than the other geographic regions, and are also more partial to new disposable product purification and separation products. Countries outside of the traditional US and Western European markets continue to seek better services, including analytical development, cell line development, and validation services. In addition, this year, those countries have shown a greater interest in process development, upstream and downstream. This is not unexpected, as the technology flow to lesser developed countries can come via process development and other service offerings. Even so, as these other regions gain prominence within the global market (see www.top1000bio.com [2]), their preferences will increasingly shape industry attitudes and innovations.What Works?Innovation in single use devices is clearly an area of interest in 2011. When examining the demand for new products and services, it is important to consider to what extent existing innovations have contributed to improvements in bioprocessing performance. To gain a better idea of this, we asked respondents what factors have created such improvements: specifically, “How much has each of the following improved biomanufacturing performance at your facility over the past 12 months?” The top 6 out of 7 areas for implementation of improvements involved process development, operations and control. This is in line with the industry’s current concentration on increasing productivity, particularly in manufacturing. The largest portion of respondents, at 72.6%, cited overall better control of processes. This was followed by improved downstream operations, at 67.7%. Two-thirds of respondents mentioned better process development, while 65.5% cited use of disposables/single-use devices. This suggests that the current demand for new single-use products is related to actual improvements experienced by respondents. Figure 2: Selected Factors Creating “Significant” or “Some” Improvements in Biomanufacturing Performance

Source: 8th Annual Report and Survey of Biopharmaceutical Manufacturing, April 2011, BioPlan Associates, Inc. www.bioplanassociates.com For the most part, respondents’ attitudes remained steady in comparison to 2010. The area that experienced the largest shift was operations staff training, which dropped 13%, from 60% in 2010 to 47% this year. Other areas that showed the largest shifts from 2010 were optimized media and improved existing quality management systems (QMS). On the other hand, overall better control of process, use of disposable/single use devices and improved upstream production operations all decreased by a modest margin from 2010. CMOs and biotherapeutic manufacturers differed considerably in their responses. CMOs overwhelmingly reported performance improvements from use of disposable/single-use devices, at an astounding 86% (compared to 63% of biomanufacturers). Surprisingly, developers reported more frequent implementation of process-related improvements. For example, 68.4% of biomanufacturers signaled that better process development had contributed to improvements, compared to 58.6% of CMOs. This is somewhat unexpected, given that CMOs have a high project turnover and are under constant pressure to get things right the first time. However, it may relate to increased FDA concerns and fallout from major pharmaceutical manufacturing failures such as Genzyme, which have put them under the spotlight. By contrast, there have been few widely publicized CMO failures, and their focus on smaller-scale manufacturing leaves them less prone to strict regulatory requirements.In comparing responses by region, the use of single-use devices was cited for improvements more often by the US and Western Europe, with just 55% of “Rest of World” countries attributing improvements to this factor. This may reflect European customer purchases or vendor marketing catching up with those in the US, while much of the ROW may not yet be heavily implementing single-use systems. Looking AheadThe industry this year and next should see a number of innovations in single use devices, from bags, to bioreactors, to tubing and connectors. Many of these products will be targeted to replace silicone, including PVDF (inert Teflon-like fluorinated polymer)-lined tubing and polypropylene-PVDF and other thermoplastic blend tubing. Materials-based innovations and new, improved, product designs enabled by these are needed for single-use bioprocessing to become more cost-effective and to support single-use/disposable equipment being adopted for manufacture of commercial products. Beyond these projected advances, few highly innovative products, such as commercial-scale perfusion bioreactors and new single-use bioreactor designs with ≥2,000 L capacity, have been introduced, and this seems unlikely to change in the near term. There seems to be broad recognition that the development of new materials, particularly new and improved plastics and variations of current plastics that might enable major design innovations, are needed. Yet, the major players that dominate the single-use/disposable bioprocessing systems market have committed to current product lines for at least a few years. In the meantime, they may see little incentive for introducing paradigm-shifting product lines. Innovations in single-use equipment, particularly in novel technical devices such as bioreactors, may instead be more likely to originate from small companies or new major corporate entrants. Many respondents’ wishes for improved single-use equipment may in fact represent a desire for decreased cost of this equipment, along with obvious improvements in productivity. This may open the door for lower cost producers, or those able to provide more functionality, quality, or validation support at the same price.References:1. 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production:  A Survey of Biotherapeutic Developers and Contract Manufacturing Organizations, BioPlan Associates, April 2011, 490 pages.2. See BioPlan’s Top 1000 Global Biopharmaceutical Facilities Index™, http://www.top1000bio.com/index.asp Accessed August 20, 2011About the Author: 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.comSurvey Methodology: The 2011 eighth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production in the series of annual evaluations by BioPlan Associates, Inc. yields a composite view and trend analysis from 352 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 31 countries. The methodology also encompassed an additional 186 direct suppliers of materials, services and equipment to this industry. This year's survey 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.