Bioprocessing efficiency continues to improve, finds BioPlan Associates in its newly-released 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production.¹ Results suggest that biomanufacturers are prioritizing manufacturing efficiency and using a number of different ways to boost productivity.

This year, we asked global respondents to identify the single most important trend or operational area that the industry must focus on. By a clear margin, the priority was “a greater focus on manufacturing efficiency and productivity.” One in five respondents cited this as the single most important trend of the year, ahead of others such as biosimilars/biogenerics (14%), the implementation and integration of single-use systems (11%) and manufacturing cost reductions (10%). The industry believes that manufacturers and their suppliers need to increase their efforts to produce more, do it more quickly, and do so with fewer resources.

Improving Biomanufacturing Performance
With the emphasis on efficiency and productivity, we examined the factors contributing to performance improvements.  Grouped at the top are two leading factors: “Overall better control of processes,” cited by 73% of respondents as creating improvements; and “Use of disposable / single use devices,” cited by 72%. Roughly 6 in 10 respondents also attribute improvements to optimized cell culture processes, and better process development, with improved upstream (59%) and downstream (57%) operations also in the mix.

We analyzed the changes during recent years in the factors that are credited with improving biomanufacturing performance. Some of the areas where we found significantly more respondents this year include:

• “Overall better control of process”: 73% this year, vs 71% in 2013
• “Use of disposable bags / single use devices”: cited by 72%, up from around 67% during the prior 4 years
• “Better Design of Experiments (DoE), in process development:” 55%, up from 51% last year; and
• “Better operations staff training”: cited by 53%, up from 49% last year.

These areas showed appreciable increases; all other factors surveyed were cited by fewer respondents than last year or years prior. Apparently, the increased attention and investments being made in bioprocessing operations are having an impact. But it is significant that of the 15 factors identified, at least one-third of respondents reported improvements in all but one. This further confirms that bioprocessing, including its diverse processes and associated services, continues to improve.

Gains attributed to better control of process and up- and downstream bioprocessing could be the result of increasing budgets. In last year’s study, survey respondents indicated that they would be increasing their process development budgets by an average of 5.5%, the largest percentage increase of any area measured. 2 Not far behind were planned spending increases on new technologies to improve efficiencies and costs for both upstream and downstream production (4.9% each).

Although budget expectations this year have tampered down slightly, these areas are still seeing planned increases, with process development (4.4%) and upstream (4.2%) and downstream (4%) production operations at or near the top of respondents’ budget plans.

For CMOs, Disposable Applications Are Most Beneficial
We evaluated the differences in how biotherapeutic developers and CMOs perceived key performance factors. In almost each instance, CMOs were more likely to report performance improvements than biotherapeutic developers.  Indeed, of the 15 areas identified, biotherapeutic developers were more likely to see improvements from only 2: Improved upstream production operations (59% crediting with “significant” or “some” improvements, compared to 56% of CMOs); and more automated control of processes (45% vs. 33%, respectively).

For their part, CMOs were especially more likely to attribute improvements to: 

• Use of disposable/single-use devices (83% vs. 71%);
• Improved downstream production operations (72% vs. 55%); and
• Better Design of Experiements (DoE), related to process development  (72% vs. 53%).

In fact, use of single-use devices was the area credited by the most CMOs with improving biomanufacturing performance.  

Improving Downstream, the Persistent Bottleneck
CMOs’ use of disposable applications to improve productivity also ties in with their improved downstream production operations. Our annual survey continues to show downstream processing being the primary remaining bioprocessing bottleneck; companies are working in different ways to de-bottleneck this issue. And perhaps not too surprisingly, CMOs are more likely than biotherapeutic developers to be turning to single-use devices to improve their downstream operations.

To identify which activities the industry is undertaking to address downstream bottlenecks, we asked participants about specific technologies and actions their facility has actually implemented to improve those operations. We found that for nearly every implementation factor, CMOs report higher levels of adoption. This is a reflection of CMOs’ dependence on efficiency, along with their higher turnover of multiple products and ability to pass on technology implementation costs to clients.

In an effort to predict growth in new technologies, we look to where differences between CMOs and biotherapeutic developers are largest, and to consider those few areas where developers are in front in terms of adoption.

The survey data shows that biotherapeutic developers outstripped CMOs in their investments in downstream process development (36% vs. 18%) and in investigating alternatives to Protein A (33% vs. 18%). But while developers were more likely to investigate Protein A alternatives, it was CMOs who were far more likely to report having switched to alternatives (18% vs. 5%).

Other similarly large discrepancies in adoption favoring CMOs include:
Cycling columns more frequently (72.7% of CMOs vs. 54.1% of biotherapeutic developers); Using or evaluating alternative ion exchange technologies (72.7% vs. 47.5%).

The results suggest that CMOs, by the nature of their profession, are using many different techniques to minimize bottlenecks and maximize capacity from their facilities. In this sense, CMOs more resemble the clinical facilities of product developers which must, by design, be more flexible to handle a diversity of processes. The data also shows that for CMOs, use of disposable applications is being credited with downstream processing improvements, which in turn are leading to overall biomanufacturing performance improvements.

Despite those improvements, downstream processing continues to rile both CMOs and biomanufacturers. This year, respondents were again asked to describe the impact their downstream purification processes were having on their overall capacity. We found that 69% of respondents (vs. 76% last year, 72% in 2012, and 69% in 2011) reported at least some degree of capacity bottleneck at their facility as a result of downstream processes.

In fact, the impact of downstream bottlenecks may be on the rise. We found a year-over-year increase in both the proportion of respondents experiencing “serious bottlenecks today” (8% vs. 7%) and “some bottleneck problems” (37% vs. 29%). By contrast, the percentage expecting “no bottlenecks” remained relatively flat at 23%. Downstream issues and production constraints appear to be a chronic complaint.

The percentage of CMOs and biodevelopers reporting “serious” or “some” capacity problems due to downstream processing both increased from last year. While no CMOs reported “serious” bottlenecks today, 6 in 10 claimed to have had “some,” the highest level since our 2009 study.

CMOs’ experiences are often harbingers of what’s to come. If this year’s large increase in downstream-blamed bottlenecks is indeed a leading indicator in bioprocessing efficiency, this suggests a trend that downstream problems will be further increasing for developers too. In the context of CMOs having to work with many more products, it would not be surprising if they reported higher downstream bottlenecks and concerns. But it is the nature of CMO business not to assume tasks for which they lack needed resources.

It seems clear that CMOs are taking the lead in evaluating new technologies. Our study separately found that CMOs were considering a range of new downstream processing solutions at a greater rate than their biotherapeutic developer counterparts. Those include a host of disposable applications, including various single-use filters, disposable UF systems and single-use prepacked columns. Similarly, when we surveyed new product development areas of interest, CMOs were more vocal in their interest in the majority of areas, with disposable purification in particular emerging as one of their key interests, indicated to be among their Top-Five by a majority of CMO respondents. So while CMOs reported more widespread capacity bottlenecks than biotherapeutic developers this year, CMOs are actively searching for and trialing new technologies with the potential to improve productivity. 

What’s Next in Bioprocessing Efficiency
The industry is maturing and now finds itself acutely aware of the need for new technologies to optimize, and in some cases revolutionize existing processes. Yet, while end-users still actively look for new technologies to solve persistent problems, these changes are underpinned by very specific needs. Approaches that shorten the time to get facilities up and running and reduce capital investments are mandatory for new facility design. Similarly, the industry is demanding better downstream processes—demands that generally focus on cheaper and more effective chromatography and purification steps.

The biopharmaceutical industry—and CMOs in particular—are continuing to invest in improved manufacturing methods, particularly concerning process control and optimization. Surprisingly, responses to these questions varied between product manufacturers and CMOs, with the former reporting more frequent implementation of process-related improvements. One might expect CMOs, with their high project turnover and need to do it right quickly and the first time, to be out in front of product manufacturers in terms of implementing process improvements. But many CMOs prefer to standardize their bioprocessing, and many follow the regulatory and manufacturing-related requirements of their clients.

CMOs are leading the way in disposables adoption, though, and appear to be satisfied with the results, crediting their disposables use with significant improvements in downstream processing and overall biomanufacturing performance. As single-use applications continue to penetrate biopharmaceutical manufacturing and the market for these applications mature, a number of trends can be expected:

• More quality will be built into single-use systems to attempt to further reduce regulatory activities and oversight;
• More single-use downstream operations will include membrane adsorbers;
• Better standards for leachables and extractables testing will emerge; and
• Problems surrounding disposable devices that are creating inconsistent growth due to changes in resins and cell line specificity, among others, will be addressed.

One can reasonably expect CMOs to continue at the forefront, pushing these changes—and benefiting from them. 

References

1. 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production:  A Survey of Biotherapeutic Developers and Contract Manufacturing Organizations, BioPlan Associates, April 2014. www.bioplanassociates.com/11th

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Eric S. Langer
BioPlan Associates, Inc.

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.  elanger@bioplanassociates.com  301-921-5979.  www.bioplanassociates.com