Over the past few years, significant increases in protein expression levels have resulted in shortages in the separation, filtration and chromatography capacity required to purify biopharmaceuticals downstream.

Avoiding downstream bottlenecks is a key challenge to ensuring adequate biopharmaceutical supply, and manufacturers and technology vendors alike are evaluating new options for improving downstream efficiency.

This article summarizes results from BioPlan’s Ninth Annual Report and Survey of Biopharmaceutical Manufacturers, from the standpoint of downstream capacity. This year’s results suggest that downstream shortages have eased somewhat, moving from being an “acute” to a “chronic” problem. Nevertheless, they continue to have an impact on budgets and overall manufacturing.

Examining results from the past few years, we see that, this year, more respondents (71.9% vs. 68.5% last year) feel that their facilities are experiencing at least some degree of capacity bottleneck as a result of downstream processes. That is the largest percentage since 2009 (74.5%), and is partly the result of continuing upstream improvements, without concurrent downstream fixes.

However, by breaking down these responses, we can also identify trends in the severity of the problem. Our study shows that 8.5% of the 302 global biopharmaceutical manufacturers surveyed are experiencing a “serious” bottleneck due to downstream processing. The extent to which downstream processing has contributed to serious bottlenecks has varied over the years — in 2008, a low 4.6% of respondents said this was the case; last year, 11.8% said the same.

Although relatively few in the industry are experiencing “serious” bottlenecks, the industry continues to see “some” (37.8%) or “minor” problems (25.6%) due to downstream processing. We note a definite upward trend in the percentage of respondents who see minor problems (up from 19.1% in 2008 to 25.6% this year). At the same time, there appear to be minor downward trends in the percentage who don’t expect a bottleneck (from 21.7% in 2008 to 17.1% this year). In addition, the percentage who don’t have a bottleneck but expect one in the next year declined from 14.5% in 2008 to 11% this year). Taken together, these results suggest that the respondents who previously were not experiencing a bottleneck or not expecting one are now seeing minor problems from downstream processing. There are both good and bad connotations to this: Obviously, the trend toward more widespread capacity constraints is disturbing; but it is encouraging that facilities newly experiencing problems are saying they are minor, rather than more severe issues.

Our survey suggests significant differences in impact when sorting by business model and geography. For instance, Western Europeans appear to be somewhat less concerned by downstream processing than American respondents. This year, slightly more than 4 in 10 (40.7%) European respondents said they were not experiencing any bottlenecks due to downstream processing, more than double the proportion of Americans (17.1%). Over the past 5 years, the proportion of Western Europeans not expecting any bottlenecks has grown from 11.1% in 2008 to 29.7% this year, while the percentage experiencing “serious” capacity problems has shown a correspondingly large decline. American respondents have indicated the reverse pattern, suggesting that while problems remain on both sides of the Atlantic, Americans’ struggles are growing at the same time as Europeans are beginning to resolve their issues.

There are also differences between biotherapeutic developers and contract manufacturing organizations (CMOs). Over the years, the percentage of biodevelopers experiencing “some” or “serious” bottlenecks as a result of downstream processes has gradually risen, from 42.5% in 2008 to 50% this year. Concurrently, the proportion of CMOs indicating these levels of constraint has seen a dramatic drop, down from 68.8% in 2008 to just 25% this year (with none of those 25% being serious problems). This is good news for the industry: If CMOs — who have strong interests in improving throughput — are reducing the problems, it is likely these performance improvements will impact biodevelopers in the near term as well. That is, if CMOs’ experiences are a leading indicator of bioprocessing efficiency, the overall trend towards increased problems may soon level off.

What is the Industry Doing About It?
New downstream technologies are emerging as the industry focuses on alternatives. However, in the near term, many of the incremental improvements, such as streamlining processes and eliminating purification steps, have reduced the urgency for innovative technologies in this area. Prior year studies showed that respondents believed they were faced with a relative lack of options beyond membrane technologies. This is also changing, as new technologies are being introduced. The industry is likewise shifting its assessment of different solutions.

This year, we identified 19 different new downstream purification technologies being considered. The most commonly mentioned bottleneck and DSP problem being disposable UF systems (47.1%); buffer dilution systems/skids (42.6%); and use of high capacity resins (41.2%). Closely following were in-line buffer dilution systems, single use disposable TFF membranes, and single-use filters. On the other end of the spectrum, few are looking at solutions such as alternatives to chromatography (19.1%), precipitation (13.2%), moving beds (8.8%), and small substrates (2.9%).

Interest in some technologies has grown steadily, while it has dropped off for others. The following are some technologies in which the industry has showed significant interest over the past few years: disposable UF systems, buffer dilution systems/skids, single-use disposable TFF membranes, single-use prepacked columns, membrane technology and development of MAb Fragments.