Downstream bottlenecks are continuing to rack biomanufacturers on both sides of the Atlantic. Yet Europeans appear to be hit more seriously, with almost 1 in 5 Western European indicating that their downstream processing is “seriously” impacting their overall capacity. [1] The data, released in BioPlan Associates’ 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, provides insights into the significant impacts that these bottlenecks are having on facilities’ capacity, and shows that neither biopharmaceutical developers nor CMOs appear to be resolving their issues. In fact, although the percentage of US firms reporting “serious” issues is significantly lower than their transAtlantic counterparts, that figure has more than tripled from 2010.  Our survey, which had responses from 352 global biomanufacturers, asked respondents to consider the impact of downstream processing on capacity and overall production, from a low grade (“I don’t expect a bottleneck”) to a severe problem (“Serious bottleneck today”), and compared the data from US and European biomanufacturers.

 

US vs. European Firms

We discovered that significantly more US respondents are seeing at least ‘some’ bottleneck problems due to downstream processing (45.3% US vs 21.6% Europe).

Even with 2011’s jump, the majority of U.S. respondents seem to have been addressing the most serious, acute problems with their downstream purification issues, but a larger percentage appears to be experiencing chronic bottleneck problems in current downstream processing compared to their European counterparts. Indeed, our data shows that US firms are by no means overcoming downstream bottleneck concerns, particularly with respect to their European partners: Over three-quarters are experiencing at least “minor” issues, compared with just over half of European firms. Also, this year, 14.7% of U.S. respondents are experiencing no downstream bottlenecks, compared with 27% of Europeans. 

The difference between the US and Western European firms – which combined, according to our Top 1000 Global Biopharmaceutical Manufacturing Index™, [2] make up close to two-thirds of global production capacity – is difficult to interpret.  On the one hand it appears that more US firms feel their downstream limitations are chronic, low-level constraints compared with their European counterparts. A large percentage European firms in general feel their bottlenecks are less of an issue; however, some firms appear to be facing serious constraints. This may be a result of the distribution of capacity in Europe, where there tends to be bi-modal distribution, with fewer mid-tier firms. Comparisons aside, our report makes clear that addressing downstream purification concerns is a high priority.

Root Causes

Bottleneck issues in downstream processing arise from increased expression levels at the bioreactor, which have held steady or increased, but have not decreased with new products coming on stream. As our respondents indicated, this leads to issues with column and buffer tank sizes limiting the throughput of the downstream operation. While several suppliers are working on solutions that modify either the process or the equipment to enable greater throughput in the downstream operations, our survey clearly demonstrates that these solutions have not yet put an end to the issue, either because implementation is still in progress or because the cost of implementation still exceeds the cost of the bottleneck.

It is interesting to note that these downstream bottlenecks often come from new products, new processes, or new CMO projects, and not from existing products made by existing processes. That is, bottlenecks appear when a new or revised process is instituted in an existing plant. Most products currently on the market are not subject to process or facility change. According to Donald Mather, Principal Process Development Scientist II at Talecris Biotherapeutics, Inc., the main task involves “reducing cost of goods and cycle time in new technologies, while maintaining quality related to the downstream processing bottleneck.” ^[1] Thus a concern with increased bottlenecks reflects plans to move additional products into production or to upgrade existing production methods, both of which imply industry growth.

Challenges and Opportunities

Downstream challenges continue from previous years: cost of chromatography materials, cost of membranes, and time for operations. Many firms would like to avoid the high cost of Protein A affinity resin, but most are reluctant to make changes to existing processes. Opportunities to address these issues include developing downstream processes with fewer steps; more durable media that support more purification cycles; less expensive media; higher capacity media; media of increased selectivity; and, some day a single-use medium.

Chromatography, as the major method for large scale protein purification, takes a leading role in downstream processing and remains the major hurdle in overcoming bottlenecks. While our report shows that chromatography resins have benefited in recent years from improved dynamic binding capacity, improvements to chromatography operations have not kept pace with the dramatic improvements in bioreactor expression levels. This disparity is reflected in the responses shown in the figure below, where nearly 75% of the respondents describe chromatography steps as limiting capacity.

Bottleneck Impacts

This year, respondents to our survey clearly indicated that downstream purification was the top area in need of improvement to address capacity constraints, with better disposables and more standardized international regulatory processes also seen as major factors for removing bottlenecks.

We asked our respondents to provide some general comments regarding the impact on their overall capacity that downstream performance was creating. These included:

• We do not have suitable equipment to speed this area up – but we’re working on it;

• We need multiple [downstream purification] trains;

• We need better affinity columns (protein A);

• Downstream capacity problems are due to high titers;

• Problems arise from rate and frequency of column operations (Resin cleaning validation);

• The problem is buffer capacity and need for in-line dilution;

• New separation equipment will be needed, but this is already planned for;

• The problem is just our chromatography column sizes and buffer and product tank sizing.

• Titers greater than 3 g/L will be difficult to process with existing equipment/ technology;

• Buffer prep and hold is issue at higher titers – can cycle columns more, but buffer is linear with titer;

• Problems are related to process staff teams and numbers, not plant capacity;

Conclusions

Downstream processing continues to be a bottleneck for many facilities around the globe. Severity of these constraints may be more a function of plant operations than geography. The differences in results in our study between US and Europe, we believe, reflect these variations.  In summary, the results of our 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production show that a majority of manufacturers are experiencing productivity bottlenecks, possibly as a result of current expansions in the production of monoclonal antibodies that require costly downstream processing equipment and consumables. Reducing the number of purification steps is one way companies are attacking the problem. But that can only go so far. The problems experienced by downstream operators remain largely the same as in previous years – yet while there are many new technologies under investigation, and being “actively considered,” few are being actively implemented, yet.

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 8, 2011

 

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

Survey 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.