Problems associated with affinity purification in antibody production continue to increase as upstream cell culture expression levels improve. As a result, many vendors and users in the biopharmaceutical industry are working to identify alternative technologies that can replace tried-and-true column chromatography.
In the fifth annual report and survey by BioPlan Associates, 434 global respondents pointed to bottlenecks created by downstream processes as one of their most serious manufacturing problems today (1). Amost two-thirds (63.8%) said their facility is experiencing some degree of bottleneck. This problem has been growing over the past five years.
Problem AreasRespondents identified 14 different areas in which their facilities face significant downstream production problems. The top area, noted by nearly 47%, was column chromatography. That was followed by process optimization (33.1%) and validation (28.3%). To produce greater quantities of biologics in existing operations, companies need to remove the bottleneck by improving recovery, raising capacity for chromatography resins, and changing to alternative processes that have higher throughput.
Planning for Downstream Bottlenecks: How should companies plan to handle downstream bottlenecks, particularly considering that many survey respondents expect the problem to increase in the future? This planning issue hits most organizations twice: first from the inability to make sufficient product in a current facility and second from the cost of downstream processing and cost-cutting pressures.
Biopharmaceutical Developers and CMOs: The effect of increased upstream yields in creating purification bottlenecks is particularly felt by contract manufacturing organizations (CMOs). This may be because many CMO facilities were constructed when downstream processing areas were matched to lower-yielding upstream processes.
The survey showed that substantially more CMOs than biopharmaceutical developers are experiencing capacity bottlenecks. Of CMO respondents, 68.8% (compared with 42.5% of biopharmaceutical developers) said that downstream processing was causing “serious” or “some” bottlenecking today. All CMOs expect to see at least some kind of bottleneck as a result of downstream purification over the next 12 months.
United States and Western Europe: Although both US and European respondents said downstream processing was affecting their overall capacity, more European than US respondents indicated they were experiencing bottleneck problems (47.2% of European compared with 35.3% of US respondents). Further, nearly a quarter (23.5%) of US biomanufacturers are experiencing no bottlenecks — compared with just 11.1% of western European biomanufacturers.
Downstream Process AlternativesOne logical consequence of these pressures is a desire to move away from expensive protein A as an affinity chromatography ligand. The survey showed general agreement that downstream purification issues are important and are changing production processes. Nearly 52% of respondents said that higher upstream productivity has forced significant changes to their downstream processing facilities. More than 46% are considering alternatives to protein A to reduce costs in new production projects. At present, however, only 19% actually plan to move away from protein A for new production projects within the next 12 months.
A scarcity of potential solutions to the challenges of increasing capacity and lowering costs of downstream processing make shifting to alternatives difficult. For the time being, many industry experts predict that we will have to live with the high cost of chromatography, particularly protein A. Because of regulatory concerns, end-users may not be pushing for alternatives with the gusto of those in less-regulated industries. Few companies want to be first to seek regulatory approval for a new idea.
Next Breakthrough Technology: With relatively few real options open for breakthrough technologies, many survey respondents said that incremental improvements in chromatography will take place. But that will not provide the doubling or tripling of capacity to match the upstream changes.
Respondents were asked to indicate areas in which they believe major improvements in downstream purification will occur by 2012. Both this year and last, those responding indicated membrane technology as the area most likely to see major improvements for downstream purification over the next five years. Following that were the development of MAb fragments and the development of synthetic proteins.
Opportunities for Improvement: The overall conclusion is that there are opportunities for improvement as we face the challenges in downstream processing. For the moment, however, both drug innovators and vendors seem to be in a holding pattern, waiting to see what the next major technical advances will be.