The biopharmaceutical industry has seen dramatic improvements in upstream manufacturing yields over the past 30 years. However, increased efficiencies in upstream operations have contributed to downstream bottlenecks, as these filtration and purification operations have failed to keep pace with upstream developments.
Indeed, according to preliminary results from our industry study, 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, a majority of biotherapeutic developers continue to suffer capacity constraints as a result of downstream processing. More than seven in 10 respondents (biomanufacturers, excluding CMOs) report experiencing at least minor problems attributed to downstream processing, including more than four in 10 experiencing more serious bottlenecks today.
This is certainly not a new problem: Downstream processing has impacted capacity and overall production for upwards of six in 10 biomanufacturers and contract manufacturing organizations (CMOs) surveyed.
There’s obviously a lot to be gained from improving downstream operations. Separate results from our survey indicate that the impact of improved downstream production operations on biomanufacturing performance at respondents’ facilities over the past year has been on par with the impact of respondents’ use of disposable/single-use devices. In past years, improved downstream production operations have also been in the top half of factors creating improvements at respondents’ facilities.
HOW TO IMPROVE DOWNSTREAM OPERATIONS
As part of our study, we measure the ways in which organizations tackle the problems associated with downstream processing, asking them which of 19 specific actions they have implemented in the past year to improve downstream purification operations.
So far this year, the top five reported activities are:
• Optimizing running conditions (62%)
• Used ion exchange membrane technologies (45%)
• Used membrane-based filtration technologies (44%)
• Cycled columns more frequently (41%)
• Developed downstream processes with fewer steps (41%)
These are similar to biomanufacturers’ responses last year, although results to date this year suggest that companies have been more likely to optimize running conditions.
NEW DOWNSTREAM TECHNOLOGIES IN CONSIDERATION
Aside from tracking the activities implemented by the industry to improve downstream operations, we also measure the new downstream purification (DSP) technologies that respondents are actively considering to address production issues or problems. It’s worth noting that this question only asks about active consideration, indicative of potential future adoption, and as a result does not include those respondents already using these technologies or those considering them but not “actively” pursuing them as an interest.
In our results to date, respondents actively considering at least one of the 22 new DSP technologies we identified were led by Continuous purification systems (60%); Disposable UF systems (48%); and Single-use filters (48%).
This year’s preliminary list of “Most Innovative Downstream Systems” from the 12th Annual Report include:
• Continuous purification systems
• Disposable UF systems
• Single use filters
• Use of high capacity resins
• Single use disposable TFF membranes
• Membrane technology
• In-line buffer dilution systems
• Buffer dilution systems/skids
• Single use-prepacked columns
• Alternatives to chromatography
• On-line analytical and control devices
• Use of filters instead of resin chromatography
• Moving beds
• 2-phase systems
• Development of MAb Fragments
While these top technologies in active consideration are similar to those seen in last year’s study, survey results to-date suggest a greater interest in continuous purification systems, which were actively considered by only 30 percent of biomanufacturers last year. It’s also notable that roughly one in five biomanufacturing respondents in this year’s study said that they worked with continuous chromatography purification (e.g. simulated moving – SMB) within the prior 12 months to improve downstream purification operations, a figure which would represent a step up from 15 percent in last year’s study.
The apparent increase in active consideration of continuous purification technologies this year is interesting, as development of these technologies tends to have lagged behind advances in upstream continuous bioprocessing, with new bioprocessing methods typically pairing continuous upstream processing with conventional batch purification. The lag in adoption of continuous purification potentially relates to its more complex nature, as many more smaller aliquots requires processing. Adoption of continuous purification may also depend on newer chromatography technologies, which are yet to be ready for mass-market adoption.
We’re likely to see a focus on this area in coming years, though, as new technologies appear that allow for continuous and semi-continuous operation. The excitement generated by these technologies owes to their potential to enable a jump in the titers processed by downstream operations. Should this come to pass, we could expect to see smaller, more modular and disposable downstream facilities be constructed, ultimately leading to fully disposable facilities, which are currently constrained by the lack of downstream options. Despite their promise, though, we do not foresee continuous purification technologies reaching widespread use at commercial scale this decade.