December 1, 2015 (Vol. 35, No. 21)
Eric S. S. Langer President and Managing Partner BioPlan Associates
When Will Technologies Be Fully Realized?
Few biologics today are made using continuous bioprocessing (CBP) equipment but technologies are being developed that improve and link upstream bioreactors with downstream purification strategies.
Displacing manufacturing processes used for existing commercial biologics is difficult, yet data from our 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production indicate a significant percentage of biomanufacturers are now evaluating newer continuous technologies for their pipeline and clinical-scale biologics.
Continuous upstream bioprocessing is not new, with fiber-based perfusion bioreactors already widely used for classic fused-cell hybridoma culture back in the 1980s, before this technology was replaced by recombinant antibody manufacturing methods.
Continuous processing involves an assembly line, vs. episodic manufacturing processing that currently dominates fed-batch processing. Rather than one process step being done, and materials then moving to the next step, continuous processes operate for much longer periods at lower levels of productivity (smaller scale) with continuity in flow of materials from one process to the next.
Currently, less than 10% of commercial biopharmaceuticals are reported as manufactured using perfusion bioreactors. Some leaders in CBP implementation are Genzyme and Bayer. Amgen recently opened an integrated $200 million CBP facility in Singapore, and Hemispherx Biopharma is developing a cell cultured immune modulator. Besides recombinant protein and antibody manufacture, continuous bioprocessing also fits well with cellular, gene therapy, and other newer classes of products in development.
There are benefits to CBP. These include reduced costs, increased productivity, improved quality, and greater flexibility.
Facilities and process lines running in continuous mode are generally more cost-effective, with the same or more product manufactured in the same or shorter time period. In addition, continuous bioprocessing can require less infrastructure, utilities, space, investment, and staff.
What’s Holding Back CBP Adoption?
Issues restricting adoption of CBP are surmountable using current technology, but a lack of practical know-how, precedents, in-use data, and industry conservatism are holding back its adoption. Most continuous bioprocessing has involved upstream processes, with continuous downstream purification tending to lag. Thus, it is common for new bioprocesses being implemented to combine continuous upstream processing with conventional batch purification.
Continuous chromatography technologies, such as simulated moving bed (SMB) and periodic counter-current chromatography, are coming, but generally are considered not yet ready for commercial-scale adoption.
In a recent BioPlan study of hurdles to continuous bioprocessing (White Paper; Continuous Bioprocessing: Industry Demanding More Data to Make Decisions), we found that although the level of interest in current CBP technologies is significant, the limited knowledge regarding CBP, economics, and implementation is holding back change. Areas of concern include: operational, product, economic, and regulatory issues, current vs. future technologies, demand for experience and case studies on CBP, comparison of CPB vs. fed-batch, and a complexity image with CBP.
The industry-pervasive views of continuous bioprocessing is that it is complex, based on our annual survey. Key areas where respondents reported perfusion as presenting more concerns (vs. fed-batch) include (Figure 1) process operational complexity, process development control challenges, contamination risks, process development general challenges, and validation challenges.
Increased complexity with continuous processing was perceived as increasing risks in manufacturing that can create very costly, sometimes disastrous operator errors. But in actual implementation, most continuous bioprocessing is likely to be rather fully automated (another advantage of continuous bioprocessing), with errors and operator involvement minimized.
Regarding process development control challenges, if a batch process is changed or improved at small scale, with most having more experience with batch processing and this more established, extrapolation to larger scale is relatively routine.
Risks of contamination of a process were perceived as higher with continuous bioprocessing.
The pervasive attitude toward continuous bioprocessing is likely based on limited information, lack of data, and need for in-use and regulatory experience with CBP technologies. Perfusion and other continuous processes are becoming more user-friendly, less prone to contamination, more regulatory-friendly, and more readily scalable than fed-batch methods.
However, industry perceptions of perfusion/continuous vs. fed-batch are lagging, and likely reflect a lack of direct experience with these technologies.