By Eric Langer, president and managing partner, BioPlan Associates, Inc.
Batch processing, both up- and downstream, has long been the dominant bioprocessing paradigm. Bioprocessing fluids are piped and transferred as a batch from one holding vessel or process equipment to the next. This finish-one-stepand- move-on-to-the-next approach works rather well, and advances over the years have resulted in a lot of experience and data. In fact, upstream and overall process yields have tended to double about every five years.
However, batch processing is not the norm in most other major product manufacturing industries. Outside of the biopharmaceutical industry, manufacturing processes tend to be continuous. This is exemplified by assembly lines and petroleum refining, where processing involves a continuous flow from one unit of operation to the next. Continuous bioprocessing for upstream operations in the pharma industry is often defined as the process of running a bioreactor at a fixed volume and fixed cell concentration for 30 to 90 days (or longer) with a constant flow of cell culture media, giving a constant harvest volume to be processed. According to some observers, within 15 years, continuous processing will become the prevalent bioprocessing platform. It’s interesting to note that continuous processing tends to be employed in more mature industries. And with recombinant proteins marketed only since the early 1980s, the biopharmaceutical industry is just now being considered mature enough to move toward continuous vs. batch processing.
From our 10th Annual Report and Survey, Figure 1 shows the likelihood of specifying a perfusion bioreactor by biomanufacturers. Here we can see that single-use, perfusion bioreactors were indicated by a quarter of respondents for commercial applications and nearly a third for clinical-scale bioprocessing. This is only slightly higher than the responses to this question in 2012. But the trend is clearly continuing.
Fed-batch cell culture, involving fully loading, running, then emptying a bioreactor, has been the dominant method for decades. This batch processing requires larger equipment that costs more, takes up more space, and requires more robust infrastructure, utilities, and labor. The process is sporadic and uneven. In contrast, continuous bioprocessing allows more predictable steady manufacture of the same or more product at smaller scales with associated cost-savings and benefits.
Continuous bioprocessing, particularly perfusion — its upstream implementation — is currently experiencing relatively rapid adoption. With perfusion, bioreactor harvest is withdrawn continuously, simplifying downstream operations and allowing purification to be done more repetitively at smaller scales, with fewer, smaller holding tanks. Most adoption of continuous bioprocessing has involved upstream perfusion, while adoption of continuous downstream purification operations is proving more difficult, with fewer technology options, and is lagging behind. Continuous chromatography methods, such as simulated moving bed (SMB) and periodic countercurrent chromatography, are generally not quite ready for widespread adoption.
But commercial products have been produced for years using elements of continuous processing. So this is not a novel area. Examples of products currently manufactured using perfusion bioreactors include Kogenate (factor VIII) from Bayer Schering, ReoPro (anti-platelet mAb) and Remicade (tumor necrosis factor mAb) from Centocor/J&J, Campath (CD52 , mAb) from Genzyme/ Sanofi, and Xyntha (a modified factor VIII) from Pfizer.
The current leading perfusion technology in terms of adoption is the alternating tangential flow-based (ATF) system from Refine Technology. At a 500 kg/ year commercial manufacturing level, using single-use equipment, annual upstream bioprocessing costs are projected at $33.1 million for perfusion vs. $106.7 million for fed-batch. In comparison, stainless steel-based costs are $44.1 million for perfusion and $103.9 million for fed-batch manufacture. These figures suggest that perfusion technologies will see increasing consideration in coming years.
Problems that have restricted wider adoption of continuous bioprocessing and, particularly, perfusion, include misperceptions and lack of knowledge within the industry. In 2011 our survey of bioprocessing professionals documented this. The industry continues to associate perfusion/continuous processing with greater difficulties. “Process complexity” was the primary concern, cited by 66.4 percent. Given a list of 17 problems encountered in bioprocessing, respondents consistently rated all of these as significantly more serious concerns with perfusion than with batch-fed systems — even though this is often not the case. In fact, perfusion/continuous processing now tends to be generally less complex, less prone to contamination, and more readily scalable than fed-batch methods. These fears and growing pains include addressing concerns of regulators who have yet to fully understand some aspects of this technology, such as defining lots/batches and doing QA/QC with continuously manufactured products.
The Future Of New Perfusion Technologies
New perfusion technologies may ultimately mature and revolutionize bioprocessing. For example, a 50 L bioreactor with cells bound to capillary fibers in development by FiberCell will be able to manufacture the same quantity of product, at better quality, than a 1,000 to 5,000 L bioreactor over the same time period using the same amount of culture media. Similar bioreactors were in common use for hybridoma (non-recombinant monoclonal antibodies) manufacture back in the 1980s. So increasing adoption in coming years will actually be nothing new. Much of the adoption of perfusion will be associated with single-use equipment, particularly as current products being developed by single-use manufacture graduate to commercial manufacture.
Likelihood Of Implementing Bioreactor (By Type)
Survey Methodology: The BioPlan annual survey of biopharmaceutical manufacturers yields a composite view and trend analysis from over 300 responsible individuals at biopharmaceutical manufacturers and CMOs in 29 countries. The survey included over 150 direct suppliers of materials, services, and equipment to this industry. This year’s study covers such issues as new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, 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.
If you want to learn more about the report, please go to bioplanassociates.com.