■By Eric Langer, President, Managing Partner, BioPlan Associates
Recombinant proteins drugs have been on the market since the arly 1980s but only recently has there been a trend toward increased adoption of continuous bioprocessing vs. batch pro- cessing. Continuous, perfusion bioprocessing is not really new, and has been used for decades for commercial biologic manu- facture, including blockbuster monoclonal antibodies. But today,
the adoption of these technologies is advancing and becoming
more sophisticated. (See 11th Annual Report and Survey of
Perfusion, the current leading continuous bioprocessing
technology in terms of adoption, was generally unavailable in
the 1980s (other than gravity settling of cells and other simple
methods). In the 1990s, industry largely moved away from implementing perfusion as new expression systems, culture media and
supplements contributed to dramatic progress with fed-batch
processing. Fed-batch bioprocessing remained dominant, familiar and efficient, while perfusion continued to have problems,
including higher equipment failure rates and questions lingering
regarding regulations. Also, the adoption of single-use systems
started, and bioprocessing upgrades and modifications often
involved adoption of or retrofitting with single-use equipment. In
the 2000s, more perfusion options, including the single-use ATF
System, became available and were selectively adopted.
By far the most benefits and greatest savings with continuous
operation and perfusion are experienced with commercial manufacturing. Conventional commercial manufacture generally involves use of bioreactors over 1,000-2,000 L, requiring large-scale
industrial operations and equipment. However, with continuous
bioprocessing, facilities can perform the same bioprocessing, in
terms of amount of product produced, more continuously, allows
use of smaller-scale bioreactors and other equipment, with in-dustrial-type operations – mixing, heating, cooling, bulk transfers,
etc. – all at smaller scale.
BATCH PROCESSING STILL DOMINANT
Batch-type processing is the classic, and still predominant,
bioprocessing paradigm, both up- and downstream. With batch-type bioprocessing, materials being processed, generally fluids,
are processed and acted upon incrementally, in stages, with each
process completed and materials then transferred to the next.
• In contrast, continuous bioprocessing could be characterized
as non- or much less-intermittent and episodic, with the bioprocessing unit operations never fully shut down, rather kept
in rather “continuous” repeated cycles of use. The majority
of biopharmaceuticals are currently being commercially manufactured using batch-type processing, particularly, fed-batch.
Improvements in expression systems, including higher yields;
Continuous Bioprocessing and Perfusion
Rapid growth seen in key areas
more diverse and better single-use equipment; improved culture media; better process modeling; use of QbD and other
quantitative approaches to up-front process design; more and
better sensors and control equipment continue to help improve overall bioprocessing.
But a number of trends and technological advances are making continuous bioprocessing more feasible and cost-effective,
including providing significant savings and flexibility compared to
comparable batch processing.
INDUSTRY ADOPTION OF PERFUSION
Today, many respondents to our annual survey predict that
perfusion will make a comeback as the manufacturing method
of choice, although significantly more improvements are needed
in downstream equipment for continuous bioprocessing.
Continuous chromatography methods, such as simulated moving bed (SMB) and periodic counter-current chromatography,
are generally considered not yet ready for widespread commer-cial-scale adoption.
In terms of market evolution, there are and will be similarities
with that for single-use systems. Continuous bioprocessing will
see increasing adoption, including for large-scale commercial
manufacturing. Much adoption of perfusion will be with single-use equipment, particularly, as current products being developed by single-use manufacture graduate to commercial manufacture, with the single-use commercial manufacturing market
projected to grow about 10x (1,000%) over the next five years.
In many respects, perfusion is already a mature and accepted
technology. This includes perfusion being used at world-class/
blockbuster scales for manufacture of multiple commercial products now for 20 years. (See Table 1)
Overall, a total of 19 recombinant protein/mAb products (likely
a few more as 2013 sales data become available) are known to be
manufactured using perfusion. These have annual sales/revenue
totaling about $20 billion, or on the order of up to 15% of worldwide biopharmaceutical sales/revenue.
THE CONTINUOUS BIOPROCESSING ALTERNATIVE
Continuous processing for product manufacture is generally
more efficient than comparable production capacity batch-based
manufacture. Perfusion is the current leading continuous bioprocessing technology in terms of biopharmaceutical industry
adoption. Perfusion is “the process of running a bioreactor at
a fixed volume and fixed cell concentration for 30-90 days [or
longer], with a constant flow of [culture] media through giving
a constant harvest volume to be processed”. With perfusion’s
continuous removal and replacement of culture media, there is