Large-scale biopharmaceutical manufacturing equipment for upstream product manufacture has changed relatively little over
the past decades. Innovation in bioprocessing equipment, particularly, bioreactors, has been slow despite some gains, such
as cost improvements, greater flexibility, higher product yields resulting from improved genetic and cell engineering, and
widespread adoption of small-scale, single-use bioprocessing equipment.
Data from BioPlan Associates' 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production show
that the industry is demanding better upstream and downstream processing. The survey, which had responses from 352 global
biomanufacturers, analyzed production, budgetary, technological, and quality issues. The study also showed that the industry
is interested in new-product innovation in single-use bioreactors, cell-culture media, and various service areas (1).
A key finding of the study was interest in upstream equipment innovation. Bioreactors are one of a company's largest bioprocessing
expenses. To illustrate interest in alternative bioreactors, more than two-thirds (68.1%) of survey respondents reported current
in-house use of single-use bioreactors, and this percentage is growing, especially in research and development and clinical-scale
production. Improvements in bioreactors, particularly for single-use, along with purification equipment, were ranked as the
areas where bioprocessing innovations were reported as most needed, with 29.2% of respondents citing bioreactors as a key
area. Survey respondents also cited the need for improvements in cell-culture media (29.2%), upstream process-development
services (18.7%), cell-line services (17.8%), and process-development services for formulation (11.0%) (1).
Partly due to the slow-changing and strict regulatory environment, single-use suppliers are focusing on relatively traditional
bag-liner-in-a-steel-bioreactor single-use systems. Much of industry's desire for improved bioreactors is related to the need
for large-scale (e.g., >1000 L batch-fed), single-use/disposable bioreactors. Today, 1000 L is the largest cost-effective
size for disposable batch-fed bioreactors. Future areas for single-use bioreactor innovations may include unitary (single-piece)
all-plastic rather than plastic-lined and even stainless steel-lined plastic bioreactors.
Contract manufacturers have more interest in improved single-use bioreactor systems compared with product developer/manufacturers,
according to the study. Interest in disposable bioreactors also differed among regions. Respondents from Europe (32.2%) showed
the highest interest compared with 26.9% from the United States, and 31% from the rest of the world (1).
The study also surveyed 175 suppliers and examined 52 equipment and functional areas. The results showed most suppliers are
involved in new-product development and that single-use bioreactors are the hottest items in new-product development; 40.5%
of respondents are working on them in some way. Expression-system platforms and cell-culture optimization also were key areas
of new-product development (1).
The study further evaluated 15 areas where biomanufacturers were actively implementing performance improvements in their facilities.
The greatest percentage of facilities had "significant" or "some" improvement from better process development (identified
by 66.8% of respondents) and optimized cell-culture processes (identified by 61.9% of respondents) (1).
Perfusion bioreactors appear to be positioned to become the next major revolution in bioprocessing and single-use equipment,
with perfusion equipment on track to compete head-to-head with conventional batch-fed bioreactors even at commercial GMP scale.
The study, however, showed that the industry's view of perfusion largely is dated.
Perfusion is not new. For example, perfusion bioreactors were widely used for hybridoma culture in the 1970s–1980s before
antibody manufacture switched to batch-fed mammalian cell bioreactor manufacture of recombinant antibodies. Perfusion bioreactors
were available from such companies as Endotronics, Cellex, Biosyn, and Biovest. Today, providers of perfusion bioreactors
include FiberCell Systems and Zellwerk (marketed in the US by Glen Mills).
Nearly all current bioprocessing today involves batch-fed bioreactors. Perfusion involves continuous slow feeding and removal
of spent media along with the desired product with the host cells retained within the bioreactor by being bound to bundles
of capillary fibers or other membranes or retained in suspension in the bioreactor by special filters. While batch-fed bioreactors
involve cells in dilute culture media suspension, perfusion bioreactors grow cells at ≥100 to 1000 times higher concentration,
with bioreactors commensurately smaller. Thus, using a small perfusion bioreactor over time with the same amount of culture
media may match or beat the product output of a much larger batch-fed bioreactor. For example, FiberCell Systems reports it
is developing desk-sized units that will have the equivalent recombinant-protein production capacity of conventional 2000–5000-L
bioreactors. Also, ATMI recently launched iCellis, the first large-scale perfusion bioreactor.
Although perfusion appears to be a viable new product candidate, the BioPlan survey shows that industry knowledge and attitudes
toward perfusion remain largely dated. Among a list of 17 problems commonly encountered in bioprocessing, respondents consistently
had more serious concerns with perfusion than with batch-fed systems. These issues included process complexity (66.1% of respondents
had serious concerns with perfusion systems compared with 4.9% for batch-fed) and contamination risks (63.9% had concerns
with perfusion compared with 3.8% for batch-fed systems) (1). These and other concerns for perfusion already are being resolved
as new bioreactors enter the market. As new products are launched in coming years, commercial-scale devices are likely to
capture significant interest as new upstream solutions.
Eric Langer is president of BioPlan Associates, tel. 301.921.5979, email@example.com
and a periodic contributor to Perspectives on Outsourcing.
1. E.A. Langer, 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates
(Rockville, MD, April 2011),