Eng. Life Sci. 2014, 14, 238243 www.els-journal.

com
Eric S. Langer
Ronald A. Rader
BioPlan Associates, Inc.,
Rockville, MD, USA
Review
Single-use technologies in biopharmaceutical
manufacturing: A 10-year review of trends and
the future
Single-use bioprocessing equipment has made considerable progress in the past
10 years. These devices now dominate small- and mid-scale bioprocessing and are
starting to graduate to larger scale manufacturing. We now have nearly a decade of
combined industry experience covering the benets of single-use vs. xed stainless
steel. Single-use systems are generally recognized as enabling rapid setup of bio-
processing at multiple scales in the same manufacturing area. A decade ago there
were signicant unknowns and concerns about single-use equipment. Today, these
plastics and equipments have much improved, and include advanced design, multi-
layer laminated plastic bags, and other integrated technologies. This article reviews
bioprocessing single-use systems market characteristics and trends over the past
decade and forecasts future developments. Much of this grounded and based on
data from the annual survey of bioprocessing professionals conducted by BioPlan
Associates, Inc., now in its 11th year. In addition to quantitative survey data, this an-
nual report includes extensive discussion and external analysis of bioprocessing and
related trends. This article also includes data from other primary research resources.
Single-use and modular systems are making capacity crunches increasingly unlikely;
in fact, estimating current and projected industry capacity may become subjective
and possibly irrelevant.
Keywords: Biopharma industry / Bioprocessing / Market trends / Single-use technology
Received: January 27, 2014; accepted: April 2, 2014
DOI: 10.1002/elsc.201300090
1 Introduction
Single-use bioprocessing equipment has made considerable
progress in the past 10 years, and will see further development
and adoption in coming years. The single-use equipment market
has grown from a few legacy and pioneer products, such as tub-
ing, and buffer bags. These held a limited market compared to
the current situation where a wide variety of products and tech-
nologies are available. In fact, in our annual global study of the
bioprocessing industry [1] we nd that single-use equipment is
nowdominating small- andmid-scale bioprocessing andstarting
to graduate to adoption for larger scale commercial manufactur-
ing. Single-use systems (SUS) are now commonly used by both
end users and contract manufacturing organizations. SUS have
advanced both technologically and in terms of their adoption.
Correspondence: Dr. Eric S. Langer (elanger@bioplanassociates
.com), BioPlan Associates, Inc. 2275 Research Blvd, Suite 500
Rockville, MD 20850, USA
Abbreviations: L&E, leachates and extractables; SUS, single-use systems
With this advancing technology, knowledge, and adoption expe-
rience of single use based bioprocessing, further future progress
and market expansion are expected.
2 Background
The biopharma industry applications associated with single-use
equipment are generally related to plastics that are gamma ir-
radiation sterilized, and used once (or reused for a single prod-
uct manufacturing campaign) and discarded. By now, there has
been nearly a decade of combined industry experience cover-
ing the benets of single-use vs. xed stainless steel, and much
discussion and writing on the topic, covering the lower capital
investment and operational costs and exibility, has been carried
out. SUS are generally recognized as enabling rapid setup of bio-
processing and progressive manufacture of multiple products at
multiple scales in the same manufacturing area.
Our single-use denition concentrates on the product as
sold and used. Legacy single-use products used for decades
include silicone and other plastic tubing. Over the past 10 years,
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single-use product lines have expanded to include devices from
basic storage bags to complex bioreactors. Now, essentially
all, particularly, upstream bioprocessing can be done with
SUS.
Downstream processing using single-use technologies, par-
ticularly many types of chromatography, lag behind; at present,
it is difcult, expensive, and rare to implement fully single-use
downstream processing. Bioreactor sensors, probes, and related
automation are another area where suitable single-use technolo-
gies and products are lagging and generally not yet available.
Single-use microbial manufacture, which is now a small niche
compared to mammalian bioprocessing systems, has also re-
sisteddevelopment of SUS, particularly bioreactors, withthe very
highly energetic mixing, higher temperatures, requirements for
heating and cooling, and other aspects restrict use of the current
plastics-based equipment technology. The great majority of SUS
is being used for mammalian cell culture. Part of the growing
dominance of mammalian cell culture is that it is amenable to
use of single-use bioreactors.
Bioreactors and mixers anchor upstream bioprocessing, and
the authors have previously reviewed aspects of this market
and its future growth [2]. In the early 2000s, just a few SUS,
such as simple WAVE bag bioreactors on rocker platforms and
a few primitive xed-wall bioreactors with plastic liners, were
available, with these generally limited in size, to a few 100 L.
Now a variety of single-use bioreactors and mixers are available
at 2000 L scale. Due to engineering limitations, with each
1000 L weighing about 2200 lbs., SUS above 2000 L are generally
not practical or cost-effective. Currently, 1000 L bioreactors
are on track to become the industry standard for new product
large- and much commercial-scale manufacturing, with a large
and growing number of companies offering an increasing range
of product options. However, technological progress in other
upstream areas has also been dramatic, including improved cell
lines, expression systems, and culture media, such that expres-
sion yields have been doubling about every 5 years, with this
expected to continue. Thus, more bioprocessing can increasingly
be done using smaller or the same-scale equipment. A decade
ago, a facility producing several 100 kg/year of monoclonal
antibodies would have required multiple 10 000 L stainless
steel bioreactors and other comparably scaled equipment,
while today, the same amount can be manufactured with a few
5001000 L bioreactors, including single use, operating contin-
uously, in parallel or at multiple facilities, and at much lower
cost.
A decade ago there were signicant unknowns and concerns
about single-use equipment polymers leachates and extractables
(L&E), which threatened to hold back adoption of SUS. This in-
cludedconcerns about relatedtoxic contaminants andregulatory
agency disapproval of products manufactured with extensive,
lengthy exposure to plastics. Today, these plastics and equip-
ment have much improved, and include multilayer laminated
plastic bags universally used in single-use bioprocessing, along
with knowledge about reduction and removal of many bad-actor
leachates. L&E continue to be perceived as a signicant issue, but
progress is being made, and both end users and suppliers recog-
nize they must work to address safety issues, including keeping
up with supply chain modications and information needed to
perform toxicology assessments.
3 Materials and methods
This article reviews bioprocessingSUSmarket characteristics and
trends over the past decade and forecasts future developments.
Muchof this groundedandbasedondata fromthe annual survey
of bioprocessing professionals conducted by BioPlan Associates,
Inc., now in its 11th year [1]. This survey annually analyzes re-
sults from hundreds of global respondents. The 10th Annual,
2013 study included responses from nearly 400 individuals, in-
cluding 238 working in biopharmaceutical manufacturing, and
158 working for bioprocessing suppliers or vendors, with sep-
arate modules for end users and vendors. This survey has long
including concentration on SUS, with these recognized as hav-
ing considerable potential. With 10 years of survey trend data,
this analysis provides unique perspectives concerning SUS and
their markets. In addition to quantitative survey data, this an-
nual report includes extensive discussion and external analysis of
bioprocessing and related trends. This article also includes data
from other primary research resources, as noted.
4 Results
4.1 SUS market estimates
Many advantages offered by SUS have resulted in their captur-
ing a majority of the small-scale market for bioreactors and
other upstream equipment, that is, for scales less than 2000 L. In
contrast, most of the big-ticket items downstream, particularly
chromatography columns, remain dominated by xed or other
reusable columns and other equipment.
The bioprocessing supplies market growth generally tracks
the overall biopharmaceutical market, with this rather steadily
increasing about 15% annually, roughly doubling about every
5 years [3]. The overall bioprocessing supplies market is
about 7% of total biopharmaceutical sales. The bioprocessing
supplies market is presumed to be fairly evenly divided between
up- and downstream applications. Stainless steel equipment
currently accounts for 90% of the market with single use at
10%; and is projected to change in 5 years to about an 80:20
split. This includes dramatic, even incredible, growth in the
SUS market, with this increasing nearly 300%, tripling; with
upstream markets growing by >320% and downstream by
>200%; and single-use market share growing from current 5%
to 15%. These data reect downstream single-use applications
remaining limited 5 years out. These projections also reect
likely market growth from many new players entering biopro-
cessing, including developing countries and a large number
of biosimilar developers, most expected to use SUS; and some
overall lowering of prices with increased competition in larger
markets and technological advances.
The most dramatic growth in SUS markets has and will
continue to be bioreactors, mixers, perfusion systems, and other
upstream applications, particularly, for GMP manufacture
(large-scale and commercial manufacturing). The single-use
market for GMP applications is projected to grow 10 times or
1000%inthe next 5 years. This growth will be drivenby products
currently in development using SUS receiving approval and
graduating to commercial scale manufacturing, which unlike
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Figure 1. Applications in bio-
pharmaceutical manufacturing:
percentage of using single-use
products.
precommercial (preclinical and clinical) manufacture sporadi-
cally spread out over years, is at highest scales and continuous for
many years. New products will likely be monoclonal antibodies,
which with their relatively low potency will continue to require
manufacture of 100 kg or much more. This increasingly
involves parallel trains, continuous bioprocessing, and/or mul-
tiple facilities worldwide anchored by 5002000 L bioreactors.
But even with this growth, xed stainless steel systems will still
dominate the GMP (and thus, overall) market 5 years out.
4.2 Market trends and perceptions
The BioPlan annual study and other sources conrmthat among
the facilities surveyed, mostly in the United States and Europe,
average purchases of single-use equipment are over $1 mil-
lion/year. But end users recognize that they are generally using
rst generation type equipment. Over the past 5 years, our study
indicates they continue to express desires for improved SUS. As
withmost emerging technology areas, once newand better prod-
ucts and technologies are introduced, and become the norm,
demand for further improvements continue, until a general level
of satisfactionis reached. Inthe bioprocessing industry, endusers
are apparently becoming concernedthat innovationinsingle-use
bioprocessing products has been slow in coming years (e.g., the
bag-in-vessel paradigmdiscussed below). This is not unexpected
in a regulated environment such as biologics, and demand for
better products continues. In our 2013 survey we found:
(i) 44%of industry respondents desiredimprovements ineven
the most basic devices such as bags and connectors;
(ii) 39% wanted improvements in single use and disposable
probes and sensors;
(iii) 34% sought better single-use bioreactors; and
(iv) 25% demanded single-use (downstream) chromatography
products.
Our study covered all aspects of bioprocessing yet, all four
of the top desired types of new products were associated with
single-use applications. This was the case in 2013, and most
every other year over the past 10 years of the survey. The trend for
better single-use products is exempliedby increasedbudgets for
these devices, especially over the past 5 years, and by increased
R&D focus among suppliers and technology innovators in the
eld.
Whenaskedto cite factors that have resultedinimprovements
in their bioprocessing, about 66% of respondents in recent years
have cited the implementation of single-use equipment. In terms
of bioreactors, the higher percentage, 65.6%, reported in 2013
would specify single use fed batch, single-use bioreactors for
any new facilities at clinical scale, and 42.0% for commercial
manufacturing. But the majority still prefers stainless steel at
commercial scale. Also, 54% of respondents agreed they would
expect (plan) to retrot existing facilities with single-use equip-
ment, generally involving hybrid or mixed-use facilities, rather
than build new ones; and nearly half (46%) expect to see fully
single-use facilities in 5 years.
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Figure 2. Percentage growth in-
creases in single-use equipment
usage, 20062013.
As shown in Fig. 1, single-use products with the reported
highest use (at any stage/scale) include 92% using disposable
lter cartridges, 88% tubing, 85% depth lters, 82% buffer con-
tainers, 81% media in single-use bags; 79% connectors, clamps,
78% bioreactors, and 77% sampling systems.
As expected, much growth in SUS has occurred in recent
years, but with this slowing as the market nears effective
saturation at the small- and mid-scales and graduation of
products to commercial scale is slow and still isolated. Products
seeing the most rapid growth rates in adoption from 2006 to
2013 (when survey for these data started) include membrane
adsorbers and bioreactors both at 20.6% annual growth; mixing
systems 19.9%; with others having <10% reported annual
growth in adoption (which, as with tubing, includes many
product types already in use).
Figure 2 shows reported 20062013 percentage growth in-
creases in single-use equipment use, with bioreactors, chro-
matography devices, and mixing systemusage each growing over
50%.
Among reasons for adopting single-use, those most cited as
very important in 2013 were decrease risk of cross-product
contamination 46.2%; eliminating cleaning requirements
41.2%; reducing time to get facility upandrunning 44.1%; and
reduce capital investment infacility and equipment 40.4%. Ev-
ery year, end users cite saving time and money, reducing risks,
increasing exibility, and accelerating campaign turnaround as
primary reasons for adopting single use over stainless steel. In
terms of stage/scale of manufacture, clinical manufacture signif-
icantly dominates usage of nearly every single-use product type,
followed by process development.
The top four concerns or potential problems associated with
single use have actually been increasing slightly in recent years.
In 2013 our study found:
(i) leachables and extractables cited by 75.9% as agreeing
that these are a concern;
(ii) breakage of bags and loss of production material cited by
67.5%;
(iii) we dont want tobecome vendor dependent (single-source
issues) 63.8%; and
(iv) material incompatibility with process uids 63.8%.
Bag construction materials (L&E and breakage) consistently
have rated as top concerns over the past decade. High costs
of disposables was cited as a concern by only 6.3% in 2013
vs. 13.0% in 2009. This may be an indication of the increased
awareness and adoption of these devices. As awareness goes up,
so will the concerns over single-use systemprices. However, from
other research we nd that price continues to not be a primary
concern, even among those currently using SUS (in bioprocess-
ing, most equipment prices are considered high). Overall, US
facilities are slightly ahead of Europe in terms of SUS adoption,
with the United States and Europe much ahead of developing
countries.
5 Discussion
Single-use systemtechnologies will advance andcontinue topro-
liferate, with more diverse technologies and products becoming
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available. However, in terms of capacity (cumulative bioreac-
tor volume), most of the current largest facilities, e.g. multiple
10 000 L bioreactors, are likely to remain in use. New capacity
will be added at lower scale, with most new large facilities still
specifying stainless steel. As such, stainless steel will continue
to dominate bioprocessing in terms of capacity and number of
large-scale and commercial facilities (see concentration data on
global facilities at www.top1000bio.com).
A number of individualized biologics, and personalized
medicines are in active development, including patient-specic
gene therapies, cultured tissues and organs, and cancer and other
therapeutic vaccines. With their inherent one-off nature and also
due to regulations, these products can all be expected to be man-
ufactured using single-use equipment.
We are already starting tosee another relatedtrendmodular
facilities, with bioprocessing unit processes housed in con-
nectable trailer-like portable clean rooms or isolator units and
whole manufacturing facilities being portable, able to be con-
structed and operational in a matter of months or even weeks.
With modular systems providing the same advantages of SUS
and at an even larger scale, modular units are likely to nd in-
terest and ready markets. This includes plug-and-play factories,
withwhole productionlines andfacilities fully clonable. Modular
systems will be particularly benecial in GMP-challenged devel-
oping countries. With many developing countries increasingly
demanding domestic manufacture, modular facilities will likely
become common in developing countries in the next decade.
China and India, with their growing middle-class populations,
and demands for state-of-the-art healthcare are regions where
biologics and biosimilars are likely to be considered for manu-
facture using modular facility strategies.
We can also expect an increase in the number of biopharma-
ceutical manufacturers and products in coming years, with the
average scale and size of new manufacturing facilities and pro-
cess lines decreasing because of factors such as process optimiza-
tion, and increasing expression yields. Currently, the biosimilars
pipeline includes over 550 products being developed by over
120 companies, including many new players [4]. Biosimilar ad-
vancements will also affect the way new single-use technologies
are developed and prioritized, with this being seen as an increas-
ing opportunity for single-use device innovators.
Single-use, particularly, upstream bioprocessing has and will
remain dominated by the plastic-bag-in-stainless-container ap-
proach, which has not changed since the rst single-use products
introductions. The use of exible bags in bioprocessing presents
a number of problems, including securing, sealing, ports, and
L&E. Novel approaches eliminating bags seeminevitable, such as
unitary (solid) self-supporting, rigid, disposable containers (no
bag), or even inert materials used to line plastic containers. Such
approaches many enable microbial bioprocessing using single-
use bioreactors. However, with many vendors and large-scale
users have invested heavily in bag technology, so few alternatives
can be expected to start to gain traction in the market 5 years
out. Changes in bags in coming years likely include increased
adoption of inert, lower, and less toxic L&E, contact-layer u-
oropolymer plastics, such as PTFE (Teon), PFA, and PVDF
(Kynar). Similarly, these and other polymers are and will be
increasingly adapted for tubing and connectors. Currently, no
Table 1. Estimates of selected bioprocessing systems markets,
20132018
Products 2013 Market 2018 Market
Biopharmaceuticals, total global sales
revenue
a)
$175 billion $300+billion
Recombinant proteins $85 billion $145+billion
Bioprocess equipment, total market $12 billion $24 billion
Bioprocess equipment, upstream
b)
$6 billion $12 billion
Bioprocess equipment, downstream
b)
$6 billion $12 billion
Stainless steel/non-SUS $10.8 billion $20.5 billion
SUS $1.2 billion $3.5 billion
SUS, upstream $850 million $2.75 billion
SUS, downstream $350 million $750 billion
R&D use (small- and mid-scale) $500 million $900 million
GMP use (large- and commercial
scale)
$160 million $1.6 billion
Bioprocess supplies, SUS, downstream $350 million $1 billion
a)
Source: BIOPHARMABiopharmaceutical Products in the United
States and European Markets, BII, available at www.biopharma.com.
b)
Downstream processing includes ll and nish, other than packaging.
Culture media, buffers, reagents not included.
real design or performance standards, even voluntary, apply to
most single-use products. With vendors (other than the domi-
nant ones) only nowdeveloping processes for standardization of
materials or designs.
Downstream, we canexpect selective, limited increased adop-
tion of single-use equipment, particularly the chromatography
systems that dominate this market and continue to resist single-
use implementations or replacement by new single-use tech-
nologies. A number of companies are starting to offer custom
prepacked chromatography columns, but these columns, so far,
are not truly single use. Protein A resins will remain, by far,
the dominant method for antibody capture, with this only cost-
effective if the resin is multiply recycled. Membrane adsorp-
tion technologies, single-use moving bed (tangential ow ltra-
tion), countercurrent chromatography, and other novel chro-
matography methods implemented as single use will start to see
more signicant adoption at mid- and larger-scales in coming
years.
6 Concluding remarks
Fears of capacity shortages were prevalent a decade ago, as mul-
tiple blockbuster monoclonal antibodies approached marketing.
But these concerns have subsided, with increased yields and ac-
cess to more rapidly deployable SUS becoming major factors
in resolving these concerns. With single-use and modular sys-
tems quickly installable and replaceable, capacity crunches are
increasingly unlikely in the future. In fact, with SUS, estimating
current and projected industry capacity becomes increasingly
difcult, subjective, and possibly irrelevant.
Besides inherent conservatism in this highly regulated indus-
try, an issue restricting progress in SUS is vendors hesitancy
and end users distress over incremental improvements. This is
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because any changes in bioprocessing products already in use,
particularly, at GMP require extensive revalidation studies by
vendors and end-users, more regulatory lings, and often costly
L&E testing, new SOPs, etc. Innovations in single-use equip-
ment may more likely originate from small companies or from
new major corporate entrants less wedded to current, increas-
ingly aging technologies. New technologies in this industry are
best adopted for totally new facilities and process lines, not
retrotting.
SUS, other than legacy products, such as tubing and lters,
which already dominate their markets, will see continued tech-
nological progress and increased adoption and use for biophar-
maceutical manufacturing. The fastest growing segments of the
single-use equipment market will be upstream bioprocessing at
large and commercial scales, as products now in development
move up to commercial manufacturing. As demonstrated by the
annual BioPlan survey and conrmed by many other sources,
adoption of SUS, generally in place of xed stainless steel sys-
tems, will continue. Modular systems may well be the next tech-
nology to experience such increased and rapid adoption over the
next decade.
The authors have declared no conict of interest.
7 References
[1] Langer, E. S. et al., 10th Annual Report and Survey of Biophar-
maceutical Manufacturing Capacity and Production, BioPlan
Associates 2013, pp. 505.
[2] Rader, R. A., Langer, E. S., Upstream Single-Use Bioprocess-
ing Systems: Future Market Trends and Growth Assessment,
BioProcess International 2012 pp. 1216.
[3] Rader, R. A., BIOPHARMA: Biopharmaceutical Products in the
US and European Markets, Biotechnology Information Institute.
www.biopharma.com.
[4] Rader, R. A., BIOPHARMA: Biosimilar and Biobetters in the
Pipeline. www.biosimilarspipeline.com.
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