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Biological molecules, such as proteins,
peptides and monoclonal antibodies, are
becoming widely used as safe, effective,
and tailored treatments for a number of
diseases, but producing them involves a
number of different steps, from production
in cells (often mammalian cells) through to
separation, purification and formulation.
Traditionally, these drugs have been
produced in stainless steel systems, in
bioreactors from a few liters to 20,000
liters or more, but these are fixed, often
hardpiped into the walls or floors, making
moving them around pretty near impossible.
They also need to be thoroughly cleaned
and sterilized between uses, and then the
cleaning steps validated, which takes time.
To increase the speed and convenience
of the process, some companies are
replacing their stainless steel equipment
with single-use systems. These use
disposable components, including fluid-
management systems, plastic bag-based
bioreactors, tubing, filters, and connectors,
which are thrown away after use (BPSA,
2013). Single-use systems have made

Single-use technology:
manufacturing not only more convenient
but also more efficient and sustainable.
They have also lowered costs and

From bioprocess convenience to drug-development driver

ultimately are driving drug development.
The industry is moving towards single-
use systems for both drug development and
manufacturing, says Jeff Odum, director of
operations and global biotechnology leader,
Integrated Project Services, an engineering
company focusing on biopharma.

by Suzanne Elvidge

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April 2 013 2
 FierceBiotech.com
The impact of single-
use technologies
Single-use technologies are
still relatively new. Disposable
wave bioreactors (flexible plastic
bioreactors that are agitated
using a rocking motion) have
only been available since the
early 2000s (Rader, et al., 2012),
and Thermo Fisher Scientific
($TMO), a laboratory equipment
and consumables provider,
launched the first stirred-tank
single-use bioreactor in 2006.
Only 10 years ago we were
evaluating single-use systems,
and now they have been adopted
and validated in development
and manufacturing, and in
many cases are relied upon
for these applications, says
Jeffrey Craig, Global Director,
Business Development at ATMI,
which manufactures single-
use bioprocess systems and
consumables. We have moved
quickly from technology evaluation
to implementation and validation,
and I would say these days that we
are in full-bore industrialization.
Biologics companies want to
speed up drug development and
manufacture, they want to be
flexible, and they want to cut costs.
They also want to get the most
out of their facilities, particularly in
locations where land, energy, and
labor costs are high, and they are
looking to single-use technologies
to help with all of these issues.
Single-use technologies have a
number of important advantages, as
Craig explains: Single-use systems
cut production line labor costs by
reducing the time, materials and
validation needed for setting up,
cleaning, sterilizing and cleaning
again. They reduce the capital cost
as well as build and setup time for
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Only 10 years ago we were evaluating
single-use systems, and now they have
been adopted and validated in development
and manufacturing, and in many cases
are relied upon for these applications.
Jeffrey Craig, Global Director, Business
Development at ATMI
new sites. The learning curve is Plant setup time
less steep than with the traditional A shorter plant setup time
steel systems. And single-use means that companies can
systems increase process flexibility, start manufacturing more
as it is possible to switch or scale quickly, which makes single-use
production quickly, rather than systems attractive to companies
having to build new lines. moving into a new region, or
simply expanding, replacing or
Speeding up the processes upgrading an existing facility.
Single-use technologies can speed Stainless steel systems
up bioprocessing by reducing work very well, so there isnt a
plant setup time, cutting the time real incentive for an up-to-date
taken to switch a production facility to switch over. However,
line over between one product as facilities get old and require
and another, and in some cases, investment, many will be replaced
improving processing speed too. with single-use systems, says
Mike Jenkins, general manager,
Catalent Pharma Solutions, a
pharmaceutical solutions provider
that uses single-use systems.
Catalent has recently built a
completely single-use site in
Madison, Wisconsin, which includes
single-use cGMP bioreactors up to
1,000 liters, producing material for
Phase I and Phase II clinical trials,
with potential to expand to Phase
III and commercial manufacturing.
This facility opened in April 2013.
We chose this approach because
the construction was faster and
the capital expenditure lower. Its
also more efficient for us. As each
of our clients has different needs,
single-use technologies mean
that we can reconfigure the space
as we need to, says Jenkins.
However, going for single-use
technology doesnt necessarily
mean scrapping everything and
starting again from scratch. Single-
use system components can be
combined with stainless steel
components to create hybrid
systems. This allows manufacturers
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to make the most of the working
infrastructure they already have,
or systems that they know to be
successful, while adding on the
advantages of single-use systems.
A lot of companies have
infrastructure that was state
of the art, but the science and
technology has now moved on,
and so the resources are idle or
underutilized, says Odum.
Single-use systems are still
not used all the way across the
industry, and some people remain
wary. A hybrid of the two may
seem less risky and more familiar
than what may seem to be a
new and untried technology.
When implementing single-use
technologies, the first step is to
look at the areas where conversion
can increase efficiency and add
flexibility, says Odum. Perhaps
the simplest place to start is with
media and buffer preparation.
This is a low-risk first step.
Novartis ($NVS) is using a mix
of disposable and stainless steel
technologies in its brand-new
$500 million biologics plant in
Singapore. The company broke
ground early in 2013 and expects
the plant to be online by 2016.
Speeding up switchover
and processing steps
Switching over production from one
biologic to another can be time-
consuming and labor-intensive,
because of the necessary cleaning,
sterilization and validation steps.
This can have a big cost impact
for companies, particularly those
manufacturing for clients, or working
on particularly tight timelines for
clinical trials. With single-use
technologies, its simply a case
of removing and replacing the
disposable components, leaving
the reactor immediately ready for
use. This means that production
lines can be kept in use for more
of the time, making them more
cost-effective and productive.
CMOs can adapt existing
infrastructure to work with
a new product or new client
with little upheaval and shorter
timelines than with stainless
steel systems, says Odum.
Quick connector technologies
and ready-to-use liquid media in
bioprocess containers that can be
pumped directly into the bioreactor
make the process even quicker and
smoother. Using single-use filtration
could cut downstream processing
time by half, by reducing preparation
and changeover time (Gupta, 2011).
As well as speeding up biologics
production for clinical trials and
marketed drugs, single-use
technologies can speed up the
steps between the bench, clinical
trials, and full-scale production.
Bench researchers can use
small-scale single-use cell culture
systems along with ready-to-
use media in early-stage drug
development to establish preliminary
scale-up protocols. This reduces
the cell culture preparation process,
shortening the timeline to complete
their critical studies, says Brandon
Pence, global director of marketing,
cell culture and bioprocessing,
Thermo Fisher Scientific.
Cutting the costs
Setting up a stainless steel
bioprocessing facility is an
expensive business. It can cost
between $50 million and $150
million (Coggins, et al., 2012),
which is a major investment for any
size company, but particularly for
small and medium enterprises.
The costs of setting up a single-
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 FierceBiotech.com
use facility are much lower (BPSA,
2013), even when factoring in
the costs of consumables, and
this cost reduction has an impact
at all stages, from R&D through
preclinical and clinical drug
manufacture to commercialization.
The desire for cost containment
is driving the move towards single-
use systems, says Deborah
Stutz, Market Manager, Global
Biopharmaceuticals, SAFC,
a provider of manufacturing
materials and services.
According to the Ninth
Annual Report and Survey of
Biopharmaceutical Manufacturing
Capacity and Production: A Study
of Biotherapeutic Developers
and Contract Manufacturing
Organizations (Coggins, et al.,
2012), single-use systems are
5 April 2 013
the most common equipment
for biomanufacturing for small-
to mid-scale amounts, such
as for R&D and clinical trials,
whereas stainless steel systems
still dominate manufacturing
at a commercial scale.
Clinical trials are the single
biggest area for single-use
technologies, as they are fast,
efficient, easy to build and
flexible, says Jenkins.
Biologics are often developed
to early-stage clinical trials, often
known as proof-of-concept,
when they show early evidence
of efficacy and safety, and then
partnered or licensed out to add
expertise or capacity. By reducing
the investment needed to set up
a drug production line, single-use
technologies could open up drug
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Every molecule has a challenge.
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but on a small scale, at lower cost
2013 Catalent Pharma Solutions. All rights reserved.
and lower risk, says Odum. Call: + 1 888 SOLUTION (765-8846)
Because single-use technologies Email: solutions@catalent.com
are much easier to scale up, Visit: www.catalent.com/biologics
companies can make decisions
about manufacturing earlier in
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As the technology gains a DEVELOPMENT DELIVERY SUPPLY
April 2 013 6
 FierceBiotech.com
When implementing single-use
technologies, the first step is to look
at the areas where conversion can
increase efficiency and add flexibility.
Jeff Odum, director of operations and global
biotechnology leader, Integrated Project
Services
foothold, the same facility could be steel systems is their flexibility.
used for drug development, scale- As the surface that is in contact
up and manufacture, as currently with the products can be thrown
this can take place in two or three away and replaced, companies
different facilities. This would no longer have to stick to one
allow all the steps to use the same reactor for one cell type. This has
system and the same resources, the added advantage that it cuts
says Odum. The FDA is looking at the risk of cross-contamination.
phase-appropriate GMP processes, Single-use technologies allow
and if this was implemented, it biopharmaceutical companies
would be possible to do all the to build flexibility into both their
steps in a single location. This builds facilities and manufacturing
in efficiency and consistency. processes, thereby improving
Setting up single-use efficiencies and reducing overall
bioprocessing doesnt even costs, says Stutz. These days
commit companies to creating thats more the requirement
entire facilities. Biologics Modular than just a nice to have.
has filed patent applications for
its preconstructed, pretested Consistency, consistency,
cGMP modular clean rooms, consistency
based on shipping containers Drug development is increasingly
(Biologics Modular, 2011). being outsourced or carried out
The improvements in efficiency at different sites of global biotech
and cost-effectiveness driven by companies. Biologics are sensitive
single-use technologies could mean to changes in production, and
companies focusing investment on even small variations can lead to
development for longer, speeding differences in the final products,
time to approval or funding more for example changes in the way
projects in the pipeline. It could the proteins fold, altering efficacy,
also have an overall impact on and even safety. Using the same
cost of goods sold, making single-use systems at each site
healthcare more affordable. could improve the reproducibility
of the end products and allow
Keeping things flexible changes in the setup at one site
One of the most obvious to be reflected at all sites.
advantages of single-use systems Moving to single-use changes
compared with traditional stainless the relationship between the
7 April 2 013
manufacturer and the single-use
technology, making it more of a
partnership. The providers of single-
use technologies must provide the
manufacturers an extremely high
degree of confidence in a reliable
continuous supply of consumables
at a constant quality, says Craig.
Single-use system vendors
are working to build quality,
reproducibility, and compatibility
into their systems.
One of the issues with single-use
systems is the lack of compatibility
between technologies produced by
different vendors. Quick connectors,
which may not be interchangeable
between component manufacturers,
partly when the technology is
proprietary, are one example.
It would be great to have these
connectors standardized, like USB
connectors are now standard across
electronic devices. All users and
vendors have their own opinions on
the best type of quick connectors.
The only problem is that not
everyone agrees! says Jenkins.
Connections can be complex, and
single-use technology and connector
technology are still evolving.
Changing the drug-
development paradigm
Because single-use systems
speed up setup, companies could
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potentially establish new facilities allow doctors to test a patient
in weeks or even days, using a and pick the right drug from a
modular approach (Coggins, et al., bank of 500 or 600 different
2012). As well as allowing smaller biologics. The company could then
companies to get involved in the manufacture this drug specifically
development and production of for the patient, explains Jenkins.
biologics, companies can use Single-use systems will also
flexible single-use production make it practical for companies
suites or facilities to manufacture to set up a number of R&D and
a short run of one protein and manufacturing sites across the
then switch quickly to another. world, allowing local development
These changes are driving of drugs for specific populations,
drug development by making it including in developing countries.
more feasible and cost-effective Not only would this cut labor and
to produce drugs for smaller distribution costs, but it would also
populations, which will have an make sure that drugs get to the
impact on orphan drug development markets where they are needed.
and on personalized medicine. Drug sponsors and
Clinical trials are the single biggest area for single-use
technologies, as they are fast, efficient, easy to build
and flexible
Mike Jenkins, general manager, Catalent Pharma Solutions
The time of the blockbusters is manufacturers who are targeting
finished, and this will drive a move emerging markets are going
towards smaller drugs and smaller directly to single-use platforms
indications, aided by the availability for manufacturing, since they are
of single-use systems, says proven technologies which drive
Hlne Pora, vice president single- time-to-market more quickly and
use systems, Pall Life Sciences, at lower costs, says Craig. I fully
a fluid management provider. expect single biopharmaceutical
Single-use systems will have a manufacturing platforms to become
key role in personalized medicine the preferred platform for new
development, as the technology facilities to develop and manufacture
makes it easier to work at the drugs and vaccines. These
smaller scale needed, even down technologies are already an integral
to creating biologics or cell-based part of global affordable medicine.
therapeutics for just one patient. Local production combined with
Timelines are very important single-use systems would support
in personalized medicine, fast vaccine production in response
particularly in cancer treatment, to a pandemic and could allow local
and single-use systems speed vaccine production if borders were
could be very important here. closed, or if an infection breaks out
Single-use technologies could in a geographically isolated area.
April 2 013 8
 FierceBiotech.com
We are close to having portable
manufacturing facilities, which could
be developed and set up in the U.S.,
and then transported to another site
where it would be validated and
then used to manufacture vaccines
as needed. It could then be packed
up and moved again, says Odum.
Changes and challenges
Purely practical points, such as
robustness or scale, could drive
other changes in drug development,
as the materials science behind
the single-use components is still
evolving, according to Stutz.
Single-use systems are not
thought to be robust enough
for the higher temperatures and
concentrations needed for microbial
manufacturing, according to the
Ninth Annual Report and Survey of
Biopharmaceutical Manufacturing
Capacity and Production (Coggins,
et al., 2012). Increasing use of
single-use systems could therefore
push investment toward products
that can be manufactured using
single-use systems and mammalian
cells, rather than bacteria or yeast.
However, single-use systems are
developing all the time, so this could
all change (Coggins, et al., 2012).
bioreactors running in parallel
(Coggins, et al., 2012), or to use
hybrid systems where large
stainless steel upstream operations
are quickly concentrated.
However, as bioprocessing
technologies develop and
productivity improves, these issues
will become less significant.
Bioreactor size is no longer
such an issue. Ten to fifteen years
ago, protein expression could be
as low as a third of a gram per
liter. Now we see expression
as will the regulators. Uptake
has gained speed over the last
few years, says Odum.
One concern of both regulators
and users is that of extractables
(chemicals that migrate from
components when exposed to a
solvent) and leachables (chemicals
that migrate from components
under normal conditions).
Companies using single-use
technologies expect to be able
to get data on extractables and
leachables from the vendors,
their environmental impact, but
moving to single-use systems
doesnt mean throwing all green
credentials out of the door.
The issue of disposal must be
balanced with the benefits of using
less water, steam, chemicals, and
other consumables in the cleaning
and sterilization of conventional
systems (BPSA, 2013). Single-use
production facilities tend to need
fewer people to run them, which
will cut the number of car journeys
along with the need for heating
and lighting, reducing the facilitys
carbon footprint even further.
This technology does create
a large amount of plastic waste,
and facility designs should
perhaps include waste handling or
recycling options, says Odum.
Single-use component
manufacturers are also brushing
up their green credentials. When
Sartorius Stedim Biotech added
capacity to its single-use bag
and filter plant in Puerto Rico, it
designed the facility to use less
energy in heating and cooling. The
company also invested in solar
Bibliography
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power, with photovoltaic panels
providing 10% of its energy needs,
and it recycles water, using 85%
less than conventional plants. This
earned the facility LEED Platinum
certification, the highest Leadership
in Energy and Environmental Design
rating, the first plant to do so.
As the single-use market
expands, the growing waste
and recycling issue could create
a business case to produce a
sustainable way to deal with the
waste, for example by recycling
or co-generating energy.
The future
Using single-use technologies,
whether for drug development
or commercialization, does
involve a lot of changes and is a
major shift for what is generally
a fairly conservative industry.
Development groups have
been very successful at working
with stainless steel systems, and
they now have to learn new skills
and work with new parameters,
says Odum. The learning
curve can be steep. Its hard to
teach an old dog new tricks.
Single-use technologies could
have applications throughout
the whole drug-development
process, from early development
to final harvest and fill/finish.
This would require an increase in
automation, and the integration
of more and better sensors and
RFID technologies, for better
monitoring and control, and to allow
end users to have batch-to-batch
reproducibility and full track records.
In the future, I believe there will
be a lot more high-level technology
used, for example more automated
processes and robotics, says
Odum. Single-use technologies
could be combined with robotics in
sterile product filling, which would
reduce human input even further.
The Holy Grail would be a 100%
single-use process, and this could
be possible in the near future. But
despite all this, its important to
remember, though, that one size
doesnt fit all, and its vital to have
a deep understanding of product
attributes and processes when
designing single-use systems. l

There are also limitations to using
single-use technologies for large-
scale processes, simply based on
the physical size of the bioreactor.
Choosing between single-
use technologies and traditional
stainless steel systems depends
on the scale. Single-use bioreactors
are effectively bags, and 6,000
liters to 10,000 liters is a big bag!
In this case, there would be an
advantage in using a stainless
steel system, says Odum.
One way around this problem
is simply to scale up using
combinations of single-use
rates of five to 19 grams per liter,
effectively making the reactors
tenfold bigger, says Jenkins.
Drug development and production
is a highly regulated environment,
and as with all new technologies,
vendors, drug developers and
drug manufacturers, along with
trade associations such as the
Bio-Process Systems Alliance
(BPSA), will need to work alongside
the regulatory authorities as
standards and guidelines evolve.
As single-use technologies
become more widely used, the
industry will get more comfortable,
and then see if anything else
needs to be done, based on
the application and use of the
product, says Jenkins.
Environmental impact
and sustainability
Expanding use of single-use
technologies will generate
a significant amount of
nonbiodegradable waste, much
of which is either incinerated or
autoclaved to remove contamination
and then disposed of in landfills
(Langer, 2012; BPSA, 2013).
Companies need to think about
Biologics Modular. 2011. Biologics Modular Files New Patent Applications: Pre-Constructed, Pre-Tested cGMP Modular Clean Rooms. PRWeb. [Online]
30 March 2011. http://www.sfgate.com/business/article/Biologics-Modular-Files-New-Patent-Applications-2365684.php.
BPSA. Single-use (Disposable) Systems FAQs. Bio-Process Systems Alliance. [Online] [Cited: 9 April 2013.] http://www.bpsalliance.org/faq.html.
Coggins, E. Faye, et al. 2012. Ninth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production: A Study of Biotherapeutic
Developers and Contract Manufacturing Organizations. s.l. : BioPlan Associates, 2012. http://www.bioplanassociates.com/images/9th_Annual_2012_
ReportTable_of_Contents.pdf
Gupta, Vikas. 2011. Delivering Process Improvements Through Single-Use Operations And Lean Strategies. Pharmaceutical Processing. 14 July 2011.
http://www.pharmpro.com/articles/2011/07/delivering-process-improvements-through-single-use-operations-and-lean-strategies
Langer, Eric. 2012. Single-Use Recycling Mismatch: BioPharmaceutical Manufacturers Missing An Opportunity. Life Science Leader. November 2012.
http://lifescienceleadermag.epubxp.com/i/90693/17
Rader, Ronald A. and Langer, Eric S. 2012. Upstream Single-Use Bioprocessing Systems: Future Market Trends and Growth Assessment. BioProcess
International. February 2012, Vol. 10, 2, pp. 12-17. http://www.bioprocessintl.com/multimedia/archive/00174/BPI_A_121002AR04_O_174212a.pdf

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