M anufacturing

Single-use
Bioprocess Containers
Economics of usage in Asia

Extensive adoption of single-use products in manufacturing has shown considerable

cost reductions by limiting initial capital costs, utilities required and cleaning validation etc.
Do they promise the same benefits in the Asian manufacturing scenario,
where overall cost of production and labour are significantly lower than in the West?

ceutical industry which is primarily

Swapnil Ballal, Head, Biopharmaceutical Bulk Manufacturing, based on biogeneric products, lower
Intas Biopharmaceuticals Ltd., India labour costs and low-cost operations. In
a scenario where the CMOs not catering
to the local market and very few innova-
tions taking place in biotechnology, the

S
ingle-use disposables have
become a common name in
the biomanufacturing indus-
try world over. All major companies
related to equipment and filtration
products are present in this domain.
They are increasing their presence
by introducing more products in the
disposable / single-use format. Some
of the well-known benefits are:
• Lower capital investments
• Cost savings in cleaning and
sterilisation
• Elimination of cleaning validation
requirements
• Speed of deployment and batch
changeover
• Flexibility of operating scales.
Increasing implementation of
single-use technologies clearly indi-
cates that their benefits are attractive
to the users.
Drivers of single-use technology
More than 1,000 biotech-based new
drug entities are in various pre-clinical
and clinical phases. A large number
of such leads are being developed by
startups and small sized firms with one
to four lead candidates in their devel-
opment pipeline. Since manufacturing
plants take years to be built and costs
run into hundreds of million dollars,
most biotechnology companies are reluc-
tant to make investments to support a
therapeutic candidate still undergoing
clinical trials. They rely on Contract
Manufacturing Organisations (CMOs)
for facilities and production expertise.
This allows them to focus their resources
on product development and establish
a proof-of-concept in clinical trials.
Meanwhile, CMOs executing short-
term production requirements benefit
from the fast turnaround and flexibility
offered by the single-use products while
limiting allied activities like changeover
and cleaning validation.
The operating dynamics in Asia
are quite different from the developed
markets. This is largely due to the busi-
ness model of the Asian biopharma-
benefits of single-use technology using
bioprocess containers as a model in
Asian scenario can be reconsidered.
Capital investments
Asia benefits from having a well-devel-
oped steel fabrication set-up for the
production of customised GMP vessels
and related fabrication. A large number
of EMEA and US FDA plants in India
and in other parts of Asia make use of
such indigenous fabricators.
A 200−500 litres mixing tank
for buffer preparation costs around US$
50,000 in India, which includes a jack-
eted pressure vessel with Clean-In-Place
(CIP) / Sterilize-In-Place (SIP) pres-
sure ratings, magnetic agitator, pH and
temperature controls. Fabrication costs
for similar units in the West are one and
half to three times higher. The differ-
ence in cost is mainly due to the overall
lower operating costs and low-cost
skilled labour and not necessarily
due to the usage of lower quality
components.

56 P h a r m a F o c u s A si A ISSUE-7 2008

On the other hand, a 200-litre bag
holder with jacket and magnetic stir-
rer would cost around US$ 40,000 to
60,000 depending upon the configu-
ration selected. Additional accessories
like tubing sealer, tubing cutter etc.
would take the cost to US$ 90,000.
pH, conductivity and temperature
control requirements further increase
the cost.
A. Sinclair & M. Monge showed
that adopting a single-use Bioprocess
Containers (BPC)-based manufacturing
system could result in overall capital
saving of about 20-40 per cent over the
traditional Stainless Steel (SS) fixed tank
set-up in US or Europe. The major differ-
ence in Cost of Goods (COG) is due to
the reduction in capital charges, smaller
size of utility systems and decreased
manpower for Quality Assurance &
Quality Control for a disposable-compo-
nent-based concept plant.
With products like SS tanks, CIP /
SIP skids and other customised engi-
neering products and piping available
in Asia at a cost that is less than 25-50
per cent that of the US and Europe, the
difference in capital investment between
a plant with BPC set-up and with fixed
SS tank decreases to a near equal level,
if not to a lower one.
Operating cost
The cost of cleaning and sterilising a
SS fixed tank is directly related to the
cost of utility required. While the reduc-
tion in absolute quantity of utility may
look very significant in terms of volume,
the cost of CIP and SIP operation may
actually be only a fraction of the cost
of the bag itself. The cost of generating
purified water / WFI is in the range
of US$ 6 to 10 for 1,000 litres. For
the cleaning of a 200-litre tank with a
highly unoptimised CIP cycle, requiring
1,000 litres of water, one would spend
less than US$ 10 of utilities in each
run, while a single 200-litres bag alone
costs above US$ 250. A process using
five bags each day working 150 days in a
year would require US$ 187,000 worth
M anufacturing
of bags alone against US$ 7,500 worth
of utilities for a fixed tank.
Elimination of cleaning validation
EU/US
requirement
Cleaning validation is portrayed as Cost of goods comparison
one of the biggest cause of stress for
Traditional Disposables
bio-manufacturers. The gap between
Concept
practice and regulatory expectation has
Labour 200.1 154.4
been decreasing over the years. As per
ranking of total GMP deficiencies by Material 61.5 57.0
EMEA between 1995 and 2005, clean-
Indirect 82.2 74.2
ing validation comes at 23rd place with Material
only 1.3 per cent deficiency attributed Consumables 40.8 76.3
to the category of cleaning validation
and only one critical deficiency out Capital 149.1 83.7
of 193 deficiencies cited during the Total 534.0 445.6
period, indicating that regulators are
Savings 0% 17%
satisfied with the approach and extent
of cleaning validation. Adapted from: A Sinclair and M Mongo, Bioprocess
Cleaning validation of buffer and International 3(9): S51-55 (October 2005)
process intermediate tanks consume Table 1
additional resources over the set-up
based on BPC. The cleaning of buffer Contribution of individual cost
tanks in itself is easier to validate since
these are not expected to contact and
head to cost of goods
contaminate the product and product Traditional
carryover issues are minimal. Cleaning
validation of intermediate holding tanks
can be reduced by intelligent and judi-
cious selection of worst case scenario
and bracketing to minimise the number
of runs required for validation.
The point being emphasised here
is that the science of cleaning valida-
tion is well established and since one
would require cleaning validation of
other plant equipment like fermenters,
chromatography systems and columns, Disposables Concept
the set-up for cleaning validation would
anyway exist and, therefore, it would
only be the case of increasing the scope
of the cleaning validation.
On the other hand, the use of bags
is most practical for contract manu-
facturers since it eliminates cleaning
validation studies for a different product
each time.
Additional validation requirements Figure 1
The use of single-use disposable systems
brings a whole new set of validation
w w w . p h a r m a f o c u s a s i a . c o m 57
M anufacturing
requirements, which are at times more
complex in nature than cleaning vali-
ASIA dation, largely due to the limited
knowledge base and regulatory expo-
sure. These are compatibility testing,
Cost of goods comparison extractables and leachables testing,
mixing efficiency testing, leak testing,
Disposables
endotoxin, short-term and long-term
Concept
stability testing and sterility validation.
Labour* 50.0 38.6
These are generally product-specific.
Material 61.5 57.0 Though reduceable for similar buffers,
they still require product-specific test-
Indirect material 82.2 74.2
ing for each product and intermediate.
Consumables 40.8 76.3 The analytical methods involved range
Capital** 104.4 71.1 from pH, conductivity to LC-MS, GC
& GC-MS based analytical tools. The
Total 339.0 317.0 cost of carrying out the same also needs
Savings 0% 6.4% to be factored. Moreover, major bag
manufacturers use different resins and
* Considering labour cost in Asia is 25% of that
of US/EU probably different moulding procedures
­** Considerig 30% lower capital for traditional and and chemicals. Simple substitution is
15% lower capital for disposable plant in Asia not possible as in the case of stainless
Table 2 steel tanks, thereby increasing the reli-
ance on a single bag manufacturer.
Contribution of individual cost Cost of Goods analysis
head to cost of goods The Cost of Goods (COG) for any
manufacturing process plays a decisive
Traditional Plant role in acceptance of the technology.
As shown in Table 1, COG compari-
son of a traditional steel vessel-based
plant and a disposable concept plant
indicates a saving of 17 per cent using
disposable technology. Contribution
of each major head is shown in
Figure 1.
Considering a 30 per cent lower
capital cost in Asia for traditional
plants and 15 per cent for disposable
Disposables Concept Plant plant (since disposables set-up is to be
imported), it is seen that the savings
using a disposable set-up are reduced to
about 6.5 per cent (Table 2 and Figure
2). If import duties on the disposable
components are added at the current
rate of 30 per cent in India, the COG
for a traditional plant would be lower
than that of the disposables.
With the continuous increase in price
of crude oil and that of the base plas-
Figure 2 tic resin, operating cost of plants using
plastics may keep on increasing, while a
58 P h a r m a F o c u s A si A ISSUE-7 2008
steel set-up once installed would not add
significantly to operating expenses.
Decreasing the disposable prod-
ucts cost by about 30 per cent and
eliminating import duties would make
the scenario for adopting disposable prod-
ucts and technologies favourable. This
cost reduction can be brought about by
offering better pricing for Asian markets
and by exploring the possibility of manu-
facturing such units in Asia itself.
Drivers for adopting single­-use
disposable containers in Asia
Users from the US and Europe whose
revenue came from contract manufactur-
ing were the early adopters of disposable
technology. Adopting the technology
brought immediate reduction in capital
with quick turnaround time.
However, in Asia, the focus is still
on the manufacturing of biologics for
captive use. Since the market for such
products is highly cost-sensitive, increase
in the overall cost of the finished product
is critical. Since many of these plants
operate mono-product lines / set-up,
the need for adopting BPC set-up may
not be very high.
In situations where living organ-
isms are handled, single-use products
can ensure the safety of the product as
well as the operators, and thus would
find early acceptance.
Contract manufacturers in Asia would
also find single-use products useful,
though such manufacturers are limited
in number as of now. Single-use products
would also find their use in scale-up and
development labs, which have limited
set-up for tank processing, allowing them
to process on a larger scale in an R&D
set-up.
One of the areas where single-
use disposables set-up can be of great
interest is finished dose manufactur-
ing. The existing fill-finish facility
can be adapted to single-use set-up
without disturbing the existing set-up,
allowing manufacturers to have a greater
degree of assurance as well as flexibility
of scale.

In addition to the above, facilities
which are limited in capacity due to
utility limitations like Water For
Injection / clean steam can benefit from
use of the single-use bioprocess bags.
Conclusion
In the European and US scenario,
there is possibly a clear capital invest-
ment benefit in adopting the single-use
bags and tanks. The same may not hold
true in most Asian countries, where
steel fabrication and labour costs are
low.
The decrease in efforts in carry-
ing out cleaning validation of fixed
system needs to be evaluated critically
against the cost of additional validation
related to compatibility of plastics with
process fluids.
Potential adopters of single-use
bioprocess vessels need to carry out
M anufacturing
a critical evaluation of economic flexibility while making full use of the
benefits while selecting between fixed advantages of single-use systems.
tank system and single-use system.
They should also perform a Acknowledgements: I wish to thank Mahesh
thorough cost-analysis on their own Kodilkar of Intas Biopharmaceuticals
before singling out one option. Ltd. and Vishal Wagh, Director, adam
Scenario of a hybrid system with fabriwerk, Mumbai for their valuable
a fixed non-product dedicated set-up contributions.
like buffer preparation, transfer and hold
with single-use product contact can also Full references are available on
be a good compromise between cost and www.pharmafocusasia.com/magazine/
Swapnil Ballal is currently heading India’s only EU-GMP approved
biopharmaceutical plant at Intas Biopharmaceuticals Ltd. Being
A uthor
associated with the Indian biotechnology industry for the past 12
years he is presently overseeing manufacturing of 4 bio-therapeu-
tics products along with contract manufacturing projects. He joined
Intas in 2000 and played key roles in the set up of the biotechnol-
ogy and R&D divisions and the manufacturing plant for biologics.
Prior to Intas, he worked for Wockhardt Research Centre. He
received his MSc in Marine Biotechnology from Goa University and
holds professional membership at PDA and ISPE.
w w w . p h a r m a f o c u s a s i a . c o m 59