Mab manufacturing

today and tomorrow.

Reducing risk, reducing cost.

Reducing costs, informing decisions, insight for innovation.

Summary
Monoclonal antibodies are expensive to develop and to
manufacture. There is a clear need to reduce costs and
manufacturing risk in order to support new chronic indications and
extend their reach in the developing world.
BioSolve Process is used to study different process scales, products
and facility operations (multi component, multi product). In this
study it is used to address some fundamental questions relating to
the large scale manufacture of an antibody at 5 tonnes per year:
What can current stainless steel technology deliver?
Modelling in BioSolve Process shows that for a traditional six
pack stainless steel facility, a cost of goods per gram of $35 can
be achieved with a capital investment of $352 million into the
manufacturing plant.
What is the potential for modular single-use facilities?
BioSolve Process shows that a modular single-use facility can
deliver a comparable cost of goods at $38/g but with a 30%
reduction in capital investment at $250 million, achieved by
shifting cost from fixed to variable costs. Combined with faster
builds and easier reconfiguration, this allows adoption of a scaleout approach that significantly reduces overall manufacturing risk.
What is the potential for continuous processing facilities?
BioSolve Process finally reveals that combining continuous
technology with modular single use technology has the potential
to reduce the capital requirement to just $80 million and a
resulting cost of goods of $32/g, with the potential for even
greater reductions to around $15/g. Continuous technology has
the potential to reduce costs and significantly reduce risk, making
it easier to widen patient access and manufacture locally.
Note that quality in process test costs have been excluded, and the
analysis is based on a standard three-column chromatography
process. In this paper, BioSolve Process is used to analyse the case
of a large-scale single product but the tool can easily be applied for
different scales, product types and multi-product facilities.
Subsequent studies will return to this theme and look further at
quality testing strategies and the quantification of risk. If you would
like to be informed when these studies are published, please
register at www.biopharmservices.com

Analysis
The largest and fastest growing segment in biopharmaceuticals is
monoclonal antibodies, which are typically used to address unmet
acute conditions in the developed world. These novel antibodies are
expensive to develop and manufacture and, as the biopharma
industry seeks to develop them for chronic indications and to
extend their use into the developing world, there is an increasing
requirement to substantially reduce the cost to the patient.

One significant component of this cost is

manufacturing. In this study, we addressed three key
questions regarding manufacturing cost:
1.What can current stainless steel technology deliver?
2.What is the potential for modular single-use facilities?
3.What is the potential for continuous processing
facilities?

Answering these questions provides insight into the current cost of

bulk drug substance in todays large scale manufacturing facilities,
while also exploring the potential for state-of-the-art technologies
to have an impact on manufacturing costs, both now and in the
future.
In the creation of this study, we used the industry standard
modelling software, BioSolve Process, to address these
questions. The study focuses on very large scale processes in
the region of five (5) tonnes per annum of bulk antibody,
targeting a large patient population in the developing world.

What can current stainless

steel technology deliver?

The current state of the art manufacturing

technologies for this scale are large six pack
stainless steel facilities. Determining what these
facilities can deliver in terms of cost is key; a
question that depends greatly on factors
including bioreactor size and titres.
Using the multi variable analysis tools in
BioSolve Process, it was possible to model three
different options at around 5000 kg/yr
throughput:
Option 1

Option 2

Option 3

Bioreactor size

10,000L; 7g/L

15,000L; 5g/L

20,000L; 4g/L

Cost of goods

$34/g

$35/g

$38/g

Capital investment

$304 million

$352 million

$399 million

All three options compare well with smaller

throughputs, which typically see cost of goods
in excess of several $100/g.
From a manufacturing cost perspective, the
option that best represents a state of the art
titre is 5g/L. Option 2 represents the required
facility in stainless steel to provide 5000
kg/yr.However, the capital investment and fixed
operating costs required to achieve this are
significant (note that the figures above only
cover direct capital investment costs).
Conclusion
While compelling in terms of cost of goods,
this approach locks the manufacturer into a
fixed technology with large overheads. If
the process is not certain and if it is not
known whether the product will achieve the
required sales, this becomes a high-risk
approach.

What is the potential for

modular single-use facilities?

When looking at the potential of using the latest

modular single use technologies, the key issue
is one of scale. The maximum disposable
bioreactor size is 2000L, so if a scale out
approach is adopted, will it give the same cost
outcomes?
BioSolve Process is an ideal tool for doing this
type of analysis as it can quickly execute
multiple process comparison analyses and
assess facility fit before users make a decision.
Modelling in BioSolve Process shows that
approximately 30 2000L bioreactors are
required to meet the target throughput, which
can be built in modules of 15 bioreactors.

But this is not the whole story. The rapid

analysis in BioSolve Process shows that the
total capital investment is $250 million for two
15 bioreactor modules. This is a significant
reduction from the $352 million capital
investment required by the optimum approach
with current stainless steel technology and
represents a key decision-point from a risk
management perspective.

The questions then become:

What is the best harvest strategy?
Should the outputs be pooled?
If so, which configuration is optimal: one,
three, five or 15 reactors?
The scenario analysis capability of BioSolve
Process can provide these answers quickly.
By running these six scenarios, the lowest cost
of goods was seen when the bioreactors are
harvested in groups of three or five. In this
case, a cost of goods of $38/g was achieved,
which is interesting as it shows a similar result
to the traditional large scale stainless steel
plant.

Conclusion
A modular single use approach allows the
facility to be rapidly turned around for
new products for minimal cost compared
to a traditional stainless steel facility. In
addition:
The capacity build can be phased in line
with the demand profile
The fixed running costs are less
The upfront capital is significantly
reduced by about 30%
The build-time to bring new capacity on
board is greatly reduced
The key conclusion is that taking a small
scale modular build out route can produce
an equivalent cost of goods, while
reducing scale and upfront capital, and
greatly increasing operational flexibility.
We will explore the financial implications
of this in a later study.

What is the potential for

continuous processing?

The final step is to examine the potential of

next generation of continuous processing
technologies combined with modular design and
single use systems.
Using the continuous processing operations
available in BioSolve Process, it was possible to
model a 2000L single-use bioreactor operated
in perfusion mode.
In this case, the relative titre (comparing
perfusion titre to traditional fed-batch) is
important. The base case with perfusion titres
was set at 1.0g/L compared to the 5g/L for fedbatch to represent legacy processes.
Recognising the significant improvements
achieved using high cell density devices and
modern cell retention devices, the impact of
improved titres up to 7.0g/L was considered.
The cost of cell culture media, which is a major
cost component in legacy perfusion processes,
was also considered.

Continuous processing can continue to be

improved by targeting media cost reduction and
also through recognition that titres are likely to
improve significantly as cell line productivity
and cell density in the bioreactor are increased.
BioSolve Process enables examination of these
factors in detail using the products sensitivity
analysis tools. In this case, titre improvements
combined with reduced media costs were
considered.
This analysis shows that it should be realistic
within a titre range of 2 g/L to achieve a target
cost of goods in the $15/g to $20/g range at 5
tonnes per annum with continuous operations.
In addition, there is a real opportunity to get
between 10 to 15 g/L with titres above 4 g/L
and optimised media costs.

When looking at the legacy titre and the

modular build, BioSolve Process shows that a
cost of goods of $32/g can be achieved for an
upfront capital investment of about $80 million.
This is a significant improvement on the
baseline stainless steel facility results,
delivering a 10% reduction in cost of goods and
a 73% reduction in upfront capital.
More potential savings can be found when cost
distribution by category is analysed, showing
that media and resin costs dominate,
representing 47% of the cost of goods.

Conclusion
Of course, for a new technology like
continuous processing there are many
unknowns, but BioSolve Process
demonstrates the significant potential to be
gained from marrying continuous
technologies with portable modular build.
This technology has the potential to
radically change the nature of large-scale
biomanufacturing. Access to this
knowledge through BioSolve Process can
make it easier for the industry to widen
patient access and implement local
manufacturing.

Background
Biopharm has over 15 years experience in assessing the impact of
new technologies and process options in the manufacture of
biopharmaceuticals. We work with all the key stakeholders
suppliers, innovators, academics and the major manufacturers. As
a consequence, not only are we made aware of new innovative
technologies early on, we have unparalleled insight into their
impact on process and manufacturing from an operational and
economic perspective.
This experience has helped us shape our modelling package,
BioSolve Process, and to embed in it our collective experience.
BioSolve Process is accepted by the bioprocessing community as
the standard for analysis of innovation. Our users feedback helps
shape the product, making it more relevant with every update.
BioSolves modelling framework has demonstrated its flexibility as
successive innovations have been readily incorporated in the
platform.
Milestone achievements include:
All the major transgenic players have used Biopharm to model
their technologies from corn and animals to eggs
Alternatives to protein A were being explored by Biopharm as far
back as 2005
Biopharm is recognised for supplying a coherent analysis of the
impact of single use technology from 2002 until today
Since investigations into the impact of continuous processing
started in 2008 Biopharm has been working closely with many of
the leading companies, users and suppliers
During this period Biopharm has worked with users and suppliers
to understand the implications of new process routes, Pichia, cell
therapy, gene therapy, vaccines etc.
In 2012 the industry recognised Biopharm founder Andrew
Sinclairs contribution by nominating him for thought leader of
the decade in the area of process knowledge management. In
2014 he was elected by his industry peers to become a Fellow of
the Royal Academy of Engineering
BioSolve software is now accepted by many leading companies as a
means of ensuring a consistent approach to innovation and process
analysis. This is achieved by using the platforms ability to
standardise and control data sets and methods. Biopharms
experience and knowledge of the platform means we are able to
analyse and assess technologies and processes in an efficient and
cost effective manner.
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