Elu•cida•tion
Addressing the Challenges of
Developing Biopharmaceutical Drugs
Stefan Schlack
T
Figure 1: Heavy competition in phase 3
pharmaceutical development
50
Drugs in Phase 3 (%)
he biopharmaceutical industry is
enjoying considerable success. Its
products account for about a fifth
of world pharmaceutical revenues, which
are growing at twice the pace of those
generated by most traditional chemically
synthesized drugs. Biopharmaceuticals
populate the list of best-selling drugs,
and a number have achieved blockbuster
status. Biotechnology stocks have
outperformed the general market as
investment has flowed into the industry.
As with other highly
profitable markets, the market for
biopharmaceuticals has become
increasingly competitive. Reflecting
this fact, in September 2015 Sandoz
launched Zarxio (filgrastim-sndz), the
first biosimilar product approved by the
US Food and Drug Administration for
use in the United States (1). Competition
from a tide of biosimilar products is on the
way, forcing biomanufacturers to consider
how best to optimize their operations
for maximum efficiency and lowest cost.
The following figures show analysis of
2016 data from Evaluate Pharma (www.
evaluategroup.com).
Figure 1 indicates the degree of
44%
40
30
24%
20
13%
18%
10
0
>3
3
2
1
Competitors in Phase 3
competition within the pharmaceutical
industry today. More than half of drugs in
phase 3 development must compete with
at least one rival product. The industry
expects that about one in four products
at this phase of clinical development will
compete for market share against more
than three other drugs. Developers must
have high-titer, optimized bioprocesses to
succeed in this increasingly competitive
environment.
The need for greater manufacturing
efficiency exacerbates an existing
challenge that biomanufacturers must
address. Critically, they must beat their
competitors in the race to identify a
High
100%
88%
50%
NA
92%
40%
A compelling strategy
for all stake-holders
Medium
Faster speed to market
Low
Communicated Therapeutic Advantage
Figure 2: Value captured as a function of time (market entry) and therapeutic advantage; limited
value is captured beyond first/best-in-class launch order.
First launch
(n = 16)
54 BioProcess International
88%
36%
8%
3%
8%
2%
Second
launch
Third launch
Fourth launch
(n = 14)
14(10)
N ovember 2016
Second player
entering market
averages 88%
revenues of firstplayer’s value capture
target molecule, protect their intellectual
property, and launch a product onto
the market so that patients can benefit.
Failure to win that race has an enormous
impact on the financial success of a
drug development project. Developing
optimized bioprocesses in this context
further compounds the challenge.
Companies whose biologic products
reach the market first, with the greatest
therapeutic advantage, capture the most
value (Figure 2). They need a compelling
strategy for their products that addresses
the requirements of all stakeholders. The
second player to enter a market achieves
an average 88% of the revenues of a first
mover. A third player can expect just 50%
of the value captured by the first company
to market.
Figure 3 shows the additional revenue
that a company can capture over a
product’s life cycle if it can launch
candidates earlier . That does not include
revenues gained through additional
months of sales, but it constitutes the
commercial benefit obtained for the
total product lifespan. Under the most
competitive scenario with five companies
competing, shortening development time
by a single month yields an additional
€44 million of revenues. A four-month
reduction in biologic development time
gives additional revenues of €174 million.
To address the need to increase speed
to clinic, biopharmaceutical companies
probably will have to adapt their
approaches to drug commercialization.
They are likely to outsource services
that external providers can perform
more efficiently and effectively than
they can, thereby expediting biologics
through early and late-stage development.
Biomanufacturers no longer need
to automatically perform cell line or
analytical development in-house. By
outsourcing to companies that provide
“off the shelf ” services, they can
accelerate development without increasing
headcount. Applying platform production
methods for biologics of the same family
reduces process development time.
High-throughput screening tools are
already widely adopted to help companies
understand optimum platform process
operating parameters. That can save
weeks of development time.
The industry will benefit from
applying quality by design (QbD)
principles and focusing on process
robustness to ensure good product quality
and operational excellence. In my view,
however, robust and well-characterized
processes are more likely to scale up on
the first attempt without needing rework
that can delay projects by months. Intense
efforts to define process design spaces will
facilitate the transfer of biologic products
across global manufacturing networks.
Such networks must be flexible and agile
to make a range of products and cope
with peaks and troughs in demand.
Fortunately, successful operation of
robust and highly controlled commercialscale bioprocesses no longer depends on
capital-intensive stainless steel plants
with associated utilities infrastructure.
Single-use technology has matured
to enable widespread implementation
of disposable yet robust commercial
processes. Applying such technologies
shortens timelines and significantly
reduces the cost required to design,
build, and commission biomanufacturing
facilities. Lower-cost facilities risks less
capital should a product fail on clinical or
commercial grounds because a competitor
reached the market first.
On the other hand, disposables allow
companies to build direct-replica facilities
in global locations, enabling rapid process
Figure 3: Additional revenues (in millions of
euros) over commercial lifespan through
earlier commercialization
Competitors Developing Drug
Elu•cida•tion
5
€44 m
€87 m €131 m €174 m
4
€30 m
€60 m
€90 m €120 m
3
€16 m
€32 m
€48 m
€64 m
2
€3 m
€6 m
€8 m
€11 m
1
2
3
4
Development Time Reduction (months)
transfer and capacity expansion if demand
becomes greater than projected. That
can be the case when companies identify
additional indications against which a
drug will work or receive market approval
in other countries. In the past, when
companies relied on dedicated, stainless
steel facilities, such events could easily
lead to production bottlenecks.
The introduction of robust yet
flexible production platforms is timely.
My company’s industry analysis in
recent years predicts that adaptive
global biomanufacturing capacity
will be strategically important for
biopharmaceutical leaders. The specificity
of biologics and increasing intensity
of competition are reducing estimated
peak sales for new products. Sponsors
are finding it difficult to identify and
commercialize biotech blockbusters.
Figure 4 illustrates a trend toward
products with lower estimated peak sales
between 2008 and 2013. The time it
takes to reach peak sales is increasing
as companies pursue a strategy of
serially expanding the number of target
indications throughout a product lifespan.
Figure 4: Estimated peak sales of drugs launched 2008–2013 (by launch year)
$2 billion +
New Launches (%)
100
80
60
13%
20%
20%
40
$1–2 billion
9%
34%
8%
23%
$.75–1 billion
$.5–.75 billion
9%
9%
13%
10%
13%
17%
13%
9%
22%
25%
$.25–.5 billion
6%
9%
33%
27%
28%
64%
34%
20
0
15%
13%
12%
2008
643
2009
977
$100–250 million
30%
30%
33%
2010
707
2011
687
2012
418
Average Peak Sales By Launch Year (US$millions)
2013
264
To sustain their growth trajectories,
sponsors must have rich candidate
pipelines and manage them effectively.
Those pipelines are becoming increasingly
diverse, adding complexity. By designing
flexibility into their global production
footprint, bioexecutives can manage
uncertainties and guard against risks
associated with pipelines of diverse drug
candidates for niche patient populations.
Flexible manufacturing capacity allows
biopharmaceutical companies to adapt
operations as they gather data on the
clinical performance of pipeline products.
This allows them to make varying
numbers of products in different annual
quantities depending on data generated
from clinic trials.
That newfound flexibility is
facilitating operations managers’ decisions
to expand their companies’ global
manufacturing footprints and access
rapidly growing markets in territories all
over the world. Governments can demand
localized manufacturing as a precondition
for approval of market licenses or provide
disincentives to overseas production
through high import taxes. Local
biomanufacturing is often beneficial
for drug producers because it simplifies
supply chains.
Figure 5 suggests the extent to
which the biopharmaceutical industry
has expanded capacity and extended
its geographic reach over recent years.
Transferring processes effectively through
global manufacturing networks will be
a core competency that companies must
master. Fortunately, as more digitization
benefits other industries, so too will it
revolutionize bioprocessing. Advanced
process analytical tools will help process
engineers construct digital fingerprints
of bioprocesses operating in one location
and compare them with those at new
sites. They can thus make interventions
to transferred processes that ensure
matching product quality attributes for
all sites.
The biopharmaceutical industry is
responding to escalated competition
through improved operational efficiencies
and shortened product development
timelines. To implement their growth
strategies, companies will need agile
and flexible global operations that
allow them to respond to uncertainties
N ovember 2016
14(10)
BioProcess International
55
Elu•cida•tion
in market demand. I expect that they will face increasingly
complex global supply chains. Those must respond to changing
market dynamics through focus on quality and robustness of
technologies, providing long-term assurance of supply, and
improving product delivery performance. Suppliers must be fully
capable of delivering products/services and supporting customers
all over the world. Innovations in all these areas will help the
industry continue to grow even as it matures.
References
1 Peters RC. Framing Biopharma Success in 2016: Corporate
Restructuring, Regulatory Initiatives, and Biosimilars Will Shape
Biopharma Development in 2016. BioPharm Int. 29(1) 2016: 8–11. •
Stefan Schlack is senior vice president of marketing and product
management at Sartorius Stedim Biotech, August-Spindler-Straße
11, 37079 Göttingen, Germany; 49-551-3080; stefan.schlack@
sartorius-stedim.com.
Figure 5: Trends toward localized production by major biopharmaceutical companies (select examples*)
Kaluga, Russia
US$100 million insulin
manufacturing plant
completed in 2015
Mumbai, India
US$136.5 million
manufacturing and packaging
facility to be complete in 2017
Ireland
US$900 million biologics
production plant
completed in 2019
Telangana, India
US$100 million insulin
production facility to be
complete in 2019
Colorado (USA)
Acquiring a bulk biologics
production facility from
Amgen in 2017
Shanghai, China
US$107.7 million diabetes and
thyroid drug production plant
to be complete in 2017
Puerto Rico
Expanding two
manufacturing facilities
Shanghai, China
US$95 million R&D and
manufacturing facility to be
complete in 2018
Algiers, Algeria
US$125 million joint venture
with two local companies
to be complete in 2017
Wuhan, China
biosimilars and biologics
manufacturing facility
completed in 2016
Singapore
US$200 million monoclonal
antibody facility
completed in 2014
* Sources: press search, www.pharmaceutical-technology.com; Fierce Pharma (manufacturing)
INDEX OF ADVERTISERS
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AJINOMOTO ALTHEA, INC.
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ASK THE EXPERT - ILC DOVER
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LONZA
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ASK THE EXPERT - NOVASEP
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MABPLEX
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FINESSE SOLUTIONS
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FUJIFILM DIOSYNTH BIOTECHNOLOGIES SR
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RICHTER-HELM
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GE HEALTHCARE, CELL THERAPIES
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THERMO FISHER SCIENTIFIC
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INFORS HT
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WACKER BIOTECH GMBH
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56 BioProcess International
14(10)
N ovember 2016