BioPharm
ELECTRONICALLY REPRINTED FROM JUNE 2015
INTERNATIONAL
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The Science & Business of Biopharmaceuticals
Biopharma Advances
Demand Specialized Expertise
Contract service providers share insights on biopharma market
developments and the implications of biosimilar drug approvals.
THE EDITORS OF BIOPHARM INTERNATIONAL
T
he approval of the first biosimilar in the
United States, as well as continuing consolidation in the biopharma and contract development and manufacturing markets, are just two
indicators of the ongoing evolution of biopharmaceutical development. Representatives of contract
service providers shared observations, trends and projections with BioPharm International.
Roundtable participants are Gary Chambers, business manager biopharma labs, Europe, SGS; Bill
Hartzel, director of strategic execution, Catalent
Pharma Solutions; Chris R. Lively, PhD, director of
biopharmaceutical ser vices, PPD; Scott Lorimer,
VP Global Operations, Patheon Biologics; Eugene
McNally, PhD, executive director, PPD Consulting;
Rekha Patel, global director, large molecules, development and analytical solutions, Catalent Pharma
Solutions; and Mark Rogers, vice-president, SGS
Life Science Services, USA.
REGULATORY AND BUSINESS TRENDS
BioPharm: What regulatory changes have positively or
negatively impacted biopharmaceutical development/
manufacturing processes?
McNally (PPD Consulting): F DA
e st a bl i she d a ne w O f f ic e of
Pharmaceutical Quality in 2014,
which we anticipate will have major
impacts on the biopharmaceutical development and manufacturing process. This reorganization
was designed to enhance quality
drug assessment by realigning several elements of the preapproval
and surveillance inspection process. Integrating risk-based review,
GMP inspection, implementation
of quality by design, and the new
FDA process validation guidance
within one office is expected to
significantly change the biopharmaceutical development and manufacturing process.
Har tzel (Catalent Pharma
Solutions): In today’s market, there
are sig nif icant manufac t ur ing
challenges in traditional glass vial
filling applications. These challenges manifest in quality issues
with the final container closure
and may be related to microbial
contamination, glass particulates,
and foreign materials that lead to
necessary market action causing
supply issues.
Lorimer (Patheon Biologics): The
greatest regulatory change in recent
times is the acceptance and approval
of biosimilars.
BioPharm: What business trends
have p osit ively or negat ively
impacted biopharmaceutical development/manufacturing processes?
Har tzel (Catalent Pharma
Solutions): Today there is a stronger
emphasis in the development lifecycle on the delivery of the molecule to the patient and not just
the molecule itself. Delivery/device
experts are being added to teams
at Phase II to improve the delivery
beyond the traditional vial.
Lively (PPD): Growing interest
in biopharmaceutical drug development necessitates partnering
between clients and contractors to
increase industry capacity, breadth
of capabilities, exper tise, and
the experience required to bring
these drugs to market. The client
will receive the most benefit by
selecting a high-quality contract
research organization (CRO) lab
that is able to meet its needs and
work collaboratively with the client to ensure timely development.
Lorimer (Patheon Biologics): The
trend of small biotech partnering with large pharma for clinical
manufacturing and development
has certainly facilitated the full
development of more novel molecules. Also, the increasing trend
toward outsourcing of GMP biologics manufacturing ensures bioprocessing and testing is performed
by expert manufact urers w ith
proven track records in quality and
biomanufacturing. This helps to
reduce the risk to clinical programs
and product safety.
TECHNICAL/SCIENTIFIC TRENDS
BioPharm: Can you describe productivity improvements your company has experienced from new
technologies?
Patel (Catalent Pharma Solutions):
Catalent Pharma Solutions has significant ongoing investments in
enhancing our large-molecule analytical capabilities and productivity to meet and advance current
industr y needs. Recent investments include the updated/new
technologies, new assay strategies,
and updated electronic systems
and processes.
Lively (PPD): Evolving characterization expectations for biologics
have driven improvements in analytical equipment, processes, and
systems. Ultra performance liquid
chromatography (UPLC) systems
have improved resolution and sensitivity, while reducing run times.
In addition, 2D high-performance
liquid chromatography (HPLC)/
Approval of the first
biosimilar in the
United States, as well
as consolidation in
the biopharma and
contract development
and manufacturing
markets, are just
two indicators of the
ongoing evolution of
biopharmaceutical
development.
high-resolution mass spectrometry (MS) allows for analysis of
samples incompatible with traditional MS. Reporter gene bioassays
apply genetically engineered cell
lines both to directly model mechanisms of action and to amplify
assays for improved performance
w it h shor ter inc ubat ions a nd
increased signal/noise relative to
standard bioassays.
Lorimer (Patheon Biologics): The
main productivity improvement
has been increasing the throughput of products in Patheon’s multiproduct biopharmaceutical GMP
facilities. Single-use disposable
bioreactors and similar single-use
bioprocess equipment minimize
plant downtime, which is traditionally required for line clearance
and product changeover. The complexity of product changeovers is
reduced by single-use technology,
which decreases the need for cleanin-place, steam-in-place, and quality control testing. Typically, line
clearance time is reduced by several days.
Rogers (SGS Life Science
Services): As an analy tical service provider, SGS is constantly
in search of means to improve
its laboratory efficiencies, particularly those that enhance turnaround time without adversely
effecting qualit y. With this in
mind, substitution of HPLC for
U P L C , r ap id m ic r o b iolo g ic a l
screening methods, and investment in automated approaches to
complex analytical problems such
as protein sequencing are now
being used within the SGS laboratory network.
Chambers (SGS): From a CRO
point of view, the main productivity improvements in analytics
have been from higher throughput systems and data analysis. The
move to these faster systems with
semiautomated data processing has
allowed us to improve turnaround
times which are passed on to clients in terms, who win on faster
to market times and faster go/no
decisions.
BioPharm: What additional technology improvements are needed
to improve the efficiency of bioprocessing?
Lorimer (Patheon Biologics):
P rocess a na ly t ica l tech nolog y
(PAT) for continuous monitoring of
bioprocesses is helping reduce the
variability on biopharmaceutical
manufacturing.
Also, biopharmaceutical development and process validation
have been accelerated by the use
of mini-bioreactor systems, which
enable a large amount of process
development data to be generated within a very short timeline.
These multi-bioreactor systems
c a n r e d u c e p r o c e s s d e v e lo p ment timelines by months when
applied to early-stage or late-stage
bioprocesses.
Rogers (SGS Life Science Services):
The development of many technologies follows a common path
f rom academia to commercial
application and nowhere is this
more evident than in the field of
bioprocessing. In almost all examples, the key to this progression
lies in the ability to simplify operational aspects of the technology
and improve throughput. This has,
in the past, been clearly demonstrated in, for example, the field of
mass spectrometry and is currently
evolving with techniques involved
in biophysical characterization.
BioPharm: What is the greatest
technical challenge facing biopharmaceutical companies today?
Hartzel (Catalent Pharma Solutions):
Cost to manufacture will continue
to be a major challenge for the
industry, especially with the rise
of biosimilars and market pressures
to drive down the cost of medicines. However, the products that
are coming to market are more
targeted, which leads to smaller
batch sizes. This is counter to the
manufacturing adage of being able
to leverage economies of scale to
drive out costs, hence the need to
focus on alternatives technologies
and innovation to reduce the manufacturing costs versus economies
of scale.
Lively (PPD): Application of analytical techniques to better characterize innovator and biosimilar
or follow-on products by physicochemical and functional methods
are required and will continue to
be driven by the complexity of
biologics development. For example, changes in formulations may
cause different leachable profiles
requiring increasing emphasis on
extractables/leachables techniques
(i.e., high-resolution MS) to support characterization of formulation effects, identification of
degradation and impurities, and
determination of their potential
impact through application of
potency bioassays.
Lorimer (Patheon Biologics): Most
of the technical challenges for
manufacturing have been overcome, and the technologies for
development a nd ma nu fac t u ring have been widely adopted.
Perhaps the greatest challenge is in
clinical development of novel and
originator molecules, where in-vitro
model systems are still not a great
predictor of clinical performance.
Rogers (SGS Life Science Services):
To highlight one technical challenge above all others in today’s
biopha r maceut ica l indust r y is
very difficult. The complexity of
biotherapeutics often results in
considerable technical difficulties as, for example, in the area
of impurities; recognition of hostcell proteins (HCPs) and identification of structural variants at
trace levels are certainly high on
the list of technical concerns. The
necessary inclusion of relatively
elaborate analytical techniques
such as sedimentation velocity
analytical ultracentrifugation (SV–
AUC) within a traditional quality control release environment is
also not without problems.
BioPharm: What are the prospects for continuous manufacturing to be firmly established in
bioprocessing? What are the roadblocks to implementation?
Lorimer (Patheon Biologics):
C ont i nuou s pro duc t ion f rom
mammalian cell cultures has been
operated in perfusion bioreactors
for many years. The main roadblock for continuous processing is
downstream processing of proteins,
which currently demands discrete
and distinct unit operations for
removal of impurities, removal
of contaminants, concentration
of the products and formulation;
each in separate, controlled steps
CMOs Add Capabilities
Consolidation in the contract development and manufacturing market has
resulted in new capabilities and facility expansions.
In May 2015, CMC Biologics announced that it is expanding its
Copenhagen, Denmark facility to increase its manufacturing capacity
through the installation of six 2000-L bioreactors. The bioreactors can
be run singly or in groups, simultaneously or sequentially, and are part
of the company’s signature Bioreactor 6Pack single-use program. The
Copenhagen installation will begin initial GMP production in November
2015 and will feature three bioreactors to start. Three bioreactors will
be added at a later date to complete the configuration. Meanwhile, the
Bioreactor 6Pack at CMC’s Seattle facility will complete its first GMP run in
mid-2015 and will be ready for commercial launch by the end of the year.
Through its recent expansions, CMC plans to expand its global capacity by
more than 30,000 liters in the United States and Europe.
Also in May 2015, SAFC announced an expansion to its St. Louis, MO
facility to support the commercial-scale production of antibody-drug
conjugates. The facility, which is expected to be online and operational
in the third quarter of 2015, was designed to meet SafeBridge category
4 compound handling requirements for highly active or cytotoxic
compounds. The expansion of an existing Carlsbad, CA location will
enable SAFC to offer fill/finish capabilities of viral products to its clients in
the gene therapy, viral vaccine, and immunotherapy sectors.
Rentschler announced in March 2015 that a 2000-L bioreactor that the
company commissioned and built in six months is up and running. The
bioreactor will be integrated into existing manufacturing suites containing
two 1000-L single-use bioreactors, according to a company statement.
The company’s twin bioreactor system—designed for running two main
bioreactors in parallel with one shared downstream processing unit—
will be functional by 2017. The twin system is estimated to double the
company’s production capacities for cell culture-derived proteins.
In December 2014, FUJIFILM Diosynth Biotechnologies U.S.A. (FDBU)
acquired Kalon Biotherapeutics, adding viral and cell-culture vaccine
expertise and capabilities. In other activity, FDBU started construction
of a three-story, 62,000-ft2 facility in Research Triangle Park, NC, in
January 2015 to house the company’s process and analytical research
and development, process sciences, and stability groups. The expected
completion date is Q4 2015.
In September 2014, PCI, a provider of packaging services, acquired Biotec
Services International, a provider of clinical-trial services and temperaturecontrolled pharmaceutical services headquartered in Bridgend, Wales, UK.
The addition expanded PCI’s presence in the European Union and added
packaging, storage and distribution capacity, and consultative services for
clinical-trial supplies. In January 2015, Biotec announced the validation
of its clinical supply facility expansion, which added almost 50% to the
company’s clinical trial materials handling capacity.
and which are not currently amenable to continuous processing.
THE RISE OF BIOSIMILARS
BioPharm: W h at i mp a c t w i l l
biosimilar dr ugs have on bio pharma businesses, bioprocessing
approaches, and the contract services market?
Rogers (SGS Life Science Services):
The European biopharma landscape has already experienced
impact of the biosimilar drug market leading to rapid expansion of
traditional small molecule, generic
manufactures into the bio arena.
Recent FDA approval of the Sandoz
biosimilar, Zarixo, may be the seed
for similar changes in the US providing a potential new line of business for established pharmaceutical
companies. Contract service providers such as SGS, who already
have considerable experience with
biosimilars, are able to offer expertise to businesses new to this market and will no doubt benefit from
such expansion in the US.
Lively (PPD): Increased investment in biosimilars is driving
interest in improving and streamlining the development processes,
as well as the sensitivity and scope
of characterization assays used to
compare biosimilars and innovator drugs. The expanding capacity needs result in partnerships
between clients and their contractors with the systems, experience,
and expertise to achieve the quality and speed required, while meeting all regulatory expectations for
product approval.
Chambers (SGS): With nearly
2 0 yea r s e x p er ience p er for ming biosimilar analysis, the biggest impact had been the massive
increase in the characterization
needed for biosimilars compared
to innovators (although higher
standards are now needed for new
innovators too). This has resulted
in challenges in data handling,
interpretation and data presentation. Biosimilars have also caused
the re-emergence of orthogonal
techniques like size exclusion
chromatography–multi-angle laser
light scattering (SEC-MALL) and
SV-AUC for aggregation and circular dichroism (CD) and fourier
transform infrared spectroscopy
(FTIR) for higher-order structure
as critical analyses to understand
and compare and detect subtle
higher-order structural differences
between innovator and biosimilar
samples.
Hartzel (Catalent Pharma Solutions):
The rise of biosimilar drugs will
dawn the next generation of biologic manufacturing and force
the industry to look at new ways
of manufacturing to drive down
costs. Therefore, the industry will
seek new manufacturing partners
with strong technical expertise to
drive out costs through innovation
and operational excellence.
Lorimer (Patheon Biologics):
G e n e r a l l y, b i o s i m i l a r d r u g s
will encourage competitiveness
w it h i n t he biopha r ma sec tor.
Biomanufacturers expect increased
pressure on cost of goods and
pricing. Biopharmaceutical contract service providers with a flexible, multi-product operation and
proven track record in the industry are well placed to ensure careful control of manufacturing costs
and product quality. Processing
approaches won’t change in terms
of technology, but there will be a
greater emphasis on operational
excellence to reduce costly inefficiencies and improve yields from
bioprocesses. As more biosimilars
come to the forefront and as the
industry trend for outsourcing
continues, increasing operational
flexibility, while maintaining the
highest quality standards, will be
the keys to success.
BUSINESS CHALLENGES
BioPharm: What is the greatest
business challenge facing biopharmaceutical companies today?
Lively (PPD): As with all pharmaceutical drug development, the
greatest challenge is getting new
life-changing and potentially lifesaving drug candidates to market. Biopharmaceuticals face more
challenges than traditional smallmolecule drug products because
the science of characterization
of such biologic drugs is rapidly
evolving, along with the regulatory
landscape. Those companies that
are best able to successfully characterize and differentiate innovator
and biosimilar products for safety
and efficacy will have the greatest
opportunity to benefit.
THE KNOWLEDGE GAP
BioPharm: In what areas do you
see knowledge or expertise gaps in
current biopharmaceutical companies? Why do these gaps exist?
Lorimer (Patheon Biologics): There
is a gap in translating good science to industrial applications of
technologies that provide for reliable, efficient, cost effective manufacturing at commercial scale.
Maintaining a focus during early
development on eventual commercial manufacturing requirements,
while balancing limited development resources requires a broad
base of coordinated, organizational skillsets and a disciplined
approach.
Hartzel (Catalent Pharma Solutions):
Device/delivery expertise is an
area that has a potential gap. For
biologics, the historic default container closure has been a traditional glass vial. As the healthcare
industry seeks ways to improve
patient care and reduce costs, the
delivery to the patient needs to
adopt new technologies and this
is why we have seen a rise of pre-
filled syringes and autoinjectors.
These technologies will continue
to evolve and so will the demand
for device/delivery experts.
Lively (PPD): One of the challenges we see is the various levels
of knowledge and expertise that
exist between biopharmaceutical
R&D and the testing and regulatory industries. That differential is
impacting those industries’ ability
to fully consider and effectively
implement expectations and guidance for physicochemical and
functional characterization expectations of biologic drugs.
Lorimer (Patheon Biologics): The
commercial biopharmaceutical
industry demands global sourcing of materials, services, supply,
and ultimately distribution to each
patient. This requires a robust integrated supply chain to deliver high
value products to patients, on-time
and at the right quality. Doing this
reliably and efficiently with long
production lead times and uncertain market sales forecasts is an
industry wide challenge.
Speed-to-market remains a key
challenge to the development of
biopharmaceuticals. Speedy firsttime-in-man clinical trials can be
a major hurdle for small biotech
companies and large pharma alike.
Rogers (SGS Life Science Services):
I believe there continues to be a
significant problem in the level of
fundamental scientific expertise
within many biopharmaceutical
businesses. In part, this may be
attributed to the ‘kit’ and ‘black
box’ approach of many modern
day technolog ies. D ue to t he
complexity of many biopharmaceuticals, their development and
success as therapeutics requires a
comprehensive range of scientific
disciplines and expertise, which
can be difficult to fully realize
internally, particularly for small
and mid-size companies. BP
Posted with permission from the June 2015 issue of BioPharm International ® www.biopharminternational.com. Copyright 2015, Advanstar Communications, Inc. All rights reserved.
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