B Why Do So Many Biopharmaceuticals Fail? FOCUS

FOCUS ON...
QUALITY
Why Do So Many
Biopharmaceuticals Fail?
There’s No Substitute for Knowing Your Product
by James R. Zabrecky
B
iopharmaceutials and the
processes used to make them
are exceedingly complex, and
the path to developing new
therapeutics is a high-risk endeavor.
The emphasis today is on controlling
product quality, safety, and efficacy
through understanding biological
mechanisms, key product attributes,
and process parameters. Such
information is also crucial for guiding
development efforts to improve chances
of success in the clinic and for gaining
regulatory approval. Analytical
methods provide the foundation for
acquiring such knowledge. Efforts
devoted to developing meaningful and
reliable analytical methods early in
development will pay huge dividends
and can make the difference between
success and failure.
Drug development is a tough
business. Costs are astronomical, and
the odds of failure are about nine out
of 10 for every new drug that enters
clinical trials. Current estimates for
bringing a new drug to market are
over US$1 billion spent on an average
timeline of 12–15 years. High
development costs and the likelihood
of failure are major reasons why the
new generation of drugs, especially
biologics, are so costly. If not for
potentially high rewards, innovation
would grind to a halt because few
companies would consider investing
the time and expense required to
develop new therapies for treatment of
unmet human medical needs.
26 BioProcess International
December 2008
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Why is it that so many promising
drug candidates fail? Finding answers
to that question should help improve
efficiency of the process and speed the
transition of new medicines from
laboratories to market. Although much
discussion and effort have been put
into trying to identify some root
causes, the reasons vary widely, and
there have been few significant
improvements in the way drugs are
developed. Very few drug candidates
now in preclinical development will
ever see the light of day on the market.
Most drug candidates are based on
fundamentally sound scientific
foundations, but they can fail in the
clinic for a variety of reasons whether
or not they represent truly viable
therapeutics. Reasons range from
flawed clinical trial design (patient
populations, treatment regimens,
doses, endpoints, and so on),
unfavorable pharmacokinetics and
pharmacodynamics, to unanticipated
placebo effects, poor compliance with
the treatment, lack of follow-up, or
faulty data interpretation. But an often
overlooked factor that may play a
significant role in success is whether a
drug ever gets to its target, in a
consistent, active form and at the right
dose, so that it has a chance to
accomplish its intended task.
That is why product
characterization during preclinical
and early stage clinical development
plays such an important role. This
critical facet of the drug development
process is often abbreviated or
deferred because of naïve notions that
drug product attributes and
underlying biological mechanisms are
understood well enough to go
forward. That is especially true for
smaller biotech companies that often
are under fiscal constraints or pressure
from investors to enter into human
clinical trials as soon as possible. It is
far too common for a promising drug
candidate to be driven into the clinic
prematurely, long before its properties
and manufacturing processes are
understood well enough to give it a
reasonable chance of success.
Moreover, once human trials are
initiated, it becomes increasingly
difficult and risky to make the critical
changes that become necessary as
more product and process knowledge
are accumulated.
The consequences of cutting
corners in product characterization are
most apparent in biological
therapeutics. Small–molecular­-weight
drugs are simpler chemical entities
and thus are amenable to
characterization by an arsenal of
analytical tools that can explicitly
define their structure and the
attributes necessary for biological
activity. In addition, we know a great
deal about how to monitor their fate
once they are delivered to patients.
Biologics, on the other hand, are
large, complex macromolecules made
up of many components that
contribute to their structure, function,
and stability. Despite considerable
advances in analytical technologies, it
may be a long time before we are
capable of fully understanding all the
chemical characteristics that govern
the properties of such proteins. But
still there is much we can learn about
the structure–function relationships
and other critical properties of
proteins and other biomolecules.
There is an opportunity to greatly
improve the odds of success through
concerted efforts to develop an
in-depth understanding of the
biological mechanisms involved in
each biomolecule’s activity and to
characterize key attributes that affect
those mechanisms.
It is no coincidence that
monoclonal antibodies have emerged
as such an important class of
biopharmaceuticals. Antibodies have
the unique properties of being nearly
identical to one another while having
the capacity for untold specificity and
diversity. We now have accumulated
considerable understanding of
antibody structure and behavior.
Unlike other therapeutic proteins,
antibodies are easily purified using
powerful affinity techniques. Their
structures, including posttranslational
modifications, have been extensively
characterized. Most important, they
are relatively stable and soluble,
allowing for a broad range of delivery
options and treatment regimens. The
developmental scenario for other
proteins and complex biologics is not
as straightforward because of more
limited historical knowledge,
28 BioProcess International
December 2008
complicated purification schemes, and
stability issues.
Mechanism of Action
In efforts to improve efficiency in drug
development processes, we are
becoming increasingly reliant on
mechanism of action­­- (MOA) based
drug discovery. Examples include
ligands, which interact at receptors to
elicit a biological response, and
monoclonal antibodies targeted to
specific antigens. Having a clearly
defined target and a strong
understanding of the underlying
biology of how a drug affects its
therapeutic response clearly aids in
product development. There is no
requirement that one have a full
understanding of the MOA to gain
approval, but the more that is known,
the better. This allows for the
development of analytical methods that
focus on product attributes that are
related to a drug’s intended purpose.
Many new therapeutics are made up
of complex mixtures of biomolecules,
and it is not always easy to identify the
principal active component(s). Other
entities or cofactors, in addition to the
primary active ingredient, may
contribute to the overall activity. In
such a case, a company must be very
careful when optimizing purification
processes because it is possible to
inadvertently remove or inactivate key
components. Activity assays may not
have the precision or specificity to
detect changes that could alter product
efficacy.
Specifications
A series of analytical procedures must
be developed and qualified early to
address the key product attributes of
identity, strength, purity, potency, and
safety. These must be incorporated into
a quality system for product release to
ensure quality and consistency.
Appropriate specifications should be
established that balance product needs,
manufacturing capabilities, industry
standards, and regulatory expectations.
When selecting release tests, it is
important to focus on attributes that
address properties of a biomolecule and
relate to its function and safety. Some
overlap is useful to aid in failure
c
The goal should be
to develop a simple,
reliable, and robust
potency assay the
earlier in the
development cycle
the better.
investigations, but companies should
avoid too much redundancy and assays
that do not provide relevant
information.
Product specifications are usually
set with broad limits early in
development, then narrowed as
processes and the level of product
understanding are refined. It may not
be necessary to validate analytical
methods until later, but they at least
should be qualified to provide a high
level of confidence that the results are
dependable. Making critical decisions
based on unreliable data can have
catastrophic consequences.
Potency
A meaningful and reliable potency
assay is probably the most important
tool in drug development. Not only
are potency assays necessary to ensure
that released drug product has the
best chance of working for a patient,
but they can be indispensable for
assessing stability and comparability,
for process and formulation
development, and for process
validation. Many biologics are
originally developed using in vivo
models, but such assays typically are
not suitable over the long-term for
product development because they are
labor intensive and time consuming,
and they lack sufficient precision. The
goal should be to develop a simple,
reliable, and robust potency assay the
earlier in the development cycle the
better. Such assays can take the form
of physicochemical methods, receptor/
antigen binding, ELISAs, enzymatic
activity, or in vitro cell based assays.
Effort should be directed toward
showing correlation between potency
assay results and in vivo responses.
A big challenge for biologics is to
find a single potency assay that
provides sufficient information to meet
the needs of product development and
satisfy regulatory requirements of
biological relevance and quantitative
ability. This is especially difficult for
complex biologics or those with poorly
understood MOAs. Often a single
potency assay will not suffice, and a
developer must consider multiple assays
that address various product attributes.
For example, a company might
combine methods that assess biological
activity with assays that measure
structural integrity or the concentration
of important product components or
cofactors. Product release can be based
on meeting individual specifications for
each method. The advantage is that
simple pass–fail criteria may be
sufficient for less precise biological
assays, and you can rely on other
methods (such as physicochemical
assays that may not be as biologically
relevant) for the quantitative aspect of
potency. Using such a combined
approach (referred to as an assay
matrix) can provide high assurance of
product activity and manufacturing
consistency.
Sometimes in the case of complex
biologics, especially vaccines, the
identity of the one or multiple active
agents is not known with certainty,
which surely can confound efforts to
design meaningful potency assays.
Patient-specific and autologous
therapies present another difficult
situation in which a drug may be
active in only one or a small subset of
patients. In such a case, surrogate
assays can be used that focus on
general attributes of the product
known to be responsible and necessary
for its activity. The challenge is to
accumulate scientific evidence to build
a strong case that a surrogate assay(s)
is biologically relevant to the drug’s
intended purpose.
to the characterization of a product.
For many reasons, not all analytical
methods are appropriate as release tests,
but such assays may serve to provide
valuable insight into the molecular and
biological properties of the product.
Characterization methods can address
product attributes such as size,
structure, purity, chemical
modifications, and biological activity.
Sometimes their results can help
predict stability, especially in
conjunction with forced degradation
studies or when correlated with adverse
events or immunogenicity issues.
Application of as many characterization
methods as possible improves the
general level of product understanding,
provides greater assurance to regulatory
agencies that a product is as it is
defined, and better prepares a company
for surprises that may occur.
In-process analytical tests are
essential to understanding and
maintaining process control. They are
used for monitoring product quality
and consistency, and for making
critical processing decisions during
manufacturing. In-process tests can
include on-, in-, and at-line
measurements that aid in the control
of a manufacturing process to ensure
that the resulting product consistently
meets predefined quality standards.
In-process assays can be used to
optimize process variables so as to
build in process control and
robustness. The emphasis is now on
proactively designing in product
quality and process control through
better understanding of the underlying
science and manufacturing design
space. Insight into important product
attributes, gained through knowledge
of product biology and structurefunction relationships, can be
leveraged for better definition of
critical manufacturing parameters.
Such efforts rely highly on
development of suitable analytical
methods used to set acceptable limits
around key process variables.
Characterization
and In-Process Methods
Because biologics are large, complex
macromolecular structures, they
inherently possess many more
potential pathways for denaturation
The analytical toolbox should include
an array of methods that can be applied
30 BioProcess International
December 2008
Stability
and degradation, and thus are more
prone to stability related issues than
small molecule drugs. Biologics are
susceptible to a number of
environmental influences including
temperature, pH, light, oxidation,
ionic strength, chemical modification,
and drying. Denaturation usually
involves changes to the threedimensional structure or aggregation
state of a molecule leading to loss of
activity or altered properties.
Degradation, on the other hand, often
involves cleavage of chemical bonds
producing new molecular species. It is
important to have an understanding of
how different denaturation or
degradation pathways affect the
activity of a product. In addition,
stability-related changes can result in
safety issues such as immunogenicity
and unwanted side effects or toxicity
from degradation products.
Stability-indicating assays should be
developed and qualified early on, and
stability programs should be designed
to focus on product attributes that are
critical to activity and safety. This
again points to the importance of
having meaningful and reliable potency
assay(s). There are advantages to
developing physicochemical methods as
stability indicators because they are
usually simpler and can provide greater
precision than bioassays. Such assays
sometimes can reveal trends that are
early predictors of stability issues.
Accelerated stability and forced
degradation studies can be useful tools
to acquire insight on product stability
in a shortened time frame.
Stability assay development should
be integrated along with a
formulation development program to
identify, as soon as possible,
stabilizing excipients and optimal
storage conditions. An appropriate
formulation is necessary to ensure
that a product is stable throughout
the duration of a clinical study and
that all patients are administered
material of uniform quality and
quantity. Variations in activity and
dose resulting from stability or
delivery issues can severely confound
the interpretation of clinical data and
make the difference between meeting
or failing to achieve statistical
significance of clinical endpoints.
Ideally, formulation development
should happen before human clinical
trials are initiated. Later formulation
changes will require comparability
studies, and they always carry the
risk of unanticipated effects on the
clinical outcome.
c
In the absence of
full product
understanding, the
biologics world is
still bound by the
concept of “the
process defines the
product.”
Process Changes
and Comparability
Although very risky, manufacturing
process changes are inevitable during
the course of clinical development,
whether for scale-up or refinements to
improve manufacturability for
commercialization. Process changes
often are implemented to improve
efficiency, consistency, or robustness or
to incorporate technological advances.
Demonstrating comparability
following a process change can be
especially challenging if appropriate
analytical methods are not in place. It
is essential to demonstrate comparable
or improved potency, stability, and
especially safety (e.g., impurities and
contaminants) following any significant
process change. Process changes
resulting in a seemingly improved
product may appear to be a good thing,
but they are not without pitfalls.
Making changes can lead to unforeseen
consequences due to changes in dose,
product pharmacokinetic (PK) and
pharmacodynamics (PD), side effects,
and so on.
In the absence of full product
understanding, the biologics world is
still bound by the old concept of “the
process defines the product.” This
32 BioProcess International
December 2008
notion has evolved into modern-day
FDA initiatives such as process
analytical technology (PAT) and
quality by design (QbD). These are
intended to promote the idea of
controlling the quality of final
products through process and product
understanding and building in better
process control using in-process
analytics and knowledge of key
variables. For complex biologics,
manufacturing processes may be
optimized to yield what is believed to
be an active ingredient, but a company
may end up, sometimes unknowingly,
with reduced activity due to removal
of a key component. This is where
meaningful potency assays play such
an important role.
Reference Standards
A reference standard is an
indispensable resource during early
product development and throughout
the product lifecycle. For most new
biologics, it is unlikely that a
recognized reference standard already
exists, so an in-house primary reference
must be made and characterized. It is
essential to set aside some material for
this purpose as soon as possible.
Establishment of a reference standard
does not have to wait for a finalized
process or extensive knowledge of
product stability. As soon as, or even
before, a process begins to resemble
what will be used to generate clinical
trial material, a batch should be
prepared and stored in aliquots for use
as reference. The safest approach is to
place the material at –70 ºC and
assume it remains stable (this has to be
tested) until further formulation
development efforts can be undertaken.
The primary reference standard should
be as representative of the final product
as possible and it should be evaluated
by all available analytical tools.
A reference standard has many
uses. It will serve as a valuable
benchmark during process
development to assess comparability
and consistency. It is essential in the
development of analytical methods
and to monitor their performance over
time. In certain cases, it may be used
as a working assay standard to
generate standard curves or as a
control to set assay acceptance criteria.
It also will be used to assess stability,
track trends in product attributes, and
to ensure against product “drift” or
“creep” over time.
Reference standards commonly
change during product development
when they run out or after significant
process changes have been made. In
such a case it is important to conduct
appropriate crossover studies using all
available analytical methods.
PK/PD
Suitable analytical methods are needed
for measuring the form, concentration,
and fate of an administered drug in
body fluids, tissues, and at its target
site of action. PK and PD studies are
necessary to gain a thorough
understanding of the relationship
between dose and in vivo
concentration, comparing the intended
response and unfavorable side effects.
This can include development of assays
for biomarkers and their validation as
reliable predictors of drug response.
Such efforts typically are conducted
throughout all phases of clinical
development and, together with
modeling studies, they can be used to
optimize dose regimens and other
aspects of clinical trial design to
improve outcomes.
Know Your Product
There is simply no substitute for
having a sound scientific
understanding of your product and the
processes used to produce it. That can
be achieved only through the diligent
application of a broad range of
analytical methods to product
characterization throughout all phases
of the development cycle. Confidence
in and reliability of analytical results
come from thorough assay
optimization, qualification, validation,
and tracking of performance over time.
The past couple of decades have
brought numerous advances in
analytical technologies, providing
powerful new tools that can be applied
to the characterization of biological
pharmaceuticals. Regulatory agencies
continue to evolve their thinking as
we accumulate more experience with
biologics and knowledge of key factors
You’ll never know
everything
there is to know
about a complex
biologic.
For Further Reading
Tufts Center for the Study of Drug
Development. Impact Report 8(3) 2006.
Tufts Center for the Study of Drug
Development. Impact Report 9(5) 2007.
ICH Harmonized Tripartate Guideline
Q5E: Comparability of Biotechnology Products
Subject to Changes in Their Manufacturing
Process. International Conference on
Harmonisation of Technical Requirements for
the Registration of Pharmaceuticals for Human
Use: Geneva, Switzerland, 2004; www.ich.org/
cache/compo/276-254-1.html.
CDER/CVM/ORA. Guidance for Industry:
PAT - A Framework for Innovative
Pharmaceutical Manufacturing and Quality
Assurance. US Food and Drug Administration:
Rockville, MD. 2004;
www.fda.gov/cder/guidance/6419fnl.htm. c
James R. Zabrecky, PhD is
principal consultant at Criterion Biotech
Consultants, 18 Arlington Road,
Waltham, MA 02453; 1-781-891-5630;
[email protected].
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that affect efficacy and patient safety.
The path to approval for new
biologics, especially MAbs, clearly is
much better laid out now than it was
20 years ago when the first such
products were developed.
You’ll never know everything there
is to know about a complex
biopharmaceutical, so you must make
a number of assumptions and take
calculated risks during the course of
clinical development. However, the
more effort you put into characterizing
and understanding your product and
process early in development, the
better prepared you will be to make
informed decisions and deal effectively
with unanticipated problems that
inevitably will arise.
Finally, given the enormous
complexity of biological systems, there
is always a certain element of luck
involved. However, it is very risky to
rely on luck, and it is important to
remember the words of Louis Pasteur:
“Chance favors the prepared mind.” It
is essential to put as much effort as
possible, early on, into understanding
a product, its manufacturing process,
and the fundamental biology behind
its mechanism of action to give it the
best possible chance at succeeding in
the clinic.
PROMO
TE
R
c
Innovation or Stagnation: Challenge and
Opportunity on the Critical Path to New Medical
Products Critical Path Initiative. US Food and
Drug Administration: Rockville, MD, 2004;
www.fda.gov/oc/initiatives/criticalpath/
whitepaper.pdf.
ICH Harmonized Tripartate Guideline
Q6B: Specifications — Test Procedures and
Acceptance Criteria for Biotechnological/Biological
Products. International Conference on
Harmonisation of Technical Requirements for
the Registration of Pharmaceuticals for Human
Use: Geneva, Switzerland, 1999; www.ich.org/
cache/compo/276-254-1.html.
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