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An overview
Contents
An introduction to
biotechnology
An introduction
to biotechnology
An introduction to
biotechnology
An introduction
to biotechnology
A brief history of
medicine development
The first medicinal drugs came from
natural sources and existed in the
form of herbs, plants, roots, vines
and fungi. Until the mid-nineteenth
century these natural remedies were
all that was available to treat some
conditions. The first synthetic drug,
chloral hydrate, was discovered in
1869 and introduced as a sedativehypnotic. The first pharmaceutical
companies were spin-offs from the
textiles and synthetic dye industry
and owe much to the rich source of
organic chemicals derived from the
distillation of coal (coal-tar). (2)
For many years, the pharmaceutical
industry traditionally developed
chemical drugs (also referred to
as small molecules), including
well-known medicines such as
acetylsalicylic acid, to treat a wide
range of illnesses. Since the 1970s,
a revolution in biotechnology has
resulted in a new class of medicine:
the biologic.
Acetylsalicylic acid
Small molecule
IgG1 antibody
Biologic medicine
21 atoms
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An introduction to
biotechnology
Defining biosimilars
What are biosimilar medicines?
Unlike generic medicines where the active
ingredients are identical, biosimilars are
similar to but not identical copies of the
originator biologic. They are similar, but
not the same. Biologics made by different
manufacturers differ from the original
product and from each other.
The complexity of biologics precludes
identical copies and are therefore
not the same as generic drugs. Due
to the complex structure of biologic
medicines and the processes involved
in production, biosimilars must be
determined on the basis of analytical,
non-clinical and clinical data to be
similar to an original biologic in terms
of structural characteristics, and safety
and efficacy. Minor differences with
the active ingredient are expected and
permitted so long as any such differences
are demonstrated not to be clinically
meaningful. (7) The patents of a growing
number of biologic medicines have
already expired or are due to expire, which
has led to an increased interest in the
development of biosimilars. (11)
Original biologic
Biosimilars
How do biosimilars
differ from the original
innovator medicines?
The active ingredient of a
biosimilar is expected to closely
resemble that of the original
biologic. Unlike generic medicines
(small molecules) where the
active ingredient is required to
be identical, the manufacturing
process through which a biologic
(large molecule) is made cannot
be exactly duplicated by another
manufacturer. (12)
There are naturally occurring
differences between an originator
and biosimilar medicine:
Biologic medicines are not
made using a set of standard
materials, but are developed
using unique biological systems
and living cells. As a result, the
active ingredient is impossible to
recreate exactly and the selected
cell lines from which the biologic
medicine originates are unique to
each manufacturer. (13)
The manufacturing process for
biologic medicines requires
dozens of steps involving
hundreds of variables and is
generally more complex than
manufacturing processes for
chemical drugs. Any variation
12
The cost of
developing biosimilars
Biosimilar manufacturers must
invest in clinical trials, manufacturing and post-approval safety
monitoring programs similar
to that of the original innovator
companies.
According to Sandoz, the cost
of developing a generic small
molecule is around $2-3 million,
whereas biosimilars have been
estimated to cost around
$75-250 million to reach
approval, (18) largely due to the
clinical studies and comparability
exercise required to demonstrate
biosimilarity.
Because of this investment,
cost savings achievable with
biosimilars may not be as great
as can be experienced with small
molecule generics. (12)
Regulating biosimilars
Regulating
biosimilars
Regulating biosimilars
Regulating
biosimilars
In 2009 the World Health Organization developed a set of globally accepted
standards to assure the safety, efficacy and quality of biosimilar medicines.
These have been developed in the wake of increased interest in biosimilars
by local regulatory authorities seeking to develop national standards. (8) (25)
Reference product
The reference product should be authorized in the country or region in question
Quality
All aspects of quality and heterogeneity should be assessed including
head-to-head comparisons with the reference product
Non-clinical data
Should include pharmacodynamic, pharmacokinetic and comparative repeat-dose
toxicity studies in a relevant species
Clinical studies
Required to demonstrate similar safety and efficacy. Immunogenicity should
always be investigated in humans before authorization
United States
Originator
Biosimilar
Clinical S&E
Clinical S&E
Clinical Pharm
Clinical Pharm
Non clinical
Non clinical
Quality
Quality
European Union
Originator
Clinical
Cross reference
Cross reference
(extrapolation?)
Non clinical
Quality
Biosimilar
Clinical
Non clinical
Comparability data
Quality
Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU (28) (29)
15
16
United States
In March 2010, the U.S. biosimilar pathway was signed into law as
part of the Affordable Care Act. In February 2012, the Food and Drug
Administration (FDA) issued three draft guidance documents on biosimilar
product development to assist industry in developing such products in the
United States. What, if any, additional guidance FDA may issue, and when,
is uncertain. (26)
The FDA recommends a stepwise approach to demonstrate biosimilarity
between a proposed medicine and the original biologic. The aim is to
demonstrate no clinically meaningful difference in terms of safety, potency
and purity. The guidance provides advice on the types of rigorous studies
that should be undertaken by the manufacturer to address uncertainty
about the proposed product.
To comply with this approach, a sponsor should include:
Structural analysis: Using state-of-the-art technology to display,
for example, primary and higher order structures, post-translational
modifications and intentional chemical modifications.
Functional assays: Appropriate studies including: bioassays,
biological assays, binding assays and enzyme kinetics. FDA
recommends that any functional assays performed should be
comparative so they can provide evidence of similarity or
reveal differences...
Animal data: Including toxicity studies, pharmacokinetic and
pharmacodynamic measurements and immunogenicity studies.
Human clinical studies: Including pharmacokinetic and
pharmacodynamic measurements, immunogenicity results and safety
and efficacy data. Studies should demonstrate that the proposed
product has neither decreased nor increased activity compared to the
reference product.
The FDA has discretion to waive any requirement deemed unnecessary. (26)
17
2001 2001 2002 2002 2003 2003 2004 2004 2005 2005 2006 2006 2007 2007
The EMA
Thepublished
EMA published
the firstthedirective
first directive
relatingrelating
to differences
to differences
in raw in
materials
raw materials
or manufacturing
or manufacturing
processes
processes
between
between
biosimilar
biosimilar
and reference
and reference
products
products
Guideline
Guideline
development
development
EU
EU
Legal Legal
Pathway
Pathway
EU
EU
Overarching
Overarching
Guidelines
Guidelines
The EMA
Thepublished
EMA published
the firstthebiosimilar
first biosimilar
regulatory
regulatory
approval
approval
pathway
pathway
for for
the EUthe
member
EU member
states states
AUS AUS
As more
As governments
more governments
develop
develop
biosimilar
biosimilar
pathways,
pathways,
the WHO
the WHO
and EUs
andestablished
EUs established
guidelines
guidelines
will continue
will continue
to serve
to serve
as a as a
template,
template,
as demonstrated
as demonstrated
by Australias
by Australias
unadulterated
unadulterated
adoption
adoption
of the of
EUthe
guidelines
EU guidelines
Biosimilar Regulations
Global guideline/regulation development
2008
2009
2010
2011
2012
TUR
KOR
CAN
ARG
USA
(draft)
MYS
JPN
ZAF
MEX
COL
(draft)
TWN
SIN
BRA
CUB
2013
EU
Revised
Guidelines*
EU
Non-clinical
and clinical
Guidelines
JOR
(draft)
WHO
SAU
IRI
IND
PER
THA
(draft)
EU
Update to Quality
Issues Guideline
20
Pharmacovigilance,
traceability & naming
Pharmacovigilance,
traceability & naming
Pharmacovigilance,
traceability & naming
Pharmacovigilance,
traceability & naming
Rigorous pharmacovigilance
programs are needed to protect
patients and ensure any adverse
events are quickly detected,
reported and attributed to the
correct product and manufacturer.
An important concern with all
biologic medicines is the risk of
an unwanted immune response,
where the patient reacts against
proteins in the medicine, limiting
its efficacy or affecting its safety. (30)
Healthcare systems must ensure
all biologic medicines, including
biosimilars, can be rapidly and
accurately identified by national
regulators, healthcare providers
and patients.
Safety monitoring and ongoing
pharmacovigilance of medicines
involves detection, assessment,
understanding and prevention of
adverse effects. As clinical trials
involve a relatively small number of
patients, potential adverse events
may be unknown at the time of
launch. (8) As with all medicines, the
safety of biosimilars is monitored
22
23
24
Substitution and
interchangeability
Substitution and
interchangeability
Substitution and
interchangeability
Substitution and
interchangeability
is encouraged to prescribe
substitutable medicines by INN,
leaving the pharmacist to decide
which brand (generic or reference
product) to dispense, whereas in
other countries the pharmacist
may dispense a generic of a
substitutable medicine even where
the doctor has prescribed the
reference product by brand. (38)
In all cases, however, the essential
features of substitution are that:
it is the pharmacist (and not the
doctor) who decides which brand
the patient receives;
the doctor is not routinely
informed of which brand the
patient has received;
the patient may potentially receive
a different brand every time their
medicine is dispensed.
25
26
Europe EMA
Decisions on substitution are made at national level. In many
EU countries, automatic substitution of biologics is officially
prohibited or not recommended. (9)
WHO
The WHO does not define standards on interchangeability for biologic
medicines. It recognizes that a number of issues associated with the
use of biologics should be defined by the national authorities. (8)
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28
UK and
Belgium recommend
prescribing by brand
name to avoid
substitution (15)
Spain and
Germany
prohibit
automatic
substitution (15)
Ireland,
Poland and
Portugal have
no clear
position (49)
In Japan,
substitution should
be avoided during
the post-marketing
surveillance
period (25)
29
30
Manufacturing
biologics
Manufacturing
biosimilars
Manufacturing
biosimilars
Manufacturing
biologics
Transforming complex therapeutic
proteins from the laboratory into the
large-scale production of safe and
effective medicines requires highly
specialized knowledge, processes,
scientific standards and ongoing
investment in quality.
31
GMP requirements
STEP 1
DNA - Cloning
Transfection
Select "best" cell
STEP 2
Cell expansion
STEP 3
Cell culture
STEP 4
Harvest
STEP 5
Purification
multiple steps
Remove impurities
Highly selective resin
Specific process conditions
STEP 6
Virus inactivation/removal
STEP 7
Filling
Filling method
No human contact
STEP 8
Finishing
Lyophilization
Syringe-fill
STEP 9
Controlled temperature
Ensure no foaming
No particles
STEP 10
Quality assurance
& characterization
STEP 11
Stability
32
Small molecule
Process
GMP requirements
Add ingredients
pressure, temperaure
STEP 1
Reaction
STEP 2
Weigh
Weigh API
& inactive chemicals
STEP 3
Mix
STEP 4
Pressure
Filling method
(no human contact)
STEP 5
Room temperature
STEP 6
Quality assurance
& characterization
Easy methods
STEP 7
Stability
Testing to ensure
product remains stable
through shelf life
To manufacture
safe and effective
biologic and biosimilar
medicines, more steps
and more stringent
processes for each
step are required than
for small molecule
medicines.
Unit Operation
Cell expansion
The manufacturing
process is unique to
every manufacturer
There is a strong relationship
between the manufacturing
processes of a biologic medicine
and the characteristics of the
final product. Due to proprietary
knowledge, it is impossible
for biosimilar manufacturers
to precisely replicate the
manufacturing process of the
original biologic or the active
ingredient of the protein product. (50)
The starting materials for most
biologic medicines are geneticallymodified cells. Once scientists
design and select a cell that
produces a medically valuable
protein, they replicate it to create a
cell line. Each cell line is unique to
the manufacturer.
Purification through
chromatopgraphy
Purified bulk drug
34
Striving to ensure a
consistent supply
Problems or interruptions to the
manufacturing process of biologic
medicines may not only affect
quality and safety, but could also
lead to delayed supplies and
distribution of urgently needed
medicines.
Along with regulators, manufacturers
have a responsibility to ensure
strategies are in place to minimize
incidences of drug shortages and
possible disruption. Manufacturer
risk management is a continuous
and holistic process designed
to ensure a consistent supply.
Strong governance can also help to
integrate and manage supply risk
across manufacturing plants
and functions.
A consistent supply of
high-quality products
requires commitment,
expertise and highquality science.
35
Amgen biosimilars
Biosimilars are therapeutic alternatives for originator
biologic medicines, and offer the potential for increased
access and reduced cost.
Amgen is a pioneer in the field of biologic medicines.
Science-based medicine and patient safety are
fundamental to our values.
Amgen is uniquely equipped to leverage its leading
position in biotechnology to produce biosimilars.
Amgen has six biosimilar molecules in development.
We expect to launch the first biosimilar in 2017.
36
Glossary
Glossary
Glossary
Glossary
Adverse event: The occurrence of an undesirable, unpleasant, or lifethreatening reaction to a medicinal product.
Amino acid: One of several molecules that join together to form proteins.
There are 20 common amino acids found in proteins.
Antibody (pl: antibodies): Antibodies (also known as
immunoglobulins, abbreviated to Ig) are proteins that are found in blood or
other bodily fluids. Antibodies are used by the immune system to identify
and neutralize foreign objects, such as bacteria and viruses.
Automatic substitution and substitution: The practice by which a
product other than the one specified on the prescription is dispensed to
the patient, without the prior informed consent of the treating physician.
A variation of substitution is practiced in some countries where, if the
physician prescribes by international non-proprietary name (INN), the
pharmacist may dispense any product with the same active ingredient.
Biologic: A product derived from a living organism (from animal products
or other biological sources) that is used in the diagnosis, prevention or
treatment of disease. Examples of biologic medicines include recombinant
proteins, allergy shots, vaccines and hematopoietic growth factors.
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Chemistry, manufacturing and control (CMC): The CMC stage of product development
focuses on how a drug was created. It should be demonstrated that the manufacturing
method is proper and valid on a technological level and that quality is ensured through
consistent production in accordance with the WHOs Good Manufacturing Procedure. Many
aspects of both the active ingredients and the product as a whole will be reviewed, including
characterization, control and stability.
Clinical trial: A test in which a drug or biologic is given to humans to establish how it works
in the body and measure the nature and extent of any intended or unintended consequences.
Committee for Medicinal Products for Human Use (CHMP): The CHMP is the
scientific committee responsible for formulating the opinion of the European Medicines Agency
on any question concerning the evaluation of human medicinal products.
Comparability exercise: The head-to-head comparison of a biotherapeutic product with
a licensed originator product, with the goal of establishing similarity in quality, safety, and
efficacy. Products should be compared in the same study using the same procedures.
Data exclusivity: The period of time during which the clinical testing data that supported
approval of the innovator medicine is protected, so that the prior approval of that originator
based on those data may not be relied upon by another applicant to help approve a copy of
that product.
DNA (Deoxyribonucleic Acid): DNA is a nucleic acid that contains the genetic information
used in the development and functioning of all cellular organisms. Molecular systems interpret
the sequence of these nucleic acids to produce proteins.
Efficacy: The desired impact that a medicine or treatment has when administered to a human.
European Medicines Agency (EMA): The EMA is responsible for evaluating marketing
applications for medicinal products to be approved in the European Union.
Federal Food, Drug and Cosmetic Act: The federal law that regulates FDAs licensing of
drugs but not the majority of biologic medicines. Instead, most biologic medicines are licensed
by FDA under the Public Health Service Act. Once licensed by FDA, however, most of the other
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provisions set forth in the Federal Food, Drug and Cosmetic Act concerning the marketing and
other regulatory requirements are applicable to both drugs and biologic medicines.
U.S. Food and Drug Administration (FDA): The federal agency responsible for
evaluating marketing applications and/or otherwise regulating the U.S. marketing of medicinal
products, medical devices, food and cosmetics to be approved in the United States.
Fusion protein: A protein made from a fusion gene, which is created by joining parts of two
different genes. Fusion genes may occur naturally in the body by transfer of DNA between
chromosomes.
Generic medicine: A generic drug is the same as a brand name drug in dosage, safety,
strength, how it is taken, quality, performance, and intended use. A generic drug product must
contain the identical amounts of the same active ingredient(s) as the brand name product.
Drug products evaluated as therapeutically equivalent can be expected to have equal effect
and no difference when substituted for the brand name product.
Genetic engineering: The direct manipulation of an organisms genes by introducing,
eliminating or rearranging specific genes using the methods of modern molecular biology,
particularly those techniques referred to as recombinant DNA techniques. These techniques
entail producing a piece of DNA (the recombinant DNA or synthetic rDNA construct) and
introducing it into an organism so that new or altered traits can be imparted to that organism.
Guidance: A document issued by a regulatory agency to provide interpretation of a law that
the regulatory agency is responsible for administering and/or enforcing and recommendations
as to how to proceed with particular issues.
Immune system: The collection of mechanisms within the body that protect against disease
by identifying and attacking foreign substances in the body.
Immunogenicity: The ability of a substance to trigger an immune response or reaction
(eg: development of specific antibodies, T-cell response, allergic or anaphylactic reaction).
INN (International non-proprietary name): Allocated by the World Health Organization,
an INN identifies pharmaceutical substances or active pharmaceutical ingredients. Each INN
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is a unique name that is globally recognized and is public property. A non-proprietary name is
also known as a generic name.
Innovator: Describes a company that invested considerably in research and development to
develop a new medicine through innovative technologies, such as biotechnology.
Innovator product: Original approved biologic medicine.
Insulin: A hormone that affects metabolism and causes the bodys cells to take up glucose
(sugar) from the blood and store it as glycogen in the liver and muscles.
Interchangeability: Where two products, that are judged to be similar, can be exchanged one
with another without a significant risk of an adverse health outcome.
Large molecule drugs: Are therapeutic proteins also known as biologic medicines.
Essentially, these are copies or optimized versions of endogenous human proteins.
Mechanism of action: The specific way by which a medicine achieves the desired outcome.
Medicines and Healthcare products Regulatory Agency (MHRA): UK government
agency that is responsible for ensuring that medicines and medical devices work and are
acceptably safe.
Monoclonal antibody: An antibody produced in the laboratory by a single clone of cells or a
cell line and consisting of identical antibody molecules.
Originator: See above for innovator.
Originator product: See above for innovator product.
Pharmaceutical medicine: Also referred to as medicine or medication any chemical
substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.
Pharmacodynamics: Studies performed to determine what a drug does to the body.
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Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
www.amgen.com