unusual that the scope for microheterogeneity
in biosimilars is narrower than theoretically
acceptable.
Step 3
The next step is the production of the biosimilar
using the relevant set of complex biotechnology
methods. First, different production clones are
tested to determine to what extent they deliver
products that are as similar as possible to the
reference drug. Complex cycles of process variation
and bioanalyses of the resulting products gradually
lead to conditions that ensure the biosimilar
resembles the reference drug in all aspects.
This process is then specified in every conceivable
detail and forms the basis for the production of
all batches of the biosimilar according to the ‘the
product is the process’ principle.
Step 4
In the fourth step, the biosimilar is comprehensively
checked – the ‘comparability exercise’. A key feature
of this step is that all tests are performed head-to-
head between the biosimilar and the reference drug
(which also applies to the required clinical study at
the end of this comparison). This is also a sequential
process.
Biosimilar development
Comparative quality
In the first step, quality, structural agreement,
physicochemical and biological comparabilities
are assessed. Possible deviations from the data of
the reference drug must be explained adequately.
Furthermore, the purity of the biosimilar is checked.
The product is only released if previously defined
specification criteria are fulfilled (see Figure 1).
Comparative non-clinical
In the second step, biosimilar and reference drug
are compared in a preclinical setting (usually in
vitro testing) and the required tests are specified
in product-specific guidelines issued by the EMA.
The pharmacokinetic and pharmacodynamic
parameters and their predefined degree of similarity
with the reference drug must be justified and
determined.
Comparative clinical
In the third step, clinical comparability is
demonstrated. These studies have more of the
character of safety studies than efficacy studies.
If the initial comparability exercise proves that the
biosimilars and reference drugs are sufficiently
similar, then it can also be expected that they will
be clinically equivalent. However, these clinical
studies are mandatory in order to prove the
tolerability of the biosimilars. The manufacturing
processes of biosimilars and reference drugs
are inevitably different, so that it cannot be
ruled out that components that are difficult or
impossible to identify analytically might provoke
clinical abnormalities. Phase I clinical studies
initially focus on toxicology, pharmacokinetics
and pharmacodynamics (purity, safety, uptake,
distribution and excretion) and a safety profile
is established.
This is followed by studies on efficacy and
safety in terms of severity and frequency of
various side effects. These are performed in one
or more representative indications in order to
demonstrate a comparable efficacy and safety,
including a comparable immunogenicity profile
for the biosimilar and reference drugs. The focus
and requirements for these Phase III studies differ
depending on the biosimilar class. However, in
accordance with the diversity and complexity of
biologic pharmaceuticals, the EMA defines the
requirements individually and in accordance with
the guidelines laid down for the manufacturers.
Figure 2 summarises the processes for biosimilar
and reference medicines.
Conclusions
Manufacturing a biosimilar requires significant
expertise to ensure that it is ‘highly similar’ to
the originator biologic with no clinically
meaningful differences in safety, efficacy, or
immunogenicity. This means extensively identifying
and comparing the structural and functional
properties of the biosimilar and selecting
optimal cell lines for culture, scaling up, and
purification of the protein. For a biosimilar,
comparative structural and functional
characterisation provide the greatest
contribution to clinical predictability.
FIGURE 3
Summary of processes for biosimilar and reference medicines 9
Risk management plan
Risk management
plan
Clinical studies:
• Safety and efficacy
• PK/PD
• Immunogenicity
Comparative clinical
studies:
• Safety and efficacy
• PK/PD
• Immunogenicity
Comparative
non-clinical studies
Non-clinical studies
Pharmaceutical
quality studies
Comparative quality
studies
Reference medicine
6 | 2019 | hospitalpharmacyeurope.com
Biosimilar medicine
Pharmaceutical
quality studies
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