FIGURE 2
Developing a biosimilar: a stepwise process
STEP 1
Comparative quality
studies
• Analytical:
physical + chemical
properties
• Functional:
biological/
pharmacological
activity
STEP 2
Comparative non-
clinical studies
• Pharmacodynamic
• Toxicology
Reference medicine
further details of the key concepts in development
of biosimilars and regulatory approval processes,
please see the dedicated article in this handbook).
The manufacturing process
Manufacturing a biologic consists of genetically
modifying a cell, which becomes the basis for a cell
line used for the production of the necessary protein
for the drug. The protein is then separated from the
cells and purified. 7
Each step of the manufacturing process can
modify the product, and the process requires
controlling numerous input parameters, each of
which can impact the safety and efficacy of the
final product. 8
The manufacturing process can be divided into
four steps. The aim is not to develop a new molecule
with unknown clinical properties, but to copy a
molecule that has undergone full clinical evaluation
(reference drug) in the best possible way so that all
available data on the reference drug can also be used
for the biosimilar.
Step 1
This involves full bioanalytical examination of the
structural characteristics of the reference drug
to determine exactly what needs to be copied.
For this purpose, the biosimilar manufacturer
purchases large quantities of the reference drug on
STEP 3
• Pharmacokinetics/
pharmacodynamics
• Efficacy and safety
+ immunogenicity
Biosimilar
Manufacturing
a biosimilar
requires significant
expertise to ensure
that it is ‘highly
similar’ to the
reference biologic,
with no clinically
meaningful
differences in
safety, efficacy and
immunogenicity
the relevant markets, whereby as many different
batches as possible should be represented. Structural
characteristics include modifications such as
oxidised or deamidated variants of different amino
acids, modified N- and C-terminal ends of protein
chains, glycosylation characteristics, the proportion
of denatured protein, and protein aggregates, among
others. This is necessary because these structural
variants also have to be copied. Of course, the
biosimilar must not be worse than the reference
drug, but it must also not be better.
Step 2
In the second step, the biosimilar manufacturer
must define variation parameters for the reference
drug on the basis of the analytical data collected
that determines the limits of microheterogeneity.
The upper and lower limits for the biosimilar must
not exceed or fall below the corresponding limits of
the reference drug. Expiration of a patent does not
necessarily mean that the manufacturing process
of the reference product becomes available to the
biosimilar developer (for example, the cell line
clone, growth medium used, etc) and full analyses
of the reference drug is required for this important
step.
By contrast, the regulatory authorities know
all the details of the reference drug including the
microheterogeneity limits. It is therefore not
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