MANUFACTURE
Manufacturing biosimilars
Manufacturing a biosimilar requires significant expertise to ensure that it is ‘highly similar’
to the reference (originator) biologic with no clinically meaningful differences in safety, efficacy,
or immunogenicity
Theodor Dingermann
PhD
Director, Institute of
Pharmaceutical Biology,
Goethe-University,
Frankfurt, Germany
The biosimilar
must have the
same amino acid
sequence as the
reference drug
– no differences
between the
original and the
copy are
permissible
Whereas generics are always exact copies of
a respective reference drug, biosimilars are
developed to closely resemble a well-established
biopharmaceutical. This is a major difference because
it is practically impossible to obtain biosimilars as
exact copies of biopharmaceuticals. This is not only
due to the much larger molecular weights of these
molecules compared with generics but also to the fact
that, unlike generic drugs, biopharmaceuticals are
always produced from living cells as a result of
biochemical processes. A biopharmaceutical is
a mixture of molecule variants, which is complex but
not arbitrary in its composition. Therefore, copying
a biopharmaceutical ultimately requires copying this
complex molecular mixture.
Basic principles
Microheterogeneity
An inherent feature of all biological products is
that they comprise complex molecular mixtures,
the individual components of which have subtle
differences to the intact biomolecule. 1 This
microheterogeneity results from variants (artefacts)
that are present at specific concentrations in all
biopharmaceuticals.
The principle of inherent microheterogeneity
applies to biosimilars as well as to innovator drugs
used as a copy template (reference drug); the
consequence is that a biosimilar can be similar but
never identical to the reference drug. However,
the structural deviations of the biosimilar from
its corresponding reference drug are by no means
arbitrary. They must not be greater than the
deviations within different batches of the reference
drug. In fact, different batches of the reference
products selected as reference drugs are always
only similar, but never identical, to each other.
Amino acid sequence
The biosimilar must have the same amino acid
sequence as the reference drug – no differences
between the original and the copy are permissible. 2
However, it is possible that individual amino
acids are modified by environmental influences
including pH, temperature, pressure, etc (for
example, oxidised variants of methionine,
cysteine, tryptophan, tyrosine and histidine;
deamidated variants of asparagine or glutamine;
hydrolysed disulfide bridges). Furthermore, details
of the glycosylation pattern may differ between
the original and the copy as well as between
different batches of the original and the copy,
respectively. These variations are part of the general
microheterogeneity of biopharmaceuticals and
thereby also of biosimilars and of reference drugs.
4 | 2019 | hospitalpharmacyeurope.com
‘The product is the process’
This refers to the importance of a rigorously
specified production process as a basis for
batch-to-batch consistency, which applies to all
biopharmaceuticals, including biosimilars. However,
this process does not have to be identical to the
process used to manufacture the batches of active
substances used in the approval studies. Processes
can be modified, or even redesigned, providing that
the changes are first approved by the European
Medicines Agency (EMA).
A study carried out in 2016, 3 determined the
number of changes in the manufacturing processes
of 29 monoclonal antibodies. A total of 404 process
modifications were found in the European public
assessment reports (EPARs) of the EMA – 50 of
which were for the production of the reference
drug Remicade ® (inflximab). A total of 32 of these
changes were serious interventions, such as
a change of cell line for the production of active
substances. On average, there were 1.8 changes
in the production process per year and per
biopharmaceutical.
The approval of a process change for an
originator biopharmaceutical is granted by the
EMA on the basis of data that the pharmaceutical
manufacturer must collect and submit to the
authority. 4 These data are obtained from ‘bridging
studies’. Active substance batches from the original
process are compared with active substance batches
from the modified process (the comparability
exercise). The most important methods used are
bioanalytical techniques, because they have high
sensitivities in detecting potential differences. 5
Therefore, these methods are of particular
importance in the context of a comparability
exercise. These analyses are supplemented by
preclinical tests and, if necessary from a regulatory
point of view, by clinical studies.
If a process change is approved, this affects
all indications for which the active substance
is approved. This also applies if a clinical study
considered necessary within the framework of the
comparability exercise was carried out in only one
(sensitive) indication. This procedure is based on the
principle of ‘extrapolation of the indication’, which
has been used in biopharmaceuticals for years
and has proven itself over time, even when major
process changes had to be decided. 6 For example,
the subcutaneous administration of the monoclonal
HER2 antibody trastuzumab (Herceptin ® ) was also
approved for neoadjuvant therapy on the basis of
data from patients with metastatic disease.
Another important aspect in the evaluation of a
biopharmaceutical is its immunogenic potential (for