16 BioPharm International eBook September 2019 www.biopharminternational.com
Regulatory Sourcebook Biosimilars
more than once. For products that
are intended to be administered mul-
tiple times, FDA encourages sponsors
to meet with the agency to discuss
their development approach, includ-
ing at this time any proposed justi-
fication as to why switching studies
are not needed.
Another important consideration
in setting up a switching study is to
define the primary endpoint for the
study. According to the guidance, the
primary endpoint should assess the
impact of switching, or alternating,
between a proposed interchangeable
product and the reference product.
The impact should be assessed on a
pharmacokinetic (PK) and pharma-
codynamic (PD) level, if available. PK
and PD endpoints, which are distin-
guished from clinical efficacy points,
are typically more sensitive to detect-
ing changes in exposure and/or activ-
ity that can arise from alternating or
switching products.
US PRODUCT VS. NON-US PRODUCT
The interchangeability guidance
also sets forth recommendations for
sponsors wishing to use data derived
from a switching study or studies
in which the comparator product is
a non-US-licensed product. In this
case, the sponsor should provide ade-
quate data and information to effec-
tively form a "bridge" between the
non-US-licensed comparator and its
counterpart, the US-licensed refer-
ence product. This would allow the
sponsor to justify the relevance of
the data obtained using the non-
US-licensed comparator. FDA notes
in the guidance that a US-licensed
reference product and the non-US-
licenses comparator product often
have subtle differences in specific
structural features (e.g., acidic vari-
ants, deamidations), process-related
impurities, or formulation.
These differences may be subtle
and may not preclude use of the
non-US-licensed comparator in cer-
tain studies to support a demonstra-
tion of biosimilarity because the
comparator in those cases is being
used as a control in an evaluation
that does not involve switching
back and forth. It becomes an issue,
however, when the evaluation does
involve switching between products
(interchangeable and comparator)
because multiple exposure to each
product has the potential to prime
the immune system to recognize
the subtle differences between prod-
ucts, which can intensify the overall
immune response.
In light of the complexity of using
a non-US-licensed comparator prod-
uct, FDA cautions that the type and
extent of data needed to justify the
use of a non-US-licensed comparator
in a switching study may be differ-
ent or more extensive than is needed
in other contexts or other studies in
which the non-US-licensed compara-
tor is used. The agency believes, how-
ever, that with adequate data and
information, it may still be reason-
able to use a non-US-licensed com-
parator in a switching study.
EFFECTIVE ANALYTICAL METHODS
High-resolution mass spectrom-
etry (HR–MS) is the go-to method
for primary structural analysis and
characterization of complex pro-
tein molecules, particularly follow-
ing post-translational modifications.
For higher-order structural analy-
sis, various biophysical techniques
are mainly employed, according to
a paper published by M. DiPaola
and I. Javeri (5).
Mass spectrometr y has been
known as a key technology for char-
acterizing an originator's biological
product (i.e., the reference product)
and for performing comparability
studies between proposed biosimilar
molecules and the reference prod-
uct. A new generation of mass spec-
trometers introduced over the past
five years (e.g., time-of-flight [ToF]
instruments quadrupole (Q)–ToF, ion
trap–ToF, or ToF–ToF, and orbital ion
trap mass spectrometers) now offer
improved high-mass resolution and
mass accuracy for characterizing pri-
mary structures (5).
For higher-order structures, how-
ever, including secondary and ter-
tiary structures, commonly used
methods resulted in low resolution
and failed to provide structural
details to illuminate distinctions in
the subtle differences among higher-
order structures. Until recently,
higher-order structures were char-
acterized using a combination of
biophysical techniques, including
intrinsic tryptophan fluorescence,
extrinsic f luorescence, far- and
near-ultraviolet circular dichroism,
Fourier-transform infrared spec-
troscopy, and differential scanning
calorimetry. Meanwhile, though it
is possible to use methods such as
multidimensional nuclear magnetic
resonance or X-ray crystallography
to obtain more detailed analysis of
higher-order structures, these meth-
ods are far too time consuming
and costly to run, according to M.
DiPaola and I. Javeri, who conclude
that mass spectrometry may be
the answer. Mass spectrometry has
been found to be useful in provid-
ing detailed analysis of higher-order
structures and in a timely manner.
REFERENCES
1. FDA, Draft Guidance for Industry:
Development of Therapeutic Protein
Biosimilars: Comparative Analytical
Assessment and Other Quality-Related
Considerations (Rockville, MD, May
2019).
2. FDA, Guidance for Industry:
Considerations in Demonstrating
Interchangeability with a Reference
Product (Rockville, MD, May 2019).
3. FDA, "Statement from Acting FDA
Commissioner Ned Sharpless, MD,
on Policy Advancements to Help Bring
Interchangeable Biosimilars to Market,"
Press Release," May 10, 2019.
4. J. Wechsler, BioPharm International 32
(7) 6–7 (2019).
5. M. DiPaola and I. Javeri, Biopharm
International 32 (9) 34–38 (2019).
BP
