Quacell Biotechnology Co., Ltd., Guangdong, China
Corresponding author details:
H. Fai Poon
Quacell Biotechnology Ltd
Zhongshan
Guangdong,China
Copyright:
© 2018 Yuan J, et al. This is
an open-access article distributed under the
terms of the Creative Commons Attribution 4.0
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use, distribution and reproduction in any
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are credited.
Long-term safety and efficacy of biosimilars are approved by using abbreviated
methods and clinical studies may not always adequate to ensure comparability of
biosimilar mAbs comparing to its reference product . Therefore, the analytical strategy
of the physicochemical comparison of a biosimilar to its reference product becomes an
important data to indicate clinical similarity in safety and efficacy. FDA recommended that
demonstration of biosimilarity between reference and biosimilar versions is based upon
data derived from analytical studies to show “high similarity” to the reference product
not withstanding minor differences in clinically inactive components. Therefore, the
physicochemical analytical comparison between biosimilar and its reference product is
the primary consideration during biosimilar development. In these review, the approach
for physicochemical characterization, biological activity and impurities assessment were
reviewed.
Biosimilar; Monoclonal Antibody; Cytotoxicity
Biosimilars offer an attractive possibility for health care cost reduction, and this are becoming an attractive consideration for most health care systems [1,2]. Long-term safety and efficacy of biosimilars are approved by using a limited number of analytical methods, and clinical studies may not always be adequate to ensure comparability of biosimilar monoclonal antibodies (mAbs) compared to its reference product [3-5]. Therefore, the analytical strategy for the physicochemical comparison of a biosimilar to its reference product becomes an important procedure to indicate clinical similarity in safety and efficacy. Therefore, biosimilars are raising new analytical challenges concerning product characterization and immunogenicity profiling [6-10]. Here we reviewed a general strategy for biosimilar products.
FDA recommend that demonstration of biosimilarity between
reference and biosimilar versions is based upon data derived from
analytical studies to show “high similarity” to the reference product
from originator not withstanding minor differences in clinically
inactive components [11-13]. Therefore, the physicochemical analytical
comparison between biosimilar and its reference product within
the acceptable statistical ranges is the primary consideration during
biosimilar development [14,15]. These acceptable range are defined
by measuring different lots of the reference products over a period
of time [15-17]. Moreover, these analytical data provide significant
insight into the cell line expression system, manufacturing process, and
scale up stability. It also provides the comparability of physicochemical
properties, functional activities, target binding and immunochemical
properties, impurities, and finished drug product stability between
reference product and reference standards [1,18-20].
Structural and physicochemical assessment of the biosimilar
product and the reference product should include all relevant
characteristics (e.g., the primary, secondary, tertiary, and quaternary
structure; and post translational modifications). Any significant
detected differences in quality attributes should be scientifically
justified during preclinical studies and clinical trials. The amino
acid sequence of the biosimilar product should be identical to the
reference product [6,21]. Peptide mapping by mass spectrometer
provides information on the primary structure of the biosimilar
product as well as the in-depth information of post-translational
modifications of different isoforms (Figure 1). These isoforms then
require multiple analytical methods to assess their physicochemical
characteristics. These analytical methods are based on the structure,
heterogeneity, and critical aspects of product performance of the
protein being characterized [22-24]. For understanding the full range
of physicochemical properties, orthogonal analytical methods are
necessary to evaluate quality attributes. Orthogonal methods that
use different physicochemical principles to assess the same attribute
can provide independent data to support the quality of a specific
attribute. Complementary analytical techniques in series, such as
peptide mapping or capillary electrophoresis combined with mass
spectrometry of the separated molecules, are other ways to provide
a meaningful comparison between products [14]. Some examples of
structural and physicochemical methods are listed in Table 1. These methods should be scientifically sound, fit for their intended use, and
provide results that are reproducible and reliable. In selecting these
tests, it is important to consider the characteristics of the protein
product, including known and potential impurities (Table 1).
Figure 1: Representative Peptide Mapping of a Mab digested by trypsin
Table 1: Structural and Physicochemical Methods for Reference Product Comparison
Biological assays are used to demonstrate the mechanism of action (MOA) of the product, as well as to predict its clinical effects. However, the data from biological assays are should only be considered as supplemental to physicochemical analysis. It is a qualitative rather than a quantitative measure of the protein product [15,25,26]. Since structural complexity may disallow physicochemical analysis to confirm the integrity of the higher order structures, the integrity of such structures can be extrapolated from the product’s biological activity. If the MOA is known for the reference product, the biological assays can also demonstrate these mechanisms of action. Multiple biological assays should be performed as part of the analytical similarity assessments. Moreover, biological activity is also indicative of the manufacturing processes ability to maintain consistency, product purity, potency, and stability [14,19,23].
The potential caveats of biological assays should be acknowledged.
For example, if the biological assays have high variability, they cannot
not be used to show biosimilarity between the biosimilar product and
the reference product. Additionally, bioactivity assays may not fully
reflect the clinical activity since bioactivity assays generally do not
predict the bioavailability of the product [8,9,19,23,27]. Thus, these
limitations should be considered when assessing the robustness of the
quality of data supporting biosimilarity and the need for additional
information that may address residual uncertainties [22,24,28]. Some
representative functional assays are listed in Table 2.
Table 2: Biological Methods for Reference Product Comparison
It is required to characterize, identify, and quantify impurities
in biologic products. A risk-based assessment should be performed
on any differences in process-related impurities identified between
the biosimilar product and the reference product. The manufacturer
should define the pattern of heterogeneity of the desired product and
demonstrate lot-to-lot consistency used in preclinical and clinical
studies. Additional pharmacological/toxicological or other studies
may be necessary if the manufacturing process produces different
impurities or higher levels of impurities than those present in the
reference product [1,23,28-30]. Therefore, it is much preferable to
remove impurities and contaminants in the downstream process
rather than to establish a preclinical testing program for their qualification and classification. Common process-related impurities
are cell substrates (e.g., host cell DNA, host cell proteins), cell culture
components (e.g., antibiotics, media components), and materials
in downstream processing steps (e.g., reagents, residual solvents,
leachables, endotoxin, bioburden) [19,23,31]. The common analytical
techniques for impurities are listed in Table 3.
Table 3: Impurities Assesment Methods for Reference Product Comparison
In this review, the approach for physicochemical characterization,
biological activity and impurities assessment were reviewed. The
analytical strategy for a biosimilar typically starts with extensive structural and functional characterization to identify critical quality
attributes (CQAs) and clinically active components. Experiments are
then used to provide insight into the relationship between CQAs and
the clinical safety & efficacy profile; and to predict expected “clinical
similarity” from the quality data. Multiple, orthogonal analytical
methods of characterization should be chosen specifically to
establish quality comparability to the reference product, and certain
attributes (e.g. product aggregation and charge heterogeneity) as
well as breakdown products during shelf life [32]. Therefore, the
comprehensive strategy integration of bioanalytical analysis should provide understanding of physicochemical properties; biological
activity; purity of the product and impurities from the manufacturing
process [33-36]. The biological and immunological methods,
such as animal studies, will be needed to further demonstrate
biosimilarity in in vivo environment before clinical studies can be
performed [8]. Depend on the regulatory agency requirements,
clinical studies will usually be required to show similar safety
profile and pharmacokinetics to the originator’s drugs before the
biosimilar can be launched to the market. Nevertheless, the body
of information from analytical studies not only supports successful
CMC and nonclinical development, but also provides insights into the
underlying absorption, distribution, metabolism, excretion (ADME)
and in-clinical development, and ultimately translated into animal
and clinical studies success.
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