264
Scientific Criteria for Demonstration of Biosimilarity
Issues in Biosimilar Manufacturing
Many of the synthetic and manufacturing processes involve proprietary techniques
to produce a biosimilar of the reference product. Specific manufacturing features
are summarized in Table 15.1. A large number of variables exist, among other fea-
tures, in the choice of the cell vector and cell expression system and cell line and
master cell banks. Likewise, conditions for expansion of the cell lines are proprie-
tary, and variables which may be highly controlled are not known to the biosimilar
manufacturer and may play into intellectual property concerns after drug approval
(Fig.15.1). Differences in synthesis can potentially result in different posttransla-
tional modifications, possiblyaffecting efficacy, safety, and immunogenicity of the
product [ 8 ]. For both the biosimilars for IFX and ADA, the FDA closely considered
Cloning and protein expression
Cloning into DNA vector
Source
DNA
Target DNA
Cell
expansion
Different cell line,
growth media,
method of expansion
Different cell line,
growth media,
bioreactor conditions
Different
operating
conditions
Different binding and
elution conditions
Different methods,
reagents, reference
standards
Purification through
chromatography
Characterization and
stability
Purified
bulk drug
Recovery through
filtration or
centrifugation
Cell production in
bioreactors
Protein production, purification and validation
Possibly same
gene sequence
Probably different
vector
Different cell expression
system
Transfer into host cell
expression
screening/selection
Fig.15.1 Biological drugs manufacturing: reprinted from Ref. [ 74 ]
C.Y. Ha and A. Kornbluth