GaBI Educational Workshops 1 September 2015, Le Meridien Dubai, United Arab Emirates
• Director, Global R & D and Regulatory Policy, Amgen Inc, USA
Sundar Ramanan, PhD, USA
GaBI Educational Workshops 1 September 2015, Le Meridien Dubai, United Arab Emirates
Biologicals and biosimilars – the complexity of structure and funcBon
Sundar Ramanan, PhD 1 September 2015
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Sundar Ramanan, Ph.D.
Director, Policy - R&D and Regulatory Affairs
Amgen Inc.
GaBI ME SBP Workshop, September 1, 2015, Dubai, UAE
Discussion Topics
• Overview of biosimilar development
• Elements and limitations of analytical studies
• Role of structure-function studies
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
3
Discussion Topics
• Overview of biosimilar development
• Elements and limitations of analytical studies
• Role of structure-function studies
4 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Approval is Based on the “Totality of Evidence”1
1. Foundation- Structural and functional comparisons
2. Non clinical in vitro and in
vivo testing
Biosimilar
1. Quality
Cross reference
2. Non-Clinical
3. Clinical
Cross reference
Cross reference – Prior findings of safety and
efficacy
Integrated Biosimilarity Exercise – Quality, Safety and Efficacy
Originator BLA
Biosimilar?
Biosimilar?
Biosimilar?
Biosimilar development proceeds through a stepwise similarity exercise
3. Clinical
Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 24 January 2013.
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
5
1. Foundation- Structural and functional comparisons
2. Non clinical in vitro and in
vivo testing Biosimilar?
Process design and analytical studies form the foundation of biosimilar development
3. Clinical
Before non-clinical and clinical testing can proceed: • Define the target quality profile
• Design the process
• Compare structural and functional attributes
• Use state-of-the-art analytical characterization and functional assays to assess any structural difference
• Understand the importance and limitation of functional assays
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
6
Carbohydrates & other post-translational modifications
Chemical modifications &
PEGylation
Synthesis and Folding
(a) Primary structure
(b)Secondary structure
β Pleated sheet
(c)Tertiary structure
(d) Quaternary structure
α Helix
Sugar side chains (can affect safety and efficacy)
Chemical modifications (can affect purity, safety, or potency)
[Image Source: Tim Osslund; Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time; http://kvhs.nbed.nb.ca/gallant/biology/protein_structure.html. Data source: USP-NF 1045. Biotechnology-derived articles: 3-20]
Biologics may have 4 orders of structure plus modifications that affect in vivo characteristics
7 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Biological products have very complex structures
Monoclonal antibody
Glycan modifications • G0, G1, G2 • Core fucosylation • High mannose • etc
Peptide modifications • Deamidation • Succinimide • Oxidation • N & C-terminal variants • Amino acid substitution • Disulfide isoforms Folding/Size • Truncation • Half molecules • Dimer • Multimers • Aggregates • Particles
8 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from D. Kelner (Amgen), “Comparability and Biosimilarity: Two Sides of the Same (or a Different) Coin?” presented at IBC Analytical Technologies,San Diego, CA (March 2012)
Typical analytical similarity assessment evaluates 90 to 100 unique attributes
Results from a wide breadth of assay combinations compares the analytical “footprint” of the biosimilar to the reference product.
Is it possible to “match” all attributes?
9 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu et al. (Amgen), “Analytical Similarity Assessment of Biosimilars” presented at the Spring ACS Meeting, Dallas, TX (March 2014)
QbD for biosimilars • Assess criticality based on
literature & experience
• Characterize reference product quality attributes
• Design biosimilar to minimize differences for high criticality attributes
• Assess potential clinical relevance of remaining differences
Biosimilar development can use a Quality-by-Design (QbD) approach
Product Quality Attributes
Criticality Assessment
Safety and Efficacy Data
High Criticality Attributes
Low Criticality Attributes
Product Understanding
Clinical Studies
Animal Studies
In-Vitro Studies
Prior Knowledge
Focus on the most important
attributes
Lower criticality attributes are
not “forgotten”
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity”
presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
Discussion Topics
• Overview of biosimilar development
• Elements and limitations of analytical studies
• Role of structure-function studies
11 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Analytical studies should assess several aspects of structure
• Primary structure (sequence and linkages)
• Higher order structures (folding, aggregates)
• Covalent modifications (glycosylation and chemical modifications)
• Impurities (product and process)
• Stability profile
12 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
AU
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Minutes 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 110.00 120.00 130.00 140.00 150.00 160.00 170.00 180.00
Biosimilar product should have identical amino acid sequence to the innovator
Peptide mapping
• 100% sequence confirmation
• Search for any low level amino acid substitution (sequence variant) due to translational errors, misincorporation, or mutation
• Post-translational modifications, such as glycosylation, acetylation, sulfation, phosphorylation, glycation, etc
13 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Amgen unpublished data
Mass spectroscopy combined with separation based methods can address many uncertainties
Primary structure and covalent modifications can be assessed to high fidelity
Image obtained from University of Kentucky Mass Spectrometry Facility http://www.research.uky.edu/ukmsf/example2a.html
• Amino acid sequences confirmed to ~100% coverage
• Covalent modifications, sequence variants and glycan structures detected to <1% resolution
Example: LC ESI MS/MS
14 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Analytical Similarity Assessments”
presented at the DIA/FDA Biosimilars Conference, Washington DC (September 2012)
Examples of some remaining challenges
• Accurate quantitation of minor species
• Identifying and quantifying disulfide bonding patterns
• Accounting for combinatorial effects
Advanced mass spectroscopy methods still leave some uncertainties
Correctly folded Disulfide misfolds 1 and 2
Std (15N)Sample (14N)
Std+Sample
Proteolysis
Mix
m/z
Stable Isotope Labeled Internal Standard (SILIS)
Figures courtesy of Jiang et al, PEGS 2011
15 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Analytical Similarity Assessments”
presented at the DIA/FDA Biosimilars Conference, Washington DC (September 2012)
Higher order structure and size variants are characterized by orthogonal methods
10 -4-2.0
-1.6
-1.2
-0.8
-0.4
0.0
0.4
0.8
Ab
sorb
ance
1600 1620 1640 1660 1680 1700
Wavenumbers (cm-1)
US Lot 031622EUS Lot 042212EUS Lot 050662E
ABP Lot 0010085288ABP Lot 0010085295ABP Lot 0010085297
-14
-12
-10
-8
-6
-4
-2
0
2
4
260 280 300 320
Wavelength (nm)
CD
Elli
pticity
US Lot 081492E
US Lot 092852E
US Lot 092872E
ABP Lot 0010095541
ABP Lot 0010112898
40 60 80 100
0.00000
0.00004
0.00008
0.00012
ABP Lot 0010085297ABP Lot 0010085295ABP Lot 0010085288EU Lot 02136XH02EU Lot 02129XH14EU Lot 92081XD01
US Lot 050662E
US Lot 031622EUS Lot 042212E
Cp (c
al/ C
)
Temperature ( C)
(e) Monomer, dimer, oligomers
16 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Circular Dichroism
FTIR
Analytical Ultracentrifugation
2 4 6 8 10 12 14 16 18 20
0
1
2
3
4
5
6
7
8
9
10
US lot 970031US lot 450657US lot 970032ABP lot 0010133673ABP lot 0010112870ABP lot 0010095534EU lot H0138B01EU lot H0021B06EU lot H0134B01c(
s)
Sedimentation coefficient (Svedberg)
Calorimetry
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Amgen unpublished data
Eg, unfolded protein spiked into product • Limit of detection is 8% by
near UV circular dichroism • How sensitive to partially
unfolded species?
A common limitation of spectroscopic methods is sensitivity to mixtures
Amgen unpublished data
Near UV CD
Percent UnfoldedW
eigh
ted
Spe
ctra
l D
iffer
ence
(WS
D)
0 20 40 60 80 100
Spectral changes detectableat WSD of 4.5
8.3% unfolded
17 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Analytical Similarity Assessments”
presented at the DIA/FDA Biosimilars Conference, Washington DC (September 2012)
• Focus on characterizing particles (0.1 m to 10 m) • Size, composition, quantity, structure • Relevance to immunogenicity
• Improving sensitivity, accuracy, and specificity • Protein vs. container
• Emerging nanotechnology-based approaches for < 1 m particles
• Quantitative and qualitative comparisons remain difficult
Particulate characterization technology is improving
Aggregation (<0.1 m)
AUC
1
10
100
1000
10000
0 5 10 15 20Par
ticl
e C
on
cen
trat
ion
(#/
mL
)
Diameter (µm)
LOQ
Light obscuration
Particulation (>1 m)
MFI
Amgen unpublished data
Amgen unpublished data
5 10 15
Aggregate
Monomer
sedimentation coefficient (S)
c(s)
5 10 15
Aggregate
Monomer
sedimentation coefficient (S)
c(s)18 The Role of Analytical and Structure–Function Studies
in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Analytical Similarity Assessments”
presented at the DIA/FDA Biosimilars Conference, Washington DC (September 2012)
Glycosylation is a critical quality attribute that can impact biological functions
19
Glycan mapping by HILIC and Mass Spectrometry
• Over 25 mAb glycans identified
• Correlate glycan attributes with
biological function
Glycan Type Impact to function
No glycan No ADCC
Bisecting GN Increase ADCC
High mannose Clearance and effector function
Terminal Gal Increase CDC
NANA Anti-inflammatory
Afucosylated Increase ADCC
min 5 7.5 10 12.5 15 17.5 20 22.5 25
0
10
20
30
40
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Hydophobic Interaction LC (HILIC)
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Amgen unpublished data
Product isoforms need to be fully characterized using separation methods
Size variants • Truncation • Dimer • Multimers
Charge and hydrophobic variants • N-terminal modification • C-terminal modification • Deamidation • Oxidation
min 5 10 15 20 25 30
mAU
Size Exclusion HPLC
Minutes
12 13 14 15 16 17 18 19 20 21 22 23
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22UV - 280nmABP 494 14011712-2 A52Su 1
UV - 280nmErbitux EU 133839 A52Su
UV - 280nmErbitux US 10C00383 A52Su
Isoelectric Focusing
K K K
Ion Exchange HPLC
20 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Amgen unpublished data Amgen unpublished data Amgen unpublished data
Separation methods also used to examine the integrity of covalent structure
Non-reducing SDS • Partial molecules • Half molecules • Fragments • Non-disulfide
linked aggregates
Heavy Chain
Light Chain
mAU
min 5 10 15 20 25
0
10
20
30
40
HC LC
Internal Std
min 5 10 15 20 25
mAU
-2
0
2
4
6
min
1
2
3 4
5
Internal Std
Reducing SDS • Truncation • Clipped species
21 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Amgen unpublished data
Product-related and process-related impurities must be well characterized • High resolution and orthogonal methods are required to characterize
product-related species.
• Process-related impurities (HCP, DNA, leachables, etc) need to be characterized to ensure product quality.
• Particles and aggregates of various sizes need to be evaluated and characterized.
Size variants: • Truncation • Dimer • Multimers • Clipped species • Non-glycosylated HC
Charge and Hydrophobic Variants: • N-terminal modification • C-terminal modification • Deamidation • Oxidation
• Partial molecules • Half molecules • Fragments • Non-disulfide linked aggregates
Minutes12 13 14 15 16 17 18 19 20 21 22 23 24
AU
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
0.11
NGHC
Heavy Chain
MMW
LightChain
LMW HMW
Sig
nal (
280
nm)
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Time (min)15.0 20.0 25.0 30.0 35.0 40.0
Basic
Main
Acidic
22 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu et al. (Amgen), “Analytical Similarity Assessment of Biosimilars” presented at the Spring ACS Meeting, Dallas, TX (March 2014)
Amgen unpublished
data
Proteins undergo complex degradation and are sensitive to storage and handling
Protein stability
Thermal stress
Chemical stress
Physical stress
Enzymatic stress
Degradation contributes to eventual loss of biological activity and/or potential immunogenicity
Biosimilar stability is impacted by its manufacturing process and formulation
23 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu (Amgen), “Analytical Testing and Characterization of Biosimilars” presented at the Health Canada SEB/Biosimilar Scientific Forum, Ottawa, Canada (November 2013)
Forced degradation studies should demonstrate similar stability profiles Multiple accelerated thermal stress conditions (25, 40, 50°C) provide a quantitative, reproducible, and sensitive comparison of degradation profiles and rates
• Example: Size Exclusion Chromatography profiles – 50°C, T=15 days
• Rate comparisons: 0-15 days
24 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu et al. (Amgen), “Analytical Similarity Assessment of Biosimilars” presented at the Spring ACS Meeting, Dallas, TX (March 2014)
Amgen unpublished
data
Discussion Topics
• Overview of biosimilar development
• Elements and limitations of analytical studiess
• Role of structure-function studies
25 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Structural comparisons leave residual uncertainties
Sources of uncertainty Potential consequences Assay limitations (limit of detection, specificity, etc.)
Unobserved differences could potentially impact efficacy or safety
Lot to lot variability and population statistics
Equivalence of means does not prove that individual lots are biologically equivalent
Observed differences in critical attributes
Could impact safety or efficacy if differences are large enough
Observed differences in less critical attributes
• Are assumptions about criticality correct?
• Could combinations of attributes become significant?
Challenges of Structure-Function Studies for Assessing Similarity 26
Functional studies are the first step in addressing these residual uncertainties
Why functional characterization? Part 1: Required by regulators
• Functional characterization required • To confirm quality and potency of the product • To address limitations of structural assays • To confirm similar mechanism(s) of action
• presence of expected function, absence of new function • specificity of target binding
• Relevant passage from FDA guidance “Depending on the structural complexity of the protein and available analytical
technology, the physicochemical analysis may be unable to confirm the integrity of the higher order structures. Instead, the integrity of such structures can be inferred from the product’s biological activity.” (Emphasis added)
FDA Draft Guidance, Quality Considerations in Demonstrating Biosimilarity to a Reference Product, February 2012
27 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity”
presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
Matching all biological and functional properties is essential
Target binding to Complementarity-
Determining Regions (CDRs)
Binding Region for FcR
(ADCC, CDC)
Binding Region for FcRn (PK ½ life)
IgG1
N-glycan
Heavy chain
Intra-chain disulfide
Inter-chain disulfide
Light chain
Biological functions are dependent on the target antigen and the class of antibody
Concentration (nM)
0.1 1 10 100 1000 100000
500000
1e6
1.5e6
2e6
4-P Fit: y = (A - D)/( 1 + (x/C)^B ) + D: A B C D R^2EU Lot H0134B01 - (H0134B01: Concentr... 1.65e+06 1.31 49.4 -4.43e+04 0.997EU Lot H0021B06 - (H0021B06: Concentr... 1.64e+06 1.38 73.9 -4.51e+04 0.998EU Lot H0138B01 - (H0138B01: Concentr... 1.63e+06 1.38 65 -4.21e+04 0.997ABP Lot 0010095534 - (GMP1 0010095534: ... 1.68e+06 1.29 62.9 -5.2e+04 0.998ABP Lot 0010112870 - (GMP2 0010112870: ... 1.62e+06 1.43 71 -4.68e+04 0.992ABP Lot 0010133673 - (GMP3 0010133673: ... 1.64e+06 1.53 64.9 -3.38e+04 0.997US Lot 970032 - (970032: Concentratio...1.63e+06 1.41 74.4 -3.61e+04 0.998US Lot 450657 - (450657: Concentratio...1.64e+06 1.31 79.2 -5.64e+04 0.998US Lot 970031 - (970031: Concentratio...1.62e+06 1.65 72.5 -1.76e+04 0.998
__________Weighting: Fixed
28 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from J. Liu et al. (Amgen), “Analytical Similarity Assessment of Biosimilars” presented at the Spring ACS Meeting, Dallas, TX (March 2014)
Amgen unpublished data
QbD for biosimilars • Assess criticality based on
literature & experience (where available)
• Minimize differences for high criticality attributes
• Perform structure-function studies to assess remaining differences
• Relate findings to potential clinical impact
Why functional characterization? Part 2: May be essential to justify differences
Product Quality Attributes
Criticality Assessment
Safety and Efficacy Data
High Criticality Attributes
Low Criticality Attributes
Product Understanding
Clinical Studies
Animal Studies
In-Vitro Studies
Prior Knowledge
Focus on the most important
attributes
Lower criticality attributes are
not “forgotten”
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity”
presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
Prepared samples can increase sensitivity of structure-function studies
Charge Variants % Relative Potency
Acidic variants 82
Main peak 101
Basic variants 84
Amgen unpublished data
Cation exchange profile of a mAb
% variant
Po
ten
cy
Observed range
Enriched sample
Slope estimate
Improved estimate of slope informs potential criticality and permitted magnitude of differences
Notional data for illustration purposes only
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity” presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
Studies must provide relevant conclusions 1) Evaluate in vitro functional data
a) Test functional equivalence of actual batches
Is a 25% difference really acceptable?
b) Relate attribute difference to parameters from structure–function studies
• Measured difference in means
• Estimated quantitative effect
• Relate to clinically meaningful differences
Att
rib
ute
Lev
el
Reference Lots
Notional data for illustration purposes only
Biosimilar Lots
x coefficient = estimated
effect
Po
ten
cy
Attribute Level
Test for equivalence of means
80% < < 125%
Reference Lots Biosimilar Lots
Notional data for illustration purposes only
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity” presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
Studies must provide relevant conclusions 2) Evaluate PK and drug metabolism where feasible
0
2
4
6
8
10
12
14
0 10 20 30Time (day)
pE b
y U
V
In vivo vs. in vitro conversion of Glu to pyroGlu
Adapted from Liu et al. 2011, J.Biol. Chem. 286, 11211-11217
• Serum incubation in vitro: is a variant formed under physiologic conditions?
• Product recovery from PK samples
0%
1%
2%
3%
4%
5%
6%
0 10 20 30
Time post injection (Days)
Perc
ent o
f tot
al g
lyco
pept
ide
G0G1M5
0%
1%
2%
3%
4%
5%
6%
0 10 20 30
Time post injection (Days)
Perc
ent o
f tot
al g
lyco
pept
ide
G0G1M5
M5 increases initially
followed by decrease
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity” presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
101%
98%
101%
113% 99%
90%
106%
106%
0.00
0.20
0.40
0.60
0.80
1.00
1.20
3.20 3.30 3.40 3.50 3.60 3.70 3.80
SA/N
LE/N
RB-DNM-BNM-CNM-DVY-B VY-F EM DT
101%
98%
101%
113% 99%
90%
106%
106%
Process change case study
Small effects can combine in unexpected ways
• Change resulted in shifts in 2 attributes (see figure)
• Bioassays predicted equivalent potency
• Equivalent PK shown in human clinical study
• Potency difference detected in clinical PD study
• Post hoc studies with prepared fractions identified additive effects on potency
In vitro potency of prepared fractions
Attribute 1
Att
rib
ute
2
Post-change Pre-change
Amgen unpublished data
Prepared fraction
The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Figure adapted from G. Grampp (Amgen), “Challenges of Structure-Function Studies for Assessing Similarity” presented at the Spring ACS Meeting, New Orleans, LA (April 2013)
• Predicting human PK/PD • Animal studies may not account for species specific
clearance mechanisms • Insufficient power due to small number of animals
• Predicting human immune response • In silico, in vitro, and in vivo methods are insufficient to
rule-out clinically relevant differences
Additional challenges in structure-function studies
34 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
• Analytical advances permit high resolution similarity assessments for many attributes • Higher order structure and particle assessments still
subject to uncertainty • Orthogonal approaches partially compensate for lower
sensitivity
• Assessing impact of differences remains challenging • Not all clinically relevant effects can be evaluated pre-
clinically (e.g., PK and immunogenicity) • Small effects and combinations difficult to assess
Summary and Conclusions
35 The Role of Analytical and Structure–Function Studies in the Assessment of Biosimilarity
Thank you!
Challenges of Structure-Function Studies for Assessing Similarity 131
Top Related