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Comparabil i ty Studies:
The Key to a Biosimi lar' s Success
Raymond Kaiser, PhD
Global Vice President
BioPharmaceutical CMC Solutions
Covance
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2
Presentat ion Out l ine
What is BiosimilarityGlobal Regulatory CMC Expectations
Comparability Expectations
Analytical Approaches to comparability
Real World observations
Q&A
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What is a B ios im i lar?
Biosimilars are follow-on biologics
New versions of innovatorbiopharmaceutical products,
following patent expiry
The very nature of a biologic means
It is practically impossible for two different manufacturers to produce
two identical biopharmaceuticals if identical host expression
systems, processes and equivalent technologies are not used
This has to be demonstrated in an extensive comparability program
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B iosim i lar or B iosim i lar i ty means :
The biological product is highly similar
to the reference product notwithstanding minor
differences in clinically inactive components
There are no clinically meaningful differencesbetween the biological product and the reference
product in terms of the safety, purity, and potency of
the product
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Global Regu latory LandscapeEMA (The European Medicines Agency)
Established EMA approval pathway:14 biosimilars approved* within the product classes of:
human growth hormone
granulocyte colony-stimulating factor (G-CSF) erythropoietin
US FDABiologics Price and Innovation Act passed in 2010
Empowers FDA to develop standards to evaluate and approve biosimilars
FDA February 2012 draft guidance documents Risk-based totality-of-the-evidence approach
Health CanadaGuidance came out in 2010
JapanGuideline came out in 2009
WHOGuideline document came out in 2009
ROWArgentina, Australia (amending), Brazil, Jordan, Korea, Malaysia, Saudi Arabia, Singapore,
Taiwan, Turkey, Venezuela Guidelines available
Colombia, Cuba, India, Mexico, South Africa, and Thailand Draft Guidelines available
Biosimilar Regulatory Guidance documents and discussions are on-goingand expanding globally.
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Regu latory Environment - EU
Established EMA approval pathway
14 biosimilars approved within the product classes of:
Human growth hormone
Granulocyte colony-stimulating factor (G-CSF)
Erythropoietin
Key EMA guidance documents
Overarching guideline on similar biological medicinal products
From 2005, currently being updated
Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substances: quality issues
From 2005
Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substances: nonclinical and clinical issues
From 2005, currently being updated to incorporate risk-related approaches
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Regu latory Environment US
FDA approval pathway established
Biologics Price and Innovation Act passed in 2010 empowers
FDA to develop standards to evaluate and approve biosimilars
FDA February 2012 draft guidance documents
Scientific Considerations in Demonstrating Biosimilarity to aReference Product
- Risk-based totality-of-the-evidence approach
Quality Considerations in Demonstrating Biosimilarity to a Reference Protein
Product
- Overview of analytical factors to consider, includes analytical, physico-
chemical and biological characterization
Biosimilars: Questions and Answers Regarding Implementation of the Biologics
Price Competition and Innovation Act of 2009
- Provides answers to common questions that may arise in the early stages
of product development
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General Requ irements of FDA Guidance
A 351(k) application must include information demonstrating
biosimilarity based on data derived from:
Analytical studies demonstrating that the biological product ishighly similar to the reference product notwithstanding minordifferences in clinically inactive components
Animal studies (including the assessment of toxicity)A clinical study or studies (including the assessment of
immunogenicity and pharmacokinetics (PK) orpharmacodynamics (PD)) that are sufficient to demonstratesafety, purity, and potency in 1 or more appropriate conditions ofuse for which the reference product is licensed
FDA may determine, at its discretion, that an elementdescribed above is unnecessary in a 351(k) application
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Regu latory Environment - ICH Regions
How do the requirements compare?
US, EU and Japan all require comparability with reference product
Reference product must be registered under the Regulatory jurisdiction
In EU this is law
FDA will consider non-US registered reference product with studies to bridge to US
reference
Japan requires Japanese registered product
Early engagement with Regulatory Authority is vital
Extrapolation of indications will be considered
At least one Phase III comparable efficacy study (usually with equivalence design) is
required for licence
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Regu latory Comparabi l i ty Package
Extensive Analytical & In Vitro Extensive analytical characterization versus reference product(s)
If mAb specificity & affinity to epitope potency using CDC, ADCC &/or functional in vitro cell-based assays
Limited in vivo Nonclinical PK/PD studies, Toxicology (SD/MD), and Immunogenicity studies
(requirement for nonhuman primates?)
Limited Clinical Phase I
comparability of PK/PD & Immunogenicity in volunteers or patients atreference dose and regimen for targeted indications
Phase III comparability for safety and efficacy (single pivotal) based on PK/PD,
surrogate endpoints and clinical outcomes
Extensive Post-Approval REMS and pharmacovigilance planning including patient registry(ies) for
assessment of incidence of specific safety issues
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Development Challenges
Regulatory, manufacturing and marketing complexities
Biosimilar must be highly similar to innovator biologic, which can be
difficult to demonstrate as all data for innovator will be lacking
A comparability exercise has to be followed with the innovator
product at all levels of product development
Physico-chemical characterization
Biological activity
Preclinical in vivo comparability
Phase I PK and safety
Phase III efficacy and safety
Its all about comparability
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Biosimi lar i ty?
How close do the proposed
biosimilar products (figures B-E) compare to the referenceproduct (figure A)?
Advances in current state-of-
the-art analytical methodsenhance the likelihood that aproduct will be highly similarto another product by bettertargeting the original product'sphysicochemical andfunctional properties
Biosimilar Biological Product Webinar, Rachel Sherman, FDA, 15FEB2012
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Biosimilar Biological Product Webinar, Rachel Sherman, FDA, 15FEB2012
FDA View
Bi i i l t b S t ti ll E i d
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Bios imi lars must be Systematically Engineered
to Match the Reference Produc t
Mark McCamish, Novartis, International Conference on Drug Development, Austin TX,
29FEB2012
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Characterizat ion
Comprehensive Characterization
Physicochemical as well as biological
Multiple batches from innovator spanning a number of
years
Understand innovator variability
Specification changes over life of product
No label change
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B iosim i lars at Covance
Year on year doubling of analytical demand for Biosimilars since 2008
Upgraded Protein Chemistry techniques
with additional characterization to demonstrate comparability orunderstand differences
Moved toward higher defining analytics (e.g. UPLC, LC/MS)
Compounds 1000 500 250 100 20 1
IND/CTA NDA /BLA Approval
DISCOVER
Y
PreclinicalResearch Phase I Phase II Ph. IIIa IIb Phase IV
DRUG DEVELOPMENT COMMERCIALIZATIO
N
Biosimilar
NBEAmountof
Characteris
ation
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Why More Character izat ion for B iosim i lars?
Client has to show high similarity to Innovator
Proving highly similar to the reference product often
required multiple iterations of process change and
physiochemical characterization
Characterization of the Innovator (beware literature!)
Characterization of the Biosimilar
Monitor Manufacture
Process is the product
Monitor changes in Innovator
Analytical tools for characterizing biopharmaceuticals and the implications for Biosimilars. S Berkowitz,
J Mazzeo, G Jones, Nature review Vol 11, Jul 2012
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Why More Character izat ion for Biosim i lars?
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Protein Heterogeneity
Amino Acid Substitution
AA Misincorporation (e.g.METNLE)
N- and C-terminal mods
Mismatched S-S bonds
Folding
Truncation
Aggregation
Multimer Dissociation
Denaturation
Acetylation
Fatty acid acylation
Deamidation
Oxidation
Carbamylation Carboxylation
Formylation
-Carboxyglutamylation
O-linked Glycosylation N-linked Glycosylation
Methylation
Phosporylation
Sulphation PEGylation
etc.
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Analyt ical Too ls to Evaluate Protein Structu re (subset)
Protein Functionality Analytical Technique
AA Sequence and
Modifications
Mass Spectrometry (MS), peptide mapping, Edman Sequence
analysis, chromatographic separations
FoldingS-S bonding, calorimetry, HDX and Ion mobility MS, NMR, CD,
FT & Raman spectroscopy, fluorescence, chromatography
Subunit Interactions Chromatography, ion mobility MS
Heterogeneity of size,
charge, hydrophobicity
Chromatography, gel & capillary electrophoresis, light scatter
Glycosylation Anion exchange, enzymatic digestion, peptide mapping, CE, MS
PEGylation & isomers Chromatography, peptide mapping
Bioactivity, cellular and
animal bioassays
Ligand & receptor binding (ELISA, SPR), signal transduction
AggregationAnalytical ultracentrifugation, size-exclusion chromatography,
field flow fractionation, light scatter, microscopy
Proteolysis Electrophoresis, chromatography, MS
Impurities Chromatography, proteomics, immunoassays, PCR
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Mass Spectrom etry
Intact mass, comparison of Glycan variants. The
difference in 56Da attributed to incorrect amino acidsequence
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Hormone Receptor B ind ing by Biacore
-10
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350
Time s
Resp.Diff.
RU
-10
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300 350
Time s
Resp.Diff.
RU
-10
10
30
50
70
90
0 50 100 150 200 250 300 350
Time s
Resp.Diff.
RU
DS BiosimilarDP Biosimilar
Innovator
Sample Lot No. KD (nM) % Difference
1 301
2 399
3 412
1 415
2 350
3 397
Drug Substance
4.40
Innovator
Biosimilar
Sample Lot No. KD (nM) % Difference
1 202
2 172
3 118
1 138
2 188
3 158
Drug Product
-1.64
Biosimilar
Innovator
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Find ing the Dif ferences by C-IEF
7.4
19
7.5
24
Main-7.6
13
7.8
08
7.9
91
8
.145
Absorbance
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
Minutes
6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40
Blue - BiosimilarBlack - Innovator
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Carboxypep t idase Treatment
7.1
59
7.2
49
7.3
33
7.4
30
Main-7.5
33
7.6
59
7.7
31
Absorbance
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
Minutes
6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60
Blue - Innovator
Black - Biosimilar
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Forced Degradat ion
6.7
98
6.9
27
6.9
96
7.1
38
7.2
65
7.3
82
7.4
81
Main-7.5
31
7.6
03
7.7
09
7.8
05
7.9
06
8.0
41
Absorbance
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
0.100
0.110
0.120
0.130
Minutes
6.00 6.20 6.40 6.60 6.80 7.00 7.20 7.40 7.60 7.80 8.00 8.20 8.40 8.60 8.80 9.00 9.20 9.40 9.60 9.80
Black - Innovator
Blue - Biosimilar
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2626
Impact of Glycosylat ion?
Blue- Innovator
Black- Biosimilar
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2727
Simpli fy by De-sialylat ion?
Absorban
ce
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
0.30
Minutes
3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50
Blue- Innovator
Black- Biosimilar
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2828
N-Glycan Sim ilar i ty
Energ
y
0.00
200.00
400.00
600.00
800.00
1000.00
1200.00
1400.00
1600.00
1800.00
2000.00
2200.00
Minutes
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00
G0F
G1F
G1F
G0 G1G1
Man5
G2FBlue- Innovator
Black- Biosimilar
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Mass Spectrom etry
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Peptide Map
NOTE: Originators make biosimilars every time there is a
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NOTE: Originators make biosimilars every time there is amanufactur ing p rocess change
Aranesp (Darbepoetin-alfa)
MabThera/Rituxan (Rituximab)
Enbrel (Etanercept)
Ref: Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
(Sandoz)
Character izat ion of Commercial Batches of
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Character izat ion of Commercial Batches of
Darbepoetin alfa from the EU
Change in isoform distribution between two sets of batches (expiry date
April 2010 and September 2010)
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
Character izat ion of Commercial Batches
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Character izat ion of Commercial Batches
Mabth era/Rituxan (r i tux imab)
Shift in Glycosylation Profile and ADCC Potency
Differences/shift in glycosylation pattern results in different potency in cell-based assays
Product label remained unchanged indicating comparable quality
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
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Character izat ion of Commercial Batches o f Enbrel
Shift in Glycosylation Profile
Differences/shift in glycosylation pattern
Product label remained unchanged indicating comparable quality
Schiestl et al. Nat. Biotechnol. 2011; 29: 310-312
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Demonstrat ing Comparabi l i ty in an Ideal World?
Product heterogeneity is clearly understood, variants are
easily isolated and characterized Product variants and related impurities
Process related impurities
Smooth manufacturing scale up, no process changes
Methods ready to demonstrate comparability without
development. One size fits all
Enough time and a crystal ball to know what to look for
?
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What does This Look Like in the Real World?
Biosimilars are snowflakes. No two are the same
Incomplete comparability characterization
Experience rapid time pressures
Final formulation often undecided
Manufacturing difficulties with scale up
Fast turn around in-process sample analysis
Rapid development and validation for discriminating assays
Need justification and risk assessment for observed
differences
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Other Real World Observations II
Stress stability studies (w/ multiple time points) needed
Multiple lots of reference product often used. Understandimpact of ref. product shelf-life on results. Justify use
Reference product isolation procedure can impact results
Comparability continues even after release
GMPs apply for biosimilar product development
Meet with BOHs as early as possible to discuss your
analytical control strategy
O h R l W ld Ob i III
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Other Real World Observations III
Protein analysis requires an integrated set of analytical
methods
Evaluate all domains and protein modifications
Use orthogonal analytical methods to confirm observations
and expectations.
State-of-the-art techniques are expected
Realize each analytical method has strengths and
weaknesses:
Spectral methods measure averages
Qualitative vs. quantitative?
Variable sensitivity
etc.
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Summary
Biosimilar regulatory guidelines continue to evolve
Demand for biosimilar CMC development continues to grow
Demonstrating comparability requires extensive analysis
pre- and post-clinically. Must completely characterize
innovator product
We are making progress linking some, but not all, biological
properties to critical quality attributes; therefore,
Given a gradation of a biologics complexity, a one size fits all
strategy for biosimilars will not be possible
!
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Let us know how we can help you!
Reimbursement
Post-Marketing Commitments
Health Economics Assessment
Clinical Development: Special Populations
Outcomes/PE Studies
Clinical Development: Target Population
Central Labs Data: Safety and Genotyping
Phase I to Phase III Clinical Trials
Serum Production
Clinical Feasibility
DEVELOPMENT COMMERCIALIZATIONDISCOVERY
PHASE IVRESEARCH PRECLINICAL PHASE I PHASE III
Molecular Development (Program Management & Clinical)
Efficacy Model Development/Biomarker Development
Regulatory Strategy, EMA/FDA Documentation Prep & Meeting Attendance, CTA/IND/BLA Support and Submission
Viral Clearance
Immunogenicity, PK, TK
Process Development Support, Biomanufacturing Support, Biosafety Testing
Pharmacokinetics/Toxicity
Tissue Cross Reactivity
In vivo/In vi troBiopotency
Immunotoxicity: CDC & ADCC
Physicochem & Biological Characterization
Stability and Release
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Acknowledgments
Our many global clients who have challenged us withvarious Biosimilar products
Sian Estdale, Raymond Donninger, Ji Wu and the rest of
the Covance team
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Thank you . Questions?