Biosimilar Comparability

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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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33

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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4

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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5

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FDA February 2012 draft guidance documents Risk-based totality-of-the-evidence approach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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6

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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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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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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2929

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?

[email protected]