A Pioneer’s Perspective on Biosimilar Development · a Novartis company A Pioneer’s Perspective...

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A Pioneer’s Perspective on Biosimilar Development

Biopharmaceutical process development and regulatory issues

Federal University of Rio de Janeiro – COPPE, Brazil

August 6th-7th, 2009

Jan Visser, PhD

Head Technical Development, Mengeš Site, Slovenia

Sandoz Biopharmaceutical Operations (BPO)

J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009

Sandoz: A Global Generics Leader

� Global #2 – “clear blue water” to the rest

� #1-3 in roughly half of global market

� Strong portfolio of 1000 compounds

� Rich pipeline with >900 projects

� Leader in “difficult-to-make”

� Pioneer of biosimilars

� Global HQ in Holzkirchen, Germany

Sandoz key figures 2008

Net sales: USD 7.6 billion

Net income: USD 1.1 billion

Employees worldwide: 23 000

Sandoz sales by region Sandoz sales by region Sandoz sales by region Sandoz sales by region –––– 2008200820082008

10%

59%

24%

7%

Asia, Africa,

Australia

US

Europe

LatAm,Canada


Development and Production around the Globe

Argentina:Oncology (injec-

tables, oral solids)

US:Oral solids

Canada:Injectables,

ophthalmics

Germany

(Rudolstadt):Inhalers,

ophthalmics

Germany

(Holzkirchen):Patches, implants,

orals

Austria:Orals, biosimilars,

injectables, APIs

Development

Argentina:Oncology

Brazil: Oral solids,

hormones

Canada:Injectables,

ophthalmics

US: Oral solids

Germany:Oral solids, patches,

implants,….

Slovenia:Oral solids, APIs,

injectables

Turkey: Oral solids, APIs

India:Oral solids, APIs

Japan: Oral solids

China: Oral solids

Poland: Oral solids

Production

Slovenia:Orals, injectables,

biosimilars, APIs, …

India:Oral solids, APIs

Austria:Oral solids, APIs,

injectables


Biopharmaceutical Operations: A Global Network

• Joint Novartis Pharma-Sandoz organization

• In charge for biopharmaceuticals / biosimilars of :

1. different stages in technicaldevelopment,

2. clinical manufacturing

3. commercial manufacturing for DS

• 6 Sites

• ca 1200 associates

• Commercial products: 5 own (+ 6 forcustomers)

• Products in development: 47 own (+ 8 forcustomers)

• Major capacity investments in most of theBPO faciltities on-going

• Joint Novartis Pharma-Sandoz organization

• In charge for biopharmaceuticals / biosimilars of :

1. different stages in technicaldevelopment,

2. clinical manufacturing

3. commercial manufacturing for DS

• 6 Sites

• ca 1200 associates

• Commercial products: 5 own (+ 6 forcustomers)

• Products in development: 47 own (+ 8 forcustomers)

• Major capacity investments in most of theBPO faciltities on-going

Pharma facilities

Sandoz facilities


Biosimilars – Healthy for Patients and Society

Save / improve lives by offering high quality drugs

Provide savings to patients

Helping to stabilize healthcare systems by lowering costs

Freeing up resources for the discovery of new, innovative medicines


• Increasing medicine demand – lifestyle, aging

• Increasing acceptance and penetration of biosimilars

• GDP growth of emerging markets

• Stable flow of patent expiries

• Increasing access to healthcare

• Cost containment measures

Market trends favor Biosimilars


What are Biosimilars?

Source: NGx

FOBsBiosimilars

•Successor to a marketed biological medicinal product for which patent protection no longer applies

•Manufactured by recombinant DNA technology (insertion of gene into a host cell to produce the protein)

•Comparable with the reference product in terms of quality, efficacy and safety

•Can be approved for the same indications for which the referenceproduct is approved

• Is approved by EMEA in a centralized procedure �� as for innovators

Generic Biological

Biogenerics

SEBs


How are Biosimilars different from Generics?

Small molecule generics Biosimilars

• Small molecules

• Often very stable

• Mostly without a device

• Large, complex molecules

• Stability requires special handling

• Device is often a key differentiator

Product characteristics

Production• Mostly produced by chemical synthesis

• Produced in living organisms

• Highly sensitive to manufacturing changes

• Often comparatively high costs

Development• Very limited clinical trials (often only Phase I PK/PD studies)

• Significant R&D (i.e. cell lines)

• Usually extensive clinical trials, including Phase I and Phase III studies

Regulation• Abbreviated registration procedures in Europe, USand most other countries

• Regulatory pathway defined by EMEA andsome other countries

• No pathway in US under BLA (PHS Act)

• In US 505(b)(2) applications possible forproduct approved under FD&C Act


Biosimilars: The Regulatory Landscape in EU & USA

Biosimilars

are on a

sound legal

footing in

Europe

Legal basis

The legal framework is provided in

EU Directive 2001/83/EC, in Article 10,

Paragraph 4, published in EU Directive

2004/27/EC and implemented through-

out the EU at the end of Oct 2005.

The requirements are set forth in EU

Directive 2003/63/EC, Annex, Part II,

Point 4, for “Similar Biological

Medicinal Products”.

Further guidelines

In Nov 2004, the EMEA/CHMP

issued a set of guidelines for bio-

similars which address general,

quality -relevant and preclinical/

clinical requirements for specific

products

All general ICH, EMEA, FDA guide-

lines on the quality and safety of

biological products apply equally

to biopharmaceuticals and bio-

similars

PHS Act (CBER)

Most biologicals approved under

the PHS Act (e.g. EPO, interferon,

Monoclonal antibodies) for which NO

pathway for interchangeable

Biological products exists.

FD&C Act (CDER)

Historically some biologicals

(e.g. somatropin, FSH, insuline) were

approved under the FD&C Act for

which Section 505(b)(2) applies

FOB

regulations

still to be

established

in USA


Defines

principles

General

guidelines

Quality / Safety

Efficacy

Product class

specific data

requirements

Overarching Guideline (CHMP/437/04).

„Guideline on Similar Biological Medicinal Products.“

Biotechnology – derived proteins

Quality

Non-

clinical

Clinical

Insulin Somatropin GCSF Epoetin IFN-a LMWH

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Biosimilar Guidelines – Overview

mAbs

under

discussion


Quality: A full quality dossier supplemented bythe demonstration of comparability.

Quality

CTD M3+

Full CTD M3

E.g. 3.2.S DS-Manufacture

-description MP-control of materials.control of critical steps.process validation.manufacturing PD

-Control DS-Reference standard-Container closure system-Stability

Comparability vs. Reference

-Not expected QA are identical-Stepwise approach justifyingdifferences in QA-Differences QA can impactrequirements (non)clinicalpackage-Reference product description

Analytical Methods& Specifications

-Use of state-of-the-artanalytical methods-Physicochemical properties-Biological activity-Purity and impurities-Specifications definedand justified

EMEA/CHMP/BWP/49348/2005


Product specific (non)clinical guidance: Somatropin

(Non)

Clinical

Non-clinical studies

Comparative in nature and designed to detectdifferences in pharmaco-toxilogical response

Pharmacodynamic studies-in vitro (receptor-binding, cell proliferation).in vivo (weight gain in hypophysesectomised rats

Toxicological studies.repeat-dose study.local tolerance

Clinical studies

Comparative pharmaco-kinetic and –dynamic-single dose cross-over study using sc admin-IGF-1 preferred pharmacodynamic marker

Clinical efficacy & safety-children with GH deficiency target population-height velocity as primary end-point-comparative phase >= 6m, up to 12m-pre-treatment growth rate >= 6m, up to 18m-12m immunogenicity data (every 3m)

Pharmacovigilance planExtension of indication

EMEA/CHMP/BMWP/94528/2005


Omnitrope® – The First European Biosimilar

• Omnitrope®, is a rec. hGH product indicated for long-

term treatment of pediatric patients who have growth

failure due to an inadequate secretion of endogenous

GH hormone, and for long-term replacement therapy

in adults with GHD of either childhood- or adult onset.

• Omnitrope® was developed as similar biological

product to the reference product Genotropin®

(Somatropin, Pfizer)

• EU market authorization in April 2006

• US approval in May 2006

• But also…….

- First-ever biosimilar in Canada, approval Apr 2009

- First-ever biosimilar in Japan, approval Jun 2009


Other Sandoz Biosimilar Products

• Binocrit® - the First European Complex Biosimilar

• Binocrit® is a rec. epoetin alfa and was developed

as similar biological product to the reference

product Erypro®/Eprex® (Janssen-Cilag)

• EU market authorization in August 2007,

launched in major EU markets starting 2007

• Zarzio® is a rec. G-CSF and was developed as

similar biological product to the reference

product Neupogen® (Amgen)

• EU market authorization in Feb 2009, launched in

major EU markets starting 2009


QbD Development of a Biosimilar Product

Define target

Confirmation: Comprehensive comparabilityexercise

Development of biosimilar product,"Quality by Design"

Physicochemical and biological characterization

Process development

Refinement of target,

Identificationof CQA's


Starting a Biosimilar Project !

• Pre-project Activities:

� Evaluation

� Target Product Profile

� Indications

� Dosage strength & form

� Target country & reference product

� Initial target specification

• Project start:

� Technical Development Plan

� Start with QbD Technical DevelopmentPM

QA

CD

TD

IP

RA

COM


Target Specification

� At start of cell line development

� Characterise originator-batches with

extensive set of state-of-the-art methods

� Develop bioassays reflecting mode of action

� First risk-assessment to evaluate CQAs

Target cell

Effector cell

(NK cells)

FcγγγγRIIIa

C1

PCDProgrammed cell death (apoptosis)

ADCCAntibody dependentcellular cytotoxicity

CDCcomplementdependentcytotoxicity

Membrane attackcomplex

Target cell

Effector cell

(NK cells)

FcγγγγRIIIa

C1

PCDProgrammed cell death (apoptosis)

ADCCAntibody dependentcellular cytotoxicity

CDCcomplementdependentcytotoxicity

Membrane attackcomplex

• Refined target (during project):

• Initial target specification (before project start):

� Characterize additional originator batches

� Broad quality ranges obtained during cell line / process development

allow establishment of correlations phys.-chem. ↔↔↔↔ bioactivity

� Refine definition of CQAs


Typical Product Quality Attributes

Aggregation / Degradation

Biological activity

Charge Variants

Glycoforms

Process-rel. impurities

Primary & higher order structure


Key Factors Influencing Drug Substance Quality

• Host cell line & clone

• Growth medium composition

• Culture conditions (pH, T, aeration…)

• USP type & regime (fed batch, perfusion...)

• Culture history (genetic stability, process stability...)

• Individual DSP steps

• Hold times

• Storage (buffer, container, conditions..)

Impacton DS quality


QbD Biosimilar Dev.: Managing Variability !!!

Variability range at project start

Target specs

Cell Line Development

Bioprocess Development

DSP Development

Titer

DSP Yield

Scalability

Consistency

Raw Materials

Growth Characteristics

Glycoforms

Charge Variants

Biological activity

Process rel. impurities

Aggregates / Degradation

Primary and higher order structure


Dealing with Multi-Variable Decisions!

Aggregation / Degradation Biological activityCharge VariantsGlycoforms Process-rel. impuritiesPrimary & higher order structure Titer

Input: Weighting list

Output:Pool & clone ranking

Conversion:Script in R

-4-2

02

4

Distance from design specification

( X

-Xctr

) /

Xc

tr

GM

AP

_b

G0_N

GM

AP

_bG

0_F

GM

AP

_bG

0

GM

AP

_b

G1_N

GM

AP

_bG

1_16

GM

AP

_bG

1_13

GM

AP

_bG

2

GM

AP

_bG

2S

1

GM

AP

_M

an5

GM

AP

_M

an6

GM

AP

_M

an7

GM

AP

_M

an8

GM

AP

_u

nk2

GM

AP

_u

nk1

CE

X_A

P

CE

X_

0K

CE

X_

1K

CE

X_U

N.2

CE

X_

2K

SE

C_A

P

SE

C_G

P2

017

SE

C_D

P

pool29/G418 K1-PDpool30/G418 K1-PDpool28/G418 K1-PDpool53/G418 HPT2pool34/G418 K1

Weight = 0

Dis

tance t

o c

on

tro

l (orig

inato

r)

0.0

0.1

0.2

0.3

0.4

0.5

K1-PDHPT2K1HPT1 SSF3 DG44

01

00

200

300

Via

bility

, T

iter


Originators CellLines Pool18a Pool18b Pool16 clone19

0

2

4

6

8

10

bG0(-F) [%]

Understanding Structure – Function Relationships

High resolution identification and quantification of major (G0,G1,G2) and minor mAB glycan structures(down to a level of 0.1 rel.%)

Characterization of mAB glycosylation heterogeneity

Bioactivity

0 1 2 3 4 5 6 7 8 9Glycoform

0

100

200

300

400

500

600

700

Targeting ADCC-activity and fucosylation by clone selection

2x

Glycoform


• Media-components consistentlyresult in desired galactosylationstate in dose-dependent manner

• Other media-components allowtargeting of fucosylation ormannosylation

Targeting the Major Glycosylation Pattern

Targeting galactosylation by USP media-components

0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4

0,0

0,5

1,0

1,5

2,0

Media Component A

Media Component B

32,60

43,80

55,00

66,20

77,40

G0 G1 G2

NP-LC of 2AB-labeled glycans


Influencing mAb Charge Variants

variant(%)

Process parameter B

variant (%)

Process parameterA

Analysis of charge variants using cation exchange chromatography

0K 1K 2K1Q 2Q

CPB

pEpE pE

pE QpE pE

pEpEpE pE

pE

K

QpE pE

QpEpE pE

pE

KK

0K 1K 2K1Q 2Q

Targeting charge-variants via bioreactor process parameters

acidic

variant (%)

Process Parameter C

Reference

product

range

Reference

product

range

Reference

product

range


Productivity vs Quality: More is NOT always Better!

LU

0,00

0,20

0,40

0,60

0,80

1,00

1,20

1,40

1,60

1,80

Minutes

2,00 4,00 6,00 8,00 10,00 12,00 14,00 16,00 18,00 20,00 22,00 24,00 26,00 28,00 30,00 32,00 34,00 36,00 38,00 40,00

AEX Isoform Profile

• Degree of sialylation varies greatly between different clones

• Negative correlation between sialylation and product titer

Titer

Degree of sialylation


Bioprocess Type: Finding the Right Fit!

• Batch

• Repeated batch

• Fed-batch

• Perfusion

Generic Fed-Batch Process

0,0E+00

1,0E+07

2,0E+07

3,0E+07

4,0E+07

5,0E+07

0 50 100 150 200 250 300

time [hours]

VCD [cells/ml]

0

10

20

30

40

50

60

70

80

90

100

Viability [%], product titre

[relative value]

VCD [cells./ml] via [%] Product normalized

Repeated batch process

0,0E+00

2,0E+06

4,0E+06

6,0E+06

8,0E+06

1,0E+07

0 50 100 150 200 250

time [hours]

VCD [cells/ml]

0

10

20

30

40

50

60

70

80

90

100

Viability [%], product titre

[relative value]

VCD [cells /m l] via [% ] titre normalized


LU

0,00

0,10

0,20

0,30

0,40

0,50

0,60

0,70

0,80

0,90

Minutes

0,00 2,00 4,00 6,00 8,00 10,00 12,00 14,00 16,00 18,00 20,00 22,00 24,00 26,00 28,00 30,00 32,00 34,00 36,00 38,00 40,00 42,00 44,0046,00 48,00

RBFB

Bioprocess Type: Finding the Right Fit!

• Degree of sialylation varies greatly between

different process types performed with the

same clone


QbD Biosimilar Development: Comparability

Comparability

with reference product

Complete stand-alone product and process development following QbD

Clinical

Safety & Efficacy

PK/PD

Preclinical

Biological

characterization

Physicochemical

characterization


Conclusions Biosimilar Development

• Product quality of biopharmaceuticals can be targeted to

biosimilarity through QbD cell line and process development

supported by state-of-the-art analytics

• Biosimilar development is all about managing DS variability:

an initial high DS variability allows better understanding of the

relationships between structure & function and process

conditions & PQAs

• Through application of thorough science, development of

biosimilars is possible today (e.g. EPO, hGH, hG-CSF) and

possible tomorrow for more complex proteins

Define target




Process development



Define target




Process development



• So……watch this space!


Questions ?

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