Post on 27-Mar-2020
a Novartis company
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)
Slide 2 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
Slide 3 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 4 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 5 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 6 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
• 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
Slide 7 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 8 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 9 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 10 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 11 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 12 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 13 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 14 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 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
Slide 15 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 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
Slide 16 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 17 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 18 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
Typical Product Quality Attributes
Aggregation / Degradation
Biological activity
Charge Variants
Glycoforms
Process-rel. impurities
Primary & higher order structure
Slide 19 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 20 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 21 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 22 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 23 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
• 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
Slide 24 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 25 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 26 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 27 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 28 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Slide 29 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
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
Confirmation: Comprehensive comparabilityexercise
Development of biosimilar product,"Quality by Design"
Physicochemical and biological characterization
Process development
Refinement of target,
Identificationof CQA's
Define target
Confirmation: Comprehensive comparabilityexercise
Development of biosimilar product,"Quality by Design"
Physicochemical and biological characterization
Process development
Refinement of target,
Identificationof CQA's
• So……watch this space!
Slide 30 J. Visser, A Pioneer’s Perspective on Biosimilar Development, Rio de Janeiro, Brazil, 6-7 Aug 2009
Questions ?