Comparability to establish Biosimilarity
CMC Strategy Forum Europe 2014, Sorrento, Italy
Jan Visser, Head Global Analytical Characterization & Bioanalytics
Sandoz Biopharmaceuticals, Hexal AG, Germany
© 2014 Sandoz. All rights reserved. All trademarks are the property of their respective owners.
2 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Variability is inherent in biologics
Manufacturing changes
Manufacturing changes occur due to
process improvements, scale up, etc
Differences in attributes sometimes
significantly larger than batch-to-batch
variability
Non-identicality is a normal principle in
biologics
No batch of any biologic is “identical” to
the other batches
Variability is natural even in the human
body and usually not problematic
Batch-to-batch
C. Schneider: Biosimilarity: A better definition of terms and concepts.
25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam
M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology , 29: 310 - 312, 2011
0
10
20
30
40
50
60
02.2008 03.2009 05.2010 06.2011
Expiry date
G2F glycans
[rel. area %]
0
10
20
30
40
50
60
07.2009 08.2010 09.2011
Basic variants
[rel. area %]
Expiry date
Pre-shift
Post-shift
Pre-shift Post-shift
3 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Characterization of commercial batches of MabThera®/Rituxan®
Significant structural change leading to a functional change and probably related
to a change in the manufacturing process
Different product qualities interchangeably on the market
No change in product label – indicating comparable safety and efficacy
extrapolated to all indications
M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology , 29: 310 - 312, 2011...supplemented with new data!
4 | CMC Strategy Forum Europe 2014, Sorrento, Italy
C. Schneider, Ann Rheum Dis March 2013 Vol 72 No 3
Changes include e.g.
Change in the supplier of a cell
culture media
New purification methods
New manufacturing sites
Manufacturing changes are made frequently
However, the impact of manufacturing changes are well understood by
means of comparability exercises (ICHQ5E) and tightly controlled by
regulators
Changes occur at various points in
the product life cycle
5 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Comparability exercises to assess
Manufacturing changes
ICHQ5E: Comparability of biotechnological/biological products subject to
changes in their manufacturing process
“The goal of the comparability exercise is to ensure quality, safety and efficacy of
drug product produced by a changed manufacturing process…”
“A determination of comparability can be based on a combination of analytical
testing, and, in some cases, nonclinical and clinical data.”
“The demonstration of comparability does not necessarily mean that the quality
attributes of the pre-change and post-change product are identical, but that they
are highly similar…”
The concept behind comparability generally functions with many post-
marketing manufacturing changes being approved based on analytical
testing alone
6 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Revised comparability guideline as basis for
biosimilar guideline
Martina Weise, DIA Euro Meeting, March 2014
7 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Biosimilars and comparability
EMA Guideline on Similar Biological Medicinal Products (Draft 2013) and Guideline
on similar biological medicinal products containing biotechnology-derived proteins
as active substance: quality issues (Draft 2012)
“A biosimilar demonstrates similarity to the reference medicinal product in terms of quality
characteristics, biological activity, safety and efficacy based on a comprehensive
comparability exercise.”
“A stepwise approach is normally recommended throughout the development programme,
starting with a comprehensive physicochemical and biological characterisation. The extent
and nature of the non-clinical in vivo studies and clinical studies to be performed depend on
the level of evidence obtained in the previous step(s)..”
“It is not expected that all quality attributes will be identical and minor differences may be
acceptable, if appropriately justified.”
“The scientific principles of such a biosimilar comparability exercise are based on
those applied for evaluation of the impact of changes in the manufacturing process
of a biological medicinal product (as outlined in ICH Q5E).”
8 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Physicochemical characterization
Biological/Preclinical data
Clinical studies
Extent of comparability exercise
Release analytics
Continuum of comparability allows for appropriate control of variability in biologics
Comparable ≠ Identical
However, an originator biologic after an approved manufacturing change is
as safe and efficacious as the pre-change product!
However, an approved biosimilar is as safe and efficacious as its reference
product!
9 | CMC Strategy Forum Europe 2014, Sorrento, Italy
The evaluation of biosimilarity is based on comparability gained at all levels
A comprehensive analytical comparability exercise forms the foundation for
establishing biosimilarity as very sensitive to differences
Once a proposed biosimilar is shown to be ‘highly similar’ at the analytical level,
this demonstration should allow for tailored pre-clinical and clinical studies
Physicochemical and biological
characterization
Sen
sitiv
ity to
dete
ct d
iffere
nces
Higher
Lower A
naly
tic
al
co
mp
ara
bilit
y
PK/PD
Preclinical
Biological
characterization
Physicochemical
characterization
Clinical
10 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Sensitivity of analytics has greatly improved during the last decades
Year Detection limit of peptide (pmol)
1990 100
1993 10
1997 1
2000 0.1
2003 0.01
2005 0.001
2008 0.0001
2011 0.00001
Adapted from: Mire-Sluis, T.: The Regulatory Implications of the ever increasing power of Mass Spectrometry and its role in the Analysis of
Biotechnology Products – Where do we draw the line? CASSS MassSpec 2012.
Sensitivity increase in mass spectrometry
11 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Attributes e.g.:
Primary structure
Mass
Disulfide bridging
Free cysteines
Higher order
structure
N- and C-terminal
heterogeneity
Glycosylation
Glycation
Fragmentation
Oxidation
Deamidation
Aggregation
Particles
Target-binding
Fc effector
functions
Methods e.g.:
MS
Peptide mapping
Ellman‘s
CGE
SDS-PAGE
CD, FT-IR
H-D exchange
NMR, X-ray
HPLC
HPAEC
IEF
2AB NP-HPLC
SE-HPLC
FFF
AUC
DLS
MALLS
Bioassays
SPR
State-of-the-art analytics allow for the thorough characterization of biosimilars and its reference
Combination of attributes • MVDA, mathematical algorithms
Primary
Structure Higher
Order
Structure
Charge
Variants
Biological
functions
Glycosylation
Size
variants
12 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Purification process
development
Bioprocess development
Recombinant cell line development
Drug product
development
Reference
product variability
Process
development
Analytics
3. Confirmation
of biosimilarity Biological variability
2. Target directed
development
Target range
1. Target definition
Biosimilars must be systematically engineered to
match the reference product (QbD)
13 | CMC Strategy Forum Europe 2014, Sorrento, Italy
QbD elements directing biosimilar development - Quality Target Product Profile
QTPP contains the elements/considerations as described in ICH Q8 (R2)
Intended use in clinical setting, route of administration, dosage form, delivery systems;
Dosage strength(s)
Container closure system
Drug product quality criteria (e.g., sterility, purity, stability and drug release)
For biosimilar based on reference product characteristics
Additionally specific for biosimilars
Ranges of quality attributes of marketed reference product
Quality attribute ranges are based on analytical data of many individual reference product batches of different shelf life age
14 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Quality attribute ranges - Target definition
At project start:
Several originator batches are being purchased from main
geographic regions
Basic analytical methods are being developed
The amino acid sequence of the originator is being determined
Preliminary originator ranges (target specifications or goal posts) are set
During the project:
Continue to purchase originator batches and analyze upon purchase and
end-of-shelf life
Update target specifications & QTPP
15 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Target definition: global biosimilar development
Showing that reference products (RP) from main geographic areas are analytically
indistinguishable aids global biosimilar development
US and EU reference product indistinguishable for all quality attributes with the
“apparent” exception of N-terminal variants
N-terminal variants were found to significantly change during shelf life
To have good guidance during early development purchase „old“ and “new“ RP
batches and perform a dev. stability study with RP
For regulatory filing analyze RP batches upon purchase and at end of shelf life
50
55
60
65
70
75
80
85
90
95
100
0 200 400 600 800 1000
% N
-term
ina
l V
ari
an
t
Days of Remaining Shelf-Life (when analyzed)
EU intact molecule US intact molecule
0.0
5.0
10.0
15.0
20.0
25.0
0 200 400 600 800 1000
% N
-term
inal
Vari
an
t
Days of Remaining Shelf-Life (when analyzed)
US Leu clipped EU Leu clipped
EU Leu+Pro clipped US Leu+Pro clipped
N-terminal variant 1 N-terminal variant 1
N-terminal variant 2 N-terminal variant 2
16 | CMC Strategy Forum Europe 2014, Sorrento, Italy
QbD elements directing biosimilar development - Criticality assessment of Quality Attributes
Efficacy / Potency
PK/PD
Immunogenicity
Safety
Imp
act
Un
cert
ain
ty
Criticality
High = 20 High = 7
Low = 2 Low = 1
API-related quality
attributes e.g. deamidation, oxidation,
afucoslylation,...
CQA by definition e.g. strength, composition,
appearance, potency,...
Process- and
excipient-
related quality
attributes e.g. HCP,
antifoam,
endotoxins,...
Criticality Score (2-140)
Quantitative measure for an attribute‘s impact on
safety and efficacy. Using best possible surrogates
for clinical safety and efficacy
Impact (2-20)
Known or potential consequences on safety and
efficacy, considering, biological activity, PK/PD,
immunogenicity, safety
Uncertainty (1-7)
Relevance of information e.g. literature, prior
knowledge, in vitro, preclinical clinical or
combination of information
Criticality Calculation
Criticality Criticality Score
Very High 121 – 140
High 86 – 120
Moderate 56 – 85
Low 31 – 55
Very Low 2 – 30
17 | CMC Strategy Forum Europe 2014, Sorrento, Italy
How comparable do biosimilars need to be?
Biosimilar needs to be as safe and efficacious as the reference product
The more critical a quality attribute is, the more comparable it should be –
knowing your protein is essential!
The more comparable a biosimilar is to the reference analytically, the smaller
the residual uncertainty, the more tailored the non-clinical and clinical program
Criticality Criticality Score
Very High 121 – 140
High 86 – 120
Moderate 56 – 85
Low 31 – 55
Very Low 2 – 30
Lower
Higher
Strin
gen
cy
co
mp
ara
bility
ran
ge
QA
critic
ality
18 | CMC Strategy Forum Europe 2014, Sorrento, Italy
How comparable do biosimilar mAbs need to be?
M. Shapiro, ACR annual conference 2012
Know your protein and
analyse it using state-of-
the-art analytical methods!
19 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Year 1 2 3 4 5 6 7 8
Cell line
dev. Process
Opt.
Clin.
man
Comm
man
Clin.
man
Full process
dev.
Val
Process
Charact.
TPoS Confirm
comparability
Formulation
Dev.
GLP
PC PK/PD study Conf. clin. study
Exploratory PC
studies
Target specification: Originator characterization
Analytical tool box
Val
Confirm
comparability
Final
comparability
Analytical comparability exercises during biosimilar development
Develop highly similar product Confirm biosimilarity
20 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Final comparability exercise
Use of a wide range of sensitive and orthogonal analytical methods
Head-to-Head (H2H) analysis with selected originator batches
Comparison of physicochemical and biological characterization results with
H2H originator batches and “historical” target specification
Identification of variants in both biosimilar and originator
Justification of differences in QAs
Comparison of stability data:
intended conditions (=> stability profile)
accelerated, stress conditions (=> forced degradation profile)
21 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Quality Attribute
Criticality
Process Control
Testing Strategy
Capability of the process to control the quality attribute
Testing for the quality attribute
Quality Attribute Criticality considering impact on safety and
efficacy
Design Control Elements Process Control Elements Process Parameter Controls
Process Qualification
Input Material
Control Elements Raw material testing
Testing Control Elements
Stability testing
Characterization
In-process testing
Release testing
CQA Control
Strategy
CQA control strategy for biosimilars
22 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Setting specifications for biosimilars
ICH Q6B Specifications: Test Procedures and Acceptance Criteria
for Biotechnological/Biological Products
“Specifications are critical quality standards that are proposed and justified by
the manufacturer and approved by regulatory authorities as conditions of
approval.”
“Specifications are chosen to confirm the quality of the drug substance and drug
product...and should focus on those molecular and biological characteristics
found to be useful in ensuring the safety and efficacy of the product.”
Specification acceptance criteria (LL & UL) for biosimilars are initially defined by
a combination of the originator range and process capability and later by
process capability alone!
23 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Divergence a risk for biosimilars?
After approval in EU a biosimilar is managed as an independent product
Divergence = Different patterns of product drift and evolution (=shift) contributing,
over time, to clinically meaningful differences Ramanan & Grampp BioDrugs Feb 2014
Does divergence between a biosimilar and its reference product pose a bigger risk
than divergence between pre- and post-shift reference product or between
interchangeably used originator products?
Divergence between post- and pre-change product shown in PRCA Eprex case
resulting in increased regulatory scrutiny regarding primary packaging and leachates
However, to date not aware of data showing that divergence is an issue for
biosimilars or interchangeably used originator products
Quality systems of biologics manufacturers should ensure the detection and
management of drift (unintended changes) via their control strategy, while evolution
(intended changes) is well managed according to ICHQ5E guidance
24 | CMC Strategy Forum Europe 2014, Sorrento, Italy
Conclusions
The scientific principles behind the comparability exercise supporting manufacturing
changes and assessment of biosimilarity are the same!
The analytical comparability between the proposed biosimilar and reference product
forms the foundation for establishing biosimilarity as very sensitive to differences!
The QTPP, which includes ranges of QA’s of the reference product, and the QA
criticality assessment are key elements in directing biosimilar development!
The closer the proposed biosimilar and its reference product are analytically, the less
residual uncertainty and the more tailored the (non)clinical program should be!
A good quality system should prevent divergence between pre- and post-change
biologics, biosimilars and reference products, and interchangeably used biologics