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An agency of the European Union
Regulatory considerations on higher order structure determination and evaluation – an EU perspective
Dr Veronika JekerleQuality OfficeSpecialised Scientific DisciplinesEuropean Medicines Agency
Presented at CASSS-HOS 11-14 April 2016, Long Beach, USA
Contents
Higher order characterisation
• Regulatory expectations
• Observations (case studies)
Considerations on
• Comparability
• Biosimilarity
• Immunogenicity
Update from the EMA (News/Events/Guidance)
Regulatory considerations on HOS – EU perspective © V Jekerle 1
Regulatory expectations
HOS characterisation
Characterisation, identity and consistency
Structure-function relationships (HOS/Potency)
• Functional domains: specificity for binding & binding epitopes
Formulation / PK / cellular update
Stability
Safety features
• Toxicity
• Immunogenicity
• Loss of efficacy
2
Biosimilar development
Comparability assessment
New molecule characterisation
and control
Regulatory considerations on HOS – EU perspective © V Jekerle
Regulatory expectations
Guidelines
3
Note for Guidance on Specifications: Test Procedures and
Acceptance Criteria for
Biotechnological/Biological Products (ICH Q 6 B)
• Composition, physical properties, and primary structure
• higher-order structure
• structural heterogeneity due to biosynthetic processes mixture of post-translationally
modified forms (e.g. glycoforms)
• Biological activity (animal-based, cell culture, biochemical assays, ligand/receptor binding)
• Immunological properties (binding assays)
Regulatory considerations on HOS – EU perspective © V Jekerle
Regulatory expectations
Guidelines
4
Guideline on development, production, characterisation and
specifications for monoclonal antibodies and related products
(EMEA/CHMP/BWP/157653/2007)
• Amino acid sequence
• Variability of N- and C- terminal amino-acid sequences
• Free sulphydryl groups and disulfide bridges; disulfide bridge integrity mismatch
• Carbohydrate content (neutral sugars, amino sugars and sialic acids)
• Structure of carbohydrate chains, oligosaccharide pattern (antennary profile)
• Glycosylation site(s) and occupancy
• Additional glycosylation site(s) in heavy chains, their presence / absence
• Glycan structures (i.e. degree of mannosylation, galactosylation, fucosylation and sialylation)
• Distribution main glycan structures (often G0, G1 and G2)
• Immunological properties (binding assays)
• Biological activity (defined biological effect)
Regulatory considerations on HOS – EU perspective © V Jekerle
also relevant
for AB-Drug
conjugates
Regulatory expectations
Guidelines
5
Guideline on similar biological medicinal products containing
biotechnology-derived proteins as active substance: quality issues
Rev. 2014 (EMA/CHMP/BWP/247713/2012)
• Amino acid sequence (same RMP)
• N- and C-terminal amino acid sequences, free SH groups and disulfide bridges
• Modifications/truncations quantified
• Micro-heterogeneous pattern (e.g. C-terminal lysine variability).
• Post-translational modifications (e.g. glycosylation, oxidation, deamidation, truncation)
• Carbohydrate structures (i.e. overall glycan profile, site-specific glycosylation patterns, site occupancy)
• Presence of glycosylation structures / variants not observed in RMP
(� non-human structures (linkages, sequences or sugars))
• Biological activity
• Immunochemical properties
Regulatory considerations on HOS – EU perspective © V Jekerle
HOS methods – what do Regulators expect?
key points
• Guidance does not prescribe a specific technique
Feasibility /time lag between technique development and implementation as QC
method
Scientific advice on appropriateness of test method(s)
(http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000049.jsp&mid=WC0b01ac05800229b9)
• Combination of physicochemical and biological methods
• Prior knowledge/literature on product class may
reduce burden on testing panel (focus on essential elements)
Benchmark of methods?
Circular dichroism/intrinsic fluorescence/disulfide mapping/ELISA/Functional
assay (?)6 Regulatory considerations on HOS – EU perspective © V Jekerle
What do we see in our dossiers?
Monoclonal antibodies (1997 – 2016)
4 Innovators (cancer & autoimmune indication)
2 Biosimilars
1 AB-drug conjugate
Physico-chemical methods Biological methods
Characterisation Characterisation
Active substance specifications Active substance specifications
Finished product specifications Finished product specifications
Note: methods not relevant to structure (e.g. Bioburden, sterility etc. not included)7
Regulatory considerations on HOS – EU perspective © V Jekerle
Innovators - physical-chemical methods
Presentation title (to edit, click Insert > Header & Footer)8
Innovator age (4 oldest - 1 youngest)
4 3 2 1
Characterisation
AS specifications
FP specifications
Regulatory considerations on HOS – EU perspective © V Jekerle
9
Innovator age (4 oldest - 1 youngest)
4 3 2 1
Characterisation
AS specifications
FP specifications
Innovators - biological methods
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10
Biosimilar example / function
Example 1 Example 2
Characterisation
AS specifications
FP specifications
Biosimilar - physical-chemical methods
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11
Biosimilar example / function
Example 1 Example 2
Characterisation
AS specifications
FP specifications
Biosimilar - biological methods
Regulatory considerations on HOS – EU perspective © V Jekerle
Observations
Degree of characterisation does not always increase in newer applications
Degree of characterisation is dependent on indication / mechanism of action
Degree of characterisation is dependent on applicant
Applications using QbD principles employ a significantly larger test panel than
comparable indications ( can increased product knowledge be leveraged post-
marketing?)
Biosimilar applications employ a very extensive characterisation panel (Biosimilarity
exercise), which is not translated into more extensive AS/FP specifications
AS and FP specifications rely on 1 or 2 representative bioassays across the board
(even though a much larger number of assays have been established for
characterisation)
12 Regulatory considerations on HOS – EU perspective © V Jekerle
What issues did the CHMP raise?
Innovators (some examples)
• use of FTIR spectroscopy alone for HOS, request to consider also CD
• not clear whether all relevant receptor bindings have been studied (effects on
S/E sufficiently characterised)?
• Acceptance limits of acidic variants (IE-HPLC) are only based on 1 clinical
batch, which is not accepted. Limits should be based on all batch results.
• Method validation (CE-SDS method) with respect to linearity and accuracy
• Cell-based potency assay lacks precision, ELISA assay should be added to
AS/FP release specifications
• Comparison between two methods has not been shown (ADCC cell-based
bioassay and ELISA), both to be used as specifications
13 Regulatory considerations on HOS – EU perspective © V Jekerle
What issues did the CHMP raise?
Biosimilars (some examples)
• ‘major’: - demonstration of biosimilarity not shown on the basis of observed
different receptor binding, ADCC activity and small differences in S/E observed
• ‘major’: - dataset not sufficient to conclude on biosimilarity. Additional
justification /data needed to justify that observed differences (in gycosylation)
do not impact S/E
• no specification have been set for charge variants and size variants (other than
HMW)
• no specifications set for glycosylation. Means to monitor glycosylation and
glycan structures at AS release are requested
14 Regulatory considerations on HOS – EU perspective © V Jekerle
Antibody-drug conjugate
Focus on size, conjugation and levels of unconjugated mAB (impact of conjugation)
Biological methods!
15 Regulatory considerations on HOS – EU perspective © V Jekerle
AB-drug conjugate Physical-chemical methods Biological methods
Characterisation
AS specifications
FP specifications
Considerations on
Comparability, Biosimilarity &
Immunogenicity
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molecular heterogeneity to determine that HOS (secondary,
tertiary, and quaternary structure) is maintained
relevant biological activity assay
quality attributes of pre‐change and post‐change products are not
necessarily identical but highly similar
differences in quality attributes have no adverse impact on safety or
efficacy
combination of physico-chemical testing, biological assays ±
nonclinical and clinical data
Comparability
General principles (ICH Q5E)
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Evaluation of
quality attributes
no differences differences
“highly similar”
No impact on
S/E
“highly similar”
but doubt on
analytical
procedure
“highly similar”
no impact on
S/E expected
based on
experience &
relevant data
“highly similar”
impact on
S/E cannot be
excluded
significant
differences
comparable
non-clinical/
clinical studiesnon-clinical /
clinical studies
not
comparable
(outside
of scope)
comparable?
ICH Q5E Comparability of Biotechnological/Biological Products
Outcomes HOS
Regulatory considerations on HOS – EU perspective © V Jekerle
nonclinical
development
clinical development
phase I II IIIpostmarketing
Value of preclinical
data ‘lower’
Focus on product
characterisation &
product definition
Comparability exercise
Clinical bridging study
may be needed
Post-marketing follow-up
necessary?
Comparability exercise
to link earlier clinical data
to product
More substantiated if
during pivotal trial
comparability data
Comparability
Importance of comparability data (ICH Q5E)
ideally no changes
Regulatory considerations on HOS – EU perspective © V Jekerle
21
Dossier requirements for Biosimilars
CTD Module Originator Biosimilar
3
Cross reference
4
5
Cross reference
Cross reference –
class specific
Safety and Efficacy
Integrated Comparability Exercise –
product specific
Quality, Safety and Efficacy
Quality
Non-Clinical
Clinical
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Biosimilar comparability vs. Comparability
Comparability Biosimilar comparability
Material used Active substance (+ finished product)
Finished product (representative of active substance)
Comparator Earlier stages of same product (clinical development / authorised)
EU-authorised reference product (non-EU if NC/C data from non-EU RP)
Reference In-House reference standard (or Int. Std. if available)
Reference product (in particular the Quality target product profile (QTPP))
Approach Batch data and historic data, specifications
Side-by-side comparison, target product profile
Differences May be expected (depending on complexity of proposed change)
Differences expected (i.e. new process new MCB)
Strategy Analytical comparability (QC and characterisation data)
Stepwise approach – foundation on Quality data. Focus on biological activity
Clinical data Rarely needed Always requested (always needed ?)
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23
Immunogenicity
Multidisciplinary approach
Protein
sequence
HOS
Formulation
Packaging
Impurities
Administration
Dose
Frequency
Co-Medication
Co-morbidity
Age, Genotype
NutritionManufacturing
processRegulatory considerations on HOS – EU perspective © V Jekerle
24
‘Biotechnology-derived analogues to human endogenous proteins may
trigger an immune response due to variations in the amino acid
sequence or changes to the protein structure as a result of post-
translational modifications or other changes during all steps of the
manufacturing process, storage and administration.’
‘Glycosylation can influence both the physico-chemical and biological properties of a protein. The
presence and structure of carbohydrate moieties may have both a direct or indirect impact on the
immunogenicity of therapeutic proteins; the glycan can induce an immune response itself (e.g.
glycans of non-human origin), or its presence may affect the conformation of the protein in such
a way that the protein becomes immunogenic.
However, pegylation and glycosylation may also decrease immunogenicity by shielding the
immunogenic epitopes, while maintaining the native conformation of the protein.’
Regulatory considerations on HOS – EU perspective © V Jekerle
• 31 Jan 2016 (end of public consultation)
• Finalisation stage
Immunogenicity WS, EMA, 9 March 2016, S. Gross25
Without Glycan
Deglycosylation
Without core Fucose
GlcNAc/Mannose (G0)
α1,3Galactose
Galactose
N-glycoylneuraminic acid
N-acetylneuraminic acid
(Sialic acid)
No ADCC activity
Increased immunogenicity
increases ADCC activity
(Mannose binding Lectin)
and Complement activation
higher antigenicity
FcRn binding, CDC activity
higher antigenicity
decreases ADCC activity,
anti-inflammatory
Effects induced by Carbohydrate to IgG Function
from Chung et al., N Engl J Med 2008;358:1109-17 / S. Gross Immunogenicity WS March 2016 26
Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-
1,3-Galactose
25/76 cetuximab-treated subjects had hypersensitivity reaction to the drug
antibodies specific to galactose-α-1,3-galactose.
Product-related
factors
MoA
Structure
Aggregates
Formulation
Purity
Packaging
Storage/Handling…
Risk-based thinking
27
Patient-related factors
Disease
Genetic
Medication
Route of administration
Dose/Dosing regime
…
Risk
Probability
=
x
Consequences
Adapted from C. Schneider (Immunogenicity WS March 2016)
Data/knowledge driven
Impact on Benefit-Risk
Therapeutic benefit
Alternative therapies
Ability to manage risk
Risk mitigation
Follow-up/monitoring
Regular review
during lifecycle
Presentation title (to edit, click Insert> Header and Footer)28
Update from the EMA
News/Events/Guidance
Immunogenicity Workshop 9 March 2016
29 Regulatory considerations on HOS – EU perspective © V Jekerle
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2016/01/event_detail_001257.jsp&mid=WC0b01ac058004d5c3
Reflection paper on statistical methodology for the comparative
assessment of quality attributes in drug development
30 Regulatory considerations on HOS – EU perspective © V Jekerle
Status
• 1st draft in preparation
(EMA WPs consulted)
• start of public consultation Q2/3 2016
• Case studies
• Convergence with other Regulators
(e.g. FDA)
RP on statistical methodology on quality attributes
31 Regulatory considerations on HOS – EU perspective © V Jekerle
to reflect when and how far inferential statistical methods can
assist comparative evaluation of quality attributes data
• application of statistical methods comparability, biosimilarity
assessment
• limitations (non-representative nature of retrievable sample data; e.g.
batch number, variability)
• choice of characteristics to be compared
• understanding sources of variability in quality data and 'the unit of
observation'
• Random Sampling / Experimental Approach
• Definition/justification of an equivalence/similarity criterion, acceptance
range
• other…
Process validation Guideline - finalised
32 Regulatory considerations on HOS – EU perspective © V Jekerle
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_0003
55.jsp&mid=WC0b01ac0580028e8b
Acknowledgments
33 Regulatory considerations on HOS – EU perspective © V Jekerle
Dolca Fabregat-Montfort
Ina-Christine Rondak
Martijn van der Plas
Steffen Gross
Christian Schneider
Pascal Venneugues
Klara Tiitso
Peter Richardson
Thank you for your attention
http://www.ema.europa.eu/ema/
Dr Veronika Jekerle
Quality Office
European Medicines Agency
30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom
Email [email protected]
Send a question via our website www.ema.europa.eu/contact
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