Transcript Comparability Study (for Biosimilar)

Comparability Study (for
Biosimilar)
Wisit Tangkeangsirisin, PhD
Faculty of Pharmacy, Silpakorn University
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Biosimilar Definition and Concept
Regulations
Quality Assessment of Biosimilar
Example and Cases
Assignment
Biologics
Biopharmaceuticals
Recombinant Proteins
Monoclonal Antibodies
Etc.
Blood
&
Blood Products
Others
Gene therapy
Cell therapies
Tissue therapy
Allergens
Vaccines
&
Toxoids
Required only for Biosimilarity
Major Biopharmaceuticals
Recombinant Proteins
• Insulin, Epoetins,
Interferons,
Somatropin , Filgrastim
Monoclonal Antibodies
• Trastuzumab,
Rituximab, Infliximab
Immunoglobulin Fusion
Proteins
• Etanercept
Biopharmaceuticals
First
generation
Second
generation
(biobetter)
• Native Proteins, Unengineered
• murin antibodies, simple
replacement proteins
• Frequent Injection
• Engineered, modified, alteration of
amino acid sequence, alteration of
glycosylation, PEGylation
• Suitable PK
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Monoclonal Antibodies
Structurally much more complex than other proteins
Complexity
• More complex than currently developed biosimilars
Biological
Activity
• glycosylation patterns are critical-smalll differences
correlate to changes in biological activity
Predictability
• multi-functionlity (binding and immuneffector functions)
coupled with an often limited understanding of structurefunction relationship will limit predictability of in vitro data
Extrapolation
• complexity and diversity of the mechanisms of action will
be of particular challenge for indications and line
extensions
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Quality Attributes to Consider - Mab
Functional characteristics
Physico-chemical characteristics
N-terminal heterogeneity
pyroglutamate formation
Other modifications
AA modifications
deamidation, oxidation, glycation,
isomerization
Fab
Fragmentation
Cleavage in hinge region, Asp-Pro
Oligosaccharides
Fucosylation, sialyation, galactosylation…
Fc
Effector functions
Disulfide bonds
complement interaction
Fc recepter interaction
Free thiols, disulfide shuffling, thioether
C-terminal heterogeneity
Lysine processing, proline amidation
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Biologics are hard to copy
Significance and Needs
WHY BIOSIMILAR??
Why Biosimilar?
• Ensuring safety and effectiveness
• Accessibility of high cost medicine
Definition
Global Approval Pathways
Key Issues
BIOSIMILARS
NDA vs. ANDA Review Process
New Drug
NDA Requirements
Generic Drug
ANDA Requirements
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Chemistry
Manufacturing
Controls
Labeling
Testing
Animal Studies
Clinical Studies
Bioavailability
Chemistry
Manufacturing
Controls
Labeling
Testing
• Bioequivalence
Generics vs. Biosimilars
Generics
Patent
Biosimilars
Expired
Active
Pharmaceutical
Ingredients
Identical
Proof Needed
Bioequivalence Comparability
Never identical
(Highly Similar)
What Biosimilar are….
And are not?
• They are similar …… They are not the same
• They are different from innovator’s
product.
• They are not generic biologics
Which biologics are in the scope of
Biosimilar?
Vaccines
Blood Products
Recombinant Proteins
Monoclonal Antibodies
Transgenic cells/ Cell therapy
EMA guidelines – can be adapted to all biologics including blood products, vaccines
WHO guidelines and others – adapted only well established and well characterized
biotherapeutic products
BioMarket Trends Jun 15, 2012 (Vol. 32, No. 12) Biosimilar Market Posts Steady Gains
Actual Performance Varies between Regulated and Semi- and Unregulated Environments.
Biosimilarity requirements
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Same Approval Pathway as Generics for
Biologics?
• For Blood Products and Vaccines
– No, the approval pathway treats them as New
biologics.
• For Recombinant Proteins
– Yes and No
• Yes 
• No 
• Somewhat between 
Generic Approval
New biologics Approval
Biosimilar
Biosimilarity is built on five
indispensible pillars.
Modified from lecture of Dr. Thomas Schreitmueller
Approval of Biosimilar vs.
Originator Biologics
Pharmacovigilance
Clinical
(PI,II,III for each indication)
Clinical
(with extrapolation)
Non-clinical
Non-Clinical
Chemistry, Manufacturing and
Control
Originator Biologics
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Comparability exercise in Quality
Chemistry, Manufacturing and
Control
Biosimilars
Establishment of biosimilar
guidelines increased, driven by WHO
But: Variability in adoption by National Regulatory Authorities
2010
2015
Biosimilar pathways in
place
Biosimilar pathways under
development
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Global regulatory environment
• In general, regulators require:
– Comparative analytical program
– Clinical program
– Post-approval commitment to Pharmacovigilance
– High degree of analytical similarity
– High degree of pre-clinical and clinical similarity
• Regulators may permit extrapolation when
scientifically justified.
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Key Issues in Biosimilar
Dossier
• Quality Comparisons
– The most critical and extensive step
– Cell culture, impurities, glycosylations ……..
• Non-clinical Comparisons
– In vitro receptor binding & cell based assay are
fundamental
• Clinical Comparative Studies
– Most sensitive population and endpoints
– 6-12 months safety data
– Extrapolation of indications
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Current Thailand Biosimilar
Guidelines
คู่มือ และหลักเกณฑ์ การขึน้ ทะเบียนตารั บยาชีววัตถุคล้ ายคลึง 2556
Biotechnology-derived proteins
Defines philosophy
and principles
General guidelines
Quality
NonClinical
EPO Review
Unorthodox
Pathway ????
Epoetin
Clinical
2557
IFN-α Somatropin
NonClinical
NonClinical
NonClinical
Clinical
Clinical
Clinical
2559
2558
IFN-β
FSH
NonClinical
NonClinical
NonClinical
Clinical
Clinical
Clinical
GCSF
mAbs
NonClinical
Clinical
Immunogenicity
Guideline for biosimilars
Annex guidelinesspecific data
requirements
ประเภทของยาชีววัตถุในประเทศไทย
• Previous
• New Regulations
• ยาชีววัตถุใหม่
• ยาชีววัตถุท่ ไี ม่ ใช่ ยา
ใหม่
• ยาชีววัตถุใหม่
• ยาชีววัตถุคล้ ายคลึง
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EXTRAPOLATION OF
INDICATIONS
key to the biosimilar concept
needs to be justified in all cases
Extrapolation of Indications
• The Key Consequence of Biosimilar is the
EXTRAPOLATION of INDICATIONS
• Justification of the extrapolated indication
is on a case-by-case basis.
• Decision based upon mechanism of
action, type of receptors, Affinity etc.
Interchangeability
• In EU, the biosimilar approval do not
automatically allow interchangeability
• Interchangeability/switching remains a
national decision.
• Later, after 10 yrs experience of biosimilar
in the market, several countries change
regulations.
Dossier requirements for a
biosimilar vs. an originator
The State of the Art in the Development of Biosimilars
Mark McCamish and Gillian Woollett Nature Biotechnology 30, 1179–1185 (2012)
Manufacturing Process (1)
• Demonstrate the Consistency and Robustness of
manufacturing process
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cGMP implementation
Modern QA/QC procedures
In-process controls
Process validation
• Minimize Differences b/w SBP vs. RBP
– Reduction clinical testing requirements of SBP
– Minimize any predictable impact on clinical safety and efficacy of
SBP
• Differences are expected and may acceptable
– Appropriate justification  lack of impact on clinical performance
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Manufacturing Process (2)
• Current manufacturing process following
current guidelines (ICHs) and extensive quality
control is encourage
• Potential impact of Changing of on Quality
Safety and Efficacy should be identified.
• Some Differences are expected and may
acceptable
– Appropriate justification (based on scientific and
clinical experience  lack of impact on clinical
performance
Comparability Exercises in
Quality of Drug substance
General Principles
Manufacturing Processes
• To ensure the similarity of
drug substance in SBP vs.
RBP (vs. Reference
standard)
• Products should be
expressed and produced in
the same host cell type
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Expression vectors
Cell banks
Cell culture/ Fermentation
Harvest
Purification
Modification reaction
Filling / Storage
Dosage form
Container closure system
Analytical Techniques
• Using appropriate, state-of-the-art in
Biochemical, Biophysical, Biological
• Provided on
– Primary and higher-order structures
– Post translational modifications
– Biological activity
– Purity
– Impurities
– Product-related substance
– Immunochemical properties
Justification of Analytical
Methods
• Suitability
– State-of-the-art (Current and upto-date)
– Able to detect any difference
between SBP vs. RBP
• Method Validations
Physicochemical Assessment
• A comprehensive understanding and description of
the RBP vs. SBP to support development throughout
the manufacturing process to
– Understand impact of manufacturing changes
– Ensure continued and consistent biosimilar properties to
the reference product
– Build a database to support the Quality by Design (QbD)
program
• Orthogonal methods/multiple techniques employed
to fully elucidate structure (as far as possible)
including microheterogeneities
Physicochemical Assessment
Extensive enough to fully characterize primary and
higher order structure including post translational
modifications
• Primary structure, sequence
and bridging (disulphide,
thioether)
• Higher (secondary, tertiary
and quaternary) order
structure
• C and N terminal variants
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Post translational modifications
Protein concentration
Surface charge
Protein size
Aggregation
Bioassay, potency
Purity and impurities
Biosimilar filgrastim compared to reference
product (Neupogen) using three state-of-theart analytical techniques
The State of the Art in the Development of Biosimilars
2/22/2013
Wisit Tangkeangsirisin, Biosimilars
Mark McCamish and Gillian Woollett
Guideline Public Hearing
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Biological Activity Assessment
• Biological activity based on clinically relevant assays are required
• The extent is, to some degree, predicated by the physicochemical data
• All clinically relevant functional attributes to be assessed where possible
– E.g., for a mAb it may be necessary to test for both antigen binding and effector
binding in appropriate in-vitro bioassays
• Relevance may determine extent of further nonclinical (and clinical studies)
– Animal toxicity studies not useful if no suitable model
– Studies should be comparative and provide a meaningful toxicological
comparison
– Stand-alone toxicology study can be justified
– Safety pharm, repro toxicity, and carc studies not generally warranted
– Single-dose PK and PD study in animals can be useful
Specifications
• ICH Q6B : Specifications: Test Procedures and
Acceptance Criteria for Biotechnological/Biological
Products
– Data from batch-to-batch consistency, pharmaceutical
development, comparability exercise in quality, safety and
efficacy profile
• Range of acceptance should not wider than RBP
No significant differences
Significant differences
Significant differences
Significant differences
Significant differences
No significant differences
No detectable difference
No significant differences
Clinical Results
Biophysical Comparison
Full Comparability Studies for Safety and Efficacy
Bioequivalence Based Approach
Possible biophysical and clinical outcomes for biosimilars
Biosimilar Development
Understand a Reference Product
• Characterization
• Identify Critical Quality Attributes (CQA)
Creating and Producing a Biosimilar
• Identify the suitable clones
• Production process development
Throughout Comparison of the Reference Product vs Biosimilar
• Analytical testing and Clinical study
• Totality of Evidence for similarity
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Biosimilar Development
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Data requirements for comparability exercises for a moderate risk and a high risk manufacturing
change by the same manufacturer compared with a biosimilar manufacturing process.
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http://www.amgenbiosimilars.com/manufacturing/comparability-vs-biosimilarity/
Therapeutic Mab Critical
Quality Attributes
Charge Variants
Glycolysation
Immunogenicity
Aggregation & Degradation
Primary & High Order Structures
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WHY DO WE NEED STATE OF THE
ART ANALYTICS?
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Quality: Analytical
• Analytical comparison is more than “Just Meets Specs”
• Possible Analytical Comparison Outcomes
– Analytical Methods Alone Confirm High Similarity
– Analytical Methods Not Sufficient or Adequately
Discerning
– Analytical Methods Confirm Differences, but Differences
Are Shown to Be Not Practically Significant
• Eg. HX575-higher phosphorylated mannose type glycan
– Analytical Methods Confirm Differences, but Significance
of Differences on Safety and Efficacy Cannot Be Ruled out
– Analytical Methods Confirm Not Comparable
– Analytical Methods is better
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Changes in Process: Changes in
Products Quality Attributes
ARANESP
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State of the Art Analytics
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http://www.amgenbiosimilars.com/the-science/state-of-the-art-analytics/
RITUXAN
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ENBREL
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CASE STUDIES ON BIOSIMILAR
APPROVAL IN EU
Omnitrope (somatropin)
• RBP = Genotropin
• During development, changes by increase
complexity of comparability demonstration
• Esp. Additional steps to reduce Host Cell
Protein
• V. high level of non-neutralizing antibodies
(about 60%, during clinical trials (old
process))
Binocrit (Epoetin alpha)
• RBP = Eprex
• Extensive characterization and comparability
exercise in quality
• Structure comparisons
– Qualitative similar
– Quantitative differences found (increase in high
mannose-6-phosphate, Decrease in N-glycolylneuraminic acid (NGNA)
– Differences was justified
• PRCA concerns
– SC route contraindication in CKD
Silapo (epoetin zeta)
• RBP = Eprex
• Extensive characterization and comparability exercise
in quality
• Structure comparisons
– Qualitative similar
– Quantitative differences found (increase in des Oglycan forms, Decrease in NGNA
– Differences was justified
• SC route initially contraindicated
• SC indications added post-authorization upon further
clinical data
Zarzio (filgrastim)
• RBP = Neupogen
• Extensive characterization and comparability exercise in quality
• Clinical data
– Phase I: Comparative PK/PD studies in healthy volunteers.
Efficacy endpoints: neutrophil and CD34 cell counts
– Phase III: Non-comparative (single arm) clinical trial in cancer
patients undergoing chemotherapy. Safety focus
• G-CSF Guideline states:
– “The recommended clinical model for the demonstration of comparability of
the test and the reference medicinal product is the prophylaxis of severe
neutropenia after cytotoxic chemotherapy in a homogenous patient group
(…). Alternative models, including pharmacodynamic studies in healthy
volunteers, may be pursued for the demonstration of comparability if
justified”
Valtropin (somatropin)
• RBP = Humatrope
• Different expression system compared to reference
medicinal product (S. cerevisiae vs. E.coli). Process
specific HCP (yeast) assay required
• Changes during development subject to additional
comparability
• Clinical trial:
– Initially calculated to demonstrate non-inferiority
– US sourced RBP used (supportive data)
• Indication differ from Omnitrope
– Pediatric indication for Omnitrope only: Small gestational Age,
Prader-Willi Syndrome
• May 2012 Voluntarily withdrawn for commercial reasons
Insulin Marvel (Withdrawal)
• RBP = Humulin S
• Three forms (Short, Intermediate (30/70), Long acting)
• Quality Concerns
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Incomplete comparability exercise, esp Drug Product
Inadequate process validation
Missing batch traceability
More data required for extended release forms
• Clinical issues
– Comparative PK/PD: euglycaemic clamp – most sensitive model
– Similar PK Parameters, but not similar PD profiles (faster
glucose absorption
– Applicant resorted to efficacy trial with HbA1C end-point, not
sufficiently sensitive
– Limit Immunogenicity data
Alpheon (rhIFNalpha-2a;
Negative)
• RBP = Roferon-A
• Quality concerns
– Stability and impurities for drug substance and drug product
profile also not matching RBP
– Inadequate process validation in DP
– No comparability studies between clinical trial batches and
commercial batches
• Non-clinical studies were inadequate and indicated
differences
• Clinical issues
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Difference in virological relapse rates
Inconclusive data in response rate for Genotype 1 patients
Different rate of adverse events
Inadequate immunogenicity documentation
Some Concerns About
Biosimilars
• Route of Administration for approved
indications of biosimilar may not be the same
as Reference Biological Product
– Eg. Binocrit initially contraindicated in CRF by
SC route
Different glycan pattern--Not biosimilar
REALLY????????
HX575 has different glycan profiles from RBP.
But the differences are acceptable and justified.
EPO Isoforms
among Biosimilar
vs. RBP are similar.
Not Identical
“ More recently, two cases of neutralizing antibodies were reported during a
pre-marketing clinical trial of a biosimilar epoetin (HX575) in subcutaneous
administration in chronic renal failure subjects (9). In this paper, we present
data showing that contamination
by tungsten during the
manufacture of the syringes used for primary
packaging is the most likely cause of protein
denaturation and aggregation, which may have led to the
occurrence of two cases of neutralizing antibodies in the investigational
clinical trial.
Conclusion
• Quality assessment is the primary and major
part of biosimilar registrations.
• Comparability studies with RBP determine the
degree of intensity in non-clinic and clinical
assessment.
• State-of-the-Art technology should be used to
detect any potential differences.
• How to demonstrate product comparability is
challenging
• Case studies about EU biosimilar approval
confirmed case-by-case varies
Thank you
Any questions, comments and
suggestions are welcomes
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