Biosimilarity in light of protein structure
Andras Ballagi, PhD.
CTO at Diagon Ltd.
Budapest, Hungary
PEWS conference, CSIRO, Melbourne, 24. -26. July 2019.
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How the health costs are increasing in the US
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How the health costs are increasing in Australia
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Comparison of the cost of treatment by
small molecules and biopharmaceuticals
Delta: > 20 000 USD
Due to the high cost of infliximab, the mean total drug cost was
Higher in the infliximab €19 215
than the conventional treatment group €4710
Ann Rheum Dis doi:10.1136/annrheumdis-2013-205060
Delta: > 14 000 EUR
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Biosimilar definition and requirements
A biosimilar is a biological medicine highly similar to another
already approved biological medicine (the 'reference medicine').
Biosimilars are approved according to the same standards of
pharmaceutical quality, safety and efficacy that apply to all
biological medicines.
a. The biological product is highly similar to the reference
product notwithstanding minor differences in clinically
inactive components
b. There are no clinically meaningful differences between
the biological product and the reference product in terms
of the safety, purity, and potency of the product
Biologics Price Competition and Innovation Act of
2009. Retrieved from http://www.fda.gov.
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Biosimilar History
Sandoz developed the first biosimilar Omnitrope (somatropin,
Human growth hormone), and registered in Europe in 2006.
Omnitrope was registered as a new drug in the US in the same
year, because did not exist legal basis for approval in the US at
that time.
As of June 2019,
18 biosimilar products approved by the FDA and
more than 60 have been approved by the EMA.
With continued expansion of the market, experts forecast that
biosimliras can save over 50 billion US$ within 10 years.
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Developmental pathway for biosimilar approval
„Totality of evidence”, this is the standard, which means
the sum of analytical, preclinical and clinical data.
Match to the reference product in:
-
structure,
Increasing number and quality of
analytical methods,
Increasing possibilities to design protein
molecules.
-
function,
Increasing number and quality of
binding and cell based assays,
-
clinical performance
The main goal is to prove the similarity between the reference product
and the biosimilar product.
(In the case of the reference medicine the main goal is to prove the clinical efficacy and
safety rather than structural and functional characterization.)
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Stages of biosimilar development
Analytics
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Stages of biosimilar technology development
Final concentrations API,
additives, holding times,
Stability studies,
SOP-s, GMP doc.
Steps of chromatography (rates and no. of
cycles, no. of washings, holding times,
SOP-s, GMP doc.
Optimization of inoculum train,
Opt. of culture parameters (pH, temp.
culture time, media comp.),
Scale-up, Opt. of cell separation,
SOP-s, GMP documentation.
Analytics,
(physicochemical,
binding assay
and
cell based
bioassay)
Selection of gene, primary sequence determination,
synthetic gene transfer, primary and secondary cell
selection, estab. RCB, MCB, WCB.
Test of genetic stability (80-100 gen.)
Test of biosafety (free of viruses and prions, etc.)
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Category
Primary structures
Attributes
AA sequence
Total molecular weight
Disulfide bridging
Higher order structure
Free thiols
Secundary and terciary
structures
Thermodinamic stability
Deamidation, oxidation
Posttranslational
modifications
Charge heterogeneity
Size heterogeniety
Glycosylation
Binding activity
Potency
Charge variants
Isoelectric point
High molecular weight
impurities
Low molecular weight
impurities
Nonglycosylated heavy chain
Glycan profile
Affinity to the target molecule
Methods
Reduced-RP-HPLC-MS
RP-HPLC-MS
Non-Reduced-RP-HPLCMS
Ellman’s assay
CD
Diff. Scan. Calorimetry
Reduced-RP-HPLC-MS
CEX-HPLC
IEF
SEC-HPLC
Nonreduced CE-SDS
Reduced CE-SDS
NP-HPLC-FL
SPR, Bio-layer
Interferometry
Influencing cell growth or cell Cell based assay
morphology
Adopted from: Miao et al. BioMed Research International Volume 2017, Article ID 4926168
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Factors influencing similarity throughout the technology
Mellstedt H, et al. Ann Oncol. 2008;19:411-419.
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Chemical parameters influencing similarity
Glycosylation
Phosphorylation
Deamidation
Methylation
Acetylation
Lipidation
Sulphatation
Hydroxylation
Disulphide bond formation
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Attack of the Originators
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The Biosimilar Producers Strike Back
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Which Changes Matter, Which Don’t?
Valine
Threonine
The authorities require complete matching in primary structure !
Biochemistry. 1997 Feb 18;36 (7): 1581-97.
Refined structure of an intact IgG2a monoclonal antibody.
Harris LJ1, Larson SB, Hasel KW, McPherson A.
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Risks of technology development and scale up
Small scale
technology
development
Scale up
and
down
Control
Quality
attributes
Expected
COG
Stability
Establish
full scale
technology
Repeatability
Validation
Techn.
transfer
Risk
of
investment
Establish
production
facility
Risk
of
authorization
Risk of
authorization
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Scaling up monoclonal antibody technology
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Summary
Biosimilar medicines developed using the
„totality of evidence” standard.
This means that the
reference medicine and the biosimilar medicine compared
- analiticaly,
- functionality and
- in a limited and focused human
clinical program.
These verify the similarity of the two medicines.
The application of biosimilars can contribute to reduce the
health care costs, and ensure protein based medicine for
middle- and lower-income groups of the society.
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Thank you for your attention!
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