Biosimilar Testing Services
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What are Biosimilars?
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. Biosimilars are known as similar biologics, follow-up biologic, similar biological products, subsequent entry biological, second entry biological, biogenerics, multisource products, similar biotherapeutic product and off-patent biotech products. The nomenclature varies from one geography to another.
A reference product is the single biological product, already approved by FDA, against which a proposed biosimilar product is compared. A reference product is approved based on, among other things, a full complement of safety and effectiveness data. Reference product is also known as Innovator product, Originator drug, Novel Biologic and Reference Medicinal Product.
The first biosimilar approved by EMA was Omnitrope in 2005; US FDA approved Zarxio its first biosimilar in 2015. The first ‘similar biologic’ to be approved and marketed in India was for hepatitis B vaccine in 2000, in recent years almost 98 similar biologics are approved or are under development in India.
Difference between Novel Biologics and Biosimilars
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Novel Biologics |
Biosimilars |
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Novel therapeutic |
Copy of Novel Biologics |
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Time to market- more |
Time to market- comparatively lesser |
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Patentable |
Non-patentable |
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Price is higher |
Price is comparatively lower |
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Extensive clinical studies required |
Comparatively lesser clinical studies required |
Examples of few Biosimilars
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Novel Biologics |
Generic name |
Biosimilars |
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Humira (AbbVie) |
Adalimumab |
ZRC3197 (Adalimumab Biosimilar, Cadila), Cyltezo (Boehringer Ingelheim) |
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Rituxan (Genentech) |
Rituximab |
Rixathon® [Sandoz rituximab], Truxima® [Celltrion rituximab] |
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Herceptin (Genentech) |
Trasuzumab |
CanMab/Hertraz(Biocon/Mylan, India*/USA, Hervycta (DRL), |
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Neupogen (Amgen) |
Filgrastim |
Zarxio (Sandoz), Nufil (Biocon) |
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Remicade (Janssen Biotech) |
Infliximab |
Inflectra (infliximab-dyyb, Celltrion) and Renflexis (infliximab-abda, Samsung Bioepis) |
What is BPCI Act?
The aim of the Biologics Price Competition and Innovation (BPCI) Act BPCI Act is similar, in concept, to that of the Drug Price Competition and Patent Term Restoration Act of 1984 (a.k.a the “Hatch-Waxman Act”) which created abbreviated pathways for the approval of drug products. Under the BPCI Act, a sponsor may seek approval of a “biosimilar” product under new section 351(k) of the PHS Act. A biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency.
Biologics Price Competition and Innovation (BPCI) Act
- Created provision for abbreviated approval pathway for biological products; 351(k)
- To provide the public with greater access to safe and effective biological products.
- This allows for a potentially shorter and less costly drug development program for a biosimilar.
What is Biosimilar Development Program?
The goal of a biosimilar development program is to demonstrate biosimilarity between the proposed biosimilar product and the reference product, not to independently establish the safety and effectiveness of the proposed product. This generally means that biosimilar manufacturers do not need to conduct as many expensive and lengthy clinical trials, potentially leading to faster access to these products, additional therapeutic options, and reduced costs for patients.
A biosimilar product application must include data demonstrating biosimilarity to the reference product. This usually includes data from:
- Analytical studies demonstrating that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components;
- Animal studies, including an assessment of toxicity; and
- A clinical study or studies sufficient to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the indications for which the reference product is licensed. This typically includes assessing immunogenicity, pharmacokinetics (PK), and, in some cases, pharmacodynamics (PD) and may also include a comparative clinical study.
The guidelines regulating the Biosimilar development are EMEA in Europe, US-FDA in US, CDSCO-RCGM in India and WHO. Extensive analytical characterization is required to establish biosimilarity. The following table describes the different tests which are required for biosimilairty demonstration. Currently, CBA is well equipped to provide almost 80 percent of the testing services (as highlighted in green boxes) required for biosimilarity assessment. Kindly note the animal or in-vivo studies are out of scope of CBA.
CBA offers Biosimilar product characterization, Innovator product characterization, Batch release assays, and stability studies as a part of the Biosimilarity testing service offering. To know more about CBA capabilities and services, please visit: https://bioanalysis.in/protein-characterization-services/
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CDSCO |
EMEA |
USFDA |
ICH Q6B |
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Amino acid sequence (full as well as N and / or C terminal) |
Amino acid sequence (full as well as N and / or C terminal) |
Primary structure analysis- Amino acid sequence |
Amino acid sequence |
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Intact Mass assessment by LC-ESI-MS |
Intact Mass assessment by LC-ESI-MS |
Higher order structure analysis- Secondary, Tertiary, Quaternary (including aggregation) |
Amino acid composition |
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Peptide mapping |
Peptide mapping |
Enzymatic posttranslational modifications, such as glycosylation and phosphorylation |
Terminal amino acid sequence |
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Far UV Circular Dichroism Spectrum |
Sulfydryl groups(s) and disulphide bridges |
Other potential variations, such as protein deamidation and oxidation |
Peptide map |
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FTIR Analysis |
N-terminal sequence confirmation |
Intentional chemical modifications, such as PEGylation sites and characteristics |
Sulfhydryl group(s) and disulfide bridges |
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Tryptic Peptide Map-1D and 2D |
C-Terminal sequence confirmation |
Effect of excipients, |
Molecular weight or size |
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Sulfydryl groups(s) and disulphide bridges |
Glycan analysis- degree of mannosylation, galactosylation, fucosylation and sialylation. Distribution of the main glycan structures present (often G0, G1 and G2) should be determined |
Receptor Binding assay |
Isoform pattern |
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Fluorescence spectrum |
Carbohydrate content |
In-vitro bioassay |
Extinction coefficient (or molar absorptivity) |
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Near UV Circular Dichroism |
Higher order structure (using appropriate techniques) |
Apoptosis assay (if applicable) |
Electrophoretic patterns |
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UV-VIS spectroscopy |
Fluorescence spectrum |
Neonatal Receptor(FcRn) Binding Assay |
Liquid chromatographic patterns |
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Glycoforms and other modificaions like phosohorylation, acetylation, |
Circular Dichroism |
ADCC |
Spectroscopic profiles |
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Isoforms and charge variants by Isoelectricfocusing |
Receptor Binding assay |
CDC |
Cell substrate-derived impurities |
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N-terminal sequence confirmation |
CDR identification |
Neutralizing Biological activity in actual target host cell |
Cell culture-derived impurities |
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C-Terminal sequence confirmation |
Receptor Binding assay (FcRs) |
Kinetics of neutralizing biological activity during the proposed therapeutic period of protection |
Downstream-derived impurities |
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Ion exchange chromatography for charge heterogeneity |
ADCC |
Efficacy in appropriate disease/ infection model in-vitro and/or in-vivo |
Truncated forms |
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Product related variants and impurities by RPLC, SE-LC (CQA), IE-LC, SDS-PAGE, IEF, Western Blot (CQA) |
CDC |
In-vivo bioassay(if available) |
Other modified forms |
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Host cell protein analysis |
Apoptosis assay (if applicable) |
Aggregates |
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Protein content(CQA) |
Neonatal Receptor(FcRn) Binding Assay |
Animal-based biological assays |
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Receptor Binding assay |
In-vivo bioassay(if available)(KQA) |
Cell culture-based biological assays |
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In-vitro bioassay |
Molecular weight or size, isoform pattern, extinction coefficient, electrophoretic profiles, chromatographic data and spectroscopic profiles. |
Biochemical assays |
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Apoptosis assay (if applicable) |
HCP |
Purity |
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Neonatal Receptor(FcRn) Binding Assay |
HCD |
Impurities |
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Receptor Binding assay (FcRs) |
Cell culture residues, downstream processing residues |
Contaminants |
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ADCC |
Contaminants- microbial species, endotoxins |
Neutralizing Biological activity in closest animal species |
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CDC |
appropriate physicochemical and/or immunochemical assay |
Kinetics of neutralizing biological activity during the proposed therapeutic period of protection |
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Neutralizing Biological activity in actual target host cell |
Efficacy in appropriate disease/ infection model in-vitro and/or in-vivo |
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Neutralizing Biological activity in closest animal species |
In-vivo bioassay(if available)(KQA) |
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Kinetics of neutralizing biological activity during the proposed therapeutic period of protection |
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Efficacy in appropriate disease/ infection model in-vitro and/or in-vivo |
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In-vivo bioassay(if available)(KQA) |