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Cell-Based Functional Assays as Critical Quality Attributes in Biologics & Biosimilars

The rise of biologics and biosimilars has transformed drug development, bringing forward new therapies like monoclonal antibodies (mAbs) and insulins. Yet, ensuring their quality and regulatory approval hinges on a key component: cell-based functional assays (CBFAs). In this blog, we highlight insights from Venture Center’s session on how CBFAs function as critical quality attributes (CQAs) in biologics development and biosimilar approval.

From the "Only One Analytical Technique" talk series by Venture Center. 

Why Cell-Based Assays Are Critical for Biologics and Biosimilars

Biologics are large, complex molecules whose mechanism of action (MoA) often depends on cell interactions. Structural analysis can confirm sequence and folding, but only functional assays prove that a drug does what it is designed to do.

Cell-based assays are used to:

  • Demonstrate mechanism of action (e.g., ADCC, CDC, receptor binding)
  •  Compare biosimilars to innovator drugs
  • Support batch release testing and stability studies
  • Detect subtle differences in glycosylation, folding, or potency missed by physicochemical tests

For regulators like the FDA, EMA, and CDSCO, cell-based potency assays are non-negotiable. They provide assurance of safety, efficacy, and consistency.

Biosimilars vs. Innovator Biologics: A Regulatory Perspective
  • Innovator Biologics (351a Pathway): Extensive preclinical and clinical testing required.
  • Biosimilars (351k Pathway): Shorter, more streamlined. Relies heavily on analytical and functional comparability to the reference drug.

To gain approval, biosimilars must show head-to-head similarity with the innovator product in both structure and function. Functional assays like ADCC, CDC, and receptor-based assays become the backbone of biosimilar development.

Functional Assays for Monoclonal Antibodies

Monoclonal antibodies rely on two domains:

  • Fab region – Responsible for antigen binding
  • Fc region – Mediates effector functions like ADCC and CDC

Examples of Common Assays:

  • Binding assays: Flow cytometry, ELISA, BLI, SPR
  • Potency assays: Proliferation, neutralization, reporter gene assays
  • Effector function assays:
    • ADCC (Antibody-Dependent Cellular Cytotoxicity
    • CDC (Complement-Dependent Cytotoxicity)
    • ADCP (Antibody-Dependent Cellular Phagocytosis)

These assays are central to demonstrating mechanism of action and biosimilarity.

Functional Assays for Insulins

Compared to mAbs, insulins are structurally simpler. Still, their bioactivity and metabolic impact must be thoroughly tested.

Key insulin-related assays include:

  • Receptor binding assays (insulin receptor A/B, homodimer, heterodimer)
  •  Metabolic assays (glucose uptake, lipogenesis, gluconeogenesis)
  • Mitogenic assays (cell proliferation via IGF-1 receptors)

Given insulin’s chronic use, regulators are especially strict about purity, impurities, and bioactivity consistency.

Challenges in Cell-Based Assay Development
  • Variability: Cell line passage number, plating technique, and media conditions can impact results.
  • Standardization: Requires validated SOPs, reference standards, and reproducibility.
  • Complexity: Maintaining master and working cell banks, avoiding contamination, and ensuring regulatory compliance.
  • Cost and Timeline: Cell-based assays are resource-intensive but unavoidable.
Future Directions

Cell-based functional assays are evolving with:

  • Engineered and immortalized cell lines
  • Reporter gene systems (e.g., luciferase)
  •  High-throughput readouts (fluorescence, luminescence)
  • Integration of AI and automation
  • Use of 3D cell models and organoids

As novel therapies like CAR-T and bispecific antibodies advance, cell-based assays will remain at the forefront of proving drug functionality.

CBA at Venture Center: Enabling Functional Assay Excellence

The Center for BioPharma Analysis (CBA) at Venture Center, NCL Innovation Park, Pune provides:

  • GLP-compliant, NABL-accredited services
  •  End-to-end structural and functional characterization
  • Expertise in ADCC, CDC, proliferation, and reporter gene assays
  • Regulatory-aligned validation and documentation
  • Competitive pricing for cost-effective functional assays.

Whether for biosimilars, novel biologics, or insulins, CBA supports researchers and companies in India with robust assay platforms that meet global standards.

Reach out to CBA at NCL Innovation Park, Pune to get started.