By Catriona Thomson, PhD 
Associate Director of BioAnalytical Technical Services

Global sales of the top seven biologics in 2014 were in excess of US$60 billion and of these molecules, six were monoclonal antibodies1 that have patents due to expire between 2016 and 20212.  This patent cliff provides an impetus for companies to develop biosimilar molecules to maximise their impact on the current global market, as well as in emerging economies such as India, China, Mexico and Brazil.  In order to capitalise on these opportunities, developers must work to a model where speed-to-market, low development costs and buy-in from consumers are of primary importance. Therefore, the quality management concept of “Getting it Right First Time” is the cornerstone of biosimilar development. Definitions of biosimilar products stress the importance of demonstrating similarity to an innovator molecule (reference medicinal product, RMP), with emphasis on the safety and efficacy of the biosimilar for the patient3,4.

This is reflected in the extensive physicochemical and biological characterisation performed early in development with the aim of reducing the scope or requirement for costly clinical trials due to the comprehensive analytical totality of evidence supporting similarity. Having selected a clone with suitable genetic potential and productivity characteristics, advances in technology allow process development to be accelerated.

Many permutations on a small scale can be assessed with the ability to rapidly upscale optimised conditions using components and materials that are identical, except in terms of size.  Access to an extended range of “off-the-shelf” binding and functional assays with high levels of sensitivity and sample throughput help to simplify the clone selection process, and accelerate the optimisation and monitoring of process reproducibility. This allows rapid elimination of clones and conditions that are not comparable to the RMP, and definition of the final process and key quality attributes of the molecule.

The ultimate goal is to produce a biosimilar product that has “fingerprint-like similarity” to the RMP.  Although this description is yet to be fully defined, it will be based on the totality of evidence, so an extensive suite of assays is required to demonstrate biosimilarity. Complete characterisation of the biosimilar covers everything from physicochemical analysis through functional cell-based assays, and should make use of orthogonal approaches in order to have every opportunity to define and describe differences between the RMP and biosimilar populations.  Due consideration should be given to potential secondary mechanisms of action, as well as the primary ones.  Over its lifespan, the biosimilar is compared to an appropriately sized RMP population that should be selected carefully to reflect its true variation. Regulatory authorities acknowledge that biosimilars will show differences compared to innovators, and these may be accepted as long as they are not “clinically meaningful.”  Therefore, a robust approach using the most physiologically relevant assays available is required to address the differences observed.

Extrapolation of data for multiple indications was recently supported by both the FDA and EMA5.  Regulators advocate that if biosimilarity can be demonstrated by analytical characterisation, and if the product is safe and efficacious for one indication, approval should be granted for all other indications that the innovator product is licensed for.  Using sensitive analytical methods to develop optimised biosimilars, rather than assessing the impact of differences using the relatively blunt tool of a clinical trial, is an approach to put patient safety at the forefront of biosimilar development. Our experience in biosimilar characterisation indicates that the success of biosimilars will ultimately depend on rapidly producing a product with the required safety and efficacy profile, as demonstrated by comprehensive analytical characterisation using orthogonal methods, and addressing the potential clinical significance of observed differences using physiologically relevant methods.

In addition to the appealing cost reductions that biosimilars offer national health care providers, interchangeability studies and an extensive data package should inspire confidence in patients and prescribers whose buy-in is required to develop the biosimilars market.


2 Calo-Fernández, B & Martínez-Hurtado, J.L.; Pharmaceuticals 2012, 5(12), 1393-1408; doi:10.3390/ph5121393

3 Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act

4 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues 18 December 2014 EMEA/CHMP/BMWP/42832/2005 Rev1