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The pivotal role of assays in biologic and biosimilar discovery and development

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The quality, accuracy and reliability of assays is particularly critical when developing biologics and biosimilars. Assays for biologics are more complicated than for small molecules, often relying on assays which provide relative measures in contrast to the more absolute measurements gained from standard crystallisation or purity profiles.

Ralf Schumacher is responsible for leading all technical development activities for biologics including bioprocess, pharmaceutical, device development and pilot plant operations for Boehringer Ingelheim’s own biologics pipeline, and as a CMO for other companies. We interviewed him about the importance of assays at key stages of biological drug development, early target discovery/process development and clinical trials.

With the development of biological molecules, it is very important to define in detail the quality profile of the desired target molecule from the start. For example, you may know that you need a high affinity antibody, or perhaps a low affinity antibody if you want to achieve ligand displacement, or perhaps you specifically want a molecule to induce the immune system. Biologics will each have a specific quality profile based on their desired mode of action, and this, coupled with a good screening funnel will allow you to successfully find target effective molecules. It does mean that you have to understand the biology of the molecule much earlier than with classical compounds, where you have the benefit of cycles of compound optimisation using back up molecules.

The advantage with biologicals is that you will typically begin with a good safety profile and acceptable bioavailability. It is therefore the functionality of the target molecule which becomes the key focus and it is here that your panel of assays really comes to the fore.”

Assays are key here to prove that any possible target molecules fit the desired functionality and quality profile before moving on to the next stage of development. Dr Schumacher went on to explain:

“Once you’ve identified a molecule from a functional profile then you move to the CMC process development phase where you really have to assess whether the molecule identified has the right properties in terms of stability, viscosity, expressibility, developability and so on. Here assays are crucial once again to fully define the parameters and characteristics of the molecule which are important for CMC and beyond. The key focus is quality. We need to understand how to establish consistent processes as early as possible in order to produce representative material early on which stays representative for the development phase.

We use a whole range of assays. We start with in silico analysis and then we develop many assays to examine expressibility, expressing the proteins in different hosts to check what titres are possible and how well these molecules behave under stress conditions. We also design assays for biochemical and biophysical characterisation including functionality assays, for example assays to assess binding of the molecule to the corresponding target under accelerated degradation conditions such as elevated high temperatures.”

Professor Schumacher maintains that the way to find a compromise between the desire to fully establish quality and the pressure of time, is to rely on developing high-quality assay platforms that can be used to interrogate multiple targets.

Don’t invest too much in process establishment for individual molecules, but instead focus on a number of well-characterised platforms, where you really understand what you’re doing. You can then put your molecule in the platform and find your pathway into the clinic by using knowledge that you have gained from other molecules.”

One example of such a platform is large-scale cell-line generation in fermentation vessels. Once you understand the interplay between the cell and the geometry of the vessel, you can use the knowledge and go into transfection with new molecules and be on the lookout for anomalies. The idea is that the platform is based on a general understanding of the host cell and media combinations and that, when introducing a new molecule, it is as simple as applying three or four existing assays to immediately identify the basic expression and behaviour of the target molecule.

Ralf Schumacher

Ralf Schumacher
is Global Head of Bioprocess and Pharmaceutical Development at Boehringer Ingelheim. He will be speaking at the 3rd Biologics and Biosimilars Congress on the 6th – 7th March.

Click here to view the agenda for the 3rd Biologics and Biosimilars Congress.

One Response to “The pivotal role of assays in biologic and biosimilar discovery and development”

  1. Without fundamentally stating, the article is an advocate of Quality by Design when developing biological products.
    A full Quality Target Product Profile (QTPP) to comprehensively characterize should be carried out at the beginning of any process. This is used to set the appropriate range of CQA-based characteristics. These characteristics should be evaluated using the most sensitive approaches, namely methods that can identify acute differences, to drive a risk-based approach to evaluate the biological functions which are central to the mechanism of action. The definition of these parameters is imperative for the successive phases of development. This allows the principles of a Quality by Design approach to be integrated into to product development from the start and throughout all stages of the product lifecycle providing a critical understanding of both product and process.


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