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The role of analytics in the discovery and development of biopharmaceuticals

As the biopharmaceuticals market continues to grow, how do laboratory analysis methods support discovery and development? And what should be considered when selecting an analysis method?

What is the landscape in biopharmaceuticals today?

Simply put, the future is bright.

With the industry predicted to reach ~$350 billion USD by 2023 and 7 of the top 10 selling drugs in 2017 being biopharmaceuticals [1], demand is booming. The high specificity and few side effects seen with antibody, protein and other biologic based treatments have peaked interest into these complex molecules.

This translates to increased pressures on research and development teams to ensure the development pipeline is as efficient as possible – from plans and protocols to the equipment and instrumentation used.

Why are analysis methods important in this field?

Analytical methods are used throughout the pre-clinical phase for a range of measurements.

Discovery teams use them to QC check antigen, to evaluate ligand/receptor interactions, and to assess biophysical parameters of lead molecules – including multimer formation, aggregation etc.

In development, biosimilars are examined, non-specific binding is assessed, stability across production, purification and storage is considered, differing formulations are compared and batch to batch consistency is tested.

These tests are not only important for efficiency and informed decision making in house – unexpected forms or behaviors of the drug can have very real impacts on patients.

protein quality

How aggregation can affect biopharmaceutical treatments

One factor which can affect the behavior of biopharmaceuticals in vitro is aggregation.

This includes any kind of self-association interactions between protein molecules. Aggregates can include assemblies of any size (dimers through to visible particles), formed by covalent or non-covalent bonds, making soluble or insoluble species in an ordered or disordered structure.

It is known that aggregates present in protein therapeutics can trigger the formation of Anti-Drug Antibodies, or ADAs, which effectively neutralize or otherwise interfere with the intended pathway of the drug [2]. This effect has been known since the 1960s, but continues to be investigated in order to fully understand the pathways of this response [3].

The effects of aggregated species on patients can vary dramatically, from reduced efficacy through to severe reactions.

For example, in the treatment of multiple sclerosis with Interferon (IFN-ß), aggregates can trigger the production of neutralizing antibodies. These prevent IFN-ß binding and reduce the drug efficacy [4].

A formulation change in erythropoietin (epoetin-α) treatments, using polysorbate 80 as a stabilizer instead of human serum albumin, encouraged the development of micelle-associated aggregates. These triggered the development of neutralizing antibodies which also bound to the endogenous protein, preventing the production of red blood cells and causing the development of Pure Red Cell Aplasia (PRCA) in patients [4].

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Which analytical tools are used in biopharmaceutical development?

With analysis required at multiple development stages, and clearly being vital to product efficacy and safety, choosing the right method for each test is vital.

We have discussed before the different techniques available for size and concentration analyses. As the variety in complexity, technical capability and sample requirements is large, a combination of different analytical methods is often used to build a complete picture, particularly in lead molecules.

The Fluidity One instrument has been shown to effectively detect the formation of amyloid aggregates of α-synuclein, characterize the size and thermodynamics of protein-lipid interactions, and offer detection and quantification of protein-ligand interactions. In addition to this track record, it’s simplicity makes it a good choice for cross-team projects – with no complex settings (just select estimated protein size from small, medium or large), it is easy to ensure that results generated over different stages or teams are directly comparable.

Bioprocessing

Find out more by following the links above or contact us if you have any questions about protein testing in biopharmaceutical development.

References

1. PharmaCompass. Top drugs by sales in 2017: Who sold the blockbuster drugs? [Online] PharmaCompass, 2017. https://www.pharmacompass.com/radio-compass-blog/top-drugs-by-sales-in-2017-who-sold-the-blockbuster-drugs

2. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Sauerborn M, Brinks V, Jiskoot W, Schellekens H. 2010, Trends Pharmacol Sci., Vol. 31, pp. 53-59.

3. Effects of protein aggregates: an immunologic perspective. AS, Rosenberg. 2006, American Association of Pharmaceutical Scientists, Vol. 8, pp. 501-507.

4. Immunogenicity of therapeutic proteins: Influence of aggregation. Kirsty D. Ratanji, Jeremy P. Derrick, Rebecca J. Dearman, and Ian Kimber. 2014, Journal of Immunotoxicology, Vol. 11, pp. 99-109.

 

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