As work on biological molecules accounts for an increasing proportion of R&D expenditure in drug discovery and development, analytical testing is under the spotlight in the rapidly expanding biopharmaceutical sector. Not only is the cost of developing these molecules very high, this heavily regulated industry also constantly demands more appropriate and rigorous analytical measurements. Many in the sector have cited analytical bottlenecks as a major cause for concern and likely to constrain drug development.
Unlike small molecule drugs, therapeutic proteins are not synthesised or crystallised and they are intrinsically heterogeneous. As such, the definition of purity and potency for biotherapeutics is much more complex than it is for non-biological molecules. Impurities, for example, can originate from any number of sources, including the therapeutic molecule itself in the form of aggregates or ‘misfolded’ or completely denatured structural forms.
Consequently, the analytical technology needed for quality assurance and control, and which will provide the data necessary for pre-formulation and formulation, is quite different when compared with the pharmaceutical industry’s small molecule norm. This complexity and variability is leading to many new challenges for manufacturers and regulators alike.
Selecting suitable candidate molecules involves – among other analyses – various physicochemical testing processes that are designed to rule out those molecules that may become ‘problem children’ further downstream. One of the most important questions to be answered is how these molecules will behave in formulation, and a significant area of concern is protein aggregation, not least because of the potential for aggregates to trigger an immune response.
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