Biologics

Biologics represent the category of highest therapeutic impact and greatest analytical complexity in today’s pharmaceutical landscape. Unlike small molecule drugs — defined by a precise chemical structure and produced by chemical synthesis — biologics are produced by biological expression systems (mammalian cells, bacteria, yeast) and are constituted by large macromolecules — proteins, antibodies, enzymes, coagulation factors — whose structure and biological activity depend critically on manufacturing process conditions.

This process dependence is the fundamental reason why the analytical characterisation of biologics is structurally more complex than that of any other therapeutic modality. The inherent heterogeneity of these molecules — arising from variability in post-translational modifications, glycosylation, charge and size variants and the potential formation of aggregates — means that no single analytical technique can provide a complete picture of product quality. The characterisation strategy must necessarily be multimodal, applying orthogonal methods that address the different levels of molecular structure.

The regulatory framework for biologics is defined by guidelines such as ICH Q6B, which establishes the characterisation and specification requirements for biotechnological active substances, and the EMA and FDA guidelines on biosimilar development, which define the level of analytical evidence required to demonstrate biosimilarity with the reference medicine. AMSbiopharma provides the comprehensive analytical support needed to meet these demanding requirements.

The characterisation of biologics takes place in a complex regulatory environment that combines different quality frameworks depending on the development phase and the nature of the service. Immunogenicity and clinical bioanalysis services respond to the principles of Good Laboratory Practice (GLP), while CMC characterisation, quality control and batch release services fall within the requirements of Good Manufacturing Practice (GMP). Advanced characterisation of proteins and biologics may also be conducted in non-regulated environments for exploratory studies in early development phases. Please consult us to define the most appropriate regulatory framework for your programme.

What are biologics?

Biologics encompass a wide range of therapeutics derived from biological sources or produced by recombinant DNA technology. The main categories include monoclonal antibodies (mAbs) and their derivatives — bispecific antibodies, antibody fragments, Fc fusion proteins —, therapeutic replacement proteins — insulins, coagulation factors, replacement enzymes —, cytokines and interferons, antibody-drug conjugates (ADCs), heparins and glycosaminoglycans, and biosimilars of all of the above.

The structural complexity of these molecules is an intrinsic characteristic of their biological nature: mAbs, for example, are glycoproteins of approximately 150 kDa whose therapeutic activity depends not only on their primary sequence but also on their glycosylation profile, three-dimensional structure, aggregation state and the integrity of their functional Fc and Fab regions.

Innovative biologics and biosimilars

The biologics market is divided between innovative products — developed and protected by patents by originator companies — and biosimilars, which are biological products highly similar to an already-authorised reference biologic, developed once the data protection or patent of the reference product has expired. The development of biosimilars requires a particularly rigorous analytical comparability strategy: demonstrating that the biosimilar and the reference medicine are highly similar — without clinically meaningful differences — demands applying the most sensitive and discriminating analytical methods available in a systematic and comprehensive comparability exercise.

The EMA and FDA guidelines on biosimilars establish that the analytical comparability package is the central pillar of the demonstration of biosimilarity, and that robust analytical characterisation can, in many cases, significantly reduce the extent of clinical studies required for regulatory approval.

Analytical challenges in biologics

The analytical characterisation of biologics requires the application of multiple orthogonal techniques addressing each level of molecular structure: the primary structure — amino acid sequence and sequence integrity confirmation by peptide mapping with LC-MS/MS; the higher-order structure — secondary, tertiary and quaternary structure; post-translational modifications — glycosylation, oxidation, deamidation, phosphorylation; and functional attributes — binding activity, effector function, biological potency. Each of these levels can have a critical impact on the clinical safety and efficacy of the product.