Biopharmaceuticals are biotechnologically produced medical drugs, i.e. biomolecules for therapeutic or in vivo
diagnostics use. Those are proteins and nucleic acids which interfere with cellular processes in a targeted way.
1. Therapeutic proteins
These include besides monoclonal antibodies (mAb), peptide hormones, growth factors, interferons and interleucins. Monoclonal antibodies and their derivatives are among the fastest-growing sectors in pharmaceutical industries. To date, numerous mAbs for therapy of cancer, immune diseases and transplant rejection, but also for diagnostics and analysis, are brought to market. The revenue generated in 2009 by sales of therapeutic mAbs was more than $ 37 bln, and an annual growth rate of more than nine percent is expected. As of 2010, there are more than 200 novel mAbs in the pipeline, 27 of which are in clinical phase III [1, 2].
So far, particularly antisense RNA and antisense oligonucleotides are in use as medical drugs. Furthermore, the RNAi technology has enormous potential to develop effective drugs despite the withdrawal of some major pharma companies .
With more and more patents for branded biopharmaceuticals expiring, there will be an increase in biosimilars for which the regulatory agencies require a more in-depth characterisation than for small-molecule generics. In fact, EMEA considers biosimilars not as “generics” in the sense applied to small-molecule drugs, but has developed the concept of “similar biological medicinal products” to account for the molecular complexity of biopharmaceuticals . The research and development expenses of a biosimilar are ca. 100 mio $, prices are 20-30% below that of the original product.
Biopharmaceuticals are complex molecules and require characterisation by different methods in order to
describe and understand the whole range of molecular complexity.
Due to this complexity, changes in the manufacturing process appearing to be minor (change in cell line, change in growth medium, change in purification protocol, moving the production site, etc.) can have a considerable effect on the final drug product in terms of stability, efficacy and undesired side effects. As a first step to understand the impact of a change in manufacturing parameters, a number of physico-chemical parameters can be checked before more extensive biological testing occurs. Sedimentation Velocity (SV) AUC probes a number of highly relevant properties in this regard and can play a central role in assessing that two biopharmaceuticals are identical.
As an outstanding feature, the samples are measured in most cases within their original formulation (without sample preparation). The routinely accessible concentration range for proteins is 0.1 to 50 mg/mL. This means that therapeutic proteins, formulated at very high concentrations, can be analysed in a unique way via Analytical Ultracentrifugation.
As the sedimentation coefficient is sensitive to the mass and shape of a molecule, “sedimentation coefficients measured from SV [are] highly quantitative indicators of structural comparability.” . Due to the large accuracy with which the aggregate content of a biopharmaceutical preparation can be measured with Analytical Ultracentrifugation, the same experiment also yields information about the stability of different formulation/lots.
By integrating Analytical Ultracentrifugation as a powerful Extended Characterization (EC) Assay early in development, the need for these analyses in the commercial production stage may be diminished and, consequentially, QC may be more specific and efficient in the final production environment. Hence, the use of Analytical Ultracentrifugation will be most cost-benefit efficient during formulation and process development for manufacturing, particularly as part of a promising Quality by Design (QbD) strategy. Additionally, random AUC analyses of various lots as well as frequent stability studies to assess the storage life under different storage conditions provide the necessary information to avoid non-optimal or even deleterious applications of a biopharmceutical.
: Pohl-Apel, G. Monoklonale Antikörper: Vielseitige Moleküle in Therapie und Forschung, Biospektrum 2011, 17, 116–117.
: Medizinische Biotechnologie in Deutschland 2010, BCG Report.
: Aldag, J. Das Aus für RNAi-Medikamente? Biospektrum 2011, 17, 351.
: EMEA Guideline on Similar Biological Medicinal Products (2004), http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf
: Chirino, A.J. & Mire-Sluis, A. Characterizing biological products and assessing comparability following manufacturing changes. Nat. Biotech. 2004, 22, 1383–1391.