Daan J.A. Crommelin, Utrecht University

Almost 10 year ago EMA issued the first guidelines on biosimilarity for pharmaceutical proteins. Since then the concept of biosimilarity has evolved. More guidelines were and are being issued by this agency. For a growing number of protein families, including monoclonal antibodies, specific guidance documents and updates have been published. An up to date overview can be found at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp . WHO followed suit in 2009 and in 2012/2013 four FDA draft guidance documents on biosimilars saw the light.
Outside Europe and the USA generic versions of biologicals have been developed and are on the market. Sometimes a special regulatory framework for these products was in place, sometimes not. Little has been published on the quality of these products and experience in practice.

In the context of the biosimilarity discussions the effect of variations in innovator products during their life cycle, e.g. by changing elements in the manufacturing process or the formulation, received relatively little attention until the pure red cell aplasia problems started after reformulating an erythropoietin product. Later more examples were published of changes in innovator product characteristics during their life cycle (often called ‘comparability issues’). Basically, these questions are strongly related to the evaluation process for biosimilars. What makes the difference in the clinical setting? It is clear, that there is an urgent need to further develop Quality by Design principles including defining design spaces as discussed for innovator biologicals, for biosimilars as well (Schiestl et al., 2011; Rathore and Winkle, 2009; Berkowitz et al., 2012).

Parallel to the evolving biosimilarity paradigm for biologicals, a discussion on non-biological complex drugs (NBCD) was started. These therapeutic products are defined as: A Non-Biological Complex Drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that can’t be isolated and fully quantitated, characterized and/or described by physical chemical analytical means. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The difficulties posed by the development of generics of NBCD are illustrated when developing generic versions of liposome products, iron–carbohydrate (‘iron-sugar’) drugs and glatiramoids (Schellekens et al, 2010).

In conclusion, the last decade big strides have been made in the regulatory structure to evaluate biologicals and NBCD. Two elements should be kept in mind while proceeding: 1 the developments should be science based, and 2) it is (already long) time for a sincere effort to globally harmonize these rulings while they are still developing.

Rathore, A.S and Winkle, H. Quality by design for biopharmaceuticals, Nature Biotechnology 27, 26 – 34 (2009)
Schiestl, M., Stangler, T., Torella, C., Čepeljnik, T., Toll H.J. and Grau R., Nature Biotechnology 29, 310-312 (2011)
Berkowitz, S.A., Engen, J.R., Mazzeo, J.R. and Jones, G.B., Analytical tools for characterizing biopharmaceuticals and implications for biosimilars. Nature Reviews Drug Discovery 11, 527-540 (2012).
Schellekens, H., Klinger, E., Mühlebach, S., Brin, J.F., Storm and Crommelin, D.J.A, The therapeutic equivalence of complex drugs. Regulatory Toxicology and Pharamcology 59, 176-183 (2011).