Background Biosimilars are successor drug products to a biologic medicine that is already authorized and whose patent is no longer valid. As with their originator products, biosimilars are expressed using living cells and can therefore comprise a complex mixture of protein variants due to post-translational modifications that may impact the pharmacology and immunogenicity of the drug differently.
Objectives To demonstrate a scientifically-based approach for the characterisation and development of a high-quality biosimilar monoclonal antibody.
Methods The initial steps for the development of a high-quality biosimilar product involve the thorough characterisation of the targeted originator product and continuous monitoring of the originator batches to determine the variability range of the product quality attributes and thus define the “goal posts”, as a basis of allowable product variability. Comparability of the biosimilar to the originator product is built into the development process by a tightly controlled selection of expression cell clones and manufacturing process optimisation, using reiterative assessments and comprehensive, state-of-the-art technologies. The end result is a drug product that is highly comparable in physicochemical and biological properties to the originator biologic. The extensive analytical and biological characterisation data are complemented by confirmatory pre-clinical testing, enabling thus a leaner clinical development path that consists of a comparative single-dose PK and a comparative efficacy study (see “EMA Guidelines”) to establish biosimilarity. The monoclonal antibody rituximab, which is currently in clinical testing in both, the rheumatology and the oncology setting, will be used as an illustrative example of a development paradigm resulting in a highly-comparable biosimilar to the originator product.
Results Using as a reference ADCC, a key mechanism of action of rituximab, we depict how thorough understanding of structure-function relationships and control of post-translational modifications throughout the entire clone selection and manufacturing processes can result in equivalent biological activity of the biosimilar and the originator drug product.
Conclusions In biosimilars development a much greater emphasis is placed on the early technical development of the product as compared with novel biologic therapeutic development. As such, the development of a biosimilar is in the innovative forefront of establishing and defining “Quality by Design” principles as a target-directed approach. In-depth experience and continuous advancement of this approach ensures a biosimilar product that is highly comparable to the originator product and clinically as safe and efficacious.
EMEA/CHMP/BMWP/42832/2005 and EMA/CHMP/BMWP/403543/2010
Disclosure of Interest A. Da Silva Employee of: Sandoz Biopharmaceuticals, R. Grau Employee of: Novartis Pharma, T. Stangler Employee of: Sandoz Biopharmaceuticals, H. Summer Employee of: Sandoz Biopharmaceuticals, I. Meyer Employee of: Sandoz Biopharmaceuticals, A. Rohde Employee of: Sandoz Biopharmaceuticals, A. Papandrikopoulou Employee of: Sandoz Biopharmaceuticals, J. Visser Employee of: Sandoz Biopharmaceuticals