Masterarbeit

Between flexibility and standardization: the challenge of the first European Pharmacopoeia individual monograph for monoclonal antibodies. The case study of the monograph 2928 "Infliximab concentrated solution"

Dr. Sara Tognarelli (2021)

Summary
Language: English
Monoclonal antibodies (mAbs) are complex glycoproteins, which are broadly used as potent biotherapeutics since more than 30 years. Despite the experience gained in this time, the manufacturing process for monoclonal antibodies is still very challenging leading to a product that is actually a mixture of variants with slightly different characteristics (e.g. charge and glycosylation variants). Such manufacturing process is also very sensitive to changes, which could easily alter the product composition and possibly impact the safety and the efficacy of the medicinal product. It is therefore challenging, but of utmost importance to maintain batch-to-batch consistency, avoiding drifts, for example in purity and especially potency. On top of that, for many therapeutic monoclonal antibodies, biosimilar medicinal products have been or are being developed. As a matter of fact, the candidate biosimilar has to demonstrate to be highly similar to the originator only at the moment of the marketing authorisation application. Given the above-mentioned sensitivity of mAbs to changes of their manufacturing process, it is conceivable that originators and biosimilars may evolve differently over time, possibly diverging in a significant way. In the interest of the patients, it is however fundamental to avoid any drift. More standardisation and harmonisation between the various batches of the same biotherapeutic, but also between biosimilars and originator would minimise these risks. One way to achieve such standardisation and harmonisation was offered by the European Pharmacopoeia, which decided to establish the first individual monograph for a monoclonal antibody. In 2014 the European Pharmacopoeia started a pilot program with Infliximab, a monoclonal antibody directed against the Tumor Necrosis Factor alpha (TNF-α). In 2019, the first version of the European Pharmacopoeia monograph 2928 “Infliximab concentrated solution” became effective.
This master thesis aims at describing the long (and maybe not even final) path which led to the European Pharmacopoeia monograph 2928 “Infliximab concentrated solution”. Moreover, the measures tried to find a balance between freedom for the manufacturers and binding requirements will be discussed and analysed. Here, the biggest challenge was to warrant enough flexibility for the necessary changes in the manufacturing process, while setting some meaningful specifications to achieve the desired standardisation between batches and/or drugs (i.e., originator and biosimilars). In addition, the reactions to the monograph and its impact on different stakeholders, such as regulators and industry, will be discussed. Finally, suggestions on how to improve and accelerate the process of developing Individual Monographs will be proposed. In addition, I will present my view about the most promising directions to focus on for the future portfolio of the European Pharmacopoeia monographs for biotherapeutics.
In the introduction, background information on the history, organisation and functions of the European Pharmacopoeia and its monographs (with focus on biologics) will be given.
Pages: 54
Annexes: 6, 37 pages