HPE HPE Fresenius Kabi handbook - Page 5

FIGURE 2 Developing a biosimilar: a stepwise process STEP 1 Comparative quality studies • Analytical: physical + chemical properties • Functional: biological/ pharmacological activity STEP 2 Comparative non- clinical studies • Pharmacodynamic • Toxicology Reference medicine further details of the key concepts in development of biosimilars and regulatory approval processes, please see the dedicated article in this handbook). The manufacturing process Manufacturing a biologic consists of genetically modifying a cell, which becomes the basis for a cell line used for the production of the necessary protein for the drug. The protein is then separated from the cells and purified. 7 Each step of the manufacturing process can modify the product, and the process requires controlling numerous input parameters, each of which can impact the safety and efficacy of the final product. 8 The manufacturing process can be divided into four steps. The aim is not to develop a new molecule with unknown clinical properties, but to copy a molecule that has undergone full clinical evaluation (reference drug) in the best possible way so that all available data on the reference drug can also be used for the biosimilar. Step 1 This involves full bioanalytical examination of the structural characteristics of the reference drug to determine exactly what needs to be copied. For this purpose, the biosimilar manufacturer purchases large quantities of the reference drug on STEP 3 • Pharmacokinetics/ pharmacodynamics • Efficacy and safety + immunogenicity Biosimilar Manufacturing a biosimilar requires significant expertise to ensure that it is ‘highly similar’ to the reference biologic, with no clinically meaningful differences in safety, efficacy and immunogenicity the relevant markets, whereby as many different batches as possible should be represented. Structural characteristics include modifications such as oxidised or deamidated variants of different amino acids, modified N- and C-terminal ends of protein chains, glycosylation characteristics, the proportion of denatured protein, and protein aggregates, among others. This is necessary because these structural variants also have to be copied. Of course, the biosimilar must not be worse than the reference drug, but it must also not be better. Step 2 In the second step, the biosimilar manufacturer must define variation parameters for the reference drug on the basis of the analytical data collected that determines the limits of microheterogeneity. The upper and lower limits for the biosimilar must not exceed or fall below the corresponding limits of the reference drug. Expiration of a patent does not necessarily mean that the manufacturing process of the reference product becomes available to the biosimilar developer (for example, the cell line clone, growth medium used, etc) and full analyses of the reference drug is required for this important step. By contrast, the regulatory authorities know all the details of the reference drug including the microheterogeneity limits. It is therefore not hospitalpharmacyeurope.com | 2019 | 5