HPE HPE Fresenius Kabi handbook - Page 4

MANUFACTURE Manufacturing biosimilars Manufacturing a biosimilar requires significant expertise to ensure that it is ‘highly similar’ to the reference (originator) biologic with no clinically meaningful differences in safety, efficacy, or immunogenicity Theodor Dingermann PhD Director, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt, Germany The biosimilar must have the same amino acid sequence as the reference drug – no differences between the original and the copy are permissible Whereas generics are always exact copies of a respective reference drug, biosimilars are developed to closely resemble a well-established biopharmaceutical. This is a major difference because it is practically impossible to obtain biosimilars as exact copies of biopharmaceuticals. This is not only due to the much larger molecular weights of these molecules compared with generics but also to the fact that, unlike generic drugs, biopharmaceuticals are always produced from living cells as a result of biochemical processes. A biopharmaceutical is a mixture of molecule variants, which is complex but not arbitrary in its composition. Therefore, copying a biopharmaceutical ultimately requires copying this complex molecular mixture. Basic principles Microheterogeneity An inherent feature of all biological products is that they comprise complex molecular mixtures, the individual components of which have subtle differences to the intact biomolecule. 1 This microheterogeneity results from variants (artefacts) that are present at specific concentrations in all biopharmaceuticals. The principle of inherent microheterogeneity applies to biosimilars as well as to innovator drugs used as a copy template (reference drug); the consequence is that a biosimilar can be similar but never identical to the reference drug. However, the structural deviations of the biosimilar from its corresponding reference drug are by no means arbitrary. They must not be greater than the deviations within different batches of the reference drug. In fact, different batches of the reference products selected as reference drugs are always only similar, but never identical, to each other. Amino acid sequence The biosimilar must have the same amino acid sequence as the reference drug – no differences between the original and the copy are permissible. 2 However, it is possible that individual amino acids are modified by environmental influences including pH, temperature, pressure, etc (for example, oxidised variants of methionine, cysteine, tryptophan, tyrosine and histidine; deamidated variants of asparagine or glutamine; hydrolysed disulfide bridges). Furthermore, details of the glycosylation pattern may differ between the original and the copy as well as between different batches of the original and the copy, respectively. These variations are part of the general microheterogeneity of biopharmaceuticals and thereby also of biosimilars and of reference drugs. 4 | 2019 | hospitalpharmacyeurope.com ‘The product is the process’ This refers to the importance of a rigorously specified production process as a basis for batch-to-batch consistency, which applies to all biopharmaceuticals, including biosimilars. However, this process does not have to be identical to the process used to manufacture the batches of active substances used in the approval studies. Processes can be modified, or even redesigned, providing that the changes are first approved by the European Medicines Agency (EMA). A study carried out in 2016, 3 determined the number of changes in the manufacturing processes of 29 monoclonal antibodies. A total of 404 process modifications were found in the European public assessment reports (EPARs) of the EMA – 50 of which were for the production of the reference drug Remicade ® (inflximab). A total of 32 of these changes were serious interventions, such as a change of cell line for the production of active substances. On average, there were 1.8 changes in the production process per year and per biopharmaceutical. The approval of a process change for an originator biopharmaceutical is granted by the EMA on the basis of data that the pharmaceutical manufacturer must collect and submit to the authority. 4 These data are obtained from ‘bridging studies’. Active substance batches from the original process are compared with active substance batches from the modified process (the comparability exercise). The most important methods used are bioanalytical techniques, because they have high sensitivities in detecting potential differences. 5 Therefore, these methods are of particular importance in the context of a comparability exercise. These analyses are supplemented by preclinical tests and, if necessary from a regulatory point of view, by clinical studies. If a process change is approved, this affects all indications for which the active substance is approved. This also applies if a clinical study considered necessary within the framework of the comparability exercise was carried out in only one (sensitive) indication. This procedure is based on the principle of ‘extrapolation of the indication’, which has been used in biopharmaceuticals for years and has proven itself over time, even when major process changes had to be decided. 6 For example, the subcutaneous administration of the monoclonal HER2 antibody trastuzumab (Herceptin ® ) was also approved for neoadjuvant therapy on the basis of data from patients with metastatic disease. Another important aspect in the evaluation of a biopharmaceutical is its immunogenic potential (for