Issue link: https://www.e-digitaleditions.com/i/1118782
44 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m controls and acceptance parameters. By contrast, the manufacturer of a proposed product will likely have a different manufacturing process (e.g., different cell line, raw materials, equipment, processes, process controls, acceptance criteria) from that of the reference product and no direct knowledge of the manufacturing process for the reference product" (1). Subsequently, the amino-acid sequence is cloned in a suitable producer cell and then the tedious work of selecting such a clone of cells that produce as close as possible the reference product and also in commercially viable quantities (7). Once the cell line has been chosen, the cell culture process followed by the purification process and the for- mulation are developed. The expressed or secreted biosimilar candidate is exhaustively scrutinized for resemblance to the reference product using a variety of sophisticated chemical, physical, and pharmacological techniques (4). Once close resem- blance has been established, a minimum of three clinical batches are produced under GMP-condi- tions suitable for starting the clinical pharmaco- logical testing program. This program starts with a Phase I pharmacokinetic (PK), and whenever possible pharmacodynamic (PD) trial in human volunteers or patients to assess similarity with re- spect to exposure to the different preparations. The reason for this is that for several reference products there are geographically different manufacturing sites, and small differences between EU and US reference products have been observed (such as for etanercept and inf liximab). Once the results from preclinical studies have shown that the biosimilar candidate has completed all requirements for the similarity exercise, it is common practice to perform a Phase III trial in pa- tients. However, this is not a strict requirement for the EU. One of the first approved biosimilars—a biosimilar of a granulocyte colony-stimulating fac- tor from Sandoz (Zarzio, approved in EU in 2008)— was not tested in patients, but only underwent ex- tensive PK/PD trials in human volunteers (8). The conditions for the pivotal biosimilar trial deserve special consideration. The objective for this study is not to prove safety and efficacy but rather demonstrate absence of clinically mean- ingful differences as compared to the reference product. This has important consequences for the choice of patients and indications and the choice of endpoints. The choice has to be based on scientific advice from regulatory agencies to maximize the chance of finding any clinically relevant difference. For TNF-alfa inhibitors, for instance, psoriasis is a sensitive indication with a relatively clear endpoint (with mean PASI change as readout). Alternatively, rheumatoid arthritis is a good disease model, with the ACR-20 the most sensitive indication. And here a second principle of biosimilar development is eminent, that of indication extrapolation. The scientific justification of extrapolation is based on the similar mechanism of action, target/receptor interactions, and molecular signaling; product structure interactions with the target or receptor; PK, expected toxicities; and information based on mechanism of action. All of these factors are examined in the biosimilar application. Any dif- ferences in these factors can be addressed in the context of the totality of the evidence supporting a demonstration of biosimilarity. The principle of extrapolation can result in substantial cost-savings in the development of biosimilars. Once the clinical studies have been completed, the marketing license application is submitted to Biosimilars