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www.biopharminternational.com June 2018 BioPharm International eBook 11 the biosimilar to fall outside of the observed analytical-testing ranges for different critical quality attri- butes (CQA) of the reference prod- uct," says Ultee. Improvements introduced into the reference product during the devel- opment of a biobetter ensure that the biobetter will be treated as a new biological entity by the regulatory authorities, adds Sleep. Consequently, longer and generally more extensive clinical trials will be required as the biobetter must follow the new-drug approval pathway. Additionally, large clinical trials may be needed to prove clinical superiority over the reference product or biosimilar versions of the approved drug. "Given that biobetters will be treated as a new biological entity by the regulatory authorities there is an opportunity to change the produc- tion host completely if the product design allows," Sleep comments. Meanwhile, biosimilars are inher- ently targeting smaller markets because they will compete against the established reference product and other biosimilars in the same space. "It can make sound economic sense even for large established bio- pharmaceutical companies to out- source biosimilar development, allowing the biopharmaceutical com- pany to concentrate their efforts on more profitable or innovative prod- ucts, such as biobetters," notes Sleep. OPTIMIZED BIOPROCESSING Advances in bioprocessing continue to occur in incremental steps that can have an impact on all parts of the process. For example, develop- ment of the expression system at the very beginning of the bioprocess can start with the introduction of improved vectors and new host cells. Other examples of fairly recent advancement are the introduction of disposable technology, improved purification methods and resins, and introduction of new filter systems, to name a few, says Nick. "In general, the industry is conservative when it comes to change due to the extensive regulatory requirements associated with process change and the poten- tial for unforeseen consequences." He explains that the quality of a biologic is primarily dependent on the process that makes it, and, therefore, there is often reluctance to introduce radical process change. "Nevertheless, companies are exam- ining new processes most com- monly in relation to production of new products under development, which might include some biobet- ters but not the complex biosimi- lars," Nick adds. For both biosimilars and biobet- ters, advances in manufacturing technology have allowed more effi- cient production, with higher yield- ing cell lines and more streamlined downstream processes, states Ultee. "Furthermore, there have been advances in the understanding of the effects of cell line, culture param- eters, cell-culture media, and feeds on the structure of a typical recom- binant protein expressed by trans- formed host cells. This results in a better controlled process, and in the case of biosimilars, tailoring these aspects of the upstream process to result in a near identical copy of the reference product." Manufacturing processes have also significantly advanced with an increasing use of single-use, dis- posable bioprocessing systems and modular bioprocessing facilities that are being introduced to reduce capi- tal costs, reduce the risks of cross- contamination, reduce cleaning validation, and lower utility costs, according to Sleep. "Cell separation, chromatog- raphy, and diafiltration/ultrafiltra- tion bioprocessing steps have all improved since the development of the reference product incor- porating new base matrices, new ligands, increased ligand density/ specificity, higher flow rates, new column geometries, and new mem- branes all designed to improve recovery, reduce processing time, reduce fouling, and reduce costs," Sleep highlights. Biobetters have the advantage of using the latest innovations in manu- facturing technologies designed to optimize bioprocessing because they are characterized as a new biological entity. As such, biobetters will be sub- ject to the full clinical development assessment for safety, efficacy, and superiority to the reference product, Sleep notes. DIFFERENT CHALLENGES Manufacturing challenges also differ between biosimilars and biobetters. With biosimilars, the initial chal- lenge is to optimize production to generate a protein that is highly sim- ilar to the reference protein while at the same time maximizing yield, according to Nick. This begins with clone selection and culminates in fer- mentation development. "In order to remain competitive, it is also important to develop an efficient and economical process. If adequate similarity cannot be demonstrated to the satisfaction of the regulators, the product cannot be approved as a biosimilar," he says. Demonstrating biosimilarity rep- resents another major challenge because it requires extensive physico- chemical and biological testing of the biosimilar against the reference product. While physico-chemical and biological similarity represents the foundation for establishing biosimi- larity, these data are not sufficient on their own. Thus, clinical data are required to confirm biosimilarity, Nick highlights. The need to make a nearly iden- tical copy of the original reference product presents technical challenges Single-Use Systems Manufacturing