BioPharm International - November 2022

BioPharm International - November 2022

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www.biopharminternational.com Manufacturing and Facilities 2022 eBook BioPharm International ® 31 Outsourcing to consider when planning how to accomplish this bioprocessing step. Outsourcing cell-line development activities To develop and maintain cell lines at scale through- out a product's life c ycle, manufacturers need to i nvest i n a sign i f ica nt a mount of expa nsion, i n- cluding increasing facilit y footprint, equipment, instr uments, and personnel hiring and training. Companies must determine whether they have the necessary skills, capacity, and resources to complete cell line development from start to finish or whether they need to outsource some, or all of, the process to save time and costs. As part of this decision, biopharmaceutical develop- ers also need to consider how many molecules they in- tend to have in production and carry out a cost/benefit analysis. For a large manufacturer planning to create a multi-product facility, it may be worthwhile to build in-house capabilities as a long-term investment. On the other hand, virtual, small, and mid-sized compa- nies with one or more molecules in their pipeline may lack the necessary cell-line development expertise and internal resources and choose to outsource these ac- tivities to an experienced vendor. Nonetheless, some large biopharmaceutical companies still choose to out- source cell-line development requirements based on internal capacity and business objectives. Even after cell line development is complete, companies have the option to scale up and accomplish manufacturing with the help of a contract manufacturing organization (CMO) or other third parties. Top priorities when selecting a cell line development partner Success in the biopharmaceutical industry always in- volves achieving a balance between factors, such as speed, cost, technological advancement, and scale. Whether a developer is outsourcing just a few steps or the entire cell-line development process, it is essential to know which factors to weigh most heavily when comparing options for products and services. Scientific expertise. Cell line development is a lengthy and complex multi-step process. To produce high-quality molecules on the most efficient time- lines, the manufacturer or vendor that performs cell line development needs to gather a team with deep and broad scientific bioprocess expertise. Many stages along the path to produce a new production cell line often require subject matter expertise, in- cluding the final transfer step that will bring the cell lines from an external vendor to the intended manu- facturing facilities. Time to clinic is a central concern for all biophar- maceutical developers. To achieve production goals as quickly as possible, scientific operations teams must be intimately familiar with work f lows that are both efficient and error-free. This often means avoiding the use of outdated, cumbersome processes (i.e., limited dilution cloning) and eliminating un- necessary stages, such as pool generation. Eliminat- ing pool generation from the cell-line development workf low allows a much shorter timeline from DNA to research cell bank (RCB) generation, often by four to five weeks. Manufacturers also need an analytical team capa- ble of accurately characterizing the protein product during cell line development stages, particularly at the clone selection stage. Achieving high titers is pointless if the new production cell line produces a deficient molecule incapable of achieving its desired function or mechanism of action. Discovering that the molecule has a sub-par qualit y target product profile (QTPP) after the cell line has been developed is costly and will cause significant delays in getting the molecule to the clinic. To prevent these risks, t he cel l-line development operat ions tea m must measure certain key characteristics of the protein, beginning with functionality, in a biological assay or binding assay (depending on the protein's mecha- nism of action) that determines purity, aggregation potential, product related impurities, and the pro- tein's likely glycosylation profile. The team must be familiar with high-resolution analytical methods using ultra-high-performance liquid chromatog- raphy (UHPLC), liquid chromatography-mass spec- trometr y (LC-MS), capi l lar y electrophoresis, and other methods, all of which should be incorporated into the cell-line development workf low. With this knowledge, teams can select clones that produce a molecule that achieves the desired product quality attributes. Picking the right clones upfront removes the need to optimize the critical quality attributes post-cell line development. Regulatory expertise. Because many biologics are relatively new modalities, regulator y agencies demand rigorous quality control. Deviations from biosafet y standards can put developers at risk of denied regulatory applications or significant delays resulting from directives to generate new data, which can be laborious. Scientific and regulatory expertise often overlap be- cause regulatory requirements inform scientific work- flows. For example, one dimension unique to biophar- maceutical manufacturing is a manufacturer's ability to prove that a protein-based biologic was derived from a single clone. Strategies to demonstrate and assure monoclonality could include isolating single clones and capturing photographic images as the cells di- vides. Tracing the direct path from clone to the final product is essential to cell line development, along with rigorous quality control and risk management.

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