Accelerating and Streamlining Downstream Process Development

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This report will discuss how to speed up the development and streamline up and downstream processing. You will see those opportunities at close reach to further increase speed to the clinic and accelerate biologicals purification processes. Besides, you will find answers to the following questions:  Are scaled-up, and budget operations with the predominant downstream processing (DSP) operations fit for a challenging market? Does DSP with state-of-the-art purification methods warrant biotherapeutics regulatory clearance? Does shifting processes from batch to continuous manufacturing pose unnecessary financial risks? Production processes for biopharmaceuticals using protein A chromatography still suffer from platform limitations. How can we overcome those setbacks and the high operation expenses associated?

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Some estimates target the worldwide market of monoclonal antibodies (mAb) with the projected approval rate of four per year, on the order of $125 billion by 2020. Besides, several immunotherapies originated in the 1980’s, and 1990’s are to end their patents in the next few years. That is going to draw capital to the production and commercialization of biosimilars. While the role of biologics in treating human diseases has evolved substantially over the past decade so has the technology to produce and the role of the manufacturing process on the structure and activity of the molecule. The increase in cell culture titer is shifting the production and economic bottleneck from upstream processing (USP) to DSP. To purifying the cell culture harvest from upstream requires higher product titer, larger chromatography columns, membrane areas, buffer consumption, and additional chromatography or filtration cycles required. Although stable, reliable, and reproducible, protein A chromatography is considered a productivity bottleneck and is particularly expensive. New trends in non-chromatographic methodologies for DSP include membrane processes, liquid – liquid phase extraction, magnetic separation, precipitation, and crystallization. Interestingly, there is a potential for implementation of crystallization and precipitation in the purification pipeline of high-value therapeutic molecules. Moreover, current market drivers in the biotech industry require process innovation to increase manufacturing flexibility and decrease the COGs. Among the options to address that need are non-chromatographic techniques, like aqueous two-phase separation, membrane filtration, precipitation or crystallization, to chromatographic non-based in Protein A ligands, such as traditional interaction chromatography or new modalities like multimodal chromatography (MMC).

We are witnessing a reproduction of enabling tools, while analytical scientists have developed sophisticated techniques to decipher attributes critical to quality (ACQ). Also, a scenario which privileges manufacturing flexibility, decreased COGs, process intensification, flexible facilities, with reduced turnaround time and increased automation certainly benefit the innovating biotech industry. Such evolving setup is already enabling the industry to deliver the promise to serve even larger populations and reach the unmet medical needs. Spectroscopy techniques are to provide further insights into the structural basis of protein interactions with multimodal ligands.  Hence, tailoring ligands for the capture and polishing of virtually any therapeutic mAb. At the same time, advances in mapping post-translational modifications (PTMs) using HPLC/LTQ-Orbitrap technology will enable many industrial laboratories to perform quick, high-resolution analysis of PTMs.

Furthermore, an integrated continuous biomanufacturing (ICB) platform offers significant financial advantages due to multiple process intensifications resulting in savings of hundreds of millions of dollars. Finally, the synergetic power of combinatorial methods is showing how hybrid approaches, which consist of a fed-batch USP in combination with a continuously operated DSP, are fitting the production needs. We look forward to the day where anti-infective mAbs could be produced quickly in response to sudden pandemics. It would indeed require development platforms that could adapt more rapidly than the average at present.

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