Genetic Engineering & Biotechnology News

JUN15 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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20 | JUNE 15, 2018 | Genetic Engineering & Biotechnology News | See Downstream Bottlenecks on page 23 Unlike the hotel and transport industries, the biopharma- ceutical sector has been less receptive to disruptive innova- tion. Partly, this is because making a medicine in a cell is more complex than booking a room or hailing a taxi. However, it also reflects the industry's unwillingness to disrupt processes which, while inefficient, are effective and approved. But disruptive innovation does not necessarily need to in- volve disruption per se. Instead, the willingness to employ novel technologies on which the concept is based can be used to change how a sector addresses problems. Downstream processing operations, specifically the bot- tlenecks they create in the biomanufacturing process, are one area where disruptive innovation is starting to be applied. Sticking Point Downstream bottlenecks are a sticking point for the bio- pharmaceutical industry. The basic problem is that advances in upstream operations—capacity for higher density cell cul- tures and larger titers—have not been matched downstream. "While upstream process development has steadily in- creased biologic productivity with higher protein titers and cell densities, downstream process development improve- ments haven't been able to keep pace with UPSD's improve- ments, creating bottlenecks for manufacturers," says Rich- ard Ding, Ph.D., principal scientist, Downstream Develop- ment at Patheon. This mismatch is compounded because, in contrast with upstream operations, downstream processing has multiple aims, according to Abraham Lenhoff, Ph.D., Department of Chemical and Biomolecular Engineering, University of Dela- ware. "The downstream process is intended to recover a pure product by removing a wide range of impurities, most nota- bly host cell proteins (HCPs), DNA, product variants such as charge variants, and other product-related species such as aggregates. "Any downstream process in biopharmaceutical manu- facturing will include multiple steps, most of which are con- sidered orthogonal so as to work in concert to produce a product of adequate purity," notes Dr. Lenhoff. Removing Host Cell Proteins The ultimate aim of downstream processing operations is to separate the desired protein or monoclonal antibody (mAb) from cellular components, HCPs or other impurities present in the process stream. Removing unwanted proteins is one of the most challenging and time-consuming parts of the process. It is also one of the most important from a prod- uct quality perspective, says Dr. Lenhoff. "Problems have, for example, been reported due to the persistence of proteases that degrade the product, lipases that may degrade formulation components such as polysorbates, and other individual host cell proteins that may be immuno- genic," he adds. Some HCP can be removed using chromatographic tech- niques, others are harder to eliminate. Being able to identify the latter type using assays is important for the development of effective removal strategies. "For host cell proteins, an ELISA usually interrogates a significant number of individual HCPs and provides an over- all measure; the total HCP content is typically less than 10 ppm in the final drug product. "Once such impurities are identified it is usually possible to adjust or adapt the existing downstream process to im- prove clearance; an example is improved wash steps during protein A chromatography," Dr. Lenhoff explains. Protein assays are effective. However, they are time con- suming. This has increased interest in alternatives including proteomic techniques based on the mass spectrometry. "In view of the prevalence of CHO as a host cell line, most of these studies have centred on CHO HCPs, but they can be performed similarly for any cell line for which genomic and or protein sequence data are available" according to Dr. Lenhoff. Flocculation Flocculation can also be used to remove unwanted pro- teins. The technique involves prompting them to come out of solution using a clarifying agent. A key benefit is that it allows downstream technologies to function more effectively, points out Dr. Ding. "Higher cell densities mean more cell debris, DNA, and host cell pro- teins that can foul clarification depth filters. Flocculation and precipitation technologies can reduce filter load and improve filter performance." To address this, Dr. Ding's approach is to "use floccula- tion prior to Protein A loading to remove impurities and then develop a two-column process for mAb or Fc-fusion protein purification." An approach called "right sizing" is often used to Bioprocessing Disruptive innovation does not necessarily need to involve disruption per se. Instead, the willingness to employ novel technologies on which the concept is based can be used to change how a sector like biomanufacturing addresses bottleneck problems. Traimak_Ivan / Getty Images Disrupting Downstream Bottlenecks Gareth John Macdonald Disruptive innovation is the practice of reshaping a market or activity using novel processes and technologies. The idea has been around since the mid-90s, but it only started having a significant impact in the past decade, with companies like Airbnb and Uber being some of the best-known exponents.

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