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One biomanufacturing-related example which we have looked after reading those articles which you bel

One biomanufacturing-related example which we have looked after reading those articles which you believe will be significantly impacted by new advances in biotechnology as it applies to biomanufacturing. This may reflect a difference related to a new capability (representing new possibilities), improved cost, efficiency or safety in future development or commercialization.

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Article in BioProcess International · February 2020




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Wolfgang Minas

Biotech Concepts



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BioProcess International eBooks

BioProcess International eBooks

February 2020

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3 BioProcess International 18(3)e1 February 2020 E-Book

Enabling Technologies and Unit Operations

The Role of Single-Use Technologies

Process Configuration Possibilities

Status Quo in Biopharmaceuticals

The Future of Continuous Bioprocessing

From BPI Archives


About the Authors

Continuous Bioprocessing Promises and Challenges

by Babu Halan and Wolfgang Minas

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B iomanufacturing commonly is executed in batch processes, especially for downstream processing (DSP) operations. Increased fermentation titers, reduced operating scales, and efforts toward improved product quality have driven interest in developing continuous bioprocessing. Within the next 10 years, about half of all drugs under development will be biopharmaceuticals (1), making it worthwhile to develop more efficient processes.

A continuous process is defined as one consisting of integrated (physically connected), continuous unit operations with zero or minimal hold volume between operations (2). Changing to continuous processes reduces the size of traditional unit operations, thus allowing low investment costs for the same “space–time” yield. About 90% of biological products now are produced using batch and fed-batch cultivations (e.g., for upstream processing, USP) and batch-wise DSP operations. The development of platforms for continuous processing is one indication that this technology is reaching maturity (3). Industrial and academic researchers are investigating the potential of continuous systems for manufacturing biopharmaceuticals.

In the past 10 years, space–time yields in USP have provided up to 100-fold improvement. This has been driven by a number of advances such as improved expression systems, genetically engineered cell lines, optimized media, and better bioprocess controls (4). By contrast, only a few advances have been made in DSP. So the focus now has shifted toward improving this stage of biomanufacturing (5). Unlike USP, the cost of DSP increases linearly with feed-stream volume, currently accounting for nearly 80% of total production costs. Biomanufacturers are under pressure to reduce production costs without compromising product quality. So disruptive and game-changing technologies are in high demand in traditionally conservative biopharmaceutical environments (6).

Between 2011 and 2016, the US Food and Drug Administration (FDA) approved several protein therapeutics. Nearly 50% of those were monoclonal antibodies (MAbs), and coagulation factors, and enzymes accounted for 19% and 11%, respectively. Plasma proteins, fusion proteins, growth factors and hormones accounted for the remaining 22% (7). Herein we focus on bioprocesses for different drug products, including MAbs, enzymes, coagulation factors, adeno and lentiviruses, and RNA/DNA-modified products. We highlight current trends, technologies, challenges, and perspectives for continuous bioprocessing and focus on the influence of single-use technologies (SUTs) on continuous bioprocessing.

Enabling Technologies and Unit Operations Fully integrated continuous bioprocessing offers several advantages over traditional batch and fed-batch processing. They include low residence and cycle times; sustained operation with consistent product quality; reduced equipment size; high-volume productivity; streamlined process flow; and minimized waste, energy consumption, and raw material use (2, 8). Such benefits would

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reduce capital expenditure and operating costs. However, continuous bioprocessing requires deep process knowledge and implementation of process analytical technologies (PATs). Biomanufacturers also would need to address batch definition, handling of out-of- specification (OoS) materials, and related regulatory issues. In this section, we describe available unit operations that can be operated in continuous mode.

Cell Culture: Perfusion systems are well established and understood by major biomanufacturers such as Genzyme, Bayer, Janssen, BioMarin, Shire, Merck Serono, Novartis, and Pfizer. Perfusion bioreactors enable harvesting of unstable proteins with minimal degradation. The US Food and Drug Administration (FDA) has approved about 20 biologics produced in perfusion systems (9). Such systems are used up to 4,000-L scales (10) and can be operated continuously for over 60 days. The overall longevity of a process mainly is driven by a molecule’s genetic stability, which requires significant research.

Harvest/Primary Recovery: Although continuous filtration devices (e.g., belt and drum filters) commonly are used in industrial- scale microbial fermentations, they have never been adapted for use in cell cultures. Alternating tangential-flow filtration (e.g., ATF system from Refine Technology, now Repligen Corp.) can be used for cell retention and is currently the most preferred unit operation for initial clarification of cells, especially in perfusion systems. An ATF system can be operated continuously with up to 2,000-L culture volume (11). Other unit operations have been studied and are applied in process industries (e.g., continuous centrifugation, acoustic separation, aqueous two-phase separation, and membrane adsorbers). Adaptation of such technologies might be difficult for a given biological product but could be attractive for future bioprocess developers designing truly continuous operations. Table 1 lists commonly used unit operations in DSP with their availability in single-use units.

A continuous aqueous two-phase extraction (ATPE) process has been adapted for antibody purification from cell-culture supernatant based on polyethylene glycol (PEG)/phosphate extraction and subsequent washing (12). This approach is as an alternative to typical chromatographic processes supporting continuous operation, scalability, and economic feasibility (12). An ATPE unit operation can be integrated as a continuous product capture step in DSP. Although the technology has been well adapted, it is still at an early development stage for biological products. Overcoming some problems (e.g., understanding the partition mechanism) could further this technology toward upscaling (13).

Membrane Adsorbers: Dynamic capacities of chromatographic resins often create a bottleneck in protein purification. To match high bioreactor productivities, chromatographic columns are oversized. Membrane adsorbers can be alternatives to traditional chromatography processes during capture and polishing steps. Surface-functionalized membranes offer high purification

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6 BioProcess International 18(2)e1 February 2020 E-Book

productivity (14). Examples include Sartorius’s Sartobind Q, Pall’s Mustang Q, EMD Millipore/Natrix Technology’s Natrix HD-A, and Natrix HD-Sb membranes. Such adsorbers are validated for contaminant removal in a flow-through mode (negative chromatography) to bind DNA, residual proteins, host-cell proteins (HCPs), endotoxins, viruses, and aggregates. The adsorbers are disposable and come in SUT modules (14, 15).

Continuous Viral Inactivation: Bioprocesses based on mammalian-cell expressions require at least two independent steps for removal of adventitious viruses. These steps can include low-pH treatment, solvent/detergent treatment, and nanofiltration or UV treatment. The selected methods and their sequence depend on drug-product characteristics. All steps must be validated, and treatment parameters such as time, temperature, pressure, flow, and so on need to be controlled.

Traditionally, low-pH viral inactivation has been a batch process. Researchers now have developed a continuous viral inactivation system in a coiled flow inverter (CFI) module. The reactor module enables nearly plug-flow behavior at laminar-flow regimes. This continuous low-pH (pH

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