A modular and multi-functional purification strategy that enables a common framework for manufacturing scale integrated and continuous biomanufacturing

IF 2.5 3区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Leon P. Pybus, Charles Heise, Tibor Nagy, Carmen Heeran, Terri Dover, John Raven, Junichi Kori, Graeme Burton, Hiroshi Sakuyama, Benjamin Hastings, Michelle Lyons, Shinichi Nakai, Jonathan Haigh
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Abstract

Biopharmaceutical manufacture is transitioning from batch to integrated and continuous biomanufacturing (ICB). The common framework for most ICB, potentially enables a global biomanufacturing ecosystem utilizing modular and multi-function manufacturing equipment. Integrating unit operation hardware and software from multiple suppliers, complex supply chains enabled by multiple customized single-use flow paths, and large volume buffer production/storage make this ICB vision difficult to achieve with commercially available manufacturing equipment. Thus, we developed SymphonX™, a downstream processing skid with advanced buffer management capabilities, a single disposable generic flow path design that provides plug-and-play flexibility across all downstream unit operations and a single interface to reduce operational risk. Designed for multi-product and multi-process cGMP facilities, SymphonX™ can perform stand-alone batch processing or ICB. This study utilized an Apollo™ X CHO-DG44 mAb-expressing cell line in a steady-state perfusion bioreactor, harvesting product continuously with a cell retention device and connected SymphonX™ purification skids. The downstream process used the same chemistry (resins, buffer composition, membrane composition) as our historical batch processing platform, with SymphonX™ in-line conditioning and buffer concentrates. We used surge vessels between unit operations, single-column chromatography (protein A, cation and anion exchange) and two-tank batch virus inactivation. After the first polishing step (cation exchange), we continuously pooled product for 6 days. These 6 day pools were processed in batch-mode from anion exchange to bulk drug substance. This manufacturing scale proof-of-concept ICB produced 0.54 kg/day of drug substance with consistent product quality attributes and demonstrated successful bioburden control for unit-operations undergoing continuous operation.

Abstract Image

模块化和多功能纯化策略,为大规模集成和连续生物制造提供通用框架。
生物制药生产正在从批量生产向集成和连续生物制造(ICB)过渡。大多数集成连续生物制造的通用框架都有可能利用模块化和多功能制造设备实现全球生物制造生态系统。整合来自多个供应商的单元操作硬件和软件、由多个定制的一次性使用流路促成的复杂供应链以及大量缓冲剂的生产/存储,使得这一 ICB 愿景很难通过市面上的制造设备来实现。因此,我们开发了 SymphonX™,这是一种下游处理橇,具有先进的缓冲液管理功能,采用一次性通用流路设计,可在所有下游单元操作中提供即插即用的灵活性,并采用单一界面来降低操作风险。SymphonX™ 专为多产品和多工艺 cGMP 设备而设计,可执行独立的批处理或 ICB。这项研究利用稳态灌流生物反应器中的 Apollo™ X CHO-DG44 mAb 表达细胞系,通过细胞保留装置和连接的 SymphonX™ 纯化撬连续收获产品。下游工艺使用的化学成分(树脂、缓冲液成分、膜成分)与我们以往的批量处理平台相同,并使用 SymphonX™ 在线调节和缓冲液浓缩。我们在单元操作、单柱层析(蛋白质 A、阳离子和阴离子交换)和双槽批量病毒灭活之间使用了增压容器。在第一个抛光步骤(阳离子交换)之后,我们连续 6 天将产品汇集在一起。从阴离子交换到批量药物物质,这 6 天的池都是以批量模式处理的。这种生产规模的概念验证 ICB 每天可生产 0.54 千克药物,产品质量稳定,并成功地控制了连续运行的单元操作的生物负荷。
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来源期刊
Biotechnology Progress
Biotechnology Progress 工程技术-生物工程与应用微生物
CiteScore
6.50
自引率
3.40%
发文量
83
审稿时长
4 months
期刊介绍: Biotechnology Progress , an official, bimonthly publication of the American Institute of Chemical Engineers and its technological community, the Society for Biological Engineering, features peer-reviewed research articles, reviews, and descriptions of emerging techniques for the development and design of new processes, products, and devices for the biotechnology, biopharmaceutical and bioprocess industries. Widespread interest includes application of biological and engineering principles in fields such as applied cellular physiology and metabolic engineering, biocatalysis and bioreactor design, bioseparations and downstream processing, cell culture and tissue engineering, biosensors and process control, bioinformatics and systems biology, biomaterials and artificial organs, stem cell biology and genetics, and plant biology and food science. Manuscripts concerning the design of related processes, products, or devices are also encouraged. Four types of manuscripts are printed in the Journal: Research Papers, Topical or Review Papers, Letters to the Editor, and R & D Notes.
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