Integration of academic perspective into the scale-up of CHO cell bioprocessing: Manufacturing understanding

将学术观点融入 CHO 细胞生物加工规模化：制造理解

• 批准号: BB/N004000/1
• 负责人: Alan Dickson
• 金额: $ 14.52万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN004000%2F1
• 关键词: Integration; academic; perspective; into; scale

This Flexible Interchange Programme (FLIP) application will bring a senior academic (Prof Alan Dickson) from the University of Manchester into the world of Cobra Biologics, a company that manufactures biopharmaceuticals, protein medicines that have revolutionized the treatment of previously untreatable diseases. In their manufacturing processes, Cobra Biologics develop a process at small scale (cultured cells in small volumes - tea cup size) and scale this up 20,000+ times, to a scale that enables the manufacture of sufficient of the required product for commercial success. There are multiple steps of increasing scale and, although standard processes have been developed, and are followed, the nature of the biopharmaceuticals that are likely to be generated in the coming decade means that there will need to be much greater control of the processes used to increase the scale. With the need for greater control comes a need for greater basic knowledge of the processes (i.e. what works well at small-scale does not necessarily work at large-scale), information that can only be collected in limited amounts under the critical timelines of manufacturing. Whilst manufacture of tomorrows biopharmaceuticals would continue in the absence of the basic knowledge, the efficiency of processes, and the certainty of success, will be enhanced by the ability to apply greater rationality to process design and control. Such protein medicines have great potential and can be life-changing but the cost, and increasingly the economic situation, means that success (for patients and UK plc) requires the sector to work towards greater certainty in rapid manufacture. Whilst the FLIP is written in relation to Prof Dickson and Cobra Biologics, interest in certainty of production is shared across the entire industrial base and the outcome of this work will be communicated and have implications for other manufacturers of biopharmaceuticals..To address these issues, Prof Dickson will work with Cobra Biologics to review historical data on manufacturing scale-up processes for different biopharmaceutical products and processes and define events (in read-outs from the process or the quality of the product) associated with particularly successful or more troublesome examples. From these assessments, experiments will be undertaken to test indicators of process quality in "live" manufacturing processes. The tests will be undertaken at the University of Manchester and Cobra Biologics (with the strengths of each site focused on providing a extensive, comprehensive profiling of the process quality). This technology exchange will give Cobra Biologics access to the expertise of a very strong academic group whilst Prof Dickson will have access to data, and the potential to test indicators of process quality across "real" manufacturing processes, opportunities that would not arise under other circumstances. This is a true exchange of vision across the industrial/academic interface, in which both partners will learn from each other's perspectives, learnings that will be translated to subsequent research projects and commercial activities. Overall, the long-term objective is to generate the means and techniques to ensure that scale-up to manufacturing scale is guided by detailed understanding of the system with benefit in terms of quality and amount of valuable medicines.

这个灵活的交换计划（FLIP）应用程序将把曼彻斯特大学的高级学者（艾伦·迪克森教授）带入眼镜蛇生物制品的世界，眼镜蛇生物制品是一家生产生物制药和蛋白质药物的公司，这些药物彻底改变了以前无法治疗的疾病的治疗方法。在他们的生产过程中，Cobra Biologics开发了一种小规模的工艺（小体积培养细胞-茶杯大小），并将其放大20，000倍以上，达到能够生产足够的商业成功所需产品的规模。增加规模有多个步骤，尽管已经开发了标准流程，并遵循标准流程，但未来十年可能产生的生物制药的性质意味着需要对用于增加规模的流程进行更大的控制。随着需要更好的控制，需要更多的工艺基础知识（即在小规模下有效的不一定在大规模下有效），这些信息只能在制造的关键时间表下收集有限的数量。虽然明天生物制药的生产将在缺乏基本知识的情况下继续进行，但工艺的效率和成功的确定性将通过将更大的合理性应用于工艺设计和控制的能力而得到提高。这些蛋白质药物具有巨大的潜力，可以改变生活，但成本以及越来越多的经济形势意味着成功（对于患者和英国公司）需要该行业在快速制造方面努力提高确定性。虽然FLIP是针对Dickson教授和Cobra Biologics撰写的，但整个工业基础都对生产的确定性感兴趣，这项工作的结果将被传达，并对其他生物制药制造商产生影响。为了解决这些问题，Dickson教授将与Cobra Biologics合作，审查不同生物制药产品和工艺的生产规模扩大过程的历史数据，并定义与特别成功或更麻烦的例子相关的事件（从过程或产品质量中读出）。根据这些评估，将进行实验，以测试“现场”制造过程中的过程质量指标。测试将在曼彻斯特大学和Cobra Biologics进行（每个地点的优势都集中在提供广泛，全面的工艺质量分析）。此次技术交流将使Cobra Biologics获得一个非常强大的学术团体的专业知识，而Dickson教授将获得数据，并有可能在“真实的”制造过程中测试过程质量指标，这是在其他情况下不会出现的机会。这是一个真正的跨工业/学术界的视野交流，合作伙伴将从彼此的角度学习，学习将转化为后续的研究项目和商业活动。总体而言，长期目标是创造手段和技术，以确保在详细了解系统的指导下扩大生产规模，从而在贵重药品的质量和数量方面获益。

项目成果

Metabolic flux analysis during galactose and lactate co-consumption reveals enhanced energy metabolism in continuous CHO cell cultures

• DOI: 10.1016/j.ces.2019.04.049
• 发表时间: 2019-09
• 期刊: Chemical Engineering Science
• 影响因子: 4.7
• 作者: M. Torres;J. Berrios;Yandi Rigual;Y. Latorre;M. Vergara;A. Dickson;C. Altamirano

Cell Culture Engineering: Recombinant Protein Production

细胞培养工程：重组蛋白生产

• 发表时间: 2019
• 作者: Gaffney CE

Process and metabolic engineering perspectives of lactate production in mammalian cell cultures

• DOI: 10.1016/j.coche.2018.10.004
• 发表时间: 2018-12
• 期刊: Current Opinion in Chemical Engineering
• 影响因子: 6.6
• 作者: M. Torres;C. Altamirano;A. Dickson

Overexpression of transcription factor BLIMP1/prdm1 leads to growth inhibition and enhanced secretory capacity in Chinese hamster ovary cells.

转录因子 BLIMP1/prdm1 的过度表达会导致中国仓鼠卵巢细胞的生长抑制和分泌能力增强。

• DOI: 10.1016/j.ymben.2021.07.004
• 发表时间: 2021
• 期刊: Metabolic engineering
• 影响因子: 8.4
• 作者: Torres M

Reprogramming of Chinese hamster ovary cells towards enhanced protein secretion.

中国仓鼠卵巢细胞重编程以增强蛋白质分泌。

• DOI: 10.1016/j.ymben.2021.12.004
• 发表时间: 2022
• 期刊: Metabolic engineering
• 影响因子: 8.4
• 作者: Torres M