Bioprocessing of High Concentration Protein Solutions: Quality by Digital Design Approach

高浓度蛋白质溶液的生物加工:数字设计方法的质量

基本信息

  • 批准号:
    BB/K011146/1
  • 负责人:
  • 金额:
    $ 80.87万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2013
  • 资助国家:
    英国
  • 起止时间:
    2013 至 无数据
  • 项目状态:
    已结题

项目摘要

There is a need for underpinning research to support industrial development of novel protein therapeutics for more convenient delivery by subcutaneous injection (SC). This is an increasing priority for biopharmaceutical companies such that patients can administer the medicines at home, rather than having to visit hospital for a lengthy infusion. The challenge for bioprocessing research is to dissolve the dose of protein required in a small volume, usually 1 ml, that can be self injected. The protein therefore must be soluble up to 300 mg/ml, and it is desirable that the liquid can be stored at 2-8 C for 2 years or more without precipitation, aggregation or other instability. In addition, the liquid must not be too viscous, otherwise the injection will require too high a pressure or may take too long to administer. There is also a need to prevent damage to the protein during the process of forcing the liquid through a narrow needle, into the tissue under the skin. The proposed research will develop methods for use by industry to screen protein formulations for viscosity and other flow properties, using small quantities of protein. This will enable methods for viscosity reduction to be developed. It is known that similar proteins differ widely (by a factor of two or more) in their viscosity at similar concentrations, and that alterations in co-solvent can reduce the viscosity of a formulation. To achieve this, we propose to apply comprehensive rheological characterisation, RheoChip rheometry, and advanced modelling as a platform, which can be used by industry to select the protein and formulation for development of the final dosage form, at an earlier stage than it is possible today. This should save time and cost in development of many new protein medicines. The research will build on existing methods, which are already well established for rheological characterisation of water soluble polymers and BSA solutions, and adapt and apply them to the bioprocessing and injectability of high concentration protein biopharmaceutical solutions. Comprehensive rheological characterisation of protein solutions has not yet been published. In addition, there is the potential for this new knowledge to be applied in industry to improve the production of biopharmaceutical proteins, as high concentrations may be reached during bioprocessing, e.g. freeze drying, tangential flow filtration (TFF) etc. and there can be difficulties in processing viscous solutions, e.g. nanofiltration for virus removal may be impractical. The deliverables of the project will be the form of instrumentation, rheological characterisation methods more relevant than current viscosity measurement, and computational tools. The project has five work packages (WPs). WP1 and WP2 will focus on development of new enabling technologies. The output of WP1 will be the first high throughput characterisation platform for screening protein formulations under the flow conditions encountered in bioprocessing while requiring minimal sample. WP2 will construct a computational platform for predictive modelling of concentrated protein fluid flows. WP3 and WP4 will critically validate these enabling technologies using both model and industrially relevant protein solutions under the complex flows, including TFF and SC injection. The output will be an integrated approach for design and optimisation of (nonlinear) scale-up protein production, based on high throughput rheological data obtained from Rheo-chip and predictive modelling of protein flows and protein stability during processing. WP5 will correlate the rheological properties and flow behaviour of concentrated protein solutions with the effects of excipients and/or formulation conditions on the conformational stability and self-association in dilute solution. This will help to establish the molecular determinants of high viscosities and flow induced protein aggregation leading to rational design of high throughput screens.
需要进行基础研究以支持新型蛋白质治疗剂的工业开发,以通过皮下注射(SC)更方便地递送。这是生物制药公司越来越优先考虑的问题,这样患者就可以在家里服用药物,而不必去医院进行长时间的输液。生物加工研究的挑战是将所需剂量的蛋白质溶解在可以自我注射的小体积(通常为1 ml)中。因此,蛋白质的可溶性必须高达300 mg/ml,并且希望液体可以在2-8 ℃下储存2年或更长时间而没有沉淀、聚集或其它不稳定性。此外,液体不能太粘,否则注射将需要太高的压力或可能需要太长的时间来给药。还需要防止在迫使液体通过窄针进入皮肤下的组织的过程中对蛋白质的损伤。 拟议中的研究将开发出供工业使用的方法,以筛选蛋白质配方的粘度和其他流动特性,使用少量蛋白质。这将有助于开发降低粘度的方法。已知相似的蛋白质在相似浓度下的粘度相差很大(两倍或更多),并且共溶剂的改变可以降低制剂的粘度。为了实现这一目标,我们建议应用全面的流变学表征,RheoChip流变仪和先进的建模作为平台,该平台可用于工业选择蛋白质和配方,以在比今天更早的阶段开发最终剂型。这将节省许多新蛋白质药物开发的时间和成本。这项研究将建立在现有的方法,这是已经很好地建立了水溶性聚合物和BSA溶液的流变特性,并适应和应用它们的生物处理和高浓度蛋白质生物制药解决方案的注射。蛋白质溶液的全面流变特性尚未发表。此外,这一新知识有可能应用于工业,以改善生物制药蛋白质的生产,因为在生物加工过程中可能达到高浓度,例如冷冻干燥,切向流过滤(TFF)等,并且在处理粘性溶液时可能存在困难,例如用于病毒去除的纳滤可能不切实际。该项目的可交付成果将是仪器的形式、比当前粘度测量更相关的流变表征方法和计算工具。 该项目有五个工作包(WP)。WP 1和WP 2将侧重于开发新的使能技术。WP 1的输出将是第一个高通量表征平台,用于在生物加工中遇到的流动条件下筛选蛋白质制剂,同时需要最少的样品。WP 2将构建一个计算平台,用于浓缩蛋白液流的预测建模。WP 3和WP 4将在复杂的流程(包括TFF和SC注射)下使用模型和工业相关的蛋白质解决方案来严格验证这些使能技术。其结果将是一种用于设计和优化(非线性)放大蛋白质生产的综合方法,该方法基于从Rheo-chip获得的高通量流变数据以及加工过程中蛋白质流动和蛋白质稳定性的预测建模。WP 5将浓缩蛋白质溶液的流变学性质和流动行为与赋形剂和/或制剂条件对稀溶液中构象稳定性和自缔合的影响相关联。这将有助于建立高粘度和流动诱导的蛋白质聚集的分子决定因素,从而导致高通量筛选的合理设计。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Quantitative characterization of high molecular weight polymer solutions in microfluidic hyperbolic contraction flow
  • DOI:
    10.1007/s10404-014-1474-z
  • 发表时间:
    2015-05
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    A. Lanzaro;Zhuo Li;X. Yuan
  • 通讯作者:
    A. Lanzaro;Zhuo Li;X. Yuan
Interface instabilities and chaotic rheological responses in binary polymer mixtures under shear flow
剪切流下二元聚合物混合物的界面不稳定性和混沌流变响应
  • DOI:
    10.1039/c4ra08448a
  • 发表时间:
    2014-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shun Zou;Xuejun Yang;Xue-Feng Yuan;Miao Wang
  • 通讯作者:
    Miao Wang
Thermodynamics of Phase Equilibria in Food Engineering
食品工程中的相平衡热力学
  • DOI:
    10.1016/b978-0-12-811556-5.00011-9
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Curtis R
  • 通讯作者:
    Curtis R
Cluster Percolation Causes Shear Thinning Behavior in Concentrated Solutions of Monoclonal Antibodies
  • DOI:
    10.1021/acs.molpharmaceut.1c00198
  • 发表时间:
    2021-06-14
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Lanzaro, Alfredo;Roche, Aisling;Curtis, Robin
  • 通讯作者:
    Curtis, Robin
A quantitative analysis of spatial extensional rate distribution in nonlinear viscoelastic flows
非线性粘弹性流空间拉伸率分布的定量分析
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Xue-Feng Yuan其他文献

Toward large scale parallel computer simulation of viscoelastic fluid flow
粘弹性流体流动的大规模并行计算机模拟

Xue-Feng Yuan的其他文献

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{{ truncateString('Xue-Feng Yuan', 18)}}的其他基金

Development of an Integrated Platform for Quantitative Analysis of Haemodynamics in Small Blood Vessels
小血管血流动力学定量分析集成平台的开发
  • 批准号:
    G0902318/1
  • 财政年份:
    2010
  • 资助金额:
    $ 80.87万
  • 项目类别:
    Research Grant
Rheology of Complex Fluids in Microscopic Flows: Quantitative Characterisation from Molecular Dynamics to Fluid Flows
微观流动中复杂流体的流变学:从分子动力学到流体流动的定量表征
  • 批准号:
    EP/E032699/1
  • 财政年份:
    2007
  • 资助金额:
    $ 80.87万
  • 项目类别:
    Research Grant

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通过微流控石英谐振器对高浓度蛋白质制剂进行高通量可注射性筛选
  • 批准号:
    10760592
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SBIR Phase I: High-throughput injectability screening of high concentration protein formulations by multiplexed microfluidic quartz resonators
SBIR 第一阶段:通过多重微流控石英谐振器对高浓度蛋白质制剂进行高通量可注射性筛选
  • 批准号:
    2025974
  • 财政年份:
    2020
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通过扩展微流控石英粘度计的剪切速率范围来分析高浓度蛋白质制剂的可注射性
  • 批准号:
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EAGER:T1-iSDA - 为(几乎)无需仪器的蛋白质浓度测量带来类似 NAAT 的灵敏度
  • 批准号:
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SBIR II 期:用于提供高浓度蛋白质治疗药物的新配方
  • 批准号:
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低浓度、小体积光感受器膜蛋白动态结构分析方法的建立
  • 批准号:
    18K14146
  • 财政年份:
    2018
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    $ 80.87万
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    Grant-in-Aid for Early-Career Scientists
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SBIR 第一阶段:用于提供高浓度蛋白质治疗药物的新配方
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