Enabling rapid liquid and freeze-dried formulation design for the manufacture and delivery of novel biopharmaceuticals

实现快速液体和冻干配方设计，用于新型生物制药的制造和交付

• 批准号: EP/N025105/1
• 负责人: Paul Dalby
• 金额: $ 193.62万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FN025105%2F1
• 关键词: Enabling; rapid; liquid; freeze; dried

Biopharmaceuticals have been approved to treat diseases including cancers, rheumatoid arthritis, multiple sclerosis, diabetes, leukemia and neutropenia. The next-generation of protein-based therapies, or biopharmaceuticals, are of increasingly complex engineered forms, with unpredictable solution properties. Proteins are formulated at high concentrations for clinical use, leading often to undesirable aggregate formation, high viscosity, opalescence, or phase separation, rendering them unsafe, or difficult to inject or manufacture. This is a major challenge to the biopharmaceuticals industry as approximately 50% of proteins in clinical trials have been freeze-dried as they were not readily liquid-formulated on timescales of months required during development. Formulation is an empirical process using combinatorial screens that aim to optimise stability, potency and ease of delivery to patients. Engagement with 36 industry leaders at a UCL EPSRC Centre for Innovative Manufacturing workshop identified the most significant protein formulation challenges such as the prediction of shelf stability over a two year period, at a time in development when not much material is available. Current surrogate techniques that accelerate protein degradation and minimize sample consumption provide poor indicators of 2-year shelf-life. Industry would benefit significantly from i) rapid analyses that more accurately determine long-term shelf-life, ii) low concentration analyses that indicate high-concentration solution behaviour, and iii) a better ability to use calculated protein and excipient properties to predict those formulations that are most likely to meet the required attributes.State-of-the-art automated microplate and microfluidic analytics, purchased or established recently via EPSRC and BBSRC/BRIC awards at UCL and UoM provide a timely platform for generating large experimental datasets of aggregation kinetics spanning many different timescales, conformational and colloidal stabilities, rheological properties, phase-transition and glass transition temperatures, for liquid and freeze-dried formulations. A recent EPSRC funded £500k pilot-scale freeze-drying facility at UCL (EP/M028100/1), combined with DoE and 3D process simulations, will generate freeze-drying process models that elucidate the mechanisms linking critical process parameters to critical quality attributes for new formulations. Novel dipeptides emerging from recent UoM work will significantly expand the range of industry-accepted formulation excipients available. Novel microfluidic analytics will be tailored for formulation needs, bringing earlier, more sensitive, and lower-volume assessments of formulated protein heterogeneity and storage kinetics, ultimately in a high-throughput format using sealed microwells.All data will populate a web-access database at UoM to provide modeling groups access to a much-needed experimental dataset. Informatics techniques initiated at UoM in a BioProNet PoC award will enable new proteins to be compared (via properties calculated from sequence and structure) to those in the database, and use their experimentally determined formulation behaviours in a predictive manner. Correlations between calculated protein properties and critical formulation attributes will identify the molecular basis of excipient behaviour. Overall, this will benefit the biopharmaceutical formulation community with an ability to: a) identify better excipient combinations for input into formulation screens; b) predict those protein candidates most readily formulatable with current excipients and solution conditions; c) inform the rational design of novel peptide-based excipients through defined chemical modifications, d) predict long-term storage stability and concentrated solution behaviour from accessible experiments using minimal sample.

生物药物已被批准用于治疗癌症、类风湿性关节炎、多发性硬化症、糖尿病、白血病和中性粒细胞减少症等疾病。下一代基于蛋白质的疗法或生物制药具有越来越复杂的工程形式，具有不可预测的溶液性质。蛋白质以高浓度配制用于临床使用，通常导致不期望的聚集体形成、高粘度、乳光或相分离，使得它们不安全或难以注射或制造。这对生物制药行业来说是一个重大挑战，因为临床试验中约50%的蛋白质都是冻干的，因为它们在开发过程中所需的数月时间尺度上不容易液体配制。制剂是一种使用组合筛选的经验过程，旨在优化稳定性，效力和易于向患者递送。在UCL EPSRC创新制造中心研讨会上，与36位行业领导者的合作确定了最重要的蛋白质配方挑战，例如在开发过程中没有太多材料可用的情况下预测两年的货架稳定性。加速蛋白质降解和最小化样品消耗的当前替代技术提供了2年有效期的不良指标。工业界将从以下方面受益匪浅：i）更准确地确定长期保质期的快速分析，ii）指示高浓度溶液行为的低浓度分析，以及iii）更好地使用计算的蛋白质和赋形剂特性来预测最有可能满足所需属性的制剂的能力。最近通过EPSRC和BBSRC/BRIC奖项在UCL和UoM购买或建立的ESPRICTM提供了一个及时的平台，用于生成跨越许多不同时间尺度的聚集动力学、构象和胶体稳定性、流变学性质、相变和玻璃化转变温度的大型实验数据集，用于液体和冻干制剂。最近EPSRC资助的50万英镑中试规模的冷冻干燥设施在UCL（EP/M028100/1），结合能源部和3D工艺模拟，将产生冷冻干燥工艺模型，阐明关键工艺参数与新配方关键质量属性之间的联系机制。从最近的UoM工作中出现的新型二肽将显着扩大行业公认的可用制剂辅料的范围。新的微流体分析将根据配方需求量身定制，带来更早，更灵敏，更低容量的配制蛋白质异质性和储存动力学评估，最终采用密封微孔的高通量格式。所有数据将填充UoM的网络访问数据库，为建模组提供急需的实验数据集。信息学技术在UoM发起的BioProNet奖将使新的蛋白质进行比较（通过从序列和结构计算的属性），以数据库中的那些，并使用其实验确定的配方行为在预测的方式。计算的蛋白质性质和关键制剂属性之间的相关性将确定辅料行为的分子基础。总的来说，这将使生物制药制剂界受益，具有以下能力：a）鉴定用于输入制剂筛选的更好的赋形剂组合; B）预测那些最容易用当前赋形剂和溶液条件配制的蛋白质候选物; c）通过定义的化学修饰告知新的基于肽的赋形剂的合理设计，d）使用最少的样品从可获得的实验预测长期储存稳定性和浓缩溶液行为。

项目成果

Energy-entropy prediction of octanol-water logP of SAMPL7 N-acyl sulfonamide bioisosters.

• DOI: 10.1007/s10822-021-00401-w
• 发表时间: 2021-07
• 期刊: Journal of computer-aided molecular design
• 影响因子: 3.5
• 作者: Falcioni F;Kalayan J;Henchman RH
• 通讯作者: Henchman RH

Elucidation of an Expanded Aggregation-Prone Conformation of Fab Using Saxs, Md Simulations and Smfret

使用 Saxs、Md 模拟和 Smfret 阐明 Fab 的扩展易聚集构象

• 发表时间: 2018
• 期刊: PROTEIN SCIENCE
• 影响因子: 8
• 作者: Codina Nuria

Energy-entropy method using multiscale cell correlation to calculate binding free energies in the SAMPL8 host-guest challenge.

• DOI: 10.1007/s10822-021-00406-5
• 发表时间: 2021-08
• 期刊: Journal of computer-aided molecular design
• 影响因子: 3.5
• 作者: Ali HS;Chakravorty A;Kalayan J;de Visser SP;Henchman RH
• 通讯作者: Henchman RH

The Attraction of Water for Itself at Hydrophobic Quartz Interfaces.

• DOI: 10.1021/acs.jpcb.0c04545
• 发表时间: 2020-06
• 期刊: The journal of physical chemistry. B
• 作者: Q. Besford;A. Christofferson;Jas Kalayan;J. Sommer;Richard H. Henchman

Proof-of-concept analytical instrument for label-free optical deconvolution of protein species in a mixture.

用于混合物中蛋白质种类的无标记光学解卷积的概念验证分析仪器。

• DOI: 10.1016/j.chroma.2021.461968
• 发表时间: 2021
• 期刊: Journal of chromatography. A
• 作者: Hales JE