Continuous Chromatography Device to Economically Purify Clinical-grade Antibodies

用于经济地纯化临床级抗体的连续层析设备

• 批准号: 8781175
• 负责人: ROBERT C MIERENDORF
• 金额: $ 71.13万
• 依托单位: SEMBA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781175
• 关键词: Accounting; Achievement; Antibodies; Automation; Beds; Biological Products; Biomanufacturing; Bioreactors; Boat; Buffers; Cell Culture Techniques; Chemicals; Chromatography; Clinical; Clinical Trials; Computer software; Consumption; Cyclic GMP; Development; Devices; Dose; Electronics; Environment; Future; Guidelines; Healthcare Industry; Healthcare Systems; Hour; Housing; Industry; Insurance; Insurance Carriers; Ion Exchange; Legal patent; Liquid substance; Logic; Malignant Neoplasms; Manufacturer Name; Membrane; Methods; Monoclonal Antibodies; Patients; Pharmaceutical Preparations; Phase; Play; Price; Process; Production; Productivity; Proteins; Protocols documentation; Pump; Relative (related person); Research; Sanitation; Simulate; Site; Small Business Innovation Research Grant; Speed; Sterile coverings; Sterility; Strategic Planning; Stream; System; Technology; Test Result; Testing; Therapeutic Monoclonal Antibodies; Voice; base; bioprocess; cancer therapy; cost; cost effective; design; drug development; fluid flow; improved; manufacturing process; meetings; membrane assembly; neoplastic; operation; protein expression; prototype; public health relevance; seal; sensor; software systems

DESCRIPTION (provided by applicant): Monoclonal antibodies (mAbs) have become the leading drug class for cancer treatment, and over 150 anti-neoplastic mAbs are in the biopharmaceutical pipeline. Most mAb therapies must be administered in doses of 4-15 mg/kg, resulting in per patient costs of up to $100,000 per year. The high price of mAb therapy causes a significant financial burden for patients, insurance companies and the health care system. To be- come practical for the health care industry, the cost of developing and producing these drugs must be reduced. Clinical manufacturing expenses directly contribute to the overall drug development costs. Recent developments in protein expression, cell culture, and bioreactor technologies have led to substantial advancements in protein production and mAb titers. The development of downstream purification processes has not kept pace and represents a bottleneck that impedes cost-effective and robust manufacturing. Currently, downstream processing (DSP) accounts for up to 70% of the total mAb production cost. The "industry-standard" Protein A capture (PAC) is the most expensive DSP step, contributing up to 40% of the total cost per gram of product. The current PAC method still uses one large column in a sequential batch process. Continuous SMB (simulated moving bed) chromatography offers significant advantages over standard batch methods, including more efficient use of expensive adsorbent with smaller columns, reduced buffer consumption, and operation under steady-state conditions, allowing more robust process analytics. In the Phase I SBIR project (R43 CA162632-01) we investigated the feasibility of developing a continuous PAC process for the purification of clinical-grade mAbs using our lab-scale Octave(tm) SMB System. We obtained equivalent or better mAb purity when our continuous process was directly compared with the standard batch process. How- ever, the current Octave System is not designed for cGMP compliance or the scale required for clinical manufacture. In Phase II we propose to develop a large-scale continuous chromatography device for economical purification of clinical-grade antibodies, based on the Octave valve design and our Phase I findings. The Phase II device will support flow rates up to 2 L/min and processing of 500 L culture fluid containing 5-10 g/L mAb in 8-20 hours, which matches the future demand for therapeutic mAbs in the range of 200 kg/yr. The Phase II de- vice and optimized PAC process will increase productivity at least 3-fold relative to batch methods, and will feature a single-use flow path to eliminate the need for sanitation and revalidation between campaigns. This Phase II project will develop at least one prototype device that will be placed at a Beta test site. The device will be a customizable plug-and-play chromatography module compatible with future integrated continuous bioprocessing facilities. This project fits with the 2011 FDA strategic plan, which seeks development of improved product manufacturing technologies including continuous processes rather than batch approaches.

描述（由申请人提供）：单克隆抗体 (mAb) 已成为癌症治疗的主要药物类别，超过 150 种抗肿瘤 mAb 正在生物制药管道中。大多数 mAb 疗法必须以 4-15 mg/kg 的剂量给药，导致每位患者每年的费用高达 100,000 美元。单克隆抗体疗法的高昂价格给患者、保险公司和医疗保健系统带来了巨大的经济负担。为了在医疗保健行业中实用化，必须降低这些药物的开发和生产成本。临床制造费用直接影响总体药物开发成本。 蛋白质表达、细胞培养和生物反应器技术的最新发展导致蛋白质生产和单克隆抗体滴度取得了实质性进展。下游纯化工艺的发展并没有跟上步伐，成为阻碍成本效益和稳健制造的瓶颈。目前，下游加工 (DSP) 占 mAb 总生产成本高达 70%。 “行业标准”蛋白 A 捕获 (PAC) 是最昂贵的 DSP 步骤，占每克产品总成本的 40%。当前的 PAC 方法在连续批处理过程中仍然使用一根大柱。 连续 SMB（模拟移动床）色谱法比标准批量方法具有显着优势，包括更有效地使用更小的色谱柱、更有效地使用昂贵的吸附剂、减少缓冲液消耗以及在稳态条件下操作，从而实现更稳健的过程分析。在 I 期 SBIR 项目 (R43 CA162632-01) 中，我们研究了使用我们的实验室规模 Octave(tm) SMB 系统开发连续 PAC 工艺来纯化临床级 mAb 的可行性。当我们的连续工艺与标准批量工艺直接比较时，我们获得了同等或更好的 mAb 纯度。然而，当前的 Octave 系统并非针对 cGMP 合规性或临床生产所需的规模而设计。在第二阶段，我们建议基于 Octave 阀门设计和我们第一阶段的研究结果，开发一种大规模连续层析装置，用于经济地纯化临床级抗体。该二期设备将支持高达 2 L/min 的流速，并在 8-20 小时内处理含有 5-10 g/L mAb 的 500 L 培养液，这符合未来对 200 kg/ 范围内治疗性 mAb 的需求。年。相对于批量方法，第二阶段的设备和优化的 PAC 工艺将提高生产率至少 3 倍，并将采用一次性流程，消除活动之间的卫生和重新验证的需要。 该第二阶段项目将开发至少一个原型设备，并将放置在 Beta 测试站点。该设备将是一个可定制的即插即用色谱模块，与未来集成的连续生物处理设施兼容。该项目符合 2011 年 FDA 战略计划，该计划寻求开发改进的产品制造技术，包括连续工艺而不是批量方法。