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）已成为癌症治疗的领先药物，并且在生物药物管道中有150多个抗抑制性mab。大多数MAB疗法必须以4-15 mg/kg的剂量服用，每年的患者费用高达100,000美元。 MAB治疗的高价给患者，保险公司和医疗保健系统带来了巨大的财务负担。为了实现医疗保健行业的实用性，必须减少开发和生产这些药物的成本。临床制造费用直接有助于整体药物开发成本。 蛋白质表达，细胞培养和生物反应器技术的最新发展导致了蛋白质产生和mAb滴度的显着进步。下游纯化工艺的发展尚未保持步伐，代表了阻碍成本效益和健壮制造的瓶颈。目前，下游处理（DSP）占MAB总生产成本的70％。 “行业标准”蛋白A A Capture（PAC）是最昂贵的DSP步骤，占产品总成本的40％。当前的PAC方法仍在顺序批处理过程中使用一个大列。 连续的SMB（模拟移动床）色谱法比标准批处理方法具有显着优势，包括更有效地利用较小的列的昂贵的吸附剂，减少的缓冲区消耗以及在稳态条件下运行，从而可以更强大的过程分析。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八度（TM）SMB系统开发连续PAC过程以纯化临床级单元单元的可行性。直接将连续过程与标准批处理过程进行比较时，我们获得了等效或更好的mAb纯度。但是，当前的八度系统不是为CGMP合规性或临床制造所需的规模而设计的。在第二阶段，我们建议开发一种基于八度阀设计和我们的发现的大规模连续色谱装置，以经济纯化临床级抗体。 II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培养基，这与200千克/年范围内的治疗MAB的未来需求相匹配。第二阶段的措施和优化的PAC过程将相对于批处理方法提高生产率至少3倍，并具有一次性的流动路径，以消除运动之间对卫生和重新验证的需求。 该阶段II项目将至少开发一个将放置在Beta测试网站上的原型设备。该设备将是可自定义的插件色谱模块，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，包括连续过程而不是批处理方法。