Assessing PAT for process monitoring and modification of viral vector manufacture processing

该项目符合“机械化和改进先进治疗制造”竞赛的范围。具体而言，该项目将解决AAV基因疗法制造中的挑战，并将建立Allergan在英国的200名员工，作为AAV行业的关键参与者，提高其治疗产品的竞争力和生产力。该项目将在艾尔建产品开发的早期引入新技术，以提高生产中的可重复性和控制。艾尔建拥有临床前和I期开发的AAV疗法组合，主要针对全球大量患者的眼科适应症。然而，AAV载体的行业标准制造策略缺乏有效扩展的能力，无法让艾尔建实现其商业目标。AAV制造商面临的挑战之一是采用新的分析技术来执行关键质量属性的快速测量，从而实现实时控制策略。合作伙伴将：*利用联盟独特的分析和测量专业知识，确定AAV生产特定的关键工艺参数和关键质量属性，使用替代和临床相关的AAV产品的多位点分析来确定转基因对监测和表征的影响。*将开发经验数据驱动模型，将传统的离线分析与上游和下游制造过程中从破坏性在线过程分析技术（PATs）收集的数据联系起来。*使用产品CPPs和cqa确定控制策略，以确定在线检测的灵敏度。*下一代pat，拉曼光谱和多角度动态光散射探测器，将使用多种AAV产品来评估产品CQA可变性。PATs将用于演示在艾尔建的典型临床AAV产品的整个制造过程中，全程端到端在线监测和产品表征的影响。*最终原型，概念验证，在线设置将集成到艾尔建的生产过程中，以演示AAV制造中PAT的颠覆性方法。国家物理实验室正在为该联盟提供大量的测量专业知识，以帮助开发这些技术，克服挑战和限制，并为未来的考虑提供信息。国家物理实验室也将从这个项目中受益，通过参与病毒载体处理，确定未来关注的新挑战。支持艾尔建研究用于在线AAV生产的新型pat，将使总部位于英国的组织能够实施精细的控制策略，以提高可重复性、产品质量和制造成本，从而使患者群体更多地采用其新颖的先进治疗组合。

This project is aligned with the scope of the "Mechanising and Improving Advanced Therapy Manufacture" competition. Specifically, the project will address challenges in the manufacture of AAV gene therapies and will establish Allergan's UK-based 200-strong workforce as a key player within the AAV industry improving the competitiveness and productivity of their therapeutic products.The project will introduce novel technologies early within Allergan's product development to allow for improved reproducibility and control in manufacture. Allergan has a portfolio of AAV therapies in pre-clinical and Phase I development primarily targeting ophthalmic indications with large, global patient populations. However, industry-standard manufacturing strategies for AAV vectors lack the ability to be efficiently scaled to allow Allergan to meet their commercial ambition. One such challenge facing AAV manufacturers is the incorporation of new analytical technologies to perform rapid measurements of critical quality attributes allowing implementation of a real-time control strategy.The partners will:*Utilise the consortiums unique analytical and measurement expertise to identify critical process parameters and critical quality attributes specific to AAV production, using multi-site analysis of surrogate and clinically-relevant AAV products to determine transgene impact on monitoring and characterisation.*Empirical data-driven models will be developed linking traditional off-line analysis to data collected from disruptive in-line process analytical technologies (PATs) during both upstream and downstream manufacturing processes.*A control strategy will be determined using the product CPPs and CQAs to determine the sensitivity of in-line detection.* Next-generation PATs, Raman spectroscopy and multi-angled dynamic light scattering detectors, will be developed using multiple AAV products to assess product CQA variability. The PATs will be used to demonstrate the impact of full end-to-end in-line monitoring and product characterisation during a full manufacturing process of Allergan's exemplar clinical AAV product.*A final prototype, proof-of-concept, in-line set up will be integrated within Allergan's production process to demonstrate the disruptive approach to PAT in AAV manufacture.NPL are providing substantial measurement expertise to this consortium to aid in the development of these technologies, overcoming challenges and limitations, and informing future considerations. NPL will also benefit from this project through involvement in viral vector processing identifying novel challenges for future focus.Supporting Allergan in the investigation of novel PATs for in-line AAV manufacture will enable the UK-based organisation to implement refined control strategies to improve reproducibility, product quality and manufacturing costs allowing increased adoption of their novel advanced therapy portfolio by the patient population.