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

该项目与“机械化和改进先进治疗制造”竞赛的范围相一致。具体而言，该项目将解决AAV基因疗法生产中的挑战，并将使Allergan在英国的200多名员工成为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Allergan产品开发的早期引入新技术，以提高生产的重现性和控制。Allergan在临床前和I期开发中拥有一系列AAV疗法，主要针对全球大量患者人群的眼科适应症。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Allergan满足其商业野心。AAV制造商面临的挑战之一是采用新的分析技术来快速测量关键质量属性，从而实施实时控制策略。合作伙伴将：* 利用联盟独特的分析和测量专业知识来确定AAV生产的关键工艺参数和关键质量属性，使用替代和临床相关AAV产品的多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从上游和下游制造过程中的破坏性在线过程分析技术（PAT）收集的数据联系起来。将使用产品CPP和CQA确定控制策略，以确定在线检测的灵敏度。*将使用多种AAV产品开发下一代PAT、拉曼光谱和多角度动态光散射检测器，以评估产品CQA变异性。PAT将用于证明在Allergan的示例性临床AAV产品的整个生产过程中，完整的端到端在线监测和产品表征的影响。一个最终的原型，概念验证，在线设置将被集成在Allergan的生产过程中，以展示在AAV制造中PAT的破坏性方法。NPL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。NPL还将通过参与病毒载体加工来确定未来重点的新挑战，从而从该项目中受益。支持Allergan研究用于在线AAV生产的新型PAT将使这家总部位于英国的组织能够实施精细的控制策略，以提高重现性、产品质量和生产成本，从而增加患者群体对其新型先进治疗组合的采用。

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.