Mitigation of quality and compliance risks in radio-pharmaceutical production by implementation of an automated release testing technology.

项目摘要/摘要 背景资料。在2009年最终的PET药物cGMP规则(21 CFR Part 212)中，FDA确定了安全性 聚对苯二甲酸乙二酯药品生产标准和质量要求。随后的检查是在 2012年和2015年揭示了PET药物生产特有的悬而未决的问题。 有问题。由于其固有的较短的半衰期(10-110分钟)，多个PET药物批次通常 每天在多个地点制作。生产中劳动、技能和风险最密集的部分 过程是对每个批次进行放行测试或质量控制(QC)。最常见的PET药物，18F- 氟脱氧葡萄糖(FDG)，在生产完成之前需要评估10个不同的参数。 目前的程序包括18次人工操作、8次视觉评估、6台设备和8等量FDG (图1a)。这种对人工操作、主观性和无法追踪的记录的依赖阻碍了 PET药物制造的进展，限制了每天可生产的PET药物的数量 设施，使工作人员暴露在辐射风险中，并危及产品质量和第212条的遵从性。 解决办法。溯源能力开创了评估所有QC的独特概念(图1b) 通过平板阅读器上的微型平板试剂盒实现单一检测模式的参数。试剂盒 具有可产生与PET示踪剂的每个参数相关的光学信号的试剂和功能 QC。它能够完全客观和可追踪地从单份PET药物中进行释放测试 而无需任何用户交互。实施Tracer-QC应达到以下指标 对于PET药物制造商：(1)(潜在)483‘S减少25%；(2)消除75%的质量 初步审核中发现的风险；(3)QC技术员的辐射剂量减少50%；(4)20%的操作 成本降低；(5)用于QC相关活动的时间减少50%；(6)SOP减少75%。 我们的目标是将Tracer-QC定位为向整个PET药物生产行业提供指标。 这项技术的新颖性和有限的监管风险要求与FDA合作，以推动 监管科学，以实现简化的跟踪-QC实施。具体目标1：使用Tracer-QC 原型，沿着指标量化2个生产设施FDG生产的改进。 具体目标2：以FDA认为适合行业的方式验证优化的Tracer-QC解决方案- 应用广泛。具体目标3：建立能够支持全行业采用的套件生产。 预期结果：(1)提高PET药物的质量和释放试验的效率；(2) PET药物生产知识体系的现代化使其更加稳健、可预测和成本更低- 有效；(3)增强的过程控制和可靠的实时发布；(3)21 CFR第212部分：易用性 放射性制药制造商的合规性(4)简化了对PET药物生产的监督 FDA；(5)科学的质量标准；(6)操作者安全。 图1。(A)目前的PET药物释放试验和(B)示踪剂质量控制。

Project Summary/Abstract Background. In the final 2009 PET drug cGMP rule (21 CFR Part 212) the FDA established safety standards and quality requirements for PET drug manufacturing. The inspections that followed between 2012 and 2015 have revealed unsolved issues unique to PET drug production. Problem. Due to their inherent short half-life (10-110 min) multiple PET drug batches are typically produced at multiple sites on a daily basis. The most labor-, skill- and risk-intensive part of the production process is release testing or quality control (QC) done on each batch. The most common PET drug, 18F- fluorodeoxyglucose (FDG), requires assessment of 10 different parameters before production is completed. Current procedures involve 18 manual operations, 8 visual assessments, 6 devices and 8 aliquots of FDG (Figure 1a). This reliance on manual operation, subjectivity and untraceable records presents a barrier to progress in PET drug manufacturing, limits the number of PET drugs that may be produced per day per facility, exposes the personnel to radiation risks and jeopardizes product quality and Part 212 compliance. Solution. Trace-Ability has pioneered the unique concept (Figure 1b) of assessing all QC parameters with a single mode of detection enabled by a micro-plate-based kit on a plate reader. The kit has reagents and features designed to yield optical signals that correlate with each parameter of PET tracer QC. It enables completely objective and traceable release testing from a single aliquot of the PET drug without any user interaction. Implementation of Tracer-QC is expected to achieve the following metrics for PET Drug manufacturers: (1) 25% reduction in (potential) 483’s; (2) Elimination of 75% of the quality risks identified during initial audit; (3) 50% reduction of QC technician’s radiation dose; (4) 20% operating cost reduction; (5) 50% reduction of time spent on QC-related activities; (6) 75% SOP reduction. The goal is to position Tracer-QC to deliver the metrics to the entire PET drug production industry. The technology’s novelty and limited regulatory exposure call for collaboration with the FDA to advance regulatory science to enable streamlined Tracer-QC implementation. Specific Aim 1: Using Tracer-QC prototypes, quantify along the metrics the improvement in production of FDG at 2 production facilities. Specific Aim 2: Validate optimized Tracer-QC solution in a way the FDA finds appropriate for industry- wide application. Specific Aim 3: Establish kit production that can support industry-wide adoption. Expected outcomes: (1) Improved quality of PET drugs and efficiency of release testing; (2) Modernization of PET drug production body of knowledge making it more robust, predictable and cost- effective; (3) Enhanced process control and reliable real time release; (3) 21 CFR Part 212: Ease of compliance by radiopharmaceutical manufacturers (4) Simplified oversight of PET drug production by the FDA; (5) Science-based quality standard; (6) Operator safety. Figure 1. (a) Current PET drug release testing and (b) Tracer-QC.