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

项目总结/摘要 背景在最终的2009年PET药物cGMP规则（21 CFR第212部分）中，FDA确定了安全性 PET药物生产的标准和质量要求。随后的检查 2012年和2015年揭示了PET药物生产特有的未解决问题。 问题.由于其固有的短半衰期（10-110分钟），通常需要多个PET药物批次。 每天在多个地点生产。生产中劳动力、技能和风险最密集的部分 过程是对每个批次进行放行检测或质量控制（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。 目前的程序涉及18个手动操作，8个视觉评估，6个设备和8个FDG等分试样 （图1a）。这种对人工操作、主观性和不可追溯的记录的依赖， PET药物生产的进展，限制了每天生产的PET药物的数量。 设施，使人员暴露于辐射风险，并危及产品质量和第212部分的合规性。 溶液Trace-Ability开创了评估所有QC的独特概念（图1b） 通过酶标仪上的基于微孔板的试剂盒实现的单一检测模式，可以检测参数。试剂盒 具有设计用于产生与PET示踪剂的每个参数相关的光学信号的试剂和特征 QC。它可以从PET药物的单一等分试样进行完全客观和可追溯的放行测试 而无需任何用户交互。Tracer-QC的实施预计将实现以下指标 对于PET药物制造商：（1）（潜在）483减少25%;（2）消除75%的质量 在初始审核期间识别的风险;（3）QC技术员的辐射剂量减少50%;（4）操作剂量减少20%。 成本降低;（5）花费在QC相关活动上的时间减少50%;（6）SOP减少75%。 我们的目标是定位Tracer-QC，为整个PET药物生产行业提供指标。 该技术的新奇和有限的监管曝光要求与FDA合作，以推进 监管科学，以实现简化的Tracer-QC实施。具体目标1：使用Tracer-QC 原型，量化沿着的指标，在2个生产设施的FDG生产的改善。 具体目标2：以FDA认为适合行业的方式优化Tracer-QC解决方案- 广泛应用。具体目标3：建立能够支持全行业采用的试剂盒生产。 预期结果：（1）提高PET药物的质量和放行检测的效率;（2） PET药物生产知识体系的现代化，使其更强大，可预测和成本- 有效;（3）增强的过程控制和可靠的真实的时间释放;（3）21 CFR第212部分：易于 放射性药物制造商的合规性（4）简化了PET药物生产的监督 FDA;（5）基于科学的质量标准;（6）操作者安全。 图1. (a)当前PET药物放行检测和（B）示踪剂-QC。

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.