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

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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.