Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039.

Physiologically based pharmacokinetic and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, simulations were performed to assess the impact of in vitro dissolution on the in vivo performance of immediate-release film-coated tablets during development and scaling up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations. Quality control dissolution profiles with tablets were used as GastroPlus™ model inputs to estimate the in vivo dissolution in the gastrointestinal tract and to simulate human exposure. The model was used to evaluate the intraluminal performance of the dosage forms and to predict the absorption rate limits for the 450 mg dose. The predictive model performance was demonstrated for various oral dosage forms (150‒500 mg), including the non-bioequivalent batches in fasted healthy adults. To define the safe space at 450 mg, simulations were performed using theoretical dissolution profiles. A specification of Q = 80% dissolved in 60 min or less for an immediate-release oral solid dosage form reflected the boundaries of the safe space. The dissolution profile of the 450 mg commercial scale batch was within a dissolution region where bioequivalence is anticipated, not near an edge of failure for dissolution, providing additional confidence to the proposed acceptance criteria. Thus, the safe space allowed for a wider than 10% dissolution difference for bioequivalent batches, superseding f2 similarity analyses.

Commercial scale transfer of a twin-screw melt granulation process for high drug load fevipiprant tablets.

OBJECTIVE: This work summarizes select methodology of twin-screw melt granulation (TSMG) and process analytical technology that were used in the successful scaling-up and commercial transfer of high drug load (80.5% w/w) immediate release fevipiprant tablets. SIGNIFICANCE: The unique and compelling learnings from this industry work are (1) insights into Novartis AG's commercial scale transfer using TSMG and (2) rapid, nondestructive NIR methodology as a PAT tool for RTR testing. No prior literature combines these two aspects at the level of detail we present/disclose. METHODS: Scaling up of TSMG was guided by specific energy values obtained for the 27 mm (pilot scale) and 50 mm (commercial scale) twin-screw extruders (TSE). Proven acceptable ranges (PARs) were confirmed by varying the critical process parameters (CPPs) for granulation (screw speed) and tableting (dwell time and crushing strength) at three process levels (upper, target, and lower). An at-line NIR method was developed and validated for real-time release testing (RTRT). RESULTS: The combination of CPPs were selected to have the same effect on critical quality attributes (CQAs), that is, lower (-) and upper (+) process level challenged tablet aspect/appearance and dissolution, respectively. TSMG was performed using a 50 mm extruder at constant feed rate. Compression of the six final blends (∼300 kg) showed no impact of varied granulation and compression process conditions on both CQAs. A near-infrared spectroscopy method was validated to determine content uniformity, assay, identity, and to predict CQAs on uncoated tablets in preparation for a real RTRT of future batches.