(T1430-09-58) Compaction Simulation of SDI-Based Formulations to Enable Material-, Time-, and Cost-Sparing Technical Transfer

Purpose: Tablets containing spray dried intermediates (SDIs) for bioavailability enhancement are not a common dosage form manufactured in industry. However, SDI-containing formulations can be challenging to manufacture successfully “right first time” on a rotary tablet press due to the unique physicochemical properties of each SDI. Therefore, successful clinical manufacturing of SDI tablets has traditionally relied on conducting a ‘demonstration batch’ prior to clinical manufacturing to set processing parameters and avoid risks such as deviations and low yields. To reduce the time, resource, and material constraints, we have evaluated the Styl’One Evo compaction simulator as a time- and material-sparing alternative to a demonstration batch. Data evaluated includes spray dried intermediates-, crystalline-, and placebo-based formulations manufactured on an XL100, XM12, Fe1200, or Fe55 but focuses on those which contained SDIs and were manufactured on an XL100.By performing matching studies on the compaction simulator during demonstration batches and collecting data during GMP batches a comparison of the two methodologies was evaluated. This body of work evaluates the merit of incorporating a compaction simulator in the drug product development-technical transfer interface at a contract drug manufacturing organization, with a specific focus on drug products containing spray dried intermediates (SDIs).

Methods: Solid dosage formulations manufactured on at-scale tablet presses (development and/or clinical machines) during a one year period at were additionally evaluated on the Medelpharm Styl’One Evo compaction simulator. Data on blend characteristics, critical compression parameters, tablet properties, and performance were collected at both scales and compared.

Results: Of the four rotary tablet presses evaluated to date, the XL100 was the only individual press with sufficient data to evaluate as a stand-alone. Figure 1 visualizes the values for standard critical compression parameters including dosing depth (mm), main compression edge thickness (mm), pre-compression force (kN), main compression force (kN), and ejection force (N) values. The most important critical compression parameters (dosing depth, edge thickness, and main compression force) demonstrated great similarity to the GMP manufacture with the average values being within ± 3% of the value in the GMP setting. Although ejection forces (55%) and pre-compression forces (29%) were higher on the compaction simulator, these are considered less impactful. Ejection forces are higher on the compaction simulator and thus overestimate, rather than underestimate risks associated with table ejection. As for pre-compression forces, standard is to target a range of main compression force rather than a specific value, which leads to inherently variable values between both compaction simulator and demonstration batch to GMP manufacture. Furthermore, on the XL100, pre-compression force is set by an eccentric which makes tuning pre-compression force to the exact value difficult. Also visualized are critical tablet properties including average tablet weight (mg), thickness (mm), hardness/breaking force (kp), and solid fraction. All values for the compaction simulator were within ± 5% of the value in a GMP setting.

Conclusion: This data demonstrates the value of using a compaction simulator on spray dried intermediate-based formulations for material sparing technical transfer. Using this data, two GMP batches were successfully manufactured using a paper technical transfer from the compaction simulator without a traditional demonstration batch.

Acknowledgements: Thank you to Brent A. Uhrig for the help shaping and supporting the idea behind this body of work.

Data analyzed in this work broken into categories based on the rotary press employed.

Change in critical process parameters (top) and tablet properties (bottom) moving from compaction simulation or a demonstration batch to a gmp manufacture