(T1530-11-74) Optimizing the HME Process for Precise Manufacturing of Subcutaneous Drug Delivery Implants: Key Considerations for Quality and Efficiency

Purpose: Subcutaneous implants have emerged as a novel drug delivery system, usually in the form of cylindrical rods made from a polymer matrix that incorporates the active pharmaceutical ingredient (API) for sustained release. Subcutaneous implants enable site-specific, controlled release of the API, allowing for treatment durations of weeks to years. Moreover, they offer higher patient compliance compared to oral drug delivery systems. The applications of subcutaneous injectable implants span a broad range, from contraception to various chronic disease treatments. These implants are manufactured using hot melt extrusion or co-extrusion techniques. Over the past decade hot melt extrusion (HME) has rapidly gained importance in the pharmaceutical industry due to its unique advantages over traditional manufacturing methods [1]. These include a solvent-free and dust-free process, fewer processing steps, reproducibility with almost no batch-to-batch variation, and the ability to facilitate continuous manufacturing. To ensure excellent content uniformity and geometrical tolerances, the technology of automated implant manufacturing using HME is discussed in this study, with a focus on the most critical process steps.

Methods: This study's findings are derived from multiple trials conducted using commonly used biodegradable polymers such as polylactic-co-glycolic acid (PLGA), in which the API is uniformly incorporated into the melted polymer during the HME process. The HME process comprises several steps, including powder feeding, plastification and compounding, extrusion and shaping, precise diameter measurement, diameter control loop to conveying mechanism, precise cutting, and quality sorting. The Thermo Scientific^TM Pharma Mini Implant Line includes all the aforementioned process steps (see Figure 1). The Thermo Scientific^TM Pharma mini HME conical twin-screw extruder is utilized in co-rotation mode. The implants produced are evaluated via SEM imaging with the Thermo Scientific^TM Phenom XL G2 Desktop SEM. This study provides a summary of the most crucial process points for each step of the manufacturing process. Rheology is a powerful tool to get an insight about the flow properties of polymer melts. Besides this, rheometers equipped with solid sample clamps can be used to determine the glass transition of polymers utilizing dynamic mechanical thermal analysis (DMTA). DMTA is known to be much more sensitive towards detecting glass transition temperatures compared to other techniques like differential scanning calorimetry (DSC). Hence, a Thermo Scientific^TM HAAKE MARS iQ Air rheometer is used to quantify the thermo-mechanical properties of the polymers used in this study.

Results: Powder blend (API and excipients) is continuously fed into the extruder. Accurate feeding ensures tight dimensional tolerances of the implants. Homogeneous and stable blend with good flow characteristics is crucial. Preprocessing using continuous melt granulation improves flowability. Various feeders available for constant material flow, with gravimetric twin-screw feeder being optimal above 20 g/h feed rate. Polymer is melted and compounded homogeneously with all ingredients using the twin-screw extruder. Crucial process parameters include barrel and die temperature, screw speed, and throughput. Maximum throughput is limited by extruded material line speed. Throughputs into the Pharma mini HME typically range between 2 and 100 g/h, screw speeds between 10 and 360 1/min, and temperatures up to 280°C. Keep screw speed and temperature as high as necessary for processing, but as low as possible to avoid degradation of the API and generation of impurities. The material is extruded through a die with defined diameter to shape the implant accurately. The die size and temperature have a big impact on the product quality. The die temperature influences the final shape of the cut as seen on SEM pictures of ophthalmic PLGA-based implants (Figure 2). This is due to the cool down of the extrudate. Cool extrudates tend to break instead of being cut properly. The diameter is measured by a 2-axis laser gauge to check diameter and ovality. The pulling wheel speed is adjusted based on that value, resulting in a correction of the strand diameter. Strand temperature is controlled for constant conveying and accurate cutting. DMTA measurements were done in a temperature range from 30°C to 200°C with a heating rate of 2 K/min to obtain the thermo-mechanical properties of the extrudates.

Conclusion: Injectable implants offer a promising parenteral drug delivery system for the safe administration of highly potent drugs. Hot melt extrusion is a reliable technology for continuous manufacturing of implants with minimal tolerances and excellent content uniformity. The stable manufacturing process relies heavily on consistent feeding of the materials. Compounding of the ingredients and strand shaping are achieved in a single processing step utilizing the twin-screw extruder. All unit operations, from powder feeding to sorting, are seamlessly integrated into the Pharma Mini Implant Line. By applying the DMTA technique, the thermo-mechanical properties of the excipient-API extrudates can be determined. This knowledge is crucial for investigating the miscibility of the used blend, among other things.

References: [1] Almeida, A.; Clayes, B.; Remon, J.P.; Vervaet, C. in Hot-melt extrusion, ed. D. Douroumis, Wiley, 2012, 43-69.

Thermo ScientificTM Pharma Mini Implant Line for production of injectible implants .

SEM images of the implant edge after continuous cutting extruded at 135°C (left) and 145°C (right).

Thermo ScientificTM HAAKE MARS iQ Air rheometer used to quantify the thermo-mechanical properties of the polymers.