(M1330-02-11) Aseptic Spray Drying and Homogenization for the Manufacture of a Sterile Long-Acting Injectable (LAI) Formulation

Purpose: Aseptic manufacturing serves as a critical alternative for the production and stabilization of sterile drug products that cannot tolerate conventional terminal sterilization methods, such as irradiation or final sterile filtration, due to physicochemical instability or formulation constraints. The objective of this study was to develop a sterile long-acting injectable (LAI) suspension formulation through aseptic processing, employing spray drying for particle engineering and high-pressure homogenization for dispersion and size reduction under controlled sterile conditions.

Methods: Spray Drying: Spray drying was conducted using a Yamato Spray Dryer GB-210A, integrated with a custom-designed flexible film isolator and coupled to a Yamato Organic Solvent Recovery Unit GAS410, within an ISO Class 7 cleanroom environment. Prior to spray drying, active pharmaceutical ingredients (APIs) and excipients were dissolved in an appropriate solvent system and sterile filtered through an autoclaved 0.2 µm polytetrafluoroethylene (PTFE) membrane filter. All product-contact components and processing equipment were pre-sterilized to ensure aseptic conditions. The resultant spray-dried powder was aseptically harvested into pre-sterilized bottles. The harvested powder was subjected to analytical tests, including assay, impurity profiling, X-ray powder diffraction (XRPD) for solid-state characterization, residual solvent analysis, sterility testing per USP < 71 >, and bacterial endotoxin testing in accordance with USP < 85 > limits. Particle Size Reduction using Homogenization: Prior to homogenization, all processing equipment and product-contact components were pre-sterilized to maintain aseptic conditions. The spray-dried powder was reconstituted using buffer filtered through an autoclaved 0.2 µm PTFE membrane. Particle size reduction was performed using an Avestin EmulsiFlex-C3 high-pressure homogenizer operated within an ISO Class 5 cleanroom environment. The resulting nanosuspension was aseptically collected and stored in pre-sterilized containers and then vial filled. The final suspension was evaluated for critical quality attributes, including drug assay, association efficiency, impurity profile, uniformity of dosage forms, particle size distribution, pH, osmolality, sterility (USP < 71 >), and bacterial endotoxin levels in accordance with USP < 85 > specifications.

Results: The spray drying process yielded approximately 75% of the intended product mass, indicating efficient material recovery under aseptic conditions. Both the spray-dried powder and the reconstituted suspension met USP < 71 > requirements for sterility and complied with bacterial endotoxin limits as per USP < 85 >. The long-acting injectable (LAI) suspension demonstrated a particle size distribution with a Dv90 ≤ 200 nm, indicating successful nanoscale particle size reduction. All other analytical testing parameters, including assay, impurity levels, pH, osmolality, and association efficiency, were within the established acceptance criteria defined in the product specifications.

Conclusion: Sterile spray-dried powder and long-acting injectable (LAI) suspension product was successfully manufactured through a robust aseptic process involving 0.2 µm sterile filtration prior to spray drying, use of a custom-designed flexible film isolator, and deployment of pre-sterilized product-contact and processing components within an ISO Class 5 cleanroom environment. This study demonstrates that drug products unsuitable for terminal sterilization or final sterile filtration can be effectively produced using strategically designed alternative aseptic manufacturing approaches, ensuring compliance with sterility and quality requirements.

References: Exploring the Use of Aseptic Spray Drying in the Manufacture of Biopharmaceutical Injectables," Pharmaceutical Technology 40 (7) 2016.


Schematic diagram demonstrating the aseptic manufacturing of a sterile LAI suspension