Issue link: https://www.e-digitaleditions.com/i/1450659
32 Pharmaceutical Technology Europe BIO/PHARMA OUTSOURCING INNOVATION eBOOK 2022 P h a r mTe c h . c o m Spray-drying vs. HME Spray drying and hot-melt extrusion (HME) are the two most widely used technologies for CGMP manufacturing of ASDs. In spray drying, the API and excipient are dissolved in a com- mon solvent, which is then evaporated to form ASD particles. In HME, the API is dissolved and dispersed in the molten, poly- meric excipient, which is then cooled to form ASDs. An advan- tage of HME is that it doesn't require the use of solvents and the additional drying step. HME has some constraints, however, particularly for thermally sensitive APIs. "The constraints of the HME process are that both the drug and the matrix must be miscible and compatible at the temperature at which the process takes place. In addition, the components must maintain this miscibility during the cooling stage," says Van Vooren. "Another major limitation of HME is the stability of the drug at the high temperatures at which this process is performed. On the contrary, in the case of spray drying, the evaporation process is instantaneous and therefore suitable for thermosensitive products. In addi- tion, the control of the physical properties of the spray-dried product allows manufacturers to obtain a particle size and morphology suitable not only to meet the dissolution goals, but also to obtain density and f low characteristics that facil- itate the downstream processing." In HME, homogeneity may be more sensitive to process parameters (such as temperature) and equipment parameters, explains Neves. He adds that spray drying is, in general, more suitable for early clinical stages because formulations can be developed and produced with minimal amounts of API. New tools, however, may be able to address the challenge of API volume at early stages. "There is currently a significant focus on creating advanced development tools for both spray drying and HME that allow for fast, de-risked development of ASDs using minimal quantities of API," says Chin. "When the API is compatible with both the thermal and shear stresses of extrusion, HME offers a robust manufacturing process without the use of large volumes of solvents." Selecting HME or spray drying can depend on many factors, including the stage of drug development programme, time, and cost, Chin concludes. Both HME and spray drying can be used in continuous solid dosage processing. "Spray drying is a continuous manufacturing (CM) technol- ogy," says Neves. "It offers a remarkable control over the proper- ties of the manufactured powders, with significant downstream advantages. With adequate process development, spray drying can enable ASD formulations that are directly compressible, thus bypassing the need for granulation prior to tabletting. When accomplished, this will enable much simpler CM equip- ment trains and processes, benefiting overall operational effi- ciency, speed, and conformity." Development and scale-up Scaling up from development to commercial-scale spray drying present challenges related to the spray-dried bulk powder properties. "Changes in process conditions, due to the different config- uration and dimensions of the spray dryer from development to commercial scale, have a major impact on the critical qual- ity attributes of the spray dried powder, especially on the par- ticle size, its distribution, and residual solvent content," says Chin. "To understand the impact of these process changes, thermodynamic and kinetic modelling techniques, supported by engineering modifications as well as exploratory labora- tory work, have emerged to support a rapid and successful scale-up of spray drying processes." The downstream processing method should be considered in scale-up, says Neves. For example, directly compressible powders for tabletting may require specific combinations of particle size and bulk density. Inhalation delivery would require different cri- teria, such as composite powders of small particle size, controlled within narrow ranges, explain Neves. He notes that streamlined scale-up relies on a thorough process understanding, which can be aided with advanced formulation and process modelling tools. Formulation of ASDs involves screening APIs, excipients, and other ingredients to determine the optimal combination. The Hovione Intelligent PROprietary Screening methodology for ASDs (ASD-HIPROS) was launched in January 2021 and is offered from the company's Lisbon, Portugal, R&D center (1). "The service aims at developing ASDs formulations with maximum stability and performance by eliminating inviable candidates, thus saving the time and investment needed to bring the drug to the patient," says Neves. He explains that this proprietary process can assess up to 24 formulation prototypes in six weeks, requiring as little as five grams of API. "The three process steps are: in-silico computational screen- ing based on the API properties (to determine most suited polymers, surfactants, and drug loads), spray drying experi- mental prototyping of the most promising formulations, and analytical testing and solid-state characterization (to confirm proper dissolution in bio-relevant media as well as stability under stress conditions)," says Neves. Van Vooren adds that in scale-up, the large number of process parameters and product characteristics add to the complexity of the spray drying process. He explains that defining a design space where the process is controlled is key. "Approaches such as quality by design, which employs tools such as design of experiments, allow us to identify from early stages the risks related to the formulation and manufacturing process that can potentially impact prod- uct quality and, consequently, to be able to guide studies to mitigate such risks," says Van Vooren. Van Vooren adds that differences between laboratory and in- dustrial-scale equipment can cause variations in evaporation rate, particle trajectory, residence time, and other factors. "It is highly recommended to also consider the finished dosage form manufacturing requirements and technologies, since integrating the spray drying process and the finished dosage manufacturing in a single facility reduces risks and timelines, and simplifies the supply chain for the product," concludes Van Vooren. Manufacturing