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CDMOs offer expertise and capacity for spray drying.
Amorphous solid dispersions (ASDs) are increasingly used to address the need to enhance bioavailability of poorly soluble APIs. Contract development and manufacturing organizations (CDMOs) that have amassed knowledge and experience in this specialty area play a key role in the pharmaceutical industry by providing the capabilities of developing and manufacturing ASDs.
“The pipeline of poorly-soluble drugs continues to grow, and ASDs remain the best-in-class platform to address poorly-soluble drugs,” says Filipe Neves, strategic business senior director at Hovione. He says that spray drying has been proven as a technology for the current good manufacturing practice (CGMP) manufacture of ASDs and that pharmaceutical companies have gained confidence in the technology and its reliability. Spray drying is becoming widely accepted and is seeing a year-on-year increase in adoption, reports Neves.
“Today’s APIs are increasingly insoluble, and that can pose serious problems for formulators looking to manage the bioavailability of their formulations,” says Lieven Van Vooren, scientific director, Ardena, a Belgian-headquartered CDMO that acquired Spain-based Idifarma and its spray-drying capabilities in Sept. 2021.
“The formulation of an ASD is increasingly being recognized as one of the more reliable and efficient strategies for optimizing the solubility and dissolution characteristics of low aqueous solubility compounds,” Van Vooren explains.
“The increased development of biologic-based drugs has also fueled demand for spray drying as an alternative for the manufacturing and processing of biologics, instead of the more traditional liquid or lyophilized solid forms,” addsWilliam Wei Lim Chin, manager, global scientific affairs, Catalent. He says that additional growth in spray drying comes from the increased consideration of spray-dried intermediate powders for both local and systemic inhalation delivery of biologics.
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 common solvent, which is then evaporated to form ASD particles. In HME, the API is dissolved and dispersed in the molten, polymeric excipient, which is then cooled to form ASDs. An advantage 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 addition, 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 flow characteristics that facilitate 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 program, 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) technology,” says Neves. “It offers a remarkable control over the properties 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 tableting. When accomplished, this will enable much simpler CM equipment trains and processes, benefiting overall operational efficiency, speed, and conformity.”
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 configuration and dimensions of the spray dryer from development to commercial scale, have a major impact on the critical quality attributes of the spray dried powder, especially on the particle size, its distribution, and residual solvent content,” says Chin. “To understand the impact of these process changes, thermodynamic and kinetic modeling techniques, supported by engineering modifications as well as exploratory laboratory 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 tableting may require specific combinations of particle size and bulk density. Inhalation delivery would require different criteria, 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 modeling 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 screening based on the API properties (to determine most suited polymers, surfactants, and drug loads), spray drying experimental 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 product quality and, consequently, to be able to guide studies to mitigate such risks,” says Van Vooren.
Van Vooren adds that differences between laboratory and industrial-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.
CDMOs have been adding capacity for both development and commercial scales to meet the expected demand for spray drying.
In November 2021, Hovione announced that the company would add commercial spray-drying capacity and equipment as part of its expansion at its facilities in the United States, Ireland, and Portugal (2). At the US facility in NJ, the company is constructing a new building and will have additional commercial spray drying capacity online by 2023. New commercial spray dryers are also slated for the Cork, Ireland and Lisbon, Portugal facilities.
Catalent acquired the manufacturing and packaging operations of Acorda Therapeutics, Inc. in January 2021, including a 90,000-ft2 CGMP facility in Chelsea, Mass. with spray drying capacity that provides Catalent with significant commercial-scale capacity for new customer programs. Catalent said that the Chelsea facility will act as a global center of excellence within the Catalent network for spray-dried dispersion and dry powder encapsulation and packaging (3).
Catalent also announced a manufacturing collaboration with clinical-stage pharmaceutical company DisperSol Technologies in August 2021 (4). DisperSol’s clinical products are made using its proprietary KinetiSol ASD platform. As part of the collaboration, DisperSol transferred its technology by setting up its proprietary equipment in a dedicated suite in Catalent’s Somerset, NJ facility. Catalent is providing staff for development, scale-up, and commercial-stage KinetiSol production.
Spray drying is suited to ASDs but is also finding use in other fields, such as microencapsulation, nanotechnology, and vaccines, according to Van Vooren. “Spray-drying stands out as an accessible, repeatable, and scalable process that offers developers a cost-effective way to improve the solubility and bioavailability of their formulations,” Van Vooren concludes.
Pharmaceutical Technology Supplement: Bio/Pharma Outsourcing Innovation
When referring to this article, please cite it as J. Markarian, “Spray Drying Finds Growing Use for ASDs,” Bio/Pharma Outsourcing Innovation 2022 (February 2022).