Today, more than 10 products on the market include a spray-dried intermediate (SDI) as a component of their formulation – and there are hundreds more in development pipelines. With the fast-growing adoption of SDI, there is increasing pressure to rapidly develop prototype pre-clinical and clinical formulations so drug products can be seamlessly brought to commercial scale. As a result, it is increasingly important to understand the development and scale-up pathway for the progression of SDI.
What are the keys to rapid scale-up of spray-dried amorphous formulations for bioavailability enhancement?
Over the past 20 years, we have investigated and addressed several critical factors in the rapid scale-up of spray-dried amorphous formulations.
Our initial objective is to assess if we can develop formulations that provide the appropriate solutions to the problem statements that are limiting absorption – such as enhanced drug concentrations, rapid dissolution or crystallization-inhibition – without spray drying. We have developed proprietary API-sparing methods, including an amorphous solubility test and a membrane flux test, to provide guidance for key solution performance variables. Both tests can be conducted in the presence of crystallization-inhibiting polymers, which allow for rapid formulation identification.
Once we identify an optimal formulation to enable acceptable absorption, we utilize our custom heat and mass transfer models to design a preferred spray drying process. These models, which are utilized in the operation of our proprietary lab-scale spray drier, are specifically designed to minimize API requirements for feasibility assessments. The models are also designed to readily scale up to a larger spray drier as the project progresses. Through standardized spray drier design, scale up and transfer can progress smoothly to clinical and commercial scale, mitigating costly and time-consuming formulation and/or processing re-work.
We are pioneering an alternative approach to scaling up the spray drying process focused on the concept of ‘numbering up,’ or utilizing a series of smaller, high-throughput driers. As the market trends towards smaller volume (more specialized and higher value) products, there is growing demand for smaller batches and hence smaller driers. A critical advantage to this approach is high-throughput in a smaller footprint. This advantage minimizes lead times to bring new spray drying capacity online as product demand forecasts change with product maturity. This approach also enables on-demand production.
How has science-of-scale been used in early feasibility assessments of amorphous formulations?
Science-of-scale in early feasibility assessment is often less about scaleup, and more about scale down. In other words, how representative is the formulation and process that is developed for pre-clinical assessment of the API and formulation? At Capsugel, laboratory spray driers have been designed and built around the smallest commercially available pressure nozzles. This allows a spray drying process to run in pre-clinical development on a few hundred milligrams of API, and then translate directly into a larger drier with significantly larger batch sizes. Successful application of these principles means that the designated preclinical formulation and process can be replicated for the clinical and commercial formulation and process.
Has science-of-scale led to spray drying process innovations?
Yes. For example, the concept of numbering up spray driers for smaller volume products has led to high-throughput, small footprint driers that can produce commercial volumes of product while residing in a single story GMP facility. This represents a marked improvement over traditional spray drying processes that, as they are scaled, must often be placed in multi-story buildings that result in higher costs and additional operations.
Another example is a spray drying process we developed in response to APIs that are poorly soluble in both water and in typical organic solvents utilized in spray drying. When an API is poorly soluble in spray solvent, it generates low concentration spray solutions that require long processing times and larger equipment. To overcome this challenge, we developed proprietary heated spray drying processes. In extreme circumstances, a suspension of the API in a spray solvent is pumped through a heat-exchanger immediately prior to the spray nozzle. By elevating the temperature of the spray solvent to temperatures in excess of 100°C, we can often achieve solution concentrations of the API that are 10 times those measured at room temperature. This ultimately leads to a much more efficient process, with shorter processing times on smaller equipment.
Is science-of-scale utilized across other processing technologies?
Science-of-scale is utilized across a range of additional processing technologies. Similar to spray drying, companies can utilize scienceof- scale to scale and transfer fluid-bed spray layering processes. We miniaturized fluid bed technology to operate in a bulk API-sparing manner for early feasibility programs, as well as modeled the fluid-bed equipment in a way that scale-up can be achieved in an efficient manner.
Science-of-scale can also be applied to capsule filling processes. For liquid-filled hard capsule technology (LFHC), liquid fill machines have been developed for the laboratory scale that facilitate efficient assessment of lipid-based technology. For example, our proprietary CFS1200 machine precisely fills and seals volumes up to 1,200 capsules per hour for early stage development work and rapid advancement to human studies.
On the other end of the spectrum, our commercial LFHC machines manufacture more than 100 million LHFC units annually, comprising more than 25 biopharmaceutical products. These commercial machines use similar filling and sealing mechanisms and equipment as our laboratory processes.