A Scrutiny of Scale: Considerations for the Manufacture of Orally Inhaled Drug Products

Jeremy Clarke

Traditionally, scale considerations for pharmaceutical manufacturing processes have focussed on scale up of the constituent unit operations and generally have been based on empirical approaches. This paradigm is increasingly challenged by regulatory expectations for improved understanding/robustness of manufacturing processes, which drives a need for development of mechanistic models. Other challenges to the scale-up paradigm include the customisation of healthcare through personalised medicines which will demand manufacture of smaller, more frequent, ‘on demand’ product batches and technological innovations such as continuous manufacturing1, where scale-up may either be irrelevant or more modest compared to changes in equipment scale within batch processes.
Specific to Orally Inhaled Drug Products (OIDPs), the lack of a ‘SUPAC-like’ guidance to inform on required in vitro/in vivo studies to underwrite changes in manufacturing process scale and, in particular, the absence of a simple bioequivalence measure, drives a product/process ‘design freeze’ earlier in development than for immediate release solid oral dosage forms, which results in the need to develop the commercial scale manufacturing process ahead of pivotal clinical studies. Additionally as a combination product, considerations of scale must be applied to manufacturing processes for both formulation and inhalation delivery device.
In this paper, scale considerations will be reviewed for typical unit operations that comprise the manufacturing process train for a unit dose inhalation powder, identifying the process variables that impact quality of output product, highlighting key best practices and, where possible, where scale-independent mechanistic models can be used to inform technology selection, technology transfer and scale up.

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