The need for better strategies during the product lifecycle
Most drug products are administered as solids, with the solid-state properties of active pharmaceutical ingredients (APIs) having a significant impact on a drug’s solubility, dissolution rate, stability, hygroscopicity and bioavailability. Solid form screening and selection has therefore become an important activity at all stages of drug development. However, with increasing demands on developers to balance cost pressures with the need for rapid progression, especially in the early stages, the industry is calling for better strategies that pay attention to the specific requirements at different stages in the product lifecycle. With this in mind, could a more phase-appropriate approach to solid-state present the best option?
A collaborative approach to development
Many developers are now coming round to this way of thinking. There is a growing realisation that API development and manufacturing requires an iterative approach with collaborative input from medicinal chemists, solid form scientists, development chemists and formulation scientists. Adopting a phase-appropriate approach, that considers input, objectives and deliverables from multiple groups, can provide developers with a ‘road map’ to ensure screening activities become increasingly comprehensive as the needs and technical requirements at each development stage evolve. As understanding increases, the overall timeframe to appropriate selection can be reduced. If the right studies have been conducted using the right materials and in a logical order, progression to first in human studies is more efficiently achieved.
Meeting different objectives along the development journey
Every drug candidate is different, and the solid-form strategies required for an API will vary over the course of development. However, taking a phase-appropriate (and inclusive) approach means that the path for solid form studies can typically progress in a way that achieves specific objectives at the varying stages.
Discovery and lead optimisation should involve a robust set of physiochemical parameters being laid down as markers for the competing analogues in play. This includes a simple response to changes in pH/and solubility, Log P, presentation form (oil, solid, amorphous, crystalline), and whether a salt can form and aid in isolation/development.
Early and late development considerations
Early development should involve robust assessment of the various solid form versions and candidates available for progression such as a salt versus an API. This may encompass solubility across a range of pH, solid stability, solution stability, crystallinity, and thermal properties. The choices must also deliver against chemical development needs, including robustness of process, purge of impurity and process efficiency. Also required is a good understanding of how the various presentations of each version may influence the development of the drug product such as powder flow, bulk density, and morphology for simple solid dose formulations. This information provides development groups with options to consider as material transitions through Phase 1.
Late phase development should further challenge the processes in place versus the necessary specification and ensure that the solid form of choice delivers routinely against performance targets. Normally this encompasses a broader polymorphism study that may or may not identify competing versions that provide additional protection from an IP standpoint. This ensures that as scale increases and the route and impurity profile become fixed, no new forms emerge to de-rail the development programme resulting in delays. A process risk assessment should also be in place supported by a robust form and crystallisation development programme.
Road mapping to a more efficient route to market
The solid form of an API will have a significant impact on drug development activities; therefore, these studies can help to develop an extensive understanding of the solid form landscape and provide the aforementioned ‘road map’ of possible form transformations. Building a strategy for solid-state that is phase-appropriate and considers the necessary requirements at the right time in the development lifecycle can be a useful tool in establishing a more efficient and cost-effective route to market.[addtoany]