Minimising the Risk

This is the second in the latest three-part blog series from Ian Siragher, Commercial Director of Agenda 1 Analytical Services, in which he considers the steps and techniques which can lead to a successful first-in-man study.

In the last blog, I talked about the new challenges facing dose form development. This included the pressure of securing that milestone of a first-in-man study. Here are some of the tactics, both new and well-established, which can cut-out costly mistakes and minimise the risk of failure when testing a new drug.

The great white powder
Chemical Development teams are from Mars and Pharmaceutical Development teams are from Venus. At least that’s how it often seems to the Pharmaceutical Development teams faced with a newly synthesised API which they have to turn into dose form.

The goal of the chemical development team is usually focused on establishing a route of synthesis. They are rarely able to give consideration to how a particular salt form or polymorph might impact on the suitability of the material for dose form manufacture – let alone give thought to the benefits and pitfalls of secondary processing (such as micronisation).

Salt form optimisation
A recent programme we undertook demonstrated how changing the salt form of Cinnarizine increased the solubility of the drug in water by more than 500-fold. While there can be no guarantee that increased aqueous solubility will directly translate to improved bio-availability, there is no doubt that having a more readily water-soluble material increases the options open to the Pharmaceutical Development teams. Indeed, the fact that the API can be solubilised in water often comes as a great relief.

The objective of the Cinnarizine study was to establish a quick, cost-effective and focused screening template, to optimise the salt form being used in the first-in-man studies (not to be confused with the much bigger and more costly downstream screens that are often required for IP purposes). At this early drug development stage no one can be sure there is even something worth patenting.

Polymorph screening
It has always been understood that different polymorphs of an API will display differing characteristics. These can affect dose form development. Solubility can be affected; for instance Pudipeddi and Serajuddin reported up to 100 per cent increase in solubility from one polymorph to another. In 2004, Willson and Sokoloski ranked the polymorphic forms of a development API: “in terms of physical stability… measurements were made as a function of temperature and a phase diagram over a narrow temperature range was constructed.”

None of this is new knowledge, but access to such techniques, and the knowledge of their value, is not as well understood in a smaller start-up, compared to large pharmaceutical company who have it embedded in their structured development programmes.

The need for such an evaluation is probably greater than ever because the price of failure is so much higher. A number of universities and specialist providers offer both detailed and simplified polymorph screens. I believe that a smallscale, early stage screen – to ensure that the best option is taken, can make all the difference between a project’s success or failure.

Physical form optimisation
Typically the API used in an early stage formulation will not require specialised preparation (for example micronisation or spray drying). Those steps are more likely to be used where a pulmonary product is being developed. However, there is always a case for considering the size of the primary particles being manufactured, especially as size impacts surface area.

In 2006, Hlinak et al identified how the surface area of a particle impacts material flow, blending, wetting, drying, dissolution and stability. I suggest it is important to at least understand the surface area of a planned material. Undertaking a short programme to establish the extent to which small, simple manufacturing changes or a simple micronisation step after synthesis impacts surface area could pay dividends later.

New tools for old jobs
The marketplace is recognising the many stresses on small drug development companies. New techniques and approaches are available, which previously did not exist, or were confined to the ‘know-how’ of large pharmaceutical companies.

Solubility screening and optimisation
In a recent poster, Kuecept Ltd demonstrated the efficacy of their Solubility Enhancement (Solent) programme. This system is made up of a range of over 100 excipient groups appropriate to oral, transdermal or parenteral formulations. This system uses only GRAS excipients which are routinely available for purchase at cGMP grade and without any underlying licence requirements. This system can be used as a simple screen. If an API will not solubilise in any of this group to the target level, the challenge is severe.

Alternatively the process can provide the basis of a simple dose form for a first-in-man study or animal toxicology study. Kuecept make no claims that the ‘formulation’ developed at this point will be the final formulation. But it is designed to meet the goal of a fast and cost-effective route to a first-in-man study.

Toxicity studies, without the toxicity
Getting the product into man is a key step. Doing so with as much advance understanding as possible is also crucial. Animal studies are often used and no doubt will continue but they are costly and time consuming. They also don’t always provide the data required. A Sheffield-based company – Kirkstall Ltd, have pioneered what they describe as a ‘quasi vivo’ approach to understanding toxicology and other issues.

Using a series of linked 3D cell-tissue culturing systems, their approach provides the opportunity to expose selected human cell-tissue types (for example the liver or pancreas) to the drug of interest. The unique combination of 3D scaffolding and a flowing media system generates ‘life-like’ conditions for the cells, and also provides the ability to include more than one cell type in the ‘system,’ and thereby to observe cell-to-cell signalling and interaction.

This is beneficial to any company, particularly a smaller one. Such an approach provides a way to begin to set parameters for a toxicology study. This leads to rapidly understand if and how different concentration levels of drugs in a solution change the drug-cell interaction.

The final part of this blog series will be available on this Agenda 1 Analytical Services Blog in September. You can follow @Agenda1Blog on twitter for the latest updates from Agenda1 Analytical Services.