In the final installment of this three-part blog series, Ian Siragher, Commercial Director of Agenda1 Analytical Services, discusses what is needed to plan a successful first-in-man study…and sums up his thoughts on this crucial area of pharmaceutical development.
Taking the ideas I put forward in the last blog, in this entry I consider a model which could be adopted to minimise the risk of failure at the first-in-man stage. Here are five steps to optimal trial planning:
Step 1 – Determine the Solubility
A solubility screen will provide an early indicator of both problems and solutions. This type of assessment can include solubility, determined in buffers and relevant biological fluids, and can also include permeability assessment. The output from such a screen can provide a benchmark against which future form and processing changes can quickly be judged. Often a simple addition of a small mass of the API into a measured amount of the test solution can allow a visible assessment of the impact of the change on solubility.
Step 2 – Consider a Salt
Carry out a focused salt screen to optimise across a limited range of salt/base options. Forming a salt is not only about solubility, it is about stability too. Quite often, particularly for primary amines, the free base can have stability issues which are mitigated via salt formation.
Step 3 – Consider Polymorphism
Having established the salt/base form, a simple polymorph screen should be conducted to identify the tendency for polymorphism (different crystal forms). It will also display the relative thermodynamic stabilities. This will highlight potential physical stability risks as well as potential opportunities of one form over another. This assessment will point to thermal characteristics as well, and during DVS and XRPD analysis, an indication of amorphous material content will be gathered.
Step 4 – Process Risks and Benefits
If physical processing such as micronisation or spray drying is planned, then an assessment of how these changes will affect size and other physical characteristics is required. I would argue the need to look at the effects of such changes on surface area, for all the reasons that Hlinak et al identified. It has often been my experience that the desire to manufacture a nanoparticle has been driven (in reality) by a need to increase the surface area. This perhaps being because it is more achievable than reducing its size.
Step 5 – Toxicity
Having learnt how to best manufacture the API, and having begun to get sight of a formulation, the next step can be carrying out a programme of work exposing human cell lines in a cell culturing system. This can provide complementary data in regard to toxicity and modes of action. This information can be invaluable before leaping into the cost of a full trial. Then, only after having gathered this information, should a first-in-man or animal toxicology study be considered.
The boom years of pharmaceutical development have passed. The low hanging fruit has been picked and the regulatory and investor due-diligence walls around the orchard are being built higher and higher.
Failure comes in many forms, not only the failure of a trial. There can be collapse and disappointment in failing to demonstrate to an investor or in-licensing company that the future development pathway is understood and any risks are worth taking.
It is crucial, therefore, that the last thing a drug development company should do is carry out a first-in-man study. Even then it should only be conducted after fully understanding the material, formulation and possible toxicity risks. Yet, even with careful planning and preparation, human biology might still surprise. At least the risk of these surprises will be significantly reduced.