Dose formulation: Dose formulation is critical due to its effect on the release and absorption of the compound and due to its impact on the pharmacokinetic profile of the compound. The formulation developed during the early discovery phase is generally designed to maximize exposure of compound and selected based on factors such as solubility, stability, the dose volume to be used, and tolerability of the vehicle in the nonclinical species to be used. However, in the GLP toxicology phase, three different types of formulations may be required; one to support in-vivo toxicology studies; the second to support genetic toxicology studies; and the third, hERG buffer formulation using a physiological salt solution with the minimal solvent. Fully validated methods for formulation analyses is a critical requirement for GLP toxicology studies.

These validated methods are used primarily for dose confirmation analysis and for demonstrating the accuracy of dose concentration in dosing formulations. Species selection: Species selection is made based on in-vitro metabolic profile/ ADME properties and bioavailability for small molecules. For large molecules, relevant species are considered i.e. species in which the molecule is pharmacologically active. Historically, two species have been used for pre-clinical testing. Rat and dog are usually used due to the availability of abundant historical data. Other species may be used if data suggests that they are more appropriate and biologically relevant. Non-human primates and minipigs are recognized, alternative models. There’s increasing use of minipig models over dog models. Syngene recently completed an IND program for a client in which minipig was used as the non-rodent species. A complete pre-clinical package including CMC and medical write-ups was prepared and submitted based on the minipig model, ultimately leading to approval and initiation of clinical trials.