Homogeneity or uniformity of a dose formulation is a requirement for ensuring integrity of regulated preclinical safety studies. Demonstrating homogeneity ensures that the preclinical dose formulation contains active ingredient(s) uniformly throughout the formulation, thereby ensuring that the test system is being administered using the appropriate amount of test material. Accurate assessment of dose formulation homogeneity is accomplished by using an appropriate sampling protocol and validated analytical methodology.

Assessment

Assessing homogeneity for preclinical dose formulations is generally completed by sampling the prepared preclinical dose formulation at various strata in the formulation container. Sampling from the top, middle, and bottom followed by analysis using a validated analytical method is an example. Homogeneity is established by sampling from the initial preparation at both the lowest and highest dosing concentrations. Confirmation of homogeneity ensures that the formulation preparation procedure is adequate for the study.

Homogeneity should be reassessed when there is a significant change in the batch size. For instance, if 100 mL of a formulation are prepared for the first study and 1000 mL are prepared for a subsequent study, homogeneity is performed on both batches. These tests ensure that the formulation process at each scale yields a homogeneous mixture. The need for these two processes is based on mixing techniques, because different methods are used depending on batch size.

Once homogeneity has been established using a specific formulation procedure, it is crucial to maintain consistent methods for preparation throughout the study. Minor changes may affect the ability to prepare and maintain a homogeneous mixture.

Challenges

Challenges with homogeneity can vary depending on the type of formulation. There are multiple types of dose formulations used for in vivo studies, including, solutions, suspensions, and solids as described below:

• Solutions by definition are homogenous because all components dissolve in the solvent. If solubility data in the specified vehicle at the highest specified concentration do not exist, it is crucial to confirm that the dosing formulation is in fact a solution; therefore a homogeneity assessment is required for the preclinical study. This assessment is a regulatory requirement by FDA for preclinical safety studies. It ensures that assumptions based on visual observation or solubility information in another solvent other than the vehicle do not compromise the outcome of an in vivo study.
• Suspensions, where not all components are dissolved, require additional attention to ensure that the components are evenly distributed and remain distributed throughout the course of dosing. This assessment may require extra steps, such as continuous stirring or heating, while dosing. Suspensions that are stored prior to dosing may require extended stirring or heating to ensure homogeneity of the formulation prior to dosing.
• Solid-dose formulations, including gels, creams, and feeds, add additional challenges to establishing and maintaining homogeneity. Adequate mixing and blending are even more important when preparing a solid formulation. Regularity of particle size is key to feed blends because small amounts of test article are being added and mixed to relatively large amounts of feed. Several tactics may be used to improve solid homogeneity, including sieving or grinding of the test material prior to adding to the feeds, or dry blending the test article with a secondary substance prior to addition of feed. Spray-dried techniques used in the manufacturing of marketed products are typically not feasible because of scale and frequency of preparation needed for a preclinical study.