When “homogeneity” is expected—Theory of Sampling in pharmaceutical manufacturing

Abstract

Author Summary: A stream sampling method has been developed to facilitate implementation of variographic analysis and use of replication experiments in the development of pharmaceutical formulations. These methods are thoroughly developed in the Theory of Sampling but are not currently used in pharma. Pharmaceutical formulations have very strict requirements as drug products are expected to deliver a specific drug content to patients and are required to avoid possible consequences of over-dosing or under-dosing. Formulation developers currently rely on grab sampling, the use of a sample thief (spear) to extract material from areas suspected of having incomplete mixing (“dead spots”). This study applies an alternative stream sampling approach based on the Theory of Sampling in connection with testing two alternative mixing processes. The mixing process based on vibration and tumbling can be shown to provide a significantly lower end-point heterogeneity. The results show the usefulness of the variographic approach in combination with replication experiments; both are effective in identifying areas of unacceptable heterogeneity in pharmaceutical blends, and point to the need to continue improving the mixing processes described in this study.