Bulk Mix Preparation

The equipment utilized for the preparation of bulk fluid or suspension formulations is similar regardless of the excipients comprising the formulation (e.g., lipid vs. traditional excipients). Typically, the bulk formulation vessels have product-relevant facilities for primary agitation, high-shear mixing, vacuum and pressure capability, heating and cooling, and loading and unloading. Homogeneity of the bulk formulation can be maintained by suitable mixer/filler recirculation systems and by local agitation in the filling-machine hopper. Formulations incorporating fluid excipients or those with relatively low-melting points are flexible with respect to process stability and time requirements. However, additional issues arise for formulations based on thermo-softening carriers, which typically require processing at temperatures ranging from 35°C to 70°C. Such temperatures and the maximum associated time limits for holding prior to encapsulation can present product stability issues during manufacturing. In practice, this may require processing in a nitrogen atmosphere to minimize potential oxidation and/or limitation of the batch-size to that, which may be encapsulated within a period dictated by the formulation stability. A product batch with a thermal stability issue will generally be limited to a filling-period not to exceed 24 hours. In practical terms, this will allow for a maximum batch size of approximately 450 k capsules to be prepared in an eight-hour period on a filling machine operating at the typical rate of 60 k capsules per hour. Clearly, selection of excipients requiring minimal processing temperatures provides for flexibility and maximum productivity during manufacturing.

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