(572b) Selecting a Commercial Mixing System Suitable for Specific Active Pharmaceutical Ingredient Properties

A key scale up challenge for a drug product manufacturing process using a lyophilized active pharmaceutical ingredient (API) is associated with the mixing operation, where the dissolution time can increase significantly with an increase in scale and can potentially exceed allowable process time windows at respective commercial scale manufacturing sites. The low-density, buoyant nature of the API with a range of particle sizes from micrometres up to two centimetres can challenge weaker mixers and unfit types of mixing systems. Mechanisms of mixing are critical when the buoyant API also has a tendency to form large floating, gelled clumps during mixing.

The team adopted a holistic smart process engineering approach to solve this key technical challenge in an API sparing manner. Various surrogate materials were evaluated that mimicked the understood key project requirements and properties of the API, including buoyancy, gelling tendency, similar dissolution time at small scale, availability of the surrogate, and cost effectiveness. In parallel, four large-scale mixers that employed different mixing mechanisms were evaluated for commercial manufacturing of this drug product. As a first step, a low performing mixer was eliminated based on literature review, CFD coupled with power per unit volume computations, Froude number calculations and selected experiments analyzing vortex depth and other vortex properties.

To evaluate the remaining mixing systems, liquid motion and mixing efficiency were analyzed at commercial scales with buoyant surrogates. Using three different sizes of floating polystyrene beads, the proposed suitable commercial mixers were identified that would comply with manufacturing site requirements and a successful process. API dissolution was then measured with miniaturized versions of these identified top performing commercial mixers at a 5L scale. The scaled down mixers were constructed with miniaturized 3D printed impellers and scaled-down vessels.

Based on the compiled results from all these approaches, the team selected a robust commercial scale mixing system. The team demonstrated that mixing mechanisms must be selected specific to particular applications associated with properties of the process input material in order to ensure success at commercial scale. Additional mid-range scale studies also supported confidence in the selected system and can be applied to other drug product manufacturing processes when API with similar properties is used. All in all, a holistic smart process engineering, underpinned by an API sparing surrogate evaluation, scaled-down experimentation and “predict first” mechanistic modelling enabled the team to select a suitable large-scale mixer for a lyophilized product.