(460b) Pharmacy on Demand: An End-to-End Approach to Developing a High-Dose, Poorly Flowing API into a Robust Continuous Manufactured Formulation

The Pharmacy on Demand (PoD) project enables an end-to-end continuous manufacturing (CM) of API using four refrigerator-sized, portable units; synthesis, purification, crystallization and drug product. High-dose, poorly flowing API always represents a challenge for developing a robust continuous manufacturing (CM) process for solid dosage forms. We explored the nature of powder flow of Ciprofloxacin HCl and investigated multiple techniques in order to maximizing flow properties. Multiple feeders were studied, and an optimum design was selected to facilitate formulation of the targeted batch size of 1000 doses per day. Since our goal is to produce ciprofloxacin using a continuous process on a mobile platform, a simple formulation was implemented. It consisted of a filler, disintegrant, glidant and a lubricant. We investigated the effect of excipient types and levels on the formulation manufacturability and performance. Disintegration, in-vitro dissolution, tablet mass variability, hardness and assay were used as performance measures which are required to pass the United States Pharmacopeia (USP) standards. Moreover, the dissolution profiles for the tested formulations were compared to the reference listed drug. The chosen formulation passed the USP standards criteria for tablets friability <1%, % label claim (90-110%), and an in-vitro dissolution profile reaching 85% dissolved within 30 minutes. The selected formulation robustness and design space were tested by varying the input ciprofloxacin properties in terms of water content and particle size distribution (PSD) and evaluated by testing drug product (DP) performance. The selected formulation showed robustness across all the tested levels of variables and passed appearance and depicted great control of the module over online tablet masses within less than ±5% standard deviation of the target tablet mass (500 mg). In the near future, the developed formulation will be manufactured in a GMP facility for a clinical bioequivalence study required for an abbreviated New Drug Application (aNDA) filling.