reintroduction or exchange of gas, air or fluid into the chamber either during the fluid delivery phase or upon the refill (i.e., simultaneous venting). Any approach using replacement air or fluid must consider steps to avoid potential dilution of components within the chamber.

13.2.5  Flushing and Fluid Replacement

13.2.5.1  Active Pumps

Under most circumstances, fluid replacement into the device is going to be at an interval that does not correspond to the exact time when the delivery chamber is fully depleted. Unless the delivered drug product is highly stable over the total course of delivery at body temperature, the remaining fluid will contain a slightly less potent concentration of the drug. Therefore, reintegrating it with a new bolus of fluid effectively could affect the total combined potency over the next delivery period. Each subsequent dilution of the residual fluid with a new bolus results in an ever decreasing potency. For that reason, a procedure involving a flushing or overfill of the chamber is required to assure proper concentration of the active agent. Either a dual-chamber irrigation/aspiration syringe mechanism or dual-port designs on the device are means to satisfy this need. This may not always accommodate any dead space in the flow path from the reservoir to the site where the fluid gets delivered. The significance of the concentration of residual aged or degraded formulation within that dead space will be a relationship to the volume ratios between the chamber and dead space.

Mechanisms have been developed to control the fluid replacement volume and prevent damage in devices that have a reservoir with a closed valve system on the output side. In earlier work with refillable parenteral infusion pump systems, Doan and Nettecoven (1992) and Olsen (2000) designed valve features between the septum port and the reservoir which close off flow as fill level or pressure reaches maximum, thus preventing any further fill. As added protection in these systems, reservoirs were designed with bellows to offer additional expansion flexibility with respect to variations in the filling process. There have also been more recent advances to incorporate integrated refill detection capability. Ginggen (2009) has designed a detector disposed within the refill port for determining the placement of a refill needle within the refill port chamber, while generating an electronic communication in response to the placement. Such communication was claimed to be able to signal an alarm or run a diagnostic program which tests for fluid level or pressure.

13.2.5.2  Passive Systems

In the situation where the output side of the flow into the eye from the device is a simple passive mechanism, such as a semi-permeable membrane, movement of the