active agent out of the device is likely to be related to osmotic pressure or even gravitational influence as opposed to hydraulic or mechanical forces. In that case, the device chamber volume will reach some level of equilibrium with the external tissue environment. Again, as in the above case for an active pump system, the chamber content will contain a residual lower concentration of the active agent that should be purged prior to a refill.

Using a passive system makes the ability to define the refill interval more challenging. In an active system, either through a known rate of fluid delivery or feedback measure of the chamber fluid volume, a calculated refill interval can be fairly straightforward. However in a passive system which might maintain a constant fluid volume with decreasing drug concentration, the required feedback information could require more complex sensor approaches. Alternatively, well-powered clinical studies of patient efficacy could provide the information needed although this may not be the most timely or efficient process.

13.2.5.3  Solid Refill

The above discussion does not take into consideration the potential of a device to be refilled with a solid dose form of the drug, such as reintroduction of a powder, tablet, cylinder, or fiber into an already implanted device. As one might expect this to be a more invasive approach overall, it would seem to be less attractive as a design comparatively to an external refillable injection system like a pellet gun or cartridge injector (Dinius and Huizenga 1984). Nonetheless, in consideration of such a method, the solid material would still require an environment where fluid can dissolve it. If the refilled solid is not directly open to the tissue on the output side, but rather is housed in a fully enclosed chamber or container, the consideration of occupied solid volume vs. residual tissue fluid volume in that chamber would need to be considered.

13.2.6  Contamination Potential

Multiple refilling of an implanted reservoir offers potential to introduce infectious and/or noninfectious contaminants, particularly if the injection port is located underneath the tissue (Renard et al. 2001). However, as long as sterile techniques are applied in the refill operation, risk for introducing infection should be low. In a study of 890 refill procedures in 25 patients with implanted intrathecal infusion pumps, cultures of samples taken from extracted residual drug in the reservoir at the last pump refill was negative for either aerobic or anaerobic bacteria (Dario et al. 2005). In the eye, the ability to flush surfaces with antiseptic such as povidoneiodine and to have the patient apply a brief course of antibiotic prior to injection can help reduce or eliminate any chance of introducing endophthalmitis.