Needle clogging of protein solutions in prefilled syringes: A two-stage process with various determinants.

Clogging of staked-in-needle prefilled syringes (PFS) is a sporadic and scarcely predictable event, which occurs particularly in highly concentrated protein solutions and can result in the injection of incomplete doses, especially if autoinjector devices are used for administration. A systematic screening of possible causes and triggers was performed in order to find the crucial factors of influence, the underlying mechanisms and possible measures for prevention. An essential prerequisite for the formation of a solidified clog in the needle is the ingress of liquid from the barrel, which was investigated and quantified by means of neutron imaging after storage of prefilled syringes under various conditions. The needle filling ratio increases with both the storage temperature and the storage period, as a result of atmospheric gas diffusion through the needle shield. While the air pocket in the needle is reduced by this process, diffusion of water vapor does not affect the filling ratio but instead increases the protein concentration in the needle lumen, leading to an exponential rise of the viscosity and finally to the solidification of the protein solution. Maintaining the air pocket in the needle by avoiding any diffusion promoting pressure gradient is therefore the most effective protection from clogging.