(T1330-09-60) Performance of Pre-Filled Syringe Systems at Low Temperature

Purpose: There is a growing trend for delivery of drug products in prefilled syringe systems (PFS) where storage and distribution are at frozen conditions. Notable examples are live-virus vaccines, such as those for varicella (chicken pox, shingles) and MMR (measles, mumps, rubella) which require -50^oC. There are many reasons for frozen conditions: retarding degradation, extending shelf life, and reducing contamination by container leachables. There are challenges also. Syringes and plungers are designed to fit and function at room temperature. More specifically, they are designed to maintain sterility, container closure integrity, and enable acceptable initiation and sustaining forces during administration. For any PFS intended for use under frozen conditions, it must be determined experimentally whether acceptable performance can be achieved. The purpose of the present research was to develop a strategy to evaluate PFS performance both during, and after, freeze-thaw exposure, and use it to evaluate two types of PFS.

Methods: The strategy comprises three aspects: Plunger Movement. Plunger position is recorded before freezer placement, immediately after removal, and after thaw. Particular focus is on movement past the sterile barrier as defined by the sealing ribs. Container Closure Integrity (CCI). CCI is determined by laser-based headspace analysis for oxygen by comparing values as assembled and after freezer placement and thaw. Assembly is in a nitrogen-filled glove box; ingress of oxygen would indicate a loss of CCI. Initiation and Sustaining Forces. Measurement is made of force needed to initiate plunger movement and sustain a desired plunger movement rate. Comparison is made of samples before and after freezer placement and thaw.

Results: Experimental evaluation was made of water-filled PFS comprising ISO-standard 1 ml long and 2.25 ml glass staked-needle syringes (siliconized) with bromobutyl elastomer plungers (with an ethene tetrafluoroethene polymer (ETFE) laminate film facing drug product). Conditions were storage as low as -50^oC (passive freezing in mechanical freezer, vis-à-vis controlled-rate freezing) for > 24 hours followed by bench-top thaw for > 1 hour. For 1 ml long PFS, upon freezer placement plunger movement was observed: ca. 1 mm for 0.5 ml fill, and ca. 3 mm for 1 ml fill. This was not unexpected, expansion of water on freezing would promote movement. Upon thaw, plunger movement was almost to original position – possibly retarded by a frictional force. In no case was movement past the sterile barrier observed. Evaluation of CCI demonstrated no breach of any PFS. Example data are shown in Figure 1. Oxygen concentration was measured before, and after, freezer placement and thaw. No increase in oxygen concentration was observed. A breach would result in an oxygen concentration the same as freezer air (i.e., 21%), especially since upon the decrease in pressure within PFS upon freezer placement would promote air ingress. Evaluation of initiation and sustaining forces at 100 mm/min demonstrated no change in performance for any PFS resultant from freezer placement and thaw. Example data are shown in Figure 2.

Conclusion: The present research presents a strategy for evaluation of PFS performance for low temperature applications and demonstrated its use for PFS based on 1 ml long and 2.25 ml glass syringes with bromobutyl elastomers with ETFE laminate films. This strategy also should be suitable for PFS with polymer-based syringes. Continuing research is evaluating performance to -80^oC, a challenge since most elastomers have glass transition temperatures above that.

Figure 1. Container Closure Integrity after Low Temperature Exposure

Figure 2. Initiation and Sustaining Forces after Low Temperature Exposure