Sterilizable Rapid Transfer Port
For Pharmaceutical Isolators

Presented at the Joint PDA/ISPE Conference
Advanced Barrier Technology
January 17-18, 1995

Patented

The Barrier Users Group Symposium (BUGS) was formed in 1992 to pursue the use of isolation technology for the filling of parenteral products. The group was made up of several pharmaceutical and equipment supply companies. BUGS' purpose was to establish design and use criteria for isolators in an effort to reduce the cost of the manufacturing process and to increase the sterility assurance level of the packaged product.

Central Research Laboratories began working with the BUGS group in 1993. Years of experience in remote manipulation and transfer systems for nuclear applications were directly applicable for pharmaceutical isolators. CRL's specific mission was to develop a method to introduce sterile stoppers into a sterile isolator with a high sterility assurance level.

The BUGS Group identified several potential problems with conventional Rapid Transfer Ports (RTPs). First, the ring-of-concern. Second, the substantial mechanism located inside the isolator makes it difficult to sterilize and to maintain sterility. Finally, the Group would prefer to have the system operate automatically rather than depend on a glove to operate the system.

Ring-of-Concern

Prior to docking, the face of the canister and the outside of the isolator port are exposed to the environment and are potentially contaminated. When the canister is docked to the port, these suspect surfaces are isolated by seals. However, when the port is opened, the canister cover must pass through the port opening. Consequently, there must be a small mechanical clearance between the outside diameter of the canister cover and the inside diameter of the port. This small ring could contain contaminants.

The BUGS Group came up with the "Toner Test" to illustrate this problem. Copy machine toner was applied to the docking surfaces of the canister and port. The canister was docked to the port and the door was opened.

When the port door was opened, two lines of toner were visible. One line appeared at the canister flange/port flange interface and the other line appeared at the port door/canister cover interface.

Alternatives Considered

Several alternatives were considered to eliminate this ring of concern. One was to do a partial dock and steam sterilize the interfaces before final docking and transfer. Cost, complexity, and cycle time were the principle concerns with this approach.

An aseptic wipe of the interfaces prior to docking was also considered. The principle concern was reliance on administrative control. Sterility assurance could be compromised by operator inconsistencies.

UV sterilization of the interfaces was also considered using an approach similar to steam sterilization. Again, cost, complexity, and the possibility of shadowing and stacking were of principle concern.

A consensus was reached that dry heat sterilization of the interfaces would be the preferred solution. This approach would result in a fast cycle time. It would be the most reliable and the operation of the system would be relatively simple.

Dry Heat Sterilization

Dry heat sterilization utilizes an electric heater installed in the port flange right at the intersection of all the seals, at the ring-of-concern.

After the systems are docked, this critical zone is heated to approximately 200°C and held at that temperature for a predetermined period of time.

Below is a plot of temperature versus time at the critical interface. The temperature of the interface reaches 200°C in three minutes. The system holds at 200°C for 30 seconds before the automatic transfer sequence begins. An analysis of this temperature profile by the BUGS Group concluded a Spore Log Reduction of six would be achieved in just under three minutes, so the balance of the heat cycle is added safety.

Below is an illustration of the Sterilizing Transfer Port (STP), viewed from inside the isolator. The port door is electrically powered from outside the isolator. A protective collar is also electrically powered from outside the isolator. The mechanism inside the isolator was minimized as well as the need for operator intervention from inside the isolator.

The figure below illustrates the product transfer sequence. In Step 1, the canister containing sterile product is attached to the port. In Step 2, the dry heat sterilization cycle is initialized. Once the dry heat sterilization cycle is completed, in Step 3, the port door automatically opens and, in Step 4, a protective collar automatically rotates into the port. The system is now ready to transfer product.

The protective collar serves several functions. It allows the transfer of stoppers to begin immediately after the dry heat sterilization is completed because all the hot surfaces are covered and will not come in contact with the stoppers. It provides a smooth surface to facilitate the transfer and finally it prevents the stoppers from contacting and eventually damaging the port seals.

Below is a cross-section of the protective collar in position. There is a gap between the outside of the collar and the inside of the port so the only contact point of the collar is with a sterilized surface inside the canister.

Summary

In terms of performance, the dock-to-dump cycle time, depending upon the application, is 5 to 10 minutes. The system is remotely and automatically controlled with safety interlocks and minimum reliance on administrative controls. Moving parts and mechanism inside the isolator were minimized.

The system was mechanically cycled 1000 times, disassembled and inspected with minimal signs of wear or deterioration of the components.

All critical seals have been leak tested: the canister flange to port flange seal, the canister cover to canister flange seal, and the port door to canister cover seal. In all cases, leak rates were in the 10e-6 cc/second range -- essentially no leak.

Thermal mapping of the port heater was performed to verify uniform temperature distribution around the circumference of the port. Temperatures were found to be uniform to within ±3° with exception of one cold spot, the point at which the heater power leads attached to the heater. The heater design was modified to minimize the effect of the power junction.

The heater assembly was thermally cycled through 3000 heat-up and cool-down cycles. The unit was inspected after testing to verify the integrity of the design. No signs of deterioration were apparent.

The port was biologically challenged to verify the effectiveness of the dry heat sterilization approach. Below is an illustration of the port (viewed from outside the isolator) showing the locations of the thermal couples and biological indicators. T/C 1 and BI A were located at the cold spot on the heater and used as the temperature control set point. The remaining four T/Cs and BIs were located randomly around the port. The BI coupons were manufactured of the same material as the gaskets (silicone), they were inoculated with Bacillus-Subtilis spores, then placed in the port directly at the ring of concern. The canister was then docked to the port and the sterilization cycle initialized.

The graph below represents a typical temperature profile of the sterilization cycle.

Below is a table of the actual temperature vs. time for all five T/C locations.

The table below illustrates the results of the biological challenge of the port. Thirteen tests were performed with set-point temperatures ranging from 140°C to 200°C and dwell times at set-point temperatures ranging from 35 seconds to 600 seconds. Test run No. 8 was performed to verify a lower limit and all BIs were positive as expected. Test run No. 7 was performed as a theoretical borderline case and three of the five BIs were positive. Test run No. 6 was performed as a theoretical safe case and all BIs were negative as expected. The positive BIs obtained during test runs Nos. 2 and 3 were attributed to mishandling of the BIs during removal from the port and transfer to the growth media and were so noted at the time of the test. The test results confirmed the effectiveness of the dry heat sterilization approach to the ring-of-concern problem.

Acknowledgement

Central Research Laboratories acknowledges and thanks the BUGS and LUM's groups for their contributions, guidance and support during the development of the Sterilizing Transfer Port for Pharmaceutical Barrier Isolators.