Rudolph O. Marohl
Central Research Laboratories
Presented at the American Glovebox Society Conference
Lakewood, CO
July 1997
| Abstract: During the last five years the use of barrier/isolation technology in the healthcare industry has increased significantly. The industry has recognized the economic potential of the technology and anticipates future products may contain very potent compounds requiring special provisions for containment. The goal of containment is the same for both the nuclear and pharmaceutical industries but, depending on the application, there may be significant differences in the operating requirements. This paper describes the modifications required to convert a conventional Double Door Transfer Port, commonly used in the nuclear industry, for pharmaceutical manufacturing applications. | ||
Double Door Transfer Systems (DDTS) have been used in the Nuclear Industry for 30 years. These systems were first developed to allow the transfer of hazardous materials from one container to another without exposing the hazardous material to the outside environment. The transfer is accomplished by using a unique seal and engagement system which allows passage between containers while maintaining a first seal to the outside environment and a second seal to prevent the outside of the container cover and port door from becoming contaminated by the material being transferred. When the transfer is completed the containers may be separated in a clean and safe manner.
DDTS are most commonly used in glove box applications where radiation levels are relatively low and containment is the primary concern. Shielded systems are available for high radiation applications but special handling systems are recommended for ease of operation.
During the last five years the use of barrier/isolation technology in the health care industry has increased significantly. The industry has recognized the economic potential of the technology and anticipates future products may contain very potent compounds requiring special provisions for containment. The goal of containment is the same for both the nuclear and pharmaceutical industries but, depending on the application, there may be significant differences in the operating requirements.
Pharmaceutical barrier/isolators are used in sterile and toxic compound applications. For sterile applications the barrier/isolator is typically maintained at a positive pressure relative to the outside environment to ensure against leakage into the sterile containment. For toxic compound applications the barrier/isolator is typically maintained at a negative pressure relative to the outside environment to ensure against leakage into the personnel area surrounding the containment (similar to nuclear applications).
Batch operations are typically used for the manufacture and testing of pharmaceutical products. A production cycle may consist of process equipment set up and checkout, closing the barrier/isolator, remotely cleaning and sanitizing the interior of the barrier/isolator, and, finally, product testing or manufacture. After the production run the barrier/isolator is opened for maintenance and preparation for the next production cycle. In the case of toxic compounds, it may be necessary to neutralize and clean the interior of the barrier/isolator before opening as some of the residual compounds maybe very harmful to personnel and the environment.
Cleanability and cleanliness are critical. Most barrier/isolators are manufactured of highly polished stainless steel and must be easily washable/cleanable. Spray balls may be used to ensure all interior surfaces are thoroughly cleaned prior to beginning the sanitization cycle. Cracks and crevices must be minimized. Water traps cannot be tolerated. Interior surfaces must be self draining.
Equipment and process validation are very critical steps in the preparation of facilities used to manufacture pharmaceutical products. The protocols used in validation, when implemented, ensure the products produced meet product specifications and FDA requirements. Extensive testing of subsystems used in the manufacturing process are typically required prior to process validation. These tests include sterility testing, materials compatibility testing, leak testing, equipment operation tests, air flow and filtration equipment tests, materials handling equipment tests, computer software validation, and systems integration tests.
Functional equipment descriptions, operation protocols, and testing protocols are required to support subsystem testing. Testing consists of operating subsystems in accordance with established protocols to ensure the equipment performs as intended, the equipment performs reliably, and test results are repeatable. Process validation in turn consists of operating all subsystems in an integrated manner to consistently produce the desired result - an acceptable end product.
To facilitate data collection for process verification and to minimize human intervention and error, there is a strong desire by pharmaceutical companies to automate the production process to the maximum extent possible. Programmable Logic Controllers (PLC's) are preferred for process control and a Supervisory Collection And Data Acquisition (SCADA) System is preferred to document and verify process performance during production operations. Glove ports are usually provided in the barrier/isolator to allow human intervention for emergencies and non-routine tasks but are not recommended for use as an integral part of the production process.
Double Door Transfer Systems are commonly referred to in the pharmaceutical industry as Rapid Transfer Ports (RTP's). Most RTP installations are manually operated using gloves mounted in the wall of the glovebox or barrier/isolator. Historically, RTP designs incorporated mechanical mechanisms which generated forces necessary to ensure proper sealing and which ensure proper alignment of mating components.
Nuclear gloveboxes, once commissioned, remain sealed for years and frequently remain sealed until they are decommissioned. Consequently, cleanability although important to reduce potential contamination traps, is subservient to manufacturing cost.
For pharmaceutical applications, the CRL DDTS had to be redesigned to incorporate the performance characteristics required by the pharmaceutical industry. Major areas requiring redesign are as follows:
| Desired Performance | Design Changes Required |
|---|---|
| Programmable Operation | Design drive mechanisms for remote, PLC controllable operation |
| Documentable Performance | Incorporate sensors and performance data feedback. |
| Cleanable/Washable Design | Eliminate complex mechanisms and minimize cracks and crevices. |
Figure 1
Figure 1 illustrates a conventional DDTS Port. A ramp collar is used to apply the forces necessary to ensure a proper seal between the port door and the port flange. Gloves are used to manually operate the handle which activates the ramp collar. Mechanical interlocks are provided to ensure the port door cannot be opened if a canister is not docked to the port and also to ensure the canister cannot be removed if the port door is not closed and locked. These systems work very well for rapidly and safely transferring hazardous materials. Hundreds of these systems are in use in the Nuclear Industry.
It is obvious that this type of port would be very difficult to clean and sanitize for pharmaceutical applications. The complex mechanisms, cracks, and crevices had to be minimized or eliminated. To automate the existing design for remote programmable operation would have added more mechanisms to the inside of the barrier/isolator making the system unacceptable for many pharmaceutical applications.
Figure 2
Figure 2 illustrates the new CRL RTP design for pharmaceutical applications (Melahn, 1995). The operating principle of the system is identical to a conventional DDTS, however much of the mechanism which would normally be inside the barrier/isolator has been eliminated. The ramp collar and handle have been replaced by a gearbox which penetrates and is sealed to the barrier/isolator wall. A simple hinge is used to locate the port door and to transmit forces necessary to ensure proper sealing of the port door to the port flange. Mechanical interlocks have been eliminated and replaced by the port control system.
CRL RTP control components are located on the outside of the barrier/isolator. An electric motor incorporating a failsafe brake and a position sensor is attached to the gearbox and is used to open and close the port door. Sensors located on the exterior of the port detect if a canister is docked and locked to the port. Control software provides the interlock logic to prevent the port door from being opened if a canister is not locked to the port and if canister docking is automated, prevents the canister from being removed if the port door is open.
Operation of the port is normally integrated into the overall process control system for the barrier/isolator and production process. A SCADA system is typically used to monitor and permanently log transfer operations during production operations.
Several enhancements have been developed to increase the versatility of the CRL RTP. In applications where high levels of sterility assurance are required an electric heater has been incorporated into the port to sterilize the interface between the port and the canister. This system is referred to as a "Sterilizable Transfer Port" (CRL STP) and was reported at the AGS Conference in l995 (Marohl, l995).
A remotely actuated protective collar is also available (Marohl, l995). When the port door is open a protective collar is rotated into the port prior to the transfer of material. The protective collar provides a smooth surface to facilitate the material transfer and also prevents the material being transferred from contacting and eventually damaging the transfer system seals.
Automated canister handling systems have also been developed for special installations. These systems are capable of delivering the canister to the port and automatically performing the docking and undocking operations (Jennrich, 1995).
Even through containment/isolation goals are common for nuclear gloveboxes and pharmaceutical barrier/isolators, there are major differences in the operating requirements for their specific applications. There are also significant differences in the design of barrier/isolators for toxic compounds and sterile applications within the pharmaceutical industry. It is necessary to have a complete understanding of the customers process to adequately address and satisfy those differences.
Cleanliness and cleanability of all equipment and mechanisms inside the barrier/isolator is a major objective. This is not as critical in glovebox systems as once the system goes operational it is very difficult and usually not cost effective to decontaminate for reuse.
Many of the lessons learned in converting a conventional DDTS to a pharmaceutical RTP, as reported in this paper, may be applicable to other types of equipment used in barrier/isolators. Bacteria, toxic compounds, and radioactive particles all need to be controlled. The differences are in the level of control and the processes used to implement that control.
Melahn, John F., 1995. "A Barrier Isolation Syringe Fill System", ISPE Barrier Isolation Technology Conference, Rockville, Maryland.
Marohl, Rudy, 1995. "Sterilizable Transfer Port For Pharmaceutical Isolators", American Glovebox Society 1995 Proceedings.
Jennrich, C., Adams, R., Marohl, R. "A System For Introducing Pre-Packaged and Pre-Sterilized Stoppers Into A Sterilized Isolator", ISPE Barrier Isolation Technology Conference, Rockville, Maryland.